WO2012095859A1 - Polymorphs of dexlansoprazole salts - Google Patents

Polymorphs of dexlansoprazole salts Download PDF

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Publication number
WO2012095859A1
WO2012095859A1 PCT/IN2011/000782 IN2011000782W WO2012095859A1 WO 2012095859 A1 WO2012095859 A1 WO 2012095859A1 IN 2011000782 W IN2011000782 W IN 2011000782W WO 2012095859 A1 WO2012095859 A1 WO 2012095859A1
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Prior art keywords
dexlansoprazole
solvent
sodium
crystalline form
acid
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PCT/IN2011/000782
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French (fr)
Inventor
Bandi Parthasaradhi Reddy
Kura Rathnakar Reddy
Dasari Muralidhara Reddy
Matta Ramakrishna Reddy
Bandi Vamsi Krishna
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Hetero Research Foundation
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Priority to EP11855797.4A priority Critical patent/EP2663306A4/en
Publication of WO2012095859A1 publication Critical patent/WO2012095859A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • 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

Definitions

  • the present invention provides a solid of dexlansoprazole sodium.
  • the present invention also provides novel crystalline forms of dexlansoprazole sodium, processes for their preparation and pharmaceutical compositions comprising them.
  • the present invention further provides a novel amorphous form of dexlansoprazole sodium, process for its * preparation and pharmaceutical compositions comprising it.
  • the present invention further provides a novel process for the preparation of dexlansoprazole amorphous form and pharmaceutical compositions comprising it.
  • the present invention further provides a process for the preparation of dexlansoprazole crystalline form I.
  • the present invention further provides a process for the preparation of dexlansoprazole crystalline form II.
  • Lansoprazole chemically 2-[[[3-methyl-4-(2,2,2-trifluoro-ethoxy)-2- pyridinyl]methyl]sulfmyl]-lH-benzimidazole were disclosed in European Patent No. 0174726 and U.S. Patent No. 4,628,098.
  • Lansoprazole was a well-known gastric acid secretion inhibitor, and was useful for prophylaxis and therapy of digestive ulcers (e.g. gastric ulcer, duodenal ulcer) and gastritis.
  • the generic name dexlansoprazole is marketed by Takeda Pharms under the brand name DEXILANT ® .
  • U. S. Patent No. 6,462,058 ( ⁇ 58 patent) disclosed an anhydrous crystalline form (hereinafter referred to as "crystalline form I") and a crystalline 1.5 hydrate (hereinafter referred to as "crystalline form II") of R-lansoprazole and its use as an anti-ulcer agent.
  • crystalline form I anhydrous crystalline form
  • crystalline form II a crystalline 1.5 hydrate
  • U.S. Patent Nos. 6,462,058; 5,929,244 and 6,664,276; and International Patent Publication No. WO 00/78745 all described the synthesis of a crystal of R-lansoprazole. Exemplary methods for such synthesis include:
  • Optical resolution of substituted 2-(2-pyridinylmethylsulfinyl)-lH- benzimidazoles by a fractional crystallization method, which includes forming a salt between a racemate and an optically active compound (for example, (+)-mandelic acid, (- )-mandelic acid, (+)-tartaric acid, (-)-tartaric acid, camphoursulfonyl chloride, or camphanic acid).
  • an optically active compound for example, (+)-mandelic acid, (- )-mandelic acid, (+)-tartaric acid, (-)-tartaric acid, camphoursulfonyl chloride, or camphanic acid.
  • the diastereoisomeric salt is separated by fractional crystallization and then subjected to a neutralization process to give a free optical isomer.
  • the chiral column method includes a method in which a racemate or a salt is applied to a column for optical isomer separation.
  • a chiral column such as the Daicel ® series (produced by Daicel Chemical Industries, Ltd.), and eluting in water, a buffer (for example, a phosphate), an organic solvent (for example, hexane, ethanol, methanol, isopropanol, acetonitrile, triethylamine, or mixtures thereof) or mixtures of the foregoing.
  • the asymmetric oxidation process includes subjecting substituted 2-(2- pyridinylmethylsulfinyl)-lH-benzimidazoles to an asymmetric oxidation to obtain enantiomer of substituted 2-(2-pyridinylmethylsulfinyl)-lH-benzimidazoles, followed by crystallizing the resultant isomer.
  • dexlansoprazole metal salts including sodium salt was mentioned in '058 patent, but the existence of polymorphs of sodium were not mentioned. It has been found that dexlansoprazole sodium was obtained by the processes described for example in US 5,929,244 resulted as an oily substance.
  • the amorphous form obtained by the process of the present invention is found to have substantially pure as measured by high performance liquid chromatography (HPLC).
  • one object of the present invention is to provide a solid of dexlansoprazole sodium.
  • the solid of dexlansoprazole sodium of the present invention can be used for the preparation of pharmaceutical compositions and can also be used as method of purification of dexlansoprazole.
  • the solid of dexlansoprazole sodium may also serve as intermediate for preparation of dexlansoprazole.
  • Another object of the present invention is to provide a novel crystalline forms of dexlansoprazole sodium, processes for their preparation and pharmaceutical compositions comprising them.
  • Another object of the present invention is to provide a novel amorphous form of dexlansoprazole sodium, process for its preparation and pharmaceutical compositions comprising it.
  • Another object of the present invention is to provide a novel process for the preparation of dexlansoprazole amorphous form and pharmaceutical compositions comprising it.
  • Another object of the present invention is to provide a process for the preparation of dexlansoprazole crystalline form I.
  • Another object of the present invention is to provide a process for the preparation of dexlansoprazole crystalline form II.
  • the present invention provides a solid of dexlansoprazole sodium.
  • the present invention provides a crystalline form of dexlansoprazole sodium designated as form 1 characterized by peaks in the powder x-ray diffraction spectrum having 20 angle positions at about 4.3, 5.0, 6.5, 13.2, 15.7, 17.9, 20.0 and 24.6 ⁇ 0.2 degrees.
  • the present invention provides a process for the preparation of crystalline form 1 of dexlansoprazole sodium, which comprises:
  • step (a) adding above about 1.5 mole sodium 2-ethylhexanoate per mole of dexlansoprazole used in step (a) to the solution obtained in step (a);
  • step (c) adding hydrocarbon solvent to the residual mass obtained in step (c); and e) isolating crystalline form 1 of dexlansoprazole sodium.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising crystalline form 1 of dexlansoprazole sodium and pharmaceutically acceptable excipients.
  • the present invention provides a crystalline form of dexlansoprazole sodium designated as form 2 characterized by peaks in the powder x-ray diffraction spectrum having 20 angle positions at about 5.6, 7.1, 11.2, 11.9, 12.3 and 18.5 ⁇ 0.2 degrees.
  • the present invention provides a process for the preparation of crystalline form 2 of dexlansoprazole sodium, which comprises:
  • step (a) cooling the solution obtained in step (a) at below 5°C;
  • step (a) adding above about 1.5 mole sodium hydroxide per mole of dexlansoprazole used in step (a) at below 5°C;
  • step (c) adding hydrocarbon solvent to the reaction mass obtained in step (c); and e) isolating crystalline form 2 of dexlansoprazole sodium.
  • the present invention provides a pharmaceutical composition comprising crystalline form 2 of dexlansoprazole sodium and pharmaceutically acceptable excipients.
  • the present invention provides a novel amorphous form of dexlansoprazole sodium.
  • the present invention provides a process for the preparation of amorphous form of dexlansoprazole sodium, which comprises:
  • step (a) adding above about 1.5 mole sodium hydroxide per mole of dexlansoprazole used in step (a) to the solution obtained in step (a) at 0°C;
  • step (c) adding hydrocarbon solvent to the foam obtained in step (c);
  • the present invention provides a pharmaceutical composition comprising amorphous form of dexlansoprazole sodium and pharmaceutically acceptable excipients.
  • the present invention provides a process for the preparation of dexlansoprazole amorphous form, which comprises:
  • step (b) removing the solvent completely from the solution obtained in step (a); and c) drying the solid obtained in step (b) to obtain dexlansoprazole amorphous form.
  • the present invention provides a process for the preparation of dexlansoprazole amorphous form, which comprises:
  • step (d) removing the solvent from the solution obtained in step (c) to obtain a solid; and e) drying the solid obtained in step (d) to obtain dexlansoprazole amorphous form.
  • the present invention provides a pharmaceutical composition comprising dexlansoprazole amorphous form and pharmaceutically acceptable excipients.
  • the present invention provides a process for the preparation of dexlansoprazole crystalline form I, which comprises: a) dissolving an alkali metal salt of dexlansoprazole in an chlorinated solvent and water;
  • step (d) removing the solvent from the solution obtained in step (c) to obtain a solid; e) slurrying the solid obtained in step (d) with hydrocarbon solvent;
  • the present invention provides a process for the preparation of dexlansoprazole crystalline form II, which comprises:
  • Figure 1 is X-ray powder diffraction spectrum of crystalline form 1 of dexlansoprazole sodium.
  • Figure 2 is X-ray powder diffraction spectrum of crystalline form 2 of dexlansoprazole sodium.
  • Figure 3 is X-ray powder diffraction spectrum of amorphous form of dexlansoprazole sodium.
  • Figure 4 is X-ray powder diffraction spectrum of dexlansoprazole amorphous form.
  • X-ray powder diffraction spectrum was measured on a bruker axs D8 advance X- ray powder diffractometer having a copper- ⁇ radiation. Approximately lgm of sample was gently flattered on a sample holder and scanned from 2 to 50 degrees two-theta, at 0.02 degrees to theta per step and a step of 10.6 seconds. The sample was simply placed on the sample holder. The sample was rotated at 30 rpm at a voltage 40 KV and current 35 mA.
  • room temperature refers to temperature at about 25 to 35 C.
  • the solid may preferably be crystalline or amorphous.
  • a crystalline form of dexlansoprazole sodium designated as form 1 characterized by peaks in the powder X-ray diffraction spectrum having 2 ⁇ angle positions at about 4.3, 5.0, 6.5, 13.2, 15.7, 17.9, 20.0 and 24.6 ⁇ 0.2 degrees.
  • the powdered X-ray diffractogram (PXRD) of crystalline form 1 of dexlansoprazole sodium is shown in figure 1.
  • a process for the preparation of crystalline form 1 of dexlansoprazole sodium which comprises: a) providing a solution of dexlansoprazole in a solvent system comprising an alcoholic solvent, a ketonic solvent or mixture thereof;
  • step (a) adding above about 1.5 mole sodium 2-ethylhexanoate per mole of dexlansoprazole used in step (a) to the solution obtained in step (a);
  • step (c) adding hydrocarbon solvent to the residual mass obtained in step (c); and e) isolating crystalline form 1 of dexlansoprazole sodium.
  • the alcoholic solvent used in step (a) may preferably be selected from methanol, ethanol, isopropyl alcohol and n-butanol, and more preferably the alcoholic solvent is ethanol.
  • the ketonic solvent used in step (a) may preferably be selected from acetone, methyl ethyl ketone, methyl isobutyl ketone and diethyl ketone, and more preferably the ketonic solvent is acetone.
  • Dexlansoprazole used in step (a) may preferably be dexlansoprazole obtained by the known process.
  • sodium 2-ethylhexanoate used in step (b) is above 2.5 moles, more preferably above 2.0 moles and still more preferably between 2.0 to 4.0 moles per mole of the dexlansoprazole used.
  • Removal of the solvent in step (c) may be carried out at atmospheric pressure or at reduced pressure. Removal of the solvent may preferably be carried out until the solvent is almost completely distilled off
  • the hydrocarbon solvent used in step (d) may preferably be a solvent or mixture of solvents selected from cyclohexane, hexane, n-heptane, benzene, toluene and xylene, and more preferably the hydrocarbon solvent is n-heptane.
  • Crystalline form 1 of dexlansoprazole sodium may be isolated in step (e) by the methods known such as filtration or centrifugation.
  • the crystalline form 1 of dexlansoprazole sodium obtained may have water content of up to 9.0% by weight, and typically between 4.0 to 8.0% by weight.
  • a pharmaceutical composition comprising crystalline form 1 of dexlansoprazole sodium and pharmaceutically acceptable excipients, and optionally other therapeutic ingredients.
  • the crystalline form 1 may preferably be formulated into tablets, capsules, suspensions, dispersions, injectables and other pharmaceutical forms.
  • a crystalline form of dexlansoprazole sodium designated as form 2 characterized by peaks in the powder x-ray diffraction spectrum having 2 ⁇ angle positions at about 5.6, 7.1, 11.2, 11.9, 12.3 and 18.5 ⁇ 0.2 degrees.
  • the powdered x-ray diffractogram of crystalline form 2 of dexlansoprazole sodium is shown in figure 2.
  • a process for the preparation of crystalline form 2 of dexlansoprazole sodium which comprises: a) providing a solution of dexlansoprazole in an alcoholic solvent in presence of water;
  • step (a) cooling the solution obtained in step (a) at below 5°C;
  • step (a) adding above about 1.5 mole sodium hydroxide per mole of dexlansoprazole used in step (a) at below 5°C;
  • alcoholic solvent used in step (a) may preferably be a solvent or mixture of solvents selected from methanol, ethanol, isopfopyl alcohol and n-butanol, and more preferably the alcoholic solvent is ethanol.
  • Dexlansoprazole used in step (a) may preferably be dexlansoprazole obtained by the known process.
  • Step (b) may preferably be carried out at about 0°C to -10°C.
  • sodium hydroxide used in step (c) is above 2.5 moles, more preferably above 2.0 moles and still more preferably between 2.0 to 4.0 moles per mole of the dexlansoprazole used.
  • the hydrocarbon solvent used in step (d) may preferably be a solvent or mixture of solvents selected from cyclohexane, hexane, n-heptane, benzene, toluene and xylene, and more preferably the hydrocarbon solvent is n-heptane.
  • Crystalline form 2 of dexlansoprazole sodium may be isolated in step (e) by the methods known such as filtration or centrifugation.
  • the crystalline form 2 of dexlansoprazole sodium obtained may have water content of up to 9.0% by weight, and typically between 4.0 to 8.0% by weight.
  • a pharmaceutical composition comprising crystalline form 2 of dexlansoprazole sodium and pharmaceutically acceptable excipients and optionally other therapeutic ingredients.
  • the crystalline form 2 may preferably be formulated into tablets, capsules, suspensions, dispersions, injectables and other pharmaceutical forms.
  • a novel amorphous form of dexlansoprazole sodium is provided.
  • the powdered x-ray diffractogram of amorphous form of dexlansoprazole sodium is shown in figure 3.
  • a process for the preparation of amorphous form of dexlansoprazole sodium which comprises: a) providing a solution of dexlansoprazole in an alcoholic solvent;
  • step (a) adding above about 1.5 mole sodium hydroxide per mole of dexlansoprazole used in step (a) to the solution obtained in step (a) at 0°C;
  • step (c) adding hydrocarbon solvent to the foam obtained in step (c); and e) isolating amorphous form of dexlansoprazole sodium.
  • the alcoholic solvent used in step (a) may preferably be a solvent or mixture of solvents selected from methanol, ethanol, isopropyl alcohol and n-butanol, and more preferably the alcoholic solvent is ethanol.
  • Dexlansoprazole used in step (a) may preferably be dexlansoprazole obtained by the known process.
  • sodium hydroxide used in step (b) is above 2.5 moles, more preferably above 2.0 moles and still more preferably between 2.0 to 4.0 moles per mole of the dexlansoprazole used.
  • Removal of the solvent in step (c) may be carried out at atmospheric pressure or at reduced pressure. Removal of the solvent may preferably be carried out until the solvent is almost completely distilled off.
  • the hydrocarbon solvent used in step (d) may preferably be a solvent or mixture of solvents selected from cyclohexane, hexane, n-heptane, benzene, toluene and xylene, and more preferably the hydrocarbon solvent is n-heptane.
  • Amorphous form of dexlansoprazole sodium may be isolated in step (e) by the methods known such as filtration or centrifugation.
  • the amorphous form of dexlansoprazole sodium obtained may have water content of up to 9.0% by weight, and typically between 4.0 to 8.0% by weight.
  • a pharmaceutical composition comprising amorphous form of dexlansoprazole sodium and pharmaceutically acceptable excipients, and optionally other therapeutic ingredients.
  • the amorphous form of dexlansoprazole sodium may preferably be formulated into tablets, capsules, suspensions, dispersions, injectables and other pharmaceutical forms.
  • step (b) removing the solvent completely from the solution obtained in step (a); and c) drying the solid obtained in step (b) to obtain dexlansoprazole amorphous form.
  • Dexlansoprazole used in step (a) may preferably be dexlansoprazole obtained by the known process.
  • the solvent used in step (a) may preferably be a solvent or mixture of solvents selected from methanol, ethanol, isopropyl alcohol, n-butanol, dichloromethane, chloroform, carbon tetrachloride, ethylene dichloride, ethyl acetate, methyl acetate, isopropyl acetate, tert-butyl methyl acetate, ethyl formate, acetone, methyl ethyl ketone, methyl isobutyl ketone, diethyl ketone, tetrahydroiuran, 1,4-dioxane, methyl tert-butyl ether, diisopropyl ether and diethyl ether.
  • the solvents are methanol, ethanol, dichloromethane, ethyl acetate, acetone, methyl ethyl ketone, methyl tert-butyl ether and diisopropyl ether, and still more preferably the solvents are methanol, ethanol, acetone, ethyl acetate and methyl ethyl ketone.
  • Removal of the solvent in step (b) may be carried out at atmospheric pressure or at reduced pressure. Removal of the solvent may preferably be carried out until the solvent is almost completely distilled off.
  • Drying of the solid in step (c) may be carried out at 45 to 55°C under high vacuum.
  • step (d) removing the solvent from the solution obtained in step (c) to obtain a solid; and e) drying the solid obtained in step (d) to obtain dexlansoprazole amorphous form.
  • the alkali metal salt of dexlansoprazole used in step (a) is sodium salt of dexlansoprazole.
  • the chlorinated solvent used in step (a) may be a solvent or mixture of solvents selected from dichloromethane, chloroform, carbon tetrachloride and ethylene dichloride, and more preferably the chlorinated solvent is dichloromethane.
  • the acid used in step (b) may preferably be an organic acid or an inorganic acid selected from acetic acid, hexanoic acid and formic acid, and more preferably the acid is acetic acid.
  • the organic solvent used in step (c) may preferably be a solvent or mixture of solvents selected from dichloromethane, chloroform, carbon tetrachloride, ethylene dichloride, ethyl acetate, methyl acetate, isopropyl acetate, tert-butyl methyl acetate and ethyl formate, and more preferably the organic solvent is dichloromethane.
  • Removal of the solvent in step (d) may be carried out at atmospheric pressure or at reduced pressure. Removal of the solvent may preferably be carried out until the solvent is almost completely distilled off.
  • Drying of the solid in step (e) may be carried out at 45 to 55°C under high vacuum.
  • a pharmaceutical composition comprising dexlansoprazole amorphous form and pharmaceutically acceptable excipients, and optionally other therapeutic ingredients.
  • the amorphous form of dexlansoprazole may preferably be formulated into tablets, capsules, suspensions, dispersions, injectables and other pharmaceutical forms.
  • step (c) removing the solvent from the solution obtained in step (c) to obtain a solid;
  • the alkali metal salt of dexlansoprazole used in step (a) is sodium salt of dexlansoprazole.
  • the chlorinated solvent used in step (a) may be a solvent or mixture of solvents selected from dichloromethane, chloroform, carbon tetrachloride and ethylene dichloride, and more preferably the chlorinated solvent is dichloromethane.
  • the acid used in step (b) may preferably be an organic acid or an inorganic acid selected from acetic acid, hexanoic acid and formic acid, and more preferably the acid is acetic acid.
  • the organic solvent used in step (c) may preferably be a solvent or mixture of solvents selected from dichloromethane, chloroform, carbon tetrachloride, ethylene dichloride, ethyl acetate, methyl acetate, isopropyl acetate, tert-butyl methyl acetate and ethyl formate, and more preferably the organic solvent is dichloromethane.
  • Removal of the solvent may be carried out in step (d) at atmospheric pressure or at reduced pressure. Removal of the solvent may preferably be carried out until the solvent is almost completely distilled off.
  • the hydrocarbon solvent used in step (e) may preferably be a solvent or a mixture of solvents selected from cyclohexane, hexane, n-heptane, toluene, xylene and benzene. More preferably the hydrocarbon solvent is cyclohexane.
  • Dexlansoprazole crystalline form I may be isolated in step (f) by the methods known such as filtration or centrifugation.
  • the alkali metal salt of dexlansoprazole used in step (a) is sodium salt of dexlansoprazole.
  • the acid used in step (b) may preferably be an organic acid or an inorganic acid selected from acetic acid, hexanoic acid and formic acid, and more preferably the acid is acetic acid.
  • Dexlansoprazole crystalline form II may be isolated in step (d) by the methods known such as filtration or centrifugation.
  • HPLC conditions for analysis are:
  • HPLC conditions for analysis are:
  • Dexlansoprazole (10 gm, obtained by the process described in example 12 of the U.S. Patent No. 5,929,244) was dissolved in ethanol (100 ml) at room temperature to obtain a solution. To the solution was added sodium 2-ethylhexanoate (7 gm) and stirred for 30 minutes. The solvent was distilled off under vacuum to obtain a residual mass. To the residual mass was added n-heptane (200 ml) and stirred for 3 hours at room temperature. The solid obtained was collected by filtration and dried to obtain 5 gm of dexlansoprazole sodium (Optical Purity: 99.99%).
  • Dexlansoprazole sodium 10 gm, obtained by the process described in co-pending application no. PCT/IN2009/000567) was dissolved in ethanol (100 ml) in presence of water (5 ml) at room temperature to obtain a solution. The solution was then cooled to - 5°C and then added sodium hydroxide (2.2 gm). The reaction mass was stirred for 1 hour at -5°C and then added n-heptane (200 ml). The contents were stirred for 15 minutes at - 5°C and filtered. The solid obtained was dried to give 8 gm of dexlansoprazole sodium.
  • Dexlansoprazole (5 gm, HPLC Purity: 99.45%; Optical Purity: 99.6%) was dissolved in ethanol (50 ml) in presence of water (5 ml) at room temperature. The solution was then cooled to -5°C and then added sodium hydroxide (1.2 gm). The reaction mass was stirred for 1 hour at -5°C and then added n-heptane (200 ml). The contents were stirred for 15 minutes at -5°C and filtered. The solid obtained was dried to give 3.9 gm of dexlansoprazole sodium (HPLC Purity: 100%; Optical Purity: 100%).
  • Example 3 was repeated using sodium 2-ethylhexanoate instead of sodium hydroxide to obtain dexlansoprazole sodium.
  • Dexlansoprazole (25 gm, HPLC Purity: 99.52%; Optical Purity: 99.7%) was dissolved in ethanol (250 ml) and then added sodium 2-ethylhexanoate (32.5 gm). The reaction mass was stirred for 30 minutes and the solvent was distilled off under vacuum to obtain a residual mass. To the residual mass was added n-heptane (250 ml), stirred for 3 hours at room temperature and filtered. The solid obtained was dried to give 18.5 gm of crystalline form 1 of dexlansoprazole sodium (HPLC Purity: 99.98%; Optical Purity: 99.99%).
  • Example 6 Example 6:
  • Dexlansoprazole crystalline form II (10 gm) was dissolved in acetone (100 ml) at room temperature to obtain a solution. To the solution was added sodium 2- ethylhexanoate (7 gm) and stirred for 30 minutes. The solvent was distilled off under vacuum to obtain a residual mass. To the residual mass was added n-heptane (100 ml), stirred for 3 hours at room temperature and filtered. The solid obtained was dried to give 7.5 gm of crystalline form 1 of dexlansoprazole sodium (HPLC Purity: 99.9%; Optical Purity: 99.92%).
  • Dexlansoprazole crystalline form I (10 gm) was dissolved in ethanol (100 ml) and then added sodium 2-ethylhexanoate (13 gm). The reaction mass was stirred for 1 hour and the solvent was distilled off under vacuum to obtain a residual mass. To the residual mass was added n-heptane (180 ml) and stirred for 4 hours at room temperature. The solid obtained was collected by filtration and dried to obtain 8.5 gm of crystalline form 1 of dexlansoprazole sodium (HPLC Purity: 99.91 %; Optical Purity: 99.94%).
  • Dexlansoprazole (10 gm, HPLC Purity: 99.5%; Optical Purity: 99.62%) was dissolved in ethanol (100 ml) in presence of water (5 ml) and then cooled to -5°C.
  • sodium hydroxide (2.2 gm) was added and stirred for 30 minutes at -5°C.
  • n-heptane (80 ml) was added and stirred for 30 minutes at -5°C.
  • the solid obtained was collected by filtration and dried to obtain 6 gm of crystalline form 2 of dexlansoprazole sodium (HPLC Purity: 99.98%; Optical Purity: 99.99%).
  • Example 9 Example 9:
  • Dexlansoprazole crystalline form II (25 gm) was dissolved in ethanol (250 ml) in presence of water (10 ml) and then cooled to -5°C. To the solution was added sodium hydroxide (5.5 gm) and stirred for 30 minutes at -5°C. To the reaction mass was added n- heptane (200 ml) and stirred for 30 minutes at -5°C. The solid obtained was collected by filtration and dried to obtain 14 gm of crystalline form 2 of dexlansoprazole sodium (HPLC Purity: 99.95%; Optical Purity: 99.96%).
  • Dexlansoprazole crystalline form I (10 gm) was dissolved in ethanol (100 ml) in presence of water (5 ml) and then cooled to -5°C. To the solution was added sodium hydroxide (3 gm) and stirred for 30 minutes at -5°C. To the reaction mass was added n- heptane (100 ml), stirred for 30 minutes at -5°C and filtered. The solid obtained was dried to give 6 gm of crystalline form 2 of dexlansoprazole sodium (HPLC Purity: 99.92%; Optical Purity: 99.95%).
  • Dexlansoprazole (10 gm, HPLC Purity: 99.4%; Optical Purity: 99.51%) was dissolved in ethanol (100 ml) and then added sodium hydroxide (1.2 gm) at 0°C. The reaction mass was stirred for 30 minutes and the solvent was distilled off under vacuum to obtain foam. To the foam was added n-heptane (200 ml) and stirred for 2 hours at room temperature. The solid obtained was collected by filtration and dried to obtain 9 gm of amorphous form of dexlansoprazole sodium (HPLC Purity: 99.88%; Optical Purity: 99.92%).
  • Dexlansoprazole (10 gm) was dissolved in methanol (100 ml) and then added sodium hydroxide (1.2 gm) at 0°C. The reaction mass was stirred for 30 minutes and the solvent was distilled off under vacuum to obtain foam. To the foam was added n-heptane (200 ml), stirred for 2 hours at room temperature and filtered. The solid obtained was dried to obtain 8.8 gm of amorphous form of dexlansoprazole sodium (HPLC Purity: 99.9%; Optical Purity: 99.95%).
  • Dexlansoprazole (2 gm, HPLC Purity: 99.5%; Optical Purity: 99.62%) was dissolved in ethanol (15 ml) at room temperature under stirring. The reaction mass was filtered through hi-flo bed and the solvent was distilled off under vacuum to obtain a solid. The solid obtained was dried at 30 to 35°C to obtain 1.5 gm of dexlansoprazole amorphous form (HPLC Purity: 99.88%; Optical Purity: 99.92%).
  • Example 13 was repeated using acetone solvent instead of ethanol solvent to obtain dexlansoprazole amorphous form.
  • Example 13 was repeated using methanol solvent instead of ethanol solvent to obtain dexlansoprazole amorphous form.
  • Example 13 was repeated using methyl ethyl ketone solvent instead of ethanol solvent to obtain dexlansoprazole amorphous form.
  • Crystalline form 1 of dexlansoprazole sodium (5 gm, HPLC Purity: 99.98%; Optical Purity: 99.99%) as obtained in example 5 was dissolved in water (50 ml) and dichloromethane (100 ml) at room temperature. The reaction mass was then cooled to 5 to 10°C and pH of the reaction mass was adjusted to 8.0 with acetic acid (10%) at 5 to 10°C. Then the layers were separated and the aqueous layer was exacted with dichloromethane. The combined organic layer was dried with sodium sulfate and the solvent was distilled off under vacuum to obtain a solid. The solid obtained was dried to give 3.5 gm of dexlansoprazole amorphous form (HPLC Purity: 99.99%; Optical Purity: 100%).
  • Example 17 was repeated using crystalline form 2 of dexlansoprazole sodium instead of crystalline form 1 of dexlansoprazole sodium to obtain dexlansoprazole amorphous form.
  • Example 17 was repeated using amorphous form of dexlansoprazole sodium instead of crystalline form 1 of dexlansoprazole sodium to obtain dexlansoprazole amorphous form.
  • Example 20 was repeated using amorphous form of dexlansoprazole sodium instead of crystalline form 1 of dexlansoprazole sodium to obtain dexlansoprazole amorphous form.
  • Crystalline form 1 of dexlansoprazole sodium (5 gm, HPLC Purity: 99.98%; Optical Purity: 99.99%) as obtained in example 5 was dissolved in water (50 ml) and dichloromethane (100 ml) at room temperature. The reaction mass was then cooled to 5 to 10°C and pH of the reaction mass was adjusted to 8.5 to 10.0 with acetic acid (10%) at 5 to 10°C, Then the layers were separated and the aqueous layer was exacted with dichloromethane. The combined organic layer was dried with sodium sulfate and the solvent was distilled off under vacuum to obtain a solid.
  • Example 20 was repeated using crystalline form 2 of dexlansoprazole sodium instead of crystalline form 1 of dexlansoprazole sodium to obtain dexlansoprazole crystalline form I.
  • Example 20 was repeated using amorphous form of dexlansoprazole sodium instead of crystalline form 1 of dexlansoprazole sodium to obtain dexlansoprazole crystalline form I.
  • dexlansoprazole crystalline form II Crystalline form 1 of dexlansoprazole sodium (5 gm, HPLC Purity: 99.98%; Optical Purity: 99.99%) as obtained in example 5 was dissolved in water (50 ml) at room temperature. The reaction mass was then cooled to 5 to 10°C and pH of the reaction mass was adjusted to 8.0 with acetic acid (10%) at 5 to 10°C. The reaction mass was stirred for 1 hour at 5 to 10°C and filtered. The solid obtained was dried to give 3.2 gm of dexlansoprazole crystalline form II (HPLC Purity: 99.99%; Optical Purity: 100%).
  • Example 23 was repeated using crystalline form 2 of dexlansoprazole sodium instead of crystalline form 1 of dexlansoprazole sodium to obtain dexlansoprazole crystalline form II.
  • Example 23 was repeated using amorphous form of dexlansoprazole sodium instead of crystalline form 1 of dexlansoprazole sodium to obtain dexlansoprazole crystalline form II.

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Abstract

The present invention provides a solid of dexlansoprazole sodium. The present invention also provides novel crystalline forms of dexlansoprazole sodium, processes for their preparation and pharmaceutical compositions comprising them. The present invention further provides a novel amorphous form of dexlansoprazole sodium, process for its preparation and pharmaceutical compositions comprising it. The present invention further provides a novel process for the preparation of dexlansoprazole amorphous form and pharmaceutical compositions comprising it. The present invention further provides a process for the preparation of dexlansoprazole crystalline form I. The present invention further provides a process for the preparation of dexlansoprazole crystalline form II.

Description

POLYMORPHS OF DEXLANSOPRAZOLE SALTS
Filed of the Invention
The present invention provides a solid of dexlansoprazole sodium. The present invention also provides novel crystalline forms of dexlansoprazole sodium, processes for their preparation and pharmaceutical compositions comprising them. The present invention further provides a novel amorphous form of dexlansoprazole sodium, process for its* preparation and pharmaceutical compositions comprising it. The present invention further provides a novel process for the preparation of dexlansoprazole amorphous form and pharmaceutical compositions comprising it. The present invention further provides a process for the preparation of dexlansoprazole crystalline form I. The present invention further provides a process for the preparation of dexlansoprazole crystalline form II.
Background of the Invention
Lansoprazole, chemically 2-[[[3-methyl-4-(2,2,2-trifluoro-ethoxy)-2- pyridinyl]methyl]sulfmyl]-lH-benzimidazole were disclosed in European Patent No. 0174726 and U.S. Patent No. 4,628,098. Lansoprazole was a well-known gastric acid secretion inhibitor, and was useful for prophylaxis and therapy of digestive ulcers (e.g. gastric ulcer, duodenal ulcer) and gastritis. The generic name dexlansoprazole is marketed by Takeda Pharms under the brand name DEXILANT®.
U. S. Patent No. 6,462,058 (Ό58 patent) disclosed an anhydrous crystalline form (hereinafter referred to as "crystalline form I") and a crystalline 1.5 hydrate (hereinafter referred to as "crystalline form II") of R-lansoprazole and its use as an anti-ulcer agent. U.S. Patent Nos. 6,462,058; 5,929,244 and 6,664,276; and International Patent Publication No. WO 00/78745 all described the synthesis of a crystal of R-lansoprazole. Exemplary methods for such synthesis include:
a) Optical resolution of substituted 2-(2-pyridinylmethylsulfinyl)-lH- benzimidazoles by a fractional crystallization method, which includes forming a salt between a racemate and an optically active compound (for example, (+)-mandelic acid, (- )-mandelic acid, (+)-tartaric acid, (-)-tartaric acid, camphoursulfonyl chloride, or camphanic acid). The diastereoisomeric salt is separated by fractional crystallization and then subjected to a neutralization process to give a free optical isomer. b) The chiral column method includes a method in which a racemate or a salt is applied to a column for optical isomer separation. In liquid chromatography, for example, optical isomers are separated by adding the racemate to a chiral column (such as the Daicel® series (produced by Daicel Chemical Industries, Ltd.), and eluting in water, a buffer (for example, a phosphate), an organic solvent (for example, hexane, ethanol, methanol, isopropanol, acetonitrile, triethylamine, or mixtures thereof) or mixtures of the foregoing.
c) The asymmetric oxidation process includes subjecting substituted 2-(2- pyridinylmethylsulfinyl)-lH-benzimidazoles to an asymmetric oxidation to obtain enantiomer of substituted 2-(2-pyridinylmethylsulfinyl)-lH-benzimidazoles, followed by crystallizing the resultant isomer.
Resolution of lansoprazole with chiral l,l'-binaphtyl-2-2'-diyl hydrogen (BNPPA) was disclosed in co-pending Application No. PCT/IN2009/000567.
Crystalline form A of dexlansoprazole was disclosed in International publication no. WO 2010/056059.
U.S. patent no. 7,737,282 disclosed an amorphous form of dexlansoprazole.
A solid R-(+)-lansoprazole alkylamine salt was disclosed in PCT publication no. WO 2010/079504.
The preparation of sodium salt of esomeprazole was disclosed in PCT publication no. WO 94/27988, which is herein incorporated by reference.
Dexlansoprazole metal salts including sodium salt was mentioned in '058 patent, but the existence of polymorphs of sodium were not mentioned. It has been found that dexlansoprazole sodium was obtained by the processes described for example in US 5,929,244 resulted as an oily substance.
We have discovered a solid of dexlansoprazole sodium.
We have also discovered that chromatography purity and optical purity were enhanced when dexlansoprazole was isolated as a solid.
We have also discovered novel crystalline forms and amorphous form of dexlansoprazole sodium.
We have also discovered a novel process for the preparation of dexlansoprazole amorphous form. The amorphous form obtained by the process of the present invention is found to have substantially pure as measured by high performance liquid chromatography (HPLC).
We have also discovered a process for the preparation of dexlansoprazole crystalline form I.
We have also discovered a process for the preparation of dexlansoprazole crystalline form II.
Thus, one object of the present invention is to provide a solid of dexlansoprazole sodium.
The solid of dexlansoprazole sodium of the present invention can be used for the preparation of pharmaceutical compositions and can also be used as method of purification of dexlansoprazole. The solid of dexlansoprazole sodium may also serve as intermediate for preparation of dexlansoprazole.
Another object of the present invention is to provide a novel crystalline forms of dexlansoprazole sodium, processes for their preparation and pharmaceutical compositions comprising them.
Another object of the present invention is to provide a novel amorphous form of dexlansoprazole sodium, process for its preparation and pharmaceutical compositions comprising it.
Another object of the present invention is to provide a novel process for the preparation of dexlansoprazole amorphous form and pharmaceutical compositions comprising it.
Another object of the present invention is to provide a process for the preparation of dexlansoprazole crystalline form I.
Another object of the present invention is to provide a process for the preparation of dexlansoprazole crystalline form II.
Summary of the Invention
In one aspect, the present invention provides a solid of dexlansoprazole sodium. In another aspect, the present invention provides a crystalline form of dexlansoprazole sodium designated as form 1 characterized by peaks in the powder x-ray diffraction spectrum having 20 angle positions at about 4.3, 5.0, 6.5, 13.2, 15.7, 17.9, 20.0 and 24.6 ± 0.2 degrees.
In another aspect, the present invention provides a process for the preparation of crystalline form 1 of dexlansoprazole sodium, which comprises:
a) providing a solution of dexlansoprazole in a solvent system comprising an alcoholic solvent, a ketonic solvent or mixture thereof;
b) adding above about 1.5 mole sodium 2-ethylhexanoate per mole of dexlansoprazole used in step (a) to the solution obtained in step (a);
c) removing the solvent from the reaction mass obtained in step (b);
d) adding hydrocarbon solvent to the residual mass obtained in step (c); and e) isolating crystalline form 1 of dexlansoprazole sodium.
In another aspect, the present invention provides a pharmaceutical composition comprising crystalline form 1 of dexlansoprazole sodium and pharmaceutically acceptable excipients.
In another aspect, the present invention provides a crystalline form of dexlansoprazole sodium designated as form 2 characterized by peaks in the powder x-ray diffraction spectrum having 20 angle positions at about 5.6, 7.1, 11.2, 11.9, 12.3 and 18.5 ± 0.2 degrees.
In another aspect, the present invention provides a process for the preparation of crystalline form 2 of dexlansoprazole sodium, which comprises:
a) providing a solution of dexlansoprazole in an alcoholic solvent in presence of water;
b) cooling the solution obtained in step (a) at below 5°C;
c) adding above about 1.5 mole sodium hydroxide per mole of dexlansoprazole used in step (a) at below 5°C;
d) adding hydrocarbon solvent to the reaction mass obtained in step (c); and e) isolating crystalline form 2 of dexlansoprazole sodium.
In another aspect, the present invention provides a pharmaceutical composition comprising crystalline form 2 of dexlansoprazole sodium and pharmaceutically acceptable excipients. In another aspect, the present invention provides a novel amorphous form of dexlansoprazole sodium.
In another aspect, the present invention provides a process for the preparation of amorphous form of dexlansoprazole sodium, which comprises:
a) providing a solution of dexlansoprazole in an alcoholic solvent;
b) adding above about 1.5 mole sodium hydroxide per mole of dexlansoprazole used in step (a) to the solution obtained in step (a) at 0°C;
c) removing the solvent from the reaction mass obtained in step (b);
d) adding hydrocarbon solvent to the foam obtained in step (c); and
e) isolating amorphous form of dexlansoprazole sodium.
In another aspect, the present invention provides a pharmaceutical composition comprising amorphous form of dexlansoprazole sodium and pharmaceutically acceptable excipients.
In another aspect, the present invention provides a process for the preparation of dexlansoprazole amorphous form, which comprises:
a) providing a solution of dexlansoprazole in a solvent;
b) removing the solvent completely from the solution obtained in step (a); and c) drying the solid obtained in step (b) to obtain dexlansoprazole amorphous form.
In another aspect, the present invention provides a process for the preparation of dexlansoprazole amorphous form, which comprises:
a) dissolving an alkali metal salt of dexlansoprazole in an chlorinated solvent and water;
b) adjusting the pH of the reaction mass to about 8.0 to 9.0 with an acid;
c) extracting dexlansoprazole into organic solvent;
d) removing the solvent from the solution obtained in step (c) to obtain a solid; and e) drying the solid obtained in step (d) to obtain dexlansoprazole amorphous form.
In another aspect, the present invention provides a pharmaceutical composition comprising dexlansoprazole amorphous form and pharmaceutically acceptable excipients.
In another aspect, the present invention provides a process for the preparation of dexlansoprazole crystalline form I, which comprises: a) dissolving an alkali metal salt of dexlansoprazole in an chlorinated solvent and water;
b) adjusting the pH of the reaction mass to about 8.0 to 9.0 with an acid;
c) extracting dexlansoprazole into organic solvent;
d) removing the solvent from the solution obtained in step (c) to obtain a solid; e) slurrying the solid obtained in step (d) with hydrocarbon solvent; and
f) isolating dexlansoprazole crystalline form I.
Yet another aspect, the present invention provides a process for the preparation of dexlansoprazole crystalline form II, which comprises:
a) dissolving an alkali metal salt of dexlansoprazole in water;
b) adjusting the pH of the reaction mass to about 8.0 to 9.0 with an acid;
c) maintaining the reaction mass obtained in step (b); and
d) isolating dexlansoprazole crystalline form II. Brief Description of the Drawing
Figure 1 is X-ray powder diffraction spectrum of crystalline form 1 of dexlansoprazole sodium.
Figure 2 is X-ray powder diffraction spectrum of crystalline form 2 of dexlansoprazole sodium.
Figure 3 is X-ray powder diffraction spectrum of amorphous form of dexlansoprazole sodium.
Figure 4 is X-ray powder diffraction spectrum of dexlansoprazole amorphous form.
X-ray powder diffraction spectrum was measured on a bruker axs D8 advance X- ray powder diffractometer having a copper-Κα radiation. Approximately lgm of sample was gently flattered on a sample holder and scanned from 2 to 50 degrees two-theta, at 0.02 degrees to theta per step and a step of 10.6 seconds. The sample was simply placed on the sample holder. The sample was rotated at 30 rpm at a voltage 40 KV and current 35 mA.
Detailed Description of the Invention The term "room temperature" refers to temperature at about 25 to 35 C.
According to one aspect of the present invention, there is provided a solid of dexlansoprazole sodium.
The solid may preferably be crystalline or amorphous.
According to another aspect of the present invention, there is provided a crystalline form of dexlansoprazole sodium designated as form 1 characterized by peaks in the powder X-ray diffraction spectrum having 2Θ angle positions at about 4.3, 5.0, 6.5, 13.2, 15.7, 17.9, 20.0 and 24.6 ± 0.2 degrees. The powdered X-ray diffractogram (PXRD) of crystalline form 1 of dexlansoprazole sodium is shown in figure 1.
According to another aspect of the present invention, there is provided a process for the preparation of crystalline form 1 of dexlansoprazole sodium, which comprises: a) providing a solution of dexlansoprazole in a solvent system comprising an alcoholic solvent, a ketonic solvent or mixture thereof;
b) adding above about 1.5 mole sodium 2-ethylhexanoate per mole of dexlansoprazole used in step (a) to the solution obtained in step (a);
c) removing the solvent from the reaction mass obtained in step (b);
d) adding hydrocarbon solvent to the residual mass obtained in step (c); and e) isolating crystalline form 1 of dexlansoprazole sodium.
The alcoholic solvent used in step (a) may preferably be selected from methanol, ethanol, isopropyl alcohol and n-butanol, and more preferably the alcoholic solvent is ethanol.
The ketonic solvent used in step (a) may preferably be selected from acetone, methyl ethyl ketone, methyl isobutyl ketone and diethyl ketone, and more preferably the ketonic solvent is acetone.
Dexlansoprazole used in step (a) may preferably be dexlansoprazole obtained by the known process.
Preferably sodium 2-ethylhexanoate used in step (b) is above 2.5 moles, more preferably above 2.0 moles and still more preferably between 2.0 to 4.0 moles per mole of the dexlansoprazole used. Removal of the solvent in step (c) may be carried out at atmospheric pressure or at reduced pressure. Removal of the solvent may preferably be carried out until the solvent is almost completely distilled off
The hydrocarbon solvent used in step (d) may preferably be a solvent or mixture of solvents selected from cyclohexane, hexane, n-heptane, benzene, toluene and xylene, and more preferably the hydrocarbon solvent is n-heptane.
Crystalline form 1 of dexlansoprazole sodium may be isolated in step (e) by the methods known such as filtration or centrifugation.
The crystalline form 1 of dexlansoprazole sodium obtained may have water content of up to 9.0% by weight, and typically between 4.0 to 8.0% by weight.
According to another aspect of the present invention, there is provided a pharmaceutical composition comprising crystalline form 1 of dexlansoprazole sodium and pharmaceutically acceptable excipients, and optionally other therapeutic ingredients. The crystalline form 1 may preferably be formulated into tablets, capsules, suspensions, dispersions, injectables and other pharmaceutical forms.
According to another aspect of the present invention, there is provided a crystalline form of dexlansoprazole sodium designated as form 2 characterized by peaks in the powder x-ray diffraction spectrum having 2Θ angle positions at about 5.6, 7.1, 11.2, 11.9, 12.3 and 18.5 ± 0.2 degrees. The powdered x-ray diffractogram of crystalline form 2 of dexlansoprazole sodium is shown in figure 2.
According to another aspect of the present invention, there is provided a process for the preparation of crystalline form 2 of dexlansoprazole sodium, which comprises: a) providing a solution of dexlansoprazole in an alcoholic solvent in presence of water;
b) cooling the solution obtained in step (a) at below 5°C;
c) adding above about 1.5 mole sodium hydroxide per mole of dexlansoprazole used in step (a) at below 5°C;
d) adding hydrocarbon solvent to the reaction mass obtained in step (c); and e) isolating crystalline form 2 of dexlansoprazole sodium. The alcoholic solvent used in step (a) may preferably be a solvent or mixture of solvents selected from methanol, ethanol, isopfopyl alcohol and n-butanol, and more preferably the alcoholic solvent is ethanol.
Dexlansoprazole used in step (a) may preferably be dexlansoprazole obtained by the known process.
Step (b) may preferably be carried out at about 0°C to -10°C.
Preferably sodium hydroxide used in step (c) is above 2.5 moles, more preferably above 2.0 moles and still more preferably between 2.0 to 4.0 moles per mole of the dexlansoprazole used.
The hydrocarbon solvent used in step (d) may preferably be a solvent or mixture of solvents selected from cyclohexane, hexane, n-heptane, benzene, toluene and xylene, and more preferably the hydrocarbon solvent is n-heptane.
Crystalline form 2 of dexlansoprazole sodium may be isolated in step (e) by the methods known such as filtration or centrifugation.
The crystalline form 2 of dexlansoprazole sodium obtained may have water content of up to 9.0% by weight, and typically between 4.0 to 8.0% by weight.
According to another aspect of the present invention, there is provided a pharmaceutical composition comprising crystalline form 2 of dexlansoprazole sodium and pharmaceutically acceptable excipients and optionally other therapeutic ingredients. The crystalline form 2 may preferably be formulated into tablets, capsules, suspensions, dispersions, injectables and other pharmaceutical forms.
According to another aspect of the present invention, there is provided a novel amorphous form of dexlansoprazole sodium. The powdered x-ray diffractogram of amorphous form of dexlansoprazole sodium is shown in figure 3.
According to another aspect of the present invention, there is provided a process for the preparation of amorphous form of dexlansoprazole sodium, which comprises: a) providing a solution of dexlansoprazole in an alcoholic solvent;
b) adding above about 1.5 mole sodium hydroxide per mole of dexlansoprazole used in step (a) to the solution obtained in step (a) at 0°C;
c) removing the solvent from the reaction mass obtained in step (b);
d) adding hydrocarbon solvent to the foam obtained in step (c); and e) isolating amorphous form of dexlansoprazole sodium.
The alcoholic solvent used in step (a) may preferably be a solvent or mixture of solvents selected from methanol, ethanol, isopropyl alcohol and n-butanol, and more preferably the alcoholic solvent is ethanol.
Dexlansoprazole used in step (a) may preferably be dexlansoprazole obtained by the known process.
Preferably sodium hydroxide used in step (b) is above 2.5 moles, more preferably above 2.0 moles and still more preferably between 2.0 to 4.0 moles per mole of the dexlansoprazole used.
Removal of the solvent in step (c) may be carried out at atmospheric pressure or at reduced pressure. Removal of the solvent may preferably be carried out until the solvent is almost completely distilled off.
The hydrocarbon solvent used in step (d) may preferably be a solvent or mixture of solvents selected from cyclohexane, hexane, n-heptane, benzene, toluene and xylene, and more preferably the hydrocarbon solvent is n-heptane.
Amorphous form of dexlansoprazole sodium may be isolated in step (e) by the methods known such as filtration or centrifugation.
The amorphous form of dexlansoprazole sodium obtained may have water content of up to 9.0% by weight, and typically between 4.0 to 8.0% by weight.
According to another aspect of the present invention, there is provided a pharmaceutical composition comprising amorphous form of dexlansoprazole sodium and pharmaceutically acceptable excipients, and optionally other therapeutic ingredients. The amorphous form of dexlansoprazole sodium may preferably be formulated into tablets, capsules, suspensions, dispersions, injectables and other pharmaceutical forms.
According to another aspect of the present invention, there is provided a process for the preparation of dexlansoprazole amorphous form, which comprises:
a) providing a solution of dexlansoprazole in a solvent;
b) removing the solvent completely from the solution obtained in step (a); and c) drying the solid obtained in step (b) to obtain dexlansoprazole amorphous form.
Dexlansoprazole used in step (a) may preferably be dexlansoprazole obtained by the known process. The solvent used in step (a) may preferably be a solvent or mixture of solvents selected from methanol, ethanol, isopropyl alcohol, n-butanol, dichloromethane, chloroform, carbon tetrachloride, ethylene dichloride, ethyl acetate, methyl acetate, isopropyl acetate, tert-butyl methyl acetate, ethyl formate, acetone, methyl ethyl ketone, methyl isobutyl ketone, diethyl ketone, tetrahydroiuran, 1,4-dioxane, methyl tert-butyl ether, diisopropyl ether and diethyl ether. More preferably the solvents are methanol, ethanol, dichloromethane, ethyl acetate, acetone, methyl ethyl ketone, methyl tert-butyl ether and diisopropyl ether, and still more preferably the solvents are methanol, ethanol, acetone, ethyl acetate and methyl ethyl ketone.
Removal of the solvent in step (b) may be carried out at atmospheric pressure or at reduced pressure. Removal of the solvent may preferably be carried out until the solvent is almost completely distilled off.
Drying of the solid in step (c) may be carried out at 45 to 55°C under high vacuum.
According to another aspect of the present invention, there is provided a process for the preparation of dexlansoprazole amorphous form, which comprises:
a) dissolving an alkali metal salt of dexlansoprazole in an chlorinated solvent and water; *
b) adjusting the pH of the reaction mass to about 8.0 to 9.0 with an acid;
c) extracting dexlansoprazole into organic solvent;
d) removing the solvent from the solution obtained in step (c) to obtain a solid; and e) drying the solid obtained in step (d) to obtain dexlansoprazole amorphous form.
Preferably the alkali metal salt of dexlansoprazole used in step (a) is sodium salt of dexlansoprazole.
Preferably the chlorinated solvent used in step (a) may be a solvent or mixture of solvents selected from dichloromethane, chloroform, carbon tetrachloride and ethylene dichloride, and more preferably the chlorinated solvent is dichloromethane.
The acid used in step (b) may preferably be an organic acid or an inorganic acid selected from acetic acid, hexanoic acid and formic acid, and more preferably the acid is acetic acid. The organic solvent used in step (c) may preferably be a solvent or mixture of solvents selected from dichloromethane, chloroform, carbon tetrachloride, ethylene dichloride, ethyl acetate, methyl acetate, isopropyl acetate, tert-butyl methyl acetate and ethyl formate, and more preferably the organic solvent is dichloromethane.
Removal of the solvent in step (d) may be carried out at atmospheric pressure or at reduced pressure. Removal of the solvent may preferably be carried out until the solvent is almost completely distilled off.
Drying of the solid in step (e) may be carried out at 45 to 55°C under high vacuum.
According to another aspect of the present invention, there is provided a pharmaceutical composition comprising dexlansoprazole amorphous form and pharmaceutically acceptable excipients, and optionally other therapeutic ingredients. The amorphous form of dexlansoprazole may preferably be formulated into tablets, capsules, suspensions, dispersions, injectables and other pharmaceutical forms.
According to another aspect of the present invention, there is provided a process for the preparation of dexlansoprazole crystalline form I, which comprises:
a) dissolving an alkali metal salt of dexlansoprazole in an chlorinated solvent and water;
b) adjusting the pH of the reaction mass to about 8.0 to 9.0 with an acid;
c) extracting dexlansoprazole into organic solvent;
d) removing the solvent from the solution obtained in step (c) to obtain a solid;
e) slurrying the solid obtained in step (d) with hydrocarbon solvent; and
f) isolating dexlansoprazole crystalline form I.
Preferably the alkali metal salt of dexlansoprazole used in step (a) is sodium salt of dexlansoprazole.
Preferably the chlorinated solvent used in step (a) may be a solvent or mixture of solvents selected from dichloromethane, chloroform, carbon tetrachloride and ethylene dichloride, and more preferably the chlorinated solvent is dichloromethane.
The acid used in step (b) may preferably be an organic acid or an inorganic acid selected from acetic acid, hexanoic acid and formic acid, and more preferably the acid is acetic acid. The organic solvent used in step (c) may preferably be a solvent or mixture of solvents selected from dichloromethane, chloroform, carbon tetrachloride, ethylene dichloride, ethyl acetate, methyl acetate, isopropyl acetate, tert-butyl methyl acetate and ethyl formate, and more preferably the organic solvent is dichloromethane.
Removal of the solvent may be carried out in step (d) at atmospheric pressure or at reduced pressure. Removal of the solvent may preferably be carried out until the solvent is almost completely distilled off.
The hydrocarbon solvent used in step (e) may preferably be a solvent or a mixture of solvents selected from cyclohexane, hexane, n-heptane, toluene, xylene and benzene. More preferably the hydrocarbon solvent is cyclohexane.
Dexlansoprazole crystalline form I may be isolated in step (f) by the methods known such as filtration or centrifugation.
According to another aspect of the present invention, there is provided a process for the preparation of dexlansoprazole crystalline form II, which comprises:
a) dissolving an alkali metal salt of dexlansoprazole in water;
b) adjusting the pH of the reaction mass to about 8.0 to 9.0 with an acid;
c) maintaining the reaction mass obtained in step (b); and
d) isolating dexlansoprazole crystalline form II.
Preferably the alkali metal salt of dexlansoprazole used in step (a) is sodium salt of dexlansoprazole.
The acid used in step (b) may preferably be an organic acid or an inorganic acid selected from acetic acid, hexanoic acid and formic acid, and more preferably the acid is acetic acid.
Dexlansoprazole crystalline form II may be isolated in step (d) by the methods known such as filtration or centrifugation.
Chromatographic purity of dexlansoprazole is measured by HPLC.
HPLC conditions for analysis are:
Chromatographic Mode : Gradient
Column : Inertsil ODS-2,150X4.6mm, 5μ
[Make: GL-Sciences.Inc S/N 7BS50076]
Flow rate : 0.8 ml/minute Wavelength 285 nm
Injection volume 40 μΐ
Run time 60 minutes.
Optical purity of dexlansoprazole is measured by HPLC.
HPLC conditions for analysis are:
Column : Chiralpak IC, 250 x 4.6 mm, 5μπι
[Make: Daicel chemical technologies, Lot No: ICOOCE- MF022]
Flow rate 1.0 ml/minute
Detector wavelength 283 nm
Run time 20 minutes
Injection volume 20 μΐ
Column temperature 35°C
Diluent Ethanol.
The invention will now be further described by the following examples, which are illustrative rather than limiting.
Examples
Example 1 :
Preparation of dexlansoprazole sodium
Dexlansoprazole (10 gm, obtained by the process described in example 12 of the U.S. Patent No. 5,929,244) was dissolved in ethanol (100 ml) at room temperature to obtain a solution. To the solution was added sodium 2-ethylhexanoate (7 gm) and stirred for 30 minutes. The solvent was distilled off under vacuum to obtain a residual mass. To the residual mass was added n-heptane (200 ml) and stirred for 3 hours at room temperature. The solid obtained was collected by filtration and dried to obtain 5 gm of dexlansoprazole sodium (Optical Purity: 99.99%).
Example 2:
Preparation of dexlansoprazole sodium Dexlansoprazole (10 gm, obtained by the process described in co-pending application no. PCT/IN2009/000567) was dissolved in ethanol (100 ml) in presence of water (5 ml) at room temperature to obtain a solution. The solution was then cooled to - 5°C and then added sodium hydroxide (2.2 gm). The reaction mass was stirred for 1 hour at -5°C and then added n-heptane (200 ml). The contents were stirred for 15 minutes at - 5°C and filtered. The solid obtained was dried to give 8 gm of dexlansoprazole sodium.
Example 3:
Preparation of dexlansoprazole sodium
Dexlansoprazole (5 gm, HPLC Purity: 99.45%; Optical Purity: 99.6%) was dissolved in ethanol (50 ml) in presence of water (5 ml) at room temperature. The solution was then cooled to -5°C and then added sodium hydroxide (1.2 gm). The reaction mass was stirred for 1 hour at -5°C and then added n-heptane (200 ml). The contents were stirred for 15 minutes at -5°C and filtered. The solid obtained was dried to give 3.9 gm of dexlansoprazole sodium (HPLC Purity: 100%; Optical Purity: 100%).
Example 4:
Preparation of dexlansoprazole sodium
Example 3 was repeated using sodium 2-ethylhexanoate instead of sodium hydroxide to obtain dexlansoprazole sodium.
Example 5:
Preparation of crystalline form 1 of dexlansoprazole sodium
Dexlansoprazole (25 gm, HPLC Purity: 99.52%; Optical Purity: 99.7%) was dissolved in ethanol (250 ml) and then added sodium 2-ethylhexanoate (32.5 gm). The reaction mass was stirred for 30 minutes and the solvent was distilled off under vacuum to obtain a residual mass. To the residual mass was added n-heptane (250 ml), stirred for 3 hours at room temperature and filtered. The solid obtained was dried to give 18.5 gm of crystalline form 1 of dexlansoprazole sodium (HPLC Purity: 99.98%; Optical Purity: 99.99%). Example 6:
Preparation of crystalline form 1 of dexlansoprazole sodium
Dexlansoprazole crystalline form II (10 gm) was dissolved in acetone (100 ml) at room temperature to obtain a solution. To the solution was added sodium 2- ethylhexanoate (7 gm) and stirred for 30 minutes. The solvent was distilled off under vacuum to obtain a residual mass. To the residual mass was added n-heptane (100 ml), stirred for 3 hours at room temperature and filtered. The solid obtained was dried to give 7.5 gm of crystalline form 1 of dexlansoprazole sodium (HPLC Purity: 99.9%; Optical Purity: 99.92%).
Example 7:
Preparation of crystalline form 1 of dexlansoprazole sodium
Dexlansoprazole crystalline form I (10 gm) was dissolved in ethanol (100 ml) and then added sodium 2-ethylhexanoate (13 gm). The reaction mass was stirred for 1 hour and the solvent was distilled off under vacuum to obtain a residual mass. To the residual mass was added n-heptane (180 ml) and stirred for 4 hours at room temperature. The solid obtained was collected by filtration and dried to obtain 8.5 gm of crystalline form 1 of dexlansoprazole sodium (HPLC Purity: 99.91 %; Optical Purity: 99.94%).
Example 8:
Preparation of crystalline form 2 of dexlansoprazole sodium
Dexlansoprazole (10 gm, HPLC Purity: 99.5%; Optical Purity: 99.62%) was dissolved in ethanol (100 ml) in presence of water (5 ml) and then cooled to -5°C. To the solution was added sodium hydroxide (2.2 gm) and stirred for 30 minutes at -5°C. To the reaction mass was added n-heptane (80 ml) and stirred for 30 minutes at -5°C. The solid obtained was collected by filtration and dried to obtain 6 gm of crystalline form 2 of dexlansoprazole sodium (HPLC Purity: 99.98%; Optical Purity: 99.99%). Example 9:
Preparation of crystalline form 2 of dexlansoprazole sodium
Dexlansoprazole crystalline form II (25 gm) was dissolved in ethanol (250 ml) in presence of water (10 ml) and then cooled to -5°C. To the solution was added sodium hydroxide (5.5 gm) and stirred for 30 minutes at -5°C. To the reaction mass was added n- heptane (200 ml) and stirred for 30 minutes at -5°C. The solid obtained was collected by filtration and dried to obtain 14 gm of crystalline form 2 of dexlansoprazole sodium (HPLC Purity: 99.95%; Optical Purity: 99.96%).
Example 10:
Preparation of crystalline form 2 of dexlansoprazole sodium
Dexlansoprazole crystalline form I (10 gm) was dissolved in ethanol (100 ml) in presence of water (5 ml) and then cooled to -5°C. To the solution was added sodium hydroxide (3 gm) and stirred for 30 minutes at -5°C. To the reaction mass was added n- heptane (100 ml), stirred for 30 minutes at -5°C and filtered. The solid obtained was dried to give 6 gm of crystalline form 2 of dexlansoprazole sodium (HPLC Purity: 99.92%; Optical Purity: 99.95%).
Example 11 :
Preparation of amorphous form of dexlansoprazole sodium
Dexlansoprazole (10 gm, HPLC Purity: 99.4%; Optical Purity: 99.51%) was dissolved in ethanol (100 ml) and then added sodium hydroxide (1.2 gm) at 0°C. The reaction mass was stirred for 30 minutes and the solvent was distilled off under vacuum to obtain foam. To the foam was added n-heptane (200 ml) and stirred for 2 hours at room temperature. The solid obtained was collected by filtration and dried to obtain 9 gm of amorphous form of dexlansoprazole sodium (HPLC Purity: 99.88%; Optical Purity: 99.92%).
Example 12: Preparation of amorphous form of dexlansoprazole sodium
Dexlansoprazole (10 gm) was dissolved in methanol (100 ml) and then added sodium hydroxide (1.2 gm) at 0°C. The reaction mass was stirred for 30 minutes and the solvent was distilled off under vacuum to obtain foam. To the foam was added n-heptane (200 ml), stirred for 2 hours at room temperature and filtered. The solid obtained was dried to obtain 8.8 gm of amorphous form of dexlansoprazole sodium (HPLC Purity: 99.9%; Optical Purity: 99.95%).
Example 13:
Preparation of dexlansoprazole amorphous form
Dexlansoprazole (2 gm, HPLC Purity: 99.5%; Optical Purity: 99.62%) was dissolved in ethanol (15 ml) at room temperature under stirring. The reaction mass was filtered through hi-flo bed and the solvent was distilled off under vacuum to obtain a solid. The solid obtained was dried at 30 to 35°C to obtain 1.5 gm of dexlansoprazole amorphous form (HPLC Purity: 99.88%; Optical Purity: 99.92%).
Example 14:
Preparation of dexlansoprazole amorphous form
Example 13 was repeated using acetone solvent instead of ethanol solvent to obtain dexlansoprazole amorphous form.
Example 15:
Preparation of dexlansoprazole amorphous form
Example 13 was repeated using methanol solvent instead of ethanol solvent to obtain dexlansoprazole amorphous form.
Example 16: Preparation of dexlansoprazole amorphous form
Example 13 was repeated using methyl ethyl ketone solvent instead of ethanol solvent to obtain dexlansoprazole amorphous form.
Example 17:
Preparation of dexlansoprazole amorphous form
Crystalline form 1 of dexlansoprazole sodium (5 gm, HPLC Purity: 99.98%; Optical Purity: 99.99%) as obtained in example 5 was dissolved in water (50 ml) and dichloromethane (100 ml) at room temperature. The reaction mass was then cooled to 5 to 10°C and pH of the reaction mass was adjusted to 8.0 with acetic acid (10%) at 5 to 10°C. Then the layers were separated and the aqueous layer was exacted with dichloromethane. The combined organic layer was dried with sodium sulfate and the solvent was distilled off under vacuum to obtain a solid. The solid obtained was dried to give 3.5 gm of dexlansoprazole amorphous form (HPLC Purity: 99.99%; Optical Purity: 100%).
Example 18:
Preparation of dexlansoprazole amorphous form
Example 17 was repeated using crystalline form 2 of dexlansoprazole sodium instead of crystalline form 1 of dexlansoprazole sodium to obtain dexlansoprazole amorphous form.
Example 19:
Preparation of dexlansoprazole amorphous form
Example 17 was repeated using amorphous form of dexlansoprazole sodium instead of crystalline form 1 of dexlansoprazole sodium to obtain dexlansoprazole amorphous form. Example 20:
Preparation of dexlansoprazole crystalline form I
Crystalline form 1 of dexlansoprazole sodium (5 gm, HPLC Purity: 99.98%; Optical Purity: 99.99%) as obtained in example 5 was dissolved in water (50 ml) and dichloromethane (100 ml) at room temperature. The reaction mass was then cooled to 5 to 10°C and pH of the reaction mass was adjusted to 8.5 to 10.0 with acetic acid (10%) at 5 to 10°C, Then the layers were separated and the aqueous layer was exacted with dichloromethane. The combined organic layer was dried with sodium sulfate and the solvent was distilled off under vacuum to obtain a solid. To the solid was added cyclohexane (50 ml) at 40°C and then heated to 50°C. The reaction mass was maintained for 15 minutes at 50°C and then cooled to room temperature. The contents were maintained for 1 hour at room temperature and filtered. The solid obtained was dried to give 3.5 gm of dexlansoprazole crystalline form I (HPLC Purity: 99.99%; Optical Purity: 100%).
Example 21 :
Preparation of dexlansoprazole crystalline form I
Example 20 was repeated using crystalline form 2 of dexlansoprazole sodium instead of crystalline form 1 of dexlansoprazole sodium to obtain dexlansoprazole crystalline form I.
Example 22:
Preparation of dexlansoprazole crystalline form I
Example 20 was repeated using amorphous form of dexlansoprazole sodium instead of crystalline form 1 of dexlansoprazole sodium to obtain dexlansoprazole crystalline form I.
Example 23:
Preparation of dexlansoprazole crystalline form II Crystalline form 1 of dexlansoprazole sodium (5 gm, HPLC Purity: 99.98%; Optical Purity: 99.99%) as obtained in example 5 was dissolved in water (50 ml) at room temperature. The reaction mass was then cooled to 5 to 10°C and pH of the reaction mass was adjusted to 8.0 with acetic acid (10%) at 5 to 10°C. The reaction mass was stirred for 1 hour at 5 to 10°C and filtered. The solid obtained was dried to give 3.2 gm of dexlansoprazole crystalline form II (HPLC Purity: 99.99%; Optical Purity: 100%).
Example 24:
Preparation of dexlansoprazole crystalline form II
Example 23 was repeated using crystalline form 2 of dexlansoprazole sodium instead of crystalline form 1 of dexlansoprazole sodium to obtain dexlansoprazole crystalline form II.
Example 25:
Preparation of dexlansoprazole crystalline form II
Example 23 was repeated using amorphous form of dexlansoprazole sodium instead of crystalline form 1 of dexlansoprazole sodium to obtain dexlansoprazole crystalline form II.

Claims

We claim:
1. A solid of dexlansoprazole sodium.
2. The compound as claimed in claim 1, wherein the solid is crystalline or amorphous.
3. A crystalline form 1 of dexlansoprazole sodium which is characterized by peaks in the powder x-ray diffraction spectrum having 2Θ angle positions at about 4.3, 5.0, 6.5, 13.2, 15.7, 17.9, 20.0 and 24.6 ± 0.2 degrees.
4. A crystalline form 1 of dexlansoprazole sodium, characterized by an x-ray powder diffractogram as shown in figure 1.
5. A process for the preparation of crystalline form 1 of dexlansoprazole sodium as claimed in claim 3, which comprises:
a. providing a solution of dexlansoprazole in a solvent system comprising an alcoholic solvent, a ketonic solvent or mixture thereof;
b. adding above about 1.5 mole sodium 2-ethylhexanoate per mole of dexlansoprazole used in step (a) to the solution obtained in step (a);
c. removing the solvent from the reaction mass obtained in step (b);
d. adding hydrocarbon solvent to the residual mass obtained in step (c); and e. isolating crystalline form 1 of dexlansoprazole sodium.
6. The process as claimed in claim 5, wherein the alcoholic solvent used in step (a) is selected from methanol, ethanol, isopropyl alcohol and n-butanol.
7. The process as claimed in claim 6, wherein the alcoholic solvent is methanol.
8. The process as claimed in claim 5, wherein the ketonic solvent used in step (a) is selected from acetone, methyl ethyl ketone, methyl isobutyl ketone and diethyl ketone.
9. The process as claimed in claim 8, wherein the ketonic solvent is acetone.
10. The process as claimed in claim 5, wherein the sodium 2-ethylhexanoate used in step (b) is above 2.5 moles.
11. The process as claimed in claim 10, wherein the sodium 2-ethylhexanoate used in step (b) is above 2.0 moles.
12. The process as claimed in claim 11, wherein the sodium 2-ethylhexanoate used in step (b) is between 2.0 to 4.0 moles.
13. The process as claimed in claim 5, wherein the hydrocarbon solvent used in step (d) is a solvent or mixture of solvents selected from cyclohexane, hexane, n-heptane, benzene, toluene and xylene.
14. The process as claimed in claim 13, wherein the hydrocarbon solvent is n-heptane.
15. A crystalline form 2 of dexlansoprazole sodium which is characterized by peaks in the powder x-ray diffraction spectrum having 2Θ angle positions at about 5.6, 7.1, 11.2, 11.9, 12.3 and 18.5 ± 0.2 degrees.
16. A crystalline form 2 of dexlansoprazole sodium, characterized by an x-ray powder diffractogram as shown in figure 2.
17. A process for the preparation of crystalline form 2 of dexlansoprazole sodium as claimed in claim 15, which comprises:
a. providing a solution of dexlansoprazole in an alcoholic solvent in presence of water;
b. cooling the solution obtained in step (a) at below 5°C;
c. adding above about 1.5 mole sodium hydroxide per mole of dexlansoprazole used in step (a) at below 5°C;
d. adding hydrocarbon solvent to the reaction mass obtained in step (c); and e. isolating crystalline form 2 of dexlansoprazole sodium.
18. The process as claimed in claim 17, wherein the alcoholic solvent used in step (a) is a solvent or mixture of solvents selected from methanol, ethanol, isopropyl alcohol and n-butanol.
19. The process as claimed in claim 18, wherein the alcoholic solvent is ethanol.
20. The process as claimed in claim 17, wherein the sodium hydroxide used in step (c) is above 2.5 moles.
21. The process as claimed in claim 20, wherein the sodium hydroxide used in step (c) is above 2.0 moles.
22. The process as claimed in claim 21, wherein the sodium hydroxide used in step (c) is between 2.0 to 4.0 moles.
23. The process as claimed in claim 17, wherein the hydrocarbon solvent used in step (d) may preferably be a solvent or mixture of solvents selected from cyclohexane, hexane, n-heptane, benzene, toluene and xylene.
24. The process as claimed in claim 23, wherein the hydrocarbon solvent is n-heptane.
25. Amorphous form of dexlansoprazole sodium which is characterized by an x-ray powder diffractogram as shown in figure 3.
26. A process for the preparation of amorphous form of dexlansoprazole sodium as claimed in claim 25, which comprises:
a. providing a solution of dexlansoprazole in an alcoholic solvent;
b. adding above about 1.5 mole sodium hydroxide per mole of dexlansoprazole used in step (a) to the solution obtained in step (a) at 0°C;
c. removing the solvent from the reaction mass obtained in step (b);
d. adding hydrocarbon solvent to the foam obtained in step (c); and
e. isolating amorphous form of dexlansoprazole sodium.
27. The process as claimed in claim 26, wherein the alcoholic solvent used in step (a) may preferably be a solvent or mixture of solvents selected from methanol, ethanol, isopropyl alcohol and n-butanol.
28. The process as claimed in claim 27, wherein the alcoholic solvent is ethanol.
29. The process as claimed in claim 26, wherein the sodium hydroxide used in step (b) is above 2.5 moles.
30. The process as claimed in claim 29, wherein the sodium hydroxide used in step (b) is above 2.0 moles.
31. The process as claimed in claim 30, wherein the sodium hydroxide used in step (b) is between 2.0 to 4.0 moles.
32. The process as claimed in claim 26, wherein the hydrocarbon solvent used in step (d) may preferably be a solvent or mixture of solvents selected from cyclohexane, hexane, n-heptane, benzene, toluene and xylene.
33. The process as claimed in claim 32, wherein the hydrocarbon solvent is n-heptane.
34. A process for the preparation of dexlansoprazole amorphous form, which comprises: a. providing a solution of dexlansoprazole in a solvent;
b. removing the solvent completely from the solution obtained in step (a); and c. drying the solid obtained in step (b) to obtain dexlansoprazole amorphous form.
35. The process as claimed in claim 34, wherein the solvent used in step (c) is a solvent or mixture of solvents selected from methanol, ethanol, isopropyl alcohol, n-butanol, dichloromethane, chloroform, carbon tetrachloride, ethylene dichloride, ethyl acetate, methyl acetate, isopropyl acetate, tert-butyl methyl acetate, ethyl formate, acetone, methyl ethyl ketone, methyl isobutyl ketone, diethyl ketone, tetrahydrofuran, 1,4- dioxane, methyl tert-butyl ether, diisopropyl ether and diethyl ether.
36. The process as claimed in claim 35, wherein the solvents are methanol, ethanol, dichloromethane, ethyl acetate, acetone, methyl ethyl ketone, methyl tert-butyl ether and diisopropyl ether.
37. The process as claimed in claim 36, wherein the solvents are methanol, ethanol, acetone, ethyl acetate and methyl ethyl ketone.
38. A process for the preparation of dexlansoprazole amorphous form, which comprises: a. dissolving an alkali metal salt of dexlansoprazole in an chlorinated solvent and water;
b. adjusting the pH of the reaction mass to about 8.0 to 9.0 with an acid;
c. extracting dexlansoprazole into organic solvent;
d. removing the solvent from the solution obtained in step (c) to obtain a solid; and e. drying the solid obtained in step (d) to obtain dexlansoprazole amorphous form.
39. The process as claimed in claim 38, wherein the alkali metal salt of dexlansoprazole used in step (a) is sodium salt of dexlansoprazole.
40. The process as claimed in claim 38, wherein the chlorinated solvent used in step (a) is a solvent or mixture of solvents selected from dichloromethane, chloroform, carbon tetrachloride and ethylene dichloride.
41. The process as claimed in claim 40, wherein the chlorinated solvent is dichloromethane.
42. The process as claimed in claim 38, wherein the acid used in step (b) is an organic acid or an inorganic acid selected from acetic acid, hexanoic acid and formic acid.
43. The process as claimed in claim 42, wherein the acid is acetic acid.
44. The process as claimed in claim 38, wherein the organic solvent used in step (c) is a solvent or mixture of solvents selected from dichloromethane, chloroform, carbon tetrachloride, ethylene dichloride, ethyl acetate, methyl acetate, isopropyl acetate, tert-butyl methyl acetate and ethyl format.
45. The process as claimed in claim 44, wherein the organic solvent is dichloromethane.
46. A process for the preparation of dexlansoprazole crystalline form I, which comprises: a. dissolving an alkali metal salt of dexlansoprazole in an chlorinated solvent and water;
b. adjusting the pH of the reaction mass to about 8.0 to 9.0 with an acid;
c. extracting dexlansoprazole into organic solvent;
d. removing the solvent from the solution obtained in step (c) to obtain a solid;
e. slurrying the solid obtained in step (d) with hydrocarbon solvent; and
f. isolating dexlansoprazole crystalline form I.
47. The process as claimed in claim 46, wherein the alkali metal salt of dexlansoprazole used in step (a) is sodium salt of dexlansoprazole.
48. The process as claimed in claim 46, wherein the chlorinated solvent used in step (a) is a solvent or mixture of solvents selected from dichloromethane, chloroform, carbon tetrachloride and ethylene dichloride.
49. The process as claimed in claim 48, wherein the chlorinated solvent is dichloromethane.
50. The process as claimed in claim 46, wherein the acid used in step (b) is an organic acid or an inorganic acid selected from acetic acid, hexanoic acid and formic acid.
51. The process as claimed in claim 50, wherein the acid is acetic acid.
52. The process as claimed in claim 46, wherein the organic solvent used in step (c) is a solvent or mixture of solvents selected from dichloromethane, chloroform, carbon tetrachloride, ethylene dichloride, ethyl acetate, methyl acetate, isopropyl acetate, tert-butyl methyl acetate and ethyl format.
53. The process as claimed in claim 52, wherein the organic solvent is dichloromethane.
54. The process as claimed in claim 46, wherein the hydrocarbon solvent used in step (e) is a solvent or a mixture of solvents selected from cyclohexane, hexane, n-heptane, toluene, xylene and benzene.
55. The process as claimed in claim 54, wherein the hydrocarbon solvent is cyclohexane.
56. A process for the preparation of dexlansoprazole crystalline form II, which comprises:
a. dissolving an alkali metal salt of dexlansoprazole in water;
b. adjusting the pH of the reaction mass to about 8.0 to 9.0 with an acid; c. maintaining the reaction mass obtained in step (b); and
d. isolating dexlansoprazole crystalline form II.
57. The process as claimed in claim 56, wherein the alkali metal salt of dexlansoprazole used in step (a) is sodium salt of dexlansoprazole.
58. The process as claimed in claim 56, wherein the acid used in step (b) is an organic acid or an inorganic acid selected from acetic acid, hexanoic acid and formic acid.
59. The process as claimed in claim 58, wherein the acid is acetic acid.
60. A pharmaceutical composition that comprises crystalline form 1 of dexlansoprazole sodium and pharmaceutically acceptable excipients, and optionally other therapeutic ingredients.
61. A pharmaceutical composition that comprises crystalline form 2 of dexlansoprazole sodium and pharmaceutically acceptable excipients, and optionally other therapeutic ingredients.
62. A pharmaceutical composition that comprises amorphous form of dexlansoprazole sodium and pharmaceutically acceptable excipients, and optionally other therapeutic ingredients.
63. A pharmaceutical composition that comprises dexlansoprazole amorphous form and pharmaceutically acceptable excipients, and optionally other therapeutic ingredients.
64. The pharmaceutical composition as claimed in claim 60, 61, 62 and 63, wherein the polymorphic forms are formulated into tablets, capsules, suspensions, dispersions, injectables and other pharmaceutical forms.
PCT/IN2011/000782 2011-01-12 2011-11-11 Polymorphs of dexlansoprazole salts WO2012095859A1 (en)

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CN106668018A (en) * 2016-12-29 2017-05-17 南京海融制药有限公司 Sustained release capsule of sodium dexlansoprazole and preparation method thereof
CN106749186A (en) * 2016-12-29 2017-05-31 南京海融制药有限公司 A kind of novel crystal forms of R-lansoprazole sodium and preparation method thereof
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CN106668018A (en) * 2016-12-29 2017-05-17 南京海融制药有限公司 Sustained release capsule of sodium dexlansoprazole and preparation method thereof
CN106749186A (en) * 2016-12-29 2017-05-31 南京海融制药有限公司 A kind of novel crystal forms of R-lansoprazole sodium and preparation method thereof
CN106727381A (en) * 2016-12-29 2017-05-31 南京海融制药有限公司 A kind of oral disintegrating tablet of R-lansoprazole sodium and preparation method thereof
CN106749186B (en) * 2016-12-29 2019-03-05 南京海融制药有限公司 A kind of novel crystal forms and preparation method thereof of R-lansoprazole sodium
CN106668018B (en) * 2016-12-29 2019-12-06 南京海融制药有限公司 Dexlansoprazole sodium sustained-release capsule and preparation method thereof
CN109836413A (en) * 2017-11-27 2019-06-04 银谷制药有限责任公司 A kind of Dexlansoprazole sodium crystal and its preparation method and application

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