WO2009143767A1 - Co-cristaux d’atorvastatine hémi-calcium et de butanone, leurs procédés de préparation et leurs utilisations en tant qu’inhibiteur de l’enzyme hmg-coa - Google Patents

Co-cristaux d’atorvastatine hémi-calcium et de butanone, leurs procédés de préparation et leurs utilisations en tant qu’inhibiteur de l’enzyme hmg-coa Download PDF

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WO2009143767A1
WO2009143767A1 PCT/CN2009/071988 CN2009071988W WO2009143767A1 WO 2009143767 A1 WO2009143767 A1 WO 2009143767A1 CN 2009071988 W CN2009071988 W CN 2009071988W WO 2009143767 A1 WO2009143767 A1 WO 2009143767A1
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calcium salt
atorvastatin hemi
butanone
atorvastatin
calcium
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PCT/CN2009/071988
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English (en)
Chinese (zh)
Inventor
张和胜
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天津和美生物技术有限公司
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Publication of WO2009143767A1 publication Critical patent/WO2009143767A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics

Definitions

  • Atorvastatin hemi-calcium salt butanone co-crystal its preparation and application as an inhibitor of HMG-CoA enzyme
  • the present invention discloses atorvastatin hemi-calcium salt butanone co-crystals, a process for the preparation thereof and use as an HMG-CoA enzyme inhibitor.
  • VLDL Very low low density lipoprotein
  • IDL medium density lipoprotein
  • LDL low density lipoprotein
  • statins By inhibiting the HMG-CoA enzyme, statins can effectively block the synthesis of cholesterol in the liver, thereby effectively reducing low-density lipoprotein. High LDL levels can lead to coronary heart disease and cause thrombosis. Therefore, reducing LDL can effectively prevent cardiovascular disease, especially coronary heart disease or other hypercholesterolemia syndrome.
  • Atorvastatin is the most widely used variety of statins.
  • the lactone of atorvastatin and its calcium salt form are mentioned in the United States patent (US-4681893, US-5273995).
  • Atorvastatin hemi-calcium salt trihydrate was named Lipitor by Pfizer and had sales of more than $12 billion in 2007.
  • U.S. Patent Nos. 2002/0099224; 5273995; 5298627; 5003080; 5097045; 5124482; 5149837 disclose the preparation of atorvastatin.
  • the semi-calcium salt of atorvastatin is disclosed in US-5273995.
  • Forms I, II, III, IV of atorvastatin hemi-calcium salt are disclosed in U.S. Patent No. 5,959,156, US Pat. No. 6,121,462.
  • the V configuration of atorvastatin hemi-calcium salt is disclosed in patent WO-01/36384.
  • Other configurations of atorvastatin hemi-calcium salt are disclosed in the patents WO-02/43732, WO-02/41834, WO-03/070702.
  • a single molecule can form a wide variety of salts or crystal types. Because of the different roles and orientations of adjacent molecules in a crystal, different solvates or polymorphs of the same molecule can have different physical properties.
  • An important physics of drugs Its nature is its solubility, especially in the gastric juice. The efficacy of the drug is related to the concentration of the drug that can be achieved in the blood. The solubility of the same molecule in the gastric and intestinal fluids directly affects the absorption of the drug by the GI system. Thus, a salt or crystalline form of a drug having suitable solubility properties may have a better therapeutic effect than a slow dissolved salt or crystalline form.
  • Atorvastatin hemi-calcium salt trihydrate is less water soluble and has an absolute oral bioavailability of only 12%.
  • the development of high water-soluble salts of atorvastatin will increase the oral bioavailability of atorvastatin. Therefore, it is valuable to develop new salts or polymorphs of drugs.
  • the invention discloses a butanone co-crystal of atorvastatin hemi-calcium salt of formula (I), wherein n is 0. 25-4.
  • the dihydrate formed by the combination of the cocrystal and water is present in a stable crystalline form (designated as Form H in the present invention), and its water solubility (0.46 mg/ml) is comparable to commercially available atorvastatin hemi-calcium.
  • the salt trihydrate is much higher, and under the same test method, the latter has a water solubility of only 0.198 mg/ml.
  • the crystalline form H provided by the present invention provides a better choice for patients with HMG-CoA enzyme inhibitor drugs.
  • the atorvastatin hemi-calcium salt form H provided by the invention has a better solubility, so that the preparation process of atorvastatin hemi-calcium salt is simpler, and can be prepared into various new dosage forms which are more favorable for patients to take. It is expected that the oral atorvastatin formulation prepared from Form H will have a higher oral bioavailability than the atorvastatin oral formulation made by the currently commercially available crystalline form.
  • the present invention discloses novel co-crystals of atorvastatin hemi-calcium salt and methyl ethyl ketone and various solvates or corresponding amorphous or polymorphs thereof.
  • the invention also discloses a preparation method of atorvastatin hemi-calcium salt butanone cocrystal: atorvastatin hemi-calcium salt or solvate thereof is dissolved in methyl ketone or a mixture of methyl ethyl ketone and water to obtain a clear solution, and then allowed to stand A solid precipitated. The resulting solid is vacuumed at room temperature Drying, that is, atorvastatin hemi-calcium salt butanone co-crystallized.
  • the atorvastatin hemi-calcium salt solvate described in the present invention may be atorvastatin hemi-calcium salt containing one or more water of crystallization, or other solvates of atorvastatin hemi-calcium salt, including but not limited to the following: An ethanolate of statin hemi-calcium salt, a 1-propanolate of atorvastatin hemi-calcium salt, a 1,2-propanediol compound of atorvastatin hemi-calcium salt, atorvastatin hemi-calcium salt acetonate, Water and ethanol co-crystals of statin hemi-calcium salt, water and 1-propanol co-crystal of atorvastatin hemi-calcium salt, water and acetone co-crystal of atorvastatin hemi-calcium salt.
  • the invention also discloses a second preparation method of atorvastatin hemi-calcium salt butanone cocrystal: atorvastatin hemi-calcium salt or solvate powder thereof in methyl ketone or a mixture of methyl ethyl ketone and water at 0-100° The mixture was stirred for 0.5-48 hours, and the solid was collected by filtration, and dried under vacuum at room temperature to obtain a crystallization of atorvastatin hemi-calcium salt butanone.
  • the invention also discloses a third preparation method of atorvastatin hemi-calcium salt butanone cocrystal: dissolving atorvastatin in methyl ethyl ketone, mixing with aqueous solution of calcium hydroxide or calcium hydrogencarbonate, heating, and standing to precipitate solid .
  • the present invention also discloses a fourth preparation method of atorvastatin hemi-calcium salt butanone cocrystal: the atorvastatin alkaline salt is dissolved in methyl ethyl ketone, the calcium salt aqueous solution is added, and the solid is precipitated by heating under reflux.
  • the ampamicin alkaline salt described therein includes, but is not limited to, atorvastatin sodium salt, atorvastatin potassium salt, atorvastatin amine salt, atorvastatin ammonium salt;
  • the calcium salt includes, but is not limited to, calcium chloride. , calcium acetate.
  • the content of the atorvastatin hemi-calcium salt butanone cocrystal of the present invention in the pharmaceutically active ingredient (by weight) should be above 60%; the preferred embodiment is the pharmacological activity of the atorvastatin hemi-calcium salt butanone co-crystal
  • the content of the ingredients (by weight) should be above 80%; the optimal solution is that the content of atorvastatin hemi-calcium salt butanone co-crystals in the pharmaceutically active ingredient (by weight) should be above 90%.
  • the invention also discloses a preparation method of atorvastatin hemi-calcium salt-butanone dihydrate: atorvastatin hemi-calcium salt or a hydrate thereof is dissolved in a mixture of methyl ethyl ketone or methyl ethyl ketone and water to obtain a clear solution, and then The solid was precipitated. The resulting solid was dried under vacuum at room temperature to obtain atorvastatin hemi-calcium salt-butanone dihydrate.
  • the atorvastatin hemi-calcium salt as described in the present invention may be atorvastatin hemi-calcium containing one or more crystal waters. a salt, or a co-crystal of water of atorvastatin hemi-calcium salt with other solvents, including but not limited to water and ethanol co-crystals of atorvastatin hemi-calcium salt, water of atorvastatin hemi-calcium salt and 1-propane Alcohol co-crystals, water of atorvastatin hemi-calcium salt and acetone co-crystals.
  • the invention also discloses a second preparation method of atorvastatin hemi-calcium salt-butanone dihydrate: atorvastatin hemi-calcium salt or solvate powder thereof in methyl ketone or a mixture of methyl ethyl ketone and water at 0-100 The mixture was stirred at ° C for 0.5-48 hours, and the solid was collected by filtration, and dried under vacuum at room temperature to obtain atorvastatin hemi-calcium salt-butanone dihydrate.
  • the invention also discloses a third preparation method of atorvastatin hemi-calcium salt-butanone dihydrate: the atorvastatin is dissolved in methyl ethyl ketone, mixed with an aqueous solution of calcium hydroxide or calcium hydrogencarbonate, heated, and allowed to stand still. solid.
  • the invention also discloses a fourth preparation method of atorvastatin hemi-calcium salt-butanone dihydrate: the atorvastatin basic salt is dissolved in methyl ethyl ketone, the calcium salt aqueous solution is added, and the solid is precipitated by heating under reflux.
  • the ampamicin alkaline salt described therein includes, but is not limited to, atorvastatin sodium salt, atorvastatin potassium salt, atorvastatin amine salt, atorvastatin ammonium salt;
  • the calcium salt includes, but is not limited to, calcium chloride. , calcium acetate.
  • the content (by weight) in the pharmaceutically active ingredient should be more than 60%; the preferred embodiment is atorvastatin hemi-calcium salt
  • the content of monobutyl ketone dihydrate in the active ingredient of the drug (by weight) should be above 80%; the best solution is the content of atorvastatin hemi-calcium salt monobutyl ketone dihydrate in the active ingredient of the drug (by weight) It should be above 90%.
  • the invention also discloses atorvastatin hemi-calcium salt crystal form H, which is a stable crystalline form of atorvastatin hemi-calcium salt-butanone dihydrate, and has the following 2 ⁇ , d-plane spacing and greater than 30
  • the relative intensity of % represents the X-ray powder diffraction pattern (Fig. 1):
  • Form H can be further defined by its differential thermal analysis (DSC) characteristics (Fig. 2), infrared (IR) absorption characteristics (Fig. 3), and Raman spectral absorption characteristics (Fig. 4).
  • DSC differential thermal analysis
  • IR infrared
  • Fig. 4 Raman spectral absorption characteristics
  • the invention also discloses a preparation method of atorvastatin hemi-calcium salt crystal form H: atorvastatin hemi-calcium salt or a hydrate thereof is dissolved in a mixture of methyl ethyl ketone or methyl ethyl ketone and water, and after obtaining a clear solution, the solid is precipitated. . The obtained solid was dried under vacuum at room temperature to obtain atorvastatin hemi-calcium salt-butanone dihydrate crystal form H.
  • the atorvastatin hemi-calcium salt as described in the present invention may be atorvastatin hemi-calcium salt containing one or more water of crystallization, or a co-crystal of water of atorvastatin hemi-calcium salt and other solvents, including but Water and ethanol co-crystals of atorvastatin hemi-calcium salt, water and 1-propanol co-crystals of atorvastatin hemi-calcium salt, water and acetone co-crystals of atorvastatin hemi-calcium salt are not limited.
  • the invention also discloses a second preparation method of atorvastatin hemi-calcium salt-butanone dihydrate crystal form H: atorvastatin hemi-calcium salt or a solvate powder thereof in methyl ketone or a mixture of methyl ethyl ketone and water 0- lOO 'C under stirring for 0.5-48 hours, the solid was collected by filtration, and dried under vacuum at room temperature to obtain atorvastatin hemi-calcium salt-butanone dihydrate crystal form H.
  • the invention also discloses a third preparation method of atorvastatin hemi-calcium salt-butanone dihydrate crystal form H: the atorvastatin is dissolved in methyl ethyl ketone, mixed with an aqueous solution of calcium hydroxide or calcium hydrogencarbonate, and heated. The solid was precipitated by standing.
  • the invention also discloses a fourth preparation method of atorvastatin hemi-calcium salt-butanone dihydrate crystal form H: the atorvastatin basic salt is dissolved in methyl ethyl ketone, the calcium salt aqueous solution is added, and the mixture is heated and refluxed, and then left to stand still. solid.
  • the ampamicin alkaline salt described therein includes, but is not limited to, atorvastatin sodium salt, atorvastatin potassium salt, atorvastatin amine salt, atorvastatin ammonium salt;
  • the calcium salt includes, but is not limited to, calcium chloride. , calcium acetate.
  • the content of the pharmaceutically active ingredient should be more than 60%;
  • the content of statin hemi-calcium salt-butanone dihydrate crystal form H in the active ingredient of the drug (by weight) should be above 80%;
  • the best solution is atorvastatin hemi-calcium salt-butanone dihydrate crystal form H
  • the content (by weight) in the pharmaceutically active ingredient should be above 90%.
  • the compound of the formula (I) disclosed in the present invention can be prepared into any dosage form capable of achieving therapeutic effects, including but not limited to solid dosage forms (eg Tablets, powder, suppositories, Capsules, tablets, suspensions or solutions.
  • solid dosage forms eg Tablets, powder, suppositories, Capsules, tablets, suspensions or solutions.
  • the compound represented by the formula (I) and the solvate thereof disclosed in the present invention can be prepared into a sustained release preparation.
  • the preparation of the compound containing the compound of the formula (I) and the solvate thereof provided by the present invention for use as a medicament can be optionally used pharmaceutically acceptable
  • Pharmaceutical dressings such as cellulose derivatives, including but not limited to powdered cellulose, microcrystalline cellulose, microcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, Hydroxypropyl methylcellulose, carboxyethyl cellulose salt or other substituted and unsubstituted cellulose, starch or pregelatinized starch.
  • the inorganic additives mainly include calcium carbonate or calcium phosphate.
  • the pharmaceutical preparation containing the compound of the formula (I) and the solvate thereof provided by the present invention may or may not contain other suitable additives such as paraffin, sugar, sugar alcohol (such as dry alcohol and sorbitol). , polyacrylate, pectin or dextrin river gelatin.
  • the pharmaceutical preparation containing the compound of the formula (I) and the solvate thereof provided by the present invention may or may not contain a filler including a binder such as gum arabic, pregelatinized starch, sodium alginate, Glucose or other binder used in granulation and compression.
  • a binder such as gum arabic, pregelatinized starch, sodium alginate, Glucose or other binder used in granulation and compression.
  • the preparation of the pharmaceutical preparation containing the compound of the formula (I) and the solvate thereof provided by the present invention may or may not be added with a filler including a disintegrating agent such as sodium starch glycolate, polyvinylpyrrolidone or low substitution. Hydroxypropyl cellulose and the like.
  • a disintegrating agent such as sodium starch glycolate, polyvinylpyrrolidone or low substitution. Hydroxypropyl cellulose and the like.
  • the filler further includes a tablet lubricant, a flavoring agent, a sweetener, a preservative;
  • the capsule preparation may contain a solid component made of gelatin or other common capsule material;
  • the tablet and the powder may be prepared as an enteric film wrap sheet.
  • the enteric film may be composed of cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, polyvinyl alcohol phthalic acid, a copolymer of styrene and maleic acid, One or more of the copolymers of methacrylic acid or methyl methacrylate.
  • the atorvastatin hemi-calcium salt butanone dihydrate disclosed in the present invention can be prepared into any dosage form capable of achieving therapeutic effects, including but not limited to solid dosage forms (eg, tablets, powders, suppositories, capsules, tablets). ), suspension or solution preparation.
  • the atorvastatin hemi-calcium salt butanone dihydrate disclosed in the present invention can be prepared into a sustained release preparation.
  • the preparation of the averva provided by the present invention is prepared.
  • the dosage form of T-former H for use as a medicament may be selected from pharmaceutically acceptable medicinal dressings, such as cellulose derivatives, including but not limited to powdered cellulose, microcrystalline cellulose, microcellulose, methylcellulose, ethyl Cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, carboxyethyl cellulose salt or other substituted and unsubstituted cellulose, starch or pregelatinized starch.
  • the inorganic additives mainly include calcium carbonate or calcium phosphate.
  • the pharmaceutical preparation containing the atorvastatin hemi-calcium salt butanone dihydrate provided by the present invention may or may not contain other suitable additives such as paraffin, sugar, sugar alcohol (such as dry alcohol and sorbitol). , polyacrylate, pectin or dextrin river gelatin.
  • the pharmaceutical preparation containing the atorvastatin hemi-calcium salt butanone dihydrate provided by the present invention may or may not contain a filler, such as gum arabic, pregelatinized starch, sodium alginate, glucose. Or other binders used in granulation and compression.
  • a filler such as gum arabic, pregelatinized starch, sodium alginate, glucose. Or other binders used in granulation and compression.
  • the pharmaceutical preparation containing the atorvastatin hemi-calcium salt butanone dihydrate provided by the present invention may or may not be added with a filler including a disintegrating agent such as sodium starch glycolate, polyvinylpyrrolidone or low substituted hydroxy group. Propyl cellulose and the like.
  • the filler further includes a tablet lubricant, a flavoring agent, a sweetener, a preservative;
  • the capsule preparation may contain a solid component made of gelatin or other common capsule material;
  • the tablet and the powder may be prepared as an enteric film wrap sheet.
  • the enteric film may be composed of cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, polyvinyl alcohol phthalic acid, a copolymer of styrene and maleic acid, One or more of the copolymers of methacrylic acid or methyl methacrylate.
  • the atorvastatin hemi-calcium salt monobutanone dihydrate form H disclosed in the present invention can be prepared into any dosage form capable of achieving therapeutic effects, including but not limited to solid dosage forms (eg, tablets, powders, suppositories). , capsules, tablets), suspension or solution preparations.
  • the atorvastatin hemi-calcium salt monobutanone dihydrate crystal form H disclosed in the present invention can be prepared as a sustained release preparation.
  • a dosage form containing the atorvastatin hemi-calcium salt monobutanone dihydrate form H provided by the present invention is prepared for use as a medicament
  • Pharmaceutically acceptable medicinal dressings such as cellulose derivatives, may be used, including but not limited to powdered cellulose, microcrystalline cellulose, microcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, Hydroxypropyl cellulose, hydroxypropyl methylcellulose, carboxyethyl cellulose salt or other substitutions and Unsubstituted cellulose, starch or pre-gelatinized starch.
  • the inorganic additives mainly include calcium carbonate or calcium hydrogen phosphate.
  • the pharmaceutical preparation containing the atorvastatin hemi-calcium salt monobutanone dihydrate crystal form H provided by the present invention may or may not contain other suitable additives such as paraffin, sugar, sugar alcohol (such as dry alcohol and Sorbitol), polyacrylate, pectin or dextrin river gelatin.
  • suitable additives such as paraffin, sugar, sugar alcohol (such as dry alcohol and Sorbitol), polyacrylate, pectin or dextrin river gelatin.
  • the pharmaceutical preparation containing the atorvastatin hemi-calcium salt monobutanone dihydrate crystal form H provided by the present invention may or may not contain a filler, such as a gum, a gelatinized starch, a seaweed. Sodium, glucose or other binders used in granulation and compression.
  • the preparation of the pharmaceutical preparation containing the atorvastatin hemi-calcium salt monobutanone dihydrate crystal form H provided by the present invention may or may not be added with a filler including a disintegrating agent such as sodium starch glycolate, polyvinylpyrrolidone. Or low-substituted hydroxypropyl cellulose and the like.
  • a disintegrating agent such as sodium starch glycolate, polyvinylpyrrolidone. Or low-substituted hydroxypropyl cellulose and the like.
  • the filler further includes a tablet lubricant, a flavoring agent, a sweetener, a preservative;
  • the capsule preparation may contain a solid component made of gelatin or other common capsule material;
  • the tablet and the powder may be prepared as an enteric film wrap sheet.
  • the enteric film may be composed of cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, polyvinyl alcohol phthalic acid, a copolymer of styrene and maleic acid, One or more of the copolymers of methacrylic acid or methyl methacrylate.
  • the compound represented by the formula (I) and the solvate thereof disclosed in the present invention are used in a unit dosage of 0.5 mg to 160 mg for the drug; the preferred unit dosage is 2.5 mg to 80 mg; the most convenient unit dosage is 10 mg, 20 mg. , 40mg, 80mg, and can be taken once or more times a day.
  • the atorvastatin hemi-calcium salt-butanone dihydrate disclosed in the present invention is used as a unit for a dose of 0.5 mg-160 mg; the preferred unit dose is 2.5 mg-80 mg; the most convenient unit dosage is 10mg, 20mg, 40mg, 80mg, and can be taken once or more times a day.
  • the atorvastatin hemi-calcium salt monobutanone dihydrate crystal form H disclosed in the present invention is used as a unit for a dosage of 0.5 mg to 160 mg; a preferred unit dosage is 2.5 mg to 80 mg; The unit dosage is 10mg, 20mg, 40mg, 80mg, and can be taken once or more times a day.
  • the compound represented by the formula (I) and the solvate thereof disclosed in the present invention can be used as a medicament for preparing an HMG-CoA enzyme inhibitor, It is used to treat physiological abnormalities that are improved by inhibition of HMG-CoA enzymes, including but not limited to coronary heart disease, diseases caused by thrombosis, diseases caused by elevated low-density lipoprotein levels, or hypercholesterolemia.
  • the compounds of the formula (I) and solvates thereof disclosed in the present invention can also be used for the preparation of a medicament for the treatment of osteoporosis.
  • the atorvastatin hemi-calcium salt-butanone dihydrate disclosed in the present invention can be used as a medicament for preparing an HMG-CoA enzyme inhibitor for treating physiological abnormalities which are improved by inhibiting HMG-CoA enzyme, including but It is not limited to coronary heart disease, diseases caused by thrombosis, diseases caused by an increase in low-density lipoprotein levels, or hypercholesterolemia.
  • the atorvastatin hemi-calcium salt monobutanone dihydrate disclosed in the present invention can also be used for the preparation of a medicament for treating osteoporosis.
  • the atorvastatin hemi-calcium salt-butanone dihydrate crystal form H disclosed in the present invention can be used as a medicament for preparing an HMG-CoA enzyme inhibitor for treating an improved physiological condition by inhibiting HMG-CoA enzyme.
  • Abnormalities including but not limited to coronary heart disease, diseases caused by thrombosis, diseases caused by elevated low-density lipoprotein levels, or hypercholesterolemia.
  • the atorvastatin hemi-calcium salt monobutanone dihydrate crystal form H disclosed in the present invention can also be used for the preparation of a medicament for treating osteoporosis.
  • Atorvastatin hemi-calcium salt-butanone dihydrate crystal form H Tianjin Hemei Biotechnology Co., Ltd.
  • Ammonium chloride Tianjin Chemical Reagent No.3 Factory (batch number 2005041808)
  • the wet weight gain of atorvastatin hemi-calcium salt-butanone dihydrate crystal form H is 0.43%. According to the Chinese Pharmacopoeia standard, it is slightly hygroscopic.
  • FIG. 1 X-ray powder diffraction pattern of atorvastatin hemi-calcium salt monobutanone dihydrate crystal form H
  • FIG. 2 atorvastatin hemi-calcium salt monobutanone dihydrate crystal form H Infrared absorption spectrum spectrum
  • Figure 3 Raman absorption spectrum of atorvastatin hemi-calcium salt-butanone dihydrate crystal form H
  • Figure 4 Atorvastatin hemi-calcium salt-butanone dihydrate crystal Thermal analysis and differential thermal analysis of type H.
  • Figure 5 Solubility measurement curve
  • the maximum absorption wavelength is 241 nm after scanning by ultraviolet spectrum
  • atorvastatin hemi-calcium salt 10 g was dissolved by heating in 500 mL of anhydrous butanone, and crystals were precipitated at room temperature, and the solid was collected by filtration, and dried to obtain atorvastatin hemi-calcium salt butanone cocrystal.
  • Example 2 Atorvastatin hemi-calcium salt-butanone dihydrate co-crystal (Form H)
  • atorvastatin hemi-calcium salt trihydrate (Lipitor) was dissolved in 500 mL of methyl ethyl ketone, and crystals were precipitated at room temperature. The solid was collected by filtration, and dried to obtain atorvastatin hemi-calcium salt-butanone dihydrate co-crystal ( Form H).
  • Example 4 Atorvastatin hemi-calcium salt-butanone dihydrate co-crystal (crystal form H) A mixture of lg calcium hydrogencarbonate in 10 mL of water was added to a solution of 10 g of atorvastatin dissolved in 500 mL of methyl ethyl ketone, and the mixture was heated under reflux for 2 hours. Crystals were precipitated at room temperature, and the solid was collected by filtration, and the dried atorvastatin hemi-calcium salt was Butanone dihydrate co-crystal (Form H). Melting point: 185-188 ° C. The X-ray powder diffraction pattern showed no difference from the crystal form in Example 2.
  • Example 5 Atorvastatin hemi-calcium salt-butanone dihydrate co-crystal (crystal form H)
  • Microcrystalline cellulose 25%
  • the main drug and the auxiliary material are weighed according to the prescription, and mixed, and 1% HPMC soft material is added in portions, and the soft material is granulated through a 24-mesh sieve.
  • the particles were dried in an oven at 60 ° C for 2.5 hours and then sized with a 30 mesh sieve.
  • the magnesium stearate is added in proportion to the actual measured amount of the particles, and the mixture is compressed and then compressed.

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Abstract

L’invention concerne des co-cristaux d’atorvastatine hémi-calcium et de butanone, leurs procédés de préparation et leurs utilisations en tant qu’inhibiteur de l’enzyme HMG-CoA. Le dihydrate formé à partir de l’atorvastatine hémi-calcium et de la butanone de formule I et d’eau existe sous la forme cristalline stable (cristal H) dont la solubilité dans l’eau (0,46 mg/ml) est bien supérieure à celle du trihydrate d’atorvastatine hémi-calcium disponible sur le marché, celle de ce dernier n’étant que de 0,198 mg/ml dans les mêmes conditions d’évaluation.
PCT/CN2009/071988 2008-05-30 2009-05-26 Co-cristaux d’atorvastatine hémi-calcium et de butanone, leurs procédés de préparation et leurs utilisations en tant qu’inhibiteur de l’enzyme hmg-coa WO2009143767A1 (fr)

Applications Claiming Priority (2)

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CN2008100533462A CN101538237B (zh) 2008-05-30 2008-05-30 阿伐他汀半钙盐丁酮共结晶物、其制备和作为HMG-CoA酶抑制剂的应用
CN200810053346.2 2008-05-30

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1489463A (zh) * 2000-11-30 2004-04-14 ������ҩ��ҵ���޹�˾ 阿托伐他汀半钙的新晶型及其制备方法,以及其它晶型的新制备方法
CN1960972A (zh) * 2004-04-16 2007-05-09 辉瑞产品公司 用于形成无定形阿托伐它汀钙的方法
CN101039906A (zh) * 2004-10-18 2007-09-19 特瓦制药工业有限公司 通过将盐溶解于有机溶剂并除去该溶剂来制备无定形阿托伐他汀半钙的方法，所述有机溶剂为醇和酮和 /或酯的混合物

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1489463A (zh) * 2000-11-30 2004-04-14 ������ҩ��ҵ���޹�˾ 阿托伐他汀半钙的新晶型及其制备方法,以及其它晶型的新制备方法
CN1960972A (zh) * 2004-04-16 2007-05-09 辉瑞产品公司 用于形成无定形阿托伐它汀钙的方法
CN101039906A (zh) * 2004-10-18 2007-09-19 特瓦制药工业有限公司 通过将盐溶解于有机溶剂并除去该溶剂来制备无定形阿托伐他汀半钙的方法，所述有机溶剂为醇和酮和 /或酯的混合物

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