WO2002083637A1 - Process for the production of amorphous atorvastatin calcium - Google Patents

Process for the production of amorphous atorvastatin calcium Download PDF

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Publication number
WO2002083637A1
WO2002083637A1 PCT/IN2001/000110 IN0100110W WO02083637A1 WO 2002083637 A1 WO2002083637 A1 WO 2002083637A1 IN 0100110 W IN0100110 W IN 0100110W WO 02083637 A1 WO02083637 A1 WO 02083637A1
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WIPO (PCT)
Prior art keywords
atorvastatin calcium
aqueous
calcium
employed
crude
Prior art date
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Ceased
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PCT/IN2001/000110
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English (en)
French (fr)
Inventor
Virendra Kumar Agarwal
Manish Harshadbhai Vakil
Kanwal Pandita
Nirogi Venakata Satya Ramakrishna
Pankaj Ramanbhai Patel
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Zydus Lifesciences Ltd
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Cadila Healthcare Ltd
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Publication date
Application filed by Cadila Healthcare Ltd filed Critical Cadila Healthcare Ltd
Publication of WO2002083637A1 publication Critical patent/WO2002083637A1/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • 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
    • 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

  • the present invention relates to a novel process for the production of atorvastatin calcium.
  • the present invention relates to a novel process for the production of amorphous atorvastatin calcium.
  • the present invention relates to a novel process for the production of amorphous atorvastatin calcium from a diol protected tert-butyl ester (a) BACKGROUND OF THE INVENTION
  • Atorvastatin is chemically [R-(R*,R*)]-2-(4-FLUOROPHENYL)- ⁇ , ⁇ - DIHYDROXY-5-(l-METHYLETHYL)-3-PHENYL-4-[(PHENYLAMINO) CARBONYL]-lH-PYRROLE-l-HEPTANOIC ACID.
  • Atorvastatin calcium a synthetic HMG-CoA reductase inhibitor, is used for the treatment of hyperlipidemia and hypercholesterolemia, both of which are risk factors for arteriosclerosis and coronary heart disease. Open dihydroxy carboxylic acid, lactone and various salt forms of atorvastatin have been synthesized.
  • R-form of the ring opened acid form has surprising inhibition of the biosynthesis of cholesterol.
  • Atorvastatin in its calcium salt form i.e. [R-(R*,R*)]-2-(4-fluorophenyl)- ⁇ , ⁇ -dihydroxy-5-(l-methylethyl)-3-phenyl-4- [(phenylamino)carbonyl]-lH-pyrrole-l-he ⁇ tanoic acid calcium salt (2:1) having formula 1:
  • Atorvastatin is, preferably, prepared as its calcium salt, i.e. [R-(R*,R*)]-2-
  • PCT appUcation, WO 97/03958 and WO 97/03959 disclose novel crystalline forms of atorvastatin calcium designated as Form I, Form II, Form III and Form IV and method for their preparation which provide more favorable filtration and drying characteristics.
  • PCT application, WO 97/03960 and US Patent 6087511 describe the procedures for converting the crystaUine form of atorvastatin calcium to the amorphous form. The process disclosed therein involve dissolving form I atorvastatin calcium in a non hydroxylic solvent Uke tetrahydrofuran or a mixture of tetrahydrofuran and toluene.
  • an object of the present invention to provide a process for the preparation of amorphous atorvastatin calcium which avoids aU the disadvantages of the prior art
  • the present invention discloses a novel process for the preparation of amorphous atorvastatin calcium from the above mentioned intermediate (a) on commercial scale, while in earlier prior arts, crystaUine form - I of atorvastatin calcium is employed for the preparation of amorphous atorvastatin calcium.
  • the present invention also discloses a novel process of converting form - I of atorvastatin calcium into amorphous form, which is suitable for converting all the crystalline forms of atorvastatin calcium in to amorphous form on commercial scale.
  • the process of the present invention eUminates the problems of prior arts.
  • the present invention also discloses for the first time a process of manufacturing amorphous atorvastatin calcium directly from diol protected tertbutyl ester (a).
  • the crude stage may contain some amount of calcium hydroxide which is easily removed completely in the subsequent purification stage.
  • atorvastatin calcium prepared by the process of the present invention was found to be amorphous as revealed by X-ray powder diffraction data (figure -1 & 2).
  • the present invention does not make use of any crystalline form to get amorphous atorvastatin calcium like other prior arts.
  • the crude amorphous atorvastatin calcium so obtained contains some amount of calcium hydroxide formed during the reaction of calcium chloride with free sodium hydroxide present in the reaction mixture.
  • the crude material is purified by dissolving it in methanol (10% w/v) giving opalescence due to calcium hydroxide.
  • the crude material is dissolved in methanol at 30 - 35 °C (10% w/v) and treated with activated carbon and filtered through hyflow bed over nutsch filter.
  • the clear solution thus obtained is again filtered through 5-micron candle filter to get absolutely clear and transparent methanolic solution of atorvastatin calcium. This solution is added slowly to fine filtered D.M.
  • the aqueous acid is selected from hydrochloric acid , sulphuric acid , and formic acid; aqueous hydrochloric acid is being most preferred.
  • the aqueous hydroxide solution is selected from sodium hydroxide, potassium hydroxide, and lithium hydroxide. In a most preferred embodiment, aqueous sodium hydroxide is employed.
  • the crude salt as well as the purified products are isolated by filtration and then dried.
  • the diol protected tert-butyl ester of the structure (a) is treated with 20 - 40 times w/v methanol. More preferably, the amount of methanol employed is 28 times w/v.
  • the HC1 employed is preferably 2 -6% aqueous w/v, more preferably 4% w/v in a molar ratio of 1.5 - 4, preferably 2.0.
  • the reaction temperature is preferably maintained at a range of from 20-40°C preferably, 30 -35°C for 8 - 20 hours preferably for 15 hours.
  • the dilute aqueous sodium hydroxide solution employed ranges from 5 - 20% w/v, preferably 10% w/v in molar ratio of 1 - 1.5, more preferably, 1.35, (after calculating the amount of sodium hydroxide required for neutraUzation of hydrochloric acid present in the reaction mixture).
  • the reaction mass is stirred for 2 - 6 hours, preferably, for 5 hours
  • the pH of the reaction mixture is preferably maintained 7.0 - 9.5, more preferably 8.5 by addition of 4% w/v aqueous hydrochloric acid. In preferred embodiment, pH is always maintained at a level > 7.0.
  • the aqueous calcium chloride solution is preferably employed in the range of 2 - 6% w/v preferably 4 - 5 % in the molar ratio of 1 - 2, more preferably 1.65.
  • the reaction temperature is maintained at a temperature in the range of 50 - 55°C for 15 - 60 minutes preferably for 60 minutes.
  • the precipitated material is preferably cooled to 25 - 40°C, more preferably to 30 - 35°C, which is further cooled to 0 - 20°C preferably, to 10 -
  • the stirring is continued for 30 - 120 minutes preferably, for 60 minutes at 10 - 15°C
  • the material is centrifuged easily and is preferably washed with D.M. Water to remove excess calcium chloride.
  • the present invention describes the method of converting diol protected tert-butyl ester (a) of atorvastatin directly into crude amorphous atorvastatin calcium which contains some amount of calcium hydroxide which is removed in subsequent purification step.
  • the whole process consists of following key operations
  • HPLC analysis also shows formation of 4 intermediates (b,c,d and e) as shown in scheme - 1 with distribution pattern as follows. This is an illustrative pattern. The percentage and distribution may vary depending on the reaction conditions, (i) atorvastatin diol tert-butyl ester (b) - 72.00% (ii) atorvastatin diol methyl ester (c) - 21.16%
  • pH of the reaction mixture is adjusted between 7.0 - 9.5, preferably 8.5 by addition of 4% w/v aqueous hydrochloric acid, pH lower than 7.0 results in the formation of lactone compound (d) in the final product, this also results in the decrease of the calcium content below the required amount i.e. 3.50 % w/w on dry basis.
  • the volume of the reaction mixture is then adjusted so that it contains 5 -15 times, preferably 10 times methanol and 5 - 10 times, preferably 7 times water with respect to diol protected tert-butyl ester (a) initially taken.
  • reaction mixture is then washed with 5 - 15 times preferably 10 times as that of diol protected tert-butyl ester (a) taken for reaction with organic solvents insoluble in water such as toluene, xylene, dnsopropyl ether, diethyl ether, dichloromethane preferably diisopropyl ether to remove starting material i.e. unreacted diol protected tert-butyl ester (a) from the reaction mixture.
  • organic solvents insoluble in water such as toluene, xylene, dnsopropyl ether, diethyl ether, dichloromethane preferably diisopropyl ether to remove starting material i.e. unreacted diol protected tert-butyl ester (a) from the reaction mixture.
  • Aqueous methanolic layer after extraction with diisopropyl ether is charged into another S.S.Reactor, finaUy pH is checked and if necessary, is adjusted to 8.5, the reaction mixture is heated to 40 - 60°C preferably to 50 - 55°C.
  • Aqueous calcium chloride solution in the range of 2 - 6% w/v preferably 4 - 5% in the molar ratio of 1 - 2 preferably 1.65 is added during 30 - 90 minutes preferably 60 minutes at 50 - 55°C with the smooth and uniform precipitation of atorvastatin calcium. If mode of addition is reversed, a sticky material is obtained under similar condition of operations.
  • the precipitated material is stirred at 50 - 55°C for 15 - 60 minutes preferably for 60 minutes.
  • the precipitated material is cooled to 25 - 40°C preferably to 30 - 35°C, which is further cooled to 0 - 20°C preferably to 10 - 15°C. 12) The stirring is continued for 30 - 120 minutes preferably for 60 minutes at 10 - 15°C 13) The material is centrifuged easily and is washed with D.M. Water to remove excess calcium chloride.
  • Crude amorphous atorvastatin calcium is dissolved in methanol at 30 - 60°C preferably at 30 - 35°C in 5 - 15 times in volume preferably 7 times in volume as that of crude atorvastatin calcium and treated with activated carbon 2 - 10% w/w preferably 5% w/w at 30 - 35°C for 15 - 60 minutes preferably for 30 minutes.
  • Methanolic solution of atorvastatin calcium is then filtered through hyflow bed contained in a nutsche filter under vacuum and the bed is washed with fresh methanol.
  • methanolic atorvastatin calcium is adjusted to 8 - 12 times in volume preferably 10 times in volume as that of crude atorvastatin calcium by addition of fine filtered methanol.
  • D.M.Water is charged 1 - 3 times preferably 2 times in volume as that of methanolic solution of atorvastatin calcium through 5 micron candle filter which is heated to 40 - 60°C preferably to 50- 55°C.
  • Methanolic solution of atorvastatin calcium is added slowly during 15 - 60 minutes preferably in 30 minutes at 50 - 55°C with free flowing and uniform formation of amorphous atorvastatin calcium in the reactor.
  • the precipitated material is stirred at 50 - 55°C for 10 - 40 minutes preferably for 20 - 30 minutes.
  • the precipitated material is cooled to 25 - 40°C preferably to 30 - 35°C which is further cooled to 0 - 20°C preferably to 10 - 15°C.
  • Crystalline forms of atorvastatin calcium are conveniently converted into amorphous atorvastatin calcium using purification procedures disclosed herein exemplified by conversion of form - I of atorvastatin calcium in to amorphous atorvastatin calcium.
  • the process disclosed herein employs only one solvent in the manufacturing process i.e methanol that can be easily recovered, and recycled.
  • the process disclosed herein produces amorphous product consistently on commercial scale with allowable Umits of residual solvent (methanol ⁇ 500 - 1000 ppm)
  • the process disclosed herein is carried out by using relatively safer solvent (methanol) with flash point of +11°C. 11.
  • methanol relatively safer solvent
  • the process disclosed herein gives amorphous form directly without interconversion of any crystalUne form into amorphous form.
  • Figure 1 depicts X-ray powder diffractogram of amorphous atorvastatin calcium crude. The horizontal axis presents 2 ⁇ and the vertical axis corresponds to peak intensity.
  • Figure 2 shows X-ray powder diffractogram of amorphous atorvastatin calcium pure. The horizontal axis presents 2 ⁇ and the vertical axis corresponds to peak intensity.
  • Figure 3 shows X-ray powder diffractogram of form - I of atorvastatin calcium.
  • the horizontal axis presents 2 ⁇ and the vertical axis corresponds to peak intensity.
  • Figure 4 illustratesX-ray powder diffractogram of amorphous atorvastatin calcium prepared by converting form - I of atorvastatin calcium.
  • the horizontal axis presents 2 ⁇ and the vertical axis corresponds to peak intensity.
  • Scheme 1 describes Schematic representation and distribution of the intermediates formed during the treatment of methanolic solution of diol protected tert-butyl ester (a) with dilute hydrochloric acid and subsequent conversion of aU the intermediates into a single product atorvastatin sodium and then to atorvastatin calcium.
  • Example 1 [R-(R*,R*)]-2-(4-fluorophenyl)- ⁇ / ⁇ -dihydroxy-5-(l-methylethyl)-3-phenyl-4- [(phenylamino) carbonyl]-lH pyrrole-1-heptanoic acid hemicalcium salt (Crude amorphous atorvastatin calcium).
  • 20 Kg. of diol protected tert-butyl ester (a) is suspended in 560 It. methanol in GLR and treated with 55 It. of 4% aqueous w/v hydrochloric acid for 15 hours at 30 - 35°C then a solution of 4 Kg. sodium hydroxide in 40 It.
  • reaction mixture is added in 1 hour and stirring is continued for 5 hours.
  • the pH of reaction mixture is adjusted to 8.5 by addition of 1 It. of 4% w/v aqueous hydrochloric acid.
  • the volume of the reaction mixture is reduced to approximately 50% by distiUing below 60°C under vacuum (distiUed volume 270 - 275 It), the analysis of the contents left behind in the reactor shows water content to be 83 It. and methanol content to be 178 It. Then 23 It. methanol and 57 It. water are added to the reaction mixture, reaction mixture is washed with 200 It. of diisopropylether.
  • Aqueous methanolic solution containing atorvastatin sodium is charged into another S.S.Reactor and finaUy pH is checked and if necessary adjusted to 8.5 and the contents are heated to 50 - 55°C to which a aqueous solution of 2.8 Kg. calcium chloride in 60 It. water is added in 1 hour at 50 - 55°C with the precipitation of atorvastatin calcium, the precipitated mass is stirred for 1 hr at 50 - 55°C which is cooled to 30 - 35°C (within 60 minutes), then cooled to 10 - 15°C (within 60 minutes), the precipitated material is further stirred for 1 hr at 10 - 15°C .
  • the example disclosed herein is a purification stage in which calcium hydroxide in atorvastatin calcium is being removed.
  • D.M.Water is taken through 5 micron candle filter and heated to 50 - 55°C, filtered methanolic solution of atorvastatin calcium is added in 30 minutes at 50 - 55°C in the reactor containing water with precipitation of pure atorvastatin calcium, which is stirred for another 20 minutes, at 50 - 55°C, the contents in reactor are cooled to 30 - 35°C (within 90 minutes) then cooled to 10 - 15°C (within 2 hours), the precipitated material is further stirred at 10 - 15°C for 1 hour. Pure amorphous atorvastatin calcium is centrifuged and washed with 40 lt D.M.Water.
  • Example 3 The example disclosed herein is a convenient procedure to convert crystalline forms of atorvastatin calcium in to amorphous atorvastatin calcium, exemplified here by converting form - I of atorvastatin calcium in to amorphous form.
  • 20 gm atorvastatin calcium form - I (figure 3) is dissolved in 160 ml methanol at 45 - 50°C and then is treated with 2 gm activated carbon for 15 minutes at 45 - 50°C. the solution is cooled to 25 -35°C and is filtered through hyflow bed with 2 x 20 ml methanol wash. The volume of filtrate is adjusted to 200 ml by addition of fresh methanol.
  • the precipitated material is cooled to 30 - 35°C then to 10 - 15°C stirring is continued for 1 hr at 10 -15°C
  • the material is filtered and washed with 2 x 50 ml of D.M.Water, dried at 50 -60°C for 8 hours till the water content 4 - 6 % is achieved, giving 18.0 gm dried atorvastatin calcium.
  • X-ray powder diffraction data suggests the material to be amorphous (figure 4)

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pyrrole Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
PCT/IN2001/000110 2001-04-11 2001-06-13 Process for the production of amorphous atorvastatin calcium Ceased WO2002083637A1 (en)

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WO2005005384A1 (en) * 2003-07-15 2005-01-20 Eos Eczacibasi Ozgun Kimyasal Urunler Sanyi Ve Ticaret A.S. Process for the preparation of amortphous atorvastatin calcium without interconversion of any crystalline form
EP1577297A1 (en) * 2004-03-17 2005-09-21 Ranbaxy Laboratories, Ltd. Process for the production of atorvastatin calcium in amorphous form
US6992194B2 (en) 2000-11-30 2006-01-31 Teva Pharmaceutical Industries, Ltd. Crystal forms of atorvastatin hemi-calcium and processes for their preparation as well as novel processes for preparing other forms
WO2006046109A1 (en) * 2004-10-28 2006-05-04 Warner-Lambert Company Llc Process for forming amorphous atorvastatin
WO2006048888A1 (en) * 2004-11-01 2006-05-11 Jubilant Organosys Limited Novel process for the preparation of amorphous atorvastatin calcium salt
WO2006087404A1 (es) * 2005-02-16 2006-08-24 Ercros Industrial, S.A. Cristalización tras dejar enfriaratorv ast atina calcica amorfa estabilizada y procedimiento para su obtención
US7122681B2 (en) 2002-02-19 2006-10-17 Teva Pharmaceutical Industries, Ltd. Desolvation process for the production of atorvastatin hemi-calcium essentially free of bound organic solvent
US7144915B2 (en) 2001-06-29 2006-12-05 Warner-Lambert Company, Llc Crystalline forms of [R-(R*,R*)]-2-(4-fluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid calcium salt (2:1)
ES2270722A1 (es) * 2005-09-15 2007-04-01 Ercros Industrial, S.A. Procedimiento para la obtencion de atorvastatina calcica amorfa.
US7208608B2 (en) * 2002-02-01 2007-04-24 Zentiva A. S. Method of manufacturing an amorphous form of the hemi-calcium salt of (3R,5R) 7-3-phenyl-4-phenylcarbamoyl-2-(4-fluorophenyl)-5-isopropyl-pyrrol-1-yll-3, 5-dihydroxyheptanoic acid (actorvastatin)
WO2007057755A1 (en) 2005-11-21 2007-05-24 Warner-Lambert Company Llc Novel forms of [r-(r*,r*)]-2-(4-fluorophenyl)-b,b-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1h-pyrrole-1-hept anoic acid magnesium
EP1793815A2 (en) 2004-09-30 2007-06-13 Dr. Reddy's Laboratories Ltd. Amorphous atorvastatin calcium
WO2007061849A3 (en) * 2005-11-23 2008-01-31 Merck & Co Inc Method of generating amorphous solid for water-insoluble pharmaceuticals
US7411075B1 (en) 2000-11-16 2008-08-12 Teva Pharmaceutical Industries Ltd. Polymorphic form of atorvastatin calcium
EP1977738A1 (en) 2003-06-12 2008-10-08 Warner-Lambert Company LLC Pharmaceutical compositions comprising atorvastatin manufactured without granulation
US7501450B2 (en) 2000-11-30 2009-03-10 Teva Pharaceutical Industries Ltd. Crystal forms of atorvastatin hemi-calcium and processes for their preparation as well as novel processes for preparing other forms
US7511140B2 (en) 2002-08-13 2009-03-31 Astrazeneca Ab Process for preparing the calcium salt of rosuvastatin
US7534810B2 (en) 2004-05-05 2009-05-19 Pfizer Inc. Salt forms of [R—(R*,R*)]-2-(4-fluorophenyl)-β, δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid
WO2009007856A3 (en) * 2007-07-11 2009-06-25 Actavis Group Ptc Ehf Novel polymorph of atorvastatin calcium and use thereof for the preparation of amorphous atorvastatin calcium
EP2075246A1 (en) 2007-12-27 2009-07-01 M. J. Institute of Research A process for preparation of amorphous form of atorvastatin hemi-calcium salt
US7655692B2 (en) 2003-06-12 2010-02-02 Pfizer Inc. Process for forming amorphous atorvastatin
US7790197B2 (en) 2003-06-09 2010-09-07 Warner-Lambert Company Llc Pharmaceutical compositions of atorvastatin
US8026376B2 (en) 2004-07-20 2011-09-27 Pfizer, Inc. Forms of [R-(R*,R*)]-2-(4-fluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoicacid calcium salt (2:1)
US8063213B2 (en) 2003-06-05 2011-11-22 Astrazeneca Uk Limited Production of rosuvastatin calcium salt
US8436167B2 (en) 2003-09-10 2013-05-07 Astrazeneca Uk Limited Chemical compounds
US9034913B2 (en) 2005-09-21 2015-05-19 Pfizer Inc. Process for annealing amorphous atorvastatin
US9371291B2 (en) 2003-10-24 2016-06-21 Astrazeneca Uk Limited Process for the manufacture of the calcium salt of rosuvastatin (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]-pyrimidin-5-yl](3R,5S)-3,5-Dihydroxyhept-6-enoic acid and crystalline intermediates thereof
CN113321607A (zh) * 2020-02-28 2021-08-31 北京福元医药股份有限公司沧州分公司 一种阿托伐他汀钙中间体的纯化方法

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WO2007052296A2 (en) * 2005-08-23 2007-05-10 Kopran Research Laboratories Ltd A process of preparing amorphous atorvastatin calcium
WO2009082362A1 (en) * 2007-11-05 2009-07-02 Ulkar Kimya San. Ve Tic. A.S. A method for producing statins in pure form
WO2009090544A2 (en) * 2008-01-16 2009-07-23 Matrix Laboratories Limited Process for producing amorphous atorvastatin calcium
WO2009139730A1 (en) * 2008-05-13 2009-11-19 Ulkar Kimya San. Ve Tic. A.S. Preparation of novel non-crystalline forms of atorvastatin calcium
CN114213270B (zh) * 2021-12-17 2024-05-28 江苏阿尔法药业股份有限公司 一种利用连续流微通道反应器合成阿托伐他汀钙中间体的方法

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