WO2012085191A1 - Forme cristalline de la pravastatine et son procédé de préparation - Google Patents

Forme cristalline de la pravastatine et son procédé de préparation Download PDF

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Publication number
WO2012085191A1
WO2012085191A1 PCT/EP2011/073767 EP2011073767W WO2012085191A1 WO 2012085191 A1 WO2012085191 A1 WO 2012085191A1 EP 2011073767 W EP2011073767 W EP 2011073767W WO 2012085191 A1 WO2012085191 A1 WO 2012085191A1
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WO
WIPO (PCT)
Prior art keywords
pravastatin
organic solvent
sodium
solvent
intensity
Prior art date
Application number
PCT/EP2011/073767
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English (en)
Inventor
De Robertus Mattheus Pater
Piotr Wnukowski
Original Assignee
Dsm Sinochem Pharmaceuticals Netherlands B.V.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
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Publication date
Application filed by Dsm Sinochem Pharmaceuticals Netherlands B.V. filed Critical Dsm Sinochem Pharmaceuticals Netherlands B.V.
Publication of WO2012085191A1 publication Critical patent/WO2012085191A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/16—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D309/28—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member 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
    • C07D309/30—Oxygen atoms, e.g. delta-lactones
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/02—Esters of acyclic saturated monocarboxylic acids having the carboxyl group bound to an acyclic carbon atom or to hydrogen
    • C07C69/22—Esters of acyclic saturated monocarboxylic acids having the carboxyl group bound to an acyclic carbon atom or to hydrogen having three or more carbon atoms in the acid moiety
    • C07C69/33—Esters of acyclic saturated monocarboxylic acids having the carboxyl group bound to an acyclic carbon atom or to hydrogen having three or more carbon atoms in the acid moiety esterified with hydroxy compounds having more than three hydroxy groups

Definitions

  • the present invention relates to a novel form of pravastatin, notably pravastatin sodium, and a method for the preparation of a novel form of pravastatin.
  • Pravastatin is an inhibitor of the enzyme (3S)-hydroxy-3-methylglutaryl- coenzyme A (HMG-CoA) reductase.
  • the sodium salt of pravastatin, pravastatin sodium (1) is a potent cholesterol-lowering agent which is commercially available for the treatment of hyperlipidemia.
  • Pravastatin can be prepared by microbial oxidation of the fermentatively obtained precursor compactin, the sodium salt of which has structure (2), such as described for instance in US 4,346,227. Recently, an improved approach has been described in WO 2007/147827 in which pravastatin is prepared directly in a host cell equipped with genes for compactin biosynthesis and a gene for conversion of compactin into pravastatin.
  • Pravastatin sodium and hydrates thereof can exist in several polymorphic forms. Polymorphism is the property to assume more than one crystalline form in the solid state whereas each polymorph can assume distinct physical properties.
  • One of the most widely accepted tools for investigating polymorphic structure is X-ray diffraction, a technique whereby the angles at which X-ray radiation is reflected from a crystal is a measure for a specific crystalline structure. Because of the different orientation and intermolecular interactions of adjacent molecules (complexes) in the bulk solid, different polymorphs have different physical properties and are therefore distinct solids sharing only the same molecular formula but displaying different advantageous and/or disadvantageous physical properties.
  • pravastatin sodium Some polymorphs of pravastatin sodium are known and have been described as obtainable from a process wherein both an aprotic and a protic solvent are used, for example in US 7,001 ,919 (EP 1523978) and references cited therein.
  • the present invention discloses a form of pravastatin sodium that is hitherto unknown.
  • the pravastatin sodium or hydrates thereof of the present invention has an X-ray powder diffraction pattern characterized in that it comprises peaks at 4.52 ⁇ 0.1 , 4.90 ⁇ 0.1 , 9.12 ⁇ 0.1 , and 9.87 ⁇ 0. 1 degrees measured at reflection angle 2 theta.
  • the intensity of any of the aforementioned peaks (in cps) is at least 10% of the intensity of the peak with the highest intensity. More preferably, the intensity of the peaks in the region from 5 deg. 2-theta to 9 deg.
  • 2-theta an area wherein prior art crystalline pravastatin forms show significant peaks, is below 4% of the intensity of the peak with the highest intensity. Smaller but distinct peaks are also present at 10.32 ⁇ 0.1 and 13.71 ⁇ 0.1 degrees measured at reflection angle 2-theta.
  • the X-ray diffraction patterns mentioned above are, in a second embodiment, measured in the presence of an internal standard which preferably is silicon.
  • the pravastatin sodium of the present invention can be obtained from the process as described in the second aspect wherein only aprotic solvents are used.
  • the product is of high purity resulting from the fact that unwanted lactonization occurs only at very low levels and hence pravastatin lactone (3) is not present, or present in very low levels, as contaminant in the final product.
  • step (b) Adding a second organic solvent to the organic phase obtained after step (a);
  • step (c) Adding a sodium salt to the mixture obtained in step (b);
  • said first organic solvent is a ketone with 5 or more carbon atoms such as methyl isobutyl ketone or an ester such as ethyl acetate or methyl acetate and said second organic solvent is a ketone with less than 5 carbon atoms such as acetone or 2-butanone.
  • said first organic solvent is methyl isobutyl ketone and said second organic solvent is acetone.
  • the ratio between the first organic solvent and the second organic solvent preferably is between 10: 1 to 1 : 1 , more preferably between 5: 1 to 2: 1.
  • the exact optimum may vary from one solvent mixture to the other.
  • said first organic solvent is methyl isobutyl ketone and said second organic solvent is acetone said ratio preferably is between 4: 1 to 3:2, more preferably from 7:2 to 2: 1.
  • the concentration of pravastatin in the first organic solvent preferably is from 10 g/L to 100 g/L, more preferably from 20 g/L to 80 g/L. Best results were obtained with a concentration from 40 g/L to 65 g/L both from process economics and the finding that at higher concentrations unwanted coloring occurs.
  • the final step (d) is followed by a washing step which is followed by a drying step. Washing is preferably carried out using the same second solvent or a mixture of the first and second solvent. This approach will greatly facilitate solvent recovery and process economics. Nevertheless, alternative solvents used for washing and known to the skilled person may also be employed.
  • a temperature of about 0°C or higher is applied, more preferably a temperature close to ambient temperature (18-25°C i.e. around 20°C).
  • ambient temperature preferably a temperature close to ambient temperature (18-25°C i.e. around 20°C).
  • suitable temperatures are from 25-70°C, preferably from 30-50°C.
  • the pH-value at which step (a) as described above takes place is from 3 to 5, preferably from 3.5 to 4.5.
  • pH-adjusted is to be performed using acid or base. In most cases this will be acid such as formic acid, hydrochloric acid, phosphoric acid, sulphuric acid and the like.
  • Suitable sodium salts for use in step (c) are sodium carbonate, sodium chloride, sodium ethyl hexanoate, sodium hydroxide, sodium nitrate, sodium phosphate and the like.
  • sodium carbonate was successfully replaced or partly replaced with sodium ethyl hexanoate resulting in a lower chance of unwanted inclusion of sodium carbonate particles in the end product.
  • Addition times of sodium carbonate may be from instantaneous to 24 hours; favourable results, i.e. lack of inclusion of sodium carbonate, were observed when addition to place between 10 min and 2 hours.
  • Figure 1 is the XRD spectrum of compound (1).
  • X-axis 2-theta value (deg).
  • Y-axis intensity (cps). The following distinct peaks can be discerned: Peak no.
  • the dotted lines are the expected positions of the internal calibration standard silicon.
  • Powders were used without grinding to minimize water uptake.
  • X-ray diffraction experiments were performed using a BRUKER D8 Advance diffractometer in ⁇ - ⁇ geometry using a VANTEC line detector; a series of data sets were recorded from each sample to monitor potential changes due to humidity.
  • a first screening was performed using relatively short data collection times in order to gain a rapid overview on the initial diffraction patterns.
  • a much longer experiment has been performed in order to improve data quality (reliability of rather weak diffraction peaks). From changes among the latter it could be concluded whether and to which extend data acquisition times needed to be adopted in order to minimize changes due to exposure of the samples to humidity.
  • all samples were mixed with Si-powder to provide an internal calibration standard. Based on the known peak positions of Si, a correction of the diffraction patterns according to the known values could be performed, thus providing an accuracy in peak positions of less than 0,1°.
  • the data have been corrected for background signal arising from sample holder and peak positions have been assigned via the peak search routine implemented in the data evaluation software EVA. 2 ⁇ - Values below 4° were not measured.
  • Pravastatin samples were analyzed using the following HPLC-method.
  • Pravastatin sodium salt (7.96 g, purity 95.1 %; 17 mmol) was dissolved in water (120 mL) and the mixture was extracted at pH 4 with methyl isobutyl ketone (120 mL). Acetone (40 mL) was added to the methyl isobutyl ketone extract. Under diligent stirring 2.85 mL of an aqueous solution of 300 g/L sodium carbonate (8.1 mmol) was added in 1 hour at 20°C. A homogeneous suspension was obtained after 1 hour of stirring. Next 2-ethyl hexanoic acid (0.4 ml, 2.5 mmol) was added and stirring at room temperature was continued overnight. The mixture was filtered and the precipitate was washed with 2x30 mL methyl isobutyl ketone/acetone (3/1 , v/v) and dried under vacuum at 50°C for 24 hours, yielding pravastatin sodium.
  • Pravastatin 2 ,2'-(ethylenedioxy)diethyl amine salt (prepared as described in WO 2009/121869, 4.23 g, purity 98.2%; 8.5 mmol pravastatin) was dissolved in water (35 mL). Methyl isobutyl ketone (55 mL) was added and the pH was adjusted to 4 with 10% sulfuric acid. The phases were separated and the methyl isobutyl ketone phase was washed with water (25 mL).
  • methyl isobutyl ketone phase was filtered through a 0.45 ⁇ filter and the volume of the filtrate was adjusted to 59 mL with methyl isobutyl ketone and the resulting solution was diluted with acetone (20 mL). Under stirring 1.38 mL of an aqueous solution of 300 g/L sodium carbonate (3.9 mmol) was added in portions of 100 ⁇ in 30 minutes. Next 2-ethyl hexanoic acid (0.27 mL, 1.7 mmol) was added and the mixture was stirred at 20°C overnight.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

La présente invention concerne une nouvelle forme de pravastatine, notamment le sodium de pravastatine, et un procédé de préparation d'une nouvelle forme de pravastatine.
PCT/EP2011/073767 2010-12-23 2011-12-22 Forme cristalline de la pravastatine et son procédé de préparation WO2012085191A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP10196835.2 2010-12-23
EP10196835 2010-12-23

Publications (1)

Publication Number Publication Date
WO2012085191A1 true WO2012085191A1 (fr) 2012-06-28

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114031496A (zh) * 2021-11-30 2022-02-11 广东蓝宝制药有限公司 一种高纯度普伐他汀1,1,3,3-四甲基丁胺的制备方法

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4346227A (en) 1980-06-06 1982-08-24 Sankyo Company, Limited ML-236B Derivatives and their preparation
EP1523978A2 (fr) 1999-12-14 2005-04-20 Biogal Gyogyszergyar Rt. Formes cristallines de pravastatine sodique
US7001919B2 (en) 1999-12-14 2006-02-21 Teva Gyogyszergyar Reszvenytarsasag Forms of pravastatin sodium
WO2007147827A2 (fr) 2006-06-22 2007-12-27 Dsm Ip Assets B.V. Production de pravastatine
WO2009121869A1 (fr) 2008-04-02 2009-10-08 Dsm Ip Assets B.V. Sels d'acides carboxyliques avec des diamines

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4346227A (en) 1980-06-06 1982-08-24 Sankyo Company, Limited ML-236B Derivatives and their preparation
EP1523978A2 (fr) 1999-12-14 2005-04-20 Biogal Gyogyszergyar Rt. Formes cristallines de pravastatine sodique
US7001919B2 (en) 1999-12-14 2006-02-21 Teva Gyogyszergyar Reszvenytarsasag Forms of pravastatin sodium
WO2007147827A2 (fr) 2006-06-22 2007-12-27 Dsm Ip Assets B.V. Production de pravastatine
WO2009121869A1 (fr) 2008-04-02 2009-10-08 Dsm Ip Assets B.V. Sels d'acides carboxyliques avec des diamines

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114031496A (zh) * 2021-11-30 2022-02-11 广东蓝宝制药有限公司 一种高纯度普伐他汀1,1,3,3-四甲基丁胺的制备方法

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