FORM 2
THE PATENTS ACT 1970
(39 OF 1970)
&
The Patent Rules, 2003
COMPLETE SPECIFICATION
A Process for Preparation of Crystalline Albendazole
SeQuent Scientific Limited
A Company Incorporated Under The Companies Act, 1956
Having Registered Office at 301, 'Dosti Pinnacle', 3rd Floor,
Plot No.E7, Road No.22, Wagle Industrial Area,
Thane (W)-400 604
Maharashtra, India
The following specification particularly describes the nature of the invention and the manner in which it has to be performed:

Field of Invention
The present invention relates to a novel, cost-effective process for preparation of polymorphic form of Albendazole. Specifically, it relates to the novel process for the preparation of crystalline Albendazole Form-I.
Background of the Invention
Albendazole having chemical name methyl-[6-(propylthio)-lH-benzimidazol-2-yl] carbamate of formula I, is a member of the benzimidazole compounds used as a drug indicated for the treatment of a variety of worm infestations. Albendazole was first discovered at the SmithKline Animal Health Laboratories in 1972. It is a broad spectrum anthelmintic, effective against roundworms, tapeworms, and flukes of domestic animals and humans. It is efficient antiparasitic agent that has good result of treatment not only to pinworm, ascarid, hookworm and whipworm in the animal bodies such as pig, ox, sheep, but it is also suitable for the treatment to prop up testis trematode, cestode, Echinococcus hydatid cyst, trichina, cysticercus worm etc.

There are a number of literature references available, which describe the process for preparation of albendazole. But there is only a limited references reported related to polymorphic forms of albendazole and its preparation.
EP224249 reports anhydrous benzimidazole derivatives and their preparation. This patent also describes further the use of these anhydrous benzimidazole derivatives in pharmaceutical compositions.
Journal of Pharmaceutical Sciences 2010, 99(9), 3731-3742 reports two
crystalline polymorphic forms of Albendazole, Form-I and Form-II. According to this
article, Form-I is reported to be commercially available albendazole whereas Form-II is

new. This journal reports the albendazole polymorphic Form-I with the contagion of other albendazole polymorphic Form-11, which is not pure.
A major drawback in above known process is the formation of mixture of albendazole containing polymorphic Form-I and the other form. The albendazole obtained by prior art process contains 5% to 50% mixture of polymorphic Form-I and Form-II, which is not consistently produced.
Thus there is a need to develop a process for the preparation of albendazole containing pure polymorphic Form-I, which is cost effective and easy to handle on a commercial scale. Especially there is a need to develop a process which obviates the formation of mixture of polymorphic Form-1 and Form-II.
Thus it is highly desirable to prepare a stable polymorphic form which is pure and suitable for pharmaceutical formulation. Thus it is highly desirable to prepare a stable polymorphic form of albendazole which is suitable for pharmaceutical formulation and prepared without using solvent. The present inventors have developed a process which is robust and avoids solvents for preparing a novel crystalline albendazole, which is stable chemically and polymorphically on storage and is unaffected by external parameters such as ambient humidity.
Summary of the Invention
According to the principal aspect of the invention there is disclosed a stable crystalline albendazole Form-I. The stable crystalline albendazole Form-I of the present invention is characterised by having X-ray powder diffraction pattern as given in figure 1 and having prominent 20 peaks at 7.0, 17.99, 22.23, 24.48 and 24.73 with ± 0.2.
According to another aspect of the present invention, the crystalline albendazole Form-I obtained by the process of the present invention is greatly pure, preferably 99% and is free from other crystalline polymorphic forms.

Another aspect of the invention is to provide a process for preparation of the stable crystalline albendazole Form-I comprising:
a) drying wet albendazole under high vacuum;
b) heating the albendazole; and
c) cooling to get pure crystalline albendazole.
Yet another aspect of the present invention is in the preparation of crystalline albendazole Form-I by heating albendazole obtained.
Brief Description of the Diagram/Figure
Figurel: Illustrates X-ray diffractogram of the crystalline polymorphic albendazole Form-I.
Detailed Description of the Invention
Accordingly in an embodiment of the invention, the stable crystalline polymorphic albendazole Form-I of the present invention is characterised by having X-ray powder diffraction pattern as given in figure 1 and having prominent 20 peaks at 7.0, 17.99, 22.23, 24.48 and 24.73 with ± 0.2.
In another embodiment of the invention, the crystalline albendazole Form-I obtained by the process of the present invention is pure, preferably 99% and is free from other crystalline polymorphic forms.
In other embodiment of the invention, the wet albendazole having mixture of Form-I and Form-II is dried under high vacuum at temperature between 40 to 90°C, preferably at 60 - 70°C for about 2-6 hours. Further, it is heated to 90 - 140°C, preferably at 120 - 130°C and maintained for about 4-8 hours, preferably 5-6 hours and cooled to room temperature.
In yet another embodiment of the invention, albendazole Form-I is treated with an organic solvent, preferably a chlorinated solvent selected from methylenedichloride,

ethylenedichloride, chloroform, carbon tetrachloride, etc. most preferably dichloromethane. The product obtained is further dried preferably in the temperature range 60 to 90°C under vacuum.
In still another embodiment of the invention, the wet albendazole having pure Form-11 is dried under high vacuum at temperature between 40 to 90°C, preferably at 60 - 70°C for about 2-6 hrs. Further, the reaction mixture is heated to 100 - 150°C, preferably at 120 - 130°C and maintained for about 4-8 hours, preferably 5-6 hours. Finally, the product is cooled to room temperature to get pure crystalline albendazole Form-I.
In yet another embodiment of the present invention, crystalline albendazole Form-I is prepared by heating albendazole.
In another embodiment of the present invention, crystalline albendazole Form-I is obtained by heating albendazole above 100°C.
In an embodiment of the present invention, crystalline albendazole Form-I is obtained by heating albendazole to 120°C.
In yet another embodiment of the present invention, crystalline albendazole Form-1 is prepared by heating solid albendazole.
In still further embodiment, the process of present invention has following advantages:
1. Albendazole obtained by process of the present invention is consistently pure form containing polymorphic Form-I. However, in the prior art processes, albendazole obtained contain 5% to 50% mixture of polymorphic Form-I and Form-II and also not consistent.

2. In the process of the present invention, treating albendazole with chlorinated solvent for obtaining pure albendazole containing polymorphic Form-I is not reported in prior art.
The present invention is illustrated by the following examples, which are not to limit the scope of the invention.
Example 1: Preparation of methyl-|6-(propylthio)-lH-benzimidazol-2-yl|carbamate
(I)
4-Propylthio-o-phenylenediamine (25 g) was treated with acetone (25 mL). Then water (23 mL) and cone. HC1 (36 g) was added to it. Exothermic reaction was observed with the rise in temperature upto 48°C. Reaction mass was cooled to room temperature and methyl-N-cyanocarbamate was added. The reaction mass was heated to 80-85°C and maintained for 2 hours. The reaction mass was filtered and washed with hot water, water, methanol and finally with acetone.
Weight: 30-35 g.
Example 2: Preparation of methyI-[6-(propylthio)-lH-benzimidazoI-2-yl| carbamate Form-I
(a) Preparation of Albendazole Form-I
Albendazole wet (25 g) having mixture of Form-I and Form-II (~ 60:40) was taken in petridish and placed in vacuum oven. Vacuum was applied and the material was dried at 60 - 70°C for 4 - 5 hours. The vacuum was released through nitrogen and further it is heated to 120 - 130°C without vacuum and maintained for 5 - 6 hours. Then it is cooled to room temperature, to afford 22 g of albendazole Form-I.
Weight: 21-23 g.
(b) Preparation of Albendazole Form-I
Albendazole wet (25 g) having mixture of Form-I and Form-I 1 (~ 60:40) was taken in petridish and placed in vacuum oven. Vacuum was applied and the material was dried at 60 - 70°C for 4 - 5 hours. The vacuum was released through nitrogen and further it is

heated to 120 - 130°C without vacuum and maintained for 5-6 hours. Then it is cooled to room temperature, to afford 22 g of albendazole Form-I. Above material was treated with methylenedichloride, filtered and dried under vacuum. Weight: 18-20 g.
(c) Preparation of Albendazole Form-I
Albendazole wet (10 g) having pure Form-II was taken in petridish and placed in vacuum oven. Vacuum was applied and the material was dried at 60 - 70°C for 4 - 5 hours. The vacuum was released through nitrogen and further it is heated to 120 - 130°C without vacuum and maintained for 5-6 hours. Then it is cooled to room temperature, to afford 8.0 g of albendazole Form-1. Weight: 8-10 g.

We claim:
1. A process for the preparation of stable crystalline albendazole Form-I comprising:
a) drying wet albendazole under high vacuum;
b) heating the albendazole; and
c) cooling to get pure crystalline albendazole.

2. A process according to claim 1, wherein the drying in step (a) is carried out at temperature in the range of 60-70°C.
3. A process according to claim 1, wherein the heating in step (b) is carried out at temperature in the range of 120-130°C.
4. A process according to claim 1, wherein the cooling in step (c) is carried out at room temperature in the range of 25-35°C.
5. Crystalline albendazole Form-I according to claim 1 is represented by the powdered X-ray diffractogram substantially as given in figure 1.
6. Crystalline albendazole Form-I according to claim 5 is further characterised by 29 peaks at 7.0, 17.99, 22.23, 24.48 and 24.73.
7. A process for preparing albendazole Form-I by heating solid albendazole.
8. The process for preparing albendazole Form-I according to claim 7 wherein the heating was carried out above 100°C.
9. The process for preparing albendazole Form-I according to claim 8 wherein the heating was carried out at 120°C.
10. Albendazole Form-I according to claim 7.