[go: up one dir, main page]

WO2016092525A1 - Darunavir n-propanol solvate and process for preparation thereof - Google Patents

Darunavir n-propanol solvate and process for preparation thereof Download PDF

Info

Publication number
WO2016092525A1
WO2016092525A1 PCT/IB2015/059564 IB2015059564W WO2016092525A1 WO 2016092525 A1 WO2016092525 A1 WO 2016092525A1 IB 2015059564 W IB2015059564 W IB 2015059564W WO 2016092525 A1 WO2016092525 A1 WO 2016092525A1
Authority
WO
WIPO (PCT)
Prior art keywords
darunavir
propanol solvate
propanol
preparation
solvate
Prior art date
Application number
PCT/IB2015/059564
Other languages
French (fr)
Inventor
Nitin Vilas PATIL
Akshat Bhatnagar
Krishnat Hanmant KUMBHAR
Devendrakumar Paramsukh VARMA
Rajesh Vyas
Nandu Bhise
Girij Pal Singh
Original Assignee
Lupin Limited
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 Lupin Limited filed Critical Lupin Limited
Publication of WO2016092525A1 publication Critical patent/WO2016092525A1/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/04—Ortho-condensed systems

Definitions

  • This present invention relates to darunavir n-propanol solvate and process for preparation thereof. Further, invention relates to pharmaceutical compositions comprising darunavir n-propanol solvate and one or more pharmaceutically acceptable excipients and process for preparation thereof.
  • protease inhibitors are a class of antiviral drugs that are widely used to treat HIV/AIDS and hepatitis caused by hepatitis C virus.
  • Protease inhibitors prevent viral replication by selectively binding to viral proteases (e.g. HIV-1 protease) and blocking proteolytic cleavage of protein precursors that are necessary for the production of infectious viral particles.
  • viral proteases e.g. HIV-1 protease
  • Darunavir is a new HIV protease inhibitor and approved by the FDA under the name of Prezista .
  • Prezista is administered in combination with a low-dose of ritonavir and other active anti-HIV drugs.
  • Prezista ® is presented with darunavir ethanolate as a film coated tablets.
  • Darunavir ethanolate (as described in Figure- 1) is in white to off-white hygroscopic powder. It is chemically known as [(lS,2R)-3-[[(4-aminophenyl)sulfonyl](2-methylpropyl)-amino]-2- hydroxy- l-(phenylmethyl)propyl] carbamic acid (3R,3aS,6aR)-hexahydrofuro-[2,3-b]furan- 3-yl ester monoethanolate.
  • U.S.Pat. Nos. 7,700,645 and 8,518,987 refer to ethanolate and hydrate solvate of darunavir respectively.
  • the approved Product Information for PREZISTA ® disclosesthat during storage of darunavir ethanolate tablets, partial conversion from ethanolate solvate to hydrate solvate might occur.No test data is provided in such Product Information to substantiate this occurrence, whether in whole or in part.
  • the present invention provides a pharmaceutical composition of darunavir n-propanol solvate which is stable throughout its shelf life and is clinically bioequivalent under FDA standards to the marketed compositions of darunavir.
  • darunavir n-propanol solvate of invention is more stable, cost-effective, and viable at plant scale.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising darunavir n-propanol solvate which isstable throughout shelf life. Further, these compositions are clinically bioequivalent under FDA standards to the marketed dosage forms of darunavir, PREZISTA®. The present compositions are further free of any solvate forms of darunavir as depicted in U.S. Pat. Nos.7,700,645, U.S. Pat. Nos. 8,518,987 or PCT Application no. WO/2011/083287 Al.
  • This invention provides a new solvate form of darunavir i.e. darunavir n-propanol solvate.
  • the invention additionally provides a method for preparing darunavir n-propanol solvate, which is viable at plant scale and also helpful for achieving higher stablility.
  • present invention provides pharmaceutical compositions of darunavir n-propanol solvate and one or more pharmaceutically acceptable excipients and a process for preparation thereof.
  • Figure 2 depicts TG thermogram of darunavir n-propanol solvate.
  • Figure 3 depicts DSC pattern of darunavir n-propanol solvate.
  • Figure 4 depicts 1H- NMR pattern of darunavir n-propanol solvate.
  • Figure 5 depicts powder X-ray diffraction pattern of darunavir n-propanol solvate.
  • Figure 6 depicts TG thermogram of darunavir n-propanol solvate.
  • the present invention provides solvate form of darunavir i.e. darunavir n-propanol solvate and process for preparation thereof. Further, invention relates to pharmaceutical compositions comprising darunavir n-propanol solvate and one or more pharmaceutically acceptable excipients and process for preparation thereof.
  • the process for preparation of novel solvate of darunavir comprising the step of: a) reacting darunavir with n-propanol; b) heating the reaction mass and gradually cooling; and c) isolating darunavir n-propanol solvate.
  • darunavir used as a starting material is obtained by the processes known in the art.
  • the mixture typically is heated to a temperature of about 50°C to about 100°C preferably 70°C to 80°C for a period of time of about 10 minutes to about 1 hour or longer.
  • the resulting solution is gradually cooled to about 25 °C to about 30°C i.e. ambient temperature, for minimum three hours and stirred for an hour at ambient temperature and darunavir n-propanol solvate precipitates and can be collected by filtration.
  • the crystalline product generally is dried for about 1 hour or more, preferably in a vacuum, at about 20°C to about 60°C. The product so formed is highly stable and crystalline.
  • Molar equivalents of n-propanol employed for this invention varies with respect to darunavir equivalents.
  • the present invention has checked the content of n-propanol in darunavir n-propanol solvate and it shows 7.9% to 11.9%.
  • the isolation of the crystalline solid is carried out by the conventional techniques known in the prior art such as filtration, concentration, and evaporation etc.
  • a solid darunavir n-propanol solvate by the following properties: i) a thermogravimetric analysis curve (TGA) obtained after heating the sample from 20°C to 300°C at a scan rate of 10°C/minute shows in FIG. 2 & 6;
  • TGA thermogravimetric analysis curve
  • DSC differential scanning calorimetric
  • the powder x-ray diffraction pattern was measured at room temperature using a Cu Ka filled tube (45 kV 40 mA) as the x- ray source. Data collection was done in 2theta continuous scan mode in the range of 3.5° to 40°. (3) Thermogravimetric analysis
  • Thermogravimetric analysis was performed using a Pyris 1 TGA PERKIN ELMER measurement unit. 2-5 mg samples were placed in open Platinum pans and heated from 20 °C to 300 °C in a dry nitrogen atmosphere at a heating rate of 10 °C/min.
  • Melting point was measured using a LAB India- MR- VIS measuring unit.
  • n-propanol (2520 ml) was added into the reaction mass.
  • the reaction mass was warmed to dissolve the solid. Gradually it was cooled to room temperature and filtered under reduced pressure. The product was dried under reduced pressure.
  • compositions of darunavir n-propanol solvate comprise but are not limited to suspensions, solutions, emulsions, ointments, liniments, lotions, creams, gels, suppositories, transdermal patches, powders and osmotic pumps, tablets (single layered tablets, multilayered tablets, mini tablets, bioadhesive tablets, caplets, matrix tablets, tablet within a tablet, mucoadhesive tablets, modified release tablets, pulsatile release tablets, and timed release tablets), pellets, beads, granules, sustained release formulations, capsules, microcapsules, tablets in capsules, microspheres, matrix formulations, microencapsulation.
  • compositions of invention are in the form of tablet comprising 1 mg to 1600 mg of darunavir n-propanol solvate and one or more pharmaceutically acceptable excipients. More preferably the composition comprises 800 mg, 600 mg, 300 mg, 150 mg or 75 mg of darunavir n-propanol solvate. In another embodiment, a pharmaceutical composition comprising darunavir n- propanol solvateand one or more pharmaceutically acceptable excipients.
  • a pharmaceutical composition comprising darunavir n- propanol solvate and one or more pharmaceutically acceptable excipients, wherein Darunavir n-propanol solvate having a powder X-ray diffraction pattern as described in FIG. 5.
  • compositions of invention comprise but not limited to diluents, binders, pH stabilizing agents, disintegrants, surfactants, glidants and lubricants known in the art.
  • excipient employed will depend upon how much active agent is to be used. One excipient(s) can perform more than one function.
  • the pharmaceutical composition may optionally be coated wherein the coating can be film coating, sugar coating, extended release coating, enteric coating, partial enteric coating or leaky enteric coating, bioadhesive coating and other coatings known in the art. These coatings may help the pharmaceutical composition to release the drug at and for the required time.
  • the coating comprises a hydrophilic or hydrophobic substance(s) or the combinations thereof.
  • compositions of inventions can be used for the treating of HIV infection or preventing AIDS.

Landscapes

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

Abstract

This invention provides a novel solvate of darunavir i.e darunavir n-propanol solvate. This invention also provides a process for preparation of darunavir n-propanol solvate, which is cost-effective, robust, and viable at plant scale. The present invention also provides pharmaceutical compositions of darunavir n-propanol solvate.

Description

DARUNAVIR N-PROPANOL SOLVATE AND PROCESS
FOR PREPARATION THEREOF
Field of invention
This present invention relates to darunavir n-propanol solvate and process for preparation thereof. Further, invention relates to pharmaceutical compositions comprising darunavir n-propanol solvate and one or more pharmaceutically acceptable excipients and process for preparation thereof.
Background of invention
The protease inhibitors are a class of antiviral drugs that are widely used to treat HIV/AIDS and hepatitis caused by hepatitis C virus. Protease inhibitors prevent viral replication by selectively binding to viral proteases (e.g. HIV-1 protease) and blocking proteolytic cleavage of protein precursors that are necessary for the production of infectious viral particles.
Darunavir is a new HIV protease inhibitor and approved by the FDA under the name of Prezista . Prezista is administered in combination with a low-dose of ritonavir and other active anti-HIV drugs.
Figure imgf000003_0001
Figure - 1
Prezista® is presented with darunavir ethanolate as a film coated tablets. Darunavir ethanolate (as described in Figure- 1) is in white to off-white hygroscopic powder. It is chemically known as [(lS,2R)-3-[[(4-aminophenyl)sulfonyl](2-methylpropyl)-amino]-2- hydroxy- l-(phenylmethyl)propyl] carbamic acid (3R,3aS,6aR)-hexahydrofuro-[2,3-b]furan- 3-yl ester monoethanolate.
U.S.Pat. Nos. 7,700,645 and 8,518,987 refer to ethanolate and hydrate solvate of darunavir respectively.
The approved Product Information for PREZISTA®disclosesthat during storage of darunavir ethanolate tablets, partial conversion from ethanolate solvate to hydrate solvate might occur.No test data is provided in such Product Information to substantiate this occurrence, whether in whole or in part.
Nevertheless, accepting the assertions in the above made by the authors of the patent documents and Product Information as true, we have prepared. The present invention provides a pharmaceutical composition of darunavir n-propanol solvate which is stable throughout its shelf life and is clinically bioequivalent under FDA standards to the marketed compositions of darunavir.
Further, darunavir n-propanol solvate of invention is more stable, cost-effective, and viable at plant scale.
The present invention also providesa pharmaceutical composition comprising darunavir n-propanol solvate which isstable throughout shelf life. Further, these compositions are clinically bioequivalent under FDA standards to the marketed dosage forms of darunavir, PREZISTA®. The present compositions are further free of any solvate forms of darunavir as depicted in U.S. Pat. Nos.7,700,645, U.S. Pat. Nos. 8,518,987 or PCT Application no. WO/2011/083287 Al.
Summary of invention
This invention provides a new solvate form of darunavir i.e. darunavir n-propanol solvate. The invention additionally provides a method for preparing darunavir n-propanol solvate, which is viable at plant scale and also helpful for achieving higher stablility. Further, present invention provides pharmaceutical compositions of darunavir n-propanol solvate and one or more pharmaceutically acceptable excipients and a process for preparation thereof.
Brief Description of the drawings
Figure 2 depicts TG thermogram of darunavir n-propanol solvate.
Figure 3 depicts DSC pattern of darunavir n-propanol solvate.
Figure 4 depicts 1H- NMR pattern of darunavir n-propanol solvate.
Figure 5 depicts powder X-ray diffraction pattern of darunavir n-propanol solvate.
Figure 6 depicts TG thermogram of darunavir n-propanol solvate.
Detailed description
The present invention provides solvate form of darunavir i.e. darunavir n-propanol solvate and process for preparation thereof. Further, invention relates to pharmaceutical compositions comprising darunavir n-propanol solvate and one or more pharmaceutically acceptable excipients and process for preparation thereof.
In one aspect of the invention, the process for preparation of novel solvate of darunavir comprising the step of: a) reacting darunavir with n-propanol; b) heating the reaction mass and gradually cooling; and c) isolating darunavir n-propanol solvate.
In the present invention,darunavir used as a starting material is obtained by the processes known in the art.
The mixture typically is heated to a temperature of about 50°C to about 100°C preferably 70°C to 80°C for a period of time of about 10 minutes to about 1 hour or longer. The resulting solution is gradually cooled to about 25 °C to about 30°C i.e. ambient temperature, for minimum three hours and stirred for an hour at ambient temperature and darunavir n-propanol solvate precipitates and can be collected by filtration. The crystalline product generally is dried for about 1 hour or more, preferably in a vacuum, at about 20°C to about 60°C. The product so formed is highly stable and crystalline.
Molar equivalents of n-propanol employed for this invention varies with respect to darunavir equivalents.
The present invention has checked the content of n-propanol in darunavir n-propanol solvate and it shows 7.9% to 11.9%. The isolation of the crystalline solid is carried out by the conventional techniques known in the prior art such as filtration, concentration, and evaporation etc.
According to another aspect of the present invention, there is provided a solid darunavir n-propanol solvate by the following properties: i) a thermogravimetric analysis curve (TGA) obtained after heating the sample from 20°C to 300°C at a scan rate of 10°C/minute shows in FIG. 2 & 6;
ii) a differential scanning calorimetric (DSC) thermogram as depicted in FIG. 3; iii) a H-NMR spectrogram as depicted in FIG. 4;
iv) a powder X-ray diffraction pattern as described in FIG. 5.
Analytical Methods
(1) XH-NMR
The ^-NMR spectrums was recorded in CDC13 using Bruker, 400 MHZ NMR Spectrometer.
(2) Powder X-ray Diffraction
Using a PANalytical X'Pert powder diffraction meter, the powder x-ray diffraction pattern was measured at room temperature using a Cu Ka filled tube (45 kV 40 mA) as the x- ray source. Data collection was done in 2theta continuous scan mode in the range of 3.5° to 40°. (3) Thermogravimetric analysis
Thermogravimetric analysis was performed using a Pyris 1 TGA PERKIN ELMER measurement unit. 2-5 mg samples were placed in open Platinum pans and heated from 20 °C to 300 °C in a dry nitrogen atmosphere at a heating rate of 10 °C/min.
(4) Differential Scanning Calorimetry
Differential Scanning Calorimetry was performed using a Diamond DSC PERKIN ELMER differential instrument. 2-3 mg samples were placed in crimped aluminum pans and heated from 50 °C to 280 °C in a dry nitrogen atmosphere at a heating rate of 10 °C/minute.
(5) Gas Chromatography (GC)
Gas Chromatography studies were performed using a PERKIN ELMER CLARUS - 600, 680, 500 & auto system XL with headspace sampler and Shimadzu GC-2010.
(6) Melting Point
Melting point was measured using a LAB India- MR- VIS measuring unit.
The present invention will now be further illustrated by reference to the following examples, which do not limit the scope of the invention any way.
Example 1
In a round bottom flask, 1500 ml of n-propanol was added followed by 100 gms of darunavir. The reaction temperature was raised to 70°C to 80°C and was cooled to room temperature. This reaction mass was stirred. After stirring, the resultant solid was filtered and washed with 100ml n-propanol twice. The solid was dried at 50°C under reduced pressure. Yield: 97gms. The melting point of darunavir n-propanol solvate was 99.7°C to 102.5°C and the content of n-propanol measured by GC was 9.72 (%). The TG thermogram, DSC pattern, 1H- NMR pattern and powdered X-ray diffractogram of the obtained product as described in Fig. 2, 3, 4, 5 and 6 respectively.
Example 2
In a round bottom flask, ethyl acetate (3780 ml), methanol (420 ml), triethyl amine (67.5 ml) and nitro-darunavir (280 gm) were charged. The reaction mass was warmed to dissolve the solid, and then cooled the reaction mass to 25 to 30°C and was hydrogenated the reaction by using 10% Palladium on carbon (28 gm; 50% wet) and water (210 ml) in autoclave at 5-6Kg/cm hydrogen pressure. After completion of the reaction, the reaction mass was filtered to remove catalyst and solvent was distilled out under reduced pressure and the concentrated mass was stripped out with n-propanol (2X840 ml). The n-propanol (2520 ml) was added into the reaction mass. The reaction mass was warmed to dissolve the solid. Gradually it was cooled to room temperature and filtered under reduced pressure. The product was dried under reduced pressure. The solid weighted 255 gms., Melting point: 101.7 tol02.2°C, n-propanol: 9.9%.
According to another aspect of the present invention, pharmaceutical compositions of darunavir n-propanol solvate comprise but are not limited to suspensions, solutions, emulsions, ointments, liniments, lotions, creams, gels, suppositories, transdermal patches, powders and osmotic pumps, tablets (single layered tablets, multilayered tablets, mini tablets, bioadhesive tablets, caplets, matrix tablets, tablet within a tablet, mucoadhesive tablets, modified release tablets, pulsatile release tablets, and timed release tablets), pellets, beads, granules, sustained release formulations, capsules, microcapsules, tablets in capsules, microspheres, matrix formulations, microencapsulation.
In another embodiment, pharmaceutical compositions of invention are in the form of tablet comprising 1 mg to 1600 mg of darunavir n-propanol solvate and one or more pharmaceutically acceptable excipients. More preferably the composition comprises 800 mg, 600 mg, 300 mg, 150 mg or 75 mg of darunavir n-propanol solvate. In another embodiment, a pharmaceutical composition comprising darunavir n- propanol solvateand one or more pharmaceutically acceptable excipients.
In another embodiment, a pharmaceutical composition comprising darunavir n- propanol solvate and one or more pharmaceutically acceptable excipients, wherein Darunavir n-propanol solvate having a powder X-ray diffraction pattern as described in FIG. 5.
The term "pharmaceutically acceptable excipients" used in the pharmaceutical compositions of invention comprise but not limited to diluents, binders, pH stabilizing agents, disintegrants, surfactants, glidants and lubricants known in the art.
The amount of excipient employed will depend upon how much active agent is to be used. One excipient(s) can perform more than one function.
In yet another embodiment, the pharmaceutical composition may optionally be coated wherein the coating can be film coating, sugar coating, extended release coating, enteric coating, partial enteric coating or leaky enteric coating, bioadhesive coating and other coatings known in the art. These coatings may help the pharmaceutical composition to release the drug at and for the required time. The coating comprises a hydrophilic or hydrophobic substance(s) or the combinations thereof.
In another embodiment, pharmaceutical compositions of inventions can be used for the treating of HIV infection or preventing AIDS.

Claims

1. Darunavir n-propanol solvate.
2. The darunavir n-propanol solvate according to claim 1, having a thermogravimetric analysis curve (TGA) obtained after heating the sample from 20°C to 300°C. at a scan rate of 10°C/minute as shown in FIG. 2.
3. The darunavir n-propanol solvate according to claim 1, having a differential scanning calorimetric (DSC) thermogram as depicted in FIG. 3;
4. The darunavir n-propanol solvate according to claim 1, having ^-NMR spectrogram as depicted in FIG. 4.
5. The darunavir n-propanol solvate according to claim 1, having a powder X-ray diffraction pattern as described in FIG. 5.
6. A process for the preparation of darunavir n-propanol solvate according to claim 1, comprising the steps of: a) reacting darunavir with n-propanol; b) heating the reaction mass and gradually cooling; and c) isolating the darunavir n-propanol solvate.
7. A process for the preparation of darunavir n-propanol solvate according to claim 2, wherein the heating temperature ranges from about 50°C to about 100°C.
8. A process for the preparation of darunavir n-propanol solvate according to claim 2, wherein the cooling temperature ranges from about 25°C to about 30°C.
9. A pharmaceutical composition comprising darunavir n-propanol solvate and one or more pharmaceutically acceptable excipients.
10. The pharmaceutical composition according to Claim 9, wherein the darunavir n-propanol solvate has a powder X-ray diffraction pattern as depicted in FIG. 5.
PCT/IB2015/059564 2014-12-12 2015-12-12 Darunavir n-propanol solvate and process for preparation thereof WO2016092525A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN3990MU2014 2014-12-12
IN3990/MUM/2014 2014-12-12

Publications (1)

Publication Number Publication Date
WO2016092525A1 true WO2016092525A1 (en) 2016-06-16

Family

ID=55080138

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2015/059564 WO2016092525A1 (en) 2014-12-12 2015-12-12 Darunavir n-propanol solvate and process for preparation thereof

Country Status (1)

Country Link
WO (1) WO2016092525A1 (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10407438B2 (en) 2016-10-27 2019-09-10 Gilead Sciences, Inc. Crystalline forms of darunavir

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003106461A2 (en) * 2002-05-16 2003-12-24 Tibotec Pharmaceuticals Ltd Pseudopolymorphic forms of a hiv protease inhibitor
WO2011073993A1 (en) * 2009-12-16 2011-06-23 Hetero Research Foundation Polymorphs of darunavir
WO2011083287A2 (en) 2010-01-05 2011-07-14 Cipla Limited Darunavir polymorph and process for preparation thereof
WO2013108105A2 (en) * 2012-01-18 2013-07-25 Aurobindo Pharma Limited Novel solvates of darunavir

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003106461A2 (en) * 2002-05-16 2003-12-24 Tibotec Pharmaceuticals Ltd Pseudopolymorphic forms of a hiv protease inhibitor
US7700645B2 (en) 2002-05-16 2010-04-20 Tibotec Pharmaceuticals Ltd. Pseudopolymorphic forms of a HIV protease inhibitor
US8518987B2 (en) 2002-05-16 2013-08-27 Janssen R&D Ireland Pseudopolymorphic forms of a HIV protease inhibitor
WO2011073993A1 (en) * 2009-12-16 2011-06-23 Hetero Research Foundation Polymorphs of darunavir
WO2011083287A2 (en) 2010-01-05 2011-07-14 Cipla Limited Darunavir polymorph and process for preparation thereof
WO2013108105A2 (en) * 2012-01-18 2013-07-25 Aurobindo Pharma Limited Novel solvates of darunavir

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10407438B2 (en) 2016-10-27 2019-09-10 Gilead Sciences, Inc. Crystalline forms of darunavir

Similar Documents

Publication Publication Date Title
CN105646584B (en) Tenofovir Chinese mugwort draws phenol amine fumarate crystal form and its preparation method and application
JP6603306B2 (en) A new hydrate of dolutegravir sodium
WO2015176602A1 (en) Tenofovir alafenamide complex, preparation method therefor and use thereof
CN104039775A (en) Modulators of ATP-binding cassette transporters
WO2011095059A1 (en) Polymorphs of dasatinib, preparation methods and pharmaceutical compositions thereof
TWI338006B (en) Mycophenolate mofetil impurity
US7521569B2 (en) Process to obtain dibenzylbutyrolactonic lignans, process to obtain synthetic derivatives from lignans bearing anti-Chagas chemoprophylactic and therapeutical activities
WO2016092525A1 (en) Darunavir n-propanol solvate and process for preparation thereof
TWI384986B (en) Maleic acid monosalt of antiviral agent and pharmaceutical composition containing the same
HUE030504T2 (en) Process for the production of ralfinamide methanesulfonate salts or their R-enantiomers
CN102282125A (en) Novel processes and pure polymorphs
EP3894424B1 (en) Mesylate salt of an amino-lupane compound with hiv maturation inhibitory activity
RU2647576C1 (en) Cyclobutyl (s)-2-[[[r)-2-(6-aminopurin-9-yl)-1-methyl-etoxy]methyl-phenoxy-phosphoryl]amino]-propanoates, method of their production and application
EP3102565B1 (en) Processes for the preparation of intermediates of raltegravir
CN114853781B (en) HIV-1 reverse transcriptase targeted covalent inhibitor and preparation method and application thereof
CN111936497A (en) Isothermal reactive crystallization process for preparing crystalline forms of pimodivir hydrochloride hemihydrate
US20190248773A1 (en) Process for the preparation of pure and stable crystalline raltegravir potassium form 3
JP2016534047A (en) Tenofovir Disoproxil Dihydrogen Phosphate
EP2793862B1 (en) Co-processing method and formulation for hiv attachment inhibitor prodrug compound and excipients
CN102219752B (en) Crystal form D of 1-(2,6-difluorobenzyl)-1H-1,2,3-triazole-4-carboxamide
CN114369134A (en) Lupane triterpenoid derivative meglumine salt amorphous substance and preparation method and application thereof
CN113683534A (en) Crystal forms of camostat mesylate and its solvates and their preparation methods and uses
JP2021513506A (en) How to prepare large-scale trimidone
CN110577555A (en) Preparation method and application of amorphous tenofovir octadecyloxyethyl ester
HK40015133A (en) Cyclobutyl (s)-2-[[[(r)-2-(6-aminopurin-9-yl)-1-methyl-ethoxy]methyl-phenoxy-phosphoryl]amino]-propanoates, and method for producing and using same

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 15823021

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 15823021

Country of ref document: EP

Kind code of ref document: A1