US20090023949A1 - Amorphous ibandronic acid - Google Patents
Amorphous ibandronic acid Download PDFInfo
- Publication number
- US20090023949A1 US20090023949A1 US12/218,197 US21819708A US2009023949A1 US 20090023949 A1 US20090023949 A1 US 20090023949A1 US 21819708 A US21819708 A US 21819708A US 2009023949 A1 US2009023949 A1 US 2009023949A1
- Authority
- US
- United States
- Prior art keywords
- ibandronic acid
- hours
- temperature
- stirred
- reaction mixture
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
- MPBVHIBUJCELCL-UHFFFAOYSA-N Ibandronate Chemical compound CCCCCN(C)CCC(O)(P(O)(O)=O)P(O)(O)=O MPBVHIBUJCELCL-UHFFFAOYSA-N 0.000 title claims abstract description 289
- 229960005236 ibandronic acid Drugs 0.000 title claims abstract description 210
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 88
- 238000000034 method Methods 0.000 claims abstract description 55
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims abstract description 36
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims abstract description 24
- 239000002904 solvent Substances 0.000 claims abstract description 23
- 238000001694 spray drying Methods 0.000 claims abstract description 15
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims abstract description 11
- 239000000243 solution Substances 0.000 claims description 85
- 230000008569 process Effects 0.000 claims description 34
- 239000007864 aqueous solution Substances 0.000 claims description 15
- 238000004519 manufacturing process Methods 0.000 claims description 10
- 238000004108 freeze drying Methods 0.000 claims description 3
- 238000007738 vacuum evaporation Methods 0.000 claims description 3
- 238000002360 preparation method Methods 0.000 abstract description 5
- 238000004090 dissolution Methods 0.000 abstract description 4
- 239000011541 reaction mixture Substances 0.000 description 123
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 103
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 99
- 239000000203 mixture Substances 0.000 description 69
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 60
- 239000002244 precipitate Substances 0.000 description 57
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 54
- 239000007787 solid Substances 0.000 description 54
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 51
- 238000010992 reflux Methods 0.000 description 42
- ISIJQEHRDSCQIU-UHFFFAOYSA-N tert-butyl 2,7-diazaspiro[4.5]decane-7-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCCC11CNCC1 ISIJQEHRDSCQIU-UHFFFAOYSA-N 0.000 description 40
- 239000013078 crystal Substances 0.000 description 38
- 239000012071 phase Substances 0.000 description 38
- 239000008346 aqueous phase Substances 0.000 description 37
- 238000003828 vacuum filtration Methods 0.000 description 37
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 34
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 description 32
- 239000000725 suspension Substances 0.000 description 28
- 238000002441 X-ray diffraction Methods 0.000 description 26
- 238000010586 diagram Methods 0.000 description 25
- 238000000634 powder X-ray diffraction Methods 0.000 description 24
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 18
- 238000010438 heat treatment Methods 0.000 description 18
- 238000003756 stirring Methods 0.000 description 18
- 239000002002 slurry Substances 0.000 description 16
- 239000007788 liquid Substances 0.000 description 15
- 239000000546 pharmaceutical excipient Substances 0.000 description 15
- 229920002545 silicone oil Polymers 0.000 description 15
- 239000002253 acid Substances 0.000 description 14
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 14
- 239000000047 product Substances 0.000 description 14
- 238000001035 drying Methods 0.000 description 13
- 239000003921 oil Substances 0.000 description 13
- 235000019198 oils Nutrition 0.000 description 13
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 12
- 229910052710 silicon Inorganic materials 0.000 description 12
- 239000010703 silicon Substances 0.000 description 12
- GNFTZDOKVXKIBK-UHFFFAOYSA-N 3-(2-methoxyethoxy)benzohydrazide Chemical compound COCCOC1=CC=CC(C(=O)NN)=C1 GNFTZDOKVXKIBK-UHFFFAOYSA-N 0.000 description 11
- 239000002552 dosage form Substances 0.000 description 10
- 239000008194 pharmaceutical composition Substances 0.000 description 10
- FGIUAXJPYTZDNR-UHFFFAOYSA-N potassium nitrate Chemical compound [K+].[O-][N+]([O-])=O FGIUAXJPYTZDNR-UHFFFAOYSA-N 0.000 description 10
- 239000007921 spray Substances 0.000 description 10
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 9
- 239000003085 diluting agent Substances 0.000 description 9
- 238000001704 evaporation Methods 0.000 description 9
- -1 nitrogen-containing bisphosphonate Chemical class 0.000 description 9
- 239000000523 sample Substances 0.000 description 9
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- 239000008187 granular material Substances 0.000 description 8
- 238000004128 high performance liquid chromatography Methods 0.000 description 8
- 239000007789 gas Substances 0.000 description 7
- 229910052757 nitrogen Inorganic materials 0.000 description 7
- 239000003960 organic solvent Substances 0.000 description 7
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 239000004480 active ingredient Substances 0.000 description 6
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 238000002425 crystallisation Methods 0.000 description 6
- 230000008025 crystallization Effects 0.000 description 6
- 239000000843 powder Substances 0.000 description 6
- FGUUSXIOTUKUDN-IBGZPJMESA-N C1(=CC=CC=C1)N1C2=C(NC([C@H](C1)NC=1OC(=NN=1)C1=CC=CC=C1)=O)C=CC=C2 Chemical compound C1(=CC=CC=C1)N1C2=C(NC([C@H](C1)NC=1OC(=NN=1)C1=CC=CC=C1)=O)C=CC=C2 FGUUSXIOTUKUDN-IBGZPJMESA-N 0.000 description 5
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- 229920002472 Starch Polymers 0.000 description 5
- 238000007907 direct compression Methods 0.000 description 5
- 239000012535 impurity Substances 0.000 description 5
- 229960004592 isopropanol Drugs 0.000 description 5
- 229910017604 nitric acid Inorganic materials 0.000 description 5
- 239000002245 particle Substances 0.000 description 5
- OGHBATFHNDZKSO-UHFFFAOYSA-N propan-2-olate Chemical compound CC(C)[O-] OGHBATFHNDZKSO-UHFFFAOYSA-N 0.000 description 5
- 239000008107 starch Substances 0.000 description 5
- 235000019698 starch Nutrition 0.000 description 5
- 239000003826 tablet Substances 0.000 description 5
- 108010010803 Gelatin Proteins 0.000 description 4
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 4
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 4
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical class [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 4
- 229920002125 Sokalan® Polymers 0.000 description 4
- 150000001298 alcohols Chemical class 0.000 description 4
- 239000002775 capsule Substances 0.000 description 4
- 239000001913 cellulose Substances 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 239000012043 crude product Substances 0.000 description 4
- 229910001873 dinitrogen Inorganic materials 0.000 description 4
- 239000003480 eluent Substances 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 238000009472 formulation Methods 0.000 description 4
- 229920000159 gelatin Polymers 0.000 description 4
- 239000008273 gelatin Substances 0.000 description 4
- 229940014259 gelatin Drugs 0.000 description 4
- 235000019322 gelatine Nutrition 0.000 description 4
- 235000011852 gelatine desserts Nutrition 0.000 description 4
- 239000000543 intermediate Substances 0.000 description 4
- 238000004255 ion exchange chromatography Methods 0.000 description 4
- 238000002955 isolation Methods 0.000 description 4
- 229920000609 methyl cellulose Polymers 0.000 description 4
- 235000010981 methylcellulose Nutrition 0.000 description 4
- 239000001923 methylcellulose Substances 0.000 description 4
- 229960002900 methylcellulose Drugs 0.000 description 4
- 238000001556 precipitation Methods 0.000 description 4
- 239000012488 sample solution Substances 0.000 description 4
- 239000008247 solid mixture Substances 0.000 description 4
- 229940032147 starch Drugs 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- 238000002411 thermogravimetry Methods 0.000 description 4
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 description 3
- SPZRVRHYNLYPJC-UHFFFAOYSA-N 2-[methyl(pentyl)amino]propanoic acid Chemical compound CCCCCN(C)C(C)C(O)=O SPZRVRHYNLYPJC-UHFFFAOYSA-N 0.000 description 3
- 241000220479 Acacia Species 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- NIXOWILDQLNWCW-UHFFFAOYSA-N Acrylic acid Chemical compound OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 3
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 3
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 3
- 229920002907 Guar gum Polymers 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 3
- 239000005913 Maltodextrin Substances 0.000 description 3
- 229920002774 Maltodextrin Polymers 0.000 description 3
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 3
- 229920000881 Modified starch Polymers 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 3
- 235000010443 alginic acid Nutrition 0.000 description 3
- 229920000615 alginic acid Polymers 0.000 description 3
- 239000000783 alginic acid Substances 0.000 description 3
- 229960001126 alginic acid Drugs 0.000 description 3
- 150000004781 alginic acids Chemical class 0.000 description 3
- 238000005349 anion exchange Methods 0.000 description 3
- 230000008901 benefit Effects 0.000 description 3
- 229940028101 boniva Drugs 0.000 description 3
- 229960001631 carbomer Drugs 0.000 description 3
- 229940063834 carboxymethylcellulose sodium Drugs 0.000 description 3
- 229920001429 chelating resin Polymers 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 230000000052 comparative effect Effects 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 238000010828 elution Methods 0.000 description 3
- 235000010417 guar gum Nutrition 0.000 description 3
- 239000000665 guar gum Substances 0.000 description 3
- 229960002154 guar gum Drugs 0.000 description 3
- 229940015872 ibandronate Drugs 0.000 description 3
- 239000002198 insoluble material Substances 0.000 description 3
- 239000000314 lubricant Substances 0.000 description 3
- 229940035034 maltodextrin Drugs 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 3
- 239000008108 microcrystalline cellulose Substances 0.000 description 3
- 229940016286 microcrystalline cellulose Drugs 0.000 description 3
- 238000012544 monitoring process Methods 0.000 description 3
- 239000007800 oxidant agent Substances 0.000 description 3
- 230000001590 oxidative effect Effects 0.000 description 3
- PTMHPRAIXMAOOB-UHFFFAOYSA-N phosphoramidic acid Chemical class NP(O)(O)=O PTMHPRAIXMAOOB-UHFFFAOYSA-N 0.000 description 3
- 235000019814 powdered cellulose Nutrition 0.000 description 3
- 229920003124 powdered cellulose Polymers 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- 235000010413 sodium alginate Nutrition 0.000 description 3
- 239000000661 sodium alginate Substances 0.000 description 3
- 229940005550 sodium alginate Drugs 0.000 description 3
- 239000012453 solvate Substances 0.000 description 3
- 239000000600 sorbitol Substances 0.000 description 3
- 235000010356 sorbitol Nutrition 0.000 description 3
- 239000000454 talc Substances 0.000 description 3
- 235000012222 talc Nutrition 0.000 description 3
- 229910052623 talc Inorganic materials 0.000 description 3
- 229940033134 talc Drugs 0.000 description 3
- 238000001757 thermogravimetry curve Methods 0.000 description 3
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 description 2
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 2
- SDTMFDGELKWGFT-UHFFFAOYSA-N 2-methylpropan-2-olate Chemical compound CC(C)(C)[O-] SDTMFDGELKWGFT-UHFFFAOYSA-N 0.000 description 2
- XPCTZQVDEJYUGT-UHFFFAOYSA-N 3-hydroxy-2-methyl-4-pyrone Chemical compound CC=1OC=CC(=O)C=1O XPCTZQVDEJYUGT-UHFFFAOYSA-N 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- 241000416162 Astragalus gummifer Species 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 2
- 239000004375 Dextrin Substances 0.000 description 2
- 229920001353 Dextrin Polymers 0.000 description 2
- 239000004097 EU approved flavor enhancer Substances 0.000 description 2
- 239000001856 Ethyl cellulose Substances 0.000 description 2
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- 101100184723 Homo sapiens PMPCA gene Proteins 0.000 description 2
- 239000004354 Hydroxyethyl cellulose Substances 0.000 description 2
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 description 2
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
- 229930195725 Mannitol Natural products 0.000 description 2
- 102100025321 Mitochondrial-processing peptidase subunit alpha Human genes 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 229920001615 Tragacanth Polymers 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- SNAAJJQQZSMGQD-UHFFFAOYSA-N aluminum magnesium Chemical compound [Mg].[Al] SNAAJJQQZSMGQD-UHFFFAOYSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 description 2
- 229920003123 carboxymethyl cellulose sodium Polymers 0.000 description 2
- 229940084030 carboxymethylcellulose calcium Drugs 0.000 description 2
- 229940082500 cetostearyl alcohol Drugs 0.000 description 2
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 2
- 229960004106 citric acid Drugs 0.000 description 2
- 229940075614 colloidal silicon dioxide Drugs 0.000 description 2
- 239000003086 colorant Substances 0.000 description 2
- 235000019425 dextrin Nutrition 0.000 description 2
- RBLGLDWTCZMLRW-UHFFFAOYSA-K dicalcium;phosphate;dihydrate Chemical compound O.O.[Ca+2].[Ca+2].[O-]P([O-])([O-])=O RBLGLDWTCZMLRW-UHFFFAOYSA-K 0.000 description 2
- 238000000113 differential scanning calorimetry Methods 0.000 description 2
- 238000001938 differential scanning calorimetry curve Methods 0.000 description 2
- 239000007884 disintegrant Substances 0.000 description 2
- 239000003995 emulsifying agent Substances 0.000 description 2
- HHFAWKCIHAUFRX-UHFFFAOYSA-N ethoxide Chemical compound CC[O-] HHFAWKCIHAUFRX-UHFFFAOYSA-N 0.000 description 2
- 235000019325 ethyl cellulose Nutrition 0.000 description 2
- 229920001249 ethyl cellulose Polymers 0.000 description 2
- CBOQJANXLMLOSS-UHFFFAOYSA-N ethyl vanillin Chemical group CCOC1=CC(C=O)=CC=C1O CBOQJANXLMLOSS-UHFFFAOYSA-N 0.000 description 2
- 238000011049 filling Methods 0.000 description 2
- 239000000796 flavoring agent Substances 0.000 description 2
- 235000013355 food flavoring agent Nutrition 0.000 description 2
- 235000019264 food flavour enhancer Nutrition 0.000 description 2
- 235000011187 glycerol Nutrition 0.000 description 2
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 description 2
- UBHWBODXJBSFLH-UHFFFAOYSA-N hexadecan-1-ol;octadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO.CCCCCCCCCCCCCCCCCCO UBHWBODXJBSFLH-UHFFFAOYSA-N 0.000 description 2
- 150000004677 hydrates Chemical class 0.000 description 2
- BHEPBYXIRTUNPN-UHFFFAOYSA-N hydridophosphorus(.) (triplet) Chemical compound [PH] BHEPBYXIRTUNPN-UHFFFAOYSA-N 0.000 description 2
- 239000008172 hydrogenated vegetable oil Substances 0.000 description 2
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 description 2
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 2
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 2
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 2
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 2
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 2
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 238000011068 loading method Methods 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 239000000594 mannitol Substances 0.000 description 2
- 235000010355 mannitol Nutrition 0.000 description 2
- 229960001855 mannitol Drugs 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 239000000825 pharmaceutical preparation Substances 0.000 description 2
- 229940127557 pharmaceutical product Drugs 0.000 description 2
- 239000011574 phosphorus Substances 0.000 description 2
- 229910052698 phosphorus Inorganic materials 0.000 description 2
- 229920000191 poly(N-vinyl pyrrolidone) Polymers 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 229920000193 polymethacrylate Polymers 0.000 description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 2
- 239000004323 potassium nitrate Substances 0.000 description 2
- 235000010333 potassium nitrate Nutrition 0.000 description 2
- 229940069328 povidone Drugs 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 235000015424 sodium Nutrition 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 2
- 239000004299 sodium benzoate Substances 0.000 description 2
- 235000010234 sodium benzoate Nutrition 0.000 description 2
- 229920003109 sodium starch glycolate Polymers 0.000 description 2
- 239000008109 sodium starch glycolate Substances 0.000 description 2
- 229940079832 sodium starch glycolate Drugs 0.000 description 2
- VBDRTGFACFYFCT-UHFFFAOYSA-M sodium;hydroxy-[(1r)-1-hydroxy-3-[methyl(pentyl)amino]-1-phosphonopropyl]phosphinate;hydrate Chemical compound O.[Na+].CCCCCN(C)CCC(O)(P(O)(O)=O)P(O)([O-])=O VBDRTGFACFYFCT-UHFFFAOYSA-M 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- OULAJFUGPPVRBK-UHFFFAOYSA-N tetratriacontyl alcohol Natural products CCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCO OULAJFUGPPVRBK-UHFFFAOYSA-N 0.000 description 2
- 235000010487 tragacanth Nutrition 0.000 description 2
- 229940116362 tragacanth Drugs 0.000 description 2
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 2
- 235000019731 tricalcium phosphate Nutrition 0.000 description 2
- 238000010792 warming Methods 0.000 description 2
- 230000004580 weight loss Effects 0.000 description 2
- 238000005550 wet granulation Methods 0.000 description 2
- NOOLISFMXDJSKH-UTLUCORTSA-N (+)-Neomenthol Chemical compound CC(C)[C@@H]1CC[C@@H](C)C[C@@H]1O NOOLISFMXDJSKH-UTLUCORTSA-N 0.000 description 1
- ALRXDIKPRCRYAU-UHFFFAOYSA-N 2-methylpropan-2-ol Chemical compound CC(C)(C)O.CC(C)(C)O ALRXDIKPRCRYAU-UHFFFAOYSA-N 0.000 description 1
- CYDQOEWLBCCFJZ-UHFFFAOYSA-N 4-(4-fluorophenyl)oxane-4-carboxylic acid Chemical compound C=1C=C(F)C=CC=1C1(C(=O)O)CCOCC1 CYDQOEWLBCCFJZ-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 239000005995 Aluminium silicate Substances 0.000 description 1
- 108010011485 Aspartame Proteins 0.000 description 1
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical class OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 1
- 229940122361 Bisphosphonate Drugs 0.000 description 1
- 208000020084 Bone disease Diseases 0.000 description 1
- 239000004255 Butylated hydroxyanisole Substances 0.000 description 1
- NHBYYFUIMONZRB-UHFFFAOYSA-L C.C.C.CCCCCN(C)CCC(=O)Cl.CCCCCN(C)CCC(=O)O.CCCCCN(C)CCC(=O)P(C)(C)=O.CCCCCN(C)CCC(C)(C)O.CCCCCN(C)CCC(O)(P(=O)(O)O)P(=O)(O)O.CCCCCN(C)CCC(O)(P(=O)([O-])O)P(=O)(O)O.CCCCCN(C)CCC(O)(P(=O)([O-])O)P(=O)(O)O.C[PH](C)=O.O.[Na+].[Na+] Chemical compound C.C.C.CCCCCN(C)CCC(=O)Cl.CCCCCN(C)CCC(=O)O.CCCCCN(C)CCC(=O)P(C)(C)=O.CCCCCN(C)CCC(C)(C)O.CCCCCN(C)CCC(O)(P(=O)(O)O)P(=O)(O)O.CCCCCN(C)CCC(O)(P(=O)([O-])O)P(=O)(O)O.CCCCCN(C)CCC(O)(P(=O)([O-])O)P(=O)(O)O.C[PH](C)=O.O.[Na+].[Na+] NHBYYFUIMONZRB-UHFFFAOYSA-L 0.000 description 1
- VOQXLGROXHTHSS-UHFFFAOYSA-M C.C.CCCCCN(C)CCC(O)(P(=O)(O)O)P(=O)(O)O.CCCCCN(C)CCC(O)(P(=O)([O-])O)P(=O)(O)O.O.[Na+] Chemical compound C.C.CCCCCN(C)CCC(O)(P(=O)(O)O)P(=O)(O)O.CCCCCN(C)CCC(O)(P(=O)([O-])O)P(=O)(O)O.O.[Na+] VOQXLGROXHTHSS-UHFFFAOYSA-M 0.000 description 1
- 101100136727 Caenorhabditis elegans psd-1 gene Proteins 0.000 description 1
- 108010076119 Caseins Proteins 0.000 description 1
- PTHCMJGKKRQCBF-UHFFFAOYSA-N Cellulose, microcrystalline Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC)C(CO)O1 PTHCMJGKKRQCBF-UHFFFAOYSA-N 0.000 description 1
- 241000206576 Chondrus Species 0.000 description 1
- 229920002785 Croscarmellose sodium Polymers 0.000 description 1
- NOOLISFMXDJSKH-UHFFFAOYSA-N DL-menthol Natural products CC(C)C1CCC(C)CC1O NOOLISFMXDJSKH-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 102000002322 Egg Proteins Human genes 0.000 description 1
- 108010000912 Egg Proteins Proteins 0.000 description 1
- YIKYNHJUKRTCJL-UHFFFAOYSA-N Ethyl maltol Chemical compound CCC=1OC=CC(=O)C=1O YIKYNHJUKRTCJL-UHFFFAOYSA-N 0.000 description 1
- 229920003134 Eudragit® polymer Polymers 0.000 description 1
- 229930091371 Fructose Natural products 0.000 description 1
- 239000005715 Fructose Substances 0.000 description 1
- RFSUNEUAIZKAJO-ARQDHWQXSA-N Fructose Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O RFSUNEUAIZKAJO-ARQDHWQXSA-N 0.000 description 1
- 238000010268 HPLC based assay Methods 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- 206010020584 Hypercalcaemia of malignancy Diseases 0.000 description 1
- HYMLWHLQFGRFIY-UHFFFAOYSA-N Maltol Natural products CC1OC=CC(=O)C1=O HYMLWHLQFGRFIY-UHFFFAOYSA-N 0.000 description 1
- 208000037848 Metastatic bone disease Diseases 0.000 description 1
- 229920003091 Methocel™ Polymers 0.000 description 1
- 241000238367 Mya arenaria Species 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 208000010191 Osteitis Deformans Diseases 0.000 description 1
- 208000003076 Osteolysis Diseases 0.000 description 1
- 208000001132 Osteoporosis Diseases 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 208000027868 Paget disease Diseases 0.000 description 1
- 229920003072 Plasdone™ povidone Polymers 0.000 description 1
- 239000004372 Polyvinyl alcohol Substances 0.000 description 1
- HDSBZMRLPLPFLQ-UHFFFAOYSA-N Propylene glycol alginate Chemical compound OC1C(O)C(OC)OC(C(O)=O)C1OC1C(O)C(O)C(C)C(C(=O)OCC(C)O)O1 HDSBZMRLPLPFLQ-UHFFFAOYSA-N 0.000 description 1
- WINXNKPZLFISPD-UHFFFAOYSA-M Saccharin sodium Chemical compound [Na+].C1=CC=C2C(=O)[N-]S(=O)(=O)C2=C1 WINXNKPZLFISPD-UHFFFAOYSA-M 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- DRHKJLXJIQTDTD-OAHLLOKOSA-N Tamsulosine Chemical compound CCOC1=CC=CC=C1OCCN[C@H](C)CC1=CC=C(OC)C(S(N)(=O)=O)=C1 DRHKJLXJIQTDTD-OAHLLOKOSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 235000011054 acetic acid Nutrition 0.000 description 1
- 239000012615 aggregate Substances 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 235000012211 aluminium silicate Nutrition 0.000 description 1
- 239000003708 ampul Substances 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 239000000605 aspartame Substances 0.000 description 1
- 235000010357 aspartame Nutrition 0.000 description 1
- IAOZJIPTCAWIRG-QWRGUYRKSA-N aspartame Chemical compound OC(=O)C[C@H](N)C(=O)N[C@H](C(=O)OC)CC1=CC=CC=C1 IAOZJIPTCAWIRG-QWRGUYRKSA-N 0.000 description 1
- 229960003438 aspartame Drugs 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 239000000305 astragalus gummifer gum Substances 0.000 description 1
- 238000000889 atomisation Methods 0.000 description 1
- 239000000440 bentonite Substances 0.000 description 1
- 229910000278 bentonite Inorganic materials 0.000 description 1
- 229940092782 bentonite Drugs 0.000 description 1
- SVPXDRXYRYOSEX-UHFFFAOYSA-N bentoquatam Chemical compound O.O=[Si]=O.O=[Al]O[Al]=O SVPXDRXYRYOSEX-UHFFFAOYSA-N 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 210000000988 bone and bone Anatomy 0.000 description 1
- 235000019282 butylated hydroxyanisole Nutrition 0.000 description 1
- CZBZUDVBLSSABA-UHFFFAOYSA-N butylated hydroxyanisole Chemical compound COC1=CC=C(O)C(C(C)(C)C)=C1.COC1=CC=C(O)C=C1C(C)(C)C CZBZUDVBLSSABA-UHFFFAOYSA-N 0.000 description 1
- 229940043253 butylated hydroxyanisole Drugs 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- XAAHAAMILDNBPS-UHFFFAOYSA-L calcium hydrogenphosphate dihydrate Chemical compound O.O.[Ca+2].OP([O-])([O-])=O XAAHAAMILDNBPS-UHFFFAOYSA-L 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- 229940078456 calcium stearate Drugs 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 239000005018 casein Substances 0.000 description 1
- BECPQYXYKAMYBN-UHFFFAOYSA-N casein, tech. Chemical compound NCCCCC(C(O)=O)N=C(O)C(CC(O)=O)N=C(O)C(CCC(O)=N)N=C(O)C(CC(C)C)N=C(O)C(CCC(O)=O)N=C(O)C(CC(O)=O)N=C(O)C(CCC(O)=O)N=C(O)C(C(C)O)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=O)N=C(O)C(CCC(O)=O)N=C(O)C(COP(O)(O)=O)N=C(O)C(CCC(O)=N)N=C(O)C(N)CC1=CC=CC=C1 BECPQYXYKAMYBN-UHFFFAOYSA-N 0.000 description 1
- 235000021240 caseins Nutrition 0.000 description 1
- 239000004359 castor oil Substances 0.000 description 1
- 235000019438 castor oil Nutrition 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 229960000541 cetyl alcohol Drugs 0.000 description 1
- 239000002738 chelating agent Substances 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 239000008395 clarifying agent Substances 0.000 description 1
- 239000008119 colloidal silica Substances 0.000 description 1
- 238000005056 compaction Methods 0.000 description 1
- 238000007906 compression Methods 0.000 description 1
- 230000006835 compression Effects 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 235000008504 concentrate Nutrition 0.000 description 1
- 229960001681 croscarmellose sodium Drugs 0.000 description 1
- 229960000913 crospovidone Drugs 0.000 description 1
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 description 1
- 238000010908 decantation Methods 0.000 description 1
- 229940096516 dextrates Drugs 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- FSBVERYRVPGNGG-UHFFFAOYSA-N dimagnesium dioxido-bis[[oxido(oxo)silyl]oxy]silane hydrate Chemical compound O.[Mg+2].[Mg+2].[O-][Si](=O)O[Si]([O-])([O-])O[Si]([O-])=O FSBVERYRVPGNGG-UHFFFAOYSA-N 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000007908 dry granulation Methods 0.000 description 1
- 235000013345 egg yolk Nutrition 0.000 description 1
- 210000002969 egg yolk Anatomy 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- MVPICKVDHDWCJQ-UHFFFAOYSA-N ethyl 3-pyrrolidin-1-ylpropanoate Chemical compound CCOC(=O)CCN1CCCC1 MVPICKVDHDWCJQ-UHFFFAOYSA-N 0.000 description 1
- 229960004667 ethyl cellulose Drugs 0.000 description 1
- 229940093503 ethyl maltol Drugs 0.000 description 1
- 229940073505 ethyl vanillin Drugs 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 230000037406 food intake Effects 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 229960002737 fructose Drugs 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 229960002598 fumaric acid Drugs 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 239000003365 glass fiber Substances 0.000 description 1
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 1
- 229940075507 glyceryl monostearate Drugs 0.000 description 1
- FETSQPAGYOVAQU-UHFFFAOYSA-N glyceryl palmitostearate Chemical compound OCC(O)CO.CCCCCCCCCCCCCCCC(O)=O.CCCCCCCCCCCCCCCCCC(O)=O FETSQPAGYOVAQU-UHFFFAOYSA-N 0.000 description 1
- 229940046813 glyceryl palmitostearate Drugs 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 239000011261 inert gas Substances 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 229960004903 invert sugar Drugs 0.000 description 1
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 208000029791 lytic metastatic bone lesion Diseases 0.000 description 1
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 description 1
- 239000001095 magnesium carbonate Substances 0.000 description 1
- 229910000021 magnesium carbonate Inorganic materials 0.000 description 1
- 235000014380 magnesium carbonate Nutrition 0.000 description 1
- 239000000395 magnesium oxide Substances 0.000 description 1
- CPLXHLVBOLITMK-UHFFFAOYSA-N magnesium oxide Inorganic materials [Mg]=O CPLXHLVBOLITMK-UHFFFAOYSA-N 0.000 description 1
- 235000012245 magnesium oxide Nutrition 0.000 description 1
- 239000000391 magnesium silicate Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 229940057948 magnesium stearate Drugs 0.000 description 1
- 229940099273 magnesium trisilicate Drugs 0.000 description 1
- 229910000386 magnesium trisilicate Inorganic materials 0.000 description 1
- 235000019793 magnesium trisilicate Nutrition 0.000 description 1
- AXZKOIWUVFPNLO-UHFFFAOYSA-N magnesium;oxygen(2-) Chemical compound [O-2].[Mg+2] AXZKOIWUVFPNLO-UHFFFAOYSA-N 0.000 description 1
- 229940043353 maltol Drugs 0.000 description 1
- 208000027202 mammary Paget disease Diseases 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 229940041616 menthol Drugs 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000001788 mono and diglycerides of fatty acids Substances 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 235000010987 pectin Nutrition 0.000 description 1
- 239000001814 pectin Substances 0.000 description 1
- 229920001277 pectin Polymers 0.000 description 1
- 229960000292 pectin Drugs 0.000 description 1
- 235000020030 perry Nutrition 0.000 description 1
- UXCDUFKZSUBXGM-UHFFFAOYSA-N phosphoric tribromide Chemical compound BrP(Br)(Br)=O UXCDUFKZSUBXGM-UHFFFAOYSA-N 0.000 description 1
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 1
- IPNPIHIZVLFAFP-UHFFFAOYSA-N phosphorus tribromide Chemical compound BrP(Br)Br IPNPIHIZVLFAFP-UHFFFAOYSA-N 0.000 description 1
- 239000004014 plasticizer Substances 0.000 description 1
- 229960000540 polacrilin potassium Drugs 0.000 description 1
- 229920002451 polyvinyl alcohol Polymers 0.000 description 1
- 229940068984 polyvinyl alcohol Drugs 0.000 description 1
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 description 1
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- WVWZXTJUCNEUAE-UHFFFAOYSA-M potassium;1,2-bis(ethenyl)benzene;2-methylprop-2-enoate Chemical compound [K+].CC(=C)C([O-])=O.C=CC1=CC=CC=C1C=C WVWZXTJUCNEUAE-UHFFFAOYSA-M 0.000 description 1
- 230000002028 premature Effects 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- USGIERNETOEMNR-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO.CCCO USGIERNETOEMNR-UHFFFAOYSA-N 0.000 description 1
- IKNCGYCHMGNBCP-UHFFFAOYSA-N propan-1-olate Chemical compound CCC[O-] IKNCGYCHMGNBCP-UHFFFAOYSA-N 0.000 description 1
- 235000010409 propane-1,2-diol alginate Nutrition 0.000 description 1
- 239000000770 propane-1,2-diol alginate Substances 0.000 description 1
- RUOJZAUFBMNUDX-UHFFFAOYSA-N propylene carbonate Chemical compound CC1COC(=O)O1 RUOJZAUFBMNUDX-UHFFFAOYSA-N 0.000 description 1
- 229940032159 propylene carbonate Drugs 0.000 description 1
- 239000010453 quartz Substances 0.000 description 1
- 235000019204 saccharin Nutrition 0.000 description 1
- 229940081974 saccharin Drugs 0.000 description 1
- 239000000901 saccharin and its Na,K and Ca salt Substances 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 235000002639 sodium chloride Nutrition 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 235000011083 sodium citrates Nutrition 0.000 description 1
- 239000001540 sodium lactate Substances 0.000 description 1
- 235000011088 sodium lactate Nutrition 0.000 description 1
- 229940005581 sodium lactate Drugs 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 229940080313 sodium starch Drugs 0.000 description 1
- 229940045902 sodium stearyl fumarate Drugs 0.000 description 1
- NASFKTWZWDYFER-UHFFFAOYSA-N sodium;hydrate Chemical compound O.[Na] NASFKTWZWDYFER-UHFFFAOYSA-N 0.000 description 1
- LXLBEOAZMZAZND-UHFFFAOYSA-M sodium;hydroxy-[1-hydroxy-3-[methyl(pentyl)amino]-1-phosphonopropyl]phosphinate Chemical compound [Na+].CCCCCN(C)CCC(O)(P(O)(O)=O)P(O)([O-])=O LXLBEOAZMZAZND-UHFFFAOYSA-M 0.000 description 1
- 239000007909 solid dosage form Substances 0.000 description 1
- 239000012439 solid excipient Substances 0.000 description 1
- 239000011343 solid material Substances 0.000 description 1
- 230000003381 solubilizing effect Effects 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 229960004274 stearic acid Drugs 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 229960004793 sucrose Drugs 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 229960001367 tartaric acid Drugs 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
- 235000010493 xanthan gum Nutrition 0.000 description 1
- 239000000230 xanthan gum Substances 0.000 description 1
- 229920001285 xanthan gum Polymers 0.000 description 1
- 229940082509 xanthan gum Drugs 0.000 description 1
- XOOUIPVCVHRTMJ-UHFFFAOYSA-L zinc stearate Chemical compound [Zn+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O XOOUIPVCVHRTMJ-UHFFFAOYSA-L 0.000 description 1
- 229940057977 zinc stearate Drugs 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
- C07F9/3804—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)] not used, see subgroups
- C07F9/3839—Polyphosphonic acids
- C07F9/3873—Polyphosphonic acids containing nitrogen substituent, e.g. N.....H or N-hydrocarbon group which can be substituted by halogen or nitro(so), N.....O, N.....S, N.....C(=X)- (X =O, S), N.....N, N...C(=X)...N (X =O, S)
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
- A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
Definitions
- Ibandronate Sodium is a third-generation nitrogen-containing bisphosphonate characterized by an aliphatic tertiary amine side chain.
- Ibandronate Sodium is a white crystalline powder.
- the free acid has MW 319.23 (CAS No.: 114084-78-5).
- the monosodium salt (anhydrous) of the acid has MW 341.23 (CAS No.: 138844-81-2).
- the monosodium salt monohydrate has MW 359.23 (CAS No.: 138926-19-9).
- Boniva® The monosodium salt of ibandronic acid is marketed under the trade name Boniva®.
- Boniva® was developed by Hoffmann-La Roche for the treatment of bone disorders such as: hypercalcaemia of malignancy, osteolysis, Paget's disease, osteoporosis and metastatic bone disease.
- Boniva® is also marketed in Europe under the name Bondronat for cancer-related bone complications. Bondronat is available in ampoule with 1 ml concentrate for solution for infusion contains 1.125 mg of Ibandronic acid monosodium salt monohydrate, corresponding to 1 mg of ibandronic acid.
- Ibandronic acid can be used as an intermediate in the process for the preparation of Ibandronate sodium.
- the present invention provides amorphous ibandronic acid.
- the present invention provides a method of preparing amorphous ibandronic acid that includes the step of isolating amorphous ibandronic acid from an aqueous solution of ibandronic acid which isolating step is selected from a vacuum evaporation step or a lyophilization step.
- the present invention relates to a method of making amorphous ibandronic comprising the step of spray drying an aqueous solution of ibandronic acid.
- the present invention provides solid ibandronic acid.
- the present invention provides a process for preparing solid Ibandronic acid comprising the steps of:
- step f) may be dissolved in water prior to the addition of the alcohol in step g). After the addition of the alcohol, the reaction mixture may be heated in order to facilitate the formation of the precipitate.
- the present invention provides crystalline ibandronic acid in several crystalline forms and hydrates and solvates, especially alcoholates, thereof.
- the present invention also provides ibandronic acid alcoholates.
- the present invention provides a solid crystalline form of ibandronic acid, denominated form S1, characterized by a powder X-ray diffraction pattern having reflections at about 8.2, 11.5, 11.9, 13.9, 18.6 and 22.2 ⁇ 0.2 deg. 2-theta.
- the present invention further provides processes for preparing ibandronic acid form S1.
- the present invention provides a solid crystalline form of ibandronic acid, denominated form S2, characterized by a powder X-ray diffraction pattern having reflections at about 8.1, 14.2, 16.1, 18.2 and 24.4 ⁇ 0.2 deg. 2-theta.
- the present invention further provides a process for preparing ibandronic acid form S2.
- the present invention provides a solid crystalline form of ibandronic acid, denominated form S3, characterized by a powder X-ray diffraction pattern having reflections at about 4.4, 8.8, 11.3, 17.6 and 26.4 ⁇ 0.2 deg. 2-theta.
- the present invention further provides a process for preparing ibandronic acid form S3.
- the present invention provides a solid crystalline form of ibandronic acid, denominated form S4, characterized by a powder X-ray diffraction pattern having reflections at about 4.4, 8.6, 11.2, 17.3, 20.8, 22.5 and 26.0 ⁇ 0.2 deg. 2-theta.
- the present invention further provides a process for preparing ibandronic acid form S4.
- the present invention provides a solid crystalline form of ibandronic acid, denominated form S5, characterized by a powder X-ray diffraction pattern having reflections at about 4.5, 8.9, 12.0, 16.0, 16.3, 21.4, 22.1 and 26.9 ⁇ 0.2 deg. 2-theta.
- the present invention further provides processes for preparing ibandronic acid form S5.
- the present invention provides a solid crystalline form of ibandronic acid, denominated form S6, characterized by a powder X-ray diffraction pattern having reflections at about 5.7, 11.7, 14.3, 18.5, 21.2 and 21.7 ⁇ 0.2 deg. 2-theta.
- the present invention further provides processes for preparing ibandronic acid form S6.
- the present invention provides a solid crystalline form of ibandronic acid, denominated form S7, characterized by a powder X-ray diffraction pattern having reflections at about 4.6, 11.5, 16.3, 16.8, 21.0 and 22.8 ⁇ 0.2 deg. 2-theta.
- the present invention further provides processes for preparing ibandronic acid form S7.
- the present invention provides a solid crystalline form of ibandronic acid, denominated form S8, characterized by a powder X-ray diffraction pattern having reflections at about 4.5, 6.0, 11.9, 12.3, 16.2, 17.8 and 21.7 ⁇ 0.2 deg. 2-theta.
- the present invention further provides processes for preparing ibandronic acid form S8.
- the present invention provides a solid crystalline form of ibandronic acid, denominated form S10, characterized by a powder X-ray diffraction pattern having reflections at about 4.8, 6.1, 12.0, 12.3, 16.4, 18.0 and 21.7 ⁇ 0.2 deg. 2-theta.
- the present invention further provides processes for preparing ibandronic acid form S10.
- the present invention provides a solid crystalline form of ibandronic acid, denominated form S12, characterized by a powder X-ray diffraction pattern having reflections at about 4.7, 9.0, 11.6, 20.9, 21.1, 21.7, 22.9 and 26.3 ⁇ 0.2 deg. 2-theta.
- the present invention further provides a process for preparing ibandronic acid form S5.
- the present invention provides a solid crystalline form of ibandronic acid, denominated form S13, characterized by a powder X-ray diffraction pattern having reflections at about 4.5, 8.9, 12.0, 16.0, 16.3, 21.3 and 22.1 ⁇ 0.2 deg. 2-theta.
- the present invention further provides processes for preparing ibandronic acid form S13.
- the present invention provides a process for purifying Ibandronic acid from inorganic impurities by crystallization from an organic solvent selected from the group consisting of C 2-4 alcohols and acetonitrile.
- the present invention provides a HPLC method of assaying ibandronic acid comprising the steps of: providing a sample solution of a sample of ibandronic acid in a diluent, loading the sample solution (ca. 50 ⁇ L) onto a 250 ⁇ 4.1 mm, Hamilton type PRP-X100 anion exchange column, eluting the sample from the column at 2.0 ml/min. with an eluent including nitric acid (HNO 3 : 35 vol-%), potassium nitrate (KNO 3 : 45 vol-%) and ethanol (20 vol-%), and measuring the ibandronic acid content of the eluent at 240 nm wavelength with a UV detector to identify the relevant fractions.
- the present invention provides A process for purifying ibandronic acid from inorganic impurities comprising the steps of: providing a solution of ibandronic acid containing inorganic impurities in water or methanol; and b) combining the solution with a C 2 -C 4 alcohol, especially wherein the C 2-4 alcohol is selected from the group consisting of ethanol, 1-propanol, isopropanol (IPA) and tert-butanol whereby ibandronic acid precipitates.
- IPA isopropanol
- FIG. 1 illustrates an x-ray diffraction diagram of amorphous ibandronic acid.
- FIG. 2 illustrates a DSC thermogram of amorphous ibandronic acid.
- FIG. 3 illustrates a TGA thermogram of ibandronic acid.
- FIG. 4 illustrates an x-ray diffraction diagram of ibandronic acid form S1.
- FIG. 5 illustrates an x-ray diffraction diagram of ibandronic acid form S2.
- FIG. 6 illustrates an x-ray diffraction diagram of ibandronic acid form S3.
- FIG. 7 illustrates an x-ray diffraction diagram of ibandronic acid form S4.
- FIG. 8 illustrates an x-ray diffraction diagram of ibandronic acid form S5.
- FIG. 9 illustrates an x-ray diffraction diagram of ibandronic acid form S6.
- FIG. 10 illustrates an x-ray diffraction diagram of ibandronic acid form S7.
- FIG. 11 illustrates an x-ray diffraction diagram of ibandronic acid form S8.
- FIG. 12 illustrates an x-ray diffraction diagram of ibandronic acid form S10.
- FIG. 13 illustrates an x-ray diffraction diagram of ibandronic acid form S12.
- FIG. 14 illustrates an x-ray diffraction diagram of ibandronic acid form S13.
- the present invention provides processes which utilize halo-phosphorous compounds.
- Such compounds include, but are not limited to, phosphorous trichloride, phosphorous oxychloride, phosphorous pentachloride, phosphorous tribromide, phosphorous oxybromide, phosphorous pentabromide.
- C 2 -C 4 alcohols are used.
- the C 2 -C 4 alcohols have the general structure ROH wherein R is a linear or branched alkyl group having 2 to 4 carbon atoms.
- Ethanol, n-propanol (1-propanol), iso-propanol (2-propanol, IPA), and t-butanol (2-methylpropan-2-ol) are preferred C2-C4 alcohols.
- the present invention also provides processes that, in particular embodiments, utilize strong acids which do not act as oxidants for amino-phosphonic acids.
- non-oxidizing acids include, but are not limited to, para-toluene sulfonic acid, HCl, HBr, and trichloroacetic acid.
- the present invention provides amorphous ibandronic acid.
- Amorphous ibandronic acid has an x-ray diffraction diagram not unexpected for an essentially amorphous solid.
- FIG. 1 shows a representative x-ray diffraction diagram of amorphous ibandronic acid.
- FIG. 2 shows a representative thermogram from differential scanning calorimetry (DSC) for amorphous ibandronic acid.
- DSC differential scanning calorimetry
- FIG. 3 shows a representative thermogram from thermogravimetric analysis (TGA).
- Amorphous ibandronic acid can be prepared by a method that includes an isolation step.
- An isolation step is a step (procedure) in which a solvent, for example water is removed from a solution of ibandronic acid and can be called a “water-removal” step.
- This step comprises isolation of amorphous ibandronic acid from a solution of ibandronic acid in a solvent selected from the group consisting of acetonitrile (ACN), dimethylsulfoxide (DMSO), methanol, and water.
- the solvent is water.
- the isolation step can be a vacuum evaporation (i.e. concentration) step, a lyophilization step, or a spray drying step.
- spray drying broadly refers to processes involving breaking up liquid mixtures into small droplets (atomization) and rapidly removing solvent from the mixture.
- the typical spray drying apparatus comprises a drying chamber, atomizing means for atomizing a solvent-containing feed into the drying chamber, a source of drying gas that flows into the drying chamber to remove solvent from the atomized-solvent-containing feed, an outlet for the products of drying, and product collection means located downstream of the drying chamber.
- atomizing means for atomizing a solvent-containing feed into the drying chamber
- source of drying gas that flows into the drying chamber to remove solvent from the atomized-solvent-containing feed
- an outlet for the products of drying and product collection means located downstream of the drying chamber.
- the product collection means includes a cyclone connected to the drying apparatus. In the cyclone, the particles produced during spray drying are separated from the drying gas and evaporated solvent, allowing the particles to be collected.
- a filter may also be used to separate and collect the particles produced by spray drying.
- the process of the invention is not limited to the use of such drying apparatuses as described above.
- Spray drying may be performed in a conventional manner in the processes of the present invention (see, e.g., Remington: The Science and Practice of Pharmacy, 19th Ed., vol. II, pg. 1627, herein incorporated by reference).
- the drying gas used in the invention may be any suitable gas, although inert gases such as nitrogen, nitrogen-enriched air, and argon are preferred. Nitrogen gas is a particularly preferred drying gas for use in the process of the invention.
- the amorphous ibandronic acid product produced by spray drying may be recovered by techniques commonly used in the art, such as using a cyclone or a filter. Spray drying of ibandronic acid from a solution of ibandronic acid in water results in amorphous ibandronic acid.
- the present invention also provides solid ibandronic acid.
- intermediate compounds are Solid substances rather than liquid, it enables the possibility of isolating and purifying the intermediate by crystallization thereby improving the quality of the final product.
- the present invention also provides solid ibandronic acid.
- Solid ibandronic acid can be prepared by a process that includes the steps of:
- the halo-phosphorous compound of step a) is added in small aliquots, especially dropwise.
- the diluent in step a) is selected from the group consisting of silicone oil, toluene and a mixture of toluene and phosphoric acid.
- the temperature in step a) is about 75° C.
- the mixture in step b) is heated to a temperature of about 80° C.
- the C 2-4 alcohol in step g) is selected from the group consisting of ethanol, 1-propanol, isopropyl alcohol (IPA) and tert-butanol.
- the alcohol in step g) is ethanol or IPA.
- the residue of step f) can be combined with water prior to the addition of the alcohol in step g).
- the reaction mixture is optionally heated in order to facilitate the formation of the precipitate.
- the present invention further provides crystalline ibandronic acid, hydrates and solvates thereof.
- the present invention also provides ibandronic acid alcoholates.
- crystalline forms possess the advantage of being readily filterable, easily dried, and stable for extended periods of time without the need for specialized storage conditions.
- the present invention provides a solid crystalline form of ibandronic acid, denominated form S1, characterized by a powder X-ray diffraction pattern having reflections at about 8.2, 11.5, 11.9, 13.9, 18.6 and 22.2 ⁇ 0.2 deg. 2-theta.
- Solid crystalline ibandronic acid form S1 is further characterized by X-ray powder diffraction pattern having reflections at about 21.6, 23.8, 24.7 and 28.1 ⁇ 0.2 deg. 2-theta.
- a typical x-ray diffraction diagram for ibandronic acid form S1 is given in FIG. 4 .
- Form S1 can be a hemihydrate.
- Ibandronic acid form S1 can be prepared by combining an organic solvent selected from the group consisting of tert-butanol, ethanol, and acetone, with an aqueous solution of ibandronic acid, and maintaining the resulting combination for up to about 24 hours to obtain a precipitate of ibandronic acid form S1.
- the organic solvent is selected from the group consisting of tert-butanol, ethanol and acetone.
- Form S1 can be also prepared by combining amorphous ibandronic acid and an organic solvent at a temperature that ranges from room temperature to reflux, and maintaining the reaction mixture for a sufficient time to obtain form S1 in a slurry.
- the organic solvent is selected from the group consisting of tert-butanol, ethanol and acetone.
- Ibandronic acid form S1 can also be prepared in a process that includes the steps of dissolving amorphous ibandronic acid in water, adding acetone to obtain in a slurry, and stirring the slurry for a sufficient time to obtain form S1.
- Form S1 can be also prepared by a process that includes the steps of:
- the halo-phosphorous compound of step a) is added in small aliquots, most preferably dropwise.
- the temperature in step a) is about 75° C.
- the reaction mixture in step b) is heated to a temperature of about 80° C.
- the present invention further provides a solid crystalline form of ibandronic acid, denominated form S2, characterized by a powder X-ray diffraction pattern having reflections at about 8.1, 14.2, 16.1, 18.2 and 24.4 ⁇ 0.2 deg. 2-theta.
- Solid crystalline ibandronic acid form S2 can be further characterized by X-ray reflections at about 10.9, 19.2, 22.3, 23.3, and 28.2 ⁇ 0.2 deg. 2-theta.
- a typical x-ray diffraction diagram for ibandronic acid form S2 is given in FIG. 5 .
- Ibandronic acid form S2 can be prepared by providing a solution of amorphous ibandronic acid in methanol; adding acetonitrile solvent to the solution to obtain a slurry and recovering ibandronic acid form S2.
- the present invention provides a solid crystalline form of ibandronic acid, denominated form S3, characterized by a powder X-ray diffraction pattern having reflections at about 4.4, 8.8, 11.3, 17.6 and 26.4 ⁇ 0.2 deg. 2-theta.
- Solid crystalline ibandronic acid form S3 can be further characterized by X-ray reflections at about 21.6, 23.8, 24.7 and 28.1 ⁇ 0.2 deg. 2-theta.
- a typical x-ray diffraction diagram for ibandronic acid form S3 is given in FIG. 6 .
- Form S3 can exist as a tert-butanolate.
- Ibandronic acid form S3 can be prepared by adding tert-butanol, to an aqueous solution of ibandronic acid, and maintaining the resulting mixture for at least about 24 hours or more to obtain form S3.
- the present invention provides a solid crystalline form of ibandronic acid, denominated Form S4, characterized by a powder X-ray diffraction pattern having reflections at about 4.4, 8.6, 11.2, 17.3, 20.8, 22.5 and 26.0 ⁇ 0.2 deg. 2-theta.
- Solid crystalline ibandronic acid Form S4 can be further characterized by X-ray reflections at about 16.2, 20.5 and 21.3 ⁇ 0.2 deg. 2-theta.
- a typical x-ray diffraction diagram for ibandronic acid Form S4 is given in FIG. 7 .
- Form S4 can be a propanolate.
- Ibandronic acid Form S4 can be prepared by combining at room temperature an aqueous solution of ibandronic acid and 1-propanol until precipitation occurs, and isolating Form S4. Preferably the combination is stirred for at least about 3 hours. Optionally, the combination is heated to a reflux temperature, in order to obtain a stirrable mixture, which is then cooled to room temperature.
- the present invention provides a solid crystalline form of ibandronic acid, denominated Form S5, characterized by a powder X-ray diffraction pattern having reflections at about 4.5, 8.9, 12.0, 16.0, 16.3, 21.4, 22.1 and 26.9 ⁇ 0.2 deg. 2-theta.
- Solid crystalline ibandronic acid Form S1 can be further characterized by X-ray reflections at about 5.9, 10.5 and 17.8 ⁇ 0.2 deg. 2-theta.
- a typical x-ray diffraction diagram for ibandronic acid Form S5 is given in FIG. 8 .
- Form S5 exists as a hemihydrate or an iso-propanolate (isopropyl alcohol solvate).
- Ibandronic acid Form S5 can be prepared by a process that includes the steps of:
- the halo-phosphorous compound of step a) is added in small aliquots, most preferably dropwise.
- the temperature in step a) is about 75° C.
- the reaction mixture in step b) is heated to a temperature of about 80° C.
- the residue of step f) can be dissolved in water prior to the addition of the IPA in step g).
- the mixture of the IPA and the residue is cooled to facilitate precipitation.
- Form S5 can be also prepared by a process including the steps of:
- the temperature in step a) is about 75° C.
- the reaction mixture in step b) is heated to a temperature of about 80° C.
- the halo-phosphorous compound of step a) is added slowly, in small aliquots, most preferably dropwise.
- a strong acid which does not act as oxidant for amino-phosphonic acids may be added to the reaction mixture of step c). The acid is thought to hydrolize the phosphorous intermediates that form during the previous steps.
- the acid is concentrated HCl.
- Ibandronic acid Form S5 can be prepared by stirring a combination of amorphous ibandronic acid with an organic solvent selected from the group consisting of tetrahydrofuran (THF) and ethanol; and recovering Form S5. The combination is optionally heated to reflux temperature.
- THF tetrahydrofuran
- the present invention provides a solid crystalline form of ibandronic acid, denominated Form S6, characterized by a powder X-ray diffraction pattern having reflections at about 5.7, 11.7, 14.3, 18.5, 21.2 and 21.7 ⁇ 0.2 deg. 2-theta.
- Solid crystalline ibandronic acid Form S6 can be further characterized by X-ray reflections at about 14.8, 22.7, 22.8 and 30.6 ⁇ 0.2 deg. 2-theta.
- a typical x-ray diffraction diagram for ibandronic acid form S6 is given in FIG. 9 .
- Form S6 can exist as a hemihydrate, tert-butanolate, or a mixture of both.
- Ibandronic acid Form S6 can be prepared by a process including the steps of:
- the halo-phosphorous compound of step a) is added slowly, in small aliquots, especially dropwise.
- the temperature in step a) is about 75° C.
- the reaction mixture in step b) is heated to a temperature of about 80° C.
- Form S6 can be also prepared by a process that includes the steps of:
- the halo-phosphorous compound of step a) is added dropwise.
- the acid in step c) is a strong acid which does not act as oxidant for amino-phosphonic acids.
- the acid in step c) is concentrated HCl.
- the temperature in step a) is about 75° C.
- the present invention provides a solid crystalline form of ibandronic acid, denominated Form S7, characterized by a powder X-ray diffraction pattern having reflections at about 4.6, 11.5, 16.3, 16.8, 21.0 and 22.8 ⁇ 0.2 deg. 2-theta.
- Solid crystalline ibandronic acid Form S7 can be further characterized by X-ray reflections at about 9.0, 17.7, 19.8 and 21.8 ⁇ 0.2 deg. 2-theta.
- a typical x-ray diffraction diagram for ibandronic acid Form S7 is given in FIG. 10 .
- Form S7 can exist as a hemihydrate, a 1-propanolate, or an iso-propanolate.
- Ibandronic acid Form S7 can be prepared by a process including the steps of:
- the halo-phosphorous compound of step a) is added slowly, in small aliquots, most preferably dropwise.
- the temperature in step a) is about 70° C.
- the reaction mixture in step b) is heated to a temperature of about 80° C.
- Form S7 can be also prepared by a process including the steps of:
- the halo-phosphorous compound of step a) is added slowly, in small aliquots, most preferably dropwise.
- the temperature in step a) is about 75° C.
- the reaction mixture in step b) is heated to a temperature of about 80° C.
- the present invention provides a solid crystalline form of ibandronic acid, denominated Form S8, characterized by a powder X-ray diffraction pattern having reflections at about 4.5, 6.0, 11.9, 12.3, 16.2, 17.8 and 21.7 ⁇ 0.2 deg. 2-theta.
- Solid crystalline ibandronic acid Form S8 can be further characterized by X-ray reflections at about 9.0, 16.5 and 18.9, ⁇ 0.2 deg. 2-theta.
- a typical x-ray diffraction diagram for ibandronic acid Form S8 is given in FIG. 11 .
- Form S8 can be exist as an ethanolate or an iso-propanolate.
- Ibandronic acid Form S8 can be prepared by a process including the steps of:
- the halo-phosphorous compound of step a) is added slowly, in small aliquots, most preferably dropwise.
- the temperature in step a) is about 75° C.
- the reaction mixture in step b) is heated to a temperature of about 80° C.
- the residue of step f) may be dissolved in water prior to the addition of the C 2-4 alcohol in step g).
- the C 2-4 alcohol in step g) is selected from the group consisting of ethanol, 1-propanol and IPA.
- the C 2-4 alcohol in step g) is ethanol.
- the present invention provides a solid crystalline form of ibandronic acid, denominated Form S10, characterized by a powder X-ray diffraction pattern having reflections at about 4.8, 6.1, 12.0, 12.3, 16.4, 18.0 and 21.7 ⁇ 0.2 deg. 2-theta.
- Solid crystalline ibandronic acid Form S10 can be further characterized by X-ray reflections at about 18.9, 20.9 and 22.8 ⁇ 0.2 deg. 2-theta.
- a typical x-ray diffraction diagram for ibandronic acid Form S10 is given in FIG. 12 .
- Form S10 can exist as an ethanolate.
- Ibandronic acid Form S10 can be prepared by a process comprising the steps of:
- the halo-phosphorous compound of step a) is added slowly, in small aliquots, most preferably dropwise.
- the reaction mixture in step b) is heated to a temperature of about 80° C.
- the residue of step f) may be dissolved in water prior to the addition of the ethanol in step g).
- the reaction mixture in step g) may be seeded with amorphous ibandronic acid following the addition of the ethanol in step g).
- the present invention provides a solid crystalline form of ibandronic acid, denominated Form S12, characterized by a powder X-ray diffraction pattern having reflections at about 4.7, 9.0, 11.6, 20.9, 21.1, 21.7, 22.9 and 26.3 ⁇ 0.2 deg. 2-theta.
- Solid crystalline ibandronic acid form S12 may be further characterized by X-ray reflections at about 13.8, 17.1 and 18.4 ⁇ 0.2 deg. 2-theta.
- a typical x-ray diffraction diagram for ibandronic acid Form S12 is given in FIG. 13 .
- Form S12 can be a hemihydrate and/or an isopropanolate.
- Ibandronic acid Form S12 can be prepared by a process including the steps of:
- the halo-phosphorous compound of step a) is added slowly, in small aliquots, especially dropwise.
- the temperature in step a) is about 70° C.
- the reaction mixture in step b) is heated to a temperature of about 80° C.
- the present invention provides a solid crystalline form of ibandronic acid, denominated Form S13, characterized by a powder X-ray diffraction pattern having reflections at about 4.5, 8.9, 12.0, 16.0, 16.3, 21.3 and 22.1 ⁇ 0.2 deg. 2-theta.
- Solid crystalline ibandronic acid Form S13 can be further characterized by X-ray reflections at about 10.5, 17.8 and 26.9 ⁇ 0.2 deg. 2-theta.
- a typical x-ray diffraction diagram for ibandronic acid Form S13 is given in FIG. 14 .
- Form S13 can exist as an isopropanolate.
- Ibandronic acid Form S13 can be prepared by a process including the steps of:
- the halo-phosphorous compound of step a) is added slowly, in small aliquots, especially dropwise.
- the temperature in step a) is about 75° C.
- the reaction mixture in step b) is heated to a temperature of about 80° C.
- Ibandronic acid Form S13 can be also prepared by a process including the steps of:
- Form S13 can be also prepared by providing a solution of ibandronic acid in water at a temperature of about 38° C. to about 50°, cooling the solution to room temperature, followed by the addition of IPA, and maintaining the mixture at temperature for a sufficient time to obtain Form S13.
- ibandronic acid is dissolved in water at a temperature of about 40° C. to provide the solution.
- the present invention also provides a process for purifying Ibandronic acid from inorganic impurities (i.e. reducing the amount of inorganic impurities in) that includes the step of dissolving ibandronic acid in water or methanol, and crystallizing by addition of a C 2-4 alcohol.
- the C 2-4 alcohol is selected from the group consisting of ethanol, 1-propanol, IPA and tert-butanol.
- the present invention further provides a HPLC method of assaying ibandronic acid comprising the steps of: dissolving an ibandronic acid sample in a diluent to obtain a sample solution, loading the sample solution (ca. 50 ⁇ L) onto a 250 ⁇ 4.1 mm, Hamilton type PRP-X100 anion exchange column, eluting the sample from the column at 2.0 ml/min using a mixture of nitric acid (HNO 3 : 35 vol-%), potassium nitrate (KNO 3 : 45 vol-%) and ethanol (20 vol-%) as eluent, and measuring the ibandronic acid content of the relevant sample at 240 nm wavelength with a UV detector.
- the diluent is water.
- Some processes of the present invention involve crystallization out of a particular solvent.
- the conditions concerning crystallization can be modified without affecting the form of the polymorph obtained. For example, when mixing ibandronic acid in a solvent to form a solution, warming of the mixture may be necessary to completely dissolve the starting material. If warming does not clarify the mixture, the mixture may be diluted or filtered. To filter, the hot mixture may be passed through paper, glass fiber or other membrane material, or a clarifying agent such as celite. Depending upon the equipment used and the concentration and temperature of the solution, the filtration apparatus may need to be preheated to avoid premature crystallization. The conditions may also be changed to induce precipitation.
- a preferred way of inducing precipitation is to reduce the solubility of the solvent (reduce it “solubilizing power”).
- the solubility of the solvent that is its ability to dissolve ibandronic acid—can be reduced, for example, by reducing the temperature of the solvent.
- the present invention provides a process for preparing ibandronate sodium (the sodium salt of ibandronic acid) comprising converting any of the solid or crystalline forms of ibandronic acid hereinabove described to ibandronate sodium by combining the ibandronic acid with an aqueous solution of sodium hydroxide at ambient temperature (about 20° to about 28° C.), concentrating the solution, especially at reduced pressure, to obtain a residue; combining the residue with acetone whereby a precipitate is formed, and recovering ibandronate monosodium.
- ibandronate sodium the sodium salt of ibandronic acid
- the present invention provides ibandronic acid having an assay of ⁇ 99%.
- the present invention provides pharmaceutical formulations that include at least on pharmaceutically acceptable excipient and one or more of the novel crystalline forms of the present invention
- compositions of the present invention contain solid ibandronic acid or crystalline forms thereof, such as one of those disclosed herein, optionally in a mixture with amorphous ibandronic acid.
- the pharmaceutical formulations of the present invention can and typically do contain one or more pharmaceutically acceptable excipients. Such excipients are included in the formulations for a variety of purposes.
- Diluents increase the bulk of a solid pharmaceutical composition, and may make a pharmaceutical dosage form containing the composition easier for the patient and care giver to handle.
- Diluents for solid compositions include, for example, microcrystalline cellulose (e.g. Avicel®), microfine cellulose, lactose, starch, pregelatinized starch, calcium carbonate, calcium sulfate, sugar, dextrates, dextrin, dextrose, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, kaolin, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, polymethacrylates (e.g. Eudragit®), potassium chloride, powdered cellulose, sodium chloride, sorbitol and talc.
- microcrystalline cellulose e.g. Avicel®
- microfine cellulose lactose
- starch pregelatinized starch
- calcium carbonate calcium sulfate
- sugar dextrates
- dextrin
- Solid pharmaceutical compositions that are compacted into a dosage form, such as a tablet may include excipients whose functions include helping to bind the active ingredient and other excipients together after compression.
- Binders for solid pharmaceutical compositions include acacia, alginic acid, carbomer (e.g. carbopol), carboxymethylcellulose sodium, dextrin, ethyl cellulose, gelatin, guar gum, hydrogenated vegetable oil, hydroxyethyl cellulose, hydroxypropyl cellulose (e.g. Klucel®), hydroxypropyl methyl cellulose (e.g. Methocel®), liquid glucose, magnesium aluminum silicate, maltodextrin, methylcellulose, polymethacrylates, povidone (e.g. Kollidon®, Plasdone®), pregelatinized starch, sodium alginate and starch.
- carbomer e.g. carbopol
- carboxymethylcellulose sodium, dextrin ethyl cellulose
- gelatin
- the dissolution rate of a compacted solid pharmaceutical composition in the patient's stomach may be increased by the addition of a disintegrant to the composition.
- Disintegrants include alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium (e.g. Ac-Di-Sol®, Primellose®), colloidal silicon dioxide, croscarmellose sodium, crospovidone (e.g. Kollidon®, Polyplasdone®), guar gum, magnesium aluminum silicate, methyl cellulose, microcrystalline cellulose, polacrilin potassium, powdered cellulose, pregelatinized starch, sodium alginate, sodium starch glycolate (e.g. Explotab®) and starch.
- alginic acid include alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium (e.g. Ac-Di-Sol®, Primellose®), colloidal silicon dioxide, croscarmellose sodium, crospovidone (e.g. Kollidon®, Polyplasdone®
- Glidants can be added to improve the flowability of a non-compacted solid composition and to improve the accuracy of dosing.
- Excipients that may function as glidants include colloidal silicon dioxide, magnesium trisilicate, powdered cellulose, starch, talc and tribasic calcium phosphate.
- a dosage form such as a tablet
- the composition is subjected to pressure from a punch and dye.
- Some excipients and active ingredients have a tendency to adhere to the surfaces of the punch and dye, which can cause the product to have pitting and other surface irregularities.
- a lubricant can be added to the composition to reduce adhesion and ease the release of the product from the dye.
- Lubricants include magnesium stearate, calcium stearate, glyceryl monostearate, glyceryl palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil, mineral oil, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc and zinc stearate.
- Flavoring agents and flavor enhancers make the dosage form more palatable to the patient.
- Common flavoring agents and flavor enhancers for pharmaceutical products include maltol, vanillin, ethyl vanillin, menthol, citric acid, fumaric acid, ethyl maltol and tartaric acid.
- Solid and liquid compositions may also be dyed using any pharmaceutically acceptable colorant to improve their appearance and/or facilitate patient identification of the product and unit dosage level.
- liquid pharmaceutical compositions of the present invention ibandronic acid and any other solid excipients are suspended in a liquid carrier such as water, vegetable oil, alcohol, polyethylene glycol, propylene glycol or glycerin.
- a liquid carrier such as water, vegetable oil, alcohol, polyethylene glycol, propylene glycol or glycerin.
- Liquid pharmaceutical compositions may contain emulsifying agents to disperse uniformly throughout the composition an active ingredient or other excipient that is not soluble in the liquid carrier.
- Emulsifying agents that may be useful in liquid compositions of the present invention include, for example, gelatin, egg yolk, casein, cholesterol, acacia, tragacanth, chondrus, pectin, methyl cellulose, carbomer, cetostearyl alcohol and cetyl alcohol.
- Liquid pharmaceutical compositions of the present invention may also contain a viscosity enhancing agent to improve the mouth-feel of the product and/or coat the lining of the gastrointestinal tract.
- a viscosity enhancing agent include acacia, alginic acid bentonite, carbomer, carboxymethylcellulose calcium or sodium, cetostearyl alcohol, methyl cellulose, ethylcellulose, gelatin guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, maltodextrin, polyvinyl alcohol, povidone, propylene carbonate, propylene glycol alginate, sodium alginate, sodium starch glycolate, starch tragacanth and xanthan gum.
- Sweetening agents such as sorbitol, saccharin, sodium saccharin, sucrose, aspartame, fructose, mannitol and invert sugar may be added to improve the taste.
- Preservatives and chelating agents such as alcohol, sodium benzoate, butylated hydroxyl toluene, butylated hydroxyanisole and ethylenediamine tetraacetic acid may be added at levels safe for ingestion to improve storage stability.
- a liquid composition may also contain a buffer such as guconic acid, lactic acid, citric acid or acetic acid, sodium guconate, sodium lactate, sodium citrate or sodium acetate. Selection of excipients and the amounts used may be readily determined by the formulation scientist based upon experience and consideration of standard procedures and reference works in the field.
- a buffer such as guconic acid, lactic acid, citric acid or acetic acid, sodium guconate, sodium lactate, sodium citrate or sodium acetate.
- the solid compositions of the present invention include powders, granulates, aggregates and compacted compositions.
- the dosages include dosages suitable for oral, buccal, rectal, parenteral (including subcutaneous, intramuscular, and intravenous), inhalant and ophthalmic administration. Although the most suitable administration in any given case will depend on the nature and severity of the condition being treated, the most preferred route of the present invention is oral.
- the dosages may be conveniently presented in unit dosage form and prepared by any of the methods well-known in the pharmaceutical arts.
- Dosage forms include solid dosage forms like tablets, powders, capsules, suppositories, sachets, troches and losenges, as well as liquid syrups, suspensions and elixirs.
- the dosage form of the present invention may be a capsule containing the composition, preferably a powdered or granulated solid composition of the invention, within either a hard or soft shell.
- the shell may be made from gelatin and optionally contain a plasticizer such as glycerin and sorbitol, and an opacifying agent or colorant.
- compositions and dosage forms may be formulated into compositions and dosage forms according to methods known in the art.
- a composition for tableting or capsule filling may be prepared by wet granulation.
- wet granulation some or all of the active ingredients and excipients in powder form are blended and then further mixed in the presence of a liquid, typically water, that causes the powders to clump into granules.
- the granulate is screened and/or milled, dried and then screened and/or milled to the desired particle size.
- the granulate may then be tableted, or other excipients may be added prior to tableting, such as a glidant and/or a lubricant.
- a tableting composition may be prepared conventionally by dry blending.
- the blended composition of the actives and excipients may be compacted into a slug or a sheet and then comminuted into compacted granules. The compacted granules may subsequently be compressed into a tablet.
- a blended composition may be compressed directly into a compacted dosage form using direct compression techniques.
- Direct compression produces a more uniform tablet without granules.
- Excipients that are particularly well suited for direct compression tableting include microcrystalline cellulose, spray dried lactose, dicalcium phosphate dihydrate and colloidal silica. The proper use of these and other excipients in direct compression tableting is known to those in the art with experience and skill in particular formulation challenges of direct compression tableting.
- a capsule filling of the present invention may comprise any of the aforementioned blends and granulates that were described with reference to tableting, however, they are not subjected to a final tableting step.
- X-ray diffraction data were obtained with a scintag X-Ray powder diffractometer model X'TRA, Cu-tube, solid state detector, a round standard aluminum sample holder with round zero background quartz plate was used. Scanning parameters: Range: 2-40 deg.28: continues scan, Rate: 5 deg./min.
- DSC data were obtained with a DSC821e, Mettler Toledo instrument.
- the sample weight was 3-5 mg.
- the heating (scan) rate was 10° C./min.
- Number of holes in the crucible 3.
- TGA data were obtained using a Mettler TG50, sample weight: 7-15 mg, heating 30 rate: 10° C./min.
- Spray drying technique were obtained using “Buchi Mini Spray dryer B-290”.
- the spray parameters are: evaporating capacity—1 lit/hr water (higher for organic solvents); the maximum temperature input—220° C.; Air flow—max of 35 m2/hr; spray gas-compressed air or nitrogen 200-800 lit/hr, 5-8 bar; Nozzel diameter—0.7 mm (standard); Nozzel cap—1.4 mm and 1.5 mm.
- Phosphorous trichloride (3.3 mL) was added to a stirred suspension of MPPA.HCl (8 g) in silicon oil (40 mL) at 75° C. Two additional portions of phosphorous trichloride (2 ⁇ 3.3 mL) were added during 2 hours after heating the reaction mixture to 81° C. Two portions of phosphorus acid (2 ⁇ 3.1 g) were thereafter added during 2 hours. The reaction mixture was stirred at 81° C. for 22 hours. Water (40 mL) was added drop-wise at 81° C. The resulting phases were separated and the aqueous phase was heated to 90° C. for 16 hours. The obtained solution was cooled to room temperature and then was evaporated to obtain an oily residue.
- Phosphorous trichloride (3.3 mL) was added to a stirred suspension of MPA.HCl (8 g) in silicon oil (40 mL) at 75° C. Two additional portions of phosphorous trichloride (2 ⁇ 3.3 mL) were added during 2 hours after heating the reaction mixture to 81° C. Then two portions of phosphorus acid (2 ⁇ 3.1 g) were added during 2 hours. The reaction mixture was stirred at 81° C. for 22 hours. Water (40 mL) was added drop-wise at 81° C. Then the phases were separated and the aqueous phase was heated to 90° C. for 16 hours. The obtained solution was cooled to room temperature and then was evaporated to obtain an oily residue.
- the oily residue was dissolved in water (7 mL) at room temperature. The obtained solution was heated to 70° C. Then hot IPA (280 mL) (73° C.) was added drop-wise. The solution was cooled to room temperature. The solution was stirred at room temperature for 21 hours. Then the IPA was decanted-off and the residue was dried in vacuum oven at 50° C. for 21 hours to obtain 4.6 g of amorphous ibandronic acid.
- Amorphous ibandronic acid (3.0 g) was dissolved in water (4 mL) at room temperature.
- Acetone (70 mL) was added to the stirred solution.
- White slurry was obtained while stirring at room temperature for 68 hours.
- the precipitate was isolated by vacuum filtration, washed with acetone (2 ⁇ 25 mL) and dried in a vacuum oven at 50° C. for 24 hours to obtain 2.5 g of ibandronic acid crystal form S1.
- ibandronic acid crystal form S1 40% w/w aqueous solution of ibandronic acid (22.2 g) was concentrated under vacuum. To the concentrated solution (15.71 g), tert-butanol was added drop-wise at room temperature in two portions (2 ⁇ 50 mL) and the mixture was stirred at this temperature for 4 hours. The obtained precipitate was isolated by vacuum filtration, washed with tert-butanol (1 ⁇ 1.5 mL) and dried in a vacuum oven at 5° C. for 24 hours to obtain 5.5 g of ibandronic acid crystal form S1.
- Amorphous ibandronic acid (3.0 g) was dissolved in methanol (12 mL) at room temperature. Acetone (40 mL) was added in one portion to the stirred solution. The obtained slurry was stirred at room temperature for 72 hours. The resulting precipitate was isolated by vacuum filtration, washed with acetone (2 ⁇ 12.5 mL) and dried in a vacuum oven at 50° C. for 22 hours to obtain 2.5 g of ibandronic acid crystal form S1.
- Amorphous ibandronic acid (3.0 g) was stirred in acetone (15 mL) at reflux temperature for 5 hours. The slurry was cooled to room temperature and then it was stirred at this temperature for 16 hours. The product was dried in a vacuum oven at 50° C. for 24 hours to obtain 2.8 g of ibandronic acid crystal form S1.
- Amorphous ibandronic acid (3.0 g) was stirred in absolute ethanol (20 mL) at reflux temperature for 2.5 hours. The slurry was cooled to room temperature and then it was stirred at this temperature for 40.5 hours. The product was isolated by vacuum filtration, washed with absolute ethanol (2 ⁇ 20 mL) and dried in a vacuum oven at 40° C. for 25 hours to obtain 2.8 g of ibandronic acid crystal form S1.
- ibandronic acid crystal form S1 40% w/w aqueous solution of ibandronic acid (10.95 g) was concentrated under vacuum. To the concentrated solution (7.5 g), acetone was added at room temperature in two portions (2 ⁇ 45 mL) and the mixture was stirred at this temperature for 22 hours. The obtained precipitate was isolated by vacuum filtration, washed with Acetone (2 ⁇ 20 mL) and dried in a vacuum oven at 50° C. for 70 hours to obtain 2.9 g of ibandronic acid crystal form S1.
- Amorphous ibandronic acid (3.0 g) was dissolved in methanol (12 mL) at room temperature.
- Acetonitrile (ACN) 40 mL was added in one portion to the stirred solution.
- the obtained slurry was stirred at room temperature for 72 hours.
- the precipitate was isolated by vacuum filtration, washed with ACN (2 ⁇ 20 mL) and dried in a vacuum oven at 50° C. for 21.5 hours to obtain 2.4 g of ibandronic acid crystal form S2.
- ibandronic acid crystal form S3 40% w/w aqueous solution of ibandronic acid (11 g) was concentrated under vacuum. To the concentrated solution (7.6 g), tert-butanol (50 mL) was added at room temperature. The obtained slurry was stirred at this temperature for 72 hours. Then the precipitate was isolated by vacuum filtration, washed with tert-butanol (2 ⁇ 40 mL) and dried in a vacuum oven at 50° C. for 22.5 hours to obtain 4.2 g of ibandronic acid crystal form S3.
- Phosphorous trichloride (10.9 mL) was added drop-wise to a stirred suspension of MPA.HCl (7 g) and phosphorous acid (10.3 g) in silicon oil (49 mL) at 75° C. The reaction mixture was heated to 80° C. Two additional portions of phosphorous trichloride (1 ⁇ 1.5 ml and 1 ⁇ 1 mL) were added gradually to the stirred reaction mixture at ⁇ 80° C. The reaction mixture was stirred at this temperature for 50 hours. Water (49 mL) was added drop-wise at 79° C. The phases were separated and the aqueous phase was heated to reflux for 15.5 hours. The obtained solution was cooled to room temperature and then was evaporated until dryness to obtain an oily residue (27.2 g).
- Phosphorous trichloride (8.2 mL) was added drop-wise to a stirred suspension of MPA.HCl (7 g) and phosphorous acid (3.9 g) in toluene (35 mL) at 75° C. The reaction mixture was heated to 95° C. and was stirred at this temperature for 23 hours. The toluene was decanted-off and the residue was stirred under reflux (96° C.) with 6N HCl (104 mL) for 43 hours. The obtained solution was cooled to room temperature and was then concentrated to obtain an oily residue (8.1 g). The oily residue was dissolved in water (4 mL).
- Phosphorous oxychloride 50 mL was added drop-wise to a stirred suspension of MPA.HCl (30 g) and phosphorous acid (44 g) in silicone oil (210 mL) at 75° C. The reaction mixture was heated to 81° C. Two additional portions of phosphorous oxychloride (1 ⁇ 6.7 ml and 1 ⁇ 4 mL) were added gradually to the stirred reaction mixture at 81° C. The reaction mixture was stirred at this temperature for 50 hours. Water (210 mL) was added drop-wise to the solution and the mixture was stirred for 1 hr. Then the phases were separated and the aqueous phase was heated to reflux for 16.5 hours.
- the obtained solution was cooled to room temperature and then was evaporated until dryness to obtain an oily residue (125.6 g).
- the oily residue was dissolved in water (19 mL).
- IPA 17.60 mL
- the obtained solution was stirred at this temperature for 24 hours and then was cooled to 7° C. and stirred this temperature for 72 hrs.
- the obtained precipitate was isolated by vacuum filtration, washed with IPA (2 ⁇ 100 mL) and dried in a vacuum oven at 50° C. for 25 hours to obtain 22 g of ibandronic acid crystal form S5.
- Amorphous ibandronic acid (3.0 g) was stirred in THF (20 mL) at reflux temperature for 2.5 hours to obtain almost complete dissolution. The mixture was cooled to room temperature and then it was stirred at this temperature for 21 hours. The obtained precipitate was isolated by vacuum filtration under nitrogen flow, washed with THF (2 ⁇ 15 mL) and dried in a vacuum oven at 40° C. for 23.5 hours to obtain 2.7 g of ibandronic acid crystal form S5.
- Amorphous ibandronic acid (3.0 g) was stirred in Absolute Ethanol (30 mL) at room temperature. The slurry was stirred at room temperature for 72 hours. The product was isolated by vacuum filtration, washed with Absolute Ethanol (2 ⁇ 20 mL) and dried in a vacuum oven at 50° C. for 22 hours to obtain 2.9 g of ibandronic acid crystal form S5.
- Phosphorous oxychloride (17 mL) was added drop-wise to a stirred suspension of MPA.HCl (10 g) and phosphorous acid (14.8 g) in toluene (70 mL) at 75° C. The reaction mixture was heated to 80° C. and was stirred at this temperature for 26 hours. The reaction mixture was cooled to room temperature. The toluene was decanted-off and the residue was stirred under reflux with water (70 mL) for 15.5 hours. The obtained solution was cooled to room temperature and then was evaporated until dryness to obtain an oily residue (34.3 g). IPA (834 mL) was added gradually to the oily reside while stirring at room temperature during 72 hours. The obtained precipitate was isolated by vacuum filtration, washed with IPA (2 ⁇ 84 mL) and dried in a vacuum oven at 50° C. for 23 hours to obtain 12.8 g of ibandronic acid crystal form S5.
- Phosphorous trichloride (15.6 mL) was added drop-wise to a stirred suspension of MPA.HCl (10 g) and phosphorous acid (14.7 g) in silicon oil (70 mL) at 75° C. The reaction mixture was heated to 80° C. Two additional portions of phosphorous trichloride (1 ⁇ 2 ml and 1 ⁇ 1.3 mL) were added gradually to the stirred reaction mixture at 80° C. The reaction mixture was stirred at this temperature for 48hours. Water (70 mL) was added drop-wise at 80° C. The phases were separated and the aqueous phase was heated to reflux for 16 hours. The obtained solution was cooled to room temperature and then was evaporated until dryness to obtain an oily residue (38.2 g).
- Phosphorous trichloride (10.9 mL) was added drop-wise to a stirred suspension of MPPA.HCl (7 g) and phosphorous acid (10.3 g) in silicon oil (49 mL) at 75° C. The reaction mixture was heated to 80° C. Two additional portions of phosphorous trichloride (1 ⁇ 1.5 ml and 1 ⁇ 1 mL) were added gradually to the stirred reaction mixture at ⁇ 80° C. The reaction mixture was stirred at this temperature for 50 hours. Water (49 mL) was added drop-wise at 79° C. The phases were separated and the aqueous phase was heated to reflux for 15.5 hours. The obtained solution was cooled to room temperature and then was evaporated until dryness to obtain an oily residue (27.2 g).
- Phosphorous trichloride (8.2 mL) was added drop-wise to a stirred suspension of MPA.HCl (7 g) and phosphorous acid (3.9 g) in toluene (35 mL) at 75° C. The reaction mixture was heated to 95° C. and was stirred at this temperature for 23 hours. The Toluene was decanted-off and the residue was stirred under reflux (96° C.) with 6H HCl (104 mL) for 43 hours. The obtained solution was cooled to room temperature and then was evaporated until dryness to obtain an oily residue (8.1 g). The oily residue was dissolved in water (4 mL).
- tert-butanol (204 mL) was added drop-wise at room temperature and the mixture was stirred at this temperature for 72 hours.
- the obtained precipitate was isolated by vacuum filtration, washed with tert-butanol (2 ⁇ 40 mL) and dried in a vacuum oven at 50° C. for 23 hours to obtain 2.8 g of ibandronic acid crystal form S6.
- Phosphorous trichloride (15.6 mL) was added drop-wise to a stirred suspension of MPA.HCl (10 g) and phosphorous acid (14.7 g) in silicon oil (70 mL) at 70° C. The reaction mixture was heated to 80° C. and was stirred at this temperature for 23.5 hours. Water (70 mL) was added drop-wise at 80° C. Then the phases were separated and the aqueous phase was heated to reflux for 18 hours. The obtained solution was cooled to room temperature and then was evaporated until dryness to obtain an oily residue (24.5 g). IPA (443 mL) was added gradually to the oily residue and the mixture was stirred at room temperature for 18 hours. The obtained precipitate was isolated by vacuum filtration, washed with IPA (1 ⁇ 80 mL) and dried in a vacuum oven at 50° C. for 24 hours to obtain 9.8 g of ibandronic acid crystal form S7.
- Phosphorous trichloride (18.7 mL) was added drop-wise to a stirred suspension of MPA.HCl (12 g) and phosphorous acid (17.6 g) in silicone oil (84 mL) at 75° C. The reaction mixture was heated to 80° C. Two additional portions of phosphorous trichloride (1 ⁇ 2.5 ml and 1 ⁇ 1.5 mL) were added gradually to the stirred reaction mixture at 80° C. The reaction mixture was stirred at this temperature for 51.5 hours. Water (84 mL) was added drop-wise to the solution, stirred for 15 minutes. The phases were separated and the aqueous phase was heated to reflux for 16 hours. The obtained solution was cooled to room temperature and stirred at this temperature for 12 hours.
- Phosphorous trichloride (18.7 mL) was added drop-wise to a stirred suspension of MPA.HCl (12 g) and phosphorous acid (17.6 g) in silicone oil (84 mL) at 75° C. The reaction mixture was heated to 80° C. Two additional portions of phosphorous trichloride (1 ⁇ 2.5 ml and 1 ⁇ 1.5 mL) were added gradually to the stirred reaction mixture at 80° C. The reaction mixture was stirred at this temperature for 51.5 hours. Water (84 mL) was added drop-wise to the solution and the mixture stirred for 15 minutes. The phases were separated and the aqueous phase was heated to reflux for 16 hours. The obtained solution was cooled to room temperature and stirred at this temperature for 12 hours.
- Phosphorous oxychloride (20 mL) was added drop-wise to a stirred suspension of MPA.HCl (12 g) and phosphorous acid (17.6 g) in Silicone oil (84 mL) at 75° C. The reaction mixture was heated to 80° C. Two additional portions of phosphorous oxychloride (1 ⁇ 2.7 ml and 1 ⁇ 1.6 mL) were added gradually to the stirred reaction mixture at 80° C. The reaction mixture was stirred at this temperature for 50 hours. Water (84 mL) was added drop-wise to the solution, stirred for 20 minutes. The phases were separated and the aqueous phase was heated to reflux for 17 hours. The obtained solution was cooled to room temperature and stirred at this temperature for 12 hours.
- Phosphorous trichloride (15.6 mL) was added drop-wise to a stirred suspension of MPA.HCl (10 g) and phosphorous acid (14.7 g) in silicon oil (70 mL) at 75° C. The reaction mixture was heated to 80° C. Two additional portions of phosphorous trichloride (1 ⁇ 2 ml and 1 ⁇ 1.3 mL) were added gradually to the stirred reaction mixture at 80° C. The reaction mixture was stirred at this temperature for 48 hours. Water (70 mL) was added drop-wise at 80° C. Then the phases were separated and the aqueous phase was heated to reflux for 16 hours. The obtained solution was cooled to room temperature and then was evaporated until dryness to obtain an oily residue (38.2 g).
- Absolute ethanol (766 mL) was added to the oily residue at room temperature and the mixture was stirred at this temperature for 53 hours.
- the obtained precipitate was isolated by vacuum filtration, washed with absolute ethanol (2 ⁇ 61 mL) and dried in a vacuum oven at 50° C. for 25.5 hours to obtain 7.7 g of ibandronic acid crystal form S8.
- Phosphorous trichloride (57 mL) was added drop-wise to a stirred suspension of MPA.HCl (30 g) and phosphorous acid (44 g) in silicon oil (210 mL) at 75° C. The reaction mixture was heated to 80° C. Two additional portions of phosphorous trichloride (1 ⁇ 6.25 ml and 1 ⁇ 3.75 mL) were added gradually to the stirred reaction mixture at 80° C. The reaction mixture was stirred at this temperature for 48 hours. Water (210 mL) was added drop-wise at 80° C. and stirred at this temperature for 30 minutes. Then the phases were separated and the aqueous phase was heated to reflux for 17 hours.
- Phosphorous oxychloride 50 mL was added drop-wise to a stirred suspension of MPA.HCl (30 g) and phosphorous acid (44 g) in silicon oil (210 mL) at 75° C. The reaction mixture was heated to 80° C. Two additional portions of phosphorous oxychloride (1 ⁇ 6.7 ml and 1 ⁇ 4 mL) were added gradually to the stirred reaction mixture at 80° C. The reaction mixture was stirred at this temperature for 51 hours. Water (210 mL) was added drop-wise at 80° C. and stirred at this temperature for 30 minutes. Then the phases were separated and the aqueous phase was heated to reflux for 16.5 hours.
- Phosphorous trichloride (18.7 mL) was added drop-wise to a stirred suspension of MPA.HC 1 (12 g) and phosphorous acid (17.6 g) in silicone oil (84 mL) at 75° C. The reaction mixture was heated to 80° C. Two additional portions of phosphorous trichloride (1 ⁇ 2.5 ml and 1 ⁇ 1.5 mL) were added gradually to the stirred reaction mixture at 80° C. The reaction mixture was stirred at this temperature for 52 hours. Water (84 mL) was added drop-wise to the solution, stirred for 15 minutes. Then the phases were separated and the aqueous phase was heated to reflux for 16 hours. The obtained solution was cooled to room temperature and stirred at this temperature for 13 hours.
- Phosphorous oxychloride (20 mL) was added drop-wise to a stirred suspension of MPA.HCl (12 g) and phosphorous acid (17.6 g) in silicone oil (84 mL) at 75° C. The reaction mixture was heated to 80° C. Two additional portions of phosphorous oxychloride (1 ⁇ 2.7 ml and 1 ⁇ 1.6 mL) were added gradually to the stirred reaction mixture at 80° C. The reaction mixture was stirred at this temperature for 50 hours. Water (84 mL) was added drop-wise to the solution, stirred for 20 minutes. The phases were separated and the aqueous phase was heated to reflux for 13 hours. The obtained solution was cooled to room temperature and stirred at this temperature for 12 hours.
- Phosphorous oxychloride (11.7 mL) was added drop-wise to a stirred suspension of MPA.HCl (7 g) and phosphorous acid (10.3 g) in silicon oil (49 mL) at 75° C. The reaction mixture was heated to 80° C. An additional portion of phosphorous oxychloride (1 ⁇ 1.6 mL) was added to the reaction mixture at 80° C. after 45.5 hours. The reaction mixture was stirred at 80° C. for additional 2.5 hours. Water (49 mL) was added drop-wise at 80° C. The phases were separated and the aqueous phase was heated to 100° C. for 18 hours. The obtained solution was cooled to room temperature and then was concentrated to obtain an oily residue (26.7 g).
- Phosphorous trichloride 50 mL was added drop-wise to a stirred suspension of MPA.HCl (30 g) and phosphorous acid (44 g) in silicone oil (210 mL) at 75° C. The reaction mixture was heated to 80° C. Two additional portions of phosphorous trichloride (1 ⁇ 6.25 ml and 1 ⁇ 3.75 mL) were added gradually to the stirred reaction mixture at 80° C. The reaction mixture was stirred at this temperature for 48.5 hours. Water (210 mL) was added drop-wise to the solution and the mixture stirred for 15 minutes. The phases were separated and the aqueous phase was heated to reflux for 16.5 hours.
- the obtained solution was cooled to room temperature and then was concentrated to obtain an oily residue (121.3 g).
- the oily residue was dissolved in water (18 mL).
- IPA (1698 mL) was added at room temperature and the mixture was stirred at this temperature for 22 hours and then was cooled to 4° C. and stirred this temperature for 4 hrs.
- the obtained precipitate was isolated by vacuum filtration, washed with IPA (2 ⁇ 43 mL) and dried in a vacuum oven at 50° C. for 47 hours to obtain 39 g of ibandronic acid crystal form S13.
- Ibandronic acid (97 g) was dissolved in water (90 mL) at 40° C. The solution was cooled to room temperature and IPA (1100 mL) was added, stirred at this temperature for 22 hrs. The obtained precipitate was isolated by vacuum filtration, washed with IPA (2 ⁇ 50 mL) and dried in a vacuum oven at 50° C. for 25 hours to obtain 97.6 g of ibandronic acid crystal form S13.
- Example 9 of U.S. Pat. No. 4,927,814 15 g N-Methyl-N-pentylaminopropionic acid (MPA.HCl) were kept for 23 hours at 100° C. with 8.8 g phosphorous acid and 18.7 ml phosphorous trichloride in 75 ml chlorobenzene. The solvent was then decanted off and the residue was stirred under reflux with 222 ml 6N HCl for 12.5 hours. Insoluble material was filtered off and the filtrate was concentrated and applied to column of Amberlite IR 120 (H+). The elution with water was monitored by HPLC. The desired fractions were combined, evaporated and stirred up with acetone to obtain a sticky oily precipitate as a crude product. (The HPLC method for monitoring the ion-exchange chromatography is the one described in this application).
- N-Methyl-N-pentylaminopropionic acid (MPA.HCl) were kept for 23 hours at 100° C. with 8.8 g phosphorous acid and 18.7 ml phosphorous trichloride in 75 ml chlorobenzene. The solvent was then decanted off and the residue was stirred under reflux with 222 ml 6N HCl for 12.5 hours. Insoluble material was filtered off and the filtrate was concentrated and applied to column of Amberlite IR 120 (H+). The elution with water was monitored by HPLC. The desired fractions were combined, evaporated and stirred up with methyl ethyl ketone (MEK) to obtain a sticky oily precipitate as a crude product.
- MPA.HCl N-Methyl-N-pentylaminopropionic acid
- Ibandronic acid (9 g) was dissolved in water (18 ml) at room temperature. The solution was divided into three portions, and each portion was spray dried using a Buchi mini spray dryer B-290 using a standard nozzle 0.7 mm in diameter with a nozzle cap of 1.4 or 1.5 mm. The solution feed rate was about 1 L/h. The spray gas was set at 200-800 L/h at a pressure of 5-8 bar. In each instance, amorphous ibandronic acid was obtained.
- nitrogen gas was at an inlet temperature of 50° C.
- the evaporated solvent and nitrogen left the spray dryer at a temperature of 41-36° C.
- nitrogen gas was at an inlet temperature of 100° C.
- the evaporated solvent and nitrogen left the spray dryer at a temperature of 71-72° C.
- nitrogen gas was at an inlet temperature of 150° C.
- the evaporated solvent and nitrogen left the spray dryer at a temperature of 100° C.
- Each of the three product was analyzed by powder x-ray diffraction and found to be amorphous.
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Physical Education & Sports Medicine (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Rheumatology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Biochemistry (AREA)
- Molecular Biology (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Cephalosporin Compounds (AREA)
Abstract
Amorphous ibandronic acid is provided with methods for its preparation. The methods include dissolution of ibandronic acid in a solvent such as acetonitrile, DMSO, methanol, or water, and spray drying.
Description
- This application is a divisional application of U.S. Ser. No. 11/525,804, titled “Solid and Crystalline Ibandronic Acid” and filed Sep. 22, 2006, which is a continuation of prior application U.S. Ser. No. 11/331,995 filed Jan. 12, 2006, which is a continuation of prior application U.S. Ser. No. 11/165,481 filed Jun. 22, 2005, which claims the benefit of the Jun. 23, 2004, filing date of U.S.
Provisional Patent Application 60/582,500, of the Oct. 18, 2004, filing date of U.S.Provisional Patent Application 60/620,016, and the benefit of the Jun. 16, 2005, filing date of the U.S.Provisional Patent Application 60/690,868, the contents of all of which are incorporated herein by reference. - Ibandronate Sodium is a third-generation nitrogen-containing bisphosphonate characterized by an aliphatic tertiary amine side chain.
- Ibandronate Sodium is a white crystalline powder. The free acid has MW 319.23 (CAS No.: 114084-78-5). The monosodium salt (anhydrous) of the acid has MW 341.23 (CAS No.: 138844-81-2). The monosodium salt monohydrate has MW 359.23 (CAS No.: 138926-19-9).
- The preparation of ibandronic acid monosodium salt is described in, for example, U.S. Pat. No. 4,927,814. The '814 patent describes the following schemes:
- The preparation of ibandronic acid is taught in U.S. Pat. No. 4,927,814, wherein an ion-exchange chromatography is used in work-up. The present inventors repeated the procedure described in the '814 patent. No solid material was obtained, but an oily precipitate was the crude product. The skilled artisan knows that solids are easier to manipulate than oils. Clearly there is a need for a method of making a solid ibandronic acid.
- The monosodium salt of ibandronic acid is marketed under the trade name Boniva®. Boniva® was developed by Hoffmann-La Roche for the treatment of bone disorders such as: hypercalcaemia of malignancy, osteolysis, Paget's disease, osteoporosis and metastatic bone disease. Boniva® is also marketed in Europe under the name Bondronat for cancer-related bone complications. Bondronat is available in ampoule with 1 ml concentrate for solution for infusion contains 1.125 mg of Ibandronic acid monosodium salt monohydrate, corresponding to 1 mg of ibandronic acid.
- Ibandronic acid can be used as an intermediate in the process for the preparation of Ibandronate sodium.
- The discovery of new polymorphic forms of a pharmaceutically useful compound provides a new opportunity to improve the performance characteristics of a pharmaceutical product. It enlarges the repertoire of materials that a formulation scientist has available for designing, for example, a pharmaceutical dosage form of a drug with a targeted release profile or other desired characteristic. There is a need in the art for polymorphic forms of ibandronic acid.
- In one aspect, the present invention provides amorphous ibandronic acid.
- In another aspect, the present invention provides a method of preparing amorphous ibandronic acid that includes the step of isolating amorphous ibandronic acid from an aqueous solution of ibandronic acid which isolating step is selected from a vacuum evaporation step or a lyophilization step.
- In still a further aspect, the present invention relates to a method of making amorphous ibandronic comprising the step of spray drying an aqueous solution of ibandronic acid.
- In yet another aspect, the present invention provides solid ibandronic acid.
- In one aspect, the present invention provides a process for preparing solid Ibandronic acid comprising the steps of:
- a) combining, at a temperature of about 72° C. to about 78° C., a halo-phosphorous compound and phosphorous acid with N-methyl-N-pentyl propionic acid hydrochloride in a diluent to obtain a reaction mixture;
- b) maintaining the reaction mixture, while heating to a temperature of about 80° C. to about 100° C.;
- c) further combining the reaction mixture with water, whereby two phases, one aqueous and one nonaqueous, are obtained;
- d) separating the two phases obtained;
- e) maintaining the aqueous phase at a temperature of about 95° C. to about 100° C.;
- f) evaporating the aqueous phase to obtain a residue;
- g) combining an alcohol with the residue to obtain whereby a suspension is obtained; and
- h) recovering solid ibandronic acid from the suspension, for example by filteration or centrifugation; and optionally, drying the recovered solid ibandronic acid
- The residue of step f) may be dissolved in water prior to the addition of the alcohol in step g). After the addition of the alcohol, the reaction mixture may be heated in order to facilitate the formation of the precipitate.
- In another aspect, the present invention provides crystalline ibandronic acid in several crystalline forms and hydrates and solvates, especially alcoholates, thereof. The present invention also provides ibandronic acid alcoholates.
- In yet another aspect, the present invention provides a solid crystalline form of ibandronic acid, denominated form S1, characterized by a powder X-ray diffraction pattern having reflections at about 8.2, 11.5, 11.9, 13.9, 18.6 and 22.2±0.2 deg. 2-theta. The present invention further provides processes for preparing ibandronic acid form S1.
- In one aspect, the present invention provides a solid crystalline form of ibandronic acid, denominated form S2, characterized by a powder X-ray diffraction pattern having reflections at about 8.1, 14.2, 16.1, 18.2 and 24.4±0.2 deg. 2-theta. The present invention further provides a process for preparing ibandronic acid form S2.
- In another aspect, the present invention provides a solid crystalline form of ibandronic acid, denominated form S3, characterized by a powder X-ray diffraction pattern having reflections at about 4.4, 8.8, 11.3, 17.6 and 26.4±0.2 deg. 2-theta. The present invention further provides a process for preparing ibandronic acid form S3.
- In yet another aspect, the present invention provides a solid crystalline form of ibandronic acid, denominated form S4, characterized by a powder X-ray diffraction pattern having reflections at about 4.4, 8.6, 11.2, 17.3, 20.8, 22.5 and 26.0±0.2 deg. 2-theta. The present invention further provides a process for preparing ibandronic acid form S4.
- In one aspect, the present invention provides a solid crystalline form of ibandronic acid, denominated form S5, characterized by a powder X-ray diffraction pattern having reflections at about 4.5, 8.9, 12.0, 16.0, 16.3, 21.4, 22.1 and 26.9±0.2 deg. 2-theta. The present invention further provides processes for preparing ibandronic acid form S5.
- In another aspect, the present invention provides a solid crystalline form of ibandronic acid, denominated form S6, characterized by a powder X-ray diffraction pattern having reflections at about 5.7, 11.7, 14.3, 18.5, 21.2 and 21.7±0.2 deg. 2-theta. The present invention further provides processes for preparing ibandronic acid form S6.
- In yet another aspect, the present invention provides a solid crystalline form of ibandronic acid, denominated form S7, characterized by a powder X-ray diffraction pattern having reflections at about 4.6, 11.5, 16.3, 16.8, 21.0 and 22.8±0.2 deg. 2-theta. The present invention further provides processes for preparing ibandronic acid form S7.
- In one aspect, the present invention provides a solid crystalline form of ibandronic acid, denominated form S8, characterized by a powder X-ray diffraction pattern having reflections at about 4.5, 6.0, 11.9, 12.3, 16.2, 17.8 and 21.7±0.2 deg. 2-theta. The present invention further provides processes for preparing ibandronic acid form S8.
- In another aspect, the present invention provides a solid crystalline form of ibandronic acid, denominated form S10, characterized by a powder X-ray diffraction pattern having reflections at about 4.8, 6.1, 12.0, 12.3, 16.4, 18.0 and 21.7±0.2 deg. 2-theta. The present invention further provides processes for preparing ibandronic acid form S10.
- In yet another aspect, the present invention provides a solid crystalline form of ibandronic acid, denominated form S12, characterized by a powder X-ray diffraction pattern having reflections at about 4.7, 9.0, 11.6, 20.9, 21.1, 21.7, 22.9 and 26.3±0.2 deg. 2-theta. The present invention further provides a process for preparing ibandronic acid form S5.
- In one aspect, the present invention provides a solid crystalline form of ibandronic acid, denominated form S13, characterized by a powder X-ray diffraction pattern having reflections at about 4.5, 8.9, 12.0, 16.0, 16.3, 21.3 and 22.1±0.2 deg. 2-theta. The present invention further provides processes for preparing ibandronic acid form S13.
- In another aspect, the present invention provides a process for purifying Ibandronic acid from inorganic impurities by crystallization from an organic solvent selected from the group consisting of C2-4 alcohols and acetonitrile.
- In yet another aspect, the present invention provides a HPLC method of assaying ibandronic acid comprising the steps of: providing a sample solution of a sample of ibandronic acid in a diluent, loading the sample solution (ca. 50 μL) onto a 250×4.1 mm, Hamilton type PRP-X100 anion exchange column, eluting the sample from the column at 2.0 ml/min. with an eluent including nitric acid (HNO3: 35 vol-%), potassium nitrate (KNO3: 45 vol-%) and ethanol (20 vol-%), and measuring the ibandronic acid content of the eluent at 240 nm wavelength with a UV detector to identify the relevant fractions.
- In still a further aspect, the present invention provides A process for purifying ibandronic acid from inorganic impurities comprising the steps of: providing a solution of ibandronic acid containing inorganic impurities in water or methanol; and b) combining the solution with a C2-C4 alcohol, especially wherein the C2-4 alcohol is selected from the group consisting of ethanol, 1-propanol, isopropanol (IPA) and tert-butanol whereby ibandronic acid precipitates.
-
FIG. 1 illustrates an x-ray diffraction diagram of amorphous ibandronic acid. -
FIG. 2 illustrates a DSC thermogram of amorphous ibandronic acid. -
FIG. 3 illustrates a TGA thermogram of ibandronic acid. -
FIG. 4 illustrates an x-ray diffraction diagram of ibandronic acid form S1. -
FIG. 5 illustrates an x-ray diffraction diagram of ibandronic acid form S2. -
FIG. 6 illustrates an x-ray diffraction diagram of ibandronic acid form S3. -
FIG. 7 illustrates an x-ray diffraction diagram of ibandronic acid form S4. -
FIG. 8 illustrates an x-ray diffraction diagram of ibandronic acid form S5. -
FIG. 9 illustrates an x-ray diffraction diagram of ibandronic acid form S6. -
FIG. 10 illustrates an x-ray diffraction diagram of ibandronic acid form S7. -
FIG. 11 illustrates an x-ray diffraction diagram of ibandronic acid form S8. -
FIG. 12 illustrates an x-ray diffraction diagram of ibandronic acid form S10. -
FIG. 13 illustrates an x-ray diffraction diagram of ibandronic acid form S12. -
FIG. 14 illustrates an x-ray diffraction diagram of ibandronic acid form S13. - The present invention provides processes which utilize halo-phosphorous compounds. Such compounds include, but are not limited to, phosphorous trichloride, phosphorous oxychloride, phosphorous pentachloride, phosphorous tribromide, phosphorous oxybromide, phosphorous pentabromide.
- In particular embodiments of the present invention, C2-C4 alcohols are used. The C2-C4 alcohols have the general structure ROH wherein R is a linear or branched alkyl group having 2 to 4 carbon atoms. Ethanol, n-propanol (1-propanol), iso-propanol (2-propanol, IPA), and t-butanol (2-methylpropan-2-ol) are preferred C2-C4 alcohols.
- The present invention also provides processes that, in particular embodiments, utilize strong acids which do not act as oxidants for amino-phosphonic acids. Such non-oxidizing acids include, but are not limited to, para-toluene sulfonic acid, HCl, HBr, and trichloroacetic acid.
- The present invention provides amorphous ibandronic acid. Amorphous ibandronic acid has an x-ray diffraction diagram not unexpected for an essentially amorphous solid.
FIG. 1 shows a representative x-ray diffraction diagram of amorphous ibandronic acid. -
FIG. 2 shows a representative thermogram from differential scanning calorimetry (DSC) for amorphous ibandronic acid. The DSC thermogram does not exhibit any feature that can be clearly associated with a first-order transition like crystal melting. -
FIG. 3 shows a representative thermogram from thermogravimetric analysis (TGA). - Amorphous ibandronic acid can be prepared by a method that includes an isolation step. An isolation step is a step (procedure) in which a solvent, for example water is removed from a solution of ibandronic acid and can be called a “water-removal” step. This step comprises isolation of amorphous ibandronic acid from a solution of ibandronic acid in a solvent selected from the group consisting of acetonitrile (ACN), dimethylsulfoxide (DMSO), methanol, and water. Preferably, the solvent is water. The isolation step can be a vacuum evaporation (i.e. concentration) step, a lyophilization step, or a spray drying step.
- The term “spray drying” broadly refers to processes involving breaking up liquid mixtures into small droplets (atomization) and rapidly removing solvent from the mixture.
- In a typical spray drying apparatus, there is a strong driving force for evaporation of solvent from the droplets, which may be provided by providing a drying gas. Spray drying processes and equipment are described in Perry's Chemical Engineer's Handbook, pgs. 20-54 to 20-57 (Sixth Edition 1984).
- By way of non-limiting example only, the typical spray drying apparatus comprises a drying chamber, atomizing means for atomizing a solvent-containing feed into the drying chamber, a source of drying gas that flows into the drying chamber to remove solvent from the atomized-solvent-containing feed, an outlet for the products of drying, and product collection means located downstream of the drying chamber. Examples of such apparatuses include Niro Models PSD-1, PSD-2 and PSD-4 (Niro A/S, Soeborg, Denmark). Typically, the product collection means includes a cyclone connected to the drying apparatus. In the cyclone, the particles produced during spray drying are separated from the drying gas and evaporated solvent, allowing the particles to be collected. A filter may also be used to separate and collect the particles produced by spray drying. The process of the invention is not limited to the use of such drying apparatuses as described above.
- Spray drying may be performed in a conventional manner in the processes of the present invention (see, e.g., Remington: The Science and Practice of Pharmacy, 19th Ed., vol. II, pg. 1627, herein incorporated by reference). The drying gas used in the invention may be any suitable gas, although inert gases such as nitrogen, nitrogen-enriched air, and argon are preferred. Nitrogen gas is a particularly preferred drying gas for use in the process of the invention. The amorphous ibandronic acid product produced by spray drying may be recovered by techniques commonly used in the art, such as using a cyclone or a filter. Spray drying of ibandronic acid from a solution of ibandronic acid in water results in amorphous ibandronic acid.
- The present invention also provides solid ibandronic acid. When intermediate compounds are Solid substances rather than liquid, it enables the possibility of isolating and purifying the intermediate by crystallization thereby improving the quality of the final product.
- The present invention also provides solid ibandronic acid.
- Solid ibandronic acid can be prepared by a process that includes the steps of:
- a) combining, at a temperature of about 70° C. to about 78° C., a halo-phosphorous compound and phosphorous acid with N-methyl-N-pentyl propionic acid hydrochloride in a diluent;
- b) maintaining the reaction mixture, while heating to a temperature of about 80° C. to about 100° C.;
- c) combining the reaction mixture with water, whereby two phases are obtained;
- d) separating the two phases obtained;
- e) maintaining the aqueous phase at a temperature of about 95° C. to about 110° C.;
- f) evaporating the aqueous phase to obtain a residue;
- g) combining a C2-4 alcohol or acetone with the reaction mixture to obtain a precipitate; and
- h) recovering the precipitate of solid ibandronic acid.
- Preferably, the halo-phosphorous compound of step a) is added in small aliquots, especially dropwise. Preferably, the diluent in step a) is selected from the group consisting of silicone oil, toluene and a mixture of toluene and phosphoric acid. Preferably, the temperature in step a) is about 75° C.
- Preferably, the mixture in step b) is heated to a temperature of about 80° C.
- Preferably, the C2-4 alcohol in step g) is selected from the group consisting of ethanol, 1-propanol, isopropyl alcohol (IPA) and tert-butanol. Most preferably, the alcohol in step g) is ethanol or IPA. The residue of step f) can be combined with water prior to the addition of the alcohol in step g). After the addition of the C2-4 alcohol, the reaction mixture is optionally heated in order to facilitate the formation of the precipitate.
- The present invention further provides crystalline ibandronic acid, hydrates and solvates thereof. The present invention also provides ibandronic acid alcoholates. As a general rule, crystalline forms possess the advantage of being readily filterable, easily dried, and stable for extended periods of time without the need for specialized storage conditions.
- In another embodiment, the present invention provides a solid crystalline form of ibandronic acid, denominated form S1, characterized by a powder X-ray diffraction pattern having reflections at about 8.2, 11.5, 11.9, 13.9, 18.6 and 22.2±0.2 deg. 2-theta. Solid crystalline ibandronic acid form S1 is further characterized by X-ray powder diffraction pattern having reflections at about 21.6, 23.8, 24.7 and 28.1±0.2 deg. 2-theta. A typical x-ray diffraction diagram for ibandronic acid form S1 is given in
FIG. 4 . Form S1 can be a hemihydrate. - Ibandronic acid form S1 can be prepared by combining an organic solvent selected from the group consisting of tert-butanol, ethanol, and acetone, with an aqueous solution of ibandronic acid, and maintaining the resulting combination for up to about 24 hours to obtain a precipitate of ibandronic acid form S1. Preferably, the organic solvent is selected from the group consisting of tert-butanol, ethanol and acetone.
- Form S1 can be also prepared by combining amorphous ibandronic acid and an organic solvent at a temperature that ranges from room temperature to reflux, and maintaining the reaction mixture for a sufficient time to obtain form S1 in a slurry. Preferably, the organic solvent is selected from the group consisting of tert-butanol, ethanol and acetone.
- Ibandronic acid form S1 can also be prepared in a process that includes the steps of dissolving amorphous ibandronic acid in water, adding acetone to obtain in a slurry, and stirring the slurry for a sufficient time to obtain form S1.
- Form S1 can be also prepared by a process that includes the steps of:
- a) combining, at a temperature of about 70° C. to about 78° C., a halo-phosphorous compound and phosphorous acid with N-methyl-N-pentyl propionic acid hydrochloride in toluene;
- b) maintaining the reaction mixture, while heating to a temperature of about 80° C. to about 100° C.;
- c) removing the toluene and adding water to the reaction mixture;
- d) maintaining the reaction mixture at a reflux temperature;
- e) evaporating to obtain a residue;
- f) combining ethanol with the residue to obtain a precipitate; and
- g) recovering crystalline ibandronic acid form S1.
- Preferably, the halo-phosphorous compound of step a) is added in small aliquots, most preferably dropwise. Preferably, the temperature in step a) is about 75° C. Preferably, the reaction mixture in step b) is heated to a temperature of about 80° C.
- In a further embodiment, the present invention further provides a solid crystalline form of ibandronic acid, denominated form S2, characterized by a powder X-ray diffraction pattern having reflections at about 8.1, 14.2, 16.1, 18.2 and 24.4±0.2 deg. 2-theta. Solid crystalline ibandronic acid form S2 can be further characterized by X-ray reflections at about 10.9, 19.2, 22.3, 23.3, and 28.2±0.2 deg. 2-theta. A typical x-ray diffraction diagram for ibandronic acid form S2 is given in
FIG. 5 . - Ibandronic acid form S2 can be prepared by providing a solution of amorphous ibandronic acid in methanol; adding acetonitrile solvent to the solution to obtain a slurry and recovering ibandronic acid form S2.
- In a further embodiment, the present invention provides a solid crystalline form of ibandronic acid, denominated form S3, characterized by a powder X-ray diffraction pattern having reflections at about 4.4, 8.8, 11.3, 17.6 and 26.4±0.2 deg. 2-theta. Solid crystalline ibandronic acid form S3 can be further characterized by X-ray reflections at about 21.6, 23.8, 24.7 and 28.1±0.2 deg. 2-theta. A typical x-ray diffraction diagram for ibandronic acid form S3 is given in
FIG. 6 . Form S3 can exist as a tert-butanolate. - Ibandronic acid form S3 can be prepared by adding tert-butanol, to an aqueous solution of ibandronic acid, and maintaining the resulting mixture for at least about 24 hours or more to obtain form S3.
- In another embodiment, the present invention provides a solid crystalline form of ibandronic acid, denominated Form S4, characterized by a powder X-ray diffraction pattern having reflections at about 4.4, 8.6, 11.2, 17.3, 20.8, 22.5 and 26.0±0.2 deg. 2-theta. Solid crystalline ibandronic acid Form S4 can be further characterized by X-ray reflections at about 16.2, 20.5 and 21.3±0.2 deg. 2-theta. A typical x-ray diffraction diagram for ibandronic acid Form S4 is given in
FIG. 7 . Form S4 can be a propanolate. - Ibandronic acid Form S4 can be prepared by combining at room temperature an aqueous solution of ibandronic acid and 1-propanol until precipitation occurs, and isolating Form S4. Preferably the combination is stirred for at least about 3 hours. Optionally, the combination is heated to a reflux temperature, in order to obtain a stirrable mixture, which is then cooled to room temperature.
- In yet another embodiment, the present invention provides a solid crystalline form of ibandronic acid, denominated Form S5, characterized by a powder X-ray diffraction pattern having reflections at about 4.5, 8.9, 12.0, 16.0, 16.3, 21.4, 22.1 and 26.9±0.2 deg. 2-theta. Solid crystalline ibandronic acid Form S1 can be further characterized by X-ray reflections at about 5.9, 10.5 and 17.8±0.2 deg. 2-theta. A typical x-ray diffraction diagram for ibandronic acid Form S5 is given in
FIG. 8 . Form S5 exists as a hemihydrate or an iso-propanolate (isopropyl alcohol solvate). - Ibandronic acid Form S5 can be prepared by a process that includes the steps of:
- a) combining, at a temperature of about 70° C. to about 78° C., a halo-phosphorous compound and phosphorous acid with N-methyl-N-pentyl propionic acid hydrochloride in a silicone oil to obtain a reaction mixture;
- b) heating the reaction mixture to a temperature of about 80° C. to about 100° C., and maintaining while stirring;
- c) combining water with the reaction mixture, whereby two phases, one aqueous, one nonaqueous, are obtained;
- d) separating the two phases obtained;
- e) maintaining the aqueous phase at a reflux temperature;
- f) evaporating the aqueous phase to obtain a residue;
- g) adding IPA to the residue,
- h) maintaining the reaction mixture for 24 hours or more to obtain a precipitate; and
- i) recovering crystalline ibandronic acid Form S5.
- Preferably, the halo-phosphorous compound of step a) is added in small aliquots, most preferably dropwise. Preferably, the temperature in step a) is about 75° C. Preferably, the reaction mixture in step b) is heated to a temperature of about 80° C. The residue of step f) can be dissolved in water prior to the addition of the IPA in step g). Optionally, the mixture of the IPA and the residue is cooled to facilitate precipitation.
- Form S5 can be also prepared by a process including the steps of:
- a) combining, at a temperature of about 70° C. to about 78° C., a halo-phosphorous compound and phosphorous acid with N-methyl-N-pentyl propionic acid hydrochloride in toluene to form a multi-phase reaction mixture
- b) maintaining the reaction mixture, while heating to a temperature of about 80° C. to about 100° C.;
- c) removing the toluene, especially by decanting or any other liquid-liquid separation technique, and combining water with the reaction mixture;
- d) maintaining the reaction mixture at a reflux temperature, and evaporating to obtain a residue;
- e) adding IPA to the residue to obtain a slurry; and
- f) recovering crystalline ibandronic acid Form S5 from the slurry.
- Preferably, the temperature in step a) is about 75° C. Preferably, the reaction mixture in step b) is heated to a temperature of about 80° C. Preferably, the halo-phosphorous compound of step a) is added slowly, in small aliquots, most preferably dropwise. In addition to water, a strong acid which does not act as oxidant for amino-phosphonic acids may be added to the reaction mixture of step c). The acid is thought to hydrolize the phosphorous intermediates that form during the previous steps. Preferably, the acid is concentrated HCl.
- Ibandronic acid Form S5 can be prepared by stirring a combination of amorphous ibandronic acid with an organic solvent selected from the group consisting of tetrahydrofuran (THF) and ethanol; and recovering Form S5. The combination is optionally heated to reflux temperature.
- In another embodiment, the present invention provides a solid crystalline form of ibandronic acid, denominated Form S6, characterized by a powder X-ray diffraction pattern having reflections at about 5.7, 11.7, 14.3, 18.5, 21.2 and 21.7±0.2 deg. 2-theta. Solid crystalline ibandronic acid Form S6 can be further characterized by X-ray reflections at about 14.8, 22.7, 22.8 and 30.6±0.2 deg. 2-theta. A typical x-ray diffraction diagram for ibandronic acid form S6 is given in
FIG. 9 . Form S6 can exist as a hemihydrate, tert-butanolate, or a mixture of both. - Ibandronic acid Form S6 can be prepared by a process including the steps of:
- a) combining, at a temperature of about 70° C. to about 78° C., a halo-phosphorous compound and phosphorous acid with N-methyl-N-pentyl propionic acid hydrochloride in a silicone oil to obtain a reaction mixture;
- b) heating the reaction mixture to a temperature of about 80° C. to about 100° C., and maintaining while stirring;
- c) combining water with the reaction mixture, whereby two phases, one aqueous, one nonaqueous, are obtained;
- d) separating the two phases obtained;
- e) maintaining the aqueous phase at a reflux temperature;
- f) evaporating the aqueous phase to obtain a residue;
- g) dissolving the residue in water, followed by the addition of tert-butanol to obtain a precipitate; and
- h) recovering crystalline ibandronic acid Form S6.
- Preferably, the halo-phosphorous compound of step a) is added slowly, in small aliquots, especially dropwise. Preferably, the temperature in step a) is about 75° C. Preferably, the reaction mixture in step b) is heated to a temperature of about 80° C.
- Form S6 can be also prepared by a process that includes the steps of:
- a) combining, at a temperature of about 70° C. to about 78° C., a halo-phosphorous compound and phosphorous acid with N-methyl-N-pentyl propionic acid hydrochloride in toluene to obtain a multiphase reaction mixture;
- b) maintaining the reaction mixture, while heating to a temperature of at least about 95° C.;
- c) separating the toluene by decantation or any technique for liquid-liquid separation, and adding an acid to the reaction mixture;
- d) maintaining the reaction mixture at a reflux temperature, and evaporating to obtain a residue;
- e) dissolving the residue in water, followed by the addition of tert-butanol to obtain a precipitate;
- f) recovering crystalline ibandronic acid Form S6.
- Preferably, the halo-phosphorous compound of step a) is added dropwise. Preferably, the acid in step c) is a strong acid which does not act as oxidant for amino-phosphonic acids. Most preferably, the acid in step c) is concentrated HCl. Preferably, the temperature in step a) is about 75° C.
- In another embodiment, the present invention provides a solid crystalline form of ibandronic acid, denominated Form S7, characterized by a powder X-ray diffraction pattern having reflections at about 4.6, 11.5, 16.3, 16.8, 21.0 and 22.8±0.2 deg. 2-theta. Solid crystalline ibandronic acid Form S7 can be further characterized by X-ray reflections at about 9.0, 17.7, 19.8 and 21.8±0.2 deg. 2-theta. A typical x-ray diffraction diagram for ibandronic acid Form S7 is given in
FIG. 10 . Form S7 can exist as a hemihydrate, a 1-propanolate, or an iso-propanolate. - Ibandronic acid Form S7 can be prepared by a process including the steps of:
- a) combining, at a temperature of about 70° C. to about 78° C., a halo-phosphorous compound and phosphorous acid with N-methyl-N-pentyl propionic acid hydrochloride in a silicone oil to obtain a reaction mixture;
- b) heating the reaction mixture to a temperature of about 80° C. to about 100° C., and maintaining while stirring;
- c) combining the reaction mixture with water, whereby two phases, one aqueous, one nonaqueous, are obtained;
- d) separating the two phases obtained;
- e) maintaining the aqueous phase at a reflux temperature;
- f) concentrating the aqueous phase to obtain a residue;
- g) adding IPA or n-propanol? to the residue,
- h) maintaining the reaction mixture for less than 24 hours to obtain a precipitate; and
- i) recovering crystalline ibandronic acid Form S7.
- Preferably, the halo-phosphorous compound of step a) is added slowly, in small aliquots, most preferably dropwise. Preferably, the temperature in step a) is about 70° C. Preferably, the reaction mixture in step b) is heated to a temperature of about 80° C.
- Form S7 can be also prepared by a process including the steps of:
- a) combining, at a temperature of about 70° C. to about 78° C., a halo-phosphorous compound and phosphorous acid with N-methyl-N-pentyl propionic acid hydrochloride in toluene to obtain a multiphase reaction mixture;
- b) maintaining the reaction mixture, while heating to a temperature of about 80° C. to about 100° C.;
- c) separating the toluene, for example by decanting or any technique for liquid-liquid separation, and combining water with the reaction mixture;
- d) maintaining the reaction mixture at a reflux temperature, and concentrating to obtain a residue;
- e) combining 1-propanol with the residue obtain a precipitate;
- f) recovering crystalline ibandronic acid Form S7.
- Preferably, the halo-phosphorous compound of step a) is added slowly, in small aliquots, most preferably dropwise. Preferably, the temperature in step a) is about 75° C. Preferably, the reaction mixture in step b) is heated to a temperature of about 80° C.
- In yet another embodiment, the present invention provides a solid crystalline form of ibandronic acid, denominated Form S8, characterized by a powder X-ray diffraction pattern having reflections at about 4.5, 6.0, 11.9, 12.3, 16.2, 17.8 and 21.7±0.2 deg. 2-theta. Solid crystalline ibandronic acid Form S8 can be further characterized by X-ray reflections at about 9.0, 16.5 and 18.9, ±0.2 deg. 2-theta. A typical x-ray diffraction diagram for ibandronic acid Form S8 is given in
FIG. 11 . Form S8 can be exist as an ethanolate or an iso-propanolate. - Ibandronic acid Form S8 can be prepared by a process including the steps of:
- a) combining, at a temperature of about 70° C. to about 78° C., a halo-phosphorous compound and phosphorous acid with N-methyl-N-pentyl propionic acid hydrochloride in a silicone oil to obtain a reaction mixture;
- b) heating the reaction mixture to a temperature of about 80° C. to about 100° C., and maintaining while stirring;
- c) combining the reaction mixture with water, whereby two phases, one aqueous, one nonaqueous, are obtained;
- d) separating the two phases obtained;
- e) maintaining the aqueous phase at a reflux temperature;
- f) concentrating the aqueous phase to obtain a residue;
- g) adding a C2-4 alcohol to the residue to obtain a precipitate; and
- h) recovering crystalline ibandronic acid Form S8.
- Preferably, the halo-phosphorous compound of step a) is added slowly, in small aliquots, most preferably dropwise. Preferably, the temperature in step a) is about 75° C. Preferably, the reaction mixture in step b) is heated to a temperature of about 80° C. The residue of step f) may be dissolved in water prior to the addition of the C2-4 alcohol in step g). Preferably, the C2-4 alcohol in step g) is selected from the group consisting of ethanol, 1-propanol and IPA. Most preferably, the C2-4 alcohol in step g) is ethanol.
- In another embodiment, the present invention provides a solid crystalline form of ibandronic acid, denominated Form S10, characterized by a powder X-ray diffraction pattern having reflections at about 4.8, 6.1, 12.0, 12.3, 16.4, 18.0 and 21.7±0.2 deg. 2-theta. Solid crystalline ibandronic acid Form S10 can be further characterized by X-ray reflections at about 18.9, 20.9 and 22.8±0.2 deg. 2-theta. A typical x-ray diffraction diagram for ibandronic acid Form S10 is given in
FIG. 12 . Form S10 can exist as an ethanolate. - Ibandronic acid Form S10 can be prepared by a process comprising the steps of:
- a) combining, at a temperature of about 70° C. to about 78° C., a halo-phosphorous compound and phosphorous acid with N-methyl-N-pentyl propionic acid hydrochloride in a silicone oil to obtain a reaction mixture;
- b) heating the reaction mixture to a temperature of about 80° C. to about 100° C., and maintaining while stirring;
- c) combining the reaction mixture with water, whereby two phases, one aqueous, one nonaqueous, are obtained;
- d) separating the two phases obtained;
- e) maintaining the aqueous phase at a reflux temperature;
- f) concentrating the aqueous phase to obtain a residue;
- g) adding ethanol to the residue to obtain a slurry; and
- h) recovering from the slurry crystalline ibandronic acid Form S10.
- Preferably, the halo-phosphorous compound of step a) is added slowly, in small aliquots, most preferably dropwise. Preferably, the reaction mixture in step b) is heated to a temperature of about 80° C. The residue of step f) may be dissolved in water prior to the addition of the ethanol in step g). The reaction mixture in step g) may be seeded with amorphous ibandronic acid following the addition of the ethanol in step g).
- In another embodiment, the present invention provides a solid crystalline form of ibandronic acid, denominated Form S12, characterized by a powder X-ray diffraction pattern having reflections at about 4.7, 9.0, 11.6, 20.9, 21.1, 21.7, 22.9 and 26.3±0.2 deg. 2-theta. Solid crystalline ibandronic acid form S12 may be further characterized by X-ray reflections at about 13.8, 17.1 and 18.4±0.2 deg. 2-theta. A typical x-ray diffraction diagram for ibandronic acid Form S12 is given in
FIG. 13 . Form S12 can be a hemihydrate and/or an isopropanolate. - Ibandronic acid Form S12 can be prepared by a process including the steps of:
- a) combining, at a temperature of about 70° C. to about 78° C., a halo-phosphorous compound and phosphorous acid with N-methyl-N-pentyl propionic acid hydrochloride in a silicone oil to obtain a reaction mixture;
- b) heating the reaction mixture to a temperature of about 80° C. to about 100° C., and maintaining while stirring;
- c) combining water with the reaction mixture, whereby two phases, one aqueous, one nonaqueous, are obtained;
- d) separating the two phases obtained;
- e) maintaining the aqueous phase at a reflux temperature;
- f) concentrating the aqueous phase to obtain a residue;
- g) combining the residue with 1-propanol to obtain a precipitate; and
- h) recovering crystalline ibandronic acid Form S12.
- Preferably, the halo-phosphorous compound of step a) is added slowly, in small aliquots, especially dropwise. Preferably, the temperature in step a) is about 70° C. Preferably, the reaction mixture in step b) is heated to a temperature of about 80° C.
- In yet another embodiment, the present invention provides a solid crystalline form of ibandronic acid, denominated Form S13, characterized by a powder X-ray diffraction pattern having reflections at about 4.5, 8.9, 12.0, 16.0, 16.3, 21.3 and 22.1±0.2 deg. 2-theta. Solid crystalline ibandronic acid Form S13 can be further characterized by X-ray reflections at about 10.5, 17.8 and 26.9±0.2 deg. 2-theta. A typical x-ray diffraction diagram for ibandronic acid Form S13 is given in
FIG. 14 . Form S13 can exist as an isopropanolate. - Ibandronic acid Form S13 can be prepared by a process including the steps of:
- a) combining, at a temperature of about 70° C. to about 78° C., a halo-phosphorous compound and phosphorous acid with N-methyl-N-pentyl propionic acid hydrochloride in a silicone oil to obtain a reaction mixture;
- b) heating the reaction mixture to a temperature of about 80° C. to about 100° C., and maintaining while stirring;
- c) combining the reaction mixture with water, whereby two phases, one aqueous, one nonaqueous, are obtained;
- d) maintaining the reaction mixture at a temperature of about 100° C.;
- e) separating the two phases obtained;
- f) maintaining the aqueous phase at a temperature of about 75° C. to about 100° C.;
- g) concentrating the aqueous phase to obtain a residue;
- h) adding IPA to the residue to obtain a precipitate; and
- i) recovering crystalline ibandronic acid Form S13.
- Preferably, the halo-phosphorous compound of step a) is added slowly, in small aliquots, especially dropwise. Preferably, the temperature in step a) is about 75° C. Preferably, the reaction mixture in step b) is heated to a temperature of about 80° C.
- Ibandronic acid Form S13 can be also prepared by a process including the steps of:
- a) combining, at a temperature of at least about 95° C., a halo-phosphorous compound and phosphorous acid with N-methyl-N-pentyl propionic acid hydrochloride to obtain a reaction mixture;
- b) maintaining while stirring the reaction mixture at a temperature of about 95° C. to about 100° C.;
- c) combining the reaction mixture with water;
- d) cooling the reaction mixture to room temperature and concentrating to obtain a residue;
- e) dissolving the residue in water, followed by the addition of IPA to obtain a precipitate; and
- f) recovering crystalline ibandronic acid Form S13.
Preferably, the halo-phosphorous compound of step a) is added slowly, in small aliquots, especially dropwise. - Form S13 can be also prepared by providing a solution of ibandronic acid in water at a temperature of about 38° C. to about 50°, cooling the solution to room temperature, followed by the addition of IPA, and maintaining the mixture at temperature for a sufficient time to obtain Form S13. Preferably, ibandronic acid is dissolved in water at a temperature of about 40° C. to provide the solution.
- The following table summarizes the weight loss by TGA and water content of the novel crystalline forms of ibandronic acid described hereinabove.
-
Weight loss by Water content by Form TGA [%] Karl Fisher [%] amorphous 5.1 4.2 S1 3.0 7.7 1.9 2.0 2.2 2.0 5.2 2.2 2.0 1.1 1.1 S2 1.9 S3 17.8 0.5 S4 14.8 0.1 15.2 0.1 55 13.0 0.7 14.1 1.1 2.7 2.3 1.2 1.1 S6 10.1 2.9 10.9 1.8 S7 13.4 1.2 11.4 1.9 S8 5.5 0.3 5.6 0.1 5.3 S10 5.5 0.6 S12 14.0 2.4 S13 15.0 1.0 15.4 - In a further embodiment, the present invention also provides a process for purifying Ibandronic acid from inorganic impurities (i.e. reducing the amount of inorganic impurities in) that includes the step of dissolving ibandronic acid in water or methanol, and crystallizing by addition of a C2-4 alcohol. Preferably, the C2-4 alcohol is selected from the group consisting of ethanol, 1-propanol, IPA and tert-butanol.
- In yet another embodiment, the present invention further provides a HPLC method of assaying ibandronic acid comprising the steps of: dissolving an ibandronic acid sample in a diluent to obtain a sample solution, loading the sample solution (ca. 50 μL) onto a 250×4.1 mm, Hamilton type PRP-X100 anion exchange column, eluting the sample from the column at 2.0 ml/min using a mixture of nitric acid (HNO3: 35 vol-%), potassium nitrate (KNO3: 45 vol-%) and ethanol (20 vol-%) as eluent, and measuring the ibandronic acid content of the relevant sample at 240 nm wavelength with a UV detector. Preferably, the diluent is water.
- Some processes of the present invention involve crystallization out of a particular solvent. One skilled in the art knows that the conditions concerning crystallization can be modified without affecting the form of the polymorph obtained. For example, when mixing ibandronic acid in a solvent to form a solution, warming of the mixture may be necessary to completely dissolve the starting material. If warming does not clarify the mixture, the mixture may be diluted or filtered. To filter, the hot mixture may be passed through paper, glass fiber or other membrane material, or a clarifying agent such as celite. Depending upon the equipment used and the concentration and temperature of the solution, the filtration apparatus may need to be preheated to avoid premature crystallization. The conditions may also be changed to induce precipitation. A preferred way of inducing precipitation is to reduce the solubility of the solvent (reduce it “solubilizing power”). The solubility of the solvent—that is its ability to dissolve ibandronic acid—can be reduced, for example, by reducing the temperature of the solvent.
- In yet another embodiment, the present invention provides a process for preparing ibandronate sodium (the sodium salt of ibandronic acid) comprising converting any of the solid or crystalline forms of ibandronic acid hereinabove described to ibandronate sodium by combining the ibandronic acid with an aqueous solution of sodium hydroxide at ambient temperature (about 20° to about 28° C.), concentrating the solution, especially at reduced pressure, to obtain a residue; combining the residue with acetone whereby a precipitate is formed, and recovering ibandronate monosodium.
- In yet another embodiment, the present invention provides ibandronic acid having an assay of ≧99%.
- In a further embodiment, the present invention provides pharmaceutical formulations that include at least on pharmaceutically acceptable excipient and one or more of the novel crystalline forms of the present invention
- Pharmaceutical formulations of the present invention contain solid ibandronic acid or crystalline forms thereof, such as one of those disclosed herein, optionally in a mixture with amorphous ibandronic acid. In addition to the active ingredient(s), the pharmaceutical formulations of the present invention can and typically do contain one or more pharmaceutically acceptable excipients. Such excipients are included in the formulations for a variety of purposes.
- Diluents increase the bulk of a solid pharmaceutical composition, and may make a pharmaceutical dosage form containing the composition easier for the patient and care giver to handle. Diluents for solid compositions include, for example, microcrystalline cellulose (e.g. Avicel®), microfine cellulose, lactose, starch, pregelatinized starch, calcium carbonate, calcium sulfate, sugar, dextrates, dextrin, dextrose, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, kaolin, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, polymethacrylates (e.g. Eudragit®), potassium chloride, powdered cellulose, sodium chloride, sorbitol and talc.
- Solid pharmaceutical compositions that are compacted into a dosage form, such as a tablet, may include excipients whose functions include helping to bind the active ingredient and other excipients together after compression. Binders for solid pharmaceutical compositions include acacia, alginic acid, carbomer (e.g. carbopol), carboxymethylcellulose sodium, dextrin, ethyl cellulose, gelatin, guar gum, hydrogenated vegetable oil, hydroxyethyl cellulose, hydroxypropyl cellulose (e.g. Klucel®), hydroxypropyl methyl cellulose (e.g. Methocel®), liquid glucose, magnesium aluminum silicate, maltodextrin, methylcellulose, polymethacrylates, povidone (e.g. Kollidon®, Plasdone®), pregelatinized starch, sodium alginate and starch.
- The dissolution rate of a compacted solid pharmaceutical composition in the patient's stomach may be increased by the addition of a disintegrant to the composition. Disintegrants include alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium (e.g. Ac-Di-Sol®, Primellose®), colloidal silicon dioxide, croscarmellose sodium, crospovidone (e.g. Kollidon®, Polyplasdone®), guar gum, magnesium aluminum silicate, methyl cellulose, microcrystalline cellulose, polacrilin potassium, powdered cellulose, pregelatinized starch, sodium alginate, sodium starch glycolate (e.g. Explotab®) and starch.
- Glidants can be added to improve the flowability of a non-compacted solid composition and to improve the accuracy of dosing. Excipients that may function as glidants include colloidal silicon dioxide, magnesium trisilicate, powdered cellulose, starch, talc and tribasic calcium phosphate.
- When a dosage form such as a tablet is made by the compaction of a powdered composition, the composition is subjected to pressure from a punch and dye. Some excipients and active ingredients have a tendency to adhere to the surfaces of the punch and dye, which can cause the product to have pitting and other surface irregularities. A lubricant can be added to the composition to reduce adhesion and ease the release of the product from the dye. Lubricants include magnesium stearate, calcium stearate, glyceryl monostearate, glyceryl palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil, mineral oil, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc and zinc stearate.
- Flavoring agents and flavor enhancers make the dosage form more palatable to the patient. Common flavoring agents and flavor enhancers for pharmaceutical products that may be included in the composition of the present invention include maltol, vanillin, ethyl vanillin, menthol, citric acid, fumaric acid, ethyl maltol and tartaric acid.
- Solid and liquid compositions (suspensions or emulsions) may also be dyed using any pharmaceutically acceptable colorant to improve their appearance and/or facilitate patient identification of the product and unit dosage level.
- In liquid pharmaceutical compositions of the present invention, ibandronic acid and any other solid excipients are suspended in a liquid carrier such as water, vegetable oil, alcohol, polyethylene glycol, propylene glycol or glycerin.
- Liquid pharmaceutical compositions may contain emulsifying agents to disperse uniformly throughout the composition an active ingredient or other excipient that is not soluble in the liquid carrier. Emulsifying agents that may be useful in liquid compositions of the present invention include, for example, gelatin, egg yolk, casein, cholesterol, acacia, tragacanth, chondrus, pectin, methyl cellulose, carbomer, cetostearyl alcohol and cetyl alcohol.
- Liquid pharmaceutical compositions of the present invention may also contain a viscosity enhancing agent to improve the mouth-feel of the product and/or coat the lining of the gastrointestinal tract. Such agents include acacia, alginic acid bentonite, carbomer, carboxymethylcellulose calcium or sodium, cetostearyl alcohol, methyl cellulose, ethylcellulose, gelatin guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, maltodextrin, polyvinyl alcohol, povidone, propylene carbonate, propylene glycol alginate, sodium alginate, sodium starch glycolate, starch tragacanth and xanthan gum.
- Sweetening agents such as sorbitol, saccharin, sodium saccharin, sucrose, aspartame, fructose, mannitol and invert sugar may be added to improve the taste.
- Preservatives and chelating agents such as alcohol, sodium benzoate, butylated hydroxyl toluene, butylated hydroxyanisole and ethylenediamine tetraacetic acid may be added at levels safe for ingestion to improve storage stability.
- According to the present invention, a liquid composition may also contain a buffer such as guconic acid, lactic acid, citric acid or acetic acid, sodium guconate, sodium lactate, sodium citrate or sodium acetate. Selection of excipients and the amounts used may be readily determined by the formulation scientist based upon experience and consideration of standard procedures and reference works in the field.
- The solid compositions of the present invention include powders, granulates, aggregates and compacted compositions. The dosages include dosages suitable for oral, buccal, rectal, parenteral (including subcutaneous, intramuscular, and intravenous), inhalant and ophthalmic administration. Although the most suitable administration in any given case will depend on the nature and severity of the condition being treated, the most preferred route of the present invention is oral. The dosages may be conveniently presented in unit dosage form and prepared by any of the methods well-known in the pharmaceutical arts.
- Dosage forms include solid dosage forms like tablets, powders, capsules, suppositories, sachets, troches and losenges, as well as liquid syrups, suspensions and elixirs.
- The dosage form of the present invention may be a capsule containing the composition, preferably a powdered or granulated solid composition of the invention, within either a hard or soft shell. The shell may be made from gelatin and optionally contain a plasticizer such as glycerin and sorbitol, and an opacifying agent or colorant.
- The active ingredient and excipients may be formulated into compositions and dosage forms according to methods known in the art.
- A composition for tableting or capsule filling may be prepared by wet granulation. In wet granulation, some or all of the active ingredients and excipients in powder form are blended and then further mixed in the presence of a liquid, typically water, that causes the powders to clump into granules. The granulate is screened and/or milled, dried and then screened and/or milled to the desired particle size. The granulate may then be tableted, or other excipients may be added prior to tableting, such as a glidant and/or a lubricant.
- A tableting composition may be prepared conventionally by dry blending. For example, the blended composition of the actives and excipients may be compacted into a slug or a sheet and then comminuted into compacted granules. The compacted granules may subsequently be compressed into a tablet.
- As an alternative to dry granulation, a blended composition may be compressed directly into a compacted dosage form using direct compression techniques. Direct compression produces a more uniform tablet without granules. Excipients that are particularly well suited for direct compression tableting include microcrystalline cellulose, spray dried lactose, dicalcium phosphate dihydrate and colloidal silica. The proper use of these and other excipients in direct compression tableting is known to those in the art with experience and skill in particular formulation challenges of direct compression tableting.
- A capsule filling of the present invention may comprise any of the aforementioned blends and granulates that were described with reference to tableting, however, they are not subjected to a final tableting step.
- Having described the invention with reference to certain preferred embodiments, other embodiments will become apparent to one skilled in the art from consideration of the specification. The invention is further defined by reference to the following examples describing in detail the preparation of the composition and methods of use of the invention. It will be apparent to those skilled in the art that many modifications, both to materials and methods, may be practiced without departing from the scope of the invention.
- X-ray diffraction data were obtained with a scintag X-Ray powder diffractometer model X'TRA, Cu-tube, solid state detector, a round standard aluminum sample holder with round zero background quartz plate was used. Scanning parameters: Range: 2-40 deg.28: continues scan, Rate: 5 deg./min.
- DSC data were obtained with a DSC821e, Mettler Toledo instrument. The sample weight was 3-5 mg. The heating (scan) rate was 10° C./min. Number of holes in the crucible: 3.
- TGA data were obtained using a Mettler TG50, sample weight: 7-15 mg, heating 30 rate: 10° C./min.
- Karl Fischer data were obtained using a Mettler Toledo DL38, sample weight: 100-200 mg.
- Spray drying technique were obtained using “Buchi Mini Spray dryer B-290”. The spray parameters are: evaporating capacity—1 lit/hr water (higher for organic solvents); the maximum temperature input—220° C.; Air flow—max of 35 m2/hr; spray gas-compressed air or nitrogen 200-800 lit/hr, 5-8 bar; Nozzel diameter—0.7 mm (standard); Nozzel cap—1.4 mm and 1.5 mm.
- An aqueous solution (40% w/w) of Ibandronic acid (150 mL) was evaporated under vacuum (20-30 mmHg) until dryness while heating the flask in a water bath (up to 70° C.) to obtain Amorphous Ibandronic acid (67 gr).
- An aqueous solution (40% w/w) of Ibandronic acid (303 gr) was freeze-dried (−50° C., 0.5 mmHg) for 3 days to obtain Amorphous Ibandronic acid (120 gr).
- Phosphorous trichloride (3.3 mL) was added to a stirred suspension of MPPA.HCl (8 g) in silicon oil (40 mL) at 75° C. Two additional portions of phosphorous trichloride (2×3.3 mL) were added during 2 hours after heating the reaction mixture to 81° C. Two portions of phosphorus acid (2×3.1 g) were thereafter added during 2 hours. The reaction mixture was stirred at 81° C. for 22 hours. Water (40 mL) was added drop-wise at 81° C. The resulting phases were separated and the aqueous phase was heated to 90° C. for 16 hours. The obtained solution was cooled to room temperature and then was evaporated to obtain an oily residue. The oily residue was dissolved in water (7 mL) at room temperature. To the obtained solution, IPA (280 mL) was added. The obtained sticky precipitate was heated to reflux and then was cooled to room temperature, after complete dissolution. Then the IPA was decanted-off and the residue was dried in vacuum oven at 50° C. for 20 hours to obtain 4.4 g of amorphous ibandronic acid.
- Phosphorous trichloride (3.3 mL) was added to a stirred suspension of MPA.HCl (8 g) in silicon oil (40 mL) at 75° C. Two additional portions of phosphorous trichloride (2×3.3 mL) were added during 2 hours after heating the reaction mixture to 81° C. Then two portions of phosphorus acid (2×3.1 g) were added during 2 hours. The reaction mixture was stirred at 81° C. for 22 hours. Water (40 mL) was added drop-wise at 81° C. Then the phases were separated and the aqueous phase was heated to 90° C. for 16 hours. The obtained solution was cooled to room temperature and then was evaporated to obtain an oily residue. The oily residue was dissolved in water (7 mL) at room temperature. The obtained solution was heated to 70° C. Then hot IPA (280 mL) (73° C.) was added drop-wise. The solution was cooled to room temperature. The solution was stirred at room temperature for 21 hours. Then the IPA was decanted-off and the residue was dried in vacuum oven at 50° C. for 21 hours to obtain 4.6 g of amorphous ibandronic acid.
- Amorphous ibandronic acid (3.0 g) was dissolved in water (4 mL) at room temperature. Acetone (70 mL) was added to the stirred solution. White slurry was obtained while stirring at room temperature for 68 hours. The precipitate was isolated by vacuum filtration, washed with acetone (2×25 mL) and dried in a vacuum oven at 50° C. for 24 hours to obtain 2.5 g of ibandronic acid crystal form S1.
- 40% w/w aqueous solution of ibandronic acid (22.2 g) was concentrated under vacuum. To the concentrated solution (15.71 g), tert-butanol was added drop-wise at room temperature in two portions (2×50 mL) and the mixture was stirred at this temperature for 4 hours. The obtained precipitate was isolated by vacuum filtration, washed with tert-butanol (1×1.5 mL) and dried in a vacuum oven at 5° C. for 24 hours to obtain 5.5 g of ibandronic acid crystal form S1.
- 40% w/w aqueous solution of ibandronic acid (16.8 g) was concentrated under vacuum. To the concentrated solution (12.1 g), absolute Ethanol (100 mL) was added drop-wise at room temperature and the mixture was stirred at this temperature for 4.5 hours. The obtained precipitate was isolated by vacuum filtration, washed with absolute Ethanol (2×25 mL) and dried in a vacuum oven at 50° C. for 23 hours to obtain 5.2 g of ibandronic acid crystal form S1.
- Amorphous ibandronic acid (3.0 g) was dissolved in methanol (12 mL) at room temperature. Acetone (40 mL) was added in one portion to the stirred solution. The obtained slurry was stirred at room temperature for 72 hours. The resulting precipitate was isolated by vacuum filtration, washed with acetone (2×12.5 mL) and dried in a vacuum oven at 50° C. for 22 hours to obtain 2.5 g of ibandronic acid crystal form S1.
- Amorphous ibandronic acid (3.0 g) was stirred in acetone (15 mL) at reflux temperature for 5 hours. The slurry was cooled to room temperature and then it was stirred at this temperature for 16 hours. The product was dried in a vacuum oven at 50° C. for 24 hours to obtain 2.8 g of ibandronic acid crystal form S1.
- Amorphous ibandronic acid (3.0 g) was stirred in absolute ethanol (20 mL) at reflux temperature for 2.5 hours. The slurry was cooled to room temperature and then it was stirred at this temperature for 40.5 hours. The product was isolated by vacuum filtration, washed with absolute ethanol (2×20 mL) and dried in a vacuum oven at 40° C. for 25 hours to obtain 2.8 g of ibandronic acid crystal form S1.
- 40% w/w aqueous solution of ibandronic acid (10.95 g) was concentrated under vacuum. To the concentrated solution (7.5 g), acetone was added at room temperature in two portions (2×45 mL) and the mixture was stirred at this temperature for 22 hours. The obtained precipitate was isolated by vacuum filtration, washed with Acetone (2×20 mL) and dried in a vacuum oven at 50° C. for 70 hours to obtain 2.9 g of ibandronic acid crystal form S1.
- Phosphorous oxychloride (17 mL) was added drop-wise to a stirred suspension of MPA.HCl (10 g) and phosphorous acid (14.8 g) in toluene (70 mL) at 75° C. The reaction mixture was heated to 80° C. and was stirred at this temperature for 26 hours. The reaction mixture was cooled to room temperature. The toluene was decanted-off and the residue was stirred under reflux with water (70 mL) for 15.5 hours. The obtained solution was cooled to room temperature and then was evaporated to obtain an oily residue (34.3 g). Absolute ethanol (853 mL) was added gradually to the oily reside while stirring at room temperature during 45 hours. The obtained precipitate was isolated by vacuum filtration, washed with absolute ethanol (2×97 mL) and dried in a vacuum oven at 50° C. for 24 hours to obtain 6.7 g of ibandronic acid crystal form S1.
- Amorphous ibandronic acid (3.0 g) was dissolved in methanol (12 mL) at room temperature. Acetonitrile (ACN) (40 mL) was added in one portion to the stirred solution. The obtained slurry was stirred at room temperature for 72 hours. The precipitate was isolated by vacuum filtration, washed with ACN (2×20 mL) and dried in a vacuum oven at 50° C. for 21.5 hours to obtain 2.4 g of ibandronic acid crystal form S2.
- 40% w/w aqueous solution of ibandronic acid (11 g) was concentrated under vacuum. To the concentrated solution (7.6 g), tert-butanol (50 mL) was added at room temperature. The obtained slurry was stirred at this temperature for 72 hours. Then the precipitate was isolated by vacuum filtration, washed with tert-butanol (2×40 mL) and dried in a vacuum oven at 50° C. for 22.5 hours to obtain 4.2 g of ibandronic acid crystal form S3.
- 40% w/w aqueous solution of ibandronic acid (19.7 g) was concentrated under vacuum. To the concentrated solution (12.5 g), 1-propanol (150 mL) was added gradually at room temperature. The un-stirrable product was heated to reflux to obtain viscous stirrable mixture. The mixture was cooled to room temperature and stirred at this temperature for 16 hours. The obtained precipitate was isolated by vacuum filtration, washed with 1-propanol (2×17 mL) and dried in a vacuum oven at 50° C. for 24 hours to obtain 6.6 g of ibandronic acid crystal form S4.
- 40% w/w aqueous solution of ibandronic acid (23.7 g) was concentrated under vacuum. To the concentrated solution (14 g), 1-propanol (100 mL) was added drop-wise at room temperature and the mixture was stirred at this temperature for 3 hours. The obtained precipitate was isolated by vacuum filtration, washed with 1-propanol (2×35 mL) and dried in a vacuum oven at 50° C. for 24 hours to obtain 10.2 g of ibandronic acid crystal form S4.
- Phosphorous trichloride (10.9 mL) was added drop-wise to a stirred suspension of MPA.HCl (7 g) and phosphorous acid (10.3 g) in silicon oil (49 mL) at 75° C. The reaction mixture was heated to 80° C. Two additional portions of phosphorous trichloride (1×1.5 ml and 1×1 mL) were added gradually to the stirred reaction mixture at ˜80° C. The reaction mixture was stirred at this temperature for 50 hours. Water (49 mL) was added drop-wise at 79° C. The phases were separated and the aqueous phase was heated to reflux for 15.5 hours. The obtained solution was cooled to room temperature and then was evaporated until dryness to obtain an oily residue (27.2 g). The oily residue was dissolved in water (4 mL). To the obtained solution, IPA (209 mL) was added drop-wise at room temperature and the mixture was stirred at this temperature for 24 hours. The obtained precipitate was isolated by vacuum filtration, washed with IPA (2×52 mL) and dried in a vacuum oven at 50° C. for 24 hours to obtain 9.9 g of ibandronic acid crystal form S5.
- Phosphorous trichloride (8.2 mL) was added drop-wise to a stirred suspension of MPA.HCl (7 g) and phosphorous acid (3.9 g) in toluene (35 mL) at 75° C. The reaction mixture was heated to 95° C. and was stirred at this temperature for 23 hours. The toluene was decanted-off and the residue was stirred under reflux (96° C.) with 6N HCl (104 mL) for 43 hours. The obtained solution was cooled to room temperature and was then concentrated to obtain an oily residue (8.1 g). The oily residue was dissolved in water (4 mL). To the obtained solution, IPA (196 mL) was added drop-wise at room temperature and the mixture was stirred at this temperature for 72 hours. The obtained precipitate was isolated by vacuum filtration, washed with IPA (2×40 mL) and dried in a vacuum oven at 50° C. for 24 hours to obtain 4.5 g of ibandronic acid crystal form S5.
- Phosphorous oxychloride (50 mL) was added drop-wise to a stirred suspension of MPA.HCl (30 g) and phosphorous acid (44 g) in silicone oil (210 mL) at 75° C. The reaction mixture was heated to 81° C. Two additional portions of phosphorous oxychloride (1×6.7 ml and 1×4 mL) were added gradually to the stirred reaction mixture at 81° C. The reaction mixture was stirred at this temperature for 50 hours. Water (210 mL) was added drop-wise to the solution and the mixture was stirred for 1 hr. Then the phases were separated and the aqueous phase was heated to reflux for 16.5 hours. The obtained solution was cooled to room temperature and then was evaporated until dryness to obtain an oily residue (125.6 g). The oily residue was dissolved in water (19 mL). To the obtained solution, IPA (1760 mL) was added at room temperature and the mixture was stirred at this temperature for 24 hours and then was cooled to 7° C. and stirred this temperature for 72 hrs. The obtained precipitate was isolated by vacuum filtration, washed with IPA (2×100 mL) and dried in a vacuum oven at 50° C. for 25 hours to obtain 22 g of ibandronic acid crystal form S5.
- Amorphous ibandronic acid (3.0 g) was stirred in THF (20 mL) at reflux temperature for 2.5 hours to obtain almost complete dissolution. The mixture was cooled to room temperature and then it was stirred at this temperature for 21 hours. The obtained precipitate was isolated by vacuum filtration under nitrogen flow, washed with THF (2×15 mL) and dried in a vacuum oven at 40° C. for 23.5 hours to obtain 2.7 g of ibandronic acid crystal form S5.
- Amorphous ibandronic acid (3.0 g) was stirred in Absolute Ethanol (30 mL) at room temperature. The slurry was stirred at room temperature for 72 hours. The product was isolated by vacuum filtration, washed with Absolute Ethanol (2×20 mL) and dried in a vacuum oven at 50° C. for 22 hours to obtain 2.9 g of ibandronic acid crystal form S5.
- Phosphorous oxychloride (17 mL) was added drop-wise to a stirred suspension of MPA.HCl (10 g) and phosphorous acid (14.8 g) in toluene (70 mL) at 75° C. The reaction mixture was heated to 80° C. and was stirred at this temperature for 26 hours. The reaction mixture was cooled to room temperature. The toluene was decanted-off and the residue was stirred under reflux with water (70 mL) for 15.5 hours. The obtained solution was cooled to room temperature and then was evaporated until dryness to obtain an oily residue (34.3 g). IPA (834 mL) was added gradually to the oily reside while stirring at room temperature during 72 hours. The obtained precipitate was isolated by vacuum filtration, washed with IPA (2×84 mL) and dried in a vacuum oven at 50° C. for 23 hours to obtain 12.8 g of ibandronic acid crystal form S5.
- Phosphorous trichloride (15.6 mL) was added drop-wise to a stirred suspension of MPA.HCl (10 g) and phosphorous acid (14.7 g) in silicon oil (70 mL) at 75° C. The reaction mixture was heated to 80° C. Two additional portions of phosphorous trichloride (1×2 ml and 1×1.3 mL) were added gradually to the stirred reaction mixture at 80° C. The reaction mixture was stirred at this temperature for 48hours. Water (70 mL) was added drop-wise at 80° C. The phases were separated and the aqueous phase was heated to reflux for 16 hours. The obtained solution was cooled to room temperature and then was evaporated until dryness to obtain an oily residue (38.2 g). IPA (746 mL) was added to the oily residue at room temperature and the mixture was stirred at this temperature for 53.5 hours. The obtained precipitate was isolated by vacuum filtration, washed with IPA (2×83 mL) and dried in a vacuum oven at 50° C. for 24.5 hours to obtain 11.1 g of ibandronic acid crystal form S5.
- Phosphorous trichloride (10.9 mL) was added drop-wise to a stirred suspension of MPPA.HCl (7 g) and phosphorous acid (10.3 g) in silicon oil (49 mL) at 75° C. The reaction mixture was heated to 80° C. Two additional portions of phosphorous trichloride (1×1.5 ml and 1×1 mL) were added gradually to the stirred reaction mixture at ˜80° C. The reaction mixture was stirred at this temperature for 50 hours. Water (49 mL) was added drop-wise at 79° C. The phases were separated and the aqueous phase was heated to reflux for 15.5 hours. The obtained solution was cooled to room temperature and then was evaporated until dryness to obtain an oily residue (27.2 g). The oily residue was dissolved in water (3.8 mL). To the obtained solution, tert-butanol (191 mL) was added at room temperature and the mixture was stirred at this temperature for 42 hours. The obtained precipitate was isolated by vacuum filtration, washed with tert-butanol (2×38 mL) and dried in a vacuum oven at 50° C. for 25.5 hours to obtain 6.2 g of ibandronic acid crystal form S6.
- Phosphorous trichloride (8.2 mL) was added drop-wise to a stirred suspension of MPA.HCl (7 g) and phosphorous acid (3.9 g) in toluene (35 mL) at 75° C. The reaction mixture was heated to 95° C. and was stirred at this temperature for 23 hours. The Toluene was decanted-off and the residue was stirred under reflux (96° C.) with 6H HCl (104 mL) for 43 hours. The obtained solution was cooled to room temperature and then was evaporated until dryness to obtain an oily residue (8.1 g). The oily residue was dissolved in water (4 mL). To the obtained solution, tert-butanol (204 mL) was added drop-wise at room temperature and the mixture was stirred at this temperature for 72 hours. The obtained precipitate was isolated by vacuum filtration, washed with tert-butanol (2×40 mL) and dried in a vacuum oven at 50° C. for 23 hours to obtain 2.8 g of ibandronic acid crystal form S6.
- Phosphorous trichloride (15.6 mL) was added drop-wise to a stirred suspension of MPA.HCl (10 g) and phosphorous acid (14.7 g) in silicon oil (70 mL) at 70° C. The reaction mixture was heated to 80° C. and was stirred at this temperature for 23.5 hours. Water (70 mL) was added drop-wise at 80° C. Then the phases were separated and the aqueous phase was heated to reflux for 18 hours. The obtained solution was cooled to room temperature and then was evaporated until dryness to obtain an oily residue (24.5 g). IPA (443 mL) was added gradually to the oily residue and the mixture was stirred at room temperature for 18 hours. The obtained precipitate was isolated by vacuum filtration, washed with IPA (1×80 mL) and dried in a vacuum oven at 50° C. for 24 hours to obtain 9.8 g of ibandronic acid crystal form S7.
- Phosphorous oxychloride (17 mL) was added drop-wise to a stirred suspension of MPA.HCl (10 g) and phosphorous acid (14.8 g) in toluene (70 mL) at 75° C. The reaction mixture was heated to 80° C. and was stirred at this temperature for 26 hours. Then the reaction mixture was cooled to room temperature. The toluene was decanted-off and the residue was stirred under reflux with water (70 mL) for 15.5 hours. The obtained solution was cooled to room temperature and then was evaporated until dryness to obtain an oily residue (34.3 g). 1-Propanol (695 mL) was added gradually to the oily reside while stirring at room temperature during 18 hours. The obtained precipitate was isolated by vacuum filtration, washed with 1-propanol (2×39 mL) and dried in a vacuum oven at 50° C. for 24 hours to obtain 10.8 g of ibandronic acid crystal form S7.
- Phosphorous trichloride (18.7 mL) was added drop-wise to a stirred suspension of MPA.HCl (12 g) and phosphorous acid (17.6 g) in silicone oil (84 mL) at 75° C. The reaction mixture was heated to 80° C. Two additional portions of phosphorous trichloride (1×2.5 ml and 1×1.5 mL) were added gradually to the stirred reaction mixture at 80° C. The reaction mixture was stirred at this temperature for 51.5 hours. Water (84 mL) was added drop-wise to the solution, stirred for 15 minutes. The phases were separated and the aqueous phase was heated to reflux for 16 hours. The obtained solution was cooled to room temperature and stirred at this temperature for 12 hours. A portion (23 mL) of this solution (24.8 g) was concentrated to obtain an oily residue (11.26 g). The oily residue was dissolved in water (1.7 mL). To the obtained solution, IPA (87 mL) was added drop-wise at room temperature and the mixture was stirred at this temperature for 70 hours. The obtained precipitate was isolated by vacuum filtration, washed with IPA (2×25 mL) and dried in a vacuum oven at 50° C. for 25 hours to obtain 3.27 g of ibandronic acid crystal form S8.
- Phosphorous trichloride (18.7 mL) was added drop-wise to a stirred suspension of MPA.HCl (12 g) and phosphorous acid (17.6 g) in silicone oil (84 mL) at 75° C. The reaction mixture was heated to 80° C. Two additional portions of phosphorous trichloride (1×2.5 ml and 1×1.5 mL) were added gradually to the stirred reaction mixture at 80° C. The reaction mixture was stirred at this temperature for 51.5 hours. Water (84 mL) was added drop-wise to the solution and the mixture stirred for 15 minutes. The phases were separated and the aqueous phase was heated to reflux for 16 hours. The obtained solution was cooled to room temperature and stirred at this temperature for 12 hours. A portion (23 mL) from this solution (27 g) was evaporated until dryness to obtain an oily residue (11 g). The oily residue was dissolved in water (1.6 mL). To the obtained solution, 1-propanol (160 mL) was added drop-wise at room temperature and the mixture was stirred at this temperature for 20 hours. The obtained precipitate was isolated by vacuum filtration, washed with IPA (2×10 mL) and dried in a vacuum oven at 50° C. for 25 hours to obtain 3.16 g of ibandronic acid crystal form S8.
- Phosphorous oxychloride (20 mL) was added drop-wise to a stirred suspension of MPA.HCl (12 g) and phosphorous acid (17.6 g) in Silicone oil (84 mL) at 75° C. The reaction mixture was heated to 80° C. Two additional portions of phosphorous oxychloride (1×2.7 ml and 1×1.6 mL) were added gradually to the stirred reaction mixture at 80° C. The reaction mixture was stirred at this temperature for 50 hours. Water (84 mL) was added drop-wise to the solution, stirred for 20 minutes. The phases were separated and the aqueous phase was heated to reflux for 17 hours. The obtained solution was cooled to room temperature and stirred at this temperature for 12 hours. A portion (24 mL) from this solution (24 g) was concentrated to obtain an oily residue (21.65 g). The oily residue was dissolved in water (1.9 mL). To the obtained solution, IPA (177 mL) was added drop-wise at room temperature and the mixture was stirred at this temperature for 23 hours. The obtained precipitate was isolated by vacuum filtration, washed with IPA (2×20 mL) and dried in a vacuum oven at 50° C. for 26.5 hours to obtain 2.37 g of ibandronic acid crystal form S8.
- Phosphorous trichloride (15.6 mL) was added drop-wise to a stirred suspension of MPA.HCl (10 g) and phosphorous acid (14.7 g) in silicon oil (70 mL) at 75° C. The reaction mixture was heated to 80° C. Two additional portions of phosphorous trichloride (1×2 ml and 1×1.3 mL) were added gradually to the stirred reaction mixture at 80° C. The reaction mixture was stirred at this temperature for 48 hours. Water (70 mL) was added drop-wise at 80° C. Then the phases were separated and the aqueous phase was heated to reflux for 16 hours. The obtained solution was cooled to room temperature and then was evaporated until dryness to obtain an oily residue (38.2 g). Absolute ethanol (766 mL) was added to the oily residue at room temperature and the mixture was stirred at this temperature for 53 hours. The obtained precipitate was isolated by vacuum filtration, washed with absolute ethanol (2×61 mL) and dried in a vacuum oven at 50° C. for 25.5 hours to obtain 7.7 g of ibandronic acid crystal form S8.
- Phosphorous trichloride (57 mL) was added drop-wise to a stirred suspension of MPA.HCl (30 g) and phosphorous acid (44 g) in silicon oil (210 mL) at 75° C. The reaction mixture was heated to 80° C. Two additional portions of phosphorous trichloride (1×6.25 ml and 1×3.75 mL) were added gradually to the stirred reaction mixture at 80° C. The reaction mixture was stirred at this temperature for 48 hours. Water (210 mL) was added drop-wise at 80° C. and stirred at this temperature for 30 minutes. Then the phases were separated and the aqueous phase was heated to reflux for 17 hours. The solution was cooled to room temperature and then concentrated to obtain an oily residue (121.1 g). The oily residue was dissolved in water (18 mL). Absolute ethanol (3027 mL) was added to the solution at room temperature and the mixture was stirred at this temperature for 72 hours. Cooling to 5° C. and stirring at this temperature for 7 hours. The obtained precipitate was isolated by vacuum filtration, washed with absolute ethanol (2×48 mL) and dried in a vacuum oven at 50° C. for 23.5 hours to obtain 35.64 g of ibandronic acid crystal form S8.
- Phosphorous oxychloride (50 mL) was added drop-wise to a stirred suspension of MPA.HCl (30 g) and phosphorous acid (44 g) in silicon oil (210 mL) at 75° C. The reaction mixture was heated to 80° C. Two additional portions of phosphorous oxychloride (1×6.7 ml and 1×4 mL) were added gradually to the stirred reaction mixture at 80° C. The reaction mixture was stirred at this temperature for 51 hours. Water (210 mL) was added drop-wise at 80° C. and stirred at this temperature for 30 minutes. Then the phases were separated and the aqueous phase was heated to reflux for 16.5 hours. The solution was cooled to room temperature and then was evaporated until dryness to obtain an oily residue (128.5 g). The oily residue was dissolved in water (19 mL). Absolute ethanol (3210 mL) was added to the solution at room temperature and the mixture was stirred at this temperature for 39 hours. The mixture was seeded with ibandronic acid and stirred for 4.5 hours. The mixture was cooled to 0° C. and stirred at this temperature for 72 hours. The obtained precipitate was isolated by vacuum filtration, washed with absolute ethanol and dried in a vacuum oven at 50° C. for 23 hours to obtain 13.82 g of ibandronic acid crystal form S10.
- Phosphorous trichloride (15.6 mL) was added drop-wise to a stirred suspension of MPA.HCl (10 g) and phosphorous acid (14.7 g) in silicon oil (70 mL) at 70° C. The reaction mixture was heated to 80° C. and was stirred at this temperature for 23.5 hours. Water (70 mL) was added drop-wise at 80° C. The phases were separated and the aqueous phase was heated to reflux for 18 hours. The obtained solution was cooled to room temperature and then concentrated to obtain an oily residue (24.5 g). Absolute ethanol (597 mL) was added to the oily residue and the mixture was stirred at room temperature for 20.5 hours. The obtained precipitate was isolated by vacuum filtration, washed with absolute ethanol (2×20 mL) and dried in a vacuum oven at 50° C. for 31 hours to obtain 7.3 g of ibandronic acid crystal form S10.
- Phosphorous trichloride (18.7 mL) was added drop-wise to a stirred suspension of MPA.HC1 (12 g) and phosphorous acid (17.6 g) in silicone oil (84 mL) at 75° C. The reaction mixture was heated to 80° C. Two additional portions of phosphorous trichloride (1×2.5 ml and 1×1.5 mL) were added gradually to the stirred reaction mixture at 80° C. The reaction mixture was stirred at this temperature for 52 hours. Water (84 mL) was added drop-wise to the solution, stirred for 15 minutes. Then the phases were separated and the aqueous phase was heated to reflux for 16 hours. The obtained solution was cooled to room temperature and stirred at this temperature for 13 hours. A portion (23 mL) from this solution (27.31 g) was evaporated until dryness to obtain an oily residue (11.25 g). The oily residue was dissolved in water (1.7 mL). To the obtained solution, abs. ethanol (270 mL) was added drop-wise at room temperature and the mixture was stirred at this temperature for 20 hours. The obtained precipitate was isolated by vacuum filtration, washed with abs ethanol (2×12.5 mL) and dried in a vacuum oven at 50° C. for 24 hours to obtain 8.56 g of ibandronic acid crystal form S10.
- Phosphorous oxychloride (20 mL) was added drop-wise to a stirred suspension of MPA.HCl (12 g) and phosphorous acid (17.6 g) in silicone oil (84 mL) at 75° C. The reaction mixture was heated to 80° C. Two additional portions of phosphorous oxychloride (1×2.7 ml and 1×1.6 mL) were added gradually to the stirred reaction mixture at 80° C. The reaction mixture was stirred at this temperature for 50 hours. Water (84 mL) was added drop-wise to the solution, stirred for 20 minutes. The phases were separated and the aqueous phase was heated to reflux for 13 hours. The obtained solution was cooled to room temperature and stirred at this temperature for 12 hours. A portion (24 mL) from this solution (29 g) was concentrated to obtain an oily residue (12.8 g). The oily residue was dissolved in water (1.9 mL). To the obtained solution, abs. ethanol (300 mL) was added drop-wise at room temperature and the mixture was stirred at this temperature for 25 hours. The obtained precipitate was isolated by vacuum filtration, washed with abs. ethanol (2×20 mL) and dried in a vacuum oven at 50° C. for 24 hours to obtain 1.81 g of ibandronic acid crystal form S10.
- Phosphorous trichloride (15.6 mL) was added drop-wise to a stirred suspension of MPA.HCl (10 g) and phosphorous acid (14.7 g) in silicon oil (70 mL) at 70° C. The reaction mixture was heated to 80° C. and was stirred at this temperature for 23.5 hours. Water (70 mL) was added drop-wise at 80° C. The phases were separated and the aqueous phase was heated to reflux for 18 hours. The obtained solution was cooled to room temperature and then was evaporated until dryness to obtain an oily residue (24.5 g). 1-Propanol was added to the oily residue at room temperature in two portions (2×25 mL) and the mixture was stirred at this temperature for 17.5 hours. The obtained precipitate was isolated by vacuum filtration, washed with 1-propanol (2×20 mL) and dried in a vacuum oven at 50° C. for 22.5 hours to obtain 10.1 g of ibandronic acid crystal form S12.
- Phosphorous oxychloride (11.7 mL) was added drop-wise to a stirred suspension of MPA.HCl (7 g) and phosphorous acid (10.3 g) in silicon oil (49 mL) at 75° C. The reaction mixture was heated to 80° C. An additional portion of phosphorous oxychloride (1×1.6 mL) was added to the reaction mixture at 80° C. after 45.5 hours. The reaction mixture was stirred at 80° C. for additional 2.5 hours. Water (49 mL) was added drop-wise at 80° C. The phases were separated and the aqueous phase was heated to 100° C. for 18 hours. The obtained solution was cooled to room temperature and then was concentrated to obtain an oily residue (26.7 g). The oily residue was dissolved in water (4 mL). To the obtained solution, IPA (360 mL) was added drop-wise while stirring at room temperature during 48 hours. The obtained precipitate was isolated by vacuum filtration, washed with IPA (1×20 mL) and dried in a vacuum oven at 50° C. for 24.5 hours to obtain 1.84 g of ibandronic acid crystal form S13.
- MPA.HCl (7 g) was added to melted phosphorous acid (3.4 g) while stirring in an oil-bath at 95° C. Phosphorous trichloride (5.8 mL) was added drop-wise. The mixture was stirred at 95-100° C. (in an oil-bath) for 25.5 hours. Without cooling, but removing the oil-bath, water (21 mL) was added drop-wise. The reaction mixture was stirred at 97° C. for 16 hours. The obtained solution was cooled to room temperature. Insoluble particles were filtered off and the filtrate was concentrated to obtain an oily residue (12.9 g). The oily residue was dissolved in water (1.9 mL). To the obtained solution, IPA (290 mL) was added gradually while stirring at room temperature during 100 hours. The obtained precipitate was isolated by vacuum filtration, washed with IPA (2×30 mL) and dried in a vacuum oven at 50° C. for 24 hours to obtain 8.11 g of ibandronic acid crystal form S13.
- Phosphorous trichloride (50 mL) was added drop-wise to a stirred suspension of MPA.HCl (30 g) and phosphorous acid (44 g) in silicone oil (210 mL) at 75° C. The reaction mixture was heated to 80° C. Two additional portions of phosphorous trichloride (1×6.25 ml and 1×3.75 mL) were added gradually to the stirred reaction mixture at 80° C. The reaction mixture was stirred at this temperature for 48.5 hours. Water (210 mL) was added drop-wise to the solution and the mixture stirred for 15 minutes. The phases were separated and the aqueous phase was heated to reflux for 16.5 hours. The obtained solution was cooled to room temperature and then was concentrated to obtain an oily residue (121.3 g). The oily residue was dissolved in water (18 mL). To the obtained solution, IPA (1698 mL) was added at room temperature and the mixture was stirred at this temperature for 22 hours and then was cooled to 4° C. and stirred this temperature for 4 hrs. The obtained precipitate was isolated by vacuum filtration, washed with IPA (2×43 mL) and dried in a vacuum oven at 50° C. for 47 hours to obtain 39 g of ibandronic acid crystal form S13.
- Ibandronic acid (97 g) was dissolved in water (90 mL) at 40° C. The solution was cooled to room temperature and IPA (1100 mL) was added, stirred at this temperature for 22 hrs. The obtained precipitate was isolated by vacuum filtration, washed with IPA (2×50 mL) and dried in a vacuum oven at 50° C. for 25 hours to obtain 97.6 g of ibandronic acid crystal form S13.
- Repetition of Example 9 of U.S. Pat. No. 4,927,814 15 g N-Methyl-N-pentylaminopropionic acid (MPA.HCl) were kept for 23 hours at 100° C. with 8.8 g phosphorous acid and 18.7 ml phosphorous trichloride in 75 ml chlorobenzene. The solvent was then decanted off and the residue was stirred under reflux with 222 ml 6N HCl for 12.5 hours. Insoluble material was filtered off and the filtrate was concentrated and applied to column of Amberlite IR 120 (H+). The elution with water was monitored by HPLC. The desired fractions were combined, evaporated and stirred up with acetone to obtain a sticky oily precipitate as a crude product.
(The HPLC method for monitoring the ion-exchange chromatography is the one described in this application). - Repetition of Example 9 of U.S. Pat. No. 4,927,814—with Methyl Ethyl Ketone Used Instead of Acetone
- 15 g N-Methyl-N-pentylaminopropionic acid (MPA.HCl) were kept for 23 hours at 100° C. with 8.8 g phosphorous acid and 18.7 ml phosphorous trichloride in 75 ml chlorobenzene. The solvent was then decanted off and the residue was stirred under reflux with 222 ml 6N HCl for 12.5 hours. Insoluble material was filtered off and the filtrate was concentrated and applied to column of Amberlite IR 120 (H+). The elution with water was monitored by HPLC. The desired fractions were combined, evaporated and stirred up with methyl ethyl ketone (MEK) to obtain a sticky oily precipitate as a crude product.
- (The HPLC method for monitoring the ion-exchange chromatography is the one described in this application).
- Repetition of Example 9 of U.S. Pat. No. 4,927,814—with Acetonitrile Used Instead of Acetone
- 15 g N-Methyl-N-pentylaminopropionic acid (MPA.HCl) were kept for 23 hours at 100° C. with 8.8 g phosphorous acid and 18.7 ml phosphorous trichloride in 75 ml chlorobenzene. The solvent was then decanted off and the residue was stirred under reflux with 222 ml 6N HCl for 12.5 hours. Insoluble material was filtered off and the filtrate was concentrated and applied to column of Amberlite IR 120 (H+). The elution with water was monitored by HPLC. The desired fractions were combined, evaporated and stirred up with acetonitrile to obtain a sticky oily precipitate as a crude product. (The HPLC method for monitoring the ion-exchange chromatography is the one described in this application).
-
- Column: Hamilton type PRP-X100, Anion exchange, 250*4.1 mm
- Temp.: 35° C.
- Eluent: 35% HNO3, 45% KNO3, 20% EtOH
- Flow: 2.0 mL/min
- Diluent: H2O
- Injection volume: 50 μL
- Detector: 240 nm
The following samples were analyzed according to the above method: -
Ex- am- ple Crystallization % area of % area of % area of No. medium Polymorph PO4 −3 PO3 −3 Cl− 32 EtOH S8 0.4 ND* 33 EtOH S10 0.2 0.2 ND* *ND = not detected - Ibandronic acid (9 g) was dissolved in water (18 ml) at room temperature. The solution was divided into three portions, and each portion was spray dried using a Buchi mini spray dryer B-290 using a standard nozzle 0.7 mm in diameter with a nozzle cap of 1.4 or 1.5 mm. The solution feed rate was about 1 L/h. The spray gas was set at 200-800 L/h at a pressure of 5-8 bar. In each instance, amorphous ibandronic acid was obtained.
- For
portion 1, nitrogen gas was at an inlet temperature of 50° C. The evaporated solvent and nitrogen left the spray dryer at a temperature of 41-36° C. - For
portion 2, nitrogen gas was at an inlet temperature of 100° C. The evaporated solvent and nitrogen left the spray dryer at a temperature of 71-72° C. - For portion 3, nitrogen gas was at an inlet temperature of 150° C. The evaporated solvent and nitrogen left the spray dryer at a temperature of 100° C.
- Each of the three product was analyzed by powder x-ray diffraction and found to be amorphous.
- Ibandronic acid (4.5 g) was dissolved in water (45 ml) at room temperature. A solution of 1N aq. NaOH (14 ml) was added in one portion. The reaction mixture was stirred at room temperature for 2.5 hours. Then the solution was concentrated under reduced pressure and was poured into Acetone (45 ml) at room temperature. A white precipitate was obtained immediately. The obtained slurry was stirred at room temperature for 72 hours. The product was isolated by vacuum filtration, washed with Acetone (2×20 ml) and dried in a vacuum oven at 50° C. for 22 hours to obtain 4.45 g of ibandronate monosodium salt (pH=4.26).
Claims (4)
1. Amorphous ibandronic acid.
2. A method of making amorphous ibandronic acid comprising the steps of subjecting a solution of ibandronic acid in a solvent selected from the group consisting of: acetonitrile (ACN), dimethylsulfoxide (DMSO), methanol, and water, to a solvent-removal step selected from vacuum evaporation, lyophilization, and spray drying.
3. The process of claim 2 , wherein the solvent is water.
4. A method of making amorphous ibandronic acid comprising the step of spray drying an aqueous solution of ibandronic acid.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US12/218,197 US20090023949A1 (en) | 2004-06-23 | 2008-07-10 | Amorphous ibandronic acid |
Applications Claiming Priority (7)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US58250004P | 2004-06-23 | 2004-06-23 | |
US62001604P | 2004-10-18 | 2004-10-18 | |
US69086805P | 2005-06-16 | 2005-06-16 | |
US16548105A | 2005-06-22 | 2005-06-22 | |
US33199506A | 2006-01-12 | 2006-01-12 | |
US11/525,804 US7511174B2 (en) | 2004-06-23 | 2006-09-22 | Solid and crystalline ibandronic acid |
US12/218,197 US20090023949A1 (en) | 2004-06-23 | 2008-07-10 | Amorphous ibandronic acid |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US11/525,804 Division US7511174B2 (en) | 2004-06-23 | 2006-09-22 | Solid and crystalline ibandronic acid |
Publications (1)
Publication Number | Publication Date |
---|---|
US20090023949A1 true US20090023949A1 (en) | 2009-01-22 |
Family
ID=35285644
Family Applications (3)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US11/525,804 Expired - Fee Related US7511174B2 (en) | 2004-06-23 | 2006-09-22 | Solid and crystalline ibandronic acid |
US12/218,197 Abandoned US20090023949A1 (en) | 2004-06-23 | 2008-07-10 | Amorphous ibandronic acid |
US12/288,025 Abandoned US20090069598A1 (en) | 2004-06-23 | 2008-10-15 | Solid and crystalline ibandronic acid |
Family Applications Before (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US11/525,804 Expired - Fee Related US7511174B2 (en) | 2004-06-23 | 2006-09-22 | Solid and crystalline ibandronic acid |
Family Applications After (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US12/288,025 Abandoned US20090069598A1 (en) | 2004-06-23 | 2008-10-15 | Solid and crystalline ibandronic acid |
Country Status (6)
Country | Link |
---|---|
US (3) | US7511174B2 (en) |
EP (1) | EP1687007A2 (en) |
CA (1) | CA2571433A1 (en) |
IL (1) | IL180106A0 (en) |
MX (1) | MX2007000087A (en) |
WO (1) | WO2006002348A2 (en) |
Families Citing this family (24)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1713489B1 (en) | 2004-08-23 | 2011-01-19 | Teva Pharmaceutical Industries Ltd | Crystalline form of ibandronate sodium and processes for preparation thereof |
KR100908530B1 (en) * | 2005-02-01 | 2009-07-20 | 에프. 호프만-라 로슈 아게 | Ibandronate polymorph ratio |
LT2662380T (en) * | 2005-02-01 | 2019-03-12 | Atnahs Pharma Uk Limited | Medical use of Ibandronate polymorph A |
WO2007074475A2 (en) * | 2005-12-27 | 2007-07-05 | Natco Pharma Limited | Novel polymorphic forms of ibandronate |
US20080009466A1 (en) * | 2006-04-25 | 2008-01-10 | Sharon Avhar-Maydan | Crystalline forms of ibandronic acid and processes for preparation thereof |
KR101425429B1 (en) | 2006-06-23 | 2014-08-01 | 씨아이피엘에이 엘티디. | Process for the Synthesis of Ibandronate Sodium |
EP2046342A4 (en) * | 2006-07-28 | 2011-05-04 | Reddys Lab Ltd Dr | Crystalline form a of ibandronic acid and process for the preparation |
WO2008060609A1 (en) * | 2006-11-16 | 2008-05-22 | Teva Pharmaceutical Industries Ltd. | Crystalline forms of ibandronate sodium |
CA2570949A1 (en) | 2006-12-12 | 2008-06-12 | Apotex Pharmachem Inc. | Ibandronate sodium propylene glycol solvate and processes for the preparation thereof |
KR101150662B1 (en) | 2007-04-11 | 2012-05-29 | 에프. 호프만-라 로슈 아게 | Multi step synthesis of ibandronate |
KR20100014728A (en) * | 2007-04-19 | 2010-02-10 | 닥터 레디스 레보러터리즈 리미티드 | Ibandronate sodium polymorphs |
CA2689504A1 (en) * | 2007-06-19 | 2008-12-24 | Albemarle Corporation | Processes for manufacturing bisphosphonic acids |
US9523188B2 (en) * | 2007-06-22 | 2016-12-20 | Diversakore Llc | Framing structure |
US9096999B2 (en) * | 2007-06-22 | 2015-08-04 | Diversakore Llc | Framing structure |
US8800229B2 (en) * | 2007-06-22 | 2014-08-12 | Diversakore Holdings, Llc | Framing structure |
US20090042839A1 (en) * | 2007-08-09 | 2009-02-12 | Sharon Avhar-Maydan | Crystalline forms of ibandronate sodium |
US20090099390A1 (en) * | 2007-09-24 | 2009-04-16 | Teva Pharmaceutical Industries Ltd. | Crystalline forms of ibandronic acid and processes for the preparation thereof |
EP2180003A1 (en) | 2008-10-21 | 2010-04-28 | Zentiva, k.s. | Preparation of ibandronate trisodium |
TR201110524A2 (en) * | 2011-01-06 | 2012-07-23 | Bi̇lgi̇ç Mahmut | New water-soluble formulations for use in the treatment of bone diseases. |
TR201110526A2 (en) * | 2011-01-06 | 2012-07-23 | Bi̇lgi̇ç Mahmut | Water-soluble pharmaceutical formulations for use in the treatment of bone diseases. |
TWI665190B (en) | 2013-11-15 | 2019-07-11 | 阿克比治療有限公司 | Solid forms of {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid, compositions, and uses thereof |
US20180168579A1 (en) | 2016-12-21 | 2018-06-21 | Ethicon Endo-Surgery, Llc | Surgical end effector with two separate cooperating opening features for opening and closing end effector jaws |
CN109668975A (en) * | 2017-10-17 | 2019-04-23 | 齐鲁制药有限公司 | In relation to the detection method of substance in Ibandronate |
CN113804795B (en) * | 2021-10-08 | 2023-05-16 | 河南润弘制药股份有限公司 | Method for detecting nitrate impurity in nitroglycerin solution and injection |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4927814A (en) * | 1986-07-11 | 1990-05-22 | Boehringer Mannheim Gmbh | Diphosphonate derivatives, pharmaceutical compositions and methods of use |
US20020035058A1 (en) * | 1996-05-15 | 2002-03-21 | The University Of Sheffield | Isopentenyl pyrophosphate isomerase (IPI) and/or prenyl transferase inhibitors |
US6419955B1 (en) * | 1998-10-09 | 2002-07-16 | Hoffmann-La Roche Inc. | Process for making bisphosphonate compositions |
US7038083B2 (en) * | 2002-05-17 | 2006-05-02 | Teva Pharmaceutical Industries, Ltd. | Process for making bisphosphonic acids using diluents other than halogenated hydrocarbons |
US7214818B2 (en) * | 2004-10-29 | 2007-05-08 | Hoffmann-La Roche Inc. | Method for synthesizing bisphosphonate |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
PL1656386T3 (en) * | 2003-08-21 | 2010-05-31 | Sun Pharmaceuticals Ind Ltd | A process for preparation of bisphosphonic acid compounds |
CA2551230A1 (en) * | 2003-12-23 | 2005-07-14 | Lyogen Limited | A process for the preparation of alkyl- and aryl-diphosphonic acids and salts thereof |
-
2005
- 2005-06-22 MX MX2007000087A patent/MX2007000087A/en unknown
- 2005-06-22 WO PCT/US2005/022410 patent/WO2006002348A2/en not_active Application Discontinuation
- 2005-06-23 CA CA002571433A patent/CA2571433A1/en not_active Abandoned
- 2005-06-23 EP EP05763415A patent/EP1687007A2/en not_active Withdrawn
-
2006
- 2006-09-22 US US11/525,804 patent/US7511174B2/en not_active Expired - Fee Related
- 2006-12-14 IL IL180106A patent/IL180106A0/en unknown
-
2008
- 2008-07-10 US US12/218,197 patent/US20090023949A1/en not_active Abandoned
- 2008-10-15 US US12/288,025 patent/US20090069598A1/en not_active Abandoned
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4927814A (en) * | 1986-07-11 | 1990-05-22 | Boehringer Mannheim Gmbh | Diphosphonate derivatives, pharmaceutical compositions and methods of use |
US20020035058A1 (en) * | 1996-05-15 | 2002-03-21 | The University Of Sheffield | Isopentenyl pyrophosphate isomerase (IPI) and/or prenyl transferase inhibitors |
US6419955B1 (en) * | 1998-10-09 | 2002-07-16 | Hoffmann-La Roche Inc. | Process for making bisphosphonate compositions |
US7038083B2 (en) * | 2002-05-17 | 2006-05-02 | Teva Pharmaceutical Industries, Ltd. | Process for making bisphosphonic acids using diluents other than halogenated hydrocarbons |
US7214818B2 (en) * | 2004-10-29 | 2007-05-08 | Hoffmann-La Roche Inc. | Method for synthesizing bisphosphonate |
Also Published As
Publication number | Publication date |
---|---|
WO2006002348A2 (en) | 2006-01-05 |
WO2006002348A3 (en) | 2006-05-04 |
US7511174B2 (en) | 2009-03-31 |
IL180106A0 (en) | 2007-05-15 |
EP1687007A2 (en) | 2006-08-09 |
US20070161606A1 (en) | 2007-07-12 |
CA2571433A1 (en) | 2006-01-05 |
US20090069598A1 (en) | 2009-03-12 |
WO2006002348A8 (en) | 2007-06-21 |
MX2007000087A (en) | 2007-11-06 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US7511174B2 (en) | Solid and crystalline ibandronic acid | |
US7563918B2 (en) | Solid and crystalline ibandronate sodium and processes for preparation thereof | |
US7105557B2 (en) | Polymorphs of valsartan | |
US7915423B2 (en) | Solid states of pantoprazole sodium, processes for preparing them and processes for preparing known pantoprazole sodium hydrates | |
US11608318B2 (en) | Solid state forms of Omecamtiv mecarbil and Omecamtiv mecarbil diHCl | |
US20080255366A1 (en) | Crystalline Trihydrate of Zoledronic Acid | |
EP1507531B1 (en) | Stable pharmaceutical compositions of desloratadine | |
US20040235904A1 (en) | Crystalline and amorphous solids of pantoprazole and processes for their preparation | |
US20090099390A1 (en) | Crystalline forms of ibandronic acid and processes for the preparation thereof | |
JP2005532356A (en) | Polymorph XVI of fexofenadine hydrochloride | |
US20080009466A1 (en) | Crystalline forms of ibandronic acid and processes for preparation thereof | |
EP2046342A2 (en) | Crystalline form a of ibandronic acid and process for the preparation | |
US20220220149A1 (en) | Solid state forms of sage-217 and processes for preparation thereof | |
EP1950204A1 (en) | Amorphous form of valsartan |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
STCB | Information on status: application discontinuation |
Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION |