Title of Invention

CRYSTALLINE FORM I OF 2-METHYL-4-(4-METHYL-1-PIPERAZINYL)-10H-THIENO[2,3-B][1,5]BENZODIAZEPINE

Abstract Crystalline Form I of 2-methyl-4-(4-methyl-l-piperazinyl)-10H-thieno[2,3-b][l,5]benzodiazepine characterised by x-ray powder diffraction peaks at approximately 9.94, 8.53, 8.19, 6.86, 6.35, 5.47, 4.83, 4.71, 4.53, 4.22, 4.08, 3.82, 3.75, 3.69, 3.50, 3.34, 3.11, 2.94, 2.82, 2.76, 2.59, 2.34, 2.03, 1.92 d (interplanar spacing) values; infrared absorbance bands at approximately 1456, 1365, 905, 757, 662 & 604 cm"1 and having stable colour at ambient conditions of storage; and the process of its preparation comprising at least two repetitive steps of crystallization from one or more organic solvent by dissolving 2-methyl-4-(4-methyl-l-piperazinyl)-10H-thieno[2,3-b][l,5]benzodiazepine in said solvent and allowing crystallization to occur; wherein in at least one step the solution is purified by treating with a solid adsorbent material and filtering; and wherein in the last step the crystalline material is subjected to drying. To The Controller of Patents, The Patent Office, Mumbai-400 013
Full Text FORM 2
THE PATENTS ACT, 1970 (39 OF 1970)
COMPLETE SPECIFICATION
(See section 10)

CRYSTALLINE FORM I OF 2-METHYL-4-(4-METHYL-l-PIPERAZINYL)-10H-THIENO[2,3-b][l,5]BENZODIAZEPINE
SUN PHARMACEUTICAL INDUSTRIES LTD.
A company incorporated under the laws of India having their office at ACME PLAZA, ANDHERI-KURLA ROAD, ANDHERI (E), MUMBAI-400059.
MAHARASHTRA, INDIA


o#


The following specification particularly describes and ascertains the nature of this invention and the manner in which it is to be performed.

CRYSTALLINE FORM I OF 2-METHYL-4-(4-METHYL-l-Pff ERAZINYL) 10H THIENO [2,3-b][l,5]BENZODIAZEPINE
This invention relates to crystalline Form I of 2-methyl-4-(4-methyl-l-piperazinyl)-10H-thieno[2,3-b][l,5]benzodiazepine, a compound of formula 1, having a stable colour at ambient conditions of storage and also to the process of its preparation. 2-methyl-4-(4-methyl-l-piperazinyl)-10H-thieno[2,3-b][l,5]benzodiazepine, commonly known as olanzapine (INN Name) is used as an antipsychotic agent.
CH3

Formula 1
PRIOR ART:
United States Patent No. 5,229,382 (hereinafter described as '382) discloses the
preparation of 2-methyl-4-(4-methyl-1 -piperazinyl)-10H-thieno[2,3-
b][l,5]benzodiazepine, or an acid addition salt thereof by reacting N-methyl piperazine with 4-amino-2-methyl-10H-thieno[2,3-b][l,5] benzodiazepine hydrochloride. The anhydrous 2-methyl-4-(4-methyl-l-piperazinyl)-10H-thieno[2,3-b][l,5]benzodiazepine obtained by the process of this patent is referred to herein as Form I. Form I has been reported to be metastable and to change its colour on standing thus being unsuitable for commercial use in pharmaceutical formulation.
2

United States Patent No. 5,736,541 (hereinafter described as '541) claims a novel crystal form (Form II) of olanzapine which is substantially pure, solvate free, anhydrous and pharmaceutically elegant. This novel crystal form is free from Form I and contamination by solvates such as water or acetonitrile and has satisfactory colour stability. The '541 patent provides olanzapine Form II having a typical x-ray powder diffraction pattern as represented by the d (interplanar spacing) values: 10.2689, 8.577, 7.4721, 7.125, 6.1459, 6.071, 5.4849, 5.2181, 5.1251, 4.9874, 4.7665, 4.7158, 4.4787, 4.3307, 4.2294, 4.141, 3.9873, 3.7206, 3.5645, 3.5366, 3.3828, 3.2516, 3.134, 3.0848, 3.0638, 3.0111, 2.8739, 2.8102, 2.7217, 2.6432, 2.6007.
Further, this patent designates the polymorph obtained by the process disclosed in '382 patent as Form I having a typical x-ray powder diffraction pattern as represented by the d (interplanar spacing) values : 9.9463, 8.5579, 8.2445, 6.8862, 6.3787, 6.2439, 5.5895, 5.3055, 4.9815, 4.8333, 4.7255, 4.6286, 4.533, 4.4624, 4.2915, 4.2346, 4.0855, 3.8254, 3.7489, 3.6983, 3.5817, 3.5064, 3.3392, 3.2806, 3.2138, 3.1118, 3.0507, 2.948, 2.8172, 2.7589, 2.6597, 2.6336, 2.5956.
The nomenclature referred to in this patent for crystalline forms of 2-methyl-4-(4-methyl-l-piperazinyl)-10H-thieno[2,3-b][l,5]benzodiazepine is adopted herein.
The process disclosed in the '541 patent consists of obtaining technical grade olanzapine (that is olanzapine containing less than about 5% undesired related substances and preferably less than 1% undesired related substances) by adding water to a methanolic reaction mixture and filtering the solids. The technical grade olanzapine obtained is crystallized from anhydrous ethyl acetate as substantially pure Form II that is free from the undesired crystal Form I or solvates such as water, alcohol, ethylacetate or acetonitrile.
United States Patent No. 5,703,232 (hereinafter described as *232) relates to lower alcohol solvates of olanzapine and a process for using such lower alcohol solvates to prepare anhydrous olanzapine crystalline form having a typical x-ray diffraction


pattern with d (interplanar spacing) values substantially as follows 10.2689, 8.577, 7.4721, 7.125, 6.1459, 6.071, 5.4849, 5.2181, 5.1251, 4.9874, 4.7665, 4.7158, 4.4787, 4.3307, 4.2294, 4.141, 3.0873, 3.7206, 3.5645, 3.5366, 3.3828, 3.2516, 3.134, 3.0848, 3.0638, 3.0111, 2.8739, 2.8102, 2.7217, 2.6432, 2.6007. The patent labels this crystalline form as Form I and reverses the nomenclature adopted in the '541 patent. As compared to the '541 process where a technical grade olanzapine is precipitated by addition of excess water to a methanolic reaction mixture, the '232 process involves addition of a C1-C3 alcohol and isolating an alkanol solvate by cooling. The anhydrous crystalline form of olanzapine is prepared by recrystallizing the alkanol solvate from an appropriate solvent. The patent does not disclose anhydrous olanzapine crystalline form having a typical x-ray powder diffraction pattern as represented by d (interplanar spacing) values 9.9446, 8.5272, 8.1949, 6.8637, 6.3510, 5.4653, 4.8278, 4.7121, 4.5295, 4.2239, 4.0788, 3.8230, 3.7525, 3.6909, 3.4995, 3.3393, 3.1051, 2.9451, 2.8182, 2.7589, 2.5925, 2.3369, 2.0251, 1.9183 having a stable colour upon storage under ambient conditions or a process for its preparation using two or more repetitive crystallization steps.
The above patents do not disclose anhydrous olanzapine crystalline form I having a stable colour upon storage under ambient conditions or a process for its preparation using two or more repetitive crystallization steps.
WO 9812199 relates to the dihydrate of olanzapine. Dihydrates B, D and E are claimed as intermediates for preparing Form II. The dihydrates are dried for a period of about 27-30 hours to yield olanzapine Form II.
Prior art suggests that Form I olanzapine is pharmaceutically unsuitable because its colour changes upon storage and exposure to air. Methods like charcoal treatment to remove undesired colour from the Form I olanzapine prepared by '382 were not successful. Anhydrous olanzapine crystalline Form I having a stable colour upon storage at ambient conditions is hitherto unknown.
4

OBJECTIVE OF THE INVENTION:
The objective of the present invention is to provide crystalline Form I of 2-methyl-4-(4-methyl-l-piperazinyl)-10H-thieno[2,3-b][l,5]benzodiazepine and the process for preparation of Form I having a stable colour at ambient conditions of storage. The stable form obtained from the present invention is free from the solvent of crystallization and has desirable characteristics such as stable colour and stable crystalline form making it suitable for pharmaceutical formulation.
SUMMARY OF INVENTION :
The present invention provides crystalline Form I of 2-methyl-4-(4-methyl-l-
piperazinyl)-10H-thieno[2,3-b][l,5]benzodiazepine having a typical x-ray powder
diffraction pattern as represented by d (interplanar spacing) values 9.9446, 8.5272,
8.1949, 6.8637, 6.3510, 5.4653, 4.8278, 4.7121, 4.5295, 4.2239, 4.0788, 3.8230,
3.7525, 3.6909, 3.4995, 3.3393, 3.1051, 2.9451, 2.8182, 2.7589, 2.5925, 2.3369,
2.0251, 1.9183 and having stable colour at ambient conditions of storage. The present
invention also provides a process for preparation of the crystalline Form I comprising
at least two repetitive steps of crystallization from one or more organic solvent by
dissolving 2-methyl-4-(4-methyl-1 -piperazinyl)-10H-thieno[2,3-
b][l,5]benzodiazepine in said organic solvent and allowing crystallization to occur; wherein in at least one step the solution is purified by treating with a solid adsorbent material and filtering; and wherein in the last step the crystalline material is subjected to drying.
DETAILED DESCRIPTION OF THE INVENTION:
The crystalline Form I of 2-methyl-4-(4-methyl-l-piperazinyl)-10H-thieno[2,3-b][l,5]benzodiazepine of the present invention has a typical x-ray powder diffraction pattern as represented by d (interplanar spacing) values 9.9446, 8.5272, 8.1949,
5

6.8637, 6.3510, 5.4653, 4.8278, 4.7121, 4.5295, 4.2239, 4.0788, 3.8230, 3.7525, 3.6909, 3.4995, 3.3393, 3.1051, 2.9451, 2.8182, 2.7589, 2.5925, 2.3369, 2.0251, 1.9183 and a stable colour. The crystalline Form I of the present invention shows no change in colour, infrared spectrum and x-ray diffractogram at ambient conditions of storage such as about 15°C to 35°C and about 40% to 90% RH. The crystalline Form I of the present invention is stable even under accelerated conditions of storage, for example, no changes in colour, infra-red spectrum and x-ray diffractogram are observed upon storage at accelerated conditions for one month at 40°C and 75% relative humidity or for 25 days at 75-80°C.
The crystalline Form I of the present invention is prepared by a process comprising at
least two repetitive steps of crystallization from one or more organic solvent by
dissolving 2-methyl-4-(4-methyl-1 -piperazinyl)-10H-thieno[2,3-
b][l,5]benzodiazepine in said organic solvent and allowing crystallization to occur; wherein in at least one step the solution is purified by treating with a solid adsorbent material and filtering; and wherein in the last step the crystalline material is subjected to drying.
According to the present invention a solution of 2-methyl-4-(4-methyl-l-piperazinyl)-10H-thieno[2,3-b][l,5]benzodiazepine in the organic solvent is prepared by stirring or heating one gram of 2-methyl-4-(4-methyl-l-piperazinyl)-10H-thieno[2,3-b][l,5]benzodiazepine in 5 to 25 parts by volume of the solvent, more preferably 10 to 20 parts by volume, the most preferred being 15 parts by volume. The solution is allowed to stand for crystallization to occur. Preferably the solution is cooled to aid crystallization.
According to an embodiment of the present invention the dissolution of 2-methyl-4-(4-methyl-l-piperazinyl)-10H-thieno[2,3-b][l,5]benzodiazepine may be achieved by heating the organic solvent containing 2-methyl-4-(4-methyl-l -piperazinyl)- 10H-thieno[2,3-b][l,5]benzodiazepine. Preferably the organic solvent is heated to a temperature greater than about 40°C, most preferably to reflux temperature.
6

According to one embodiment of the present invention the organic solvent is selected from the group consisting of aliphatic, cyclic or aromatic hydrocarbons, alkanols, esters, ketones, ethers, nitriles, amides, sulfoxides and the like.
In a preferred embodiment of the present invention solvent is an alkanol selected from Ci to C4 alkanol or its admixture with water. More preferably the alkanol is ethanol.
In a particularly preferred embodiment of the present invention, the process comprises crystallization in two steps wherein in the first step the organic solvent used is a mixture of ethanol and water and in the second step the solvent is absolute ethanol. According to the present invention the mixture of ethanol and water used maybe in a ratio of 97:3 to 90:10 preferably 95:5 to 92:8 and the most preferred is 95:5 parts by volume. In this particular embodiment, the technical grade 2-methyl-4-(4-methyl-l-piperazinyl)-10H-thieno[2,3-b][l,5]benzodiazepine is dissolved in aqueous ethanol 90-97%, preferably 93-95% at a temperature of 40-80°C, preferably 77-78°C to obtain a clear solution. The clear solution is treated with the solid adsorbent material at 40-80°C, preferably at reflux temperature, filtered and the filtrate cooled to 60-65°C, preferably 8-10°C to obtain crystals of 2-methyl-4-(4-methyl-l-piperazinyl)-10H-thieno[2,3-b][l,5]benzodiazepine. In the second step, these crystals are dissolved in absolute ethanol at a temperature of 40-80°C, preferably 77-78°C to obtain a clear solution. The solution is then cooled, either rapidly to induce sudden crystallization or by a gradual cooling process with or without seeding of Form I crystals, in order to induce crystallization. The crystals are filtered containing 10 to 30% solvent hereinafter referred to wet crystals which may be subjected to drying.
According to one embodiment of the present invention the solid adsorbent material may be selected from neutral or alkaline alumina, silica, fuller's earth, activated charcoal and the like, the most preferred being activated charcoal.
7

The last or final crystallization step of the process of the present invention may be carried out with or without the presence of seed crystals.
According to one embodiment of the present invention crystallization is allowed to occur by chilling or seeding or scratching the glass of the reaction vessel or cooling and other such common techniques, preferably cooling and/or seeding.
According to the preferred embodiment of the present invention crystallization is allowed to occur by cooling the solution of 2-methyl-4-(4-methyl-l-piperazinyl)-10H-thieno[2,3-b][l,5]benzodiazepine in an organic solvent which may be seeded with a crystal of Form I of 2-methyl-4-(4-methyl-l-piperazinyl)-10H-thieno[2,3-b][l,5]benzodiazepine. The seeding with Form I crystals is done, prior to a stage, wherein the initial crystallization is just about to commence i.e. at a temperature of about 35-70°C, preferably about 55 - 70°C.
According to another embodiment of the present invention in the last or final crystallization step the solution may be cooled in an ice bath or under refrigeration or by adding liquid nitrogen to the solution. The solution may be preferably cooled to below room temperature, preferably to about 8-10°C to allow crystallization to occur. The solution may be allowed to cool for a sufficient time for crystallization to occur, for example period of 15 minutes to 8 hours. More preferably the cooling operation is performed such that the reflux temperature is brought to about 55-60°C during a period of 1 hour to 3 hours, followed by cooling to about 30-35°C during a period of 1 hour to 3 hours and then finally to 8-10°C during a period of 1 hour to 3 hours.
According to the present invention at the end of the first or any intermediate crystallization step, other than the final crystallization step, wet crystals of of 2-methyl-4-(4-methyl-l-piperazinyl)-10H-thieno[2,3-b][ 1,5]benzodiazepine are obtained. These wet crystals upon isolation may contain 10-30%w/v of the solvent.


The wet crystals may be used as such in the next or final crystallization step or they could be dried at a temperature below 50°C, under atmospheric conditions.
According to the present invention in the last or final crystallization step the product may be dried using different techniques of drying like fluid bed drying, tray drying and rotatory drying techniques with or without application of vacuum and / or under inert conditions. Dryers that have rotational means at reduced pressures are preferred. Examples of rotatory drying techniques that may be suitable include rota-cone and horizontal rotary vacuum dryers.
According to an embodiment of the present invention in the last or final crystallization step the product is dried at a temperature of about 25 to 55 C, preferably about 30 to 50°C the most preferred is about 45 to 50°C.
9

EXAMPLES
The invention is further illustrated but not restricted by the description in the following examples.
Example 1 Preparation of wet crystals of 2 - Methyl - 4 - (4 - methyl -1 - piperazinyl) -10H -thieno [2,3-b] [1,51 benzodiazepine from Technical 2 - Methyl - 4 - ( 4 - methyl - 1 — piperazinyl) -10H- thieno [2,3-b] [1.5] benzodiazepine :
Charge 1.8 L of aqueous alcohol (95%) into a 2 L three-necked round bottom flask at 30 j_2°C. Add 100 g of technical 2-methyl-4-(4-methyl-l-piperazinyl)-10H-thieno[2,3-b][l,5]benzodiazepine to the flask and start stirring. Gradually heat the contents of flask to 77-78°C so as to obtain a clear solution. Stir the contents fori 5 mins at 77-78°C. Add 2 g of charcoal at 77-78°C and stir the contents of flask for 30 mins. Filter the contents of the flask at 77-78°C on a hyflo bed through a buchner funnel. Collect the filtrate and charge into a clean and dry 2 L three-necked round bottom flask. Allow the contents of flask to cool to 28 +_2°C, then cool it further to 10°C using ice water bath and stir for 30 mins at 8-10°C. Filter the solid product and wash the product cake with chilled aqueous alcohol (95%) and suck dry to obtain 85 g (yield: 85% w/w) of wet crystals of 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][l,5]benzodiazepine.
Example 2
Preparation of Form-I of 2 - Methyl - 4 - ( 4 - methyl - 1 -piperazinyl) -10H -thieno [2,3-bl [1,51 benzodiazepine from wet crystals 2 - Methyl -4 - ( 4 - methyl - 1 - piperazinyl) -10H- thieno [2,3-b] [1,5] benzodiazepine : Method-1
85 g of wet crystals of 2-methyl-4-(4-methyl-l -piperazinyl)-10H-thieno[2,3-b][l,5]benzodiazepine along with 1.275 L of absolute ethanol is charged into 2 L
10

three-necked round bottom flask and stirred at 30 ±_20 C. The contents of the flask are gradually heated to 77-78°C to obtain a clear solution and then stirred for 15 mins at 77-78°C. The contents of the flask are allowed to cool to 55-57°C. The contents of the flask are further cooled to 30-34°C and then to 10°C. Stir the contents for 30 mins at 8-10°C. Filter the solid product and wash the product cake with chilled absolute alcohol and suck dry. Dry the product under vacuum at 47-50°C on a rotavapour until constant weight to obtain 56g of Form I. (yield 65.9%)
No change in colour, Infrared spectrum (KBr) and X-ray diffractogram was observed when the product was stored at ambient conditions of storage viz. room temperature for one month and at accelerated conditions of storage like (a) 40°C and 75% relative humidity for one month and (b) 75-80°C for 25 days.
Example 3 Method-2
50 g of wet crystals of 2-methyl-4-(4-methyl-l-piperazinyl)-10H-thieno[2,3-b][l,5]benzodiazepine along with 0.75 L of absolute ethanol is charged into 2 L three-necked round bottom flask and stirred at 30 +2°C. The contents of the flask are gradually heated to 77-78°C to obtain a clear solution and then stirred for 15 mins at 77-78°C. Remove the oil bath and gradually allow the flask to cool to 55-57°C.During the process of cooling to 55-57°C seed the solution with 2-methyl-4-(4-methyl-l-piperazinyl)-10H-thieno[2,3-b][l,5]benzodiazepine Form I at an interval of every 5°C until the seed remains undissolved. The contents of the flask are further cooled to 30-34°C and then to 10°C. Stir the contents for 30 mins at 8-10°C. Filter the solid product and wash the product cake with chilled absolute alcohol and suck dry. Dry the product under vacuum at 47-50°C on a rotavapour until constant weight to obtain 33g (yield 66% w/w) of Form I.


Example 4
Method-3
20 g of wet crystals of 2-methyl-4-(4-methyl-l-piperazinyl)-10H-thieno[2,3-b][l,5]benzodiazepine along with 0.3 L of absolute ethanol is charged into 2 L three-necked round bottom flask and stirred at 30 ±_2°C The contents of the flask are gradually heated to 77-78°C to obtain a clear solution and then stirred for 15 mins at 77-78°C. Remove the oil bath and cool it rapidly by pouring 1.0 L of liquid nitrogen so as to rapidly cool it to 10°C over a period of 5-10 minutes. Stir the contents of the flask for 15 mins at 8-10°C. Filter the solid product and wash the product cake with chilled absolute alcohol and suck dry. Dry the product under vacuum at 47-50°C on a rotavapour until constant weight to obtain 14.12g (yield 70.6% w/w) of Form I.
Example 5
50 g of wet crystals of 2-methyl-4-(4-methyl-l-piperazinyl)-10H-thieno[2,3-b][l,5]benzodiazepine is dried at 45-50°C to obtain crude of 2-methyl-4-(4-methyl-l-piperazinyl)-l 0H-thieno[2,3-b] [ 1,5]benzodiazepine.
Example 6
The crystal form of 2-methyl-4-(4-methyl-l-piperazinyl)-10H-thieno[2,3-b][ 1,5]benzodiazepine prepared as per Examples 1, 2 and 3 was subjected to powder x-ray diffraction analysis using copper x-ray source at 1.541 X.
Dated this 24th day of December, 2001.


\^VJL^i

DILIP SHANGHVI CHAIRMAN AND MANAGING DIRECTOR SUN PHARMACEUTICAL INDUSTRIES LIMITED


We claim :
1. A crystalline Form I,


s4 CH3

Formula 1
of 2-methyl-4-(4-methyl-1 -piperazinyl)-10H-thieno[2,3-b] [ 1,5]benzodiazepine, a compound of formula 1, having stable colour upon storage at ambient conditions.
2. Crystalline Form I of 2-methyl-4-(4-methyl-l-piperazinyl)- 10H-thieno[2,3-b][l,5]benzodiazepine characterised by x-ray powder diffraction peaks at approximately 9.94, 8.53, 8.19, 6.86, 6.35, 5.47, 4.83, 4.71, 4.53, 4.22, 4.08, 3.82, 3.75, 3.69, 3.50, 3.34, 3.11, 2.94, 2.82, 2.76, 2.59, 2.34, 2.03, 1.92 d (interplanar spacing) values and having stable colour upon storage at ambient conditions.
3. Crystalline Form I of 2-methyl-4-(4-methyl-l-piperazinyl)-10H-thieno[2,3-b][l,5]benzodiazepine characterized by infrared absorbance bands at approximately 1456, 1365, 905, 757, 662 and 604 cm"1 and having stable colour upon storage at ambient conditions.

4. Crystalline Form I of 2-methyl-4-(4-methyl-l-piperazinyl)- 10H-thieno[2,3-b][l,5]benzodiazepine having stable colour upon storage at ambient conditions prepared by a process comprising at least two repetitive steps of crystallization from one or more organic solvent, wherein 2-methyl-4-(4-methyl-l-piperazinyl)-10H-thieno[2,3-b][l,5]benzodiazepine is dissolved in said organic solvent and crystallization is allowed to occur; and further wherein in at least one step the solution is purified by treating with a solid adsorbent material and filtering; and in the last step the crystalline material is subjected to drying.
5. Crystalline Form I as claimed in claim 4 wherein the organic solvent is selected from a C1 to C4 alkanol; optionally admix with water wherein the Ci to C4 alkanol to water ratio is 95 to 5 parts by volume.
6. Crystalline Form I as claimed in claim 5 wherein the Ci to C4 alkanol is ethanol.


7. Crystalline Form I as claimed in claim 4 wherein the dissolution is carried out by heating to a temperature greater than about 40°C.
8. Crystalline Form I as claimed in claim 7 wherein it is heated to reflux temperature.
9. Crystalline Form I as claimed in claim 4 wherein crystallization is allowed to occur by cooling and/or seeding.

10. Crystalline Form I as claimed in claim 9 wherein seed crystals of Form I of 2-methyl-4-(4-methyl-l-piperazinyl)-10H-thieno[2,3-b][l,5]benzodiazepine are added during cooling.
11. Crystalline Form I as claimed in claim 10 wherein seed crystals are added during cooling to a temperature of about 35-70°C.
12.Crystalline Form I as claimed in claim 11 wherein seed crystals are added during cooling to a temperature of about 55-70°C.
13. Crystalline Form I as claimed in claim 9 wherein the solution is cooled to about 8-10°C.
14. Crystalline Form I as claimed in claim 4 wherein the solid adsorbent material is selected from alumina, silica, fuller's earth and activated charcoal.
15. Crystalline Form I as claimed in claim 4 wherein the process comprises two recrystallization steps wherein in the first step the organic solvent used is a mixture of ethanol and water and in the second step the solvent used is absolute ethanol.
16. Crystalline Form I as claimed in claim 4 wherein drying is carried out at 25-55°C with or without vacuum and/or under inert conditions.
17. Crystalline Form I as claimed in claim 16 wherein drying is carried out in a rotary vacuum dryer at about 45-50°C.
18. A pharmaceutical composition comprising crystalline Form I of 2-methyl-4-(4-methyl-l-piperazinyl)-10H-thieno[2,3-b][l,5]benzodiazepine as claimed in any of claims 1, 2 or 3 and a pharmaceutically acceptable carrier.
19. A pharmaceutical composition as claimed in claim 18 wherein said pharmaceutical composition has a stable colour upon storage at ambient conditions.

Documents:

1210-mum-2001 abstract.pdf

1210-mum-2001 claims.pdf

1210-mum-2001 correspondence(ipo).pdf

1210-mum-2001 correspondence.pdf

1210-mum-2001 description(granted).pdf

1210-mum-2001 form 1.pdf

1210-mum-2001 form 18.pdf

1210-mum-2001 form 2(granted).pdf

1210-mum-2001 form 2(title page).pdf

1210-mum-2001 form 3.pdf

1210-mum-2001 form 5.pdf

1210-mum-2001 other.pdf

1210-mum-2001 pct document.pdf

1210-mum-2001 search report.pdf

1210-mum-2001 u s patent.pdf

1210-mum-2001-abstract(granted)-(15-6-2007).pdf

1210-mum-2001-abstract.doc

1210-mum-2001-claims(granted)-(15-6-2007).pdf

1210-mum-2001-claims.doc

1210-mum-2001-description(granted)-(15-6-2007).pdf

1210-mum-2001-description(granted).doc

1210-mum-2001-form 2(granted)-(15-6-2007).pdf

1210-mum-2001-form 2(granted).doc


Patent Number 204579
Indian Patent Application Number 1210/MUM/2001
PG Journal Number 30/2008
Publication Date 25-Jul-2008
Grant Date 27-Feb-2007
Date of Filing 24-Dec-2001
Name of Patentee SUN PHARMACEUTICAL INDUSTRIES LTD.
Applicant Address ACME PLAZA, ANDHERI - KURLA ROAD, ANDHERI (E), MUMBAI - 400059,
Inventors:
# Inventor's Name Inventor's Address
1 1)MR. CHHABADA VIHAY CHHANGAMAL, 2) DR.REHANI RAJEEV BUDHDEV, 3) DR. THENNATI RAJAMAMANNAR SUN PHARMA ADVANCED RESEARCH CENTRE, AKOTA ROAD, AKOTA, BARODA 390020,
PCT International Classification Number A 61 K 31/551
PCT International Application Number N/A
PCT International Filing date
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 NA