WO2009068556A1 - Purification de la pravastatine - Google Patents

Purification de la pravastatine Download PDF

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Publication number
WO2009068556A1
WO2009068556A1 PCT/EP2008/066222 EP2008066222W WO2009068556A1 WO 2009068556 A1 WO2009068556 A1 WO 2009068556A1 EP 2008066222 W EP2008066222 W EP 2008066222W WO 2009068556 A1 WO2009068556 A1 WO 2009068556A1
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WO
WIPO (PCT)
Prior art keywords
pravastatin
ene
weight
diazabicyclo
composition
Prior art date
Application number
PCT/EP2008/066222
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English (en)
Inventor
De Robertus Mattheus Pater
Original Assignee
Dsm Ip Assets 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.)
Filing date
Publication date
Application filed by Dsm Ip Assets B.V. filed Critical Dsm Ip Assets B.V.
Publication of WO2009068556A1 publication Critical patent/WO2009068556A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/48—Separation; Purification; Stabilisation; Use of additives
    • C07C67/60—Separation; Purification; Stabilisation; Use of additives by treatment giving rise to chemical modification

Definitions

  • the present invention relates to the large scale purification of the HMG-CoA reductase inhibitor 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 sodium is prepared by microbial oxidation of a fermentatively obtained precursor.
  • a well known drawback of fermentatively produced pravastatin sodium is that relatively many impurities are co-produced. Two such impurities are 6-epi-pravastatin (2) and 3- ⁇ -isopravastatin (3), first described as pravastatin metabolites in humans by Funke et al. (BioMed. Environ.
  • WO 92/16276 a method is described which uses high performance liquid chromatography (HPLC).
  • HPLC high performance liquid chromatography
  • pravastatin with purity larger than 99.5% is mentioned, there is no mention as to how this methodology relates to the impurities 6-epi-pravastatin (2) and 3- ⁇ -isopravastatin (3).
  • HPLC has several disadvantages, namely the need for recycling of resin, the use of excessive amounts of solvents and the poor applicability on industrial scale. As a matter of fact, the large-scale purification of pravastatin is not disclosed in WO 92/16276.
  • a purification process is described based on displacement chromatography. Described is the purification of lab-scale (Ae. 1 gram and smaller) samples of pravastatin by displacement chromatography. Although purities of pravastatin sodium of 99.7% and 99.8% are mentioned, these purities refer to pravastatin in solution. Isolated pravastatin sodium is not disclosed.
  • US 2003/0216596 describes decomposition of impurities with inorganic acids (such as HBr, HCI, H 2 SO 4 HCIO 4 , H 3 PO 4 and HNO 3 ) or bases (such as alkali metal carbonates, bicarbonates, hydrides, hydroxides and alkoxides).
  • inorganic acids such as HBr, HCI, H 2 SO 4 HCIO 4 , H 3 PO 4 and HNO 3
  • bases such as alkali metal carbonates, bicarbonates, hydrides, hydroxides and alkoxides.
  • purified isolated pravastatin sodium at semi large scale Ae. up to 32 gram samples having purities up to 99.67% and amounts of 6-epi-pravastatin (2) are reported to be 0.1 % by weight.
  • 3- ⁇ -isopravastatin (3) nor a suggestion as to whether the method of US 2003/0216596 would be suitable to reduce the presence of this impurity.
  • the method relies on the use of organic solvents,
  • the first aspect of the present invention is to provide a method for the purification of pravastatin or a pharmacologically acceptable salt thereof. It has been found that treatment of an aqueous solution comprising pravastatin with a nitrogen-containing base having a pK a value of 12 or higher substantially lowers the presence of unwanted impurities, notably 6-epi-pravastatin (2) and 3- ⁇ -isopravastatin (3). Surprisingly it has been established that 6-epi-pravastatin (2) and 3- ⁇ -isoprava- statin (3) are prone to degradation at much higher rates than pravastatin in the presence of certain bases under aqueous conditions.
  • Preferred bases are those that have sufficient solubility in water to achieve the preferred pH-range of from pH 10 to pH 14, or to achieve the more preferred pH-range of from pH 1 1 to pH 13, or to achieve the most preferred pH-range of from pH 1 1.5 to pH 12.5.
  • preferred bases are bases with a solibility in water of more than 0.1 mmol.l “1 , preferably more than 1 mmol.l “1 , more preferably more than 10 mmol.l “1 , most preferably more than 50 mmol.l “1 and still most preferably more than 250 mmol.l “1 .
  • pK a is a measure of the tendency of a molecule or ion to keep a proton, H + , at its dissociation center(s). It is related to dissociation capabilities of chemical species.
  • the pK a value is the negative logarithm of the equilibrium acid dissociation constant, K a .
  • pK a values are measured in water at 25 ⁇ 1°C.
  • particularly suitable bases are organic bases, preferably nitrogen-containing bases.
  • Preferred classes of bases are the azabicyclo bases such as the diazabicyclo bases such as the 1 ,5-diazabicyclo[4.3.0]non-5-enes and the 1 ,8-diazabicyclo[5.4.0]undec-7-enes and the triazabicyclo bases such as the 1 ,5,7-triazabicyclo-[4.4.0]dec-5-enes.
  • Another preferred class of bases is that of the guanidines.
  • Yet another preferred class of bases is that of the quaternairy ammonium hydroxides.
  • suitable bases are 1 ,5-diazabicyclo[4.3.0]non-5-ene, 1 ,8-diazabicyclo[5.4.0]undec-7-ene, guanidine, heptamethylisobiguanide, pentamethyl- guanidine, tetraethylammonium hydroxide, tetraethylguanidine, tetramethylammonium hydroxide, tetramethylguanidine and 1 ,5,7-triazabicyclo-[4.4.0]dec-5-ene.
  • the impurity degradation reaction is carried out within a temperature range of from -4 0 C to 100 0 C, preferably of from O 0 C to 75 0 C, more preferably of from 1O 0 C to 55 0 C and most preferably of from 2O 0 C to 4O 0 C takes.
  • the duration of the impurity degration reaction typically within the range of 1 hour to 48 hours, preferably of from 2 hours to 24 hours, more preferably of from 3 hours to 12 hours, most preferably of from 4 hours to 10 hours.
  • the impurity degradation reaction is carried out in a (semi-)continuous process pH- and temperature conditions can be more extreme than outlined above whereas local residence times are relatively short, i.e. of from 5 seconds to 1 hour, preferably of from 30 seconds to 30 minutes, more preferably of from 1 minute to 15 minutes, most preferably of from 5 minutes to 10 minutes.
  • an aqueous solution comprising pravastatin is a fermentation broth comprising pravastatin.
  • a suitable base as mentioned above in an amount sufficient to reach a suitable pH-value, again as outlined above.
  • pravastatin is isolated from the reaction mixture. Said isolation can take place through whole-broth extraction, crystallization, adsorption chromatography, spray-drying, broth-filtration and other industrially applicable separation techniques or combinations thereof.
  • an aqueous solution comprising pravastatin is an aqueous solution obtained further downstream the pravastatin isolation process.
  • This can be the fermentation broth after removal of the biomass, it can be the fermentation broth after extraction into an organic solvent followed by back-extraction into water, it can be a solution of crude pravastatin obtained by crystallization, precipitation, freeze- drying or spray-drying. Following degradation of impurities using a suitable base under conditions as outlined above, isolation of pravastatin then takes place as described under the first embodiment.
  • the method of the present invention focuses on degradation of impurities in the aqueous phase thereby leaving no restrictions on the choice of solvent to be used in any preceding or following extraction steps.
  • the second aspect of the invention relates to new salts of pravastatin.
  • the preferred bases described in the first aspect of the present invention can also form salts with pravastatin which can be isolated. Formation of such a salt gives the possibility to introduce a further purification step in the process. By contacting pravastatin with a nitrogen-containing base having a pK a value of 12 or higher, the corresponding pravastatin amine salt can be formed.
  • amine salts of pravastatin were formed from 1 ,5-diazabicyclo[4.3.0]non-5-ene, 1 ,8-diazabicyclo[5.4.0]undec-7-ene, guanidine, 1 ,5,7-triazabicyclo-[4.4.0]dec-5-ene, guanidine, heptamethylisobiguanide, pentamethylguanidine, tetraethylguanidine and tetramethylguanidine.
  • the third aspect of the invention relates to the active pharmaceutical pravastatin itself or acceptable pharmaceutical salts thereof, notably the sodium salt.
  • the method of the present invention hitherto is the first disclosure of successful removal of 3- ⁇ -isopravastatin (3) from mixtures comprising both pravastatin and 3- ⁇ -isopravastatin (3). Furthermore, the method is suitable for use on an industrial scale. Therefore, industrial batches of pravastatin are obtainable by the method of the present invention.
  • the present invention discloses a composition
  • a composition comprising pravastatin sodium and epi-pravastatin (2) the quantity of which is 0.2% or less by weight of the composition and 3- ⁇ -isopravastatin (3) the quantity of which is 0.2% or less by weight of the composition.
  • the quantity of epi-pravastatin (2) is less than 0.1% by weight of the composition, more preferably less than 0.05% by weight of the composition.
  • the quantity of 3- ⁇ -isopravastatin (3) in the composition is preferably less than 0.1 % by weight of the composition, more preferably less than 0.05% by weight of the composition.
  • the assay of pravastatin sodium in the composition preferably is 99.6% or higher, more preferably 99.7% or higher, most preferably 99.8% or higher, still most preferably 99.9% or higher by weight of the composition.
  • the present invention discloses pravastatin sodium of high purity on an industrial scale.
  • the present invention suitably yields pravastatin sodium batches larger than 50 g, preferably of from 100 g to 10 tonnes, more preferably of from 500 g to 5 tonnes, most preferably of from 1 kg to 1000 kg, still most preferably of from 10 kg to 100 kg.
  • the above pravastatin batches have only minor impurities as the assay of pravastatin sodium is 99.4% or higher, more preferably 99.6% or higher, most preferably 99.7% or higher, still most preferably 99.8% or higher by weight of the composition and the assay of epi-pravastatin (2) is 0.2% or lower, preferably 0.15% or lower, more preferably 0.10% or lower, most preferably 0.15% or lower by weight of the composition and/or the assay of 3- ⁇ -isopravastatin (3) is 0.2% or lower, preferably 0.15% or lower, more preferably 0.10% or lower, most preferably 0.15% or lower by weight of the composition
  • highly purified industrially produced pravastatin is incorporated into a granule.
  • the term granule is meant to include a pill and a tablet.
  • Said granule comprises pravastatin sodium and epi-pravastatin (2) the quantity of which is 0.2% or less, preferably 0.1% or less, more preferably 0.05% or less by weight of the quantity of pravastatin sodium and 3- ⁇ -isopravastatin (3) the quantity of which is 0.2% or less, preferably 0.1 % or less, more preferably 0.05% or less by weight of the quantity of pravastatin sodium.
  • HPLC analysis was based on reversed phase liquid chromatography followed by UV- detection at 239 nm.
  • Apparatus Dionex ultimate 3000 binary pump, Dionex ultimate 3000 Diode array detector, Dionex ultimate 3000 autosampler, Dionex ultimate 3000 column compartment. Conditions:
  • UV-detection 238 nm Injection volume 10 ⁇ l Sample tray temp: 5O 0 C
  • Mobile phase A 0.1% formic acid in methanol-Milli-Q purified water (6+4)v/v
  • Mobile phase A Mix 600ml methanol, 400ml MilliQ-purified water and 1 ml formic acid.
  • Example 1 was repeated, however at 55°C instead of 25°C. The results are in Table 2.
  • Example 1 was repeated, however at 40 0 C instead of 25°C and at pH 12 instead of pH 12.5.
  • the results are in Table 3.
  • Example 1 was repeated, however at pH 1 1.5 instead of pH 12.5. The results are in Table 4.
  • Example 1 was repeated, however at 55°C instead of 25°C and at pH 1 1.5 instead of pH 12.5. The results are in Table 5.
  • the phases were separated, giving 440 ml of aqueous phase, containing pravastatin (53.9% relative area), epi-pravastatin (2.7% relative area) and 3- ⁇ -isopravastatin (1.3% relative area).
  • Tetramethylguanidine (3.2 ml) was added to the aqueous phase and the mixture was stirred at 40-44 0 C for 19 hours.
  • the mixture contained 43.3% (relative area) pravastatin whereas both epi-pravastatin and 3- ⁇ -isopravastatin were below the detection limit.
  • Example 1 was repeated, however at pH 12.25 instead of pH 12.5. The results are in Table 7.
  • Example 1 was repeated, however at pH 12.0 instead of 12.5. The results are in Table 8.
  • a broth (100 ml) containing pravastatin was spiked with pravastatin sodium salt (0.2 g) and the pH was adjusted to 8 with tetramethylammonium hydroxide (25% in water). After stirring for 5 minutes the mixture was centrifuged and the supernatant was divided into two portions. The pH of portion 1 was adjusted to 12.5 with tetramethylammonium hydroxide (25% in water) and that of portion 2 to 12.3 with tetramethylammonium hydroxide (25% in water). Stirring of both portions was continued at 20 0 C for 23 hours and samples were taken at the start and after a reaction time of 1 , 3, 6 and 23 hours. They were analyzed by HPLC (Table 9: pH 12.5; Table 10: pH 12.3).
  • aqueous solution 500 ml
  • pravastatin sodium 31.25 g
  • the organic phase was dried on MgSO 4 , filtered and the filter was washed with ethyl acetate until 500 ml of filtrate was obtained (solution 1 ).
  • a solution of TMG (0.71 ml, 5.6 mmol) in ethyl acetate (10 ml) was added dropwise to 40 ml of solution 1 (5.6 mmol pravastatin) at room temperature after which pravastatin TMG salt precipitated as an oil.
  • Example 12 Preparation of pravastatin 1 ,8-diazabicyclo[5.4.0]undec-7-ene (DBU) salt a) A solution of DBU (0.844 ml, 5.6 mmol) in ethyl acetate (10 ml) was added dropwise to 40 ml of solution 1 (5.6 mmol pravastatin) prepared as in Example 11 at 5O 0 C after which pravastatin DBU salt precipitated as an oil. b) Experiment a) was repeated however 40 ml of solution 1 was diluted with ethanol (2 ml); again pravastatin DBU salt precipitated as an oil.
  • DBU pravastatin 1 ,8-diazabicyclo[5.4.0]undec-7-ene

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

Abstract

La présente invention porte sur un procédé de purification de la pravastatine ou d'un sel pharmaceutiquement acceptable de celle-ci, par traitement d'une solution aqueuse comprenant de la pravastatine par une base en teneur en azote ayant une valeur de pKa de 12 ou plus. De plus, la présente invention porte sur une composition comprenant de la pravastatine sodique et de la 6-épi-pravastatine, dont la quantité est de 0,2 % ou moins en poids de la composition, et de la 3-α-isopravastatine, dont la quantité est de 0,2 % ou moins en poids de la composition.
PCT/EP2008/066222 2007-11-29 2008-11-26 Purification de la pravastatine WO2009068556A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
EP07121875.4 2007-11-29
EP07121875 2007-11-29
EP08102824.3 2008-03-20
EP08102824 2008-03-20

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WO2009068556A1 true WO2009068556A1 (fr) 2009-06-04

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2522806C1 (ru) * 2012-11-27 2014-07-20 Федеральное государственное бюджетное учреждение науки Центр "Биоинженерия" Российской академии наук Усовершенствованный способ очистки правастатина
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 (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1327624A1 (fr) * 2000-10-16 2003-07-16 Sankyo Company, Limited Procede de purification de la pravastatine ou de son sel pharmacologiquement acceptable
US20040138294A1 (en) * 1998-09-18 2004-07-15 Rok Grahek Process for obtaining HMG-CoA reductase inhibitors of high purity
EP1452519A1 (fr) * 2003-02-25 2004-09-01 Balkanpharma-Razgrad AD Procédé d'isolation et purification de pravastatine sodique
WO2005033067A1 (fr) * 2003-10-07 2005-04-14 Biocon Limited Sel de l'acide 1,2,6,7,8,8a-hexahydro-?,?,6-trihydroxy-2-methyl-8-[(2s)-2-methyl-1-oxobutoxy]-, (?r,? r,1s,2s,6s,8s,8ar)- 1-naphthaleneheptanoique et d'un diamide n,n-dimethyl-imidodicarbonimidique

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040138294A1 (en) * 1998-09-18 2004-07-15 Rok Grahek Process for obtaining HMG-CoA reductase inhibitors of high purity
EP1327624A1 (fr) * 2000-10-16 2003-07-16 Sankyo Company, Limited Procede de purification de la pravastatine ou de son sel pharmacologiquement acceptable
EP1452519A1 (fr) * 2003-02-25 2004-09-01 Balkanpharma-Razgrad AD Procédé d'isolation et purification de pravastatine sodique
WO2005033067A1 (fr) * 2003-10-07 2005-04-14 Biocon Limited Sel de l'acide 1,2,6,7,8,8a-hexahydro-?,?,6-trihydroxy-2-methyl-8-[(2s)-2-methyl-1-oxobutoxy]-, (?r,? r,1s,2s,6s,8s,8ar)- 1-naphthaleneheptanoique et d'un diamide n,n-dimethyl-imidodicarbonimidique

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
FUNKE P T ET AL: "DETERMINATION OF PRAVASTATIN SODIUM AND ITS MAJOR METABOLITES IN HUMAN SERUM-PLASMA BY CAPILLARY GAS CHROMATOGRAPHY-NEGATIVE ION CHEMICAL IONIZATION MASS SPECTROMETRY", BIOMEDICAL AND ENVIRONMENTAL MASS SPECTROMETRY, vol. 18, no. 10, 1989, pages 904 - 909, XP002477855, ISSN: 0887-6134 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2522806C1 (ru) * 2012-11-27 2014-07-20 Федеральное государственное бюджетное учреждение науки Центр "Биоинженерия" Российской академии наук Усовершенствованный способ очистки правастатина
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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