WO2009139730A1 - Fabrication de nouvelles formes non cristallines d'atorvastatine calcique - Google Patents

Fabrication de nouvelles formes non cristallines d'atorvastatine calcique Download PDF

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Publication number
WO2009139730A1
WO2009139730A1 PCT/TR2008/000050 TR2008000050W WO2009139730A1 WO 2009139730 A1 WO2009139730 A1 WO 2009139730A1 TR 2008000050 W TR2008000050 W TR 2008000050W WO 2009139730 A1 WO2009139730 A1 WO 2009139730A1
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WIPO (PCT)
Prior art keywords
atorvastatin calcium
ethyl acetate
water
ester
atorvastatin
Prior art date
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Ceased
Application number
PCT/TR2008/000050
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English (en)
Inventor
Tuncer Aslan
Yildiz Gulkok
Tuba Bicer
Selda Turhan
Melek Koroglu
Serdar Unlu
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
ULKAR KIMYA SAN VE TIC AS
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ULKAR KIMYA SAN VE TIC AS
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Priority to PCT/TR2008/000050 priority Critical patent/WO2009139730A1/fr
Publication of WO2009139730A1 publication Critical patent/WO2009139730A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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

Definitions

  • This invention relates to a process for producing novel non crystalline forms of Atorvastatin Calcium which is known by the chemical name [R-(R* ,R*)]-2-(4- Fluorophenyl) ⁇ , ⁇ -dihydroxy-5-(l-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl)-lH pyrrole- 1-heptanoic acid hemi calcium salt.
  • Atorvastatin Calcium is a drug that currently most therapeutically effective agent for reducing low density lipoprotein(LDL) particle concentration in the blood stream of patients at risk for cardiovascular diseases.
  • Atorvastatin works by inhibiting HMG-CoA reductase, an enzyme in the metabolic pathway for the synthesis of the cholesterol. This enzyme catalyses the conversion of HMG-CoA to mevalonate which is the rate determining step in the biosynthesis of cholesterol.
  • LDL low density lipoprotein
  • Atorvastatin Calcium and its intermediates are described in the US patents 5,003,080; 5,097,045; 5,103,024; 5,124,482; 5,149,837; 5,155,251; 5,216,174; 5,245,047; 5,248,793; 5,273,995; 5,280,126; 5,298,627; 5,342,952; 5,385,929; 5,397,792; European Patent 409,281; and WO 89/07598 which are incorporated here as references.
  • Non crystalline forms which may affect the stability and bioavailability of the API and dosage forms ⁇ Bryn S. R. Solid-State Chemistry of Drugs, Academic Press, New York 1982, page 79).
  • Amorphous Atorvastatin Calcium can be prepared following the US patents numbers 6,087,51 1 and 6,274,740. There are also many patent applications for the preparation of the amorphous Atorvastatin Calcium.
  • Atorvastatin Calcium WO 02/059087 Al reports a method of preparing a non crystalline form of Atorvastatin Calcium starting from an intermediate in the synthesis of the Atorvastatin.
  • Atorvastatin Calcium and their hydrates show stability problem due to the high surface area or high degree of hydration which can result formation of degradation product such as Atorvastatin lactone or oxidation products.
  • Atorvastatin Calcium As drug substance and drug product.
  • Atorvastatin calcium is prepared following the patent application no TR 2007 07566 and US patent no 5,273,995. This crude amorph form has solubility problem for example it is not soluble in methanol and due to the low solubility it has low cell up take which is also affects bioavailability. So it was necessary to find new non crystalline forms of Atorvastatin Calcium which must show a better solubility and cell up take.
  • Non crystalline forms of Atorvastatin Calcium in this invention are obtained in an ethyl acetate/water system which helps to get a pure product.
  • literature non crystalline forms of Atorvastatin Calcium were prepared by using different methods but never a binary system is used.
  • Amorph atorvastatin Calcium is precipitated, centrifuged and dried by using a Fluid Bed Drier (FBD).
  • Atorvastatin Calcium obtained this way contains 10,000 to 30,000 ppm ethyl acetate proved by Head-space GC and NMR). All attempts to drop residual solvent were unsuccessful. Even an effective system like FBD is not enough to drop the ethyl acetate below 5000 ppm.
  • Two different ways are possible to get non crystalline form of atovastatin calcium containing ethyl acetate less than 5000 ppm.
  • One of them is drying wet crude amorph Atorvastatin Calcium having methanol less than 2-3% and dissolving it in ethyl acetate then adding into water.
  • the ethyl acetate/water ratio must be around 1/5.8 respectively.
  • Second process is that taking directly crude wet amorph Atorvastatin Calcium and precipitating it in ethyl acetate/water then filtering and drying by using FBD.
  • This product contains around 7,000 to 30,000 ppm ethyl acetate and then suspending it into ethyl acetate/water in a ratio of x/x v/v and removing ethyl acetate under reduced pressure to get novel non-crystaline form of Atorvastatin Calcium after drying in FBD.
  • Atorvastatin Lactone One of the main problems with the non crystalline form of
  • Atorvastatin Calcium is its instability as a drug product also as a drug substance when compared with crystalline form I of Atorvastatin Calcium. According to present invention it is found that presence of ethyl acetate stabilizes non crystalline form of Atorvastatin Calcium. When amorph form of Atorvastatin Calcium which is prepared following US patent no 5,273,995 and non crystalline form of Atorvastin Calcium prepared in this invention are dried at 50-60 0 C under vacuum, Atorvastatin lacton impurity in
  • Atorvastatin Calcium which is prepared according to US patent no 5,273,995 is increases from 0.03% to to 0.8-1% but no increase of the impurity is observed in non crystalline form of Atorvastatin Calcium produced in this invention (lacton impurity is around
  • Fig 1 shows a representative X-ray diffractogram of amorphous form Atorvastatin Calcium produced following US patent no 5,298,627.
  • Fig 2 shows a representative X-ray diffractogram of solvated non crystaline form of Atorvastatin Calcium.
  • Fig 3 shows a representative X-ray diffractogram of novel non crystaline form of Atorvastatin Calcium which was obtained from solvated non crystaline form of Atorvastatin Calcium.
  • Fig 4 shows a representative X-ray diffractogram of novel non crystaline form of Atorvastatin Calcium
  • a Schmadzu RX ) X 6000 X-ray diffractometer is used for the measurements of X-ray diffractograms.
  • the scanning range was 2-40 degrees two-theta.
  • the samples were grounded before analysis.
  • Atorvastatin Calcium is prepared following the patent application no TR 2007 07566 and US patent no 5,273,995. As described in the experimental part Atorvastatin intermediate (4R-cis)-l,l-Dimethylethyl-6-[2-[-(4-fluorophenyl)-5-(l - isopropyl)-3 -phenyl-4-
  • Non crystalline forms of Atorvastatin Calcium can be obtained following two different processes from this crude wet product. According to first process, after suspension of the wet crude Atorvastatin Calcium into water, the product is taken and used directly in the next step without drying. Thus wet crude product is precipitated in a binary system of ethyl acetate/water, centrifuged and dried by using FBD. This product contains around 15,000-30,000 ppm ethyl acetate and has the following XRD diffractogram as shown in Figure 2.
  • a 2000 L GLR was charged with 137 kg methanol, 63 kg of aceton, 27.5 kg of water and 26.6 kg of (4R-cis)-l,l-Dimethylethyl-6-[2-[-(4-fluorophenyl)-5-(l-isopropyl)-3-phenyl- 4- [(phenylaminocarbonyl)- 1 H[pyrrol- 1 -yl]2,2-dimethylethyl- 1 ,3 -dixoane-4-acetate, namely diol protected tertiarybutyl ester of Atorvastatin at room temperature. To this suspension was added 2.84 kg (1 eqv.) of hydroxylamine hydrochloride.
  • the suspension was heated to 55-°65 C and became a clear solution. The mixture was stirred at this temperature for 35-45 minutes. TLC analysis showed that most of the starting material was converted to the corresponding acid and esters. Acetone and methanol was removed under reduced pressure. To the residue 137 kg of methanol and 6.5 kg of hydroxylamine hydrochloride was added. The solution was heated to 55-°65 0 C and stirred at this temperature for 15-30 minutes. TLC analysis showed that all the starting material was consumed. The solution was concentrated under reduced pressure. To the residue 246 kg of ethyl acetate and 267 kg of water was added and the phases were separated. The organic phase was washed with two times 267 kg of water.
  • the organic phase containing mixture of the compound of the formula (II) and (III) was concentrated under reduced pressure. To the residue 95 kg of methanol and NaOH solution ( 2 eqv. 3.28 kg NaOH was dissolved in 26.7 kg of water) were added. The mixture was stirred at 35-45 0 C for 30-40 minutes. TLC analysis showed that all the starting materials were converted into the sodium salt of Atorvastatin. A CaCl 2 solution (0.5 eqv., 3 kg of CaCl 2 " 2H 2 O dissolved in 26 kg of water) was added to the Atorvastatin sodium solution at 35-45 0 C. The solution was stirred for 10-30 minutes and filtered over 0.5 micron filter to remove any solid particles.
  • the XRD is given in Figure 3.
  • the suspension was heated to 60-65 0 C and became a clear solution. TLC analysis showed that most of the starting material was converted to the corresponding acid and esters. Acetone and methanol was removed under reduced pressure. To the residue 256.75 g of methanol and 12.25 g of hydroxylamine hydrochloride was added. The solution was heated to 60-°65 0 C . TLC analysis showed that all the starting material was consumed. The solution was concentrated under reduced pressure. To the residue 461.5 g of ethyl acetate and 50O g of water was added and the phases were separated. The organic phase was washed with three times 500 g of water. The organic phase containing mixture of the compound of the formula (II) and (III) was concentrated under reduced pressure.
  • the product was filtered and washed with a 80-100 ml mixture of methanol water (1 :1) and then washed with 100 g of water.
  • the wet product was dried and obtained 73 g as a white powder.
  • Atorvastatin calcium 1050 g of water was added.
  • the precipitation was completed in 1.0 - 1.5 hrs.
  • the suspension was filtered and dried at 50- 60 0 C for 12 -15 hrs and 33 g in 75 % yield non crystalline Atorvastatin Calcium having an ethyl acetate content 2908 ppm is obtained as a white powder.
  • the XRD is given in

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pyrrole Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention porte sur un procédé pour la fabrication de formes non cristallines d'atorvastatine calcique.
PCT/TR2008/000050 2008-05-13 2008-05-13 Fabrication de nouvelles formes non cristallines d'atorvastatine calcique Ceased WO2009139730A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
PCT/TR2008/000050 WO2009139730A1 (fr) 2008-05-13 2008-05-13 Fabrication de nouvelles formes non cristallines d'atorvastatine calcique

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/TR2008/000050 WO2009139730A1 (fr) 2008-05-13 2008-05-13 Fabrication de nouvelles formes non cristallines d'atorvastatine calcique

Publications (1)

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WO2009139730A1 true WO2009139730A1 (fr) 2009-11-19

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002059087A1 (fr) * 2001-01-23 2002-08-01 Lek Pharmaceutical And Chemical Company D.D. Preparation de calcium d'atorvastatine non cristallin
WO2002083638A1 (fr) * 2001-04-11 2002-10-24 Cadila Healthcare Limited Procede de production d'atorvastatine calcique sous forme amorphe
WO2003068739A1 (fr) * 2002-02-01 2003-08-21 Zentiva A.S. Procede de fabrication d'une forme amorphe du sel d'hemicalcium d'acide (3r, 5r) 7-[3-phenyl-4-phenylcarbamoyl-2-(4-fluorophenyl)-5-isopropyl-pyrrol-l-yl]-3, 5-dihydroxyheptanoique (atorvastatine)

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002059087A1 (fr) * 2001-01-23 2002-08-01 Lek Pharmaceutical And Chemical Company D.D. Preparation de calcium d'atorvastatine non cristallin
WO2002083638A1 (fr) * 2001-04-11 2002-10-24 Cadila Healthcare Limited Procede de production d'atorvastatine calcique sous forme amorphe
WO2003068739A1 (fr) * 2002-02-01 2003-08-21 Zentiva A.S. Procede de fabrication d'une forme amorphe du sel d'hemicalcium d'acide (3r, 5r) 7-[3-phenyl-4-phenylcarbamoyl-2-(4-fluorophenyl)-5-isopropyl-pyrrol-l-yl]-3, 5-dihydroxyheptanoique (atorvastatine)

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