WO2009157005A1 - Crystalline forms of atorvastatin hemi-magnesium salt and a process thereof - Google Patents

Crystalline forms of atorvastatin hemi-magnesium salt and a process thereof Download PDF

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WO2009157005A1
WO2009157005A1 PCT/IN2008/000503 IN2008000503W WO2009157005A1 WO 2009157005 A1 WO2009157005 A1 WO 2009157005A1 IN 2008000503 W IN2008000503 W IN 2008000503W WO 2009157005 A1 WO2009157005 A1 WO 2009157005A1
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magnesium salt
crystalline
atorvastatin
atorvastatin hemi
crystalline form
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PCT/IN2008/000503
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French (fr)
Inventor
Chandrashekar Aswathanarayanappa
Srinivas Pullela Venkata
Abhilash Mullasseril
Divya Kangath
Umesh Sannachikkanna
Rohit Gupta
Srinivasa Shetty
Srinivasa Thimmashetty
Nitin Sopanrao Patil
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Biocon Limited
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Publication of WO2009157005A1 publication Critical patent/WO2009157005A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil

Definitions

  • novel polymorphs of Atorvastatin Hemi-magnesium salts and the process of preparing them.
  • the novel polymorphs according to the invention are crystalline in nature characterized by X-ray diffraction (XRD), differential scanning calorimetry (DSC), and Infrared Spectroscopy.
  • Pharmaceutical compositions containing these forms are particularly useful in treatment of hyperlipidemia and hypercholesterolemia in patients in need thereof.
  • the present invention provides polymorphic forms of Atorvastatin hemi-magnesium denominated as crystalline forms B7, B8 and B9.
  • Atorvastatin is a member belonging to the class of drugs called statins.
  • Statin drugs are one of the most therapeutically effective drugs available for reducing low density lipoprotein (LDL) particle concentration in the blood stream of patients at risk for cardiovascular disease.
  • LDL low density lipoprotein
  • Atorvastatin is the common chemical name of [R-(R* ,R*)]-2-(4-fluorophenyl)- beta, delta - dihydroxy-5-(l-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-lH-pyrrole-l-heptanoic acid that have been described, in U.S. Pat. Nos. 4,681,893, 5,273,995.
  • the present invention includes a new crystalline forms of Atorvastatin hemi-magnesium salts.
  • Atorvastatin formulations of Atorvastatin and polymorphs as well as processes and key intermediates. These include US4,681,893, US 5,273,995, US5,003,080, US5,097,045, US5, 103,024, US5,124,482, US5,149,837, US5, 155,251, US5 5 969,156, US6,087,511 and US6, 121,461 which are incorporated herein by reference.
  • amorphous Atorvastatin hemi-magnesium salt is described in detail in WO2007/063551, the contents of which are incorporated herein by reference in its entirety.
  • Polymorphism which is the occurrence of different crystal forms is a property of some molecules and molecular complexes.
  • a single molecule, like Atorvastatin magnesium may give rise to a variety of crystalline forms having distinct crystal structures and physical properties like melting point, X-ray diffraction pattern, IR pattern, and solid state NMR spectrum.
  • One crystalline form may give rise to thermal behavior different from that of another crystalline form. Thermal behavior can be measured in the laboratory by such techniques as capillary melting point, differential scanning calorimetry ("DSC”), which has been used to distinguish various polymorphic forms.
  • DSC differential scanning calorimetry
  • polymorphs are distinct solids sharing the same molecular formula yet having distinct advantageous physical properties compared to other crystalline forms of the same compound or complex.
  • the object of the present invention is to provide novel polymorphs of hemi-magnesium salts of Atorvastatin and processes for their preparation which are very suitable for use on an industrial scale.
  • a further object of the present invention is to provide pharmaceutical compositions including these polymorphs, preferably solid oral dosage forms.
  • the main object of the present invention is to obtain a crystalline form of atorvastatin hemi- magnesium salt B7.
  • Still another object of the present invention is to obtain a process for the preparation of crystalline Atorvastatin forms.
  • Still another object of the present invention is to obtain a crystalline form of atorvastatin hemi- magnesium salt B7 with purity of atleast 99%.
  • Still another object of the present invention is to obtain a crystalline form of atorvastatin hemi- magnesium salt B8 with purity of atleast 99%.
  • Still another object of the present invention is to obtain a crystalline form of atorvastatin hemi- magnesium salt B9 with purity of atleast 99%.
  • Still another object of the present invention is to obtain a pharmaceutical composition
  • a pharmaceutical composition comprising crystalline atorvastatin hemi-magnesium salt selected from a group comprising B7, B8 or B9 or combinations thereof optionally along with pharmaceutically acceptable excipients.
  • the present invention relates to a crystalline form of atorvastatin hemi-magnesium salt characterized by X-ray diffraction pattern comprising 2 theta values 3.87, 4.85, 5.62, 7.76, 9.72, 11.4, 11.77, 12.61, 14.52, 15.08, 15.68, 16.33, 16.99, 17.79, 18.24, 18.88, 19.59, 19.96, 20.33, 22.05, 22.80, 24.15, 24.62, 25.49 ⁇ 0.2; a crystalline form of atorvastatin hemi- magnesium salt characterized by X-ray diffraction pattern comprising 2 theta values 3.99, 7.33, 7.91, 8.55, 9.24, 11.02, 11.45, 11.90, 13.06, 14.26, 14.68, 15.19, 17.24, 17.44, 18.50, 18.97, 19.28, 20.51, 22.04, 23.76 ⁇ 0.2; a crystalline form of atorvastatin hemi-magnesium salt characterized by X-ray
  • Fig 1 XRD Diffraction pattern of Amorphous Atorvastatin Hemi-magnesium salt.
  • Fig 2 XRD Diffraction pattern of crystalline Atorvastatin Hemi-magnesium salt form B7.
  • Fig 3 XRD Diffraction pattern of crystalline Atorvastatin Hemi-magnesium salt form B8.
  • Fig 4 XRD Diffraction pattern of crystalline Atorvastatin Hemi-magnesium salt form B9.
  • Fig 5 DSC thermogram of crystalline Atorvastatin Hemi-magnesium salt form B7.
  • Fig 6 DSC thermogram of crystalline Atorvastatin Hemi-magnesium salt form B8.
  • Fig 7 DSC thermogram of crystalline Atorvastatin Hemi-magnesium salt form B9.
  • the present invention relates to a crystalline form of atorvastatin hemi-magnesium salt characterized by X-ray diffraction pattern comprising 2 theta values 3.87, 4.85, 5.62, 7.76, 9.72,
  • the present invention relates a crystalline form of atorvastatin hemi-magnesium salt characterized by X-ray diffraction pattern comprising 2 theta values 3.99, 7.33, 7.91, 8.55, 9.24, 11.02, 11.45, 11.90, 13.06, 14.26, 14.68, 15.19, 17.24, 17.44, 18.50, 18.97, 19.28, 20.51, 22.04,
  • the present invention relates a crystalline form of atorvastatin hemi-magnesium salt characterized by X-ray diffraction pattern comprising 2 theta values 3.80, 4.00, 5.93, 7.22, 7.57,
  • the crystalline form is B7.
  • the crystalline form is B8.
  • the crystalline form is B9.
  • the present invention relates to a crystalline form of atorvastatin hemi-magnesium salt form B7 having a DSC thermogram which is characterized by endothermic peaks at about 98 0 C, 134.99
  • the present invention relates to a crystalline form of atorvastatin hemi-magnesium salt form B 8 having a DSC thermogram which is characterized by endothermic peaks at about 81.99 0 C and
  • the present invention relates to a crystalline form of atorvastatin hemi-magnesium salt form B 9 having a DSC thermogram which is characterized by endothermic peaks at about 108.58 0 C and
  • the present invention relates to a process for the preparation of crystalline Atorvastatin form B7, said process comprising steps of:
  • the present invention relates a process for the preparation of crystalline atorvastatin form B8, said process comprising steps of:
  • the solvent used is selected from a group comprising water or a mixture of organic solvents and water.
  • the organic solvent is hydroxylic or non- hydroxylic solvent.
  • the organic solvent is selected from the group comprising acetone, methanol, ethanol, ethyl acetate, isopropyl alcohol, THF, dichloromethane, t-butanol, iso-butanol, carbon-tetrachloride, 1,4-dioxan, n-butanol, di-isopropyl ether, di- ethylether or mixtures thereof.
  • the mixture is heated to a temperature of about
  • the present invention relates a crystalline form of atorvastatin hemi-magnesium salt B7 with purity of atleast 99%.
  • the present invention relates a crystalline form of atorvastatin hemi-magnesium salt B 8 with purity of atleast 99%.
  • the present invention relates a crystalline form of atorvastatin hemi-magnesium salt B9 with purity of atleast 99%.
  • the present invention relates a pharmaceutical composition
  • a pharmaceutical composition comprising crystalline atorvastatin hemimagnesium salt selected from a group comprising B7, B8 or B9 or combinations thereof optionally along with pharmaceutically acceptable excipients.
  • the present invention discloses new forms of Atorvastatin hemi-magnesium salts. We hereby disclose new polymorphs of said compound as well as the processes for preparing the same.
  • the present invention provides polymorphic forms of Atorvastatin hemi-magnesium denominated as crystalline forms B7, B8 and B9.
  • a further aspect of the present invention relates to pharmaceutical compositions and dosage form containing the novel forms of Atorvastatin hemi-magnesium or a mixture of one or more of said polymorphs.
  • the pharmaceutical compositions of said polymorphs can be used in treatment of hyperlipidemia and hypercholesterolemia in patients in need thereof.
  • the present invention relates to a crystalline form B7 of Atorvastatin hemi-magnesium salt characterized by X-ray diffraction pattern comprising 2 theta values 3.87, 4.85, 5.62, 7.76, 9.72, 1 1.4, 11.77, 12.61, 14.52, 15.08, 15.68, 16.33, 16.99, 17.79, 18.24, 18.88, 19.59, 19.96, 20.33,
  • the present invention relates to a crystalline form B 8 of Atorvastatin hemi-magnesium salt characterized by X-ray diffraction pattern comprising 2 theta values 3.99, 7.33, 7.91, 8.55, 9.24, 11.02, 11.45, 11.90, 13.06, 14.26, 14.68, 15.19, 17.24, 17.44, 18.50, 18.97, 19.28, 20.51, 22.04, 23.76 ⁇ 0.2.
  • the present invention relates to a crystalline form B9 of Atorvastatin hemi-magnesium salt characterized by X-ray diffraction pattern comprising 2 theta values 3.80, 4.00, 5.93, 7.22, 7.57, 7.98, 8.50, 8.96, 9.70, 10.47, 10.75, 11.45, 11.95, 12.68, 13.17, 13.51, 13.93, 14.48, 14.92, 15.45, 16.41, 17.01, 17.60, 18.12, 18.82, 19.449, 20.36, 21.06, 23.04, 23.46, 24.68, 25.46, 27.17, 28.26 ⁇ 0.2.
  • the present ' invention provides polymorphic forms of Atorvastatin hemi-magnesium denominated as crystalline forms B 7, B 8 and B9.
  • the crystalline form of Atorvastatin hemi- magnesium is B7.
  • the crystalline form of Atorvastatin hemi- magnesium is B8.
  • the crystalline form of Atorvastatin hemi-magnesium is B9.
  • One of the embodiments of the invention relates to a crystalline form of Atorvastatin hemi- magnesium salt form B7 having a DSC thermogram which is characterized by endothermic peaks at about 98 0 C, 134.99 0 C and 167.29 0 C.
  • One of the embodiments of the invention relates to a crystalline form of Atorvastatin hemi- magnesium salt form B8 having a DSC thermogram which is characterized by an endothermic peak at about 81.99 0 C and 110.22 0 C.
  • One of the embodiments of the invention relates to a crystalline form of Atorvastatin hemi- magnesium salt form B9 having a DSC thermogram which is characterized by an endothermic peak at about 108.58 0 C and 165.87 0 C.
  • ATV-I (acetonide) is represented with the structure
  • ATV-I (Boronate) is represented with the structure
  • the term "polymorph” refers to a compound (e.g., Atorvastatin) which, when present as a solid, exists as different forms.
  • the Atorvastatin polymorph includes solid forms of a compound such as crystals, microcrystals, foams, and powders, among others.
  • the Atorvastatin polymorphs of the present invention are crystalline.
  • Polymorphs typically differ in their physical properties due to the order of the molecules in the lattice of the polymorph. In addition, the physical properties of the polymorph can differ due to the presence of solvates or other molecules incorporated into the lattice of the polymorph.
  • the process for the preparation of crystalline Atorvastatin forms comprises steps of
  • the amorphous form of atorvastatin hemi-magnesium salt is treated with water or a mixture of two or more suitable solvents or a mixture of solvent and water under a suitable temperature range and the mixture can then be filtered and dried, preferably under vacuum, to obtain crystalline Atorvastatin hemi-magnesium salt.
  • the organic solvent may be selected from a group comprising hydroxylic or non-hydroxylic solvents or a mixture thereof. More particularly, the organic solvent may be selected from a group comprising acetone, methanol, ethanol, ethyl acetate, isopropyl alcohol, THF, dichloromethane, t-butanol, iso-butanol, carbon tetrachloride, 1,4-dioxan, n-butanol, di-isopropyl ether, di-ethylether and mixtures thereof.
  • the used solvents can be removed by various drying methods such as vacuum drying, rapid solvent evaporation, spray drying, freeze drying, solvent precipitation, roller drying and the like.
  • the present invention contemplates temperature variations during heating the mixture. Heating may be carried out at temperature ranging from 4O 0 C to 100 0 C. Most preferably, mixture may be heated to a temperature of about 4O 0 C. The stirring may be conducted for at least 1- 5 days, more preferably 1 day, most preferably 3 days. Every aspect or attribute of the method of obtaining the polymorph has a significant role to play.
  • Atorvastatin hemi-magnesium polymorph Forms is accomplished using techniques known to those of skill in the art. Specifically, verification can be performed using techniques including melting point, infrared spectroscopy (IR), nuclear magnetic resonance spectroscopy (NMR), combustion analysis, Raman spectroscopy. Other techniques including differential scanning calorimetry (DSC) and X-ray diffraction (XRD) are also useful in distinguishing polymorphs.
  • IR infrared spectroscopy
  • NMR nuclear magnetic resonance spectroscopy
  • Raman spectroscopy Raman spectroscopy
  • DSC differential scanning calorimetry
  • XRD X-ray diffraction
  • the present invention also relates to pharmaceutical compositions comprising crystalline Atorvastatin hemi-magnesium forms selected from the group comprising B7, B8 and B9 or combinations thereof optionally along with pharmaceutically acceptable excipients.
  • the excipients are selected from the group comprising granulating agents, binding agents, lubricating agents, disintegrating agents, sweetening agents, coloring agents, flavoring agents, coating agents, plasticizers, preservatives, suspending agents, emulsifying agents, and spheronization agents.
  • the present invention further provides compositions containing crystalline forms of the invention and one or more of other ingredients.
  • the composition contains at least about 50%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 97%, at least about 98.0%, at least about 98.1%, at least about 98.2%, at least about 98.3%, at least about 98.4%, at least about 98.5%, at least about 98.6%, at least about 98.7%, at least about 98.8%, at least about 98.9%, at least about 99.0%, at least about 99.1%, at least about 99.2%, at least about 99.3%, at least about 99.4%, at least about 99.5%, at least about 99.6%, at least about 99.7%, at least about 99.8%, or at least about 99.9% by weight of a crystalline form of the invention or mixture thereof.
  • Atorvastatin hemi-magnesium polymorphic forms are useful for reducing the plasma low density lipoprotein level of a patient suffering from or susceptible to hypercholesterolemia.
  • it will typically be administered to human patients in a unit dose of from about 0.5 mg to about 100 mg.
  • a dose of from about 2.5 to about 80 mg per day, more particularly from about 2.5 to about 20 mg per day causes a lowering of the plasma low density lipoprotein. Whether such lowering is sufficient or whether the dose or dose frequency should be increased is a determination that is within the skill level of appropriately trained medical personnel.
  • Dosage forms include solid dosage forms, like tablets, powders, capsules, suppositories, sachets, troches and lozenges as well as liquid suspensions and elixirs. While the description is not intended to be limiting, the invention is also not intended to pertain to true solutions of atorvastatin hemi-magnesium whereupon the properties that distinguish the solid forms of atorvastatin hemi- magnesium are lost. However, the use of the novel forms to prepare such solutions is considered to be within the contemplation of the invention.
  • Tablet formulations can be made by conventional compression, wet granulation, or dry granulation methods and utilize pharmaceutically acceptable diluents, binding agents, lubricants, disintegrants, surface modifying agents (including surfactants), suspending or stabilizing agents (including, but not limited to, magnesium stearate, stearic acid, sodium lauryl sulfate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, microcrystalline ceUulose,sodiumcarboxymethyl cellulose, carboxymethylcellulose calcium, polyvinylpyrrolidine, alginic acid, acacia gum, xanthan gum, sodium citrate, complex silicates, calcium carbonate, glycine, sucrose, sorbitol, dicalcium phosphate, calcium sulfate, lactose, kaolin, mannitol " , sodium chloride, low melting waxes, and ion exchange resins.
  • Surface modifying agents
  • surface modifying agents include, but are not limited to, poloxamer 188, benzalkonium chloride, calcium stearate, cetostearl alcohol, cetomacrogol emulsifying wax, sorbitan esters, colloidal silicon dioxide, phosphates, sodium dodecylsulfate, magnesium aluminum silicate, and triethanolamine.
  • Capsule dosages will contain the solid composition within a capsule which may be made of gelatin or other conventional encapsulating material.
  • Tablets and powders may be coated. Tablets and powders may be coated with an enteric coating.
  • the enteric coated powder forms may have coatings comprising phthalic acid cellulose acetate, hydroxypropylmethyl- cellulose phthalate, polyvinyl alcohol phthalate, carboxymethylethylcellulose, a copolymer of styrene and maleic acid, a copolymer of methacrylic acid and methyl methacrylate, and like materials, and if desired, they may be employed with suitable plasticizers and/or extending agents.
  • a coated tablet may have a coating on the surface of the tablet or may be a tablet comprising a powder or granules with an enteric-coating.
  • compositions described herein containing Atorvastatin hemi-magnesium polymorph Forms can be formulated in any form suitable for the desired route of delivery using a pharmaceutically effective amount of the polymorph.
  • the compositions of the invention can be delivered by a route such as oral, dermal, transdermal, intrabronchial, intranasal, intravenous, intramuscular, subcutaneous, parenteral, intraperitoneal, intranasal, vaginal, rectal, sublingual, intracranial, epidural, intratracheal, or by sustained release.
  • delivery is oral.
  • the reaction mass was concentrated to about 400 mL and water (1.0 L) and methyl tert-butyl ether (MTBE, 400 mL) were added. Sufficient quantity of methanol was added to get two clear layers and MTBE layer was separated. Aqueous layer was further washed with MTBE (3X400 mL). The aqueous layer was kept under vacuum at 40-45o C till solids was observed and kept at 20-25 0 C for 3 h and the solids were filtered. The solids were dissolved in a mixture of ethyl acetate (10V based on the wet weight of the solid Atorvastatin- Na) and water (IV based on the wet weight of the solid Atorvastatin-Na).
  • Fig. 1 The amorphous Atorvastatin hemi-magnesium salt obtained has been depicted in Fig. 1.
  • the yield of the amorphous Atorvastatin magnesium was 65g and the purity was 99.3%
  • the reaction mass was concentrated to about 400 mL and water (1.0 L) and methyl tert-butyl ether (MTBE, 400 mL) were added. Sufficient quantity of methanol was added to get two clear layers and MTBE layer was separated. Aqueous layer was further washed with MTBE (3X400 mL). The aqueous layer was kept under vacuum at 40-45o C till solids was observed and kept at 20-25 o C for 3 h and the solids were filtered. The solids were dissolved in a mixture of ethyl acetate (10V based on the wet weight of the solid Atorvastatin-Na) and water (IV based on the wet weight of the solid Atorvastatin-Na).
  • Fig. 1 The amorphous Atorvastatin hemi-magnesium salt obtained has been depicted in Fig. 1.
  • the reaction mass was concentrated to about 400 mL and water (1.0 L) and methyl tert-butyl ether (MTBE, 400 mL) were added. Sufficient quantity of methanol was added to get two clear layers and MTBE layer was separated. Aqueous layer was further washed with MTBE (3X400 mL). The aqueous layer was kept under vacuum at 40-45o C till solids was observed and kept at 20-25 o C for 3 h and the solids were filtered. The solids were dissolved in a mixture of ethyl acetate (10V based on the wet weight of the solid Atorvastatin-Na) and water (IV based on the wet weight of the solid Atorvastatin-Na).
  • Fig. 1 The amorphous Atorvastatin hemi-magnesium salt obtained has been depicted in Fig. 1.
  • the yield of the amorphous Atorvastatin magnesium was 65g and the purity was 98.%
  • ATV-I Boranate 100 g was added to a mixture of water (10Y) and methanol (3 V). Basified with NaOH solution (30%, IV) and refluxed for four hours at 100°C. The reaction completion was monitored by TLC. After the reaction completion the mass was cooled to 30 0 C, washed with MTBE (3x3V). The aqueous layer was subjected to vacuum at 30 0 C to obtain the solid and kept for 1 ⁇ hours at RT. The solid was filtered and dissolved in a mixture of ethyl acetate (10V) and water (10% based on ethyl acetate volume). The pH of the mass was adjusted to 8-8.5 using 1.5N HCl.
  • Fig. 1 The amorphous Atorvastatin hemi-magnesium salt obtained has been depicted in Fig. 1.
  • the yield of the amorphous Atorvastatin magnesium was 65 g and the purity was 98%
  • ATV-I Boranate was added to a mixture of water (10V) and methanol (3 V). Basified with NaOH solution (30%, IV) and refluxed for four hours at 100°C. The reaction completion was monitored by TLC. After the reaction completion the mass was cooled to 30 0 C, washed with MTBE (3x3 V). The aqueous layer was subjected to vacuum at 30°C to obtain the solid and kept for 1 ⁇ hours at RT. The solid was filtered and dissolved in a mixture of ethyl acetate (10V) and water (10% based on ethyl acetate volume). The pH of the mass was adjusted to 8-8.5 using 1.5N HCl.
  • Fig. 1 The amorphous Atorvastatin hemi-magnesium salt obtained has been depicted in Fig. 1.
  • the yield of the amorphous Atorvastatin magnesium was 69g and the purity was 98.87%.
  • ATV-I Boranate was added to a mixture of water (10V) and methanol (3 V). Basified with NaOH solution (30%, IV) and refluxed for four hours at 100 0 C. The reaction completion was monitored by TLC. After the reaction completion the mass was cooled to 3O 0 C, washed with MTBE (3x3V). The aqueous layer was subjected to vacuum at 3O 0 C to obtain the solid and kept for l ⁇ hours at RT. The solid was filtered and dissolved in a mixture of ethyl acetate (10V) and water (10% based on ethyl acetate volume). The pH of the mass was adjusted to 8-8.5 using 1.5N HCl.
  • Fig. 1 The amorphous Atorvastatin hemi-magnesium salt obtained has been depicted in Fig. 1.
  • the yield of the amorphous Atorvastatin magnesium was 6Og and the purity was 98%
  • Atorvastatin- magnesium amorphous 25 g obtained from Example 1 or Example 4 Magnesium chloride was charged to a mixture of acetone and water (1:1; 15V) and stirred for 3 days at ambient temperature. Then filtered and dried in under vacuum at 40-45 0 C for 16 h.
  • the crystalline Atorvastatin magnesium polymorph obtained from said Example 7 is depicted with XRD pattern that shows characteristic peaks at 2 ⁇ values of 3.87, 7.76, 9.72, 12.61, 19.96.
  • polymorph showed characteristic by X-ray diffraction 2 theta angle values of 3.87, 4.85, 5.62, 7.76, 9.72, 11.4, 11.77, 12.61, 14.52, 15.08, 15.68, 16.33, 16.99, 17.79, 18.24, 18.88, 19.59, 19.96, 20.33, 22.05, 22.80, 24.15, 24.62, 25.49 ⁇ 0.2 that has been depicted in Fig.2.
  • the crystalline Atorvastatin Magnesium B7 is having a DSC thermogram substantially as shown in FIG. 5 and is characterized by an endothermic peaks at about 98 0 C, 134.99 0 C and 167.29 0 C.
  • Atorvastatin- magnesium amorphous 25 g obtained from Example 2 or example 5 using Magnesium nitrate was charged to a mixture of acetone and water (1:1; 15V) and stirred for lday and allowed to stand 2days at ambient temperature. Then filtered and dried in under vacuum at 40-45 0 C for 16 h.
  • the crystalline Atorvastatin magnesium polymorph obtained from said Example 8 is depicted with XRD pattern that shows characteristic peaks at 2 theta values of 3.99, 7.91, 8.55, 11.90, 17.24, 18.50, 22.04. This form has been depicted as crystalline Atorvastatin hemi-magnesium form B8.
  • polymorph showed characteristic by X-ray diffraction 2 theta angle values of 3.99, 7.33, 7.91, 8.55, 9.24, 11.02, 11.45, 11.90, 13.06, 14.26, 14.68, 15.19, 17.24, 17.44, 18.50, 18.97, 19.28, 20.51, 22.04, 23.76 ⁇ 0.2 that has been depicted in Fig. 3.
  • the crystalline Atorvastatin Magnesium B8 is having a DSC thermogram substantially as shown in FIG. 6 and is characterized by an endothermic peak at about 81.99 0 C and 110.22 0 C.
  • the yield of the crystalline Atorvastatin magnesium was 13g and the purity was 99.37%
  • ATV-I Boranate (10Og) added to a mixture of water (10V) and methanol (3V). Basified with NaOH solution (30%, IV) and refluxed for four hours at 100°C. The reaction completion was monitored by TLC. After the reaction completion the mass was cooled to 30°C, washed with MTBE (3x3V). The aqueous layer was subjected to vacuum at 30 0 C to obtain the solid and kept for l ⁇ hours at RT. The solid was filtered and dissolved in a mixture of acetone (1 L) and water (1 L). The pH was adjusted to 8-8.5 using 1.5N HCl. To this added Magnesium acetate solution (17g, 0.079 moles in 68mL water) at 25-30°C under stirring. Heated the reaction mass to 40- 45°C and stirred for 1.5 h. cooled the reaction mass to 25-30 0 C and continued stirring for 3days. Filtered and dried in VTD at 45-50 0 C.
  • reaction mass was concentrated to about 400 mL and water (1.0 L) and methyl tert-butyl ether (MTBE, 400 mL) were added. Sufficient quantity of methanol was added to get two clear layers and MTBE layer was separated. Aqueous layer was further washed with MTBE (3X400 mL). The aqueous layer was kept under vacuum at 40-45o C till solids was observed and kept at 20-25 o C for 3 h and the solids were filtered. The solid was dissolved in a mixture of acetone (1 L) and water (1 L). The pH was adjusted to 8-8.5 using 1.5N HCl.
  • MTBE methyl tert-butyl ether
  • the yield of the crystalline Atorvastatin magnesium was 5Og and the purity was 99.5%.
  • the mixture was then concentrated under vacuum to dryness at 45-47°C.
  • the concentrated mass was dissolved in a mixture of water (1400ml), methanol (600ml) and MTBE (600ml). Later the MTBE layer was separated and pH of the aqueous solution was adjusted to 7-7.5 using cone. HCl. The aqueous layer was then washed with 400ml of MTBE thrice. The aqueous layer was then concentrated to haziness at 45-47 0 C. After concentration the solution was cooled for lhr and filtered to get solid mass of ATV-Na.
  • the yield of the crystalline Atorvastatin magnesium was 58g and the purity was 99.5%.
  • ATV-I Boranate (10Og) added to a mixture of water (10V) and methanol (3V). Basified with NaOH solution (30%, IV) and refluxed for four hours at 100 0 C. The reaction completion was monitored by TLC. After the reaction completion the mass was cooled to 30°C, washed with MTBE (3x3 V). The aqueous layer was subjected to vacuum at 30 0 C to obtain the solid and kept for l ⁇ hours at RT. The solid was filtered and dissolved in a mixture of methanol (1 L) and water (1 L). The pH was adjusted to 8-8.5 using 1.5N HCl. The contents were heated to 40-45° C.
  • the yield of the crystalline Atorvastatin magnesium was 55g and the purity was 99.4%.
  • Atorvastatin-magnesium amorphous 25 g obtained from Example 3 or Example 6 using Magnesium acetate was charged to a mixture of acetone (250 mL), Acetonitrile (250 mL) and water (50 mL) and stirred for 3 days at ambient temperature. Then filtered and dried in under vacuum at 40-45 0 C for 16 h.
  • the crystalline Atorvastatin magnesium polymorph obtained from said Example 9, 10, 11, 12, 13, is depicted with XRD pattern that shows characteristic peaks at 2 ⁇ values of 3.80, 4.00, 5.93, 7.98, 8.50, 8.96, 10.75, 11.95, 12.68, 14.48, 17.60, 18.12, 18.82, 19.44, 21.06, 23.04.
  • This form has been depicted as crystalline Atorvastatin hemi-magnesium form B9.
  • the Examples 9, 10, 11, 12 and 13 yield crystalline form B9 of Atorvastatin hemi-magnesium salt characterized by X-ray diffraction pattern comprising 2 theta values 3.80, 4.00, 5.93, 7.22, 7.57, 7.98, 8.50, 8.96, 9.70, 10.47, 10.75, 11.45, 11.95, 12.68, 13.17, 13.51, 13.93, 14.48, 14.92, 15.45, 16.41, 17.01, 17.60, 18.12, 18.82, 19.449, 20.36, 21.06, 23.04, 23.46, 24.68, 25.46, 27.17, 28.26 ⁇ 0.2.
  • the XRD chromatogram has been depicted in FIG. 4.
  • the crystalline Atorvastatin Magnesium B9 is having a DSC thermogram substantially as shown in FIG. 7 and is characterized by an endothermic peak at about 108.58 0 C and 165.87 0 C.
  • the yield of the crystalline Atorvastatin magnesium was 15g and the purity was 99.7%

Abstract

The present invention relates to crystalline forms of atorvastatin hemi-magnesium salt and a process for the preparation of crystalline forms. It also relates to a pharmaceutical composition comprising these crystalline forms or combinations thereof optionally along with pharmaceutically acceptable excipients.

Description

"CRYSTALLINE FORMS OF ATORVASTATIN HEMI-MAGNESIUM SALT AND A
PROCESS THEREOF"
FIELD OF THE INVENTION
Provided are novel polymorphs of Atorvastatin Hemi-magnesium salts and the process of preparing them. The novel polymorphs according to the invention are crystalline in nature characterized by X-ray diffraction (XRD), differential scanning calorimetry (DSC), and Infrared Spectroscopy. Pharmaceutical compositions containing these forms are particularly useful in treatment of hyperlipidemia and hypercholesterolemia in patients in need thereof. The present invention provides polymorphic forms of Atorvastatin hemi-magnesium denominated as crystalline forms B7, B8 and B9.
BACKGROUND OF THE INVENTION
Atorvastatin is a member belonging to the class of drugs called statins. Statin drugs are one of the most therapeutically effective drugs available for reducing low density lipoprotein (LDL) particle concentration in the blood stream of patients at risk for cardiovascular disease.
Atorvastatin is the common chemical name of [R-(R* ,R*)]-2-(4-fluorophenyl)- beta, delta - dihydroxy-5-(l-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-lH-pyrrole-l-heptanoic acid that have been described, in U.S. Pat. Nos. 4,681,893, 5,273,995. The present invention includes a new crystalline forms of Atorvastatin hemi-magnesium salts.
Many patents disclose Atorvastatin, formulations of Atorvastatin and polymorphs as well as processes and key intermediates. These include US4,681,893, US 5,273,995, US5,003,080, US5,097,045, US5, 103,024, US5,124,482, US5,149,837, US5, 155,251, US55969,156, US6,087,511 and US6, 121,461 which are incorporated herein by reference.
Additionally, a number of published international Patent Applications have disclosed crystalline forms of Atorvastatin, as well as processes for preparing the same that include WO2006/021969; WO2006/11761; WO2007/057755; WO2007/099552 and WO2007/118873
Preparation of amorphous Atorvastatin hemi-magnesium salt is described in detail in WO2007/063551, the contents of which are incorporated herein by reference in its entirety. Polymorphism which is the occurrence of different crystal forms is a property of some molecules and molecular complexes. A single molecule, like Atorvastatin magnesium, may give rise to a variety of crystalline forms having distinct crystal structures and physical properties like melting point, X-ray diffraction pattern, IR pattern, and solid state NMR spectrum. One crystalline form may give rise to thermal behavior different from that of another crystalline form. Thermal behavior can be measured in the laboratory by such techniques as capillary melting point, differential scanning calorimetry ("DSC"), which has been used to distinguish various polymorphic forms.
The difference in the physical properties of different crystalline forms results from the orientation and intermolecular interactions of adjacent molecules or complexes in the bulk solid. Accordingly, polymorphs are distinct solids sharing the same molecular formula yet having distinct advantageous physical properties compared to other crystalline forms of the same compound or complex.
The identification of new polymorphic forms of a pharmaceutically useful compound provides a new opportunity to improve the performance characteristics of a pharmaceutical product. It enlarges the repertory of materials that a formulation scientist has available for designing, for example, a pharmaceutical dosage form of a drug with a targeted release profile or other desired characteristics. There is a need in the art for novel polymorphic forms to address these aforesaid requirements.
The object of the present invention is to provide novel polymorphs of hemi-magnesium salts of Atorvastatin and processes for their preparation which are very suitable for use on an industrial scale. A further object of the present invention is to provide pharmaceutical compositions including these polymorphs, preferably solid oral dosage forms.
OBJECTS OF THE INVENTION
The main object of the present invention is to obtain a crystalline form of atorvastatin hemi- magnesium salt B7.
Another main object of the present invention is to obtain a crystalline form of atorvastatin hemi- magnesium salt B8. Yet another main object of the present invention is to obtain a crystalline form of atorvastatin hemi-magnesium salt B9.
Still another object of the present invention is to obtain a process for the preparation of crystalline Atorvastatin forms.
Still another object of the present invention is to obtain a crystalline form of atorvastatin hemi- magnesium salt B7 with purity of atleast 99%.
Still another object of the present invention is to obtain a crystalline form of atorvastatin hemi- magnesium salt B8 with purity of atleast 99%.
Still another object of the present invention is to obtain a crystalline form of atorvastatin hemi- magnesium salt B9 with purity of atleast 99%.
Still another object of the present invention is to obtain a pharmaceutical composition comprising crystalline atorvastatin hemi-magnesium salt selected from a group comprising B7, B8 or B9 or combinations thereof optionally along with pharmaceutically acceptable excipients.
SUMMARY OF THE INVENTION
Accordingly, the present invention relates to a crystalline form of atorvastatin hemi-magnesium salt characterized by X-ray diffraction pattern comprising 2 theta values 3.87, 4.85, 5.62, 7.76, 9.72, 11.4, 11.77, 12.61, 14.52, 15.08, 15.68, 16.33, 16.99, 17.79, 18.24, 18.88, 19.59, 19.96, 20.33, 22.05, 22.80, 24.15, 24.62, 25.49 ± 0.2; a crystalline form of atorvastatin hemi- magnesium salt characterized by X-ray diffraction pattern comprising 2 theta values 3.99, 7.33, 7.91, 8.55, 9.24, 11.02, 11.45, 11.90, 13.06, 14.26, 14.68, 15.19, 17.24, 17.44, 18.50, 18.97, 19.28, 20.51, 22.04, 23.76 ± 0.2; a crystalline form of atorvastatin hemi-magnesium salt characterized by X-ray diffraction pattern comprising 2 theta values 3.80, 4.00, 5.93, 7.22, 7.57, 7.98, 8.50, 8.96, 9.70, 10.47, 10.75, 11.45, 11.95, 12.68, 13.17, 13.51, 13.93, 14.48, 14.92, 15.45, 16.41, 17.01, 17.60, 18.12, 18.82, 19.449, 20.36, 21.06, 23.04, 23.46, 24.68, 25.46, 27.17, 28.26 ± 0.2; a crystalline form of atorvastatin hemi-magnesium salt form B7 having a DSC thermogram which is characterized by endothermic peaks at about 98 0C, 134.99 0C and 167.29 0C; a crystalline form of atorvastatin hemi-magnesium salt form B8 having a DSC thermogram which is characterized by endothermic peaks at about 81.990C and 110.22 0C; a crystalline form of atorvastatin hemi-magnesium salt form B 9 having a DSC thermogram which is characterized by endothermic peaks at about 108.58 0C and 165.870C; a process for the preparation of crystalline Atorvastatin form B7, said process comprising steps of (a) treating amorphous atorvastatin hemi-magnesium in a solvent; (b) optionally heating the mixture with stirring for at least 3 days followed by isolating the crystalline form of atorvastatin hemi-magnesium salt by filtration; and (c) drying to obtain the crystalline atorvastatin hemi-magnesium salt form B7; a process for the preparation of crystalline atorvastatin form B8 according to claim 5 or 8, said process comprising steps of (a) treating amorphous atorvastatin in a solvent; (b) optionally heating the mixture with stirring at least 1 day followed by isolating the crystalline form of atorvastatin hemi-magnesium salt by filtration; and drying to obtain the crystalline atorvastatin hemi-magnesium salt form B8; a crystalline form of atorvastatin hemi-magnesium salt B7 with purity of atleast 99%; a crystalline form of atorvastatin hemi-magnesium salt B8 with purity of atleast 99%; a crystalline form of atorvastatin hemi-magnesium salt B9 with purity of atleast 99%; and a pharmaceutical composition comprising crystalline atorvastatin hemimagnesium salt selected from a group comprising B7, B 8 or B9 or combinations thereof optionally along with pharmaceutically acceptable excipients.
BRIEF DESCRIPTION OF ACCOMPANYING FIGURES
Fig 1: XRD Diffraction pattern of Amorphous Atorvastatin Hemi-magnesium salt. Fig 2: XRD Diffraction pattern of crystalline Atorvastatin Hemi-magnesium salt form B7. Fig 3: XRD Diffraction pattern of crystalline Atorvastatin Hemi-magnesium salt form B8. Fig 4: XRD Diffraction pattern of crystalline Atorvastatin Hemi-magnesium salt form B9. Fig 5: DSC thermogram of crystalline Atorvastatin Hemi-magnesium salt form B7. Fig 6: DSC thermogram of crystalline Atorvastatin Hemi-magnesium salt form B8. Fig 7: DSC thermogram of crystalline Atorvastatin Hemi-magnesium salt form B9.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to a crystalline form of atorvastatin hemi-magnesium salt characterized by X-ray diffraction pattern comprising 2 theta values 3.87, 4.85, 5.62, 7.76, 9.72,
11.4, 11.77, 12.61, 14.52, 15.08, 15.68, 16.33, 16.99, 17.79, 18.24, 18.88, 19.59, 19.96, 20.33,
22.05, 22.80, 24.15, 24.62, 25.49 ± 0.2.
The present invention relates a crystalline form of atorvastatin hemi-magnesium salt characterized by X-ray diffraction pattern comprising 2 theta values 3.99, 7.33, 7.91, 8.55, 9.24, 11.02, 11.45, 11.90, 13.06, 14.26, 14.68, 15.19, 17.24, 17.44, 18.50, 18.97, 19.28, 20.51, 22.04,
23.76 ± 0.2.
The present invention relates a crystalline form of atorvastatin hemi-magnesium salt characterized by X-ray diffraction pattern comprising 2 theta values 3.80, 4.00, 5.93, 7.22, 7.57,
7.98, 8.50, 8.96, 9.70, 10.47, 10.75, 11.45, 11.95, 12.68, 13.17, 13.51, 13.93, 14.48, 14.92, 15.45,
16.41, 17.01, 17.60, 18.12, 18.82, 19.449, 20.36, 21.06, 23.04, 23.46, 24.68, 25.46, 27.17, 28.26
± 0.2.
In another embodiment of the present invention, the crystalline form is B7.
In another embodiment of the present invention, the crystalline form is B8.
In another embodiment of the present invention, the crystalline form is B9.
The present invention relates to a crystalline form of atorvastatin hemi-magnesium salt form B7 having a DSC thermogram which is characterized by endothermic peaks at about 98 0C, 134.99
0C and 167.29 0C.
The present invention relates to a crystalline form of atorvastatin hemi-magnesium salt form B 8 having a DSC thermogram which is characterized by endothermic peaks at about 81.99 0C and
110.22 0C.
The present invention relates to a crystalline form of atorvastatin hemi-magnesium salt form B 9 having a DSC thermogram which is characterized by endothermic peaks at about 108.58 0C and
165.870C.
The present invention relates to a process for the preparation of crystalline Atorvastatin form B7, said process comprising steps of:
(a) treating amorphous atorvastatin hemi-magnesium in a solvent;
(b) optionally heating the mixture with stirring for at least 3 days followed by isolating the crystalline form of atorvastatin hemi-magnesium salt by filtration; and
(c) drying to obtain the crystalline atorvastatin hemi-magnesium salt form B7.
The present invention relates a process for the preparation of crystalline atorvastatin form B8, said process comprising steps of:
(a) treating amorphous atorvastatin in a solvent;
(b) optionally heating the mixture with stirring at least 1 day followed by isolating the crystalline form of atorvastatin hemi-magnesium salt by filtration; and
(c) drying to obtain the crystalline atorvastatin hemi-magnesium salt form B8. In another embodiment of the present invention, the solvent used is selected from a group comprising water or a mixture of organic solvents and water.
In another embodiment of the present invention, the organic solvent is hydroxylic or non- hydroxylic solvent.
In another embodiment of the present invention, the organic solvent is selected from the group comprising acetone, methanol, ethanol, ethyl acetate, isopropyl alcohol, THF, dichloromethane, t-butanol, iso-butanol, carbon-tetrachloride, 1,4-dioxan, n-butanol, di-isopropyl ether, di- ethylether or mixtures thereof.
In another embodiment of the present invention, the mixture is heated to a temperature of about
4O0C.
The present invention relates a crystalline form of atorvastatin hemi-magnesium salt B7 with purity of atleast 99%.
The present invention relates a crystalline form of atorvastatin hemi-magnesium salt B 8 with purity of atleast 99%.
The present invention relates a crystalline form of atorvastatin hemi-magnesium salt B9 with purity of atleast 99%.
The present invention relates a pharmaceutical composition comprising crystalline atorvastatin hemimagnesium salt selected from a group comprising B7, B8 or B9 or combinations thereof optionally along with pharmaceutically acceptable excipients.
The present invention discloses new forms of Atorvastatin hemi-magnesium salts. We hereby disclose new polymorphs of said compound as well as the processes for preparing the same. The present invention provides polymorphic forms of Atorvastatin hemi-magnesium denominated as crystalline forms B7, B8 and B9.
A further aspect of the present invention relates to pharmaceutical compositions and dosage form containing the novel forms of Atorvastatin hemi-magnesium or a mixture of one or more of said polymorphs. The pharmaceutical compositions of said polymorphs can be used in treatment of hyperlipidemia and hypercholesterolemia in patients in need thereof.
The present invention relates to a crystalline form B7 of Atorvastatin hemi-magnesium salt characterized by X-ray diffraction pattern comprising 2 theta values 3.87, 4.85, 5.62, 7.76, 9.72, 1 1.4, 11.77, 12.61, 14.52, 15.08, 15.68, 16.33, 16.99, 17.79, 18.24, 18.88, 19.59, 19.96, 20.33,
22.05, 22.80, 24.15, 24.62, 25.49 ± 0.2.
The present invention relates to a crystalline form B 8 of Atorvastatin hemi-magnesium salt characterized by X-ray diffraction pattern comprising 2 theta values 3.99, 7.33, 7.91, 8.55, 9.24, 11.02, 11.45, 11.90, 13.06, 14.26, 14.68, 15.19, 17.24, 17.44, 18.50, 18.97, 19.28, 20.51, 22.04, 23.76 ± 0.2.
The present invention relates to a crystalline form B9 of Atorvastatin hemi-magnesium salt characterized by X-ray diffraction pattern comprising 2 theta values 3.80, 4.00, 5.93, 7.22, 7.57, 7.98, 8.50, 8.96, 9.70, 10.47, 10.75, 11.45, 11.95, 12.68, 13.17, 13.51, 13.93, 14.48, 14.92, 15.45, 16.41, 17.01, 17.60, 18.12, 18.82, 19.449, 20.36, 21.06, 23.04, 23.46, 24.68, 25.46, 27.17, 28.26 ± 0.2.
The present ' invention provides polymorphic forms of Atorvastatin hemi-magnesium denominated as crystalline forms B 7, B 8 and B9.
According to one embodiment of the invention, the crystalline form of Atorvastatin hemi- magnesium is B7.
According to yet another embodiment of the invention, the crystalline form of Atorvastatin hemi- magnesium is B8.
According to still another embodiment of the invention, the crystalline form of Atorvastatin hemi-magnesium is B9.
One of the embodiments of the invention relates to a crystalline form of Atorvastatin hemi- magnesium salt form B7 having a DSC thermogram which is characterized by endothermic peaks at about 980C, 134.990C and 167.29 0C.
One of the embodiments of the invention relates to a crystalline form of Atorvastatin hemi- magnesium salt form B8 having a DSC thermogram which is characterized by an endothermic peak at about 81.990C and 110.22 0C. One of the embodiments of the invention relates to a crystalline form of Atorvastatin hemi- magnesium salt form B9 having a DSC thermogram which is characterized by an endothermic peak at about 108.580C and 165.870C.
ATV-I (acetonide) is represented with the structure
Figure imgf000009_0001
ATV-I (Boronate) is represented with the structure
Figure imgf000009_0002
As used herein, the term "polymorph" refers to a compound (e.g., Atorvastatin) which, when present as a solid, exists as different forms. Desirably, the Atorvastatin polymorph includes solid forms of a compound such as crystals, microcrystals, foams, and powders, among others. Preferably, the Atorvastatin polymorphs of the present invention are crystalline. Polymorphs typically differ in their physical properties due to the order of the molecules in the lattice of the polymorph. In addition, the physical properties of the polymorph can differ due to the presence of solvates or other molecules incorporated into the lattice of the polymorph. Typically, polymorphs are readily distinguished using techniques such as melting point, rate of dissolution, Infrared and Raman spectroscopy, and X-ray diffraction such as crystal and powder techniques. According to one preferred embodiment, the process for the preparation of crystalline Atorvastatin forms comprises steps of
(a) Treating amorphous Atorvastatin in water or a mixture of organic solvents and water.
(b) Optionally heating the mixture with stirring for at least 1 day followed by isolating the crystalline form of atorvastatin hemi-magnesium salt by filtration
(c) Drying to obtain the crystalline atorvastatin hemi-magnesium salt form.
In one embodiment, the amorphous form of atorvastatin hemi-magnesium salt is treated with water or a mixture of two or more suitable solvents or a mixture of solvent and water under a suitable temperature range and the mixture can then be filtered and dried, preferably under vacuum, to obtain crystalline Atorvastatin hemi-magnesium salt.
The organic solvent may be selected from a group comprising hydroxylic or non-hydroxylic solvents or a mixture thereof. More particularly, the organic solvent may be selected from a group comprising acetone, methanol, ethanol, ethyl acetate, isopropyl alcohol, THF, dichloromethane, t-butanol, iso-butanol, carbon tetrachloride, 1,4-dioxan, n-butanol, di-isopropyl ether, di-ethylether and mixtures thereof.
As may be appreciated and cognized by a skilled artisan, the used solvents can be removed by various drying methods such as vacuum drying, rapid solvent evaporation, spray drying, freeze drying, solvent precipitation, roller drying and the like.
The present invention contemplates temperature variations during heating the mixture. Heating may be carried out at temperature ranging from 4O0C to 1000C. Most preferably, mixture may be heated to a temperature of about 4O0C. The stirring may be conducted for at least 1- 5 days, more preferably 1 day, most preferably 3 days. Every aspect or attribute of the method of obtaining the polymorph has a significant role to play.
Characterization of Atorvastatin hemi-magnesium polymorph Forms is accomplished using techniques known to those of skill in the art. Specifically, verification can be performed using techniques including melting point, infrared spectroscopy (IR), nuclear magnetic resonance spectroscopy (NMR), combustion analysis, Raman spectroscopy. Other techniques including differential scanning calorimetry (DSC) and X-ray diffraction (XRD) are also useful in distinguishing polymorphs.
The present invention also relates to pharmaceutical compositions comprising crystalline Atorvastatin hemi-magnesium forms selected from the group comprising B7, B8 and B9 or combinations thereof optionally along with pharmaceutically acceptable excipients.
In another embodiment of the invention, the excipients are selected from the group comprising granulating agents, binding agents, lubricating agents, disintegrating agents, sweetening agents, coloring agents, flavoring agents, coating agents, plasticizers, preservatives, suspending agents, emulsifying agents, and spheronization agents.
The present invention further provides compositions containing crystalline forms of the invention and one or more of other ingredients. In some embodiments, the composition contains at least about 50%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 97%, at least about 98.0%, at least about 98.1%, at least about 98.2%, at least about 98.3%, at least about 98.4%, at least about 98.5%, at least about 98.6%, at least about 98.7%, at least about 98.8%, at least about 98.9%, at least about 99.0%, at least about 99.1%, at least about 99.2%, at least about 99.3%, at least about 99.4%, at least about 99.5%, at least about 99.6%, at least about 99.7%, at least about 99.8%, or at least about 99.9% by weight of a crystalline form of the invention or mixture thereof.
Atorvastatin hemi-magnesium polymorphic forms are useful for reducing the plasma low density lipoprotein level of a patient suffering from or susceptible to hypercholesterolemia. For this purpose, it will typically be administered to human patients in a unit dose of from about 0.5 mg to about 100 mg. For most patients, a dose of from about 2.5 to about 80 mg per day, more particularly from about 2.5 to about 20 mg per day, causes a lowering of the plasma low density lipoprotein. Whether such lowering is sufficient or whether the dose or dose frequency should be increased is a determination that is within the skill level of appropriately trained medical personnel.
Dosage forms include solid dosage forms, like tablets, powders, capsules, suppositories, sachets, troches and lozenges as well as liquid suspensions and elixirs. While the description is not intended to be limiting, the invention is also not intended to pertain to true solutions of atorvastatin hemi-magnesium whereupon the properties that distinguish the solid forms of atorvastatin hemi- magnesium are lost. However, the use of the novel forms to prepare such solutions is considered to be within the contemplation of the invention.
Tablet formulations can be made by conventional compression, wet granulation, or dry granulation methods and utilize pharmaceutically acceptable diluents, binding agents, lubricants, disintegrants, surface modifying agents (including surfactants), suspending or stabilizing agents (including, but not limited to, magnesium stearate, stearic acid, sodium lauryl sulfate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, microcrystalline ceUulose,sodiumcarboxymethyl cellulose, carboxymethylcellulose calcium, polyvinylpyrrolidine, alginic acid, acacia gum, xanthan gum, sodium citrate, complex silicates, calcium carbonate, glycine, sucrose, sorbitol, dicalcium phosphate, calcium sulfate, lactose, kaolin, mannitol", sodium chloride, low melting waxes, and ion exchange resins.) Surface modifying agents include nonionic and anionic surface modifying agents. Representative examples of surface modifying agents include, but are not limited to, poloxamer 188, benzalkonium chloride, calcium stearate, cetostearl alcohol, cetomacrogol emulsifying wax, sorbitan esters, colloidal silicon dioxide, phosphates, sodium dodecylsulfate, magnesium aluminum silicate, and triethanolamine.
Capsule dosages, of course, will contain the solid composition within a capsule which may be made of gelatin or other conventional encapsulating material. Tablets and powders may be coated. Tablets and powders may be coated with an enteric coating. The enteric coated powder forms may have coatings comprising phthalic acid cellulose acetate, hydroxypropylmethyl- cellulose phthalate, polyvinyl alcohol phthalate, carboxymethylethylcellulose, a copolymer of styrene and maleic acid, a copolymer of methacrylic acid and methyl methacrylate, and like materials, and if desired, they may be employed with suitable plasticizers and/or extending agents. A coated tablet may have a coating on the surface of the tablet or may be a tablet comprising a powder or granules with an enteric-coating.
The compositions described herein containing Atorvastatin hemi-magnesium polymorph Forms can be formulated in any form suitable for the desired route of delivery using a pharmaceutically effective amount of the polymorph. For example, the compositions of the invention can be delivered by a route such as oral, dermal, transdermal, intrabronchial, intranasal, intravenous, intramuscular, subcutaneous, parenteral, intraperitoneal, intranasal, vaginal, rectal, sublingual, intracranial, epidural, intratracheal, or by sustained release. Preferably, delivery is oral.
The forms B7, B8 and B9 exhibit different physical characteristics which are evident from then- X-ray powder diffraction patterns. While the invention will be described in conjunction with these specific embodiments, it will be understood that it is not intended to limit the invention to such specific embodiments. On the contrary, it is intended to cover alternatives, modifications and equivalents as may be included within the spirit and scope of the invention as defined by the claims. In the following description, numerous specific details are set forth in order to provide a thorough understanding of the present invention. The present invention may be practiced without some or all of these specific details. In order instance a well known process operations have not been described in detail, in order not to obscure the present invention.
The invention is further elaborated with the help of following examples. However, these examples should not be construed to limit the scope of invention.
PREPARATION OF ATORVASTATIN MAGNESIUM AMORPHOUS:
Example-1:
To a solution of ATV-I (acetonide) (100 g, 0.153 mol) in Acetonitrile (1.8 L), HCl (1 N, 210 mL) was added over a period of 30 minutes and stirred for 2 to 2.5 h at ambient temperature. The reaction completion was monitored by TLC (mobile phase Petether:Ethylacetate::5:5). Aqueous sodium hydroxide solution (10%, 153 mL) was added to the reaction mixture and stirred for 3 to 4 h at ambient temperature. The reaction completion was monitored by TLC (mobile phase Cholrofom: Methanol:: 9:1). After completion of reaction, pH of the reaction mixture was adjusted to 9.0-9.5 using IN HCl. The reaction mass was concentrated to about 400 mL and water (1.0 L) and methyl tert-butyl ether (MTBE, 400 mL) were added. Sufficient quantity of methanol was added to get two clear layers and MTBE layer was separated. Aqueous layer was further washed with MTBE (3X400 mL). The aqueous layer was kept under vacuum at 40-45o C till solids was observed and kept at 20-250C for 3 h and the solids were filtered. The solids were dissolved in a mixture of ethyl acetate (10V based on the wet weight of the solid Atorvastatin- Na) and water (IV based on the wet weight of the solid Atorvastatin-Na). Adjusted the pH to 8- 8.5 using 1.5N HCl. A solution of magnesium chloride hexahydrate (16.3 g, 0.08 mol) in water (570 mL) was added over a period of Ih. The mixture was stirred at 40-45o C for 1.5h. Cooled to 3O0C. The layers were separated. The organic layer was washed with water (3x10% of water based on ethyl acetate volume) and filtered through celite. Concentrated the syrup and stripped off with methanol 5times. Dried in VTD under vacuum at RT for βhours and 45-50°C for lόhours.
The amorphous Atorvastatin hemi-magnesium salt obtained has been depicted in Fig. 1.
The yield of the amorphous Atorvastatin magnesium was 65g and the purity was 99.3%
Example-2:
To a solution of ATV-I (acetonide) (100 g, 0.153 mol) in Acetonitrile (1.8 L), HCl (1 N, 210 mL) was added over a period of 30 minutes and stirred for 2 to 2.5 h at ambient temperature. The reaction completion was monitored by TLC (mobile phase Petether:Ethylacetate::5:5). Aqueous sodium hydroxide solution (10%, 153 mL) was added to the reaction mixture and stirred for 3 to 4 h at ambient temperature. The reaction completion was monitored by TLC (mobile phase Cholrofom: Methanol: :9:1). After completion of reaction, pH of the reaction mixture was adjusted to 9.0-9.5 using IN HCl. The reaction mass was concentrated to about 400 mL and water (1.0 L) and methyl tert-butyl ether (MTBE, 400 mL) were added. Sufficient quantity of methanol was added to get two clear layers and MTBE layer was separated. Aqueous layer was further washed with MTBE (3X400 mL). The aqueous layer was kept under vacuum at 40-45o C till solids was observed and kept at 20-25 o C for 3 h and the solids were filtered. The solids were dissolved in a mixture of ethyl acetate (10V based on the wet weight of the solid Atorvastatin-Na) and water (IV based on the wet weight of the solid Atorvastatin-Na). Adjusted the pH to 8-8.5 using 1.5N HCl. A solution of magnesium nitrate hexahydrate (2Og, 0.078 mol) in water (80 mL) was added. The mixture was stirred at 40-45o C for 1.5h. Cooled to 30o C. The layers were separated. The organic layer was washed with water (3x10% of water based on ethyl acetate volume) and filtered through celite. Concentrated the syrup and stripped off with methanol 5times. Dried in VTD under vacuum at RT for όhours and 45-500C for lόhours.
The amorphous Atorvastatin hemi-magnesium salt obtained has been depicted in Fig. 1.
The yield of the amorphous Atorvastatin magnesium was 69g and the purity was 98,87% ExampIe-3:
To a solution of ATV-I (acetonide) (100 g, 0.153 mol) in Acetonitrile (1.8 L), HCl (1 N, 210 mL) was added over a period of 30 minutes and stirred for 2 to 2.5 h at ambient temperature. The reaction completion was monitored by TLC (mobile phase Petether:Ethylacetate::5:5). Aqueous sodium hydroxide solution (10%, 153 mL) was added to the reaction mixture and stirred for 3 to 4 h at ambient temperature. The reaction completion was monitored by TLC (mobile phase Cholrofom: Methanol::9:l). After completion of reaction, pH of the reaction mixture was adjusted to 9.0-9.5 using IN HCl. The reaction mass was concentrated to about 400 mL and water (1.0 L) and methyl tert-butyl ether (MTBE, 400 mL) were added. Sufficient quantity of methanol was added to get two clear layers and MTBE layer was separated. Aqueous layer was further washed with MTBE (3X400 mL). The aqueous layer was kept under vacuum at 40-45o C till solids was observed and kept at 20-25 o C for 3 h and the solids were filtered. The solids were dissolved in a mixture of ethyl acetate (10V based on the wet weight of the solid Atorvastatin-Na) and water (IV based on the wet weight of the solid Atorvastatin-Na). Adjusted the pH to 8-8.5 using 1.5N HCl. A solution of magnesium acetate tetrahydrate (17g, 0.0792 mol) in water (570 mL) was added over a period of Ih. The mixture was stirred at 40-45o C for 1.5h. Cooled to 30o C. The layers were separated. The organic layer was washed with water (3x10% of water based on ethyl acetate volume) and filtered through celite. Concentrated the syrup and stripped off with methanol 5times. Dried in VTD under vacuum at RT for όhours and 45-500C for 1 όhours.
The amorphous Atorvastatin hemi-magnesium salt obtained has been depicted in Fig. 1.
The yield of the amorphous Atorvastatin magnesium was 65g and the purity was 98.%
Example-4:
ATV-I Boranate (100 g) was added to a mixture of water (10Y) and methanol (3 V). Basified with NaOH solution (30%, IV) and refluxed for four hours at 100°C. The reaction completion was monitored by TLC. After the reaction completion the mass was cooled to 300C, washed with MTBE (3x3V). The aqueous layer was subjected to vacuum at 300C to obtain the solid and kept for 1 όhours at RT. The solid was filtered and dissolved in a mixture of ethyl acetate (10V) and water (10% based on ethyl acetate volume). The pH of the mass was adjusted to 8-8.5 using 1.5N HCl. To this was added Magnesium chloride solution (16.3 g, 0.079 mol based on ATV-I boranate in 4V of water based on Mg chloride). The mass was heated to 40-450C and maintained for lhour. The mass was cooled to RT and the layer was separated. The organic layer was washed with water (3x10% of water based on ethyl acetate volume) and filtered through celite. Concentrated the syrup and stripped off with methanol 5times. Dried in VTD under vacuum at RT for όhours and 45-5O0C for 1 όhours.
The amorphous Atorvastatin hemi-magnesium salt obtained has been depicted in Fig. 1.
The yield of the amorphous Atorvastatin magnesium was 65 g and the purity was 98%
Example-5:
ATV-I Boranate was added to a mixture of water (10V) and methanol (3 V). Basified with NaOH solution (30%, IV) and refluxed for four hours at 100°C. The reaction completion was monitored by TLC. After the reaction completion the mass was cooled to 300C, washed with MTBE (3x3 V). The aqueous layer was subjected to vacuum at 30°C to obtain the solid and kept for 1 όhours at RT. The solid was filtered and dissolved in a mixture of ethyl acetate (10V) and water (10% based on ethyl acetate volume). The pH of the mass was adjusted to 8-8.5 using 1.5N HCl. To this was added Magnesium nitrate solution (20g, 0.078 mol in 4 V of water based on Mg nitrate). The mass was heated to 40-450C and maintained for lhour. The mass was cooled to RT and the layer was separated. The organic layer was washed with water (3x10% of water based on ethyl acetate volume) and filtered through celite. Concentrated the syrup and stripped off with methanol 5times. Dried in VTD under vacuum at RT for όhours and 45-500C for 1 όhours.
The amorphous Atorvastatin hemi-magnesium salt obtained has been depicted in Fig. 1.
The yield of the amorphous Atorvastatin magnesium was 69g and the purity was 98.87%.
Example-6:
ATV-I Boranate was added to a mixture of water (10V) and methanol (3 V). Basified with NaOH solution (30%, IV) and refluxed for four hours at 1000C. The reaction completion was monitored by TLC. After the reaction completion the mass was cooled to 3O0C, washed with MTBE (3x3V). The aqueous layer was subjected to vacuum at 3O0C to obtain the solid and kept for lόhours at RT. The solid was filtered and dissolved in a mixture of ethyl acetate (10V) and water (10% based on ethyl acetate volume). The pH of the mass was adjusted to 8-8.5 using 1.5N HCl. To this was added Magnesium acetate solution (0.175 w/w based on ATV-I boranate in 4V of water based on Mg acetate). The mass was heated to 40-45°C and maintained for lhour. The mass was cooled to RT and the layer was separated. The organic layer was washed with water (3x10% of water based on ethyl acetate volume) and filtered through celite. Concentrated the syrup and stripped off with methanol 5times. Dried in VTD under vacuum at RT for βhours and 45-50°C for lόhours.
The amorphous Atorvastatin hemi-magnesium salt obtained has been depicted in Fig. 1.
The yield of the amorphous Atorvastatin magnesium was 6Og and the purity was 98%
PREPARATION OF ATORVASTATIN MAGNESIUM (CRYSTALLINE)
Example 7:
Atorvastatin- magnesium amorphous 25 g (obtained from Example 1 or Example 4 Magnesium chloride) was charged to a mixture of acetone and water (1:1; 15V) and stirred for 3 days at ambient temperature. Then filtered and dried in under vacuum at 40-45 0C for 16 h.
The crystalline Atorvastatin magnesium polymorph obtained from said Example 7 is depicted with XRD pattern that shows characteristic peaks at 2Θ values of 3.87, 7.76, 9.72, 12.61, 19.96.
This form has been depicted as crystalline Atorvastatin hemi-magnesium form B7
More particularly the polymorph showed characteristic by X-ray diffraction 2 theta angle values of 3.87, 4.85, 5.62, 7.76, 9.72, 11.4, 11.77, 12.61, 14.52, 15.08, 15.68, 16.33, 16.99, 17.79, 18.24, 18.88, 19.59, 19.96, 20.33, 22.05, 22.80, 24.15, 24.62, 25.49 ± 0.2 that has been depicted in Fig.2.
The crystalline Atorvastatin Magnesium B7 is having a DSC thermogram substantially as shown in FIG. 5 and is characterized by an endothermic peaks at about 980C, 134.990C and 167.29 0C.
The yield of the crystalline Atorvastatin magnesium was 13g and the purity was 99.3%. Example 8:
Atorvastatin- magnesium amorphous 25 g (obtained from Example 2 or example 5 using Magnesium nitrate) was charged to a mixture of acetone and water (1:1; 15V) and stirred for lday and allowed to stand 2days at ambient temperature. Then filtered and dried in under vacuum at 40-450C for 16 h.
The crystalline Atorvastatin magnesium polymorph obtained from said Example 8 is depicted with XRD pattern that shows characteristic peaks at 2 theta values of 3.99, 7.91, 8.55, 11.90, 17.24, 18.50, 22.04. This form has been depicted as crystalline Atorvastatin hemi-magnesium form B8.
More particularly the polymorph showed characteristic by X-ray diffraction 2 theta angle values of 3.99, 7.33, 7.91, 8.55, 9.24, 11.02, 11.45, 11.90, 13.06, 14.26, 14.68, 15.19, 17.24, 17.44, 18.50, 18.97, 19.28, 20.51, 22.04, 23.76 ± 0.2 that has been depicted in Fig. 3.
The crystalline Atorvastatin Magnesium B8 is having a DSC thermogram substantially as shown in FIG. 6 and is characterized by an endothermic peak at about 81.990C and 110.22 0C.
The yield of the crystalline Atorvastatin magnesium was 13g and the purity was 99.37%
Example 9:
ATV-I Boranate (10Og) added to a mixture of water (10V) and methanol (3V). Basified with NaOH solution (30%, IV) and refluxed for four hours at 100°C. The reaction completion was monitored by TLC. After the reaction completion the mass was cooled to 30°C, washed with MTBE (3x3V). The aqueous layer was subjected to vacuum at 300C to obtain the solid and kept for lόhours at RT. The solid was filtered and dissolved in a mixture of acetone (1 L) and water (1 L). The pH was adjusted to 8-8.5 using 1.5N HCl. To this added Magnesium acetate solution (17g, 0.079 moles in 68mL water) at 25-30°C under stirring. Heated the reaction mass to 40- 45°C and stirred for 1.5 h. cooled the reaction mass to 25-300C and continued stirring for 3days. Filtered and dried in VTD at 45-500C.
The yield of the crystalline Atorvastatin magnesium was 50g and the purity was 99.6% Example 10:
To a solution of ATV-I (acetonide) (100 g, 0.153 mol) in Acetonitrile (1.8 L), HCl (1 N, 210 mL) was added over a period of 30 minutes and stirred for 2 to 2.5 h at ambient temperature. The reaction completion was monitored by TLC (mobile phase Petether:Ethylacetate::5:5). Aqueous sodium hydroxide solution (10%, 153 mL) was added to the reaction mixture and stirred for 3 to 4 h at ambient temperature. The reaction completion was monitored by TLC (mobile phase Cholrofom: Methanol: :9:1). After completion of reaction, pH of the reaction mixture was adjusted to 9.0-9.5 using IN HCl. The reaction mass was concentrated to about 400 mL and water (1.0 L) and methyl tert-butyl ether (MTBE, 400 mL) were added. Sufficient quantity of methanol was added to get two clear layers and MTBE layer was separated. Aqueous layer was further washed with MTBE (3X400 mL). The aqueous layer was kept under vacuum at 40-45o C till solids was observed and kept at 20-25 o C for 3 h and the solids were filtered. The solid was dissolved in a mixture of acetone (1 L) and water (1 L). The pH was adjusted to 8-8.5 using 1.5N HCl. To this added Magnesium acetate solution (17g, 0.079 moles in 68 mL water) at 20-25° C under stirring. The reaction mass was stirred at 20-25°C for 3 days. The solids were filtered and washed with water (300 mL). The product was dried under vacuum 45-50°C for 24 h.
The yield of the crystalline Atorvastatin magnesium was 5Og and the purity was 99.5%.
Example 11:
To 20Og ATV-I (acetonide), 3.6L of acetonitrile was added, and mixed well for lOmin. HCl (1 N, 420 mL) was added slowly to the above reaction mixture over a period of 5 minutes and stirred for 2 h at ambient temperature. The progress of the reaction was monitored by TLC using a mixture of petroleum ether: ethylacetate (2:1). At the end of the reaction, 340ml of 10% aqueous sodium hydroxide solution was added to the reaction mixture and stirred for 2 h at ambient temperature. The reaction completion was monitored by TLC (mobile phase Pet ether: Ethyl acetate: 2:1). After completion of the reaction, the reaction mixture was allowed to stand overnight at ambient temperature. The mixture was then concentrated under vacuum to dryness at 45-47°C. The concentrated mass was dissolved in a mixture of water (1400ml), methanol (600ml) and MTBE (600ml). Later the MTBE layer was separated and pH of the aqueous solution was adjusted to 7-7.5 using cone. HCl. The aqueous layer was then washed with 400ml of MTBE thrice. The aqueous layer was then concentrated to haziness at 45-47 0C. After concentration the solution was cooled for lhr and filtered to get solid mass of ATV-Na.
80.65g (corresponds to 5Og) of ATV-Na was taken and dissolved in 80OmI of methanol - water mixture (1 :1 ratio). This reaction mixture was heated on an oil bath to 45 0C, after which 8.5g of magnesium acetate dissolved in 34 ml of water was added slowly. After 30 minutes, additional 100ml of methanol was added and reaction was left for three days. The obtained crystals was filtered and dried for two days under vacuum at 45 0C.
The yield of the crystalline Atorvastatin magnesium was 58g and the purity was 99.5%.
Example 12;
ATV-I Boranate (10Og) added to a mixture of water (10V) and methanol (3V). Basified with NaOH solution (30%, IV) and refluxed for four hours at 1000C. The reaction completion was monitored by TLC. After the reaction completion the mass was cooled to 30°C, washed with MTBE (3x3 V). The aqueous layer was subjected to vacuum at 300C to obtain the solid and kept for lόhours at RT. The solid was filtered and dissolved in a mixture of methanol (1 L) and water (1 L). The pH was adjusted to 8-8.5 using 1.5N HCl. The contents were heated to 40-45° C. To this added Magnesium acetate solution (17g, 0.079 moles in 68 mL water) at 40-45° C under stirring. The reaction mass was stirred at 40-45°C for 3 days. The solids were filtered and washed with water (300 mL). The product was dried under vacuum 45-500C for 24 h.
The yield of the crystalline Atorvastatin magnesium was 55g and the purity was 99.4%.
Example 13;
Atorvastatin-magnesium amorphous 25 g (obtained from Example 3 or Example 6 using Magnesium acetate) was charged to a mixture of acetone (250 mL), Acetonitrile (250 mL) and water (50 mL) and stirred for 3 days at ambient temperature. Then filtered and dried in under vacuum at 40-450C for 16 h.
The crystalline Atorvastatin magnesium polymorph obtained from said Example 9, 10, 11, 12, 13, is depicted with XRD pattern that shows characteristic peaks at 2Θ values of 3.80, 4.00, 5.93, 7.98, 8.50, 8.96, 10.75, 11.95, 12.68, 14.48, 17.60, 18.12, 18.82, 19.44, 21.06, 23.04.This form has been depicted as crystalline Atorvastatin hemi-magnesium form B9. The Examples 9, 10, 11, 12 and 13 yield crystalline form B9 of Atorvastatin hemi-magnesium salt characterized by X-ray diffraction pattern comprising 2 theta values 3.80, 4.00, 5.93, 7.22, 7.57, 7.98, 8.50, 8.96, 9.70, 10.47, 10.75, 11.45, 11.95, 12.68, 13.17, 13.51, 13.93, 14.48, 14.92, 15.45, 16.41, 17.01, 17.60, 18.12, 18.82, 19.449, 20.36, 21.06, 23.04, 23.46, 24.68, 25.46, 27.17, 28.26 ± 0.2. The XRD chromatogram has been depicted in FIG. 4.
The crystalline Atorvastatin Magnesium B9 is having a DSC thermogram substantially as shown in FIG. 7 and is characterized by an endothermic peak at about 108.580C and 165.870C.
The yield of the crystalline Atorvastatin magnesium was 15g and the purity was 99.7%
AU references cited in this specification are incorporated herein by reference herein. While the invention has been described with reference to a particularly preferred embodiment, it will be appreciated that modifications can be made without departing from the spirit of the invention. Such modifications are intended to fall within the scope of the appended claims.

Claims

We claim:
1. A crystalline form of atorvastatin hemi-magnesium salt characterized by X-ray diffraction pattern comprising 2 theta values 3.87, 4.85, 5.62, 7.76, 9.72, 11.4, 11.77, 12.61, 14.52, 15.08, 15.68, 16.33, 16.99, 17.79, 18.24, 18.88, 19.59, 19.96, 20.33, 22.05, 22.80, 24.15, 24.62, 25.49 ± 0.2.
2. A crystalline form of atorvastatin hemi-magnesium salt characterized by X-ray diffraction pattern comprising 2 theta values 3.99, 7.33, 7.91, 8.55, 9.24, 11.02, 11.45, 11.90, 13.06, 14.26, 14.68, 15.19, 17.24, 17.44, 18.50, 18.97, 19.28, 20.51, 22.04, 23.76 ± 0.2.
3. A crystalline form of atorvastatin hemi-magnesium salt characterized by X-ray diffraction pattern comprising 2 theta values 3.80, 4.00, 5.93, 7.22, 7.57, 7.98, 8.50, 8.96, 9.70, 10.47, 10.75, 11.45, 11.95, 12.68, 13.17, 13.51, 13.93, 14.48, 14.92, 15.45, 16.41, 17.01, 17.60, 18.12, 18.82, 19.449, 20.36, 21.06, 23.04, 23.46, 24.68, 25.46, 27.17, 28.26 ± 0.2.
4. The crystalline form according to claim 1 , wherein the crystalline form is Form B7.
5. The crystalline form according to claim 2, wherein the crystalline form is Form B8.
6. The crystalline form according to claim 3, wherein the crystalline form is Form B9.
7. A crystalline form of atorvastatin hemi-magnesium salt form B7 having a DSC thermogram which is characterized by endothermic peaks at about 98 0C, 134.99 0C and 167.29 0C.
8. A crystalline form of atorvastatin hemi-magnesium salt form B8 having a DSC thermogram which is characterized by endothermic peaks at about 81.99 0C and 110.22 0C.
9. A crystalline form of atorvastatin hemi-magnesium salt form B9 having a DSC thermogram which is characterized by endothermic peaks at about 108.58 0C and 165.870C.
10. A process for the preparation of crystalline Atorvastatin form B7 according to claim 4 or 7, said process comprising steps of
(a) treating amorphous atorvastatin hemi-magnesium in a solvent;
(b) optionally heating the mixture with stirring for at least 3 days followed by isolating the crystalline form of atorvastatin hemi-magnesium salt by filtration; and (c) drying to obtain the crystalline atorvastatin hemi-magnesium salt form B7.
11. A process for the preparation of crystalline atorvastatin form B8 according to claim 5 or 8, said process comprising steps of
(a) treating amorphous atorvastatin in a solvent ;
(b) optionally heating the mixture with stirring at least 1 day followed by isolating the crystalline form of atorvastatin hemi-magnesium salt by filtration; and
(c) drying to obtain the crystalline atorvastatin hemi-magnesium salt form B8.
12. The process according to claims 10 or 11, wherein the solvent used is selected from a group comprising water or a mixture of organic solvents and water.
13. The process according to claim 12, wherein the organic solvent is hydroxylic or non- hydroxylic solvent.
14. The process according to claim 13, wherein the organic solvent is selected from the group comprising acetone, methanol, ethanol, ethyl acetate, isopropyl alcohol, THF, dichloromethane, t-butanol, iso-butanol, carbon-tetrachloride, 1,4-dioxan, n-butanol, di- isopropyl ether, di-ethylether or mixtures thereof.
15. The process according to claim 10 or 11, wherein the mixture is heated to a temperature of about 4O0C.
16. A crystalline form of atorvastatin hemi-magnesium salt B7 with purity of atleast 99%
17. A crystalline form of atorvastatin hemi-magnesium salt B8 with purity of atleast 99%
18. A crystalline form of atorvastatin hemi-magnesium salt B9 with purity of atleast 99%
19. A pharmaceutical composition comprising crystalline atorvastatin hemimagnesium salt selected from a group comprising B7, B8 or B9 or combinations thereof optionally along with pharmaceutically acceptable excipients.
PCT/IN2008/000503 2008-06-26 2008-08-11 Crystalline forms of atorvastatin hemi-magnesium salt and a process thereof WO2009157005A1 (en)

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