ZA200301640B - Process for preparation of hydrates of Olanzapine and their conversion into cystalline forms of Olanzapine. - Google Patents
Process for preparation of hydrates of Olanzapine and their conversion into cystalline forms of Olanzapine. Download PDFInfo
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- ZA200301640B ZA200301640B ZA200301640A ZA200301640A ZA200301640B ZA 200301640 B ZA200301640 B ZA 200301640B ZA 200301640 A ZA200301640 A ZA 200301640A ZA 200301640 A ZA200301640 A ZA 200301640A ZA 200301640 B ZA200301640 B ZA 200301640B
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- olanzapine
- methyl
- thieno
- dichloromethane
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- KVWDHTXUZHCGIO-UHFFFAOYSA-N olanzapine Chemical compound C1CN(C)CCN1C1=NC2=CC=CC=C2NC2=C1C=C(C)S2 KVWDHTXUZHCGIO-UHFFFAOYSA-N 0.000 title claims description 91
- 229960005017 olanzapine Drugs 0.000 title claims description 84
- 238000000034 method Methods 0.000 title claims description 31
- 238000006243 chemical reaction Methods 0.000 title description 21
- 238000002360 preparation method Methods 0.000 title description 17
- 150000004677 hydrates Chemical class 0.000 title description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 99
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 33
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 28
- 239000000203 mixture Substances 0.000 claims description 21
- 238000010992 reflux Methods 0.000 claims description 18
- 238000001914 filtration Methods 0.000 claims description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 13
- 238000001035 drying Methods 0.000 claims description 12
- 239000000706 filtrate Substances 0.000 claims description 12
- 239000007787 solid Substances 0.000 claims description 12
- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical compound CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 claims description 11
- 238000001816 cooling Methods 0.000 claims description 11
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 10
- 238000003756 stirring Methods 0.000 claims description 10
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 7
- 229910052799 carbon Inorganic materials 0.000 claims description 7
- 238000005406 washing Methods 0.000 claims description 7
- ZTTWQKYKGNLCCA-UHFFFAOYSA-N 2-methyl-10H-thieno[2,3-b][1,5]benzodiazepin-4-amine Chemical compound N1C2=CC=CC=C2N=C(N)C2=C1SC(C)=C2 ZTTWQKYKGNLCCA-UHFFFAOYSA-N 0.000 claims description 6
- FDWMAKNNNPSUTL-UHFFFAOYSA-N 2-methyl-10H-thieno[2,3-b][1,5]benzodiazepin-4-amine hydrochloride Chemical compound Cl.N1C2=CC=CC=C2N=C(N)C2=C1SC(C)=C2 FDWMAKNNNPSUTL-UHFFFAOYSA-N 0.000 claims description 6
- 150000001875 compounds Chemical class 0.000 claims description 6
- FUOBHGGXKJHKDF-UHFFFAOYSA-N 2-methyl-4-(4-methylpiperazin-1-yl)-10H-thieno[2,3-b][1,5]benzodiazepine dihydrate Chemical compound O.O.C1CN(C)CCN1C1=NC2=CC=CC=C2NC2=C1C=C(C)S2 FUOBHGGXKJHKDF-UHFFFAOYSA-N 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 5
- YILNLRSTCMXJCX-UHFFFAOYSA-N 2-methyl-10h-thieno[2,3-b][1,5]benzodiazepine;hydrochloride Chemical compound Cl.C1=NC2=CC=CC=C2NC2=C1C=C(C)S2 YILNLRSTCMXJCX-UHFFFAOYSA-N 0.000 claims 2
- XBWAZCLHZCFCGK-UHFFFAOYSA-N 7-chloro-1-methyl-5-phenyl-3,4-dihydro-2h-1,4-benzodiazepin-1-ium;chloride Chemical compound [Cl-].C12=CC(Cl)=CC=C2[NH+](C)CCN=C1C1=CC=CC=C1 XBWAZCLHZCFCGK-UHFFFAOYSA-N 0.000 claims 2
- 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 claims 2
- ZVAPWJGRRUHKGP-UHFFFAOYSA-N 1h-1,5-benzodiazepine Chemical compound N1C=CC=NC2=CC=CC=C12 ZVAPWJGRRUHKGP-UHFFFAOYSA-N 0.000 claims 1
- RCMPJBBSDIVWOQ-UHFFFAOYSA-N 2-methyl-10h-thieno[2,3-b][1,5]benzodiazepine Chemical compound C1=NC2=CC=CC=C2NC2=C1C=C(C)S2 RCMPJBBSDIVWOQ-UHFFFAOYSA-N 0.000 claims 1
- DQHIXWWYDHOZKI-UHFFFAOYSA-N 2-methyl-4-(4-methylpiperazin-1-yl)-10H-thieno[2,3-b][1,5]benzodiazepine hydrate Chemical compound O.CN1CCN(CC1)C1=Nc2ccccc2Nc2sc(C)cc12 DQHIXWWYDHOZKI-UHFFFAOYSA-N 0.000 claims 1
- MFURKUWVJOJUHP-UHFFFAOYSA-N 2-methyl-4-(4-methylpiperazin-1-yl)-10H-thieno[2,3-b][1,5]benzodiazepine hydrochloride Chemical compound Cl.C1CN(C)CCN1C1=NC2=CC=CC=C2NC2=C1C=C(C)S2 MFURKUWVJOJUHP-UHFFFAOYSA-N 0.000 claims 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims 1
- 239000000843 powder Substances 0.000 claims 1
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
- IOLCXVTUBQKXJR-UHFFFAOYSA-M potassium bromide Chemical compound [K+].[Br-] IOLCXVTUBQKXJR-UHFFFAOYSA-M 0.000 description 12
- 239000000047 product Substances 0.000 description 10
- 238000000862 absorption spectrum Methods 0.000 description 6
- 238000000113 differential scanning calorimetry Methods 0.000 description 6
- 238000001757 thermogravimetry curve Methods 0.000 description 6
- 150000004683 dihydrates Chemical class 0.000 description 5
- 238000001953 recrystallisation Methods 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 238000002441 X-ray diffraction Methods 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- VMLRGLWEZFXINP-UHFFFAOYSA-N 1h-1,5-benzodiazepin-5-ium;chloride Chemical compound Cl.N1C=CC=NC2=CC=CC=C12 VMLRGLWEZFXINP-UHFFFAOYSA-N 0.000 description 1
- 208000019901 Anxiety disease Diseases 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- -1 Dihydrate B Chemical compound 0.000 description 1
- 102100028701 General vesicular transport factor p115 Human genes 0.000 description 1
- 101000767151 Homo sapiens General vesicular transport factor p115 Proteins 0.000 description 1
- 238000004566 IR spectroscopy Methods 0.000 description 1
- 208000028017 Psychotic disease Diseases 0.000 description 1
- 239000002253 acid Chemical class 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 150000004682 monohydrates Chemical class 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000000646 scanning calorimetry Methods 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
Landscapes
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Description
PROCESS FOR PREPARATION OF HYDRATES OF OLANZAPINE AND THEIR CONVERSION INTO
CRYSTALLINE FORMS OF OLANZAPINE
) The present invention relates to a method for the preparation of hydrates of 2- methyl-4-(4-methyl-1-piperazinyl)-10H-thieno [2,3-b] [1,5] benzodiazepine (hereinafter referred to as Olanzapine). The present invention also relates to a process for conversion of these hydrates into a pure crystalline form of olanzapine referred to as form-1. The present invention also relates to a method of converting Olanzapine
Form-2 to Form-1.
This invention more particularly relates to the preparation of hydrates of olanzapine and their conversion into crystalline form of Olanzapine Form-1 through recrystallization from a solvent. Olanzapine is represented by the following structure. ~ Nauk
AN
SN
Hos CH,
Olanzapine
Olanzapine is useful for treating psychotic patients and mild anxiety states.
Preparation of Olanzapine and its acid salts, having pharmaceutical properties particularly in the treatment of disorders of the central nervous system has been discussed in U.S. Patent No. 5,229,382.
U.S. Patent No. 5,229,382 does not refer to any specific polymorphic crystalline form of Olanzapine. European patent specification No. 733635A1 claims Form-2 of Olanzapine. The process under this patent describes preparation of
Form-2 from ethyl acetate. This patent also designated the product obtained ° according to the process described in U.S. Patent No. 5,229,382 as Form-1.
Furthermore, EP 733635A1 discloses the d values for Form-1 and Form-2 ’ from their X-ray Diffractograms. The values are: d value d value
Form-1 Form-2 9.94 10.26 8.55 8.57 8.24 7.47 6.88 7.12 6.37 6.14 6.24 6.07 5.58 5.48 5.30 5.21 4.98 5.12 4.83 4.98 4.72 4.76 4.62 4.71 4.53 4.47 4.46 4.33 4.29 4.22 4.23 4.14 4.08 3.98 3.82 3.72 3.74 3.56 3.69 3.53 . 25 3.58 3.38 3.50 3.25 } 3.33 3.12
1¥ 3.28 3.08 ] 3.21 3.06 ; 3.11 3.01 3.05 2.87 2.94 2.81 2.81 2.72 2.75 2.64 2.65 2.60 2.63 2.59
It is noteworthy to mention that EP 0 831 098 A2 discloses the preparation of a series of dihydrates of olanzapine namely Dihydrate B, Dihydrate D and Dihydrate E.
The d values from the X-ray Diffractograms for these forms are listed in EP 0 831 098 A2.
We conducted experiments to obtain Olanzapine Form I by recrystallization of olanzapine from acetonitrile using the process described in Example 1, sub example 4 of U.S. Patent No. 5,229,382. The process is described herein for reference: A mixture of 4-amino-2-methyl-10H-thieno-[ 2,3-b] [1,5]benzodiazepine HCI (100 g),
N-methyl piperizine (350ml), DMSO (465 ml) and toluene (465 ml) was heated to reflux. The reaction mass was maintained at reflux for 19 hours and then cooled to 50°C and water was added. The reaction mass was cooled to 0—10°C and stirred at the same temperature for 6 hours. The crude Olanzapine separated was filtered and dried in oven to a constant weight (76.5 g). The crude compound was added to acetonitrile (750 ml) at boiling temperature. The mixture was boiled for further 5 “ 25 minutes. The mixture was filtered to remove the undissolved solid. The filtrate was . treated with carbon and filtered. The filtrate was distilled to a minimum volume,
te cooled to 0-5°C and maintained at the same temperature for 1.0 hour and filtered.
The compound was dried to a constant weight in an oven (51.6g). . The polymorphic form obtained from these experiments was characterized for © its X-ray Powder Diffraction on Rigaku D / Max 2200. As clearly observed, the d values for this product (Fig. 1) matched with those of Olanzapine Form-2 claimed in
EP 733635A1. It is therefore inferred that the recrystallization of Olanzapine in acetonitrile produces Form-2 and not Form-1.
Accordingly, the present invention provides a novel method for preparation of hydrates of olanzapine, which are different from those reported in the literature.
These hydrates are named Olanzapine monohydrate-I and Olanzapine dihydrate-I for convenience.
Accordingly, the present invention also provides a novel method for preparation of Olanzapine Form-1 by recrystallization of olanzapine or its hydrates in dichloromethane.
The present invention also provides a novel method for converting Olanzapine
Form-2 to Olanzapine Form-1
According to the present invention the process for the preparation of olanzapine monohydrate-I comprises: a) refluxing a mixture of 4-amino-2-methyl-10H-thieno-[2,3-b] [1,5]benzodiazepine hydrochloride, N-methyl piperazine, dimethyl sulfoxide (DMSO) and toluene for 5 to 20 hours; b) cooling the mixture to 20 to 90°C; c) adding water; d) cooling the mixture to —5 to 25°C and stirring for 2-10 hours; " 25 e) filtering the mixture and washing with water; and } . f) drying at 30 to 50°C to a constant weight.
7 WO 02/18390 PCT/US01/07258
According to the present invention the process for the preparation of ’ olanzapine dihydrate —I comprises: . a) refluxing a mixture of 4-amino-2-methyl-10H-thieno-[2,3-b] © [1,5]benzodiazepine hydrochloride, N-methyl piperazine, dimethyl sulfoxide (DMSO) and toluene for 5 to 20 hours; b) cooling the mixture to 20 to 90°C; c) adding water; d) cooling the mixture to —5 to 25°C and stirring for 2-10 hours; e) filtering the mixture and washing with water; and f) drying at ambient temperature to a constant weight.
The preferred ratio of 4-amino-2-methyl-10H-thieno-[ 2,3-b] [1,5] - benzodiazepine HC, N-methyl piperizine, DMSO and toluene that can be used for preparation of the monohydrate and dihydrate are:
N-methyl piperizine (2.0 - 8.4 moles with respect to 1.0 mole of 4-Amino-2- methyl-10H-thieno-[ 2,3-b] [1,5]benzodiazepine HCI).
DMSO (2 - 8 times by volume with respect to 1.0 mole of 4- Amino-2-methyl- 10H-thieno-[ 2,3-b] [1,5]benzodiazepine HCI).
Toluene (3 - 8 times by volume with respect to 1.0 mole of 4- Amino-2-methyl- 10H-thieno-[ 2,3-b] [1,5]benzodiazepine HCI).
According to this invention, Olanzapine Form -I is prepared by heating to reflux a suspension of olanzapine or its hydrates in dichloromethane wherein the amount of dichloro-methane used is 4.5 to 13 volume/weight of Olanzapine to obtain a clear solution. The resultant solution is then treated with carbon followed by filtration. Upon completion of this step the filtrate is cooled to 0 to 5°C and stirred at ’ 25 the same temperature for 60-90 minutes. The separated solid was filtered and washed ) with dichloromethane. The product obtained on drying in an oven at 60-70°C to a constant weight is Form-1 of Olanzapine.
7 WO 02/18390 PCT/USO1/07258
The process described in U.S. 5,229,382 was used to prepare olanzapine crude ’ and the process described in EP 733 635 A1 was used to prepare olanzapine Form-2 for our studies. However, other methods may be used to prepare olanzapine crude "and olanzapine Form-2 and any other methods that can be used to prepare olanzapine crude and olanzapine Form 2 can be used in the processes of this invention.
The following examples are provided for purposes of illustration and are not to be construed as limiting the scope of the invention.
PREPARATION OF OLANZAPINE MONOHYDRATE-1
EXAMPLE 1
A mixture of 4-amino-2-methyl-10H-thieno-[2,3-b][1,5]benzodiazepine hydrochloride (20 Kg), N-methyl piperazine (42 lit), dimethyl sulfoxide (40 lit) and toluene (95 lit) was heated to reflux. The reaction mass was maintained at reflux for 17 hours and 15 minutes and then cooled to 40-50°C. Water (95 lit) was added slowly at 40-50°C. The reaction mass was cooled to —0.6 to 1.2°C and stirred at the same temperature for six hours. The Olanzapine crude that separated was filtered and washed with water (10 lit). The product was dried at 30.5 to 31.8°C for 10 hrs and 50 minutes. Yield: 20 Kg. A 20 gm sample from the above material after prolonged heating for an additional 72 hours gave the product with a moisture content of 5.22%.
PREPARATION OF OLANZAPINE DIHYDRATE-I
EXAMPLE 2
A mixture of 4-amino-2-methyl-10H-thieno-[2,3-b][1,5]benzodiazepine hydrochloride (200 g), N-methyl piperazine (420 ml), dimethyl sulfoxide (200 ml) and toluene (940 ml) was heated to reflux. The reaction mass was maintained at reflux for 12 hours and then cooled to 40°C. Water (940 ml) was added slowly at 40—44°C.
The reaction mass was cooled to 0—5°C and stirred at the same temperature for five hours. The Olanzapine crude that separated was filtered and washed with water (100 i WO 02/18390 PCT/US01/07258 ml). The solid obtained was dried atmospherically (25-35°C) for 24 hours (Yield : oF 241 g). . PREPARATION OF FORM-1
EXAMPLE 3
Crude 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno-[2,3-b][1,5] benzodiazepine (35.0 g) was suspended in dichloromethane (160.0 ml). The suspension was heated to reflux to obtain a clear solution. The resultant solution was then treated with carbon (3.5 g) followed by filtration. Upon completion of this step the filtrate was cooled to 0 to 5°C and stirred at the same temperature for one hour.
The separated solid was filtered and washed with chilled dichloromethane (10.0ml).
The product obtained on drying in oven at 65 to 70°C to a constant weight gave
Form-1 of Olanzapine (Yield 22.0 g).
CONVERSION OF FORM-2 TO FORM-1
EXAMPLE 4
The stirred suspension of pure form-2 of 2-methyl-4-(4-methyl-1-piperazinyl)- 10H-thieno-[2,3-b][1,5]benzodiazepine (20.0 g) in dichloromethane (90.0 ml) was heated to reflux to obtain a clear solution. The clear solution was filtered and the filtrate was then cooled to 3 to 5°C and stirred at same temperature for one hour. The crystalline solid separated was filtered and washed with dichloromethane (4.0 ml).
Subsequent drying at 60 to 70°C to a constant weight yielded Olanzapine Form-1. (Yield: 12.7 g).
PREPARATION OF FORM-1 FROM MONOHYDRATE-I OF OLANZAPINE
EXAMPLE 5
Monohydrate-I of 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno-[2,3- b][1,5] benzo- diazepine (25.0 g) prepared as per Example-1 was suspended in " dichloromethane (325.0 ml). The suspension was heated to reflux to obtain a clear solution. The resultant solution was then treated with carbon (2.5 g) followed by
X WO 02/18390 PCT/US01/07258 filtration. Upon completion of this step the filtrate was distilled to a minimum ‘ volume and then cooled to 2 to 4°C and stirred at the same temperature for 90 i minutes. The product separated was filtered and washed with chilled dichloromethane (10 ml). The product obtained on drying in oven at 60 to 70°C to a constant weight gave Form-1 of Olanzapine (Yield 16.5 g)
PREPARATION OF FORM-1 FROM DIHYDRATE-I OF OLANZAPINE
EXAMPLE 6
Dihydrate-I of 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno-[2,3-b][1,5] benzodiazepine (40.0 g) prepared as per Example-2 was suspended in dichloromethane (520.0 ml). The suspension was heated to reflux to obtain a clear solution. The resultant solution was then treated with carbon (4.0 g) followed by filtration. Upon completion of this step the filtrate was distilled to a mmimum volume and the left over reaction mass was cooled to 0 to 2°C and stirred at the same temperature for one hour. The separated solid was filtered and washed with dichloromethane (10.0ml). The product obtained on drying in oven at 65 to 70°C to a constant weight renders Form-1 of Olanzapine (Yield 26.0 g).
The aforementioned crystalline forms in examples 1 to 6 have been examined for their structural and analytical data viz., Powder X-Ray Diffraction, Differential
Scanning Calorimetry, and Infrared Absorption Spectroscopy. The results obtained are discussed and the respective drawings attached (Fig. 2 -19).
The X-Ray Diffraction Pattern set out herein for examples 1 to 6 were obtained using Rigaku D / Max-2200 X-Ray Powder Diffractometer having a copper K radiation source of wavelength A=1.54 A°. The samples were scanned between 3-45 degrees 26.
The d values for the monohydrate-1 in Example-1 are herewith enclosed (Fig.
d value I/1, ’ 10.0176 100 . 6.8995 7 6.3567 12 6.1714 11 4.8756 51 4.7262 22 4.5904 34 4.4937 7 4.4315 13 4.3414 10 4.1411 6 3.9174 9 3.8669 23 3.7857 26 3.6480 9 3.5701 15 3.4451 3 3.2500 4 3.2065 4 2.9646 5 2.8715 3 2.8572 2
The d values for the dihydrate-1 in Example-2 are herewith given (Fig. 5).
d value II, 9.9949 100 9.6887 7 7.0418 2 6.4117 2 6.2495 7 6.1205 6 5.4534 6 5.2358 2 4.8230 33 4.7162 9 4.5717 15 4.4847 6 4.3924 8 4.3080 4 4.2070 3 4.0735 3 3.9974 3 3.9242 9 3.8438 12 3.7699 9 3.7386 13 3.6837 3 3.6509 4 : 25 3.6072 5 3.5256 11 3.4242 2
3.1773 2 3.1207 2 . 2.9917 2 2.9569 3 2.8733 2 2.8483 2
The X-Ray Diffraction Pattern obtained for the products from examples 3 to 6 is identical with those reported in EP 733 635 Al.
Fig.1 is a characteristic X-ray powder diffraction pattern of Form-2 obtained on recrystallization with acetonitrile (Vertical axis: Intensity (CPS); Horizontal axis:
Two Theta (degrees)).
Fig. 2 is a characteristic X-ray powder diffraction pattern of Olanzapine monohydrate-I (Vertical axis: Intensity (CPS); Horizontal axis: Two Theta (degrees)).
Fig. 3 is a characteristic infrared absorption spectrum in potassium bromide of
Olanzapine monohydrate-1 (Vertical axis, Tramission (%); Horizontal axis: Wave number (cm™)).
Fig. 4 is a characteristic of differential scanning calorimetry thermogram of
Olanzapine monohydrate-I. (Vertical axis: mW; Horizontal axis: Temperature (°C)).
Fig. 5 is a characteristic X-ray powder diffraction pattern of Olanzapine dihydrate-I (Vertical axis: Intensity (CPS); Horizontal axis: Two Theta (degrees)).
Fig. 6 is a characteristic infrared absorption spectrum in potassium bromide of
Olanzapine dihydrate-I. (Vertical axis, Tramission (%); Horizontal axis: Wave number (cm™)).
Fig. 7 is a characteristic of differential scanning calorimetry thermogram of
Olanzapine dihydrate-1. (Vertical axis: mW; Horizontal axis: Temperature (°C)).
Fig. 8 is a characteristic X-ray powder diffraction pattern of Form-1 produced ’ by recrystallizing crude Olanzapine in dichloromethane. (Vertical axis: Intensity (CPS); Horizontal axis: Two Theta (degrees)).
Fig.9 is a characteristic infrared absorption spectrum in potassium bromide of
Form-1 produced by recrystallizing crude Olanzapine in dichloromethane. (Vertical axis, Tramission (%); Horizontal axis: Wave number (cm™)).
Fig.10 is a characteristic of differential scanning calorimetry thermogram of
Form-1 produced by recrystallizing crude Olanzapine in dichloromethane. [Vertical axis: mW; Horizontal axis: Temperature (°C))].
Fig.11 is a characteristic X-ray powder diffraction pattern of Form-I obtained on conversion of Form-2 to Form-1 Olanzapine in dichloromethane (Vertical axis:
Intensity (CPS); Horizontal axis: Two Theta (degrees)).
Fig.12 is a characteristic infrared absorption spectrum in potassium bromide of
Form-1 obtained on conversion of Form-2 to Form-1 Olanzapine in dichloromethane (Vertical axis, Tramission (%); Horizontal axis: Wave number (cm ))].
Fig.13 is a characteristic of differential scanning calorimetry thermogram of
Form-1 obtained on conversion of Form-2 to Form-1 Olanzapine in dichloromethane (Vertical axis: mW; Horizontal axis: Temperature (°C))].
Fig.14 is a characteristic X-ray powder diffraction pattern of Form-1 obtained on conversion of olanzapine monohydrate-I to Form-1 Olanzapine in dichloromethane (Vertical axis: Intensity (CPS); Horizontal axis: Two Theta (degrees)).
Fig.15 is a characteristic infrared absorption spectrum in potassium bromide of
Form-1 obtained on conversion of olanzapine monohydrate-I to Form-1 Olanzapine in ’ 25 dichloromethane (Vertical axis, Tramission (%); Horizontal axis: Wave number (cm 7).
Fig.16 is a characteristic of differential scanning calorimetry thermogram of ) Form-1 obtained on conversion of olanzapine monohydrate-I to Form-1
Olanzapine in dichloromethane. (Vertical axis: mW; Horizontal axis: ’ Temperature (°C)).
Fig.17 is a characteristic X-ray powder diffraction pattern of Form-1 obtained on conversion of olanzapine dihydrate-I to Form-1 Olanzapine in dichloromethane (Vertical axis: Intensity (CPS); Horizontal axis: Two Theta (degrees)).
Fig.18 is a characteristic infrared absorption spectrum in potassium bromide of
Form-1 obtained on conversion of olanzapine dihydrate-I to Form-1 Olanzapine in dichloromethane. ([Vertical axis, Tramission (%); Horizontal axis: Wave number (em™)]). * Fig.19 is a characteristic of differential scanning calorimetry thermogram of
Form-1 obtained on conversion of olanzapine dihydrate-I to Form-1 Olanzapine in dichloromethane. (Vertical axis: mW; Horizontal axis: Temperature (°C)).
Claims (1)
- CLAIMI. A compound which is Olanzapine monohydrate-I.2. A compound which is Olanzapine dihydrate-I.3. A compound which is Olanzapine monohydrate-I having a X-ray powder. diffraction pattern as represented by the following: d value 1/1,10.176 1006.8995 76.3567 126.1714 114.8756 514.7262 224.5905 344.4937 74.4315 134.3414 104.1411 63.9174 93.8669 233.7857 263.6480 93.5701 153.4451 33.2500 4 - 25 3.2065 42.9646 5 28715 32.8572 3: 2.6868 32.6743 3 ’ 4, A compound which is Olanzapine dihydrate-I having a X-ray powder diffraction pattern as represented by the following: : D value 1/1,9.9949 1009.6887 77.0418 26.4117 26.2495 76.1205 65.4534 65.2358 24.8230 334.7162 94.5717 15 :4.4847 64.3924 84.3080 44.2070 34.0735 33.9974 33.9242 9 ‘ 25 3.8438 123.7699 93.7386 133.6837 3’ 3.6509 43.6072 5: 3.5256 113.4242 23.1773 23.1207 22.9917 22.9569 32.8733 22.8483 22.7895 2S. A process for preparing olanzapine monohydrate-I which comprises the steps of: a) refluxing a mixture of 4-amino-2-methyl-10H-thieno-[2,3- b](1,5]benzodiazepine hydrochloride, N-methyl piperazine, dimethyl sulfoxide and toluene for 5 to 20 hours; b) cooling the mixture to 20 to 90°C; c¢) adding water; d) cooling the mixture to —5 to 25°C and stirring for 2-10 hours; e) filtering the mixture and washing with water; and f) drying at 30 to 50°C to a constant weight.6. The process according to claim 5, wherein the amounts of 4-amino-2- methyl-10H-thieno-[2,3-b][1,5]benzodiazepine hydrochloride and N-methyl piperzine are in the ratio of 1:2.0-8.4.) 7. The process according to claim 5, wherein the volume of dimethyl sulfoxide is 2-8 times the number of moles of 4-amino-2-methyl-10H-thieno-[2,3- Co b]{1,5]benzodiazepine hydrochloride.8. The process according to claim 5, wherein the volume of toluene is 3-8 times the number of moles of 4-amino-2-methyl-10H-thieno-[2,3-b][1,5] benzodiazepine hydrochoride and dimethyl sulfoxide.9. A process for preparing olanzapine dihydrate —I which comprises the steps of: a) refluxing a mixture of 4-amino-2-methyl-10H-thieno-{2,3-b][1,5] benzodiazepine hydrochloride, N-methyl piperazine, dimethyl sulfoxide and toluene for 5 to 20 hours; b) cooling the mixture to 20 to 90°C; c) adding water; d) cooling the mixture to —5 to 25°C and stirring for 2-10 hours; e) filtering the mixture and washing with water; and drying at ambient temperature to a constant weight.10. The process according to claim 9, wherein the amounts of 4-amino-2- methyl-10H-thieno-{2,3-b][1,5-benzodiazepine hydrochloride and N-methyl piperzine are in the ratio of 1:2.0-8.4.11. The process according to claim 9, wherein the volume of dimethyl sulfoxide is 2-8 times the number of moles of 4-amino-2-methyl-10H-thieno-[2,3-b[1,5] benzodiazepine hydrochloride.12. The process according to claim 9, wherein the volume of toluene is 3-8 times the number of moles of 4-amino-2-methyi-10H-thieno-{2,3-b][1,5] benzodiazepine hydrochloride.13. A process for preparing Olanzapine Form-1 from Olanzapine dihydrate-I i 25 which comprises the steps of: ) a) stirring 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno-[2,3-b][ 1,5]benzodiazepine (olanzapine monohydrate —I) in dichloromethane at reflux to obtain a : clear solution; b) treating the solution with carbon; c) filtering the solution to obtain a filtrate; d) cooling the filtrate to 0 to 5° C e) stirring for 60-90 minutes; f) filtering to obtain a solid, washing and drying at 60° to 70°C to a constant weight.14. The process according to claim 13, wherein in step f) the solid is washed with dichloromethane.15. The process according to claim 13, wherein the amount of dichloromethane used in step a) is 4.5 to 13 volume/weight of 2-methyl-10H-thieno[2,3-b][ 1,5] benzodiazepine hydrochloride.16. A process for preparing olanzapine Form-1 from olanzapine monohydrate-I which comprises the steps of: a) stirring 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno-[2,3- b][1,5]benzodiazepine in dichloromethane at reflux to obtain a clear solution; b) treating the solution with carbon; ¢) filtering the solution to obtain a filtrate; d) cooling the filtrate to below 0 to 5°C; and e) stirring for 60-90 minutes, f) separating the solid, washing and drying at 60° to 70°C. to a constant weight.17. The process according to claim 16, wherein the amount of . 25 dichloromethane used is 4.5 to 13 volume/weight of 2-methyl-4-(4-methyl-1- piperazinyl)-10H-thieno-[2,3-b][1,5]benzodiazepine hydrochloride.18. The process according to claim 16, wherein is step f) the solid is washed with ) dichloromethane.19. A process for preparing Olanzapine Form-I from Olanzapine Form-2 which comprises the steps of: a) stirring 2-methyl-10H-thieno-[2,3-b][1,5]benzodiazepine hydrochloride (olazapine Form-2) in dichloromethane at reflux to obtain a clear solution; b) filtering and cooling the filtrate to 0 to 5°C; c) stirring for 60-90 minutes; and d) filtering to obtain a solid, washing and drying at 60-70°C to a constant weight.20. The process according to claim 19, wherein the amount of dichloromethane used is 4.5 to 13 volume/weight of 2-methyl-10H-thieno-{2,3-b][1,5]benzodiazepine hydrochloride.21. The process according to claim 19, wherein in step d) the solid 1s washed with dichloromethane.
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