WO2015125082A1 - Improved process for the preparation of ritonavir - Google Patents

Improved process for the preparation of ritonavir Download PDF

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Publication number
WO2015125082A1
WO2015125082A1 PCT/IB2015/051223 IB2015051223W WO2015125082A1 WO 2015125082 A1 WO2015125082 A1 WO 2015125082A1 IB 2015051223 W IB2015051223 W IB 2015051223W WO 2015125082 A1 WO2015125082 A1 WO 2015125082A1
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WO
WIPO (PCT)
Prior art keywords
ritonavir
reaction mass
process according
solvent
crystalline
Prior art date
Application number
PCT/IB2015/051223
Other languages
English (en)
French (fr)
Inventor
Siva Ram Prasad Vellanki
Madhu Murthy Nadella
Rajendar Reddy MULAMALLA
Revathi Srinivas RAMABHOTLA
Original Assignee
Mylan Laboratories 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 Mylan Laboratories Limited filed Critical Mylan Laboratories Limited
Publication of WO2015125082A1 publication Critical patent/WO2015125082A1/en

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to an improved process for the preparation of ritonavir crystalline form I.
  • Ritonavir is an antiretroviral drug used to treat Human Immunodeficiency Virus (HIV) and Acquired Immune Deficiency Syndrome (AIDS). It is an inhibitor of proteases, including HIV protease. It is often prescribed in combination with other HIV drugs as a pharmacokinetic inhibitor to prevent protease metabolism of the other co-prescribed drugs.
  • HIV Human Immunodeficiency Virus
  • AIDS Acquired Immune Deficiency Syndrome
  • Ritonavir is chemically known as 10-hydroxy-2-methyl-5-(l-methylethyl)-l-[2-(l-methylethyl)-4-thiazolyl]- 3,6-dioxo-8,l l-bis(phenylmethyl)-2,4,7,12-tetraazatridecan-13-oic acid, 5-thiazolylmethyl ester, [5S-(5R*,8R*,10R*,11R*)].
  • Ritonavir has the following structural formula:
  • Ritonavir is marketed under the brand name NORVTR® by Abb Vie, Inc. It is presently sold in a soft gelatin capsule dosage form for oral administration and is indicated for use in combination with other antiretroviral agents for the treatment of HIV infection.
  • the combination of ritonavir and lopinavir is sold in a capsule dosage form for oral administration under the brand name KALETRA®, also marketed by AbbVie, Inc. KALETRA® is also indicated for use in combination with other antiretroviral agents for the treatment of HIV infection.
  • U.S. Patent No. 5,541,206 discloses ritonavir, a process for its synthesis, and crystalline polymorphic form I of ritonavir.
  • U.S. Patent No. 6,894,171 discloses polymorphic form of ritonavir form II, as well processes for the preparation of form II.
  • U.S. Patent No. 7,148,359 discloses amorphous ritonavir as well as a process for the preparation of amorphous ritonavir.
  • U.S. Patent No. 7,205,413 discloses polymorphic Form III, Form IV, and Form V of ritonavir as well as processes for the preparation of each. Each of these four patents is also hereby incorporated by reference.
  • the present disclosure provides a novel method, which is feasible for use in an industrial setting, for the preparation of pharmaceutically suitable crystalline ritonavir form I.
  • the process for the preparation of crystalline ritonavir form I may include the steps of suspending ritonavir in a solvent, adding a second solvent, raising the temperature of the reaction mass, optionally seeding with crystalline ritonavir form I, then quickly cooling the reaction mass to obtain crystalline form I of ritonavir.
  • the present discloses an improved process for the preparation of crystalline ritonavir form I.
  • crystalline ritonavir form I may be prepared through the following steps: a) suspending ritonavir in a first solvent,
  • the first solvent may include a C 1-5 ester moiety, and may be, for example, ethyl acetate, methyl acetate, n-propyl acetate, n-butyl acetate, or mixtures thereof.
  • a second solvent may then be added.
  • this second solvent is a C5-9 hydrocarbon, and may be, for example, n-pentane, n-hexane, cyclohexane, n-heptane, or mixtures thereof.
  • n-heptane has been found to a particularly useful second solvent.
  • the temperature of the reaction mass may be raised to about 70 - 80 °C and maintained there for about 2-3 hours.
  • the reaction mass may then be rapidly, or shock, cooled to approximately 10 - 15 °C to result in the formation of a solid.
  • transferring the reaction mass into a pre-cooled vessel at 10-15 °C is a particularly effective method for rapidly cooling the reaction mass.
  • filtering the reaction mass while transferring it into the pre-cooled vessel was found to be particularly useful in efficient production of ritonavir form I.
  • the solid formed through such processes may then be filtered to obtain crystalline ritonavir form I.
  • an improved process for the preparation of crystalline ritonavir form I may be achieved by the following steps: a) suspending ritonavir in a first solvent,
  • ritonavir is suspended in a first solvent.
  • the first solvent is a C 1-5 ester, which may be, for example, ethyl acetate, methyl acetate, n-propyl acetate, n-butyl acetate, or mixtures thereof.
  • a second solvent is then added.
  • This second solvent is, in some embodiments, a C5-9 hydrocarbon, and may be, for example, n-pentane, n-hexane, cyclohexane, n-heptane, or mixtures thereof.
  • n-heptane has been found to particularly useful as a second solvent.
  • the temperature of the reaction mass is raised to about 70 - 80 °C and maintained there for about 2 - 3 hours. Seed crystals of ritonavir form I may then be added to the reaction mixture.
  • the reaction mass may then be rapidly cooled to approximately 10 - 15 °C, at which point a solid forms. It has been found in some embodiments, that transferring the mass into a pre-cooled vessel maintained at 10 - 15 °C is particularly useful for achieving rapid cooling of the reaction mixture. In other embodiments, filtering the reaction mass while transferring into a pre-cooled reaction vessel was found to achieve particularly desirable reaction results. The obtained solid may then be filtered to obtain crystalline ritonavir form I.
  • the present invention relates to an improved process for the preparation of crystalline Ritonavir form I which may be carried out by the following steps: a) suspending ritonavir in a first solvent,
  • ritonavir is suspended in a first solvent.
  • the first solvent is a C 1-5 ester, which may be, for example, ethyl acetate, methyl acetate, n-propyl acetate, n-butyl acetate, or mixtures thereof.
  • a second solvent is then added.
  • This second solvent is, in some embodiments, a C5-9 hydrocarbon, and may be, for example, n-pentane, n-hexane, cyclohexane, n-heptane, or mixtures thereof.
  • n-heptane has been found to particularly useful as a second solvent.
  • the temperature of the reaction mass is raised to about 70 - 80 °C and maintained there for about 2-3 hours.
  • the reaction mass may then be rapidly cooled to approximately 10 - 15 °C.
  • transferring the reaction mass into a pre-cooled vessel held at 10 - 15 °C was found to be particularly useful for achieving the cooling step.
  • filtering the reaction mass during the transfer of the reaction mass into a pre-cooled vessel was found to be particularly useful. Seed crystals of ritonavir form I may then be added to the reaction mixture, at which point a solid may begin to form. The obtained solid may then be filtered to obtain crystalline ritonavir form I.
  • Ritonavir or pharmaceutically acceptable salts thereof, prepared by the processes disclosed in the present invention may be incorporated into a pharmaceutical formulation for the treatment of HIV and/or AIDS in human patients.
  • the pharmaceutical formulation may be an oral dosage form, for example, tablets, capsules, or oral suspensions.
  • the dosage form may include such excipients as copovidone, sorbitan monolaurate, colloidal silicon dioxide, sodium stearyl fumarate, dibasic calcium phophsate (hydrated or anhydrous), and sorbitan monolaurate.
  • the tablet may have a film coating, which may include ingredients such as hypromellose, titanium dioxide, polyvinyl alcohol, polyethylene glycol 400, hydroxypropyl cellulose, talc, colloidal silicon dioxide, polyethylene glycol 3350, yellow ferric oxide El 72, and polysorbate 80.
  • Capsule formulations may include excipients such as butylated hydroxytoluene, ethanol, gelatin, iron oxide, oleic acid, polyoxyl 35 castor oil, and titanium dioxide.
  • the oral suspension formulations may include excipients such as acesulfame potassium, alcohol, artificial cotton candy flavor, citric acid, glycerin, high fructose corn syrup, Magnasweet-110 flavor, menthol, natural & artificial flavors, natural and artificial colors, peppermint oil, polyoxyl 40 hydrogenated castor oil, polyoxyl 35 castor oil, povidone, propylene glycol, saccharin sodium, sodium chloride, sodium citrate, citric acid, and water.
  • excipients such as acesulfame potassium, alcohol, artificial cotton candy flavor, citric acid, glycerin, high fructose corn syrup, Magnasweet-110 flavor, menthol, natural & artificial flavors, natural and artificial colors, peppermint oil, polyoxyl 40 hydrogenated castor oil, polyoxyl 35 castor oil, povidone, propylene glycol, saccharin sodium, sodium chloride, sodium citrate, citric acid, and water.
  • Ritonavir or pharmaceutically acceptable salts thereof, prepared by the processes disclosed in the present invention may also be administered in conjunction with other active pharmaceutical ingredients, including atazanavir, darunavir, fosamprenavir, saquinavir, tipranavir, lopinavir, efavirenz, nevirapine, nelfinavir, maraviroc, abacavir, and zidovudine.
  • active pharmaceutical ingredients including atazanavir, darunavir, fosamprenavir, saquinavir, tipranavir, lopinavir, efavirenz, nevirapine, nelfinavir, maraviroc, abacavir, and zidovudine.
  • Example 1 Process for the preparation of crystalline ritonavir form I
  • Ritonavir 100 g was suspended in ethyl acetate (700 mL) and n- heptane (350 mL) was added. The temperature of the reaction mass was raised to 70 - 75 °C.
  • a separate round bottom flask was cooled using a chilled water bath to a temperature of about 10 - 15 °C.
  • the reaction mass, maintained at 70 - 75 °C was filtered into the round bottom flask, maintained at 10 - 15 °C, using a micron filter aid and washed with ethyl acetate and n-heptane. The reaction mass was stirred for about two hours to precipitate a solid.
  • the product was filtered and dried to obtain substantially pure crystalline ritonavir Form I.
  • Example 2 Process for the preparation of crystalline ritonavir form I
  • Ritonavir 100 g was suspended in ethyl acetate (700 mL) and n- heptane (350 mL) was added. The temperature of the reaction mass was raised to 70 - 75 °C. A separate round bottom flask was cooled using a chilled water bath to a temperature of about 10 - 15 °C. The reaction mass, maintained at 70 - 75 °C, was filtered into the round bottom flask, maintained at 10 - 15 °C, using a micron filter aid and then washed with ethyl acetate and n-heptane. A seed crystal of ritonavir form I was added and the reaction mass was stirred for about two hours to precipitate a solid. The product was filtered and dried to obtain substantially pure crystalline ritonavir form I.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
PCT/IB2015/051223 2014-02-21 2015-02-18 Improved process for the preparation of ritonavir WO2015125082A1 (en)

Applications Claiming Priority (2)

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IN872/CHE/2014 2014-02-21
IN872CH2014 IN2014CH00872A (enrdf_load_stackoverflow) 2014-02-21 2015-02-18

Publications (1)

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WO2015125082A1 true WO2015125082A1 (en) 2015-08-27

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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5541206A (en) 1989-05-23 1996-07-30 Abbott Laboratories Retroviral protease inhibiting compounds
US5567823A (en) * 1995-06-06 1996-10-22 Abbott Laboratories Process for the preparation of an HIV protease inhibiting compound
US6037157A (en) 1995-06-29 2000-03-14 Abbott Laboratories Method for improving pharmacokinetics
US6894171B1 (en) 1998-07-20 2005-05-17 Abbott Laboratories Polymorph of a pharmaceutical
US7205413B2 (en) 2002-05-03 2007-04-17 Transform Pharmaceuticals, Inc. Solvates and polymorphs of ritonavir and methods of making and using the same
WO2008041176A2 (en) * 2006-10-03 2008-04-10 Ranbaxy Laboratories Limited Process for the preparation of form i and form ii of ritonavir

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5541206A (en) 1989-05-23 1996-07-30 Abbott Laboratories Retroviral protease inhibiting compounds
US5567823A (en) * 1995-06-06 1996-10-22 Abbott Laboratories Process for the preparation of an HIV protease inhibiting compound
US6037157A (en) 1995-06-29 2000-03-14 Abbott Laboratories Method for improving pharmacokinetics
US6894171B1 (en) 1998-07-20 2005-05-17 Abbott Laboratories Polymorph of a pharmaceutical
US7148359B2 (en) 1998-07-20 2006-12-12 Abbott Laboratories Polymorph of a pharmaceutical
US7205413B2 (en) 2002-05-03 2007-04-17 Transform Pharmaceuticals, Inc. Solvates and polymorphs of ritonavir and methods of making and using the same
WO2008041176A2 (en) * 2006-10-03 2008-04-10 Ranbaxy Laboratories Limited Process for the preparation of form i and form ii of ritonavir

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
"Physicians' Desk Reference", 2002, pages: 487 - 492
AALTONEN J ET AL: "Solid form screening - A review", EUROPEAN JOURNAL OF PHARMACEUTICS AND BIOPHARMACEUTICS, ELSEVIER SCIENCE PUBLISHERS B.V., AMSTERDAM, NL, vol. 71, no. 1, 1 January 2009 (2009-01-01), pages 23 - 37, XP025782069, ISSN: 0939-6411, [retrieved on 20080731], DOI: 10.1016/J.EJPB.2008.07.014 *
CHEMBURKAR S R ET AL: "Dealing with the impact of ritonavir polymorphs on the late stages of bulk drug process development", ORGANIC PROCESS RESEARCH AND DEVELOPMENT, CAMBRIDGE, GB, vol. 4, no. 5, 21 June 2000 (2000-06-21), pages 413 - 417, XP002398933 *

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