WO2011027324A1 - Formes polymorphes du sulfate d'atazanavir - Google Patents

Formes polymorphes du sulfate d'atazanavir Download PDF

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Publication number
WO2011027324A1
WO2011027324A1 PCT/IB2010/053964 IB2010053964W WO2011027324A1 WO 2011027324 A1 WO2011027324 A1 WO 2011027324A1 IB 2010053964 W IB2010053964 W IB 2010053964W WO 2011027324 A1 WO2011027324 A1 WO 2011027324A1
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Prior art keywords
atazanavir sulfate
crystalline form
ray powder
powder diffraction
atazanavir
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PCT/IB2010/053964
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English (en)
Inventor
Somenath Ganguly
Rita Santhakumar
T. G. Chandrashekhar
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Ranbaxy Laboratories Limited
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Publication of WO2011027324A1 publication Critical patent/WO2011027324A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • C07D213/42—Radicals substituted by singly-bound nitrogen atoms having hetero atoms attached to the substituent nitrogen atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV

Definitions

  • the present invention relates to polymorphic Forms B and P of atazanavir sulfate and methods for their preparation.
  • the present invention is also directed towards pharmaceutical compositions comprising the novel polymorphs of atazanavir sulfate and methods of treating HIV infection by administering to a patient in need thereof a therapeutically effective amount of the polymorphic Forms B and P of atazanavir sulfate.
  • the present invention also describes process for preparation of amorphous atazanavir sulfate.
  • Atazanavir sulfate is marketed in the United States under the proprietary name of Reyataz ® as a capsule dosage form equivalent to 100/150/200/300 mg by Bristol- Myers Squibb.
  • the chemical name for atazanavir sulfate is (35 , ,85',95 , ,125 , )-3,12-Bis(l,l- dimethylethyl)-8-hydroxy-4,l l-dioxo-9-(phenylmethyl)-6-[[4-(2- pyridinyl)phenyl]methyl]-2,5,6,10,13-pentaazatetradecanedioic acid dimethyl ester, sulfate (1:1).
  • Atazanavir sulfate is represented by following chemical formula:
  • Atazanavir sulfate is an inhibitor of retroviral aspartate protease and is also known to have a high degree of inhibitory activity against the HIV virus.
  • U.S. Patent No. 5,849,911 (hereinafter designated as the '911 patent) describes a series of azapeptide HIV protease inhibitors including atazanavir.
  • atazanavir having melting point of 206°C to 209°C is obtained by either crystallization from ethanol/water or precipitation with ether from methylene chloride solution of the compound.
  • atazanavir methane sulfonate is precipitated with ether from methylene chloride solution thereof followed by drying under reduced pressure; whereas atazanavir hydrochloride is precipitated by mixing dioxane solution of atazanavir with dioxane solution of hydrochloride.
  • Atazanavir sulfate is not prepared in the '911 patent.
  • U.S. Patent No. 6,087,383 (hereinafter referred to as '383 patent) describes the preparation of crystalline atazanavir sulfate in the form of Type-II crystals, which are hydrated hygroscopic and Type-I crystals, which are anhydrous/desolvated crystalline form.
  • the '383 patent discloses the preparation of Type-I crystals by crystallizing atazanavir sulfate with acetonitrile, ethanol-heptane or acetone. Type-II crystals are obtained from isopropanol crystallization.
  • U.S. Patent application 2005/0256202 (hereinafter designated as the '202 application) describes atazanavir bisulfate pattern C and Form E3 along with processes for the preparation thereof.
  • the partially crystalline pattern C is prepared by wet granulation of atazanavir sulfate or by exposing atazanavir sulfate to high relative humidity, greater than 95% for at least 24 hours.
  • the crystalline Form E3 is triethanolate of atazanavir bisulfate.
  • This patent application nominates the Type-I crystals of the U.S. Patent '383 patent as Form A.
  • IP.com Journal, 7(9 A), p. 5 (2007), (No. IPCOM000157245D) and Indian Application No. 1881/DEL/2006 describe a process for the preparation of the amorphous form of atazanavir sulfate.
  • Polymorphism is one such parameter. From a regulatory point of view there is an increasing demand on establishing the polymorphic characteristics, integrity and stability of a drug. Polymorphism is commonly defined as the ability of any substance to have two or more different crystal structures. Drug substances may also encapsulate solvent molecules when crystallized. These solvates or hydrates are referred to as pseudo polymorphs. In some cases, it is also possible that the amorphous form is the most desirable form.
  • Different polymorphs, pseudo polymorphs or the amorphous form differ in their physical properties such as melting point, solubility, etc. These can appreciably influence pharmaceutical properties such as dissolution rate and bioavailability. It is also economically desirable that the product is stable for extended periods of time without the need for specialized storage conditions. It is therefore important to evaluate
  • the present invention provides for crystalline polymorphic Form B of atazanavir sulfate.
  • Embodiments of this aspect may include one or more of the following features.
  • the crystalline Form B may include an X-ray powder diffraction peak at about 18.72+ 0.2° 2 ⁇ .
  • the crystalline Form B may also include X-ray powder diffraction peaks at about 3.06, 9.17, 18.25, 21.33 and 21.82 + 0.2° 2 ⁇ .
  • the crystalline Form B may further include X-ray powder diffraction peaks at about 6.11, 9.96, 12.21, 13.23, 19.30, 22.66, 23.77, 24.36, 25.37 and 27.06 + 0.2° 2 ⁇ .
  • the crystalline Form B may include an X-ray powder diffraction peak having d- value (d-spacing) at about 4.739 + 0.
  • the crystalline Form B may further include X- ray powder diffraction peaks having d-value (d-spacing) at about 28.820, 9.635, 4.859, 4.163 and 4.072 + 0.2A.
  • the crystalline Form B may also include X-ray powder diffraction peaks having d-value (d-spacing) at about 14.452, 8.880, 7.243, 6.688, 4.598, 3.923, 3.742, 3.652, 3.509 and 3.294 + O.2A.
  • Crystalline Form B is characterized by X-ray powder diffraction (XRPD) pattern substantially as depicted in Figure 1.
  • the crystalline Form B may also be characterized by DSC thermogram substantially as depicted in Figure 2; wherein an endothermic peak is present at about 194°C.
  • the present invention provides for crystalline
  • the crystalline Form P may include an X-ray powder diffraction peak at about 3.87 + 0.2° 2 ⁇ .
  • the crystalline Form P may further include X-ray powder diffraction peak at about 20.23 + 0.2° 2 ⁇ .
  • the crystalline Form P may also include X-ray powder diffraction peaks at about 18.03 and 18.47 + 0.2° 2 ⁇ .
  • the crystalline Form P may include X-ray powder diffraction peaks at about 7.76, 11.67, 12.77, 13.73, 14.22, 19.12, 21.17, 22.03, 22.69, 23.56 and 24.55 + 0.2° 2 ⁇ .
  • the crystalline Form P may be characterized by an X-ray powder diffraction peak having d-value (d-spacing) at about 22.785 + 0.
  • the crystalline Form P may further include an X-ray powder diffraction peak having d-value (d-spacing) at about 4.388 + 0.2A.
  • the crystalline Form P may also include X-ray powder diffraction peaks having d- value (d-spacing) at about 4.917 and 4.802 + O.2A.
  • the crystalline Form P may include X-ray powder diffraction peaks having d-value (d-spacing) at about 11.380, 7.582, 6.928, 6.449, 6.227, 4.641, 4.195, 4.033, 3.917, 3.775 and 3.624 + 0.2A.
  • the crystalline Form P is characterized by X-ray powder diffraction (XRPD) pattern substantially as depicted in Figure 4.
  • XRPD X-ray powder diffraction
  • the crystalline Form P may also be characterized by DSC thermogram substantially as depicted in Figure 5; wherein an endothermic peak is present at about 169°C.
  • the present invention provides for a process for the preparation of crystalline polymorphic Form B of atazanavir sulfate.
  • the process includes evaporating a solvent from the solution of atazanavir sulfate.
  • Embodiments of this aspect may include one or more of the following features.
  • the evaporation of solvent is performed under vacuum at about 45 °C to about 55°C.
  • the solvent used may be n-butanol.
  • the solution of atazanavir sulfate is prepared by refluxing atazanavir sulfate in n-butanol.
  • the present invention provides for a process for the preparation of crystalline polymorphic Form P of atazanavir sulfate.
  • the process includes evaporating a solvent from the solution of atazanavir sulfate.
  • Embodiments of this general aspect may include one or more of the following features.
  • the evaporation of solvent may be performed under vacuum at about 35°C to about 45°C and the solvent may be n-propanol.
  • the solution of atazanavir sulfate is prepared by dissolving atazanavir sulfate in n-propanol.
  • the present invention provides for a pharmaceutical composition that includes crystalline Form B and/or Form P of atazanavir sulfate or mixtures thereof.
  • the present invention provides for a method of treating HIV infection.
  • the method includes administering to a patient in need thereof a therapeutically effective amount of crystalline Form B and/or Form P of atazanavir sulfate or mixtures thereof
  • Figure 1 depicts the X-ray powder diffractograms (XRPD) of Form B of atazanavir sulfate.
  • FIG. 1 depicts the Differential Scanning Calorimetric (DSC) thermogram of
  • Figure 3 depicts the Infra-red spectrum (IR) of Form B of atazanavir sulfate.
  • Figure 4 depicts the XRPD of Form P of atazanavir sulfate.
  • Figure 5 depicts the DSC of Form P of atazanavir sulfate.
  • Figure 6 depicts the Infra-red spectrum (IR) of Form P of atazanavir sulfate.
  • Figure 7 depicts the XRPD of amorphous Form of atazanavir sulfate.
  • Figure 8 depicts the DSC of amorphous Form of atazanavir sulfate.
  • Figure 9 depicts the Infra-red spectrum (IR) of amorphous Form of atazanavir sulfate.
  • 'atazanavir sulfate' refers to atazanavir sulfate as well as atazanavir bisulfate.
  • a first aspect of the present invention provides crystalline form of atazanavir sulfate, herein designated as Form B, which comprises X-ray powder diffraction peak with 100% relative intensity at about 18.72 + 0.2° 2 ⁇ .
  • the crystalline Form B further includes X-ray powder diffraction peaks at about 3.06, 9.17, 18.25, 21.33 and 21.82 + 0.2° 2 ⁇ .
  • the crystalline Form B may further include X-ray powder diffraction peaks at about 6.11, 9.96, 12.21, 13.23, 19.30, 22.66, 23.77, 24.36, 25.37 and 27.06 + 0.2° 2 ⁇ .
  • the crystalline Form B further may be characterized through X-ray powder diffraction peaks having a d-value (d-spacing) at about 4.739 + 0.2 ⁇ , about 28.820, 9.635, 4.859, 4.163 and 4.072 + 0.2i.
  • the crystalline Form B may either be characterized through X-ray powder diffraction peaks having d-values (d-spacing) at about 14.452, 8.880, 7.243, 6.688, 4.598, 3.923, 3.742, 3.652, 3.509 and 3.294 + 0.2i.
  • Crystalline Form B of atazanavir sulfate is characterized by X-ray powder diffraction (XRPD) pattern substantially as shown in Figure 1.
  • Crystalline Form B of atazanavir sulfate exhibits an X-ray powder diffraction pattern with peaks expressed in 2 ⁇ angle, d-values (A) and relative intensity (%) as given in Table 1.
  • the crystalline Form B can be characterized by DSC thermogram comprising endothermic peak at about 194°C with an onset at about 180°C.
  • Crystalline Form B of atazanavir sulfate is characterized by DSC thermogram substantially as shown in Figure 2.
  • Crystalline Form B of atazanavir sulfate is also characterized by IR pattern substantially as shown in Figure 3.
  • a second aspect of the present invention provides crystalline Form of atazanavir sulfate, herein designated as Form P, which comprises X-ray powder diffraction peak with 100% relative intensity at about 3.87 + 0.2° 2 ⁇ .
  • the crystalline Form P includes X-ray powder diffraction peak at about 20.23 + 0.2° 2 ⁇ and, 18.03 and 18.47 + 0.2° 2 ⁇ .
  • the crystalline Form P may further include X-ray powder diffraction peaks at about 7.76, 11.67, 12.77, 13.73, 14.22, 19.12, 21.17, 22.03, 22.69, 23.56 and 24.55 + 0.2° 2 ⁇ .
  • the crystalline Form P includes X-ray powder diffraction peak having d-value (d- spacing) at about 22.785 + 0.2A.
  • the crystalline Form P may further include X-ray powder diffraction peak having d-value (d-spacing) at about 4.388 + 0.2A, about 4.917 and 4.802 + 0.2A, about 11.380, 7.582, 6.928, 6.449, 6.227, 4.641, 4.195, 4.033, 3.917, 3.775 and 3.624 + 0.2i.
  • Crystalline Form P of atazanavir sulfate is characterized by X-ray powder diffraction (XRPD) pattern substantially as shown in Figure 4.
  • Crystalline Form P of atazanavir sulfate exhibits an X-ray powder diffraction pattern with peaks expressed in 2 ⁇ angle, d-values (A) and relative intensity (%) as given in Table 2.
  • the crystalline Form P can be characterized by DSC thermogram comprising endothermic peak at about 169°C with an onset at about 163°C.
  • Crystalline Form P of atazanavir sulfate is characterized by DSC thermogram substantially as shown in Figure 5.
  • Crystalline Form P of atazanavir sulfate is characterized by IR pattern substantially as shown in Figure 6.
  • a third aspect of the present invention provides a process for preparation of crystalline Form B of atazanavir sulfate; the process includes evaporating solvent from the solution of atazanavir sulfate.
  • the solvent can be n-butanol.
  • the evaporation of solvent can be performed under vacuum at about 45°C to about 55°C.
  • the solution of atazanavir sulfate can be prepared by refluxing atazanavir sulfate in n-butanol.
  • Atazanavir sulfate can be refluxed at about 90°C in n-butanol for about 10 minutes to obtain the solution of atazanavir sulfate.
  • Atazanavir sulfate is refluxed at about 90°C in n-butanol for about 10 minutes followed by complete evaporation of n-butanol under vacuum at about 45 °C to about 55°C to obtain the crystalline Form B.
  • the Form B of atazanavir sulfate can be characterized by its XRPD ( Figure 1), DSC ( Figure 2) and IR ( Figure 3).
  • a fourth aspect of the present invention provides a process for preparation of crystalline Form P of atazanavir sulfate comprising evaporating solvent from the solution of atazanavir sulfate.
  • the solvent can be n-propanol.
  • the evaporation of solvent can be performed under vacuum at about 35°C to about 45°C.
  • the solution of atazanavir sulfate can be prepared by dissolving atazanavir sulfate in n-propanol through heating over a water-bath at a temperature of about 75°C to about 95°C.
  • the solution can optionally be cooled to about 5°C to about 10°C before subjecting to solvent evaporation.
  • Atazanavir sulfate is dissolved in n-propanol through heating in water-bath at a water-bath temperature of about 75°C to about 95 °C and the resultant solution is cooled to about 5°C to about 10°C followed by evaporation of n-propanol under vacuum at about 35°C to about 45°C to obtain the crystalline Form P.
  • the Form P of atazanavir sulfate can be characterized by its XRPD ( Figure 4), DSC ( Figure 5) and IR ( Figure 6).
  • a fifth aspect of the present invention provides a process for preparation of amorphous atazanavir sulfate comprising evaporating solvent from the solution of atazanavir sulfate.
  • the solvent can be n-butanol.
  • the evaporation of solvent can be performed under vacuum at about 65°C to about 75°C.
  • the solution of atazanavir sulfate can be prepared by refluxing atazanavir sulfate in n-butanol.
  • the atazanavir sulfate can be refluxed at a temperature of from about 120°C in n-butanol for about 20 minutes to obtain the solution of atazanavir sulfate.
  • the solution can optionally be cooled to about 5°C to about 10°C before subjecting to solvent evaporation.
  • Atazanavir sulfate is refluxed at about 120°C in n-butanol for about 20 minutes and the resultant solution is rapidly cooled to about 5°C to about 10°C followed by evaporation of n-butanol under vacuum at about 65°C to about 75°C to obtain the amorphous form.
  • the amorphous atazanavir sulfate can be characterized by its XRPD ( Figure 7), DSC ( Figure 8) and IR ( Figure 9).
  • the present invention provides for a process for the isolation of atazanavir sulfate from a solution comprising an evaporating solvent from the solution.
  • the solution can be prepared by refluxing atazanavir sulfate in solvent.
  • the solvent evaporation can be performed under vacuum.
  • the solution can optionally be cooled before subjecting to solvent evaporation.
  • the isolated atazanavir sulfate can be amorphous or crystalline in nature.
  • the solvent can be n-butanol, n-propanol or mixture thereof.
  • the amorphous form of atazanavir sulfate can be isolated from the solution by evaporation of the solvent under vacuum at about 65°C to about 75°C.
  • Crystalline Form B of atazanavir sulfate can be isolated from the solution comprising evaporation of the solvent under vacuum at about 45°C to about 55°C.
  • Crystalline Form P of atazanavir sulfate can be isolated from the solution comprising evaporation of the solvent under vacuum at about 35°C to about 45°C.
  • the solvent used by present inventors for the preparation of amorphous form or crystalline Form B of atazanavir sulfate is n-butanol
  • n-propanol is used as a solvent.
  • the isolated amorphous or crystalline form can be characterized by their specific XRD, IR and DSC spectra.
  • Yet another aspect of the present invention provides for a pharmaceutical composition that includes crystalline Form B, Form P or mixtures thereof of atazanavir sulfate.
  • a final aspect of the present invention provides a method of treating HIV infection, which includes administering to a patient in need thereof a therapeutically effective amount of Form B, Form P or mixtures thereof of atazanavir sulfate.
  • the atazanavir sulfate used herein as starting material for the preparation of polymorphic forms of present invention can be prepared by any conventional method such as exemplified in the U.S. '383 patent or the U.S. '202 application.
  • the Form A of atazanavir sulfate can be prepared by following the process exemplified in the U.S. '383 patent.
  • XRD The X-ray powder diffractograms (XRPD) were recorded on a Philips Analytical (PANalytical) X'pert Pro instrument using X'celarator detector. Copper K alpha- 1 line x-ray radiation source was used with tube voltage and current of 45kV and 40 mA, respectively. The XRPD were recorded in 2 ⁇ within range of 3-40° 2 ⁇ . All peak positions reported were within +0.2° 2 ⁇ .
  • DSC Differential Scanning Calorimetric thermograms were recorded using Perkin Elmer Dimond DSC instrument within temperature range of 30°C to 300°C with heating rate of 10°C/minute. The DSC peaks reported were within +0.4°C.
  • IR The Infra-red (IR) spectra were recorded on a Perkin Elmer Spectrum One FT- IR instrument using KBr pellets. The spectra were recorded within range of 450 to 4000 cm "1 .
  • Atazanavir sulfate Form A (1 g) was refluxed at 90°C in n-butanol (15 ml) for 10 minutes followed by complete evaporation of n-butanol under vacuum at 50°C.
  • the off white colored powder obtained was confirmed by XRD, IR and DSC as Form B of atazanavir sulfate.
  • Atazanavir sulfate Form A (1 g) was completely dissolved in n-propanol (10 ml) by heating over water-bath at water bath temperature of 80°C to 90°C and the resultant solution was cooled to 5°C to 8°C followed by complete evaporation of n-propanol under vacuum at 40°C.
  • the off white colored powder obtained was confirmed by XRD, IR and DSC as Form P of atazanavir sulfate.
  • Atazanavir sulfate Form A (1 g) was refluxed at 120°C in n-butanol (20 ml) for 20 minutes and the resultant solution was rapidly cooled to 5°C to 8°C followed by complete evaporation of n-butanol under vacuum at 70°C.
  • the off white to light yellow colored powder obtained was confirmed by XRD, IR and DSC as amorphous atazanavir sulfate.

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Abstract

La présente invention concerne des formes polymorphes B et P du sulfate d'atazanavir et leurs méthodes de préparation. Elle concerne également des compositions pharmaceutiques comprenant les nouvelles formes polymorphes du sulfate d'atazanavir, et des méthodes de traitement de l'infection à VIH par administration à un patient nécessitant un tel traitement d'une quantité thérapeutiquement efficace des formes polymorphes B et P du sulfate d'atazanavir. L'invention concerne en outre une méthode de préparation de sulfate d'atazanavir amorphe.
PCT/IB2010/053964 2009-09-03 2010-09-02 Formes polymorphes du sulfate d'atazanavir WO2011027324A1 (fr)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103664753A (zh) * 2012-09-04 2014-03-26 上海迪赛诺化学制药有限公司 制备阿扎那韦硫酸氢盐a型结晶的方法
WO2014125270A1 (fr) 2013-02-12 2014-08-21 Cipla House Procédé de production de sulfate d'atazanavir
CN111349042A (zh) * 2018-12-20 2020-06-30 陕西理工大学 一种阿扎那韦单晶及其制备方法

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US6087383A (en) 1998-01-20 2000-07-11 Bristol-Myers Squibb Company Bisulfate salt of HIV protease inhibitor
US20050256202A1 (en) 2004-05-04 2005-11-17 Soojin Kim Process for preparing atazanavir bisulfate and novel forms
WO2010079497A2 (fr) * 2009-01-12 2010-07-15 Hetero Research Foundation Nouveau polymorphe de sulfate d'atazanavir

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US5849911A (en) 1996-04-22 1998-12-15 Novartis Finance Corporation Antivirally active heterocyclic azahexane derivatives
US6087383A (en) 1998-01-20 2000-07-11 Bristol-Myers Squibb Company Bisulfate salt of HIV protease inhibitor
US20050256202A1 (en) 2004-05-04 2005-11-17 Soojin Kim Process for preparing atazanavir bisulfate and novel forms
WO2010079497A2 (fr) * 2009-01-12 2010-07-15 Hetero Research Foundation Nouveau polymorphe de sulfate d'atazanavir

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ORGANIC PROCESS RESEARCH AND DEVELOPMENT, vol. 12, 2008, pages 69 - 75
ORGANIC PROCESS RESEARCH AND DEVELOPMENT, vol. 6, 2002, pages 323 - 328
XING FAN ET AL.: "An Efficient and Practical Synthesis of the HIV Protease Inhibitor Atazanavir via a Highly Diastereoselective Reduction Approach", ORGANIC PROCESS RESEARCH AND DEVELOPMENT, vol. 12, no. 1, 2008, pages 69 - 75, XP002609215 *
XU ZHONGMIN ET AL: "Process Research and Development for an Efficient Synthesis of the HIV Protease Inhibitor BMS-232632", ORGANIC PROCESS RESEARCH AND DEVELOPMENT, CAMBRIDGE, GB, vol. 6, no. 3, 1 January 2002 (2002-01-01), pages 323 - 328, XP002429422 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103664753A (zh) * 2012-09-04 2014-03-26 上海迪赛诺化学制药有限公司 制备阿扎那韦硫酸氢盐a型结晶的方法
WO2014125270A1 (fr) 2013-02-12 2014-08-21 Cipla House Procédé de production de sulfate d'atazanavir
US9890121B2 (en) 2013-02-12 2018-02-13 Cipla Limited Process for preparing atazanavir sulphate
CN111349042A (zh) * 2018-12-20 2020-06-30 陕西理工大学 一种阿扎那韦单晶及其制备方法

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