"A Process For Preparing Stable Amorphous Benzimidazole Composition"

Field of the invention: The present invention relates to a process for preparing stable amorphous benzimidazole composition. The composition is useful against various gastrointestinal disorders. Background of the invention: Benzimidazole compounds such as omeprazole, lansoprazole, pantoprazole, rabeprazole or single enantiomers thereof are strong inhibitors of proton pump and thus are widely used as therapeutic agents for stomach ulcer, duodenal ulcer, gastro esophageal reflux disorders etc. by inhibiting gastric acid secretion. U.S. Patent No. 4,255,431 discloses omeprazole and therapeutically acceptable salts thereof. The advantages of providing the salts of omeprazole and particularly the magnesium salt are disclosed in U.S. Patent No. 4,738,974. U.S. Patent No. 5,900,424 discloses omeprazole magnesium salt having a degree of crystallinity, which is higher than 70% as determined by X-ray powder diffraction. The patent teaches that the isolation and purification in full manufacturing scale of the magnesium omeprazole salt as per U.S. Patent No. 4,738,974 presents a major problem. The magnesium omeprazole salt crystals so obtained are very fragile. The patent further teaches that in order to use the magnesium salt of omeprazole in full manufacturing scale in preparing pharmaceutical formulations primarily for oral administration, such as tablets, it is necessary that said magnesium omeprazole possesses a combination of properties, which makes such full scale manufacturing feasible. These physical properties are degree of crystallinity, particle diameter, density, hygroscopicity, water content and content of other solvents. U.S. Patent No. 5,690,960 teaches stable oral formulation comprising: a core containing a magnesium salt of omeprazole said salt having more than 70% crystallinity as determined by x-ray powder diffraction; a subcoating layer; and an enteric coating layer. Benzimidazole derivatives have improved storage stability by converting a crystalline product into an amorphous product. It is observed that benzimidazole derivatives emit strong heat when they decompose. So, unlike in crystalline, the local decomposition is extended slowly to other area in amorphous state, because the heat produced is not transmitted to the surrounding area rapidly. It is well known that amorphous forms in final dosage form improves dissolution of the final dosage form. Further it is known that amorphous material possess improved compression characteristics over the crystalline form. The efforts to stabilize benzimidazole compositions using amorphous form of benzimidazole compounds are reported in prior art. U.S. Patent No. 6,713,495 discloses Magnesium omeprazole having a degree of crystallinity of under 67% by weight and having a residual organic solvent content of less than 7% by weight. The U.S. Patent Application No. 20030232861 discloses Magnesium S-omeprazole having a degree of crystallinity of under 67%. Example 3 of U.S. Patent No. 6,713,495 and U.S. Patent Application No. 20030232861 disclose magnesium omeprazole and magnesium esomeprazole respectively, having a degree of crystallinity of under 25%. PCT Application WO06087613 discloses a stable oral amorphous benzimidazole composition prepared by non-aqueous layering process. The process involves dispersing amorphous benzimidazole compound and one or more pharmaceutically acceptable additives in one or more of non-aqueous solvents to obtain a dispersion and spraying the dispersion on a pharmaceutically acceptable inert carrier, the process substantially prevents the conversion of benzimidazole compound to its crystalline form. PCT Application WO06069159 discloses processes for the preparation of pharmaceutical compositions comprising the amorphous form of benzimidazoles. The process involves providing a solution of a substituted benzimidazole in an organic solvent, optionally, dissolving or dispersing one or more hydrophilic excipients in the solution; and removing solvent. The process discloses coating the inert core with the solution of a substituted benzimidazole in an organic solvent. PCT Application WO05051362 teaches stable oral benzimidazole composition comprising a core comprising amorphous or crystalline benzimidazole compound, a substantially water-insoluble and substantially non-disintegrating separating layer and an enteric coating. The formulation process involves dispersing drug in aqueous medium and spray drying to obtain granules. U.S. Patent Application No. 20020128293 teaches stable oral pharmaceutical composition comprising omeprazole and a stabilizing excipient, wherein the composition is free of alkaline compounds. Example 7 of the patent application discloses a process of wet drug layering of an inert carrier using a wurster fluid bed apparatus. U.S. Patent No. 6,576,258 discloses method for stabilizing active substances comprising benzimidazole derivatives, by means of anhydrous granulation of active substances. The patent involves non aqueous granulation process, wherein non-aqueous solvent comprising a

surfactant is used for granulating active substance and dried pharmaceutically acceptable excipients for the preparation of pellet, cores or granules. U.S. Patent No. 5,639,478 discloses enteric coated anti-ulcer compositions, which uses granulation technique for making the core, the core is then enteric coated. The patent does not disclose whether the starting material is amorphous or crystalline, and there is no mention whether the final dosage form contains amorphous or crystalline benzimidazole. U.S. Patent No. 5,294,439 discloses a stabilized physiologically active benzimidazole derivative comprising amorphous benzimidazole, wherein the crystalline form is converted to amorphous form using freeze drying technique. However, there is still a need for the development of pharmaceutical compositions of benzimidazole compounds having enhanced stability. Further, it was observed that there are few prior art references with an attempt to prepare stable oral compositions containing amorphous benzimidazole. It was surprisingly observed that by following a non-aqueous process a stable amorphous benzimidazole composition could be prepared. The process involves the conversion of the crystalline form of benzimidazole compound to the amorphous form. The final amorphous composition was observed to be stable in terms of the conversion to the crystalline form, even after storage at accelerated conditions. The present invention thus relates to the process for preparing stable amorphous benzimidazole compositions involving non-aqueous process, as herein below described and exemplified. Summary of the invention: According to one embodiment of the specification there is provided a process for preparing a stable amorphous benzimidazole composition, the process comprising the steps of: a) dispersing crystalline benzimidazole compound and optionally one or more pharmaceutically acceptable excipients in one or more non-aqueous solvents to obtain a dispersion, and spraying the dispersion on one or more pharmaceutically acceptable excipients to obtain granules; b) compressing the granules obtained in step (a) to obtain a core; c) coating the core with a separating layer; and d) coating the product of step (c) with an enteric coating. According to another embodiment of the specification there is provided a process for preparing a stable amorphous benzimidazole composition, the process comprising the steps of: a)

dispersing crystalline benzimidazole compound and optionally one or more pharmaceutically acceptable excipients in a non-aqueous solvent comprising methanol and methylene chloride in a proportion of 50: 50 to obtain a dispersion, and spraying the dispersion on one or more pharmaceutically acceptable excipients to obtain granules; b) compressing the granules obtained in step (a) to obtain a core; c) coating the core with a separating layer; and d) coating the product of step (c) with an enteric coating. Detailed description of the invention: The term 'benzimidazole compound' used herein refers to any of the compounds belonging to the category of benzimidazole used for gastrointestinal disorders and may be selected from omeprazole, lansoprazole, rabeprazole, pantoprazole, leminoprazole and pariprazole, single enantiomers, pharmaceutically accepted salts, solvates or mixtures thereof. Preferably, the benzimidazole compound is omeprazole, in the form of a pharmaceutically acceptable alkaline salt. More preferably, omeprazole is in the form of omeprazole magnesium. Preferably, the benzimidazole compound is in crystalline form. The term 'stable amorphous benzimidazole composition' as used herein refers to the oral compositions of amorphous benzimidazole compounds, which are free from crystalline benzimidazole. Preferably, the stable amorphous benzimidazole composition contains not more than 5% crystalline benzimidazole, more preferably, crystalline benzimidazole is below the limit of detection. The suitable method of determining the conversion of the crystalline form to the amorphous form is any method with substantial precision, for eg. X-ray diffraction spectroscopy. The core may be in the form of tablet or minitablet. The core is prepared using non-aqueous process wherein the crystalline benzimidazole compound is converted to amorphous benzimidazole. The non-aqueous process uses non-aqueous solvents or mixtures thereof for the preparation of the dispersion of benzimdazole compound. This dispersion is then used for the preparation of granules. The non-aqueous solvents may be selected from one or more of methanol, ethanol, isopropanol, methylene chloride, acetone or mixtures thereof. Preferably, the non-aqueous solvent is a mixture of methanol and methylene chloride in a proportion of 50:50. The 'pharmaceutically acceptable excipients' may be selected from one or more of binders, diluents, disintegrants, lubricants/glidants and solubilizers/wetting agents.

Suitable binders may be selected from one or more of cellulose derivatives such as hydroxypropylmethyl cellulose, hydroxypropyl cellulose and methylcellulose; gums such as xanthan gum, gum acacia and tragacanth; water-soluble vinylpyrrolidone polymers such as polyvinylpyrrolidone and copolymer of vinylpyrrolidone vinyl acetate; sugars such as sorbitol and mannitol. Suitable diluents may be selected from one or more of sugars such as dextrose, glucose and lactose; sugar alcohols such as sorbitol, xylitol and mannitol; cellulose derivatives such as powdered cellulose and microcrystalline cellulose; starches such as corn starch, pregelatinized starch and maize starch. Suitable disintegrants may be selected from one or more of sodium starch glycolate, croscarmellose sodium, crospovidone and corn starch. The lubricant/glidants may be selected from one or more of magnesium stearate, talc, sodium stearyl fumarate, colloidal silicon dioxide and mixtures thereof. The solubilizers/wetting agents may be selected from one or more of sodium lauryl sulphate, polysorbate 80 and mixtures thereof. In the process for preparing a stable amorphous benzimidazole composition, crystalline benzimidazole compound and optionally one or more pharmaceutically acceptable excipients may be dispersed in a non-aqueous solvent or mixtures thereof to obtain a dispersion. The resulting dispersion may be sprayed on one or more pharmaceutically acceptable excipients in a fluidized bed granulator to obtain granules. These granules may be compressed into tablets or minitablets. The tablets or minitablets are coated with a separating layer. The separating layer as used herein refers to the layer that separates the core from the enteric coating. Separating layer is made up of water soluble material, which is capable of dissolving or forming a gel in contact with water. Such material may include a water-soluble polymer. The water-soluble polymers may be selected from hydroxypropylmethylcellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, sodium alginate, sodium carboxymethyl cellulose, copolymer of vinylpyrrolidone and vinyl acetate. Preferably such polymers are hydroxypropylmethylcellulose, hydroxypropyl cellulose or polyvinylpyrrolidone. The core coated with the separating layer is further coated with an enteric coating. The enteric coating may include polymers such as cellulose acetate phthalate, hydroxypropylmethyl cellulose phthalate, polyvinyl acetate phthalate, carboxymethylethylcellulose, methacrylic acid

copolymers, such as for example, compounds known under the tradenames of Eudragit NE30D, Eudragit L, Eudragit S, Eudragit L 100 55 or mixtures thereof. The enteric coating may also contain plasticizers such as triacetin, triethyl citrate, tributyl sebecate, diethyl phthalate, polyethylene glycol and inert excipients such as talc, titanium dioxide, colloidal silicon dioxide, hydroxypropyl methylcellulose, crospovidone and mixtures thereof. The compositions of the present invention show substantial absence of crystalline benzimidazole even after storage at 40°C and 75% humidity conditions for a period of at least 1 month, preferably 6 months, as determined by X-ray diffraction method. The following non-limiting examples illustrate the process for preparing stable amorphous benzimidazole compositions disclosed in various embodiments of the specification: Procedure: 1. Omeprazole magnesium crystalline was dissolved in methylene chloride: Methanol (50:50) mixture to get 10% solution. 2. Microcrystalline Cellulose was taken in the lower chamber of fluid bed granulator (FBG). 3. Solution obtained in step 1 was sprayed on the microcrystalline cellulose using top spray mode in fluid bed granulator to get uniform size granules. The granules obtained were dried in fluid bed granulator, followed by vacuum tray dryer for sufficient time. 4. Granules obtained in step (4) were passed through 710 micron mesh and the oversize were separated. 5. Extra granular Mannitol, Sodium starch glycollate & Colloidal silicon dioxide were sifted through 355 micron mesh; and blended with granules obtained in step 4 in a double cone blender (DCB) to obtain a blend. 6. Sodium stearyl fumarate and talc was sifted through 150 micron mesh and added to blend obtained in step 5 to obtain a mixture. 7. The mixture obtained in step 6 was compressed using 7.0 mm shallow concave round tooling to obtain tablets. Separating layer 8. Hydroxypropylmethyl cellulose was dissolved in purified water under mechanical stirring followed by addition of polyethylene glycol to obtain a coating dispersion. 9. The tablets obtained in step 7 were coated with the coating dispersion of step 8. Enteric coating 10. Methacrylic acid copolymer, polyethylene glycol, titanium dioxide, ferric oxide red and polysorbate 80 were all dissolved in water under mechanical stirring to obtain an enteric coating dispersion. To the product obtained in step 9 coating was applied using the enteric coating Procedure: 1. Omeprazole magnesium crystalline and hydroxypropyl methylcellulose were dissolved in methylene chloride: methanol (50:50) mixture to get 12 % solution. 2. Microcrystalline Cellulose, Sodium starch glycollate and mannitol were taken in the lower chamber of fluid bed granulator. 3. Solution obtained in step (1) was sprayed on the mixture of Microcrystalline Cellulose, Sodium starch glycollate and Mannitol bed using top spray mode in fluid bed granulator to get uniform size granules. 4. The granules were finally dried in a vacuum tray dryer. 5. Granules obtained in step 4 were passed through 710 micron mesh and oversize were separated. 6. Extra granular portion Mannitol was sifted through 355 micron mesh; and blended with the granules of step 5 in double cone blender to obtain a blend. 7. Sodium stearyl fumarate and talc was sifted through 150 micron mesh and added to the blend obtained in step 6 and mixed to obtain a mixture. 8. The mixture of step 7 was compressed using 7.0 mm shallow concave round tooling to obtain tablet. Separating Layer 9. Hydroxypropyl methylcellulose was dissolved in water to obtain a coating dispersion. 10. The tablet obtained in step 8 was coated using coating dispersion of step 9 in perforated coating pan. Enteric coating 11. Methacrylic acid copolymer, polyethylene glycol, titanium dioxide, ferric oxide red & polysorbate 80 were all dissolved in water to obtain the enteric coating dispersion. 12. The product obtained in step 10 was coated using enteric coating dispersion of step 11 in Perforated coating pan to obtain the enteric coated tablet.

Procedure: 1. Omeprazole magnesium crystalline and hydroxypropyl methylcellulose were dissolved in methylene chloride: methanol (50:50) mixture to get 12% solution. 2. Microcrystalline Cellulose and mannitol were taken in the lower chamber of fluid bed granulator. 3. Solution obtained in step (1) was sprayed on the mixture of Microcrystalline Cellulose and Mannitol bed using top spray mode in fluid bed granulator to get uniform size granules. 4. The granules were finally dried in a vacuum tray dryer. 5. Granules obtained in step 4 were passed through 710 micron mesh and oversizes were separated. 6. Extra granular portion Mannitol was sifted through 355 micron mesh; and blended with granules obtained in step 5 in double cone blender to obtain a blend. 7. Sodium stearyl fumarate, sodium starch glycollate and talc were sifted through 150 micron mesh and added to blend obtained in step 6 to obtain a mixture. 8. The mixture obtained in step 7 was compressed using 7.0 mm shallow concave round tooling to obtain tablets. Separating Layer 9. Hydroxypropyl methylcellulose was dissolved in water followed by addition of polyethylene glycol and talc to obtain coating dispersion. 10. To the tablet obtained in step 8 coating was applied using coating dispersion of step 9 in Perforated coating pan. Enteric coating 11. Methacrylic acid copolymer, polyethylene glycol, titanium dioxide, ferric oxide red and polysorbate-80 were all dissolved in water to obtain an enteric coating dispersion. 12. To the product obtained in step 10 coating was applied using the enteric coating dispersion of step 11 in Perforated coating pan to obtain enteric coated tablet. Procedure: 1. Omeprazole magnesium crystalline and hydroxypropyl methylcellulose were dissolved in methylene chloride: methanol (50:50) mixture to get 12% solution. 2. Microcrystalline Cellulose and mannitol were taken in the lower chamber of fluid bed granulator. 3. Solution obtained in step (1) was sprayed on the mixture of Microcrystalline Cellulose and Mannitol bed using top spray mode in fluid bed granulator to get uniform size granules. 4. The granules were finally dried in a vacuum tray dryer. 5. Granules obtained in step 4 were passed through 710 micron mesh and oversizes were separated. 6. Extra granular portion Mannitol was sifted through 355 micron mesh; and blended with granules obtained in step 5 in double cone blender to obtain a blend. 7. Sodium stearyl fumarate, sodium starch glycollate and talc were sifted through 150 micron mesh and added to blend obtained in step 6 to obtain a mixture. 8. The mixture obtained in step 7 was compressed using 7.0 mm shallow concave round tooling to obtain tablets. Separating Layer 9. Hydroxypropyl methylcellulose was dissolved in water to obtain coating dispersion. 10. To the tablet obtained in step 8 coating was applied using coating dispersion of step 9 in Perforated coating pan. Enteric coating 11. Methacrylic acid copolymer, polyethylene glycol, titanium dioxide, ferric oxide red and polysorbate-80 were all dissolved in water to obtain an enteric coating dispersion. 12. To the product obtained in step 10 coating was applied using the enteric coating dispersion of step 11 in Perforated coating pan to obtain enteric coated tablet. The compositions were stored at accelerated conditions and the percentage of crystallinity determined by X-ray diffraction method was determined at various time points. The data is tabulated below: Table 1: Percentage of crystallinity, of the compositions stored in cold form blister, at 40CC and 75% RH at various time pointsThe XRD data indicated that the compositions prepared according to the process of this invention were found to contain less than 5% crystalline benzimidazole compound, even after storage at accelerated conditions for a period upto 6 months.

WE CLAIM: 1. A process for preparing a stable amorphous benzimidazole composition, the process comprising the steps of: a) dispersing crystalline benzimidazole compound and optionally one or more pharmaceutically acceptable excipients in one or more non-aqueous solvents to obtain a dispersion, and spraying the dispersion on one or more pharmaceutically acceptable excipients to obtain granules; b) compressing the granules obtained in step (a) to obtain a core; c) coating the core with a separating layer; and d) coating the product of step (c) with an enteric coating. 2. The process according to claim 1, wherein the benzimidazole compound is selected from one or more of omeprazole, lansoprazole, rabeprazole, pantoprazole, leminoprazole, pariprazole, single enantiomers, pharmaceutically accepted salts, solvates or mixtures thereof. 3. The process according to claim 2, wherein the benzimidazole compound is omeprazole magnesium. 4. The process according to claim 1, wherein the stable amorphous benzimidazole composition comprises NMT 5% by weight of crystalline benzimidazole compound. 5. The process according to claim 1, wherein the non-aqueous solvent is selected from one or more of methanol, ethanol, isopropanol, methylene chloride, acetone and mixtures thereof. 6. The process according to claim 1, wherein the pharmaceutically acceptable excipient is selected from one or more of binders, diluents, disintegrants, lubricants and wetting agents. 7. The process according to claim 6, wherein the binder is selected from one or more of cellulose derivatives selected from hydroxypropylmethyl cellulose, hydroxypropyl cellulose or methylcellulose; gums selected from xanthan gum, gum acacia or tragacanth; water-soluble vinylpyrrolidone polymers selected from polyvinylpyrrolidone or copolymer of vinylpyrrolidone vinyl acetate and sugars selected from sorbitol or mannitol; wherein the diluent is selected from one or more of sugars selected from dextrose, glucose or lactose; sugar alcohols selected from sorbitol, xylitol or mannitol; cellulose derivatives selected from powdered cellulose or microcrystalline cellulose; and starches selected from corn starch, pregelatinized starch or maize starch; wherein the disintegrant is selected from one or more of sodium starch glycolate, croscarmellose sodium, crospovidone, corn starch and mixtures thereof; wherein the lubricant is selected from one or more of magnesium stearate, talc, sodium stearyl fumarate, colloidal silicon dioxide and mixtures thereof, and wetting agent is selected from one or more of sodium lauryl sulphate, polysorbate 80 and mixtures thereof. 8. The process according to claim 1, wherein the separating layer comprises a water-soluble polymer. 9. The process according to claim 8, wherein the water-soluble polymer is selected from one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, sodium alginate, sodium carboxymethyl cellulose, and copolymer of vinylpyrrolidone and vinyl acetate. 10. A process for preparing stable amorphous benzimidazole composition substantially described and exemplified herein.