Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
• • 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
  • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants

Definitions

• the present invention relates to novel crystalline forms of (R)-2-[[[3-methyl-4(2,2,2- trifluoroethoxy)pyridin-2-yl]methyl]sulphinyl]-lH-ben2imidazole, to processes for their preparation, to pharmaceutical compositions comprising the same and to the use of such crystalline forms for the treatment of gastrointestinal (GI) disorders.
• GI gastrointestinal
• Dexlansoprazole or (R)-lansoprazole is a member of a group of drugs called proton pump inhibitors (PPIs) that inhibit gastric acid secretion.
• PPIs proton pump inhibitors
• Dexlansoprazole is used to treat heartburn caused by gastroesophageal reflux disease (GERD) and to heal erosive esophagitis (damage to the esophagus from stomach acid).
• Dexlansoprazole is chemically known as (R)-2-[[[3-methyl-4(2,2,2-trifluoroethoxy)pyridin-2- yI]methyl]sulphinyI]-lH-benzimidazole and is marketed as KAPIDEX ® .
• Dexlansoprazole has the following chemical structure:
• EP0773940B describes the preparation of (+) lansoprazole and (-) lansoprazole.
• Dexlansoprazole is known to exist in different solid state forms.
• US6462058, US6664276, US7285668 and US2007/0004779 all describe process for preparing crystalline forms of dexlansoprazole and its hydrates.
• US6462058 and US7285668 disclose crystalline dexlansoprazole characterized by X-ray powder diffraction (XRD), with characteristic peaks at interplanar spacings (d) 11.68, 6.77, 5.84, 5.73, 4.43, 4.09, 3.94, 3.89, 3.69, 3.41 & 3.1 1 Angtroms (A).
• XRD X-ray powder diffraction
• US7271 182 describes crystalline lithium, potassium, magnesium, sodium & calcium salts of dexlansoprazole and processes for the preparation thereof. However, the process described in this patent has been found to be not reproducible as products of desired purity are not obtained upon repeated purification. Further, the obtained crystalline forms have been found to be not stable on storage.
• WO2009088857 and US20100286400 disclose different hydrates of dexlansoprazole, solvates of dexlansoprazole with methanol, ethanol and isopropanol and hydrated solvates of dexlansoprazole with ethanol and isopropanol and processes for preparation thereof.
• WO2009087672 and WO2009117489 disclose amorphous dexlansoprazole and a process for the preparation thereof.
• WO2010079504 discloses an alkylamine salt of dexlansoprazole, a process for its preparation and pharmaceutical compositions thereof.
• WO201 1121546 describes a process for the preparation of amorphous alkali metal, alkaline earth metal and ammonium salts of dexlansoprazole.
• WO2010056059 discloses a crystalline form of (+)-lansoprazole, whose XRD pattern comprises a peak having a 100 x 1/10 value of at least 20% at an interplanar distance (d ⁇ 0.3 A) of 17.4, 10.0, 9.6, 8.7, 7.6, 6.6, 5.7, 5.6, 5.0, 4.8, 4.4, and 4.0 A with a melting point in the range of 151 to 156°C.
• US20110009637 discloses a crystalline form of dexlansoprazole characterized by XRD with characteristic peaks at 5.7, 5.9, 7.7, 13.3, 13.5, 17.1, 17.3, 18.2, 19.3, and 20.4 °2 ⁇ .
• US20100113527 and WO2010039885 disclose various crystalline forms of dexlansoprazole which are designated as Form X, Form XI, Form XII, Form XIII, and Form IX, and processes for their preparation.
• WO201 1092665 discloses crystalline forms of dexlansoprazole which are designated as Form A and Form B, and processes for their preparation.
• WO201 1139414 discloses crystalline forms of dexlansoprazole which are designated as Form B, Form C, Form D and Form E, and processes for their preparation.
• WO201 1020189 discloses hydrates of dexlansoprazole propylene glycolate and process for the preparation thereof.
• WO201 1098938 discloses dexlansoprazole 1,2-diol solvates and hydrates thereof. Examples include dexlansoprazole propylene glycol solvate, dexlansoprazole chloropropylene glycol solvate and dexlansoprazole 1,2-butanediol solvate.
• aqueous solubility One important property associated with solid state forms of drug substances is their aqueous solubility. Compounds having poor water solubility can lead to limited oral bioavailability when administered in patients. In such cases the discovery of new polymorphic forms and solvates of a pharmaceutically useful compound with better aqueous solubility, provide a significant opportunity to increase the performance characteristics of a pharmaceutical product, such as oral bioavailability and hence reduce the dosage required to be administered to the patient.
• An object of the present invention is to provide novel crystalline forms of (R)-2-[[[3-methyl-4- (2,2,2-trifluoroethoxy)pyridin-2-yl]-methyl]sulphinyl]-lH-benzimidazole and in particular novel crystalline solvates thereof.
• a particular object of the present invention is to provide a triol solvate of (R)-2-[[[3-methyI-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]-methyl]sulphiny]]-lH- benzimidazole.
• Another object of the present invention is to provide processes for the preparation of triol solvates of (R)-2-[[[3-methyI-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]-methyl]sulphinyl]-lH-benzimidazole.
• Another object of the present invention is to provide a pharmaceutical composition
• a pharmaceutical composition comprising a triol solvate of (R)-2-[[[3-methyl- 4-(2,2,2-trifluoroethoxy)pyridin-2-yl]-methyl]sulphinyl]-l H- benzimidazole, said composition optionally comprising one or more pharmaceutically acceptable excipients.
• Another object of the present invention is to provide a pharmaceutical composition comprising a triol solvate of (R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]-methyl]sulphinyl]-l H- benzimidazole having improved solubility.
• Another object of the present invention is to provide a pharmaceutical composition comprising a triol solvate of (R)-2-[[[3-methyl-4-(2,2,2-trif!uoroethoxy)pyridin-2-yl]-methyl]sulphinyl]-l H- benzimidazole having a reduced dose.
• Another object of the present invention is to provide a process for preparing a pharmaceutical composition
• a pharmaceutical composition comprising a triol solvate of (R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2- yl]-methyl]sulphinyl]-l H-benzimidazole, said composition optionally comprising one or more pharmaceutically acceptable excipients.
• Another object of the present invention is to provide a method of preventing or treating GI disorders by administering a novel triol solvate of (R)-2-[[[3-methyl-4-(2,2,2- trifluoroethoxy)pyridin-2-yl]-methyl]sulphinyl]-lH-benzimidazole or a pharmaceutical composition thereof.
• Another object of the present invention is to provide the use of a triol solvate of (R)-2-[[[3- methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]-methyl]sulphinyl]-l H-benzimidazole or a pharmaceutical composition thereof for the treatment of gastrointestinal disorders.
• the present invention provides a triol solvate of (R)-2-[[[3-methyl-4-(2,2,2- trifluoroethoxy)pyridin-2-yl]-methyl]sulphinyl]-lH-benzimidazole.
• the triol solvate of the present invention is preferably crystalline. More preferably, the triol solvate of the present invention is a glycerol solvate.
• Particularly preferred glycerol solvates of the present invention are those compounds designated herein as "Form A", "Form B” and "Form C".
• the novel crystalline forms of the present invention are characterised by unique XRD patterns and intrinsic dissolution profiles.
• novel crystalline forms of the present invention possess certain physical and chemical properties which render them particularly suitable for pharmaceutical development, such as good solubility, permeability and bioavailability. In addition, they are suitable for bulk handling and formulation.
• a process for preparing a triol solvate of (R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]-methyl]sulphinyl]- IH- benzimidazole afford triol solvates of (R)-2-[[[3-methyI- 4-(2,2,2-trifluoroethoxy)pyridin-2-yl]-methyl]sulphinyl]-lH-benzimidazole in high purity and high yield.
• they are environmentally friendly and suitable for use on a commercial scale.
• a pharmaceutical composition comprising a triol solvate of (R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]- methyl]sulphinyl]-lH-benzimidazole, optionally comprising one or more pharmaceutically acceptable excipients.
• a method for preparing a pharmaceutical composition comprising a triol solvate of (R)-2-[[[3-methyl-4-(2,2,2- trifluoroethoxy)pyridin-2-yl]-methyl]sulphinyl]-lH-benzimidazole, optionally comprising one or more pharmaceutically acceptable excipients.
• a method for the prevention or treatment of a GI disorder comprises administering a triol solvate of (R)-2-[[[3- methyl-4-(2, 2,2-trifluoroethoxy)pyridin-2-yl]-methyl]sulphinyl]-lH-benzimidazole to a patient in need thereof.
• triol solvate of (R)-2-[[[3-methyl- 4-(2, 2,2-trifluoroethoxy)pyridin-2-yl]-methyl]sulphinyl]-lH-benzimidazole for use in the prevention or treatment of GI disorders.
• Figure 1 shows an X-ray diffraction pattern of crystalline Form A of (R)-2-[[[3-methyl-4-(2, 2,2- trifluoroethoxy)pyridin-2-yl]-methyI]sulphinyl]-lH-benzimidazole glycerol solvate.
• Figure 2 shows an X-ray diffraction pattern of crystalline Form B of (R)-2-[[[3-methyl-4-(2, 2,2- trifluoroethoxy)pyridin-2-yl]-methyl]sulphinyl]-lH-benzimidazole glycerol solvate.
• Figure 3 shows an X-ray diffraction pattern of crystalline Form C of (R)-2-[[[3-methyl-4-(2, 2,2- trifluoroethoxy)pyridin-2-yl]-methyl]sulphinyl]-lH-benzimidazole glycerol solvate.
• Figure 4 shows the intrinsic dissolution profile of crystalline Form A of (R)-2-[[[3-methyl-4- (2,2,2-trifluoroethoxy)pyridin-2-yl]-methyI]sulphinyl]-lH-benzimidazole glycerol solvate of the present invention compared with anhydrous and sesquihydrate crystalline forms of (R)-2-[[[3- methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yI]-rnethyI]sulphinyl]- 1 H-benzimidazole, measured by a UV method.
• Figure 5 shows the intrinsic dissolution profile of crystalline Form C of (R)-2-[[[3-methyl-4- (2,2 > 2-trifluoroethoxy)pyridin-2-yl]-methyl]sulphinyl]-l H-benzimidazole glycerol solvate of the present invention compared with anhydrous and sesquihydrate .
• solvated means the formation of a crystalline complex of variable stoichiometry comprising (in this invention), a compound of Formula (1) and a solvent.
• solvate shall be interpreted accordingly.
• non-solvated means the subject compound, i.e., the compound of Formula (1) has not formed a complex of variable stoichiometry with a solvent.
• a non-hydrated compound may be referred to as an anhydrate or anhydrous form.
• the phrase "substantially the same X-ray powder diffraction pattern" is understood to mean that those X-ray powder diffraction patterns having diffraction peaks with 2 ⁇ values within ⁇ 0.2° of the diffraction pattern referred to herein are within the scope of the referred to diffraction pattern.
• the present invention provides novel crystalline forms of (R)-2-[[[3-methyl-4-(2, 2,2- trifluoroethoxy)pyridin-2-yl]-methyl]sulphinyl]-lH-benzimidazole, methods of preparing the novel forms (R)-2-[[[3-methyI-4-(2, 2,2-trifluoroethoxy)pyridin-2-yl]-methyl]sulphinyl]-lH- benzimidazole in high purity and high yield and pharmaceutical compositions comprising them.
• a triol solvate of (R)-2-[[[3- methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]-methyl]sulphinyl]-lH-benzimidazole is provided.
• the triol solvate of the present invention is preferably crystalline. More preferably, the triol solvate of the 0127
• glycerol solvate is a glycerol solvate.
• Particularly preferred glycerol solvates of the present invention are those compounds designated herein as "Form A", “Form B” and “Form C”.
• the novel crystalline forms of the present invention are characterised herein by reference to unique XRD patterns and intrinsic dissolution profiles. It will be appreciated that other conventional analytical methods including, but not limited to, infra-red, solid state MR and Raman spectroscopy may also be employed to characterise the crystalline forms of the present invention.
• the present invention provides (R)-2-[[[3-methyl-4-(2, 2,2- trifluoroethoxy)pyridin-2-yl]-methyl]sulphinyl]-lH-benzimidazole glycerol solvate Form A.
• Form A may be isolated in hydrated form or anhydrous form, preferably anhydrous form. Form A has good flow characteristics.
• (R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]-methyl]sulphinyl]-lH-benzimidazole glycerol solvate Form A is characterised by an XRD pattern with peaks at 9.48, 12.9 and 16.4 ⁇ 0.2 °2 ⁇ .
• the XRD pattern may be further characterized by peaks at 6.2, 19.94, 21.82 and 24.63 ⁇ 0.2 °2 ⁇ .
• the XRD pattern may comprise still further peaks at 3.64, 7.18, 10.74, 15.58, 18.52, 18.96, 20.30, 21.21, 22.99, 23.54, 25.17 and 29.02 ⁇ 0.2 °2 ⁇ .
• (R)-2-[[[3-methyl-4-(2,2,2- trifluoroethoxy)pyridin-2-yl]-methyl]sulphinyl]-lH-benzimidazole glycerol solvate Form A may be further characterized by an XRPD pattern with peaks at °2 ⁇ values as depicted in Table 1 below.
• (R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]-methyl]sulphinyl]-lH-benzimidazole glycerol solvate Form A may be further characterized as having an intrinsic dissolution profile substantially as shown in Table A and/or Figure 4.
• the isolated (R)-2-[[[3-methyI-4(2,2,2-trifIuoroethoxy)pyridin-2-yl]methyl]sulphinyi]-l H- benzimidazole Form A preferably contains about 20% by weight of glycerol and is preferably in the anhydrous form.
• Form B is substantially non-hygroscopic and has good flow characteristics.
• Form B is characterised by an XRD pattern with peaks at 18.18 and 22.34 ⁇ 0.2 °2 ⁇ .
• the XRD pattern may further comprise peaks at 5.60, 12.98, 13.76, 14.86, 19.73, 20.12, 20.66, 21.30, 22.88, 26.36 and 26.77 ⁇ 0.2 °2 ⁇ .
• the XRD pattern may comprise still further with peaks at 7.44, 12.56, 15.94, 16.54, 16.72, 18.48, 18.87 and 23.70 ⁇ 0.2 °2 ⁇ .
• (R)-2-[[[3-methyl-4- (2,2,2-trifluoroethoxy)pyridin-2-yI]-methyl]sulphinyl]-lH-benzimidazole glycerol solvate Form B may be further characterized by an XRPD pattern with peaks at °2 ⁇ values as depicted in Table 2 below.
• (R)-2-[[[3-methyl-4-(2,2,2-trifIuoroethoxy)pyridin-2-yl]-methyl]sulphinyl]-lH-benzimi glycerol solvate Form B may be further characterized as having substantially-the same XRPD pattern with peaks at 2 ⁇ values as depicted in Figure 2.
• Form C is characterised by an XRD pattern with peaks at 18.21, 18.88, 20.68, 22.38, 22.90 and 26.79 ⁇ 0.2 °2 ⁇ .
• the XRD pattern may be further characterized by peaks at 5.63, 13.78, 14.88, 19.74, 20.32 and 26.36 ⁇ 0.2 °2 ⁇ .
• the XRD pattern may comprise still further peaks at 7.48, 10.10, 13.22, 16.76, 21.33, 21.83, 23.71 and 28.42 ⁇ 0.2 °2 ⁇ .
• (R)-2-[[[3-methyl-4- (2,2,2-trifluoroethoxy)pyridin-2-yl]-methyl]sulphinyl]-lH-benzimidazole glycerol solvate Form C may be further characterized by an XRPD pattern with peaks at °2 ⁇ values as depicted in Table 3 below. Table 3
• glycerol solvate Form C may be further characterized as having substantially the same XRPD pattern with peaks at 2 ⁇ values as depicted in Figure 3.
• (R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]-methyl]sulphinyl]-lH-benzimidazole glycerol solvate Form C may be further characterized as having an intrinsic dissolution profile as shown in Table B and/or Figure 5.
• the isolated (R)-2-[[[3-methyl-4(2,2,2-trifluoroethoxy)pyridin-2-yl]methyl]sulphinyl]-lH- benzimidazole Form C preferably contains about 20% by weight of glycerol and preferably has a water content in the range of about from 3.0 to 5.0 % w/w.
• a process for preparing a triol solvate of (R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]-methyl]suIphinyl]-lH- benzimidazole comprising (i) dissolving or suspending (R)-2-[[[3-fnethyl-4-(2,2,2- trifluoroethoxy)pyridin-2-yl]-methyl]sulphinyl]-lH-benzimidazole or a salt or solvate thereof in a first suitable solvent; (ii) optionally adding an organic base to the solution or suspension so formed; (iii) contacting (R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]- methyl]sulphinyl]-lH-benzimidazole with a triol; and optionally thereafter (iv)
• a process for preparing (R)-2-[[[3-methyl-4(2,2,2-trifluoroemoxy)pyridin-2-yl]methyl]sulphinyl]-lH-benzimidazole glycerol solvate Form A comprising (i) dissolving (R)-2-[[[3-methyl-4-(2,2,2- trifluoroethoxy)pyridin-2-yl]-methyl]sulphinyl]-lH-benzimidazole in a first suitable solvent; (ii) distilling the reaction mass optionally in the presence of a base; (iii) adding glycerol; (iv) heating the resulting solution to a temperature in the range of about 25°C to about the reflux temperature of the solvent used; (v) adding a suitable second solvent; (vi) isolating (R)-2-[[[3-methyl-4- (2,2,2-trifluoroethoxy)pyridin-2-yl
• a process for the preparation of (R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]-methyl]sulphinyl]-lH- benzimidazole glycerol solvate Form A which process comprises: (i) dissolving (R)-2-[[[3- methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]-methyl]sulphinyl]-lH-benzimidazole in a first suitable solvent; (ii) adding a drying agent to the solution so formed; (iii) optionally adding a base; (iv) removing the first solvent, preferably under vacuum; (v) optionally stripping off the resulting residue with a further quantity of first solvent; (vi) adding glycerol and optionally a further quantity of first solvent; (vii) heating the resulting solution to a temperature in the range from about 40°C to
• a process for the preparation of (R)-2-[[(3-methy!-4-(2,2,2-trtfluoroethoxy)pyndin-2-yl]-methyl]sulphinyl]-lH- benzimidazole glycerol solvate Form A which process comprises: (i) dissolving (R)-2-[[[3- methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]-methyl]sulphinyl]-lH-benzimidazole in a first suitable solvent; (ii) adding a drying agent to the solution so formed; (iii) removing the first solvent, preferably under vacuum; (iv) optionally stripping off the residue so formed with a further quantity of first solvent; (v) adding a further quantity of first solvent; (vi) heating the resulting solution to a temperature in the range from about 40°C to about 60°C, preferably from about 40°C
• a one pot process for the preparation of (R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]-methyl]sulphinyl]-lH- benzimidazole glycerol solvate Form A which process comprises: (i) combining (+)-diethyl L- tartrate, titanium (IV) isopropoxide and water with 2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2- pyridinyl]-methyl]thio]-lH-benzimidazole in a suitable solvent, preferably toluene and heating to the resulting mixture to a temperature in the range from about 70°C to about 75°C, preferably for a period of about 5 to about 10 minutes; (ii) cooling the reaction mixture to a temperature in the range from about 25°C to about 30°C, preferably over a period of at least 30 minutes; (ii)
• the (R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]-methyl]suIphinyl]-lH- benzimidazole used in the preparation of the Form A may be in any polymorphic form or in a mixture of any polymorphic forms.
• the (R)-2-[[[3-methyl-4-(2,2,2- trifluoroethoxy)pyridin-2-yl]-methyl]sulphinyl]-lH-benzimidazole may be in hydrated, solvated, non-solvated or in a mixture of hydrated, solvated or non-solvated forms thereof.
• (R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]-methyl]sulphinyl]-lH- benzimidazole is used in sesquihydrate form, which can be prepared according to known methods, for example as disclosed in US Patent No. 5948789.
• a process for the preparation of (R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)pyridin- ! 2-yl]-methyl]sulphinyl]-lH- benzimidazole glycerol solvate Form B which process comprises: (i) dissolving (R)-2-[[[3- methyl-4-(2, 2 > 2-trifluoroethoxy)pyridin-2-yl]-methyl]sulphinyl]-lH-benzimidazole in a suitable first solvent; (ii) adding glycerol and a further quantity of first solvent; (iii) heating the resulting solution to a temperature in the range from about 40°C to about 60°C, preferably from about 40°C to about 50°C; (iv) adding a suitable second solvent; (v) cooling the reaction mass to a temperature in the range from about 25°C to about 30°C and stirring the reaction mass,
• the (TR)-2-[[[3-methyI-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]-methyl]sulphinyl]-lH- benzimidazole used in the preparation of the Form B may be in any polymorphic form or in a mixture of any polymorphic forms.
• the said (R)-2-[[[3-methyl-4-(2, 2,2- trifluoroethoxy)pyridin-2-yl]-methyl]sulphinyl]-lH-benzimidazole may be in hydrated, solvated, non-solvated or in a mixture of hydrated, solvated or non-solvated forms thereof.
• (R)-2-[[[3-methyl-4-(2, 2,2-trifluoroethoxy) pyridin-2-yl]-methyl]sulphinyl]-lH- benzimidazole is used in sesquihydrate form.
• a process for the preparation of (R)-2-[[[3-methyl-4-(2,2,2-trifIuoroethoxy)pyridin-2-yl]-methyl]sulphinyl]-lH- benzimidazole glycerol solvate Form C which process comprises: (i) dissolving (R)-2-[[[3- methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]-methyl]sulphinyl]-lH-benzimidazole in a suitable first solvent; (ii) adding glycerol to the mixture so formed and optionally a suitable aqueous base;
• a process for the preparation of (R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]-methyl]sulphinyl]-lH- benzimidazole glycerol solvate Form C which process comprises: (i) dissolving (R)-2-[[[3- methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]-methyl]sulphinyl]- 1 H-benzimidazole in a suitable first solvent; (ii) adding glycerol to the mixture so formed and optionally a suitable aqueous base; (iii) adding a further quantity of first solvent; (iv) heating the resulting solution to a temperature in the range from about 40°C to about 60°C, preferably from about 40°C to about 50°C; (v) adding a suitable second solvent; (v) cooling the reaction mass to a temperature in the
• a process for the preparation of (3 ⁇ 4)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]-methyl]sulphinyl]-lH- benzimidazole glycerol solvate Form C which process comprises: (i) combining (+)-diethyl L- tartrate, titanium (IV) isopropoxide and water with 2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2- pyridinyl]-methyl]thio]-lH-benzimidazole in a suitable solvent, preferably toluene and heating to the resulting mixture to a temperature in the range from about 70°C to about 75°C, preferably for a period of about 5 to about 10 minutes; (ii) cooling the reaction mixture to a temperature in the range from about 25°C to about 30°C, preferably over a period of at least 30 minutes; (iii)
• first water immiscible solvent adding glycerol and water, said water preferably being present in an amount from about 1 to about 10% by volume, and heating the resulting mixture to a temperature in the range from about 30°C to about 50°C, preferably from about 30°C to about 45°C;
• cooling the reaction mass to a temperature in the range from about 25°C to about 30°C, further cooling to a temperature in the range from about 0°C to about 10°C and stirring the reaction mass, preferably for at least about 2 hours;
• heating the resulting solution to a temperature in the range from about 40°C to about 60°C, preferably from about 40°C to about 50°C and adding second suitable solvent, preferably over a period of at least about 20 minutes;
• the "first solvent” used in the preparation of (R)-2- [[[3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]-methyl]sulphinyl]-lH-benzimidazole glycerol solvate Forms A, B and C is selected from the group consisting of alcohols, ketones, chloroalkanes, alkyl alkanoates or a mixture thereof.
• Particularly preferred solvents include methanol, ethanol, isopropanol, acetone, methyl ethyl ketone, dichloromethane (MDC), methyl acetate, ethyl acetate, butyl acetate and mixtures thereof.
• the solvent is ethyl acetate, dichloromethane or a mixture thereof.
• the "second solvent” used in the preparation of (R)-2- [[[3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]-methyl]sulphinyl]-lH-benzimidazole glycerol solvate Forms A, B and C is ethyl acetate or a suitable anti-solvent, for example a dialkyl ether, an aromatic hydrocarbon, an aromatic chlorohydrocarbon, a hydrocarbon, or a mixture thereof.
• anti-solvents include diisopropyl ether, methyl t-butylether, toluene, xylene, chlorobenzene, 1,2-dichlorobenzene, n-pentane, n-hexane, n-heptane, cyclopentane, cyclohexane and mixtures thereof. Most preferably, the anti-solvent is n-heptane.
• the drying agent is selected from the group consisting of anhydrous sodium sulphate, anhydrous magnesium sulphate, anhydrous zinc chloride and anhydrous calcium chloride.
• the drying agent is anhydrous sodium sulphate.
• the amount of glycerol used varies from about 5% to about 50 % w/w, preferably from about 15% to about 25% w/w.
• the above-mentioned processes to prepare (R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2- yl]-methyl]sulphinyl]-lH-benzimidazole glycerol solvate Forms A, B and C may be performed in the presence or absence of the organic base.
• the organic base is selected from the group consisting of trialkylamines, dialkylamines, monoalkylamines, branched chain alkylamines heterocyclic bases or mixtures thereof.
• organic bases include trimethylamine, triethylamine, tripropylamine, tributylamine, dimethylamine, diethylamine, dipropylamine, dibutylamine, monomethylamine, monoethylamine, monopropylamine, monobutylamine, diisopropylethylamine, pyridine, pyrrolidine, piperidine, morpholine, N-methyl morpholine, N-methyl piperidine, piperazine or mixtures thereof. Most preferably, the organic base is triethylamine.
• novel polymorphs (Forms A, B and C) of (R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy) pyridin-2-yl]-methyl]sulphinyl]-lH-benzimidazole of the present invention are substantially free from other forms of (R)-2-[[[3-methyl-4-(2, 2,2-trifluoroethoxy) pyridin-2-yl]-methyl]sulphinyl]- lH-benzimidazole.
• the processes of the present invention may be used as a method for purifying any known form of (R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]-methyl]sulphinyl]- lH-benzimidazole, as well as for the preparation of the new polymorphic forms A, B and C.
• the present invention provides the use of (R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy) pyridin-2- yl]-methyl]sulphinyl]-lH-benzimidazole glycerol solvate Form A, B or C as a starting material for the preparation of crystalline anhydrous (R)-2-[[[3-methyl-4-(2, 2,2-trifluoroethoxy) pyridin- 2-yl]-methyl]suIphinyl]-lH-benzimidazole.
• a process for the preparation of crystalline anhydrous (R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]- methyl]sulphinyl]-lH-benzimidazole which process comprises: (i) dissolving (R)-2-[[[3-methyI- 4-(2, 2,2-trifluoroethoxy)pyridin-2-yl]-methyl]sulphinyl]-lH-benzimidazol glycerol solvate Form A, B or C in a solvent selected from the group consisting of methyl acetate, ethyl acetate, propyl acetate, butyl acetate, dichloromethane and mixtures thereof, preferably ethyl acetate; (ii) adding water to the solution so formed; (iii) isolating the organic component of the mixture and drying it using a suitable drying agent, such
• a process for preparing crystalline (R)-2-[[[3-methy[-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]-methyl]sutphinyl]-lH-benzimidazole sesquihydrate which process comprises: (i) treating (R)-2-[[[3-methyl-4-(2,2,2- trifluoroethoxy)pyridin-2-yl]-methyl]sulphinyl]-lH-benzimidazole glycerol solvate Form A, B or C with water, preferably at a temperature in the range from 25°C to about 30°C, preferably for a period of about 1 to about 5 hours; (ii) isolating crystalline (R)-2-[[[3-methyl-4-(2, 2,2- trifluoroethoxy) pyridin-2-yI]-methyl]sulphinyl]-lH-benzimidazole sesquihydrate and, optional
• (R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]-methyl]sulphinyl]-lH-benzimidazole in amorphous form is known to be more soluble in water than the crystalline form, and consequently possesses greater bioavailability.
• the use of amorphous (R)-2-[[[3-methyl-4- (2,2,2-trifluoroethoxy)pyridin-2-yl]-methyl]sulphinyl]-lH-benzimidazoIe is therefore generally preferred to crystalline forms in formulating pharmaceutical compositions.
• the present invention provides a pharmaceutical composition
• a pharmaceutical composition comprising novel triol solvates of (R)-2-[[[3-methyI-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]-methyl]sulphinyl]- lH-benzimidazole (dexlansoprazole) which are crystalline in nature yet exhibiting high aqueous solubility and improved oral bioavailability.
• a pharmaceutical composition comprising a triol solvate of (R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2- yl]-methyl]sulphinyl]-lH-benzimidazole and one or more pharmaceutically acceptable excipients.
• the pharmaceutical composition comprises (R)-2-[[[3-methyl-4-(2,2,2- trifluoroethoxy)pyridin-2-yl]-methyl]sulphinyl]-lH-benzimidazole glycerol solvate.
• the pharmaceutical composition comprises (R)-2-[[[3-methyl-4-(2,2,2- trifluoroethoxy)pyridin-2-yl]-methyl]sulphinyl]-lH-benzimidazole glycerol solvate Form A, B or C, or a mixture of two or more of said crystalline forms.
• pharmaceutical composition includes tablets (single layer, bilayer, multilayer, tablet in tablet) which may be uncoated, film coated, sugar coated, powder coated, enteric coated, seal coated, capsules (filled with powders, powders for reconstitution, pellets, beads, mini-tablets, pills, micro-pellets, small tablet units, film coated tablets, MUPS, film coated tablets MUPS, orally disintegrating MUPS, disintegrating tablets, dispersible tablets, granules, microspheres, multiparticulates or combinations thereof), sachets (filled with powders, pellets, beads, mini- tablets, pills, micro-pellets, small tablet units, film coated tablets, MUPS, film coated tablets MUPS, orally disintegrating MUPS, disintegrating tablets, dispersible tablets, granules, microspheres, multiparticulates or combinations thereof) and sprinkles however other dosage forms such as liquid dosage forms (liquids, liquid dispersions, suspensions, solutions, emulsions, sprays, spot-
• modified release means that the release of the active substance i.e. novel polymorphic forms of (R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]-methyl]sulphinyl]-lH- benzimidazole, from a pharmaceutical composition is controlled in a manner to occur at a different time and/or at a different rate than that obtained from an immediate release product.
• modified release envisages the terms “controlled release”, “delayed release”, “sustained release”, “extended release”, “pulsatile release”, “dual release” or “enteric coated” under its ambit.
• the pharmaceutical composition of the present invention is an oral dosage form, preferably that is suitable for oral or buccal administration.
• the oral dosage form is in the form of tablet (single layer, bilayer, multilayer, tablet in tablet) which may be uncoated, film coated, sugar coated, powder coated, enteric coated, seal coated; capsule [filled with powders, powders for reconstitution, pellets, beads, mini-tablets, pills, micro-pellets, small tablet units, film coated tablets, MUPS, film coated tablets MUPS, orally disintegrating MUPS or multiparticulate systems (disintegrating, film coated)], disintegrating tablets, dispersible tablets, granules, and microspheres, sachets [filled with powders, powders for reconstitution, pellets, beads, mini-tablets, pills, micro-pellets, small tablet units, film coated tablets, MUPS, film coated tablets MUPS, orally disintegrating MUPS, disintegrating tablets, dispersible tablets, granules, and microspheres, sachet
• the oral dosage is in the form of sachets or sprinkles it is administered by sprinkling over regular meals or with liquid or semi-solid beverages such as but not limited to juices or water.
• immediate release compositions may be conventional, dispersible, chewable, mouth dissolving or flash melt preparations.
• Delayed release, controlled release, extended release or pulsatile release compositions may comprise hydrophilic, lipophilic or hydrophobic release rate controlling substances or their combinations to form matrix or reservoirs or combination of such matrix and reservoir systems.
• the pharmaceutical composition according to the present invention may be administered as granules or pellets directly or filled into capsules or sachets.
• the granules or pellets are in a modified release form.
• the pharmaceutical composition according to the present invention may be administered as MUPS.
• the MUPS or multiparticulate systems are in a controlled release form, immediate release form, dual release form etc.
• the pharmaceutical compositions in the form of granules, pellets and MUPS may include: (a) a core; (b) a sub coating/seal coating or separating layer coated onto the core; and (c) one or more enteric coats coated onto the sub/seal coating or separating layer.
• the pharmaceutical compositions in the form of granules, pellets and MUPS may include: a) a core, and b) one or more seal coats.
• compositions in the form of granules, pellets and MUPS may include: a) a core, and b) one or more enteric coats.
• compositions in the form of granules, pellets and MUPS may include only a core.
• sub coating/seal coating or separating layer over the core is preferably present in an amount from 0.5 to 20% of the composition.
• enteric coats coated over the sub coat/seal coat or separating layer are preferably present in an amount from 2 to 30% of the composition.
• the core would refer to either an inert core coated with the active or core containing the premix.
• the active may be coated on the inert core by techniques such as, but not limited to, powder layering, suspension coating etc.
• the core containing the premix may be obtained by techniques such as, but not limited to, blending, granulation, extrusion-spheronization etc.
• the inert core particles that may be used for the drug layering are Non Pariel seeds (NONPARIEL-101(particle diameter- 850 ⁇ -710 ⁇ , 710-500 ⁇ and 500-355 ⁇ ), O P ARIEL- 103 (particle diameter- 850 ⁇ -710 ⁇ , 710-500 ⁇ and 500-355 ⁇ ), NONPARIEL-105(particle diameter- 85 ⁇ -710 ⁇ 7, 710-500 ⁇ and 300-180 ⁇ ) or Celphere [CP-507 (Particle diameter-500-7 ⁇ ) and CP-305 (Particle diameter 300-5 ⁇ 0 ⁇ )].
• the inert core may comprise any inert inactive material such as, but not limited to, starches, microcrystalline cellulose, sugar sphere or salt, silicon dioxide, glass beads, plastic resin particles, coarse grade silicon beads etc.
• a core particle containing the active material can be produced by granulating the active along with excipients such as, but not limited to, lactose, white sugar, mannitol, corn starch and crystalline cellulose using binders such as hydroxy propyl methyl cellulose, hydroxy propyl cellulose, methyl cellulose, a poly vinyl alcohol, Macrogol, gum Arabic, gelatin and starch or mixtures thereof.
• composition of the present invention comprising one or more enteric coats coated onto the sub/seal coating or separating layer, may be advantageous in modifying the release of the active ingredient.
• the pharmaceutical composition of the present invention comprising one or more enteric coats coated onto the sub/seal coating or separating layer provides a pH dependant release. Accordingly, pharmaceutical composition of the present invention, comprising one or more enteric coats, controls the release of the active ingredient at different pH values.
• the pharmaceutical composition comprising one or more enteric coats comprises one kind of polymeric substances which is soluble in the pH range of not less than 5.
• the pharmaceutical composition comprising one or more enteric coats comprises one kind of polymeric substances which is soluble in the pH range of not less than 6.
• the pharmaceutical composition of the present invention in the form of MUPS may include the use of additional pharmaceutically acceptable excipients.
• the core may be prepared by homogenously mixing the premix and pharmaceutically acceptable excipients.
• the core is then formulated into small beads, pellets, granules, fine granules, mini- tablets or tablets, hard gelatin or soft gelatin capsules by conventional procedures.
• the inert sub coating/seal coating or separating layer (single layered or multilayered) separates the core from an enteric coating polymer that contains free carboxyl groups, which may cause degradation and/or discoloration.
• the inert sub coating/seal coating or separating layer may also serve as a pH-buffering zone in which hydrogen ions diffusing from the outside toward the alkaline core can react with hydroxyl ions diffusing from the alkaline core toward the surface of the coated articles.
• the inert sub coating/seal coating or separating layer can be applied to core (formulated as beads, pellets, granules, fine granules, mini-tablets or tablets, hard gelatin or soft gelatin capsules) by conventional coating procedures using aqueous, non -aqueous or hydro alcoholic solvent systems for the coating solutions or dispersions.
• enteric coats can be coated over to the inert sub coating/seal coating or separating layer by conventional coating procedures using water and/ or an organic solvent for the coating solutions or dispersions.
• Suitable excipients may be used for formulating the various dosage forms according to the present invention.
• Stabilizers refer to any chemical, compound or material that minimizes the degradation of the active ingredient or drug by the acidic environment of the stomach.
• Suitable stabilizers that can be incorporated in the pharmaceutical composition of the present invention may comprise one or more, but not limited to, basic inorganic salts such as sodium carbonate, sodium hydrogen carbonate, sodium hydroxide, potassium carbonate, potassium hydrogen carbonate, potassium hydroxide, heavy magnesium carbonate, light magnesium carbonate, magnesium oxide, magnesium hydroxide, magnesium metasilicate aluminate, magnesium silicate, magnesium aluminate, synthetic hydrotalcite [Mg6A12(OH)16.C03.4H20], and aluminum hydroxide- magnesium oxide [2.5MgO.Al203.xH20], precipitated calcium carbonate, calcium hydroxide or mixtures thereof and organic compounds such as meglumine, lysine, ⁇ , ⁇ '- dibenzylethylenediamine, chloroprocaine
• Suitable carriers, diluents or fillers for use in the pharmaceutical composition of the present invention may comprise one or more, but not limited to lactose (for example, spray-dried lactose, a-lactose, ⁇ -lactose), lactose available under the trade mark Tablettose, various grades of lactose available under the trade mark Pharmatose or other commercially available forms of lactose, lactitol, sucrose, pulverized sugars, saccharose, sorbitol, mannitol, dextrates, dextrins, dextrose, maltodextrin, croscarmellose sodium, microcrystalline cellulose (for example, microcrystalline cellulose available under the trade mark Avicel), hydroxypropylcellulose, L- hydroxypropylcellulose (low substituted), hydroxypropyl methylcellulose (HPMC), methylcellulose polymers (such as, for example, Methocel A, Methocel A4C, Methocel A
• glidants, anti-adherents and lubricants may also be incorporated in the pharmaceutical composition of the present invention, which may comprise one or more, but not limited to stearic acid and pharmaceutically acceptable salts or esters thereof (for example, magnesium stearate, calcium stearate, sodium stearyl fumarate or other metallic stearate), talc, waxes (for example, microcrystalline waxes), glycerides, light mineral oil, PEG, silica acid or a derivative or salt thereof (for example, silicates, silicon dioxide, colloidal silicon dioxide and polymers thereof, crospovidone, magnesium aluminosilicate and or magnesium alumino metasilicate), sucrose ester of fatty acids, hydrogenated vegetable oils (for example, hydrogenated castor oil) or mixtures thereof.
• stearic acid and pharmaceutically acceptable salts or esters thereof for example, magnesium stearate, calcium stearate, sodium stearyl fumarate or other metallic stearate
• suitable binders may also present in the in the pharmaceutical composition of the present invention, which may comprise one or more, but not limited to polyvinyl pyrrolidone (also known as povidone), polyethylene glycol(s), starch, modified starch derivatives (potato starch, rice starch, corn starch, maize starch etc.), hydrolysed starch (maltodextrin), carboxymethyl starch, hydroxypropyl starch, sodium starch glycolate, acacia, alginic acid, agar, calcium carragenan, cellulose derivatives such as ethyl cellulose, methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, sodium carboxymethylcellulose, dextrin, gelatin, gum arabic, guar gum, tragacanth, sodium alginate, sucrose, pulverized sugars or mixtures thereof or any other suitable binder.
• the binder is preferably present in an amount from 0.1 to 5% of the composition.
• suitable disintegrants may also be present in the pharmaceutical composition of the present invention, which may comprise one or more, but not limited to hydrox Ipropy I cellulose (HPC), low density HPC, carboxymethylcellulose (CMC), sodium CMC, calcium CMC, croscarmellose sodium; starches exemplified under examples of fillers and also carboxymethyl starch, hydroxylpropyl starch, modified starch, crospovidone, crystalline cellulose, F-MELT® (Type C, Type M, and Type F l), sodium starch glycolate, alginic acid or a salt thereof, such as sodium alginate or their equivalents and mixtures thereof.
• the disintegrants are preferably present in an amount from 1 to 50% of the composition.
• Suitable viscosity enhancing/thickening agents which may be used in the pharmaceutical composition of the present invention, include, but are not limited to methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethyicellulose, hydroxy ethyl propyl cellulose, starches (such as maize or corn starch, potato starch, rice starch, tapioca starch, and wheat starch), carboxyvinyl polymers (carbomers such as Carbopo)®), carboxymethyl cellulose and salts thereof, microcrystalline cellulose and arabic gum, guar gum,, and xanthan gum, and mixtures thereof.
• the viscosity enhancing/thickening agents is preferably present in an amount from 2 to 20% of the composition.
• suitable polymers that can be used in the pharmaceutical composition of the present invention include hydrophilic, hydrophobic and lipophilic polymers, and combinations thereof.
• polymers include, but are not limited to, cellulose ethers, e.g., hydroxypropyl methylcellulose (hypromellose or HPMC), hydroxypropylcellulose (HPC), hydroxyethylcellulose, ethylcellulose, and carboxymethylcellulose sodium, polyvinylpyrrolidone, including non-crosslinked polyvinylpyrrolidone, carboxymethylstarch, polyethylene glycols, polyoxyethylene, poloxamer (polyoxyethylene-polyoxypropylene copolymers), polyvinylalcohol, glucane (glucan), carrageenan, scleroglucane (scleroglucan), mannan, galactomannan, gellan, alginic acid and derivatives (e.g., sodium or calcium alginate, propylene glycol alginate), polya
• gelatin methyl vinyl ether/maleic anhydride copolymers
• polysaccharides e.g. carageenan, guar gum, xanthan gum, tragacanth and ceratonia
• alpha-, beta- or gamma- cyclodextrins e.g. dextrin
• dextrin derivatives e.g. dextrin
• polymethacrylates e.g.
• copolymers of acrylic and methacrylic acid esters containing quaternary ammonium groups acrylic acid polymers (e.g., carbomers), shellac and derivatives thereof, cellulose acetate, cellulose butyrate, cellulose diacetate, cellulose triacetate, cellulose propionate, cellulose acetate butyrate and other acetylated cellulose derivatives etc. or combinations thereof.
• acrylic acid polymers e.g., carbomers
• shellac and derivatives thereof cellulose acetate, cellulose butyrate, cellulose diacetate, cellulose triacetate, cellulose propionate, cellulose acetate butyrate and other acetylated cellulose derivatives etc. or combinations thereof.
• Suitable lipophilic substances that can be used in the pharmaceutical composition of the present invention include, but are not limited to, waxes (e.g., carnauba wax, macrocrystalline wax, beeswax, and polyethoxylated beeswax), natural fats (coconut, soya, cocoa) including modified forms such as totally or partially hydrogenated, hydrogenated castor oil, hydrogenated vegetable oil and fatty acid derivatives such as mono-, bi- and tri-substituted glycerides, phospholipids, glycerophospholipids, glyceryl palmitostearate, glyceryl behenate, glyceryl monostearate, diethyleneglycol palmitostearate, polyethyleneglycol stearate, polyethyleneglycol palmitostearate, polyoxyethylene-glycol palmitostearate, glyceryl monopalmitostearate, cetyl palmitate, fatty alcohols associated with polyethoxylate fatty alcohols, cety
• surfactants may comprise of one or more, but not limited to polysorbates, sodium dodecyl sulfate (sodium lauryl sulfate), lauryl dimethyl amine oxide, docusate sodium, cetyl trimethyl ammonium bromide (CTAB) polyethoxylated alcohols, polyoxyethylene sorbitan, octoxynol, N, N- dimethyldodecylamine-N-oxide, hexadecyltrimethylammonium bromide, polyoxyl 10 lauryl ether, brij, bile salts (sodium deoxycholate, sodium cholate), polyoxyl castor oil, nonylphenol ethoxylate cyclodextrins, lecithin, methylbenzethonium chloride, carboxylates, sulphonates, petroleum sulphonates, alkylbenzene
• CTAB cetyl trimethyl ammonium bromide
• Viscosity builders are excipients that are capable of stabilizing the formulation by increasing the viscosity of the formulation and thus preventing physical interaction of nanoparticles under the operating conditions employed.
• viscosity builders may comprise one or more, but not limited to derivatives of sugars, such as lactose, sucrose, saccharose, hydrolyzed starch (maltodextrin) or mixtures thereof.
• Polymers or polymers blends may comprise one or more hydrophilic polymers, but not limited to cellulose derivates like hydroxypropylcellulose, hydroxymethylcellulose, hydroxypropylmethylcellulose, methylcellulose polymers hydroxyethylcellulose, sodium carboxymethylcellulose, carboxymethylene and carboxymethyl hydroxyethylcellulose; acrylics like acrylic acid, acrylamide, and maleic anhydride polymers, acacia, gum tragacanth, locust bean gum, guar gum, or karaya gum, agar, pectin, carrageenan, gelatin, casein, zein and alginates, carboxypolymethylene, bentonite, magnesium aluminum silicate, polysaccharides, modified starch derivatives and copolymers or mixtures thereof,
• the pharmaceutical compositions, according to the present invention may also optionally be coated, but not limited to seal coating, film coating, enteric coating or a combination thereof.
• pharmaceutical composition may be film coated with, but not limited to, ready colour mix systems (such as Opadry colour mix systems) and Kollicoat® Protect.
• the seal coat comprises water soluble or insoluble film forming polymeric materials, such as but not limited to, sugars, zein, cellulose derivatives such as hydroxypropyl celluloses, hydroxypropyl methylcellu!oses, ethylcelluloses, and hydroxyethyl celluloses, polyvinylalcohols, providones, polyethylene glycols, poloxamers, gelatin, polylysine, polyarginine, polyglycine " , polyvinylpyrrolidines, vinyl acetate copolymer, methylcellulose, carboxymethylcellulose, hypromellose, acacia and mixtures thereof to increase adherence and coherence of the seal coat.
• polymeric materials such as but not limited to, sugars, zein, cellulose derivatives such as hydroxypropyl celluloses, hydroxypropyl methylcellu!oses, ethylcelluloses, and hydroxyethyl celluloses, polyvinylalcohols, provid
• enteric coating polymers that can be used, in the pharmaceutical composition of the present invention, include, but are not limited to, cellulose acetate phthalates (CAP), hydroxypropyl methylcellulose phthalates (HPMCP), polyvinyl acetate phthaiates (PVAP), hydroxypropyl methylcellulose acetate succinates (HPMCAS), cellulose acetate trimellitates, hydroxypropyl methylcellulose succinates, cellulose acetate succinates, cellulose acetate hexahydrophthalates, cellulose propionate phthalates, copolymers of methylmethacrylic acid and methyl methacrylate, copolymers of methyl acrylate, methylmethacrylate and methacrylic acid, copolymers of methylvinyl ether and maleic anhydride (GantrezTM ES series), ethyl methyacrylate-methylmethacrylate-chlorotrimethylammonium ethyl acryl
• CAP
• plasticizers for use in the pharmaceutical composition of the present invention may comprise one or more, but are not limited to substances such as castor oil, diacetylated monoglycerides, dibutyl sebacate, diethyl phthalate, glycerin, polyethylene glycol, propylene glycol, triacetin, and triethyl citrate.
• pH adjusting agents include, but are not limited to: sodium hydroxide, citric acid, hydrochloric acid, acetic acid, phosphoric acid, succinic acid, sodium hydroxide, potassium hydroxide, ammonium hydroxide, magnesium oxide, calcium carbonate, magnesium carbonate, magnesium aluminum silicates, malic acid, potassium citrate, sodium citrate, sodium phosphate, lactic acid, gluconic acid, tartaric acid, 1,2,3,4-butane tetracarboxylic acid, fumaric acid, diethanolamine, monoethanolamine, sodium carbonate, sodium bicarbonate, triethanolamine, or combinations thereof.
• the pH adjusting agents are preferably present in an amount from 0.02 to 5% of the composition.
• one or more pharmaceutically acceptable opacifiers such as, but not limited to, titanium dioxide (Ti02) may be used in the pharmaceutical composition covered in the present invention.
• Suitable colouring agents that may be used in the pharmaceutical composition of the present invention, include but are not limited to, natural and/or artificial compounds such as FD&C colouring agents, natural juice concentrates, pigents such as titanium oxide, silicon dioxide, iron oxides such as red oxide of iron, zinc oxide and mixtures thereof.
• Suitable sweetening agents that may be used in the pharmaceutical composition of the present invention, include but are not limited to, natural and/or artificial compounds, such as acesulfame, sucrose, mannitol, cyclamate, alitame, a dihydrochalcone sweetener, monellin, neohesperidin, neotame, stevia and sucralose, their pharmaceutically acceptable salts and mixtures thereof.
• Suitable flavouring agents which may be used in the pharmaceutical composition of the present invention, include, but are not limited to cherry, raspberry, pineapple, black currant, strawberry flavour, caramel chocolate flavour, mint flavor and the like.
• compositions may be prepared through various techniques or processes known in the art which includes, but are not limited to direct blending,, direct compression, wet granulation, dry granulation, melt granulation, melt extrusion, lyophilisation, hot melt extrusion, spray drying, solution evaporation, extrusion-spheronization or combinations thereof.
• the pharmaceutical composition according to the present invention may also comprise the drug in nano size form.
• the pharmaceutical composition according to the present invention comprising the drug in nano size form may exhibit better aqueous solubility and oral bioavailability and may, in turn, cause a reduction in the dosage of the drug.
• Nanonization of hydrophobic or poorly water-soluble drug generally involves the production of drug nanocrystals through either chemical precipitation (bottom-up technology) or disintegration (top-down technology). Different methods may be utilized to reduce the particle size of the hydrophobic or poorly water soluble drug. [Huabing Chen et al., discusses the various methods to develop nanoformulations in "Nanonization strategies for poorly water-soluble drug," Drug Discovery Today, Volume 00, Number 00, March 2010].
• nanosize refers to drug particles, preferably, having a D50 number average particle size of less than 2000 nm, preferably less than 1000 nm more preferably less than 500 nm, such as less than 100 nm, less than 200 nm, less than 300 nm, less than 400 nm, or less than 500 nm.
• particles have a particle size of less than or equal to about 2000 nm, preferably less than or equal to about 1000 nm.
• particles refers to individual particle of drug or particles of drug or drug granules or drug compositions and/or mixtures thereof.
• nanosize particles of the present invention can be obtained by any of the process such as but not limited to milling, precipitation and homogenization.
• milling comprises the process of reduction of the size of the particles as such in the solid form by using milling machines such as but not limited to ball mill, jet mill , planetary mill etc.
• Particle size reduction may also be achieved by dispersing drug particles in a liquid medium in which the drug is poorly soluble followed by applying mechanical means in the presence of grinding media to reduce the particle size of drug to the desired effective average particle size.
• the process of precipitation involves the formation of crystalline or semi-crystalline drug nanoparticles by nucleation and the growth of drug crystals.
• drug molecules are first dissolved in an appropriate organic solvent such as acetone, tetrahydrof ran or N-methyl-2 -pyrrol idone at a super saturation concentration to allow for the nucleation of drug seeds.
• Drug nanocrystals are then formed by adding the organic mixture to an antisolvent like water in the presence of stabilizers such surfactants.
• stabilizers such surfactants.
• the process of homogenization involves passing a suspension of crystalline drug and stabilizers through the narrow gap of a homogenizer at high pressure (500-2000 bar).
• the pressure creates powerful disruptive forces such as cavitation, collision and shearing, which disintegrate coarse particles to nanoparticles.
• the process of high pressure homogenization comprises drug presuspension (containing drug in the micrometer range) by subjecting the drug to air jet milling in the presence of an aqueous surfactant solution.
• the presuspension is then subjected to high-pressure homogenization in which it passes through a very small homogenizer gap of 25 ⁇ which leads to a high streaming velocity.
• High pressure homogenization is based on the principle of cavitations (i.e., the formation, growth, and implosive collapse of vapor bubbles in a liquid).
• the process of spray-freeze drying involves the atomization of an aqueous drug solution into a spray chamber filled with a cryogenic liquid (liquid nitrogen) or halocarbon refrigerant such as chlorofluorocarbon or fluorocarbon.
• a cryogenic liquid liquid nitrogen
• halocarbon refrigerant such as chlorofluorocarbon or fluorocarbon.
• the process of supercritical fluid technology involves controlled crystallization of drug from dispersion in supercritical fluids, carbon dioxide.
• the process of double emulsion/solvent evaporation technique involves preparation of oil/water (o/w) emulsions with subsequent removal of the oil phase through evaporation.
• the emulsions are prepared by emulsifying the organic phase containing drug, polymer and organic solvent in an aqueous solution containing emulsifier.
• the organic solvent diffuses out of the polymer phase and into the aqueous phase, and is then evaporated, forming drug-loaded polymeric nanoparticles.
• PRINT particle replication in non-wetting templates
• PRINT particle replication in non-wetting templates
• PRINT can precisely manipulate particle size of drug ranging from 20 nm to more than 100 nm.
• the process of thermal condensation involves use of capillary aerosol generator (CAG) to produce high concentration condensation submicron to micron sized aerosols from drug solutions.
• CAG capillary aerosol generator
• the process of ultrasonication involves application of ultrasound during particle synthesis or precipitation, which leads to smaller particles of drug and increased size uniformity.
• the process of spray drying involves supplying the feed solution at room temperature and pumping it through the nozzle where it is atomized by the nozzle gas.
• the atomized solution is then dried by preheated drying gas in a special chamber to remove water moisture from the system, thus forming dry particles of drug.
• compositions of the present invention comprise the drug particles that can be manufactured by any of the types of processes as described above.
• compositions of the present invention comprise the drug particles manufactured by any of the types of processes as described above may be formulated in dosage forms such as, but not limited to, tablets (single layer, bilayer, multilayer, tablet in tablet) which may be coated or iincoated, film coated, sugar coated, powder coated, enteric coated, seal coated; capsules (filled with powders, powders for reconstitution, pellets, beads, mini-tablets, pills, micro-pellets, small tablet units, film coated tablets, MUPS, film coated tablets MUPS, orally disintegrating MUPS, disintegrating tablets, dispersible tablets, granules, microspheres and multiparticulates or combinations thereof), soft gelatin capsules, sachets (filled with powders, pellets, beads, mini-tablets, pills, micro-pellets, small tablet units, film coated tablets, MUPS, film coated tablets MUPS, orally disintegrating MUPS, disintegrating tablets, dispersible tablets, granules, microspheres, multiparticulates or combinations thereof
• the present invention also provides a method of preventing or treating a gastrointestinal disorder, which method comprises administering a pharmaceutical composition comprising a triol solvate of (R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]-methyl]sulphinyl]- lH-benzimidazole to a patient in need thereof.
• a pharmaceutical composition comprising a triol solvate of (R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]-methyl]sulphinyl]- lH-benzimidazole to a patient in need thereof.
• the triol solvate is a glycerol solvate.
• the pharmaceutical composition comprises (R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2- yl]-methyl]sulphinyl]-lH-benzimidazole glycerol solvate Form A, B or C, or a mixture thereof.
• the present invention also provides the use of a pharmaceutical composition comprising a triol solvate of (R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]-methyI]sulphinyl]-lH- benzimidazole for the prevention or treatment of a gastrointestinal disorder.
• the triol solvate is a glycerol solvate.
• the pharmaceutical composition comprises (R)-2- [[[3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]-methyl]sulphinyl]-lH-benzimidazole glycerol solvate Form A, B or C, or a mixture thereof.
• the present invention also provides a pharmaceutical composition
• a pharmaceutical composition comprising a triol solvate of ( )-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]-methyl]suIphinyl]- lH-benzimidazoIe for use in the prevention or treatment of gastrointestinal disorders.
• the triol solvate is a ⁇ glycerol solvate.
• the pharmaceutical composition comprises (R)-2-[[[3-methyl- 4-(2,2,2-trifluoroethoxy)pyridin-2-yl]-methyl]sulphinyl]-lH-benzimidazole glycerol solvate Form A, B or C, or a mixture thereof.
• the gastrointestinal disorder is selected from heartburn caused by gastroesophageal reflux disease (GERD) and erosive esophagitis.
• GFD gastroesophageal reflux disease
• erosive esophagitis erosive esophagitis
• the pharmaceutical composition, according to the present invention may further comprise or may be administered in combination with other compounds such as, but not limited to NSAIDS, antacids, anti-emetic agents, antibiotics, HMG-CoA reductase inhibitors, ACE inhibitors, angiotensin receptor blockers, calcium channel blockers, and any other vasodilatory or antihypertensive agents or platelet aggregation inhibitors and oral anticoagulants for the treatment of for gastrointestinal disorders.
• the pharmaceutical composition, according to the present invention, with other compounds may be administered simultaneously, separately, or sequentially.
• the pharmaceutical composition, according to the present invention may be provided with other compounds in the form of a kit.
• an automated sample collector removes aliquots from dissolution medium for analysis.
• the time interval for sampling can vary, for example, from 2 to 30 minutes, depending on the properties of the drug and dissolution medium used. Suitable dissolution equipment for these operations includes LAB INDIA DISSO 2000.
• Example 1 Preparation of crystalline Form A of (R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy) pyridin-2-yl]-methyl]sulphinyl]-lH-benzimidazoIe glycerol solvate ( )-2-[[[3-methyI-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]-methyl]sulphinyl]-lH-benzimida2oIe sesquihydrate (10 g) was dissolved in ethyl acetate (200 ml), dried over anhydrous sodium sulphate.
• Example 2 Preparation of crystalline Form A of (R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy) pyridin-2-yl]-methyl]sulphinyl]-lH-benzimidazole glycerol solvate by using 25% w/w of glycerol in presence of an organic base
• reaction mixture was heated to 40°C to 45°C and n-heptane (500 ml) was added slowly at 40°C to 45°C.
• the reaction mass was cooled to 25°G to 30°C, and stirred for 60 minutes.
• the solid was isolated by filtration, washed with n-heptane (50 ml) and dried under vacuum at 25°C to 30°C for 8 to 10 hours.
• Example 3 Preparation of crystalline Form A of (R)-2-[[[3-methyl-4-(2,2,2- trifluoroethoxy)pyridin-2-yl]-methyl]sulphinyl]-lH-benziniidazole glycerol solvate by using 20% xv/xv of glycerol in presence of an organic base
• sesquihydrate (25 g) was dissolved in ethyl acetate (375 ml), dried over anhydrous sodium sulphate.
• Triethylamine (0.5 ml) was added and the solvent was removed below 40°C, stripped off with ethyl acetate (250 ml) and the residual solid was dissolved in ethyl acetate (125 ml).
• Glycerol (5.0 g) was added and the reaction mass was diluted with ethyl acetate (125 ml). The reaction mixture was heated to 40°C to 45°C and n-heptane (500 ml) was added slowly at 40°C to 45°C.
• reaction mass was cooled to 25°C to 30°C, and stirred for 60 minutes.
• the solid was isolated by filtration, washed with n-heptane (50 ml) and dried under vacuum at 25°C to 30°C for 8 to 10 hours.
• reaction mixture was heated to 40°C to 45°C and n-heptane (500 ml) was added slowly at 40°C to 45°C.
• the reaction mass was cooled to 25°C to 30°C, and stirred for 60 minutes.
• the solid was isolated by filtration, washed with n-heptane (50 ml) and dried under vacuum at 25°C to 30°C for 8 to 10 hours.
• Example 5 Preparation of crystalline Form B of (R)-2-[[[3-methyl-4-(2, 2,2-trifluoroethoxy) pyridin-2-yI]-methyI]sulphinyl]-lH-benzimidazole glycerol solvate (R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yI]-methyl]sulphinyl]- lH-benzimidazole sesquihydrate (25 g) was dissolved in ethyl acetate (100 ml). Glycerol (6.25 g) was added and the reaction mass was diluted with ethyl acetate (150 ml).
• reaction mass was heated to 40°C to 45°C and n-heptane (500 ml) was added slowly at 4D°C to 45°C.
• the reaction mass was cooled to 25°C to 30°C, and stirred for 60 minutes.
• the solid was isolated by filtration, washed with n- heptane (50 ml) and dried under vacuum at 25°C to 30°C for 8 to 10 hours.
• Example 7 Preparation of crystalline Form C of (R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy) pyridin-2-yll-methyI]sulphmyl]-lH-benzimidazoIe glycerol solvate by using 15% w/w of glycerol without organic base
• Example 8 Preparation of crystalline Form C of (R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy) pyridin-2-yI]-methyl]sulphinyl]-lH-benzimidazole glycerol solvate by using 20% w/w of glycerol in presence of an organic base
• Example 10 Preparation of anhydrous (R)-2-[[[3-methyI-4-(2,2,2-trifluoroethoxy)pyridin- 2-yI]-methyl]sulphinyI]-lH-benzimidazole from Form C Crystalline Form C of (R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]- methyl]sulphinyl]-lH-benzimidazole glycerol solvate (2.0 g) was dissolved in ethyl acetate (50 ml) and washed with water. The organic layer was dried over anhydrous sodium sulphate and distilled completely under vacuum at 40°C to 45°C.
• reaction mass was cooled to 25°C to 30°C, diluted with ethyl acetate (30 ml) and further chilled to 0°C to5°C.
• the reaction mass was stirred for 30 minutes, the solid was isolated by filtration and dried under vacuum at 40°C to 45°C for 12 to 14 hours.
• Example 14 Preparation of crystalline Form A of (R)-2-[([3-methyl-4-(2,2,2- trifluoroethoxy) pyridin-2-yl]-methyl]sulphinyl]-lH-benzimidazole glycerol solvate
• (+)-diethyI L-tartrate (3.619 g /0.0175 moles), titanium (IV) isopropoxide (2.415 g / 0.0084 moles) and water (0.06 g / 0.0033 moles) were added to toluene (75 ml) at 25°C to 30°C.
• the solution was stirred for 15 minutes and 2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyI]- methyl]thio]-lH-benzimidazoIe (10 g / 0.02829 moles) was added.
• the reaction mass was heated to 70°C to 75°C, maintained for 5 minutes and cooled to 25°C to 30°Cover 30 minutes.
• Diisopropylethylamine (2.342 g / 0.0181 moles) was added, stirred for 30 minutes and then cooled to -5°C to 0°C.
• a solution of 80% cumene hydroperoxide (14.788 g/ 0.0971 moles) in toluene (10 ml) was added at -5°C to 0°C over 60 minutes.
• the reaction was stirred for 2 to2.5 hours at -5°C to 0°C and quenched with 5% aqueous KOH solution (50 ml) maintaining temperature at about -5°C to 0°C.
• the temperature of the reaction mass was raised to 25°C - 30°C and methanol was charged (25 ml).
• the reaction mass was basified to a pH of 12.5 to 13.0 with 20% aqueous KOH solution and stirred for 10 minutes at 30°C to 35°C.
• the aqueous layer was separated at 30°C to 35°C and the organic layer was extracted with a mixture of 5% aqueous KOH (30 ml) and methanol (15 ml) at 30°C to 35°C.
• the aqueous layers were combined and washed with DC (3 x 30 ml) at 30°C to 35°C.
• the pH of the aqueous solution was adjusted to 8.5 to 9.5 with 20% acetic acid at 30°C to 35°C.
• the solid was extracted in ethyl acetate (2 x 50 ml).
• (+)-diethyl L-tartrate (36.0 g, 0.1741 moles ), titanium (IV) isopropoxide (24.0 g, 0.00835 moles) and water (0.6 g, 0.033 moles) were added to toluene (750 ml) at 25°C - 30°C.
• the solution was stirred for 15 minutes and added 2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]- methyl]thio]-lH-benzimidazole (100 g / 0.2829 moles).
• the reaction mass was heated to 70°C - 75°C, maintained for 5 minutes and cooled to 25°C - 30°C over 30 minutes.
• Diisopropylethylamine (24.0 g, 0.181 moles) was added, stirred for 30 minutes and then cooled to -5°C - 0°C.
• a solution of 80% cumene hydroperoxide (148 gf 0.971 moles) in toluene (100 ml) was added at -5°C-0°C over 60 minutes.
• the reaction was stirred for 2-2.5 hours at -5°C - 0°C and quenched with 5% aqueous KOH solution (500 ml) ' maintaining temperature at about - 5°C - 0°C.
• the temperature of the reaction mass was raised to 25°C - 30°C and methanol was charged (250 ml).
• the reaction mass was basified to a pH of 12.5 - 13.0 with 20% aqueous KOH solution and stirred for 10 minutes.
• the aqueous layer was separated and the organic layer was extracted with a mixture of 5% aqueous KOH (300 ml) and methanol ( 150 ml) .
• the aqueous layers were combined and washed with MDC.
• Ethyl acetate was (700 ml) was charged.
• the pH of the reaction mass was adjusted to 8- 9 with 20% AcOH.
• the organic layer was separated. Aqueous layer was extracted with ethyl acetate.
• n-Heptane 100 ml was added slowly at 40°C - 45°C.
• the reaction mass was cooled to 25°C - 30°C, further chilled to 5°C - 10°C and stirred for 2 hours.
• the solid was isolated by filtration, washed with n-heptane (50 ml) and dried under vacuum at 25°C - 30°C for 8 - 10 hours.
• (+)-diethyl L-tartrate (36.0 g, 0.1741 moles ), titanium (IV) isopropoxide (24.0 g, 0.00835 moles) and water (0.6 g, 0.033 moles) were added to toluene (750 ml) at 25°C - 30°C.
• the solution was stirred for 15 minutes and added 2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]- methyl]thio]-lH-benzimidazole (100 g / 0.2829 moles).
• the reaction mass was heated to 70°C - 75°C, maintained for 5 minutes and cooled to 25°C - 30°C over 30 minutes.
• Diisopropylethylamine (24.0 g, 0.181 moles) was added, stirred for 30 minutes and then cooled to -5°C- 0°C.
• a solution of 80% cumene hydroperoxide (148 gf 0.971 moles) in toluene (100 ml) was added at -5°C - 0°C over 60 minutes.
• the reaction was stirred for 2r2.5 hours at -5°C - 0°C and quenched with 5% aqueous KOH solution (500 ml) maintaining temperature at about - 5°C- 0°C.
• the temperature of the reaction mass was raised to 25°C - 30°C and methanol was charged (250 ml).
• the reaction mass was basified to a pH of 12.5 - 13.0 with 20% aqueous OH solution.
• the aqueous layer was separated and the organic layer was extracted with a mixture of 5% aqueous KOH (300 ml) and methanol (150 ml).
• MDC was (700 ml) was charged.
• the pH of the reaction mass was adjusted to 8- 9 with 20% AcOH.
• the organic layer was separated.
• Aqueous layer was extracted with MDC.
• the organic layers were combined, washed with water, dried with anhydrous sodium sulphate, filtered through hyflo bed and distilled out completely under vacuum. The residue was dissolved in ethyl acetate (1000 ml).
• the solid was stirred in MDC (700 ml) and water (500 ml). The pH of the reaction mass was adjusted to 8-9 with 20% AcOH solution (75 ml). The organic layer was separated, washed with water, filtered through hyflo bed and distilled out completely under vacuum. The residue was dissolved in ethyl acetate (700 ml ). Water (4.9ml) and Glycerol (17.5g) were added. The reaction mass was heated to 30°C - 35°C, added n-Heptane (70 ml), cooled to 25°C - 30°C, further chilled to 5°C - 10°C and stirred for 2 hours. The solid was isolated by filtration and washed with n-Heptane (70 ml) and dried under vacuum at 25°C - 30°C for 8—10 hours.
• Example 17 Preparation of tablet General process for preparing tableting mixture comprising (R)-2-[[[3-methyl-4-(2, 2,2- trifluoroethoxy) pyridin-2-yl]-methyl]sulphinyl]-lH-benzimidazole glycerol solvate:- A tableting mixture (50 mg) comprising solely (R)-2-[[[3-methyl-4-(2, 2,2-trifluoroethoxy) pyridin-2-yI]-methyl]suIphinyl]-lH-benzimidazole glycerol solvate prepared according to any of the examples 1 to 16 (i.e. with no excipients) was prepared and compressed to a pellet using a manual hand press operating at a compression pressure of 1 tonnes for 1 minute.
• a tableting mixture (50 mg) comprising solely (R)-2-[[[3-methyl-4-(2, 2,2- trifluoroethoxy) pyridin-2-yl]-methyl]sulphinyl]-lH-benzimidazoIe in anhydrous or sesquihydrate form each was prepared and compressed to a pellet using a manual hand press operating at a compression pressure of 1 tonnes for 1 minute.
• the pellet was fixed in a PFTE holder, such that only the pellet surface came into contact with the dissolution medium.
• the PFTE loaded holder was placed in the dissolution vessel containing 900 ml of 2% SLS in Phosphate buffer pH 7.5 at 37 ⁇ 0.5°C.
• One pellet was measured for each run of the design of the experiments. Stirring was performed with a paddle rotating at 100 rpm.
• the dissolution was followed up to 360min and the concentration of active ingredient, (R)-2-[[[3- methyl-4-(2, 2,2-trifluoroethoxy) pyridin-2-yl]-methyl]sulphinyl]-lH-benzimidazole, dissolved in the test medium was determined by removing samples of 10 ml at the specified time.
• Sample Aliquot 10 ml of aliquot further diluted to 50 ml with dissolution medium.
• Example 18 The percentage of (R)-2-[[[3-methyl-4-(2, 2,2-trifluoroethoxy) pyridin-2-yl]-methyl]sulphinyl]- lH-benzimidazole released from the glycerol solvate Form C as well as from the anhydrous and sesquihydrate forms of (R)-2-[[[3-methyl-4-(2, 2,2-trifluoroethoxy) pyridin-2-yl]- methyl]sulphinyl]-lH-benzimidazole was plotted against time, as shown in Figure 5. The intrinsic dissolution rate was derived from the slope of this curve. Table B shows the results in tabular form.
• the drug loaded pellets obtained in step (1) were seal coated using HPMC, talc and titanium dioxide and part of the seal coated pellets were enteric coated using Methacrylic Acid - Ethyl Acrylate Copolymer (1: 1) dispersion to form Enteric coated pellets I.
• the drug loaded pellets obtained in step (1) were seal coated using HPMC, talc and titanium dioxide and a part of the seal coated pellets obtained in step (2) were enteric coated Methacrylic Acid - Ethyl Acrylate Copolymer (1 : 1) dispersion to form Enteric coated pellets I. 3. Remaining part of seal coated pellets were then enteric coated using Methacrylic Acid - Methyl Methacrylate Copolymer (1 : 1) dispersion and Methacrylic Acid - Methyl Methacrylate Copolymer ( 1 :2) dispersion to form Enteric coated pellets II. 4.
• Enteric coated pellets I and II obtained in step (2) and (3) respectively were blended with F - Melt® Type C, microcrystalline cellulose, crospovidone, mannitol, aspartame, strawberry flavor and colloidal silicon dioxide and this blend was lubricated with magnesium stearate and compressed into tablets.
• Example 21 Film coated tablet MUPS
• the drug loaded pellets obtained in step (1) were seal coated using HPMC, talc and titanium dioxide and part of the seal coated pellets were enteric coated Methacrylic Acid - Ethyl Acrylate Copolymer (1 :1) dispersion to form Enteric coated pellets I. 3. Remaining part of seal coated pellets were then enteric coated using Methacrylic Acid - Methyl Methacrylate Copolymer ( 1 : 1) dispersion and Methacrylic Acid - Methyl Methacrylate Copolymer (1 :2) dispersion to form Enteric coated pellets II.
• Enteric coated pellets I and II obtained in step (2) and (3) respectively were blended with F - Melt® Type C, microcrystalline cellulose Crospovidone and Colloidal anhydrous silica and this blend was lubricated with sodium stearyl ftimatrate and compressed into tablets followed by coating with Opadry.
• Example 22 Sachets for oral suspension
• Titanium dioxide 1.50
• benzimidazoie glycerol solvate light magnesium carbonate, pulverised sugar and low substituted hydroxypropyl cellulose were blended together to produce a dry mix was loaded on sugar spheres in a coating machine using a binder to form drug loaded pellets.
• the drug loaded pellets obtained in step (1) were seal coated using HPMC, talc and titanium dioxide andpart of the seal coated pellets were enteric coated Methacrylic Acid - Ethyl Acrylate Copolymer (1 : 1) dispersion to form Enteric coated pellets I.
• Enteric coated pellets I and II obtained in step (2) and (3) respectively were blended with sucrose, mannitol, xanthan gum, crospovidone, colloidal silicon dioxide, citric acid, sodium citrate, red oxide of iron and strawberry flavor and this blend was lubricated with magnesium stearate and filled into sachets.

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