WO2011091513A1 - Polymorphic forms of lubiprostone - Google Patents
Polymorphic forms of lubiprostone Download PDFInfo
- Publication number
- WO2011091513A1 WO2011091513A1 PCT/CA2011/000088 CA2011000088W WO2011091513A1 WO 2011091513 A1 WO2011091513 A1 WO 2011091513A1 CA 2011000088 W CA2011000088 W CA 2011000088W WO 2011091513 A1 WO2011091513 A1 WO 2011091513A1
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- WIPO (PCT)
- Prior art keywords
- lubiprostone
- peak
- approximately
- crystalline form
- theta
- Prior art date
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- WGFOBBZOWHGYQH-MXHNKVEKSA-N lubiprostone Chemical compound O1[C@](C(F)(F)CCCC)(O)CC[C@@H]2[C@@H](CCCCCCC(O)=O)C(=O)C[C@H]21 WGFOBBZOWHGYQH-MXHNKVEKSA-N 0.000 title claims abstract description 147
- 229960000345 lubiprostone Drugs 0.000 title claims abstract description 145
- 238000000034 method Methods 0.000 claims abstract description 40
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 84
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 71
- 239000000203 mixture Substances 0.000 claims description 56
- 239000003960 organic solvent Substances 0.000 claims description 39
- 230000008569 process Effects 0.000 claims description 34
- 238000001556 precipitation Methods 0.000 claims description 23
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical class CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 20
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 20
- 238000001914 filtration Methods 0.000 claims description 18
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 16
- 239000002244 precipitate Substances 0.000 claims description 16
- 238000003756 stirring Methods 0.000 claims description 11
- 239000000706 filtrate Substances 0.000 claims description 8
- 238000001157 Fourier transform infrared spectrum Methods 0.000 claims description 7
- 238000001938 differential scanning calorimetry curve Methods 0.000 claims description 7
- 239000003208 petroleum Substances 0.000 claims description 6
- 238000001035 drying Methods 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims 10
- 239000000243 solution Substances 0.000 description 34
- 235000019439 ethyl acetate Nutrition 0.000 description 23
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 21
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 16
- 150000001875 compounds Chemical class 0.000 description 10
- 238000006243 chemical reaction Methods 0.000 description 9
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 9
- 239000012044 organic layer Substances 0.000 description 8
- 238000001228 spectrum Methods 0.000 description 8
- 238000002360 preparation method Methods 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- 238000005033 Fourier transform infrared spectroscopy Methods 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
- 239000012267 brine Substances 0.000 description 6
- KQIADDMXRMTWHZ-UHFFFAOYSA-N chloro-tri(propan-2-yl)silane Chemical compound CC(C)[Si](Cl)(C(C)C)C(C)C KQIADDMXRMTWHZ-UHFFFAOYSA-N 0.000 description 6
- 238000004440 column chromatography Methods 0.000 description 6
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 6
- IOLCXVTUBQKXJR-UHFFFAOYSA-M potassium bromide Chemical compound [K+].[Br-] IOLCXVTUBQKXJR-UHFFFAOYSA-M 0.000 description 6
- 229910052938 sodium sulfate Inorganic materials 0.000 description 6
- 235000011152 sodium sulphate Nutrition 0.000 description 6
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 6
- 239000000725 suspension Substances 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 206010010774 Constipation Diseases 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- -1 amine salt Chemical class 0.000 description 4
- 238000004090 dissolution Methods 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N Formic acid Chemical compound OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium on carbon Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- RHDGNLCLDBVESU-UHFFFAOYSA-N but-3-en-4-olide Chemical compound O=C1CC=CO1 RHDGNLCLDBVESU-UHFFFAOYSA-N 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 238000000113 differential scanning calorimetry Methods 0.000 description 3
- 239000010410 layer Substances 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 208000025865 Ulcer Diseases 0.000 description 2
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 2
- 229910052782 aluminium Inorganic materials 0.000 description 2
- 239000012296 anti-solvent Substances 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 2
- 238000011097 chromatography purification Methods 0.000 description 2
- 229940125773 compound 10 Drugs 0.000 description 2
- 229940126214 compound 3 Drugs 0.000 description 2
- 229940125898 compound 5 Drugs 0.000 description 2
- 239000013058 crude material Substances 0.000 description 2
- XEYBRNLFEZDVAW-ARSRFYASSA-N dinoprostone Chemical compound CCCCC[C@H](O)\C=C\[C@H]1[C@H](O)CC(=O)[C@@H]1C\C=C/CCCC(O)=O XEYBRNLFEZDVAW-ARSRFYASSA-N 0.000 description 2
- 235000019253 formic acid Nutrition 0.000 description 2
- MNWFXJYAOYHMED-UHFFFAOYSA-N heptanoic acid Chemical compound CCCCCCC(O)=O MNWFXJYAOYHMED-UHFFFAOYSA-N 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 229940094443 oxytocics prostaglandins Drugs 0.000 description 2
- 230000005855 radiation Effects 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 239000006188 syrup Substances 0.000 description 2
- 235000020357 syrup Nutrition 0.000 description 2
- YBRBMKDOPFTVDT-UHFFFAOYSA-N tert-butylamine Chemical compound CC(C)(C)N YBRBMKDOPFTVDT-UHFFFAOYSA-N 0.000 description 2
- 238000001757 thermogravimetry curve Methods 0.000 description 2
- 231100000397 ulcer Toxicity 0.000 description 2
- 229910021511 zinc hydroxide Inorganic materials 0.000 description 2
- CISDEVRDMKWPCP-UHFFFAOYSA-N 1-dimethoxyphosphoryl-3,3-difluoroheptan-2-one Chemical compound CCCCC(F)(F)C(=O)CP(=O)(OC)OC CISDEVRDMKWPCP-UHFFFAOYSA-N 0.000 description 1
- ZYVYEJXMYBUCMN-UHFFFAOYSA-N 1-methoxy-2-methylpropane Chemical compound COCC(C)C ZYVYEJXMYBUCMN-UHFFFAOYSA-N 0.000 description 1
- IFUYEJWYVORTEU-UHFFFAOYSA-N 3,3a,4,5,6,6a-hexahydro-2h-cyclopenta[b]furan-2-ol Chemical compound C1CCC2OC(O)CC21 IFUYEJWYVORTEU-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- MLOSJPZSZWUDSK-UHFFFAOYSA-N 4-carboxybutyl(triphenyl)phosphanium;bromide Chemical compound [Br-].C=1C=CC=CC=1[P+](C=1C=CC=CC=1)(CCCCC(=O)O)C1=CC=CC=C1 MLOSJPZSZWUDSK-UHFFFAOYSA-N 0.000 description 1
- 206010000087 Abdominal pain upper Diseases 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- 241001076939 Artines Species 0.000 description 1
- 229910016523 CuKa Inorganic materials 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- 208000007107 Stomach Ulcer Diseases 0.000 description 1
- 238000002441 X-ray diffraction Methods 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 229940040386 amitiza Drugs 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- NKLCNNUWBJBICK-UHFFFAOYSA-N dess–martin periodinane Chemical compound C1=CC=C2I(OC(=O)C)(OC(C)=O)(OC(C)=O)OC(=O)C2=C1 NKLCNNUWBJBICK-UHFFFAOYSA-N 0.000 description 1
- AQEFLFZSWDEAIP-UHFFFAOYSA-N di-tert-butyl ether Chemical compound CC(C)(C)OC(C)(C)C AQEFLFZSWDEAIP-UHFFFAOYSA-N 0.000 description 1
- 208000010643 digestive system disease Diseases 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 208000000718 duodenal ulcer Diseases 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 201000005917 gastric ulcer Diseases 0.000 description 1
- 208000018685 gastrointestinal system disease Diseases 0.000 description 1
- 150000004678 hydrides Chemical class 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 208000002551 irritable bowel syndrome Diseases 0.000 description 1
- 150000002596 lactones Chemical class 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 125000002950 monocyclic group Chemical group 0.000 description 1
- 239000004570 mortar (masonry) Substances 0.000 description 1
- 230000004899 motility Effects 0.000 description 1
- 229910052759 nickel Inorganic materials 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 229960005235 piperonyl butoxide Drugs 0.000 description 1
- 230000002980 postoperative effect Effects 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- LJCNRYVRMXRIQR-OLXYHTOASA-L potassium sodium L-tartrate Chemical class [Na+].[K+].[O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O LJCNRYVRMXRIQR-OLXYHTOASA-L 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 230000003449 preventive effect Effects 0.000 description 1
- 150000003180 prostaglandins Chemical class 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 230000002269 spontaneous effect Effects 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- DPKBAXPHAYBPRL-UHFFFAOYSA-M tetrabutylazanium;iodide Chemical compound [I-].CCCC[N+](CCCC)(CCCC)CCCC DPKBAXPHAYBPRL-UHFFFAOYSA-M 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/94—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems condensed with rings other than six-membered or with ring systems containing such rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/557—Eicosanoids, e.g. leukotrienes or prostaglandins
- A61K31/558—Eicosanoids, e.g. leukotrienes or prostaglandins having heterocyclic rings containing oxygen as the only ring hetero atom, e.g. thromboxanes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/10—Laxatives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C405/00—Compounds containing a five-membered ring having two side-chains in ortho position to each other, and having oxygen atoms directly attached to the ring in ortho position to one of the side-chains, one side-chain containing, not directly attached to the ring, a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, and the other side-chain having oxygen atoms attached in gamma-position to the ring, e.g. prostaglandins ; Analogues or derivatives thereof
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Definitions
- the present invention relates to polymorphic forms of Lubiprostone.
- Lubiprostone (1) is an E1 type prostaglandin derivative. It is marketed in USA as Amitiza ® and is used for the treatment of idiopathic chronic constipation, irritable bowel syndrome and post operative ilues. The use of Lubiprostone softens the stool, increases motility, and promotes spontaneous bowel movements (SBM). Chemically, Lubiprostone is 7-[(2R,4aR,5R,7aR)- 2-(1 ,1-difluoropentyl)-2-hydroxy-6-oxooctahydrocyclopenta[0]pyran-5- yl]heptanoic acid (Drugs of the Future, 2004, 29(4); 336-341):
- US 5,1 17,042 discloses a method of treatment for improving encephalic function which comprises administering to a subject in need of such treatment a 15-keto-prostaglandin compound in an amount effective for improvement of encephalic function.
- US 5,284,858 discloses 13,14-dihydro-15-keto prostaglandins E having remarkable preventive effects against ulcers. Further, according to US 5,284,858, 13,14-dihydro-15-ketoprostaglandins E have an advantage that they have none of the side effects which prostaglandin E intrinsically has, or can remarkably reduce such effects of the prostaglandin E. According to US 5,284,858, 13,14-dihydro-15-keto prostaglandins E are effective for animal and human use for treatment and prevention of ulcers, such as duodenal ulcer and gastric ulcer.
- US 6,414,016 provides an anti-constipation composition containing a halogenated-bi-cyclic compound as an active ingredient in a ratio of bi-cyclic/mono-cyclic structure of at least 1 :1.
- composition can be used to treat constipation without substantive side-effects, such as stomachache.
- WO2009/121228 discloses a Lubiprostone crystal, its preparation process, its pharmaceutical composition or kit, and its use for the preparation of a pharmaceutical composition for treating gastroenteropathy, especially constipation.
- the characteristic peaks of 2 ⁇ reflection angle in X-ray powder diffraction spectra of the crystal include 14.6 ⁇ 0.2°, 17.0 ⁇ 0.2° and 19.6 ⁇ 0.2°.
- the crystal has the advantages of high purity, stable property, and convenient storage and usage compared with amorphous Lubiprostone.
- the present invention relates, at least in part, to a crystalline form of Lubiprostone, namely a polymorphic form of Lubiprostone termed herein as
- APO-II and to processes for preparing APO-II.
- Illustrative embodiments of the present invention provide a crystalline form of Lubiprostone having an X-ray powder diffraction pattern comprising a peak, in terms of 2-theta, at approximately 8.98.
- Illustrative embodiments of the present invention provide a crystalline form of Lubiprostone having an X-ray powder diffraction pattern comprising a peak, in terms of 2-theta, at approximately 13.53. Illustrative embodiments of the present invention provide a crystalline form of Lubiprostone having an X-ray powder diffraction pattern comprising a peak, in terms of 2-theta, at approximately 18.06.
- Illustrative embodiments of the present invention provide a crystalline form of Lubiprostone having an X-ray powder diffraction pattern comprising a peak, in terms of 2-theta, at approximately 20.57.
- Illustrative embodiments of the present invention provide a crystalline form of Lubiprostone having an X-ray powder diffraction pattern comprising a peak, in terms of 2-theta, at approximately 20.80.
- Illustrative embodiments of the present invention provide a crystalline form of Lubiprostone having an X-ray powder diffraction pattern comprising a peak, in terms of 2-theta, at approximately 22.74.
- Illustrative embodiments of the present invention provide a crystalline form of Lubiprostone having an X-ray powder diffraction pattern comprising a peak, in terms of 2-theta, at approximately 13.53 together with any one or more peaks described herein.
- Illustrative embodiments of the present invention provide a crystalline form of Lubiprostone having an X-ray powder diffraction pattern comprising a peak, in terms of 2-theta, at approximately 18.06 together with any one or more peaks described herein
- Illustrative embodiments of the present invention provide a crystalline form of Lubiprostone having an X-ray powder diffraction pattern comprising a peak, in terms of 2-theta, at approximately 20.57 together with any one or more peaks described herein
- Illustrative embodiments of the present invention provide a crystalline form of Lubiprostone having an X-ray powder diffraction pattern comprising a peak, in terms of 2-theta, at approximately 20.80 together with any one or more peaks described herein
- Illustrative embodiments of the present invention provide a crystalline form of Lubiprostone having an X-ray powder diffraction pattern comprising a peak, in terms of 2-theta, at approximately 22.74 together with any one or more peaks described herein Illustrative embodiments of the present invention provide a crystalline form of Lubiprostone having an X-ray powder diffraction pattern substantially as shown in Figure 1.
- Illustrative embodiments of the present invention provide a crystalline form of Lubiprostone having a 1 % KBr FTIR spectrum comprising peaks, in terms of cm “1 , at approximately 3470, 2938, 1738, 1710, 1473, 1383, 1313, 1210, 1159, 979, 891 , 793, 726 and 580.
- Illustrative embodiments of the present invention provide a crystalline form of Lubiprostone having a FTIR spectrum substantially as shown in Figure 2.
- Illustrative embodiments of the present invention provide a crystalline form of Lubiprostone having a DSC thermogram comprising an endothermic peak with a peak onset temperature of approximately 76 C and a peak maximum of approximately 77 ° C.
- Illustrative embodiments of the present invention provide a crystalline form of Lubiprostone having a DSC thermogram substantially as shown in Figure 3.
- Illustrative embodiments of the present invention provide a process to prepare APO-II comprising: distilling a Lubiprostone filtrate to near dryness thereby forming a residue; dissolving the residue in a first organic solvent thereby forming a residue solution; adding a second organic solvent to the residue solution thereby forming a mixture; stirring the mixture until precipitation occurs thereby forming a precipitate; filtering the precipitate thereby isolating APO-II.
- Illustrative embodiments of the present invention provide a process to prepare APO-II comprising: dissolving Lubiprostone in a third organic solvent thereby forming a Lubiprostone solution; adding a fourth organic solvent to the Lubiprostone solution thereby forming a mixture; stirring the mixture until precipitation occurs thereby forming a precipitate; filtering the precipitate thereby isolating APO-II.
- Illustrative embodiments of the present invention provide a process to prepare APO-II comprising: dissolving Lubiprostone in a third organic solvent thereby forming a Lubiprostone solution; adding the Lubiprostone solution to a fourth organic solvent thereby forming a mixture; stirring the mixture until precipitation occurs thereby forming a precipitate; filtering the precipitate thereby isolating APO-II.
- Figure 1 is a powder X-ray diffraction (PXRD) diffractogram of APO-II.
- Figure 2 is a Fourier transform infrared (FTIR) spectrum of APO-II.
- Figure 3 is a differential scanning calorimetry (DSC) thermogram of APO-II.
- the term "substantially similar" means that the subject diffractogram, spectrum and/or data presented in a graph encompasses all diffractograms, spectra and/or data presented in graphs that vary within acceptable boundaries of experimentation that are known to a person of skill in the art. Such boundaries of experimentation will vary depending on the type of the subject diffractogram, spectrum and/or data presented in a graph, but will nevertheless be known to a person of skill in the art.
- the term “approximately” means that the peak may vary by +0.2 degrees 2 ⁇ of the subject value.
- the term “approximately” means that the peak may vary by ⁇ 5 cm “1 of the subject value.
- the term “approximately” means that the peak may vary by ⁇ 1 degree of the subject value.
- the term “peak” refers to a feature that one skilled in the art would recognize as not attributing to background noise.
- an intensity of a peak obtained may vary quite dramatically. For example, it is possible to obtain a relative peak intensity of 0.01 % when analyzing one sample of a substance, but another sample of the same substance may show a much different relative intensity for a peak at the same position. This may be due, in part, to the preferred orientation of the sample and its deviation from the ideal random sample orientation, sample preparation and the methodology applied. Such variations are known and understood by a person of skill in the art.
- the present invention comprises a crystalline form of Lubiprostone which is a polymorphic form referred to herein as APO-II.
- APO-II a polymorphic form
- An illustrative PXRD diffractogram of APO-II is given in Figure 1.
- An illustrative FTIR spectrum of APO-II is given in Figure 2.
- An illustrative DSC thermogram of APO-II is given in Figure 3.
- Illustrative relative peak intensities of APO-II are illustrated below in Table 1.
- APO-II ma be prepared according to Scheme 1.
- TIPS-CI imidazole, CH 2 CI 2 ; ii) BnBr, NaH, THF; iii) TBAF, THF; iv) oxalyl chloride, D SO, CH 2 CI 2 v) aq.
- Lubiprostone may be prepared, for instance, as illustrated in Scheme 1.
- the Lubiprostone filtrate referred to in Scheme 1 may be a starting material for use in making APO-II.
- the present invention provides a process of preparing APO-II comprising: a. distilling the Lubiprostone filtrate to near dryness thereby
- the first organic solvent used to dissolve the residue may be any organic solvent. Often the first organic solvent may be ethyl acetate, methyl fe/t-butyl ether (MTBE) and mixtures thereof.
- the volume of the first organic solvent may be about 0.5 volumes to about 5 volumes.
- the volume of the first organic solvent may be about 0.5 volumes to about 1.5 volumes.
- the second organic solvent used may be any organic solvent which exhibits anti-solvent properties with Lubiprostone. Often the second organic solvent is petroleum ether, hexanes, heptanes or mixtures thereof.
- the volume of the second organic solvent may be about 1 volumes to about 15 volumes.
- the volume of the second organic solvent may be about 3 volumes to about 10 volumes.
- the precipitation of APO-II may be performed at a temperature of about 5°C to about 40°C.
- the temperature for precipitation may be about 15°C to about 30°C. Often the temperature for precipitation is about 20°C to about 25°C.
- the present invention provides a process of preparing APO-II comprising:
- Lubiprostone mixture or alternatively adding the Lubiprostone solution and/or the filtered Lubiprostone solution to the fourth organic solvent thereby forming the Lubiprostone mixture;
- the Lubiprostone dissolved in step h may be any Lubiprostone (e.g. any polymorphic form and/or mixtures thereof).
- the third organic solvent used to dissolve the Lubiprostone may be any organic solvent. Often the third organic solvent may be ethyl acetate, MTBE and mixtures thereof. The volume of the third organic solvent may be about 0.5 volumes to about 5 volumes. The volume of the third organic solvent may be about 0.5 volumes to about 1.5 volumes.
- the fourth organic solvent used may be any organic solvent which exhibits anti-solvent properties with Lubiprostone. Often the fourth organic solvent is petroleum ether, hexanes, heptanes or mixtures thereof.
- the volume of the fourth organic solvent may be about 1 volumes to about 15 volumes.
- the volume of the fourth organic solvent may be about 3 volumes to about 10 volumes.
- the precipitation of APO-II may be performed at a temperature of about 5°C to about 40°C.
- the temperature for precipitation may be about 15°C to about 30 °C.
- the reaction temperature may be about 20°C to about 25°C.
- the amount of APO-II used in step k may be about 0.01 to about 50 w/w percent relative to the amount of Lubiprostone added in step k.
- polymorphic Form APO-II Lubiprostone may be produced.
- Powder X-Ray Diffraction Analysis The data were acquired on a PANanalytical X-Pert Pro MPD diffractometer with fixed divergence slits and an X-Celerator RTMS detector.
- the diffractometer was configured in Bragg-Brentano geometry; data was collected over a 2 theta range of 3 to 40 using CuKa radiation at a power of 40 mA and 45 kV. CuKp radiation was removed using a divergent beam nickel filter. A step size of 0.017 degrees was used. A step time of 50 seconds was used. Samples were rotated at 1 Hz to reduce preferred orientation effects. The samples were prepared by the back-loading technique.
- FTI Fourier Transform Infrared
- DSC Differential Scanning Calorimetry
- Example 1 (1 to 5 mg) were weighed into a 40 ⁇ _ aluminum pan and were crimped closed with an aluminum lid. The samples were analyzed under a flow of nitrogen (ca. 55 mL/min) at a scan rate of 10°C/minute.
- Example 1
- Lubiprostone tert- butylamine salt (20 g).
- the amine salt was suspended in ethyl acetate (6 volumes) and water (3 volumes).
- the resulting bi-phasic mixture was adjusted to about pH 5 with formic acid.
- the organic layer was separated and concentrated to obtain Lubiprostone as a syrup.
- ethyl acetate/petroleum ether (1 :9 volumes)
- a product was isolated by filtration, washed and dried under vacuum to give APO-II (>99.5% pure by HPLC, 6.18 g) as depicted in the PXRD diffractogram in Figure 1 , the FTIR spectrum in Figure 2 and the DSC thermogram in Figure 3.
- Example 2 The procedure outlined in Example 1 to obtain the concentrated Lubiprostone filtrate was followed. To the concentrated Lubiprostone filtrate (300 mg) was added ethyl acetate (1 volume). The mixture was stirred at room temperature until dissolution was achieved. To the mixture was added petroleum ether (3 volumes). The mixture was stirred at room temperature until precipitation occurred. A product was isolated by filtration, washed and dried under vacuum to give APO-II (230 mg).
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Abstract
There is provided a crystalline form of Lubiprostone, termed APO-II and methods for making APO-II. APO-II is a polymorphic form of Lubiprostone.
Description
POLYMORPHIC FORMS OF LUBIPROSTONE
TECHNICAL FIELD
The present invention relates to polymorphic forms of Lubiprostone.
BACKGROUND
Lubiprostone (1) is an E1 type prostaglandin derivative. It is marketed in USA as Amitiza® and is used for the treatment of idiopathic chronic constipation, irritable bowel syndrome and post operative ilues. The use of Lubiprostone softens the stool, increases motility, and promotes spontaneous bowel movements (SBM). Chemically, Lubiprostone is 7-[(2R,4aR,5R,7aR)- 2-(1 ,1-difluoropentyl)-2-hydroxy-6-oxooctahydrocyclopenta[0]pyran-5- yl]heptanoic acid (Drugs of the Future, 2004, 29(4); 336-341):
US 5,1 17,042 discloses a method of treatment for improving encephalic function which comprises administering to a subject in need of such treatment a 15-keto-prostaglandin compound in an amount effective for improvement of encephalic function.
US 5,284,858 discloses 13,14-dihydro-15-keto prostaglandins E having remarkable preventive effects against ulcers. Further, according to US 5,284,858, 13,14-dihydro-15-ketoprostaglandins E have an advantage that they have none of the side effects which prostaglandin E intrinsically has, or can remarkably reduce such effects of the prostaglandin E. According to US 5,284,858, 13,14-dihydro-15-keto prostaglandins E are effective for animal and human use for treatment and prevention of ulcers, such as duodenal ulcer and gastric ulcer.
US 6,414,016 provides an anti-constipation composition containing a halogenated-bi-cyclic compound as an active ingredient in a ratio of bi-cyclic/mono-cyclic structure of at least 1 :1. The halogenated-bi-cyclic
16 is represented by Formula (I):
where X1 and X2 are preferably both fluorine atoms. According to US 6,414,016, the composition can be used to treat constipation without substantive side-effects, such as stomachache.
WO2009/121228 discloses a Lubiprostone crystal, its preparation process, its pharmaceutical composition or kit, and its use for the preparation of a pharmaceutical composition for treating gastroenteropathy, especially constipation. According to WO2009/121228, the characteristic peaks of 2Θ reflection angle in X-ray powder diffraction spectra of the crystal include 14.6±0.2°, 17.0±0.2° and 19.6±0.2°. According to WO2009/121228, the crystal has the advantages of high purity, stable property, and convenient storage and usage compared with amorphous Lubiprostone.
SUMMARY
The present invention relates, at least in part, to a crystalline form of Lubiprostone, namely a polymorphic form of Lubiprostone termed herein as
APO-II and to processes for preparing APO-II.
Illustrative embodiments of the present invention provide a crystalline form of Lubiprostone having an X-ray powder diffraction pattern comprising a peak, in terms of 2-theta, at approximately 8.98.
Illustrative embodiments of the present invention provide a crystalline form of Lubiprostone having an X-ray powder diffraction pattern comprising a peak, in terms of 2-theta, at approximately 13.53.
Illustrative embodiments of the present invention provide a crystalline form of Lubiprostone having an X-ray powder diffraction pattern comprising a peak, in terms of 2-theta, at approximately 18.06.
Illustrative embodiments of the present invention provide a crystalline form of Lubiprostone having an X-ray powder diffraction pattern comprising a peak, in terms of 2-theta, at approximately 20.57.
Illustrative embodiments of the present invention provide a crystalline form of Lubiprostone having an X-ray powder diffraction pattern comprising a peak, in terms of 2-theta, at approximately 20.80.
Illustrative embodiments of the present invention provide a crystalline form of Lubiprostone having an X-ray powder diffraction pattern comprising a peak, in terms of 2-theta, at approximately 22.74.
Illustrative embodiments of the present invention provide a crystalline form of Lubiprostone having an X-ray powder diffraction pattern comprising a peak, in terms of 2-theta, at approximately 13.53 together with any one or more peaks described herein.
Illustrative embodiments of the present invention provide a crystalline form of Lubiprostone having an X-ray powder diffraction pattern comprising a peak, in terms of 2-theta, at approximately 18.06 together with any one or more peaks described herein
Illustrative embodiments of the present invention provide a crystalline form of Lubiprostone having an X-ray powder diffraction pattern comprising a peak, in terms of 2-theta, at approximately 20.57 together with any one or more peaks described herein
Illustrative embodiments of the present invention provide a crystalline form of Lubiprostone having an X-ray powder diffraction pattern comprising a peak, in terms of 2-theta, at approximately 20.80 together with any one or more peaks described herein
Illustrative embodiments of the present invention provide a crystalline form of Lubiprostone having an X-ray powder diffraction pattern comprising a peak, in terms of 2-theta, at approximately 22.74 together with any one or more peaks described herein
Illustrative embodiments of the present invention provide a crystalline form of Lubiprostone having an X-ray powder diffraction pattern substantially as shown in Figure 1.
Illustrative embodiments of the present invention provide a crystalline form of Lubiprostone having a 1 % KBr FTIR spectrum comprising peaks, in terms of cm"1, at approximately 3470, 2938, 1738, 1710, 1473, 1383, 1313, 1210, 1159, 979, 891 , 793, 726 and 580.
Illustrative embodiments of the present invention provide a crystalline form of Lubiprostone having a FTIR spectrum substantially as shown in Figure 2.
Illustrative embodiments of the present invention provide a crystalline form of Lubiprostone having a DSC thermogram comprising an endothermic peak with a peak onset temperature of approximately 76 C and a peak maximum of approximately 77°C.
Illustrative embodiments of the present invention provide a crystalline form of Lubiprostone having a DSC thermogram substantially as shown in Figure 3.
Illustrative embodiments of the present invention provide a process to prepare APO-II comprising: distilling a Lubiprostone filtrate to near dryness thereby forming a residue; dissolving the residue in a first organic solvent thereby forming a residue solution; adding a second organic solvent to the residue solution thereby forming a mixture; stirring the mixture until precipitation occurs thereby forming a precipitate; filtering the precipitate thereby isolating APO-II.
Illustrative embodiments of the present invention provide a process to prepare APO-II comprising: dissolving Lubiprostone in a third organic solvent thereby forming a Lubiprostone solution; adding a fourth organic solvent to the Lubiprostone solution thereby forming a mixture; stirring the mixture until precipitation occurs thereby forming a precipitate; filtering the precipitate thereby isolating APO-II.
Illustrative embodiments of the present invention provide a process to prepare APO-II comprising: dissolving Lubiprostone in a third organic solvent thereby forming a Lubiprostone solution; adding the Lubiprostone solution to a fourth organic solvent thereby forming a mixture; stirring the mixture until
precipitation occurs thereby forming a precipitate; filtering the precipitate thereby isolating APO-II.
Illustrative embodiments of the present invention provide a
pharmaceutical formulation comprising APO-II.
Other aspects and features of the present invention will become apparent to those ordinarily skilled in the art upon review of the following description of specific embodiments of the invention with the accompanying figures. BRIEF DESCRIPTION OF THE DRAWINGS
Drawings which illustrate embodiments of the invention are:
Figure 1 : is a powder X-ray diffraction (PXRD) diffractogram of APO-II.
Figure 2: is a Fourier transform infrared (FTIR) spectrum of APO-II.
Figure 3: is a differential scanning calorimetry (DSC) thermogram of APO-II.
DETAILED DESCRIPTION
When used in reference to a diffractogram, a spectrum and/or data presented in a graph, the term "substantially similar" means that the subject diffractogram, spectrum and/or data presented in a graph encompasses all diffractograms, spectra and/or data presented in graphs that vary within acceptable boundaries of experimentation that are known to a person of skill in the art. Such boundaries of experimentation will vary depending on the type of the subject diffractogram, spectrum and/or data presented in a graph, but will nevertheless be known to a person of skill in the art.
When used in reference to a peak in a powder X-ray diffraction (PXRD) diffractogram, the term "approximately" means that the peak may vary by +0.2 degrees 2Θ of the subject value.
When used in reference to a peak in a Fourier transform infrared (FTIR) spectrum, the term "approximately" means that the peak may vary by ±5 cm"1 of the subject value.
When used in reference to a peak in a differential scanning calorimetry (DSC) thermogram, the term "approximately" means that the peak may vary by ±1 degree of the subject value.
As used herein when referring to a diffractogram, spectrum and/or to data presented in a graph, the term "peak" refers to a feature that one skilled in the art would recognize as not attributing to background noise.
Depending on the nature of the methodology applied and the scale selected to display results obtained from an X-ray diffraction analysis, an intensity of a peak obtained may vary quite dramatically. For example, it is possible to obtain a relative peak intensity of 0.01 % when analyzing one sample of a substance, but another sample of the same substance may show a much different relative intensity for a peak at the same position. This may be due, in part, to the preferred orientation of the sample and its deviation from the ideal random sample orientation, sample preparation and the methodology applied. Such variations are known and understood by a person of skill in the art.
In an illustrative embodiment, the present invention comprises a crystalline form of Lubiprostone which is a polymorphic form referred to herein as APO-II. An illustrative PXRD diffractogram of APO-II is given in Figure 1. An illustrative FTIR spectrum of APO-II is given in Figure 2. An illustrative DSC thermogram of APO-II is given in Figure 3. Illustrative relative peak intensities of APO-II are illustrated below in Table 1.
Table 1 : Relative Peak Intensities for APO-II
2Θ Relative Peak Intensity (±10%)
8.98 100
13.53 53
17.10 12
17.63 11
18.06 27
18.13 32
20.57 11
20.80 14
20.83 14
21.88 1 1
22.74 11
According to illustrative embodiments of the present invention, APO-II ma be prepared according to Scheme 1.
i) TIPS-CI, imidazole, CH2CI2; ii) BnBr, NaH, THF; iii) TBAF, THF; iv) oxalyl chloride, D SO, CH2CI2 v) aq. Zn(OH)2, MTBE, CH2CI2; vi) DIBAL-H, CH2CI2; vii) K'OBu, THF; viii) Dess- artin periodinane, CH2CI2; ix) 10% Pd-C, H2, CH2CI2; x) purification by column chromatography (EtOAc/Hexanes); xi) t-butylamine, EtOAc, pet ether; xii) HCOOH, water, EtOAc; xiii) EtOAc, pet. ether.
SCHEME 1
Starting from commercially available lactone 2, Lubiprostone may be prepared, for instance, as illustrated in Scheme 1. The Lubiprostone filtrate referred to in Scheme 1 may be a starting material for use in making APO-II. The present invention provides a process of preparing APO-II comprising: a. distilling the Lubiprostone filtrate to near dryness thereby
forming a residue;
b. dissolving the residue in a first organic solvent thereby forming a residue solution;
c. optionally filtering the residue solution thereby forming a filtered residue solution;
d. adding a second organic solvent to the residue solution and/or the filtered residue solution thereby forming a residue mixture; e. maintaining the residue mixture until precipitation occurs thereby forming a precipitate;
f. filtering the precipitate thereby isolating APO-II; and
g. optionally drying APO-II.
The first organic solvent used to dissolve the residue may be any organic solvent. Often the first organic solvent may be ethyl acetate, methyl fe/t-butyl ether (MTBE) and mixtures thereof. The volume of the first organic solvent may be about 0.5 volumes to about 5 volumes. The volume of the first organic solvent may be about 0.5 volumes to about 1.5 volumes.
The second organic solvent used may be any organic solvent which exhibits anti-solvent properties with Lubiprostone. Often the second organic solvent is petroleum ether, hexanes, heptanes or mixtures thereof. The volume of the second organic solvent may be about 1 volumes to about 15 volumes. The volume of the second organic solvent may be about 3 volumes to about 10 volumes.
The precipitation of APO-II may be performed at a temperature of about 5°C to about 40°C. The temperature for precipitation may be about 15°C to about 30°C. Often the temperature for precipitation is about 20°C to about 25°C.
In another illustrative embodiment, the present invention provides a process of preparing APO-II comprising:
h. dissolving Lubiprostone in a third organic solvent to form a Lubiprostone solution;
i. optionally filtering the Lubiprostone solution thereby forming a filtered Lubiprostone solution;
j. adding a fourth organic solvent to the Lubiprostone solution and/or to the filtered Lubiprostone solution thereby forming a
Lubiprostone mixture; or alternatively adding the Lubiprostone solution
and/or the filtered Lubiprostone solution to the fourth organic solvent thereby forming the Lubiprostone mixture;
k. optionally adding APO-II to the Lubiprostone mixture;
I. stirring the Lubiprostone mixture until precipitation occurs thereby forming a precipitate;
m. filtering the precipitate thereby isolating APO-II; and
n. optionally drying APO-II.
The Lubiprostone dissolved in step h may be any Lubiprostone (e.g. any polymorphic form and/or mixtures thereof).
The third organic solvent used to dissolve the Lubiprostone may be any organic solvent. Often the third organic solvent may be ethyl acetate, MTBE and mixtures thereof. The volume of the third organic solvent may be about 0.5 volumes to about 5 volumes. The volume of the third organic solvent may be about 0.5 volumes to about 1.5 volumes.
The fourth organic solvent used may be any organic solvent which exhibits anti-solvent properties with Lubiprostone. Often the fourth organic solvent is petroleum ether, hexanes, heptanes or mixtures thereof. The volume of the fourth organic solvent may be about 1 volumes to about 15 volumes. The volume of the fourth organic solvent may be about 3 volumes to about 10 volumes.
The precipitation of APO-II may be performed at a temperature of about 5°C to about 40°C. The temperature for precipitation may be about 15°C to about 30 °C. Often the reaction temperature may be about 20°C to about 25°C.
The amount of APO-II used in step k may be about 0.01 to about 50 w/w percent relative to the amount of Lubiprostone added in step k.
Following the above steps a-g and/or h-n, polymorphic Form APO-II Lubiprostone may be produced.
The following examples are illustrative of some of the embodiments of the invention described herein. These examples do not limit the spirit or scope of the invention in anyway.
Examples:
Powder X-Ray Diffraction Analysis (PXRD): The data were acquired on a PANanalytical X-Pert Pro MPD diffractometer with fixed divergence slits and an X-Celerator RTMS detector. The diffractometer was configured in Bragg-Brentano geometry; data was collected over a 2 theta range of 3 to 40 using CuKa radiation at a power of 40 mA and 45 kV. CuKp radiation was removed using a divergent beam nickel filter. A step size of 0.017 degrees was used. A step time of 50 seconds was used. Samples were rotated at 1 Hz to reduce preferred orientation effects. The samples were prepared by the back-loading technique.
Fourier Transform Infrared (FTI ) Analysis: The FTIR spectrum was collected at 4 cm"1 resolution using a Perkin Elmer Paragon 1 100 single beam FTIR instrument. The samples were intimately mixed in an approximately 1 :100 ratio (w/w) with potassium bromide (KBr) using an agate mortar and pestle to a fine consistency; the mixture was compressed in a pellet die at a pressure of 4 to 6 tonnes for a period of time between 2 and 5 minutes. The resulting disk was scanned 4 times versus a collected background. Data was baseline corrected and normalized.
Differential Scanning Calorimetry (DSC) Analysis: The DSC thermograms were collected on a Mettler-Toledo 821 e instrument. Samples
(1 to 5 mg) were weighed into a 40 μΙ_ aluminum pan and were crimped closed with an aluminum lid. The samples were analyzed under a flow of nitrogen (ca. 55 mL/min) at a scan rate of 10°C/minute. Example 1 :
Preparation of APO-II:
To a suspension of compound 2
[(3af?,4S,5R,6aS)-hexahydro-5-hydroxy-4-(hydroxymethyl)-2H-cyclopenta[0]f uran-2-one] (250g, 1.45 mol) in dichloromethane (5 volumes) was added imidazole (118.6 g, 1.74 mol) followed by triisopropylsilyl chloride (TIPS-CI) (308 mL, 1.60 mol). The suspension was stirred for about 15 hours. After the consumption of the starting material, the reaction mixture was cooled to 0°C, water (2 volumes) was added and the pH adjusted to 3-4 using 1 N
hydrochloric acid. The organic layer was separated, washed with water (to pH 5-6) and brine, dried over sodium sulfate and concentrated to dryness to yield compound 3
[(3af?,4S,5R,6aS)-hexahydro-5-hydroxy-4-(triisopropylsilyloxymethyl)-2H-cycl openta[6]furan-2-one] as a clear oil in quantitative yield.
To a suspension of 60% NaH (70 g, 1.75 mol) in anhydrous tetrahydrofuran (750 mL) at 0°C was slowly added a solution of compound 3 (429 g, 1.306 mol) in tetrahydrofuran (750 mL). The mixture was then stirred at 0°C for 0.5 hour and then allowed to warm to room temperature for 1 hour. The mixture was again cooled to 0°C and benzyl bromide (273 g, 1.60 mol) and Bu4NI (107.3 g, 0.3 mol) were added sequentially. After stirring for 15 hours at room temperature, the mixture was then cooled to 0°C before quenching with saturated ammonium chloride solution (2 volumes). The organic layer was separated, washed with brine, dried over sodium sulfate and then concentrated to dryness under vacuum to yield crude product, which was further purified by column chromatography (35% ethyl acetate in heptanes) to produce compound 4
[(3aR,4S,5R,6aS)-hexahydro-4-(triisopropylsilyloxymethyl)-5-(phenylmethoxy) -2H-cyclopenta[j ]furan-2-one] in 80% yield.
To a solution of compound 4 (490 g, 1.17 mol) in tetrahydrofuran (3 volumes) at 0°C was added teAi-butylammonium fluoride (TBAF) (1 L, 1.0 mol) and the mixture was stirred for 2 hours. After completion of the reaction, the mixture was concentrated to dryness and purified by column chromatography (55% ethyl acetate in heptanes) to yield compound 5
[(3aR,4S,5R,6aS)-hexahydro-4-(hydroxymethyl)-5-(phenylmethoxy)-2H-cyclo penta[f)]furan-2-one] in quantitative yield.
To a solution of oxalyl chloride (165 mL, 1.91 mol) in dichloromethane (1.750 L) at -78°C, was added dimethylsulfoxide (DMSO) (270 mL, 3.82 mol) and the mixture was stirred for 15 minutes. A solution of compound 5 (250 g, 0.95 mol) in dichloromethane (35 mL) was then slowly added at -78°C and the
reaction mixture stirred for 0.5 hour. Triethylamine (1.2 L, 8.5 mol) was added at -78°C and the mixture stirred for 0.5 hour. After completion of the reaction, the reaction mixture was washed with water (1 L), and the organic layer was concentrated to dryness under vacuum to furnish compound 6
[(3aR,4R,5R,6aS)-hexahydro-2-oxo-5-(phenylmethoxy)-2H-cyclopenta[0]furan -4-carboxaldehyde] in 83% yield.
To a mixture of dimethyl(3,3-difluoro-2-oxoheptyl)phosphonate (210 g, 0.81 mol) in methyl i-butyl ether/water (300/10 mL) was added Zn(OH)2 (100 g, 0.81 mol) and the mixture was stirred under nitrogen for 1 hour. A solution of compound 6 (200 g, 0.77 mol) in dichloromethane (300 mL) was added and the mixture was stirred for 24 hours. After completion of the reaction, the reaction was then quenched with cold 1 hydrochloric acid (120 mL). The organic layer was separated, washed with brine, dried over sodium sulfate and concentrated to dryness under vacuum. The crude material was further purified by column chromatography (25% ethyl acetate in heptanes) to yield compound 7
[(3aR,4R,5R,6aS)-4-((E)-4,4-difluoro-3-oxo-1-octenyl)-2-oxo-5-(phenylmethox y)hexahydro-2H-cyclopenta[ib]furan] in 85% yield.
To a solution of compound 7 (250 g, 0.64 mol) in toluene (2.5 L) at -78°C was slowly added a solution of 1 M di/sobutylaluminum hydride
(DIBAL-H) in dichloromethane (16 mol) over 10 minutes. The mixture was stirred for 2 hours. After completion of the reaction, methanol (300 mL) was added, followed by saturated sodium potassium tartrate solution (3 L) and the mixture was stirred for 1 hour while allowed to warm to room temperature. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (3 L). The combined organic phase was washed with brine, dried over sodium sulfate and then concentrated to dryness under vacuum. The crude material was further purified by column chromatography (ethyl acetate / heptanes) to give compound 8
[(3aR,4R,5R,6aS)-4-((E)-4,4-difluoro-3-hydroxy-1-octenyl)-5-(phenylmethoxy) hexahydro-2H-cyclopenta[b]furan-2-ol in 80% yield.
To a suspension of (4-carboxybutyl) triphenyl phosphonium bromide (667 g, 1.52 mol) in anhydrous tetrahydrofuran (3 volumes) was added potassium ferf-butoxide (341.3 g, 3.03 mol) at 0°C and the mixture was stirred for 50 minutes before warming to room temperature. A solution of compound 8 (200 g, 0.506 mol) in tetrahydrofuran (700 mL) was added to the above mixture and the stirring continued for 3 hours. After the completion of the reaction, 1 N hydrochloric acid (2 L) was added. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (6.50 L). The combined organic phase was washed with water and brine, dried over sodium sulfate and concentrated to dryness. Compound 9
[(Z)-7-[(1R,2R,3R,5S)-2-((E)-4,4-difluoro-3-hydroxy-1-octenyl)-3-(phenylmetho xy)-5-hydroxycyclopentyl]-5-heptenoic acid was obtained by chromatographic purification (ethyl acetate / heptanes) to in 90% yield.
To a solution of compound 9 (210 g, 0.437 mol) in dichloromethane (1.2 L) was added Dess-Martin reagent (371 g, 0.874 mol) and the mixture was stirred for 2 hours. After the completion of the reaction, a saturated sodium bicarbonate solution (1.2 L) was added and the layers were separated. The organic layer was washed with brine, dried over sodium sulfate and then concentrated to dryness under vacuum. Purified compound 10
[(Z)-7-[(1 R,2R,3R)-2-((E)-4,4-difluoro-3-oxo-1-octenyl)-3-(phenylmethoxy)-5- oxocyclopentyl]-5-heptenoic acidwas obtained by chromatographic purification (ethyl acetate / heptanes) to in 75% yield.
To a solution of compound 10 (150 g) in dichloromethane (15 volumes), was added 10% palladium on carbon (35% wt) and the suspension was hydrogenated at 2 PSI for 15 hours. After the completion of the reaction, the mixture was filtered through Celite®, concentrated to near dryness and purified by column chromatography (ethyl acetate in hexanes) to give crude Lubiprostone. To a solution of crude Lubiprostone in ethyl acetate (10 vol) was added tert-butylamine (1.05 eq) at room temperature. The mixture was stirred at room temperature until precipitation of the amine salt occurred. The amine salt was isolated by filtration and dried to give Lubiprostone tert-
butylamine salt (20 g). The amine salt was suspended in ethyl acetate (6 volumes) and water (3 volumes). The resulting bi-phasic mixture was adjusted to about pH 5 with formic acid. The organic layer was separated and concentrated to obtain Lubiprostone as a syrup. Upon crystallization using ethyl acetate/petroleum ether (1 :9 volumes), the syrup produced Lubiprostone
(1 , 12 g) in approximately 70% recovery. The Lubiprostone filtrate was concentrated to near-dryness. HRMS (ESI+) [M + NH4]+ of (1): Formula: C20H36F2NO5: cal m/z: 408.25561 amu, found: 408.25626 amu .
To the concentrated Lubiprostone filtrate (10.75 g) was added ethyl acetate (2 volumes). The mixture was stirred at room temperature until dissolution was achieved. To the mixture was added hexanes (6 volumes). The mixture was stirred at room temperature for about 2 hours, stored in a freezer overnight whereupon it was stirred at -5°C for 2 hours. The solid was isolated by filtration. The solid was purified by stirring in ethyl acetate (2 volumes) and hexanes (10 volumes) at room temperature overnight. A product was isolated by filtration, washed and dried under vacuum to give APO-II (>99.5% pure by HPLC, 6.18 g) as depicted in the PXRD diffractogram in Figure 1 , the FTIR spectrum in Figure 2 and the DSC thermogram in Figure 3.
Example 2:
Preparation of APO-II:
The procedure outlined in Example 1 to obtain the concentrated Lubiprostone filtrate was followed. To the concentrated Lubiprostone filtrate (300 mg) was added ethyl acetate (1 volume). The mixture was stirred at room temperature until dissolution was achieved. To the mixture was added petroleum ether (3 volumes). The mixture was stirred at room temperature until precipitation occurred. A product was isolated by filtration, washed and dried under vacuum to give APO-II (230 mg).
Example 3:
Preparation of APO-II:
To Lubiprostone (460 mg) was added ethyl acetate (1 volume) at room temperature. The mixture was stirred until dissolution was achieved. To the
solution was added hexanes (3 volumes) and APO-II (2 mg, as obtained from the process described in examples 1 or 2) The mixture was stirred at room temperature for 2-4 hours until precipitation occurred. The product was isolated by filtration, washed and dried under vacuum to give APO-II (>99.5% pure by HPLC, 400 mg).
Example 4:
Preparation of APO-II:
To Lubiprostone (300 mg) was added ethyl acetate (1 volume) at room temperature. The mixture was stirred until dissolution was achieved. The solution was added into a mixture of hexanes (3 volumes) and APO-II (1.5 mg, as obtained from the process described in examples 1 or 2) at room temperature. The mixture was stirred for 2-4 hours until precipitation occurred. The product was isolated by filtration, washed and dried under vacuum to provide APO-II (230 mg).
Although various embodiments of the invention are disclosed herein, many adaptations and modifications may be made within the scope of the invention in accordance with the common general knowledge of those skilled in this art. Such modifications include the substitution of known equivalents for any aspect of the invention in order to achieve the same result in substantially the same way. Numeric ranges are inclusive of the numbers defining the range. Furthermore, numeric ranges are provided so that the range of values is recited in addition to the individual values within the recited range being specifically recited in the absence of the range. The word "comprising" is used herein as an open-ended term, substantially equivalent to the phrase "including, but not limited to", and the word "comprises" has a corresponding meaning. As used herein, the singular forms "a", "an" and "the" include plural references unless the context clearly dictates otherwise. Thus, for example, reference to "a thing" includes more than one such thing.
Citation of references herein is not an admission that such references are prior art to the present invention. Furthermore, material appearing in the background section of the specification is not an admission that such material is prior art to the invention. Any priority document(s) are incorporated herein
by reference as if each individual priority document were specifically and individually indicated to be incorporated by reference herein and as though fully set forth herein. The invention includes all embodiments and variations substantially as hereinbefore described and with reference to the examples and drawings.
Claims
What is claimed is:
1. APO-II polymorphic form of Lubiprostone. 2. A crystalline form of Lubiprostone having an X-ray powder diffraction pattern comprising a peak, in terms of 2-theta, at approximately 8.98.
3. A crystalline form of Lubiprostone having an X-ray powder diffraction pattern comprising a peak, in terms of 2-theta, at approximately 13.53.
4. A crystalline form of Lubiprostone having an X-ray powder diffraction pattern comprising a peak, in terms of 2-theta, at approximately 18.06.
5. A crystalline form of Lubiprostone having an X-ray powder diffraction pattern comprising a peak, in terms of 2-theta, at approximately 20.57.
6. A crystalline form of Lubiprostone having an X-ray powder diffraction pattern comprising a peak, in terms of 2-theta, at approximately 20.80. 7. A crystalline form of Lubiprostone having an X-ray powder diffraction pattern comprising a peak, in terms of 2-theta, at approximately 22.74.
8. The crystalline form of Lubiprostone of claim 2 wherein the X-ray powder diffraction pattern further comprises a peak, in terms of 2-theta, at approximately 13.53.
9. The crystalline form of Lubiprostone of claim 2 wherein the X-ray powder diffraction pattern further comprises a peak, in terms of 2-theta, at approximately 18.06.
10. The crystalline form of Lubiprostone of claim 2 wherein the X-ray powder diffraction pattern further comprises a peak, in terms of 2-theta, at approximately 20.57.
11. The crystalline form of Lubiprostone of claim 2 wherein the X-ray powder diffraction pattern further comprises a peak, in terms of 2-theta, at approximately 20.80. 2. The crystalline form of Lubiprostone of claim 2 wherein the X-ray powder diffraction pattern further comprises a peak, in terms of 2-theta, at approximately 22.74.
13. The crystalline form of Lubiprostone of claim 3 wherein the X-ray powder diffraction pattern further comprises a peak, in terms of 2-theta, at approximately
18.06.
14. The crystalline form of Lubiprostone of claim 3 wherein the X-ray powder diffraction pattern further comprises a peak, in terms of 2-theta, at approximately 20.57.
15. The crystalline form of Lubiprostone of claim 3 wherein the X-ray powder diffraction pattern further comprises a peak, in terms of 2-theta, at approximately 20.80.
16. The crystalline form of Lubiprostone of claim 3 wherein the X-ray powder diffraction pattern further comprises a peak, in terms of 2-theta, at approximately 22.74. 17. The crystalline form of Lubiprostone of claim 4 wherein the X-ray powder diffraction pattern further comprises a peak, in terms of 2-theta, at approximately 20.57.
18. The crystalline form of Lubiprostone of claim 4 wherein the X-ray powder diffraction pattern further comprises a peak, in terms of 2-theta, at approximately
20.80.
19. The crystalline form of Lubiprostone of claim 4 wherein the X-ray powder diffraction pattern further comprises a peak, in terms of 2-theta, at approximately 22.74. 20. The crystalline form of Lubiprostone of claim 5 wherein the X-ray powder diffraction pattern further comprises a peak, in terms of 2-theta, at approximately 20.80.
21. The crystalline form of Lubiprostone of claim 5 wherein the X-ray powder diffraction pattern further comprises a peak, in terms of 2-theta, at approximately
22.74.
22. The crystalline form of Lubiprostone of claim 6 wherein the X-ray powder diffraction pattern further comprises a peak, in terms of 2-theta, at approximately 22.74.
23. The crystalline form of Lubiprostone of claim 8 wherein the X-ray powder diffraction pattern further comprises a peak, in terms of 2-theta, at approximately 18.06.
24. The crystalline form of Lubiprostone of claim 8 wherein the X-ray powder diffraction pattern further comprises a peak, in terms of 2-theta, at approximately 20.57. 25. The crystalline form of Lubiprostone of claim 8 wherein the X-ray powder diffraction pattern further comprises a peak, in terms of 2-theta, at approximately 20.80.
26. The crystalline form of Lubiprostone of claim 8 wherein the X-ray powder diffraction pattern further comprises a peak, in terms of 2-theta, at approximately
22.74.
27. The crystalline form of Lubiprostone of claim 9 wherein the X-ray powder diffraction pattern further comprises a peak, in terms of 2-theta, at approximately 20.57. 28. The crystalline form of Lubiprostone of claim 9 wherein the X-ray powder diffraction pattern further comprises a peak, in terms of 2-theta, at approximately 20.80.
29. The crystalline form of Lubiprostone of claim 9 wherein the X-ray powder diffraction pattern further comprises a peak, in terms of 2-theta, at approximately
22.74.
30. The crystalline form of Lubiprostone of claim 10 wherein the X-ray powder diffraction pattern further comprises a peak, in terms of 2-theta, at approximately 20.80.
31. The crystalline form of Lubiprostone of claim 10 wherein the X-ray powder diffraction pattern further comprises a peak, in terms of 2-theta, at approximately 22.74.
32. The crystalline form of Lubiprostone of claim 11 wherein the X-ray powder diffraction pattern further comprises a peak, in terms of 2-theta, at approximately 22.74. 33. The crystalline form of Lubiprostone of claim 13 wherein the X-ray powder diffraction pattern further comprises a peak, in terms of 2-theta, at approximately 20.57.
34. The crystalline form of Lubiprostone of claim 13 wherein the X-ray powder diffraction pattern further comprises a peak, in terms of 2-theta, at approximately 20.80.
35. The crystalline form of Lubiprostone of claim 13 wherein the X-ray powder diffraction pattern further comprises a peak, in terms of 2-theta, at approximately 22.74. 36. The crystalline form of Lubiprostone of claim 14 wherein the X-ray powder diffraction pattern further comprises a peak, in terms of 2-theta, at approximately 20.80.
37. The crystalline form of Lubiprostone of claim 14 wherein the X-ray powder diffraction pattern further comprises a peak, in terms of 2-theta, at approximately 22.74.
38. The crystalline form of Lubiprostone of claim 15 wherein the X-ray powder diffraction pattern further comprises a peak, in terms of 2-theta, at approximately 22.74.
39. The crystalline form of Lubiprostone of claim 17 wherein the X-ray powder diffraction pattern further comprises a peak, in terms of 2-theta, at approximately 20.80.
40. The crystalline form of Lubiprostone of claim 17 wherein the X-ray powder diffraction pattern further comprises a peak, in terms of 2-theta, at approximately 22.74. 41. The crystalline form of Lubiprostone of claim 18 wherein the X-ray powder diffraction pattern further comprises a peak, in terms of 2-theta, at approximately 22.74.
42. The crystalline form of Lubiprostone of claim 20 wherein the X-ray powder diffraction pattern further comprises a peak, in terms of 2-theta, at approximately 22.74.
43. The crystalline form of Lubiprostone of claim 23 wherein the X-ray powder diffraction pattern further comprises a peak, in terms of 2-theta, at approximately 20.57. 44. The crystalline form of Lubiprostone of claim 23 wherein the X-ray powder diffraction pattern further comprises a peak, in terms of 2-theta, at approximately 20.80.
45. The crystalline form of Lubiprostone of claim 23 wherein the X-ray powder diffraction pattern further comprises a peak, in terms of 2-theta, at approximately 22.74.
46. The crystalline form of Lubiprostone of claim 24 wherein the X-ray powder diffraction pattern further comprises a peak, in terms of 2-theta, at approximately 20.80.
47. The crystalline form of Lubiprostone of claim 24 wherein the X-ray powder diffraction pattern further comprises a peak, in terms of 2-theta, at approximately 22.74.
48. The crystalline form of Lubiprostone of claim 25 wherein the X-ray powder diffraction pattern further comprises a peak, in terms of 2-theta, at approximately 22.74. 49. The crystalline form of Lubiprostone of claim 27 wherein the X-ray powder diffraction pattern further comprises a peak, in terms of 2-theta, at approximately 20.80.
50. The crystalline form of Lubiprostone of claim 27 wherein the X-ray powder diffraction pattern further comprises a peak, in terms of 2-theta, at approximately 22.74.
51. The crystalline form of Lubiprostone of claim 28 wherein the X-ray powder diffraction pattern further comprises a peak, in terms of 2-theta, at approximately 22.74. 52. The crystalline form of Lubiprostone of claim 30 wherein the X-ray powder diffraction pattern further comprises a peak, in terms of 2-theta, at approximately 22.74.
53. The crystalline form of Lubiprostone of claim 33 wherein the X-ray powder diffraction pattern further comprises a peak, in terms of 2-theta, at approximately 20.80.
54. The crystalline form of Lubiprostone of claim 33 wherein the X-ray powder diffraction pattern further comprises a peak, in terms of 2-theta, at approximately 22.74.
55. The crystalline form of Lubiprostone of claim 34 wherein the X-ray powder diffraction pattern further comprises a peak, in terms of 2-theta, at approximately 22.74.
56. The crystalline form of Lubiprostone of claim 36 wherein the X-ray powder diffraction pattern further comprises a peak, in terms of 2-theta, at approximately 22.74. 57. The crystalline form of Lubiprostone of claim 39 wherein the X-ray powder diffraction pattern further comprises a peak, in terms of 2-theta, at approximately 22.74.
58. The crystalline form of Lubiprostone of claim 43 wherein the X-ray powder diffraction pattern further comprises a peak, in terms of 2-theta, at approximately 20.80.
59. The crystalline form of Lubiprostone of claim 43 wherein the X-ray powder diffraction pattern further comprises a peak, in terms of 2-theta, at approximately 22.74. 60. The crystalline form of Lubiprostone of claim 44 wherein the X-ray powder diffraction pattern further comprises a peak, in terms of 2-theta, at approximately 22.74.
61. The crystalline form of Lubiprostone of claim 46 wherein the X-ray powder diffraction pattern further comprises a peak, in terms of 2-theta, at approximately 22.74.
62. The crystalline form of Lubiprostone of claim 49 wherein the X-ray powder diffraction pattern further comprises a peak, in terms of 2-theta, at approximately 22.74.
63. The crystalline form of Lubiprostone of claim 53 wherein the X-ray powder diffraction pattern further comprises a peak, in terms of 2-theta, at approximately 22.74.
64. A crystalline form of Lubiprostone having an X-ray powder diffraction pattern substantially as shown in Figure 1.
65. The crystalline form of Lubiprostone of any one of claims 1 to 64 having a 1 % KBr FTIR spectrum comprising peaks, in terms of cm"1, at approximately 3470, 2938, 1738, 1710, 1473, 1383, 1313, 1210, 1159, 979, 891 , 793, 726 and 580.
66. The crystalline form of Lubiprostone of any one of claims 1 to 64 having a FTIR spectrum substantially as shown in Figure 2.
67. The crystalline form of Lubiprostone of any one of claims 1 to 66 having a DSC thermogram comprising an endothermic peak with a peak
onset temperature of approximately 76 C and a peak maximum of approximately 77°C.
68. The crystalline form of Lubiprostone of any one of claims 1 to 66 having a DSC thermogram substantially as shown in Figure 3.
69. A process to prepare APO-II comprising:
distilling a Lubiprostone filtrate to near dryness thereby forming a residue;
dissolving the residue in a first organic solvent thereby forming a residue solution;
adding a second organic solvent to the residue solution thereby forming a mixture;
stirring the mixture until precipitation occurs thereby forming a precipitate;
filtering the precipitate thereby isolating APO-II.
70. The process of claim 69 further comprising filtering the residue solution prior to the adding.
71. The process of claim 69 or 70 further comprising drying APO-II.
72. The process of any one of claims 69 to 71 wherein the first organic solvent comprise ethyl acetate or methyl-fert-butyl-ether.
73. The process of any one of claims 69 to 72 wherein a volume of the first solvent is about 0.5 volumes to about 5 volumes.
74. The process of any one of claims 69 to 72 wherein a volume of the first solvent is about 0.5 volumes to about 1.5 volumes.
75. The process of any one of claims 69 to 74 wherein the second solvent comprises petroleum ether, hexanes or heptanes.
76. The process of any one of claims 69 or 75 wherein a volume of the second solvent is about 1 volumes to about 15 volumes.
77. The process of any one of claims 69 or 75 wherein a volume of the second solvent is about 3 volumes to about 10 volumes.
78. The process of any one of claims 69 to 77 wherein a temperature for precipitation is about 5°C to about 40°C. 79. The process of any one of claims 69 to77 wherein a temperature for precipitation is about 15°C to about 30°C.
80. The process of any one of claims 69 to 77 wherein a temperature for precipitation is about 20°C to about 25°C.
81. A process to prepare APO-II comprising:
dissolving Lubiprostone in a third organic solvent thereby forming a Lubiprostone solution;
adding a fourth organic solvent to the Lubiprostone solution thereby forming a mixture;
stirring the mixture until precipitation occurs thereby forming a precipitate;
filtering the precipitate thereby isolating APO-II. 82. A process to prepare APO-II comprising:
dissolving Lubiprostone in a third organic solvent thereby forming a Lubiprostone solution;
adding the Lubiprostone solution to a fourth organic solvent thereby forming a mixture;
stirring the mixture until precipitation occurs thereby forming a precipitate;
filtering the precipitate thereby isolating APO-II.
83. The process of claim 81 or 82 further comprising filtering the Lubiprostone solution prior to the adding.
84. The process of any one of claims 81 to 83 further comprising adding APO-II to the mixture prior to the stirring.
85. The process of any one of claims 81 to 84 further comprising drying APO-II after the isolating. 86. The process of any one of claims 81 to 85 wherein the third organic solvent comprises ethyl acetate or methyl-ferf-butyl-ether.
87. The process of any one of claims 81 to 86 wherein a volume of the third solvent is about 0.5 volumes to about 5 volumes.
88. The process of any one of claims 81 to 86 wherein a volume of the third solvent is about 0.5 volumes to about 1.5 volumes.
89. The process of any one of claims 81 to 88 wherein the fourth solvent comprises petroleum ether, hexanes or heptanes.
90. The process of any one of claims 81 to 89 wherein a volume of the fourth solvent is about 1 volumes to about 15 volumes. 91. The process of any one of claims 81 to 89 wherein a volume of the fourth solvent is about 3 volumes to about 10 volumes.
92. The process of any one of claims 81 to 91 wherein a temperature for precipitation is about 5°C to about 40°C.
93. The process of any one of claims 81 to 91 wherein a temperature for precipitation is about 15°C to about 30°C.
94. The process of any one of claims 81 to 91 wherein a temperature for precipitation is about 20°C to about 25°C.
95. A pharmaceutical formulation comprising APO-II.
Priority Applications (3)
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US13/575,680 US8785663B2 (en) | 2010-01-28 | 2011-01-28 | Polymorphic forms of Lubiprostone |
CA2788334A CA2788334A1 (en) | 2010-01-28 | 2011-01-28 | Polymorphic forms of lubiprostone |
EP11736561.9A EP2536705A4 (en) | 2010-01-28 | 2011-01-28 | Polymorphic forms of lubiprostone |
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US29917610P | 2010-01-28 | 2010-01-28 | |
US61/299,176 | 2010-01-28 |
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PCT/CA2011/000088 WO2011091513A1 (en) | 2010-01-28 | 2011-01-28 | Polymorphic forms of lubiprostone |
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US (1) | US8785663B2 (en) |
EP (1) | EP2536705A4 (en) |
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Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN104140410A (en) * | 2013-05-09 | 2014-11-12 | 江苏豪森药业股份有限公司 | Preparation method of lubiprostone |
CN104710398A (en) * | 2015-02-17 | 2015-06-17 | 齐鲁制药有限公司 | Novel crystal form of lubiprostone and preparation method of crystal form |
CN107474033A (en) * | 2016-06-07 | 2017-12-15 | 北京深蓝海生物医药科技有限公司 | A kind of method of refined Lubiprostone 1 |
US10253011B1 (en) | 2018-07-13 | 2019-04-09 | Chirogate International Inc. | Lubiprostone crystals and methods for preparing the same |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
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CN109096320B (en) * | 2017-06-21 | 2021-04-16 | 黄冈鲁班药业股份有限公司 | Method for preparing benzoyl coriolide |
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US6414016B1 (en) | 2000-09-05 | 2002-07-02 | Sucampo, A.G. | Anti-constipation composition |
WO2009121228A2 (en) | 2008-04-01 | 2009-10-08 | 上海天伟生物制药有限公司 | A lubiprostone crystal, its preparation process and its use |
WO2010083597A1 (en) | 2009-01-22 | 2010-07-29 | Apotex Pharmachem Inc. | Methods of making lubiprostone and intermediates thereof |
Family Cites Families (1)
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US8513441B2 (en) * | 2008-08-29 | 2013-08-20 | Alphora Research Inc. | Prostaglandin synthesis and intermediates for use therein |
-
2011
- 2011-01-28 WO PCT/CA2011/000088 patent/WO2011091513A1/en active Application Filing
- 2011-01-28 US US13/575,680 patent/US8785663B2/en not_active Expired - Fee Related
- 2011-01-28 CA CA2788334A patent/CA2788334A1/en not_active Abandoned
- 2011-01-28 EP EP11736561.9A patent/EP2536705A4/en not_active Withdrawn
Patent Citations (3)
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US6414016B1 (en) | 2000-09-05 | 2002-07-02 | Sucampo, A.G. | Anti-constipation composition |
WO2009121228A2 (en) | 2008-04-01 | 2009-10-08 | 上海天伟生物制药有限公司 | A lubiprostone crystal, its preparation process and its use |
WO2010083597A1 (en) | 2009-01-22 | 2010-07-29 | Apotex Pharmachem Inc. | Methods of making lubiprostone and intermediates thereof |
Non-Patent Citations (1)
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Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN104140410A (en) * | 2013-05-09 | 2014-11-12 | 江苏豪森药业股份有限公司 | Preparation method of lubiprostone |
CN104710398A (en) * | 2015-02-17 | 2015-06-17 | 齐鲁制药有限公司 | Novel crystal form of lubiprostone and preparation method of crystal form |
CN107474033A (en) * | 2016-06-07 | 2017-12-15 | 北京深蓝海生物医药科技有限公司 | A kind of method of refined Lubiprostone 1 |
US10253011B1 (en) | 2018-07-13 | 2019-04-09 | Chirogate International Inc. | Lubiprostone crystals and methods for preparing the same |
EP3594210A1 (en) | 2018-07-13 | 2020-01-15 | Chirogate International Inc. | Lubiprostone crystals and methods for preparing the same |
JP2020011956A (en) * | 2018-07-13 | 2020-01-23 | チャイロゲート インターナショナル インク.Chirogate International Inc. | Lubiprostone crystal, and process for preparing the same |
Also Published As
Publication number | Publication date |
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EP2536705A4 (en) | 2013-08-07 |
US20130096325A1 (en) | 2013-04-18 |
CA2788334A1 (en) | 2011-08-04 |
US8785663B2 (en) | 2014-07-22 |
EP2536705A1 (en) | 2012-12-26 |
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