WO2011024192A2 - Novel polymorphs of raltegravir - Google Patents

Novel polymorphs of raltegravir Download PDF

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Publication number
WO2011024192A2
WO2011024192A2 PCT/IN2010/000490 IN2010000490W WO2011024192A2 WO 2011024192 A2 WO2011024192 A2 WO 2011024192A2 IN 2010000490 W IN2010000490 W IN 2010000490W WO 2011024192 A2 WO2011024192 A2 WO 2011024192A2
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raltegravir
potassium
preparation
solvent
amorphous
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PCT/IN2010/000490
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French (fr)
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WO2011024192A3 (en
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Ramakoteswara Rao Jetti
Madhavi Jonnalagadda
Chetan Kanaiyalal Raval
Debashish Datta
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Matrix Laboratories Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to novel polymorphic forms of Raltegravir and processes for its preparation thereof.
  • the present invention further relates to an improved process for preparation of amorphous and crystalline Form 1, Form 2 and Form 3 of Raltegravir potassium salt.
  • Raltegravir is an antiretroviral drag produced by Merck & Co and marketed as potassium salt used in combination with other anti-retroviral drugs to treat human immunodeficiency virus (HIV) infection. It is a first line HIV-integrase strand transfer inhibitor drug that targets Integrase, an HIV enzyme that integrates the viral genetic material into human chromosomes.
  • Raltegravir potassium is N- [(4-fluorophenyl)methyl]-l,6-dihydro-5-hydroxy-l-methyl-2-[[(5-methyl-l,3,4- oxadiazol-2-yl)carbonyl] amino] ethyl] -6-oxo-4-pyrimidinecarboxamide monopotassium salt and is structurally represented by formula I.
  • Raltegravir potassium salt is marketed under the brand name Isentress ®.
  • Raltegravir and it's pharmaceutically acceptable salts are disclosed in US 7,169,780.
  • US 2006/0122205 Al discloses polymorphic forms of Raltegravir Potassium namely anhydrous crystalline potassium salt of Raltegravir (Form 1 and Form 3); hydrated crystalline potassium salt of Raltegravir (Form 2).
  • polymorphs of Raltegravir are not known and during our recent studies on polymorphic screening inventors found two novel polymorphic forms Form A and Form B of Raltegravir and also amorphous form of Raltegravir.
  • the Raltegravir polymorphic Form B and amorphous form of Raltegravir potassium salt of the present invention is having good stability and purity in different conditions and can also be prepared by an efficient, economic and reproducible process particularly in large scale preparation with free flowing nature.
  • OBJECT OF THE INVENTION Principle object of the present invention is to provide amorphous Raltegravir and process for preparation of the same.
  • Another principle object of the present invention is to provide novel Raltegravir Form A and process for preparation of the same.
  • Yet another principle object of the present invention is to provide novel Raltegravir Form B and process for preparation of the same.
  • Further principle object of the present invention is to provide amorphous Raltegravir potassium salt and process for preparation of the same.
  • Another principle object of the present invention is to provide improved process for preparation of Raltegravir potassium Form 1.
  • Another principle object of the present invention is to provide improved process for preparation of Raltegravir potassium Form 2.
  • Another principle object of the present invention is to provide improved process for preparation of Raltegravir potassium Form 3.
  • the main aspect of the present invention is to provide amorphous Raltegravir as shown in figure 1.
  • Another aspect of the present invention is to provide process for the preparation of amorphous Raltegravir comprising the steps of a) dissolving Raltegravir in a solvent to form a clear solution; b) removing the solvent; and c) isolating amorphous Raltegravir.
  • the present invention provides crystalline form of Raltegravir, designated as Form A.
  • Another aspect of the present invention is to provide process for the preparation of crystalline Raltegravir Form A comprising the steps of: a) suspending Raltegravir in a solvent; b) heating the suspension to form clear solution; and c) crystallizing the solution of step b) to isolate Raltegravir Form A.
  • Another aspect of the present invention is to provide alternative process for the preparation of crystalline Raltegravir Form A comprising the steps of: a) suspending Raltegravir in a solvent; b) heating the suspension to form clear solution; c) adding anti- solvent; and d) isolating Raltegravir Form A.
  • Another aspect of the present invention is to provide alternative process for the preparation of Raltegravir Form A comprising the steps of: a) suspending Raltegravir in a polar solvent; and b) isolating Raltegravir Form A.
  • the present invention provides crystalline form of Raltegravir, designated as Form B.
  • Another aspect of the present invention is to provide process for the preparation of crystalline Raltegravir Form B comprising the steps of: a) suspending Raltegravir in a polar solvent or mixtures thereof; b) optionally heating the contents to form clear solution; and c) cooling the solution to isolate Raltegravir Form B.
  • Another aspect of the present invention is to provide alternative process for the preparation of crystalline Raltegravir Form B comprising the steps of: a) dissolving Raltegravir in a solvent; b) adding isopropyl ether as anti-solvent; and c) isolating Raltegravir Form B.
  • Another aspect of the present invention is to provide alternative process for the preparation of crystalline Raltegravir Form B comprising the steps of: a) suspending amorphous Raltegravir in isopropyl ether; and b) isolating Raltegravir Form B.
  • the present invention provides amorphous Raltegravir potassium.
  • Another aspect of the present invention is to provide process for the preparation of amorphous Raltegravir potassium salt comprising the steps of: a) dissolving Raltegravir in a polar solvent; b) adding aqueous potassium hydroxide solution; c) removing the solvent; and d) isolating amorphous Raltegravir Potassium.
  • the present invention provides process for the preparation of Raltegravir Potassium Form 1 comprising the steps of: a) dissolving Raltegravir in a solvent; b) adding alcoholic potassium hydroxide solution; and c) isolating Raltegravir Potassium Form 1.
  • Another aspect of the present invention is to provide alternative process for the preparation of Raltegravir Potassium Form 1 comprising the steps of: a) suspending amorphous Raltegravir potassium in a solvent; b) heating the suspension to get the clear solution; c) cooling the reaction mass; and d) isolating Raltegravir Potassium Form 1.
  • Another aspect of the present invention is to provide alternative process for the preparation of Raltegravir Potassium Form 1 comprising the steps of: a) suspending amorphous Raltegravir potassium in solvent mixture; b) heating the suspension to get the clear solution; c) allowing the contents of step b) to evaporate slowly; and d) isolating Raltegravir potassium form 1.
  • the present invention provides process for the preparation of Raltegravir Potassium Form 2 comprising the steps of: a) suspending amorphous Raltegravir Potassium in chlorinated solvents; and b) isolating Raltegravir potassium Form 2.
  • the present invention provides process for the preparation of Raltegravir Potassium Form 3 comprising the steps of: a) suspending Raltegravir in a solvent or mixture of solvents; b) stirring the suspension to obtain a clear solution; c) adding alcoholic potassium hydroxide solution; d) adding isopropyl ether as anti-solvent; and e) isolating Raltegravir potassium Form 3.
  • the present invention provides process for the preparation of Raltegravir Potassium Form 3 comprising the steps of: a) suspending Raltegravir in a solvent or mixture of solvents; b) stirring the suspension to obtain a clear solution; c) adding alcoholic potassium hydroxide solution; and d) isolating Raltegravir potassium Form 3.
  • Figure 1 illustrate the PXRD of amorphous Raltegravir
  • Figure 2 illustrate the DSC of amorphous Raltegravir
  • FIG. 3 illustrate the IR of amorphous Raltegravir
  • FIG. 4 illustrate the PXRD of Raltegravir Form A
  • FIG. 5 illustrate the DSC of Raltegravir Form A
  • FIG. 6 illustrate the TGA/DTA of Raltegravir Form A
  • FIG. 7 illustrate the IR of Raltegravir Form A
  • FIG. 8 illustrate the PXRD of Raltegravir Form B
  • FIG. 9 illustrate the DSC of Raltegravir Form B
  • FIG. 10 illustrate the TGA/DTA of Raltegravir Form B
  • Figure 11 illustrate the IR of Raltegravir Form B
  • Figure 12 illustrate the PXRD of amorphous Raltegravir potassium.
  • Figure 13 illustrate the DSC of amorphous Raltegravir potassium.
  • Figure 14 illustrate the IR of amorphous Raltegravir potassium.
  • FIG. 15 illustrate the PXRD of Raltegravir potassium Form 1.
  • Figure 16 illustrate the PXRD of Raltegravir potassium Form 2.
  • FIG. 17 illustrate the PXRD of Raltegravir potassium Form 3.
  • the present invention provides novel polymorphic forms of Raltegravir designated as crystalline Form A, Form B and amorphous form.
  • the present invention also provides novel amorphous form of Raltegravir potassium salt.
  • the present invention further relates to processes for the preparation of the said polymorphic forms.
  • the present invention also provides processes for the preparation of Raltegravir potassium Form 1, 2 and 3.
  • the present invention provides amorphous Raltegravir characterized by PXRD pattern as shown in Figure 1.
  • the amorphous form contains the water up to approximately 1.0 to 4.0 % by weight, preferably 1.0 to 2.0 % determined by the Karl- Fisher method.
  • the DSC thermogram of amorphous Raltegravir shows three characteristic peaks ( Figure 2); first endothermal peak at an extrapolated onset temperature ranging from 30 to 90 0 C corresponding to the moisture loss, an exothermic peak at an extrapolated onset temperature ranging from 120 to 140°C, corresponding to the transition from an amorphous phase to crystalline anhydrous phase which is identified with a peak at 131.7°C, and a second endothermal peak at 216.7°C (maxima), corresponding to the complete melting of the product.
  • Amorphous Raltegravir is further characterized by IR with absorption bands (cm "1 ) at 832, 1017, 1248, 1350, 1510, 1682, 2995, and 3374 respectively; as depicted in Figure 3.
  • the present invention provides process for the preparation of amorphous Raltegravir comprising the steps of: a) dissolving Raltegravir in a solvent to form a clear solution; b) removing the solvent; and c) isolating amorphous Raltegravir.
  • Raltegravir is suspended in a solvent selected from ketone, nitrile, halogenated solvents or mixture thereof; wherein ketone is selected from acetone, methyl isobutyl ketone (MIBK); nitrile is selected from acetonitrile; halogenated solvent is selected from dichloromethane, dichloroethane.
  • Raltegravir suspension is maintained at 20-40 0 C preferably 25-30°C for 10-20 min to obtain clear solution.
  • the present invention provides crystalline form of Raltegravir, referred to herein as Form A characterized by PXRD pattern as shown in Figure 4, having peaks at about 7.74, 8.03, 11.83, 15.11, 15.50, 16.08° ⁇ 0.2° two theta values.
  • Crystalline Raltegravir Form A is further characterized by PXRD peaks at about 7.74, 8.03, 11.83, 13.57, 15.11, 15.50, 16.08, 16.35, 22.60, 23.03 ⁇ 0.2° two theta values.
  • Crystalline Raltegravir Form A is further characterized by the DSC ( Figure 5), which 0 shows two broad endothermic peaks at an extrapolated onset temperature ranging from
  • Form A shows two step weight loss of about 4-7% attributing to solvent loss. Further, crystalline Raltegravir Form A contains the water up to approximately 4.0 to 6.0 % by weight, preferably 5.0 to 6.0 % determined by the Karl-Fisher method. Crystalline
  • Raltegravir Form A is preferably a hydrate.
  • Crystalline Raltegravir Form A is further characterized by IR with absorption bands (cm " ll )) aatt 664411,, 885555,, 11000033,, 11221188,, 11334422,, 1536, 1637, 1703, 3000, 3302, 3493 and 3582 respectively; as depicted in Figure 7.
  • the present invention provides process for the preparation of crystalline Raltegravir Form A comprising the steps of: a) suspending Raltegravir in a solvent; b) heating the suspension to form clear solution; and c) crystallizing the solution of step b) to isolate Raltegravir Form A.
  • Raltegravir is suspended in solvent selected from alcohols such as methanol, nitrile such as acetonitrile, ketones such as acetone, tetrahydrofuran, dimethyl sulfoxide, N-methyl pyrrolidone.
  • solvent selected from alcohols such as methanol, nitrile such as acetonitrile, ketones such as acetone, tetrahydrofuran, dimethyl sulfoxide, N-methyl pyrrolidone.
  • solvent selected from alcohols such as methanol, nitrile such as acetonitrile, ketones such as acetone, tetrahydrofuran, dimethyl sulfoxide, N-methyl pyrrolidone.
  • the present invention provides alternative process for the preparation of crystalline Raltegravir Form A comprising the steps of: a) suspending Raltegravir in a solvent; b) heating the suspension to form clear solution; c) adding anti-solvent; and d) isolating Raltegravir Form A.
  • Raltegravir is dissolved in suspended in solvent selected from dimethyl acetamide, dimethyl formamide, dimethyl sulfoxide, N-methyl pyrrolidone, 1,4-dioxane, acetic acid and pyridine.
  • solvent selected from dimethyl acetamide, dimethyl formamide, dimethyl sulfoxide, N-methyl pyrrolidone, 1,4-dioxane, acetic acid and pyridine.
  • solvent selected from dimethyl acetamide, dimethyl formamide, dimethyl sulfoxide, N-methyl pyrrolidone, 1,4-dioxane, acetic acid and pyridine.
  • solvent selected from dimethyl acetamide, dimethyl formamide, dimethyl sulfoxide, N-methyl pyrrolidone, 1,4-dioxane, acetic acid and pyridine.
  • the suspension is heated to high temperatures preferably 30-60° to obtain clear solution.
  • the present invention provides alternative process for the preparation of Raltegravir Form A comprising the steps of: a) suspending Raltegravir in a polar solvent; and b) 0 isolating Raltegravir Form A.
  • crystalline or amorphous Raltegravir is suspended in water and stirred at 25-30°C. The obtained solid is filtered to isolate Raltegravir Form A.
  • the present invention provides crystalline form of Raltegravir, referred to herein as Form B characterized by powder X-ray diffraction pattern as shown in Figure 8, having peaks at about 6.36, 12.73, 19.88, 20.20, 21.64 ⁇ 0.2° two theta values.
  • Crystalline Raltegravir Form B is further characterized by PXRD peaks at about 6.36, 8.26, 10.92, 12.73, 13.79, 15.55, 16.57, 19.88, 20.20, 21.64 ⁇ 0.2° two theta values.
  • Crystalline Raltegravir Form B is further characterized by the DSC ( Figure 9), which shows single melting endotherm at 216.5 °C. TGA/DTA ( Figure 10), of Raltegravir Form B shows no significant weight loss ( ⁇ 0.3%) attributing anhydrous form. Further, crystalline Raltegravir Form B contains less than 0.3 % as determined by the Karl-Fisher method. Crystalline Raltegravir Form B is preferably anhydrate.
  • Crystalline Raltegravir Form B is further characterized by IR with absorption bands (cm " ') at 488, 554, 641, 837, 1006, 1216, 1355, 1566, 1679, 3242, and 3404 respectively; as depicted in Figure 11.
  • the present invention provides process for the preparation of crystalline Raltegravir Form B comprising the steps of: a) suspending Raltegravir in a polar solvent or mixtures thereof; b) optionally heating the contents to form clear solution; and c) cooling the solution to isolate Raltegravir Form B.
  • Raltegravir is suspended in a solvent selected from esters such as ethyl acetate, ketones such as acetone, alcohol such as propanol or mixtures thereof.
  • the suspension is heated to 25-3O 0 C to obtain clear solution which is later allowed to crystallization forms Raltegravir Form B.
  • the present invention provides alternative process for the preparation of crystalline Raltegravir Form B comprising the steps of: a) dissolving Raltegravir in a solvent; b) adding isopropyl ether as anti-solvent; and c) drying to isolate Raltegravir Form B.
  • Raltegravir is dissolved in solvent selected from 1,4- dioxane, acetic acid, ketones such as acetone, alcohols such as methanol, esters such as ethyl acetate, aprotic polar solvents such as dimethyl acetamide, dimethyl formamide, N- methylpyrrolidine, aromatic solvents such as pyridine.
  • solvent selected from 1,4- dioxane, acetic acid, ketones such as acetone, alcohols such as methanol, esters such as ethyl acetate, aprotic polar solvents such as dimethyl acetamide, dimethyl formamide, N- methylpyrrolidine, aromatic solvents such as pyridine.
  • solvent selected from 1,4- dioxane, acetic acid, ketones such as acetone, alcohols such as methanol, esters such as ethyl acetate, aprotic polar solvents such as dimethyl acetamide, dimethyl formamide, N-
  • the present invention provides alternative process for the preparation of crystalline Raltegravir Form B comprising the steps of: a) suspending amorphous Raltegravir in isopropyl ether; and b) isolating Raltegravir Form B.
  • amorphous Raltegravir is suspended in isopropyl ether and stirred for 12-15 hrs at 25-30°C.
  • the product is filtered to obtain Raltegravir Form B.
  • the present invention provides amorphous Raltegravir potassium as shown in Figure 12.
  • the amorphous form contains the water up to approximately 5.0 to 7.0 % by weight, preferably 6.0 to 7.0 % determined by the Karl-Fisher method.
  • the DSC thermogram of amorphous Raltegravir potassium shows three characteristic peaks (Figure 13); first endothermal peak at an extrapolated onset temperature ranging from 30 to 130°C corresponding to the moisture loss, an exothermic peak at an extrapolated onset temperature ranging from 185 to 255 0 C, corresponding to the transition from amorphous phase to an crystalline anhydrous phase which is identified with a peak at 226.2°C, and a second endothermal peak at 272.2 0 C (maxima), corresponding to the complete melting of the product.
  • Amorphous Raltegravir potassium is further characterized by IR with absorption bands (cm "1 ) at 496, 571, 640, 830, 1218, 1280, 1510, 1639, 1680, and 3393 respectively; as depicted in Figure 14.
  • the present invention provides process for the preparation of amorphous Raltegravir potassium comprising the steps of: a) dissolving Raltegravir in a polar solvent; b) adding aqueous potassium hydroxide solution; c) removing the solvent; and d) isolating amorphous Raltegravir Potassium.
  • Raltegravir is dissolved in a solvent group selected from ketones, nitriles, wherein the ketone is selected from acetone, MIBK or mixtures thereof, nitrile is acetonitrile.
  • a solvent group selected from ketones, nitriles, wherein the ketone is selected from acetone, MIBK or mixtures thereof, nitrile is acetonitrile.
  • potassium hydroxide solution is added and stirred at 25-30°C.
  • the resulting clear solution is subjected to known distillation techniques such as vacuum distillation at 45-65°C preferably 50-60°C or spray drying in a Mini Spray Dryer (Model Buchi-290). Spray dryer is maintained in such a way that outlet temperature is 70-80°C with continuous purging of nitrogen to isolate amorphous Raltegravir potassium.
  • the present invention provides process for the preparation of Raltegravir Potassium Form 1 comprising the steps of: a) dissolving Raltegravir in a solvent; b) adding alcoholic potassium hydroxide solution; and c) isolating Raltegravir Potassium Form 1.
  • Raltegravir is dissolved in a solvent group selected from ketones, nitriles, wherein the ketone is selected from acetone, MIBK or mixtures thereof; nitrile is selected from acetonitrile and stirred for 10 min at 25-30°C.
  • a solvent group selected from ketones, nitriles, wherein the ketone is selected from acetone, MIBK or mixtures thereof; nitrile is selected from acetonitrile and stirred for 10 min at 25-30°C.
  • methanolic potassium hydroxide solution is added.
  • the solid obtained is filtered to get Raltegravir Potassium Form 1.
  • the present invention provides alternative process for the preparation of Raltegravir Potassium Form 1 comprising the steps of: a) suspending amorphous Raltegravir potassium in solvent; b) heating the suspension to get a clear solution; c) cooling the reaction mass; and d) isolating Raltegravir Potassium Form 1.
  • amorphous Raltegravir potassium is suspended in a solvent selected from alcohols, ketones, and nitroalkanes, wherein alcohol is selected from methanol, ethanol, isopropanol or mixtures thereof; ketone is selected from acetone,
  • nitro-alkane is selected from nitro methane, nitro-ethane or mixtures thereof.
  • the suspension is cleared at 25-30°C or subjected to heating at 60-75°C preferably 65-70 0 C.
  • the obtained filtrate is stirred at 25-30°C to precipitate out crystalline Raltegravir potassium Form 1.
  • the present invention provides alternative process for the preparation of Raltegravir Potassium Form 1 comprising the steps of: a) suspending amorphous Raltegravir potassium in solvent mixture; b) heating the suspension to get the clear solution; c) allowing the contents of step b) to evaporate slowly; and d) isolating Raltegravir potassium form 1.
  • amorphous Raltegravir potassium salt is suspended in solvent selected from alcohols such as methanol, ketones such as acetone or mixtures thereof.
  • solvent selected from alcohols such as methanol, ketones such as acetone or mixtures thereof.
  • the suspension is stirred at 25-3O 0 C to obtain clear solution which is subjected to slow evaporation to obtain Raltegravir potassium form 1.
  • the present invention provides process for the preparation of Raltegravir Potassium Form 2 comprising the steps of: a) suspending amoiphous Raltegravir Potassium in chlorinated solvents; and b) isolating Raltegravir potassium Form 2.
  • Raltegravir is suspended in chlorinated solvents such as dichloromethane and stirred at 25-30°C for 1-3 days, preferably 2 days.
  • the resulting solid is filtered to obtain Raltegravir Potassium Form 2.
  • the present invention provides process for the preparation of Raltegravir Potassium Form 3 comprising the steps of: a) suspending Raltegravir in solvent or mixture of solvents; b) stirring the suspension to obtain a clear solution; c) adding alcoholic potassium hydroxide solution; d) adding isopropyl ether as anti-solvent; and e) isolating Raltegravir potassium Form 3.
  • Raltegravir is suspended in a solvent selected from alcohols, ketones such as methanol, acetone or mixtures thereof.
  • a solvent selected from alcohols, ketones such as methanol, acetone or mixtures thereof.
  • the suspension is stirred to get clear solution and to this clear mass, methanolic potassium hydroxide solution is added.
  • Isopropyl ether is added to the solution as an anti-solvent to isolate crystalline Raltegravir Form 3.
  • the present invention provides process for the preparation of
  • Raltegravir Potassium Form 3 comprising the steps of: a) suspending Raltegravir in a solvent or mixture of solvents; b) stirring the suspension to obtain a clear solution; c) adding alcoholic potassium hydroxide solution; and d) isolating Raltegravir potassium
  • Raltegravir is suspended in a solvent selected from ester such as ethyl acetate.
  • the suspension is stirred to get clear solution and to this clear mass, methanolic potassium hydroxide solution is added.
  • the solid obtained is filtered to isolate Raltegravir Potassium Form 3.
  • the physical stability of the amorphous and novel polymorphic form B of Raltegravir and amorphous form of Raltegravir potassium salt was determined by storing approximately 3.0 g of the sample at 40°C/75% Relative Humidity (RH). The samples were tested by PXRD after 15 days, 1 month and 2months and the observed results are shown in below table.
  • the said polymorphs of the present invention are characterized by their X-ray powder diffraction pattern.
  • the X-ray diffraction patterns of said polymorphs of the invention were measured on PANalytical, X ⁇ ert PRO powder diffractometer equipped with goniometer of ⁇ / ⁇ configuration and X'Celerator detector.
  • the Cu-anode X-ray tube was operated at 4OkV and 3OmA. The experiments were conducted over the 2 ⁇ range of 2.0°-50.0°, 0.030° step size and 50 seconds step time.
  • the DSC measurements were carried out on TA QlOOO of TA instruments. The experiments were performed at a heating rate of 10.0 °C/min over a temperature range of 30°C-300°C purging with nitrogen at a flow rate of 50ml/min. Standard aluminum crucibles covered by lids with three pin holes were used.
  • TGA was recorded using the instrument TA Q5000 of TA instruments. The experiments were performed at a heating rate of 10.0 °C/min over a temperature range of 30°C-300°C purging with nitrogen at a flow rate of 25ml/min. Karl-Fisher
  • Water content was determined on Metrohm Karl-Fisher titrator (Model: 794 Basic Titrino) using pyridine free single solution (Merck, Mumbai) with sample mass between 450mg to 550mg.
  • FT-IR Fourier transform infrared
  • Raltegravir (2g) was dissolved in acetone (20 ml) and stirred for 10-15 min at 25-30 0 C. The clear solution was then distilled out completely under vacuum at 40-50°C. The solid isolated was identified as amorphous Raltegravir.
  • Raltegravir (2g) was suspended in acetonitrile (20 ml) and stirred for 10-15 min at 25- 30°C. The clear solution was then distilled out completely under vacuum at 40-50°C. The solid isolated was identified as amorphous Raltegravir.
  • Raltegravir (2g) was suspended in acetone (20 ml) and stirred at 25-30°C to get the clear solution.
  • the resulting clear solution was subjected to spray drying in a Mini Spray Dryer (Model Buchi - 290) at the outlet temperature of 70-80°C with purging of nitrogen gas.
  • the solid obtained was identified as amorphous Raltegravir.
  • Raltegravir Form B (1 g) is suspended in indicated solvents at the indicated volumes at 25-30°C and stir for 10 minutes. This slurry is heated for complete dissolution and allowed for crystallization at room temperature. The results obtained are displayed in the next table.
  • Raltegravir amorphous or Form B (Ig) was suspended in water (20 ml) and stirred for 12- 15 hrs at 25-30 0 C. The solid obtained was filtered and identified as Form A of Raltegravir.
  • Raltegravir Form A (Ig) is suspended in indicated solvents at the indicated volumes at 25-30°C and stir for 10 minutes. This slurry is optionally heated for complete dissolution followed by addition of an antisolvent and stirred for crystallization at room temperature. The results obtained are displayed in the next table.
  • Raltegravir (Ig) was dissolved in acetonitrile (10 ml) and stirred for 15-30 min at 25- 30°C. The clear solution is then added to prechilled isopropyl ether (80 ml) at -30 to - 20°C. The solid precipitated was filtered and dried under vacuum at 40-50 0 C for 4-5 hours. The solid obtained is identified as Form B of Raltegravir.
  • Raltegravir amorphous (Ig) was suspended in isopropyl ether (20 ml) and stirred for 12- 15 hrs at 25-30°C. The solid obtained was filtered and identified as Form B of Raltegravir.
  • Raltegravir (5gm) was dissolved in acetonitrile (196 ml) and stirred for 10 min at 25- 30°C. To this clear solution 0.5N aqueous potassium hydroxide solution (22.3 ml) was added and stirred the mass for 15-20 min at 25-30°C. The resulting clear solution was then distilled out completely under vacuum at 50-60°C. The solid isolated was identified as amorphous Raltegravir Potassium salt.
  • Raltegravir (5g) was dissolved in acetone (196 ml) and stirred for 10 min at 25-30°C.
  • acetone 196 ml
  • 0.5N aqueous potassium hydroxide solution (22.3 ml) was added and stirred for 15-20 min at 25-30 0 C.
  • the resultant solution was subjected to spray drying in a Mini Spray Dryer (Model Buchi-290) at the outlet temperature of 70-80°C with purging of nitrogen gas.
  • the solid obtained was identified as amorphous Raltegravir Potassium salt.
  • Raltegravir (Ig) was dissolved in acetonitrile (40 ml) and stirred for 10 min at 25-30°C. To this clear solution 0.5N methanolic potassium hydroxide solution (4.5 ml) was added and stirred for 15-20 min at 25-30 0 C. The solid obtained was filtered and identified as Form 1 of Raltegravir Potassium salt.
  • Raltegravir (Ig) was dissolved in acetone (40 ml) and stirred for 10 min at 25-30 0 C.
  • acetone 40 ml
  • 0.5N methanolic potassium hydroxide solution 4.5 ml
  • the solid obtained was filtered and identified as Form 1 of Raltegravir Potassium salt.
  • Raltegravir potassium salt (Ig) was suspended in nitro methane (12 ml) and heated at 65-7O 0 C to get the clear solution. The solution is then filtered through hyflo bed to remove any undissolved particulate. The clear filtrate was then stirred for 1 hr at 25- 3O 0 C during which the solid was precipitated out. The product obtained was filtered and identified as Form 1 of Raltegravir Potassium salt.
  • Example 18 Preparation of Raltegravir Potassium Form 1
  • Amorphous Raltegravir potassium salt (Ig) was suspended in 1 :1 mixture of methanol and acetone (40 ml) and stirred at 25-3O 0 C to get the clear solution.
  • the solution is then filtered through hyflo bed to remove any undissolved particulate.
  • the clear filtrate was then transferred to conical flask and allowed the solvent to evaporate slowly at 25-30°C.
  • the solid obtained was identified as Form 1 of Raltegravir Potassium salt.
  • Raltegravir potassium salt (Ig) was suspended in dichloromethane (20 ml) and stirred at 25-30°C for 2 days. The resulting solid obtained was filtered and identified as Form 2 of Raltegravir Potassium salt.
  • Raltegravir (5g) was suspended in 1 :1 mixture of methanol and acetone (40 ml) and stirred at 25-3O 0 C to get the clear solution.
  • 0.5N methanolic potassium hydroxide solution (4.5 ml) was added and stirred for 15-20 min at 25-30 0 C.
  • IPE 160 ml was added and stirred for 30 min at 25-30 0 C.
  • the solid obtained was filtered and identified as Form 3 of Raltegravir Potassium salt.
  • Raltegravir (5g) was suspended in ethyl acetate (450 ml) and stirred at 25-30 0 C to get the clear solution. To this solution 0.5N methanolic potassium hydroxide solution (2.3 ml) was added and stirred for 15-30 min at 25-30 0 C. The solid obtained was filtered and identified as Form 3 of Raltegravir Potassium salt.

Abstract

The present invention relates to novel polymorphic forms of Raltegravir and processes for its preparation thereof. The present invention further relates to an improved process for preparation of amorphous and crystalline Form 1, Form 2 and Form 3 of Raltegravir Potassium salt.

Description

This application claims priority to Indian patent application No. 1765/CHE/2009 filed on July 27, 2009 the contents of which are incorporated by reference in their entirety.
FIELD OF INVENTION
The present invention relates to novel polymorphic forms of Raltegravir and processes for its preparation thereof. The present invention further relates to an improved process for preparation of amorphous and crystalline Form 1, Form 2 and Form 3 of Raltegravir potassium salt.
BACKGROUND OF THE INVENTION
Raltegravir is an antiretroviral drag produced by Merck & Co and marketed as potassium salt used in combination with other anti-retroviral drugs to treat human immunodeficiency virus (HIV) infection. It is a first line HIV-integrase strand transfer inhibitor drug that targets Integrase, an HIV enzyme that integrates the viral genetic material into human chromosomes. The chemical name for Raltegravir potassium is N- [(4-fluorophenyl)methyl]-l,6-dihydro-5-hydroxy-l-methyl-2-[[(5-methyl-l,3,4- oxadiazol-2-yl)carbonyl] amino] ethyl] -6-oxo-4-pyrimidinecarboxamide monopotassium salt and is structurally represented by formula I. Raltegravir potassium salt is marketed under the brand name Isentress ®.
Figure imgf000002_0001
Raltegravir and it's pharmaceutically acceptable salts are disclosed in US 7,169,780. US 2006/0122205 Al discloses polymorphic forms of Raltegravir Potassium namely anhydrous crystalline potassium salt of Raltegravir (Form 1 and Form 3); hydrated crystalline potassium salt of Raltegravir (Form 2). In literature, polymorphs of Raltegravir are not known and during our recent studies on polymorphic screening inventors found two novel polymorphic forms Form A and Form B of Raltegravir and also amorphous form of Raltegravir. The Raltegravir polymorphic Form B and amorphous form of Raltegravir potassium salt of the present invention is having good stability and purity in different conditions and can also be prepared by an efficient, economic and reproducible process particularly in large scale preparation with free flowing nature.
OBJECT OF THE INVENTION Principle object of the present invention is to provide amorphous Raltegravir and process for preparation of the same.
Another principle object of the present invention is to provide novel Raltegravir Form A and process for preparation of the same.
Yet another principle object of the present invention is to provide novel Raltegravir Form B and process for preparation of the same.
Further principle object of the present invention is to provide amorphous Raltegravir potassium salt and process for preparation of the same.
Another principle object of the present invention is to provide improved process for preparation of Raltegravir potassium Form 1. Another principle object of the present invention is to provide improved process for preparation of Raltegravir potassium Form 2.
Another principle object of the present invention is to provide improved process for preparation of Raltegravir potassium Form 3. SUMMARY OF THE INVENTION
The main aspect of the present invention is to provide amorphous Raltegravir as shown in figure 1.
Another aspect of the present invention is to provide process for the preparation of amorphous Raltegravir comprising the steps of a) dissolving Raltegravir in a solvent to form a clear solution; b) removing the solvent; and c) isolating amorphous Raltegravir. In another aspect, the present invention provides crystalline form of Raltegravir, designated as Form A.
Another aspect of the present invention is to provide process for the preparation of crystalline Raltegravir Form A comprising the steps of: a) suspending Raltegravir in a solvent; b) heating the suspension to form clear solution; and c) crystallizing the solution of step b) to isolate Raltegravir Form A.
Another aspect of the present invention is to provide alternative process for the preparation of crystalline Raltegravir Form A comprising the steps of: a) suspending Raltegravir in a solvent; b) heating the suspension to form clear solution; c) adding anti- solvent; and d) isolating Raltegravir Form A.
Another aspect of the present invention is to provide alternative process for the preparation of Raltegravir Form A comprising the steps of: a) suspending Raltegravir in a polar solvent; and b) isolating Raltegravir Form A.
In another aspect, the present invention provides crystalline form of Raltegravir, designated as Form B.
Another aspect of the present invention is to provide process for the preparation of crystalline Raltegravir Form B comprising the steps of: a) suspending Raltegravir in a polar solvent or mixtures thereof; b) optionally heating the contents to form clear solution; and c) cooling the solution to isolate Raltegravir Form B. Another aspect of the present invention is to provide alternative process for the preparation of crystalline Raltegravir Form B comprising the steps of: a) dissolving Raltegravir in a solvent; b) adding isopropyl ether as anti-solvent; and c) isolating Raltegravir Form B.
Another aspect of the present invention is to provide alternative process for the preparation of crystalline Raltegravir Form B comprising the steps of: a) suspending amorphous Raltegravir in isopropyl ether; and b) isolating Raltegravir Form B.
In another aspect, the present invention provides amorphous Raltegravir potassium.
Another aspect of the present invention is to provide process for the preparation of amorphous Raltegravir potassium salt comprising the steps of: a) dissolving Raltegravir in a polar solvent; b) adding aqueous potassium hydroxide solution; c) removing the solvent; and d) isolating amorphous Raltegravir Potassium.
In another aspect, the present invention provides process for the preparation of Raltegravir Potassium Form 1 comprising the steps of: a) dissolving Raltegravir in a solvent; b) adding alcoholic potassium hydroxide solution; and c) isolating Raltegravir Potassium Form 1.
Another aspect of the present invention is to provide alternative process for the preparation of Raltegravir Potassium Form 1 comprising the steps of: a) suspending amorphous Raltegravir potassium in a solvent; b) heating the suspension to get the clear solution; c) cooling the reaction mass; and d) isolating Raltegravir Potassium Form 1.
Another aspect of the present invention is to provide alternative process for the preparation of Raltegravir Potassium Form 1 comprising the steps of: a) suspending amorphous Raltegravir potassium in solvent mixture; b) heating the suspension to get the clear solution; c) allowing the contents of step b) to evaporate slowly; and d) isolating Raltegravir potassium form 1. In another aspect, the present invention provides process for the preparation of Raltegravir Potassium Form 2 comprising the steps of: a) suspending amorphous Raltegravir Potassium in chlorinated solvents; and b) isolating Raltegravir potassium Form 2.
In another aspect, the present invention provides process for the preparation of Raltegravir Potassium Form 3 comprising the steps of: a) suspending Raltegravir in a solvent or mixture of solvents; b) stirring the suspension to obtain a clear solution; c) adding alcoholic potassium hydroxide solution; d) adding isopropyl ether as anti-solvent; and e) isolating Raltegravir potassium Form 3.
In another aspect, the present invention provides process for the preparation of Raltegravir Potassium Form 3 comprising the steps of: a) suspending Raltegravir in a solvent or mixture of solvents; b) stirring the suspension to obtain a clear solution; c) adding alcoholic potassium hydroxide solution; and d) isolating Raltegravir potassium Form 3.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 illustrate the PXRD of amorphous Raltegravir
Figure 2 illustrate the DSC of amorphous Raltegravir
Figure 3 illustrate the IR of amorphous Raltegravir
Figure 4 illustrate the PXRD of Raltegravir Form A
Figure 5 illustrate the DSC of Raltegravir Form A
Figure 6 illustrate the TGA/DTA of Raltegravir Form A
Figure 7 illustrate the IR of Raltegravir Form A
Figure 8 illustrate the PXRD of Raltegravir Form B
Figure 9 illustrate the DSC of Raltegravir Form B
Figure 10 illustrate the TGA/DTA of Raltegravir Form B
Figure 11 illustrate the IR of Raltegravir Form B Figure 12 illustrate the PXRD of amorphous Raltegravir potassium.
Figure 13 illustrate the DSC of amorphous Raltegravir potassium.
Figure 14 illustrate the IR of amorphous Raltegravir potassium.
Figure 15 illustrate the PXRD of Raltegravir potassium Form 1.
Figure 16 illustrate the PXRD of Raltegravir potassium Form 2.
Figure 17 illustrate the PXRD of Raltegravir potassium Form 3.
DETAILED DESCRIPTION OF THE INVENTION The present invention provides novel polymorphic forms of Raltegravir designated as crystalline Form A, Form B and amorphous form. The present invention also provides novel amorphous form of Raltegravir potassium salt. The present invention further relates to processes for the preparation of the said polymorphic forms. The present invention also provides processes for the preparation of Raltegravir potassium Form 1, 2 and 3.
In one embodiment, the present invention provides amorphous Raltegravir characterized by PXRD pattern as shown in Figure 1. The amorphous form contains the water up to approximately 1.0 to 4.0 % by weight, preferably 1.0 to 2.0 % determined by the Karl- Fisher method.
The DSC thermogram of amorphous Raltegravir shows three characteristic peaks (Figure 2); first endothermal peak at an extrapolated onset temperature ranging from 30 to 900C corresponding to the moisture loss, an exothermic peak at an extrapolated onset temperature ranging from 120 to 140°C, corresponding to the transition from an amorphous phase to crystalline anhydrous phase which is identified with a peak at 131.7°C, and a second endothermal peak at 216.7°C (maxima), corresponding to the complete melting of the product.
Amorphous Raltegravir is further characterized by IR with absorption bands (cm"1) at 832, 1017, 1248, 1350, 1510, 1682, 2995, and 3374 respectively; as depicted in Figure 3. The present invention provides process for the preparation of amorphous Raltegravir comprising the steps of: a) dissolving Raltegravir in a solvent to form a clear solution; b) removing the solvent; and c) isolating amorphous Raltegravir.
5 According to the present invention, Raltegravir is suspended in a solvent selected from ketone, nitrile, halogenated solvents or mixture thereof; wherein ketone is selected from acetone, methyl isobutyl ketone (MIBK); nitrile is selected from acetonitrile; halogenated solvent is selected from dichloromethane, dichloroethane. Raltegravir suspension is maintained at 20-400C preferably 25-30°C for 10-20 min to obtain clear solution. The
0 clear solution is subjected to distillation or spray drying to obtain amorphous Raltegravir.
In another embodiment, the present invention provides crystalline form of Raltegravir, referred to herein as Form A characterized by PXRD pattern as shown in Figure 4, having peaks at about 7.74, 8.03, 11.83, 15.11, 15.50, 16.08° ± 0.2° two theta values.
L5
Crystalline Raltegravir Form A is further characterized by PXRD peaks at about 7.74, 8.03, 11.83, 13.57, 15.11, 15.50, 16.08, 16.35, 22.60, 23.03 ± 0.2° two theta values.
Crystalline Raltegravir Form A is further characterized by the DSC (Figure 5), which 0 shows two broad endothermic peaks at an extrapolated onset temperature ranging from
80 to 1500C corresponding to solvent loss with peak maxima at 117.6°C and 139.60C, an exothermic peak at an extrapolated onset temperature ranging from 150 to 2000C, corresponding to the transition from a solvated phase to crystalline anhydrous phase which is identified with a peak at 176.60C, and a third endothermic peak at 216.9°C 5 (maxima), corresponding to the complete melting of the product. TGA of Raltegravir
Form A shows two step weight loss of about 4-7% attributing to solvent loss. Further, crystalline Raltegravir Form A contains the water up to approximately 4.0 to 6.0 % by weight, preferably 5.0 to 6.0 % determined by the Karl-Fisher method. Crystalline
Raltegravir Form A is preferably a hydrate.
0 Crystalline Raltegravir Form A is further characterized by IR with absorption bands (cm" ll)) aatt 664411,, 885555,, 11000033,, 11221188,, 11334422,, 1536, 1637, 1703, 3000, 3302, 3493 and 3582 respectively; as depicted in Figure 7.
5 The present invention provides process for the preparation of crystalline Raltegravir Form A comprising the steps of: a) suspending Raltegravir in a solvent; b) heating the suspension to form clear solution; and c) crystallizing the solution of step b) to isolate Raltegravir Form A.
0 According to the present invention, Raltegravir is suspended in solvent selected from alcohols such as methanol, nitrile such as acetonitrile, ketones such as acetone, tetrahydrofuran, dimethyl sulfoxide, N-methyl pyrrolidone. The suspension is heated to complete dissolution. The clear solution obtained is allowed for crystallization to obtain Raltegravir Form A.
[5
The present invention provides alternative process for the preparation of crystalline Raltegravir Form A comprising the steps of: a) suspending Raltegravir in a solvent; b) heating the suspension to form clear solution; c) adding anti-solvent; and d) isolating Raltegravir Form A.
0
According to the present invention, Raltegravir is dissolved in suspended in solvent selected from dimethyl acetamide, dimethyl formamide, dimethyl sulfoxide, N-methyl pyrrolidone, 1,4-dioxane, acetic acid and pyridine. The suspension is heated to high temperatures preferably 30-60° to obtain clear solution. To this clear solution, water or 5 isopropyl ether is added as an anti-solvent. The obtained solid is filtered to isolate Raltegravir Form A.
The present invention provides alternative process for the preparation of Raltegravir Form A comprising the steps of: a) suspending Raltegravir in a polar solvent; and b) 0 isolating Raltegravir Form A. According to the present invention, crystalline or amorphous Raltegravir is suspended in water and stirred at 25-30°C. The obtained solid is filtered to isolate Raltegravir Form A.
In another embodiment, the present invention provides crystalline form of Raltegravir, referred to herein as Form B characterized by powder X-ray diffraction pattern as shown in Figure 8, having peaks at about 6.36, 12.73, 19.88, 20.20, 21.64 ± 0.2° two theta values.
Crystalline Raltegravir Form B is further characterized by PXRD peaks at about 6.36, 8.26, 10.92, 12.73, 13.79, 15.55, 16.57, 19.88, 20.20, 21.64 ± 0.2° two theta values.
Crystalline Raltegravir Form B is further characterized by the DSC (Figure 9), which shows single melting endotherm at 216.5 °C. TGA/DTA (Figure 10), of Raltegravir Form B shows no significant weight loss (<0.3%) attributing anhydrous form. Further, crystalline Raltegravir Form B contains less than 0.3 % as determined by the Karl-Fisher method. Crystalline Raltegravir Form B is preferably anhydrate.
Crystalline Raltegravir Form B is further characterized by IR with absorption bands (cm" ') at 488, 554, 641, 837, 1006, 1216, 1355, 1566, 1679, 3242, and 3404 respectively; as depicted in Figure 11.
The present invention provides process for the preparation of crystalline Raltegravir Form B comprising the steps of: a) suspending Raltegravir in a polar solvent or mixtures thereof; b) optionally heating the contents to form clear solution; and c) cooling the solution to isolate Raltegravir Form B.
According to the present invention, Raltegravir is suspended in a solvent selected from esters such as ethyl acetate, ketones such as acetone, alcohol such as propanol or mixtures thereof. The suspension is heated to 25-3O0C to obtain clear solution which is later allowed to crystallization forms Raltegravir Form B. The present invention provides alternative process for the preparation of crystalline Raltegravir Form B comprising the steps of: a) dissolving Raltegravir in a solvent; b) adding isopropyl ether as anti-solvent; and c) drying to isolate Raltegravir Form B. According to the present invention, Raltegravir is dissolved in solvent selected from 1,4- dioxane, acetic acid, ketones such as acetone, alcohols such as methanol, esters such as ethyl acetate, aprotic polar solvents such as dimethyl acetamide, dimethyl formamide, N- methylpyrrolidine, aromatic solvents such as pyridine. Raltegravir suspension is maintained at 20-40°C preferably 25-30°C for 10-20 min to obtain clear solution. To the clear solution, anti solvent such as isopropyl ether is added and stirred for crystallization at room temperature. Product obtained is Raltegravir form B.
The present invention provides alternative process for the preparation of crystalline Raltegravir Form B comprising the steps of: a) suspending amorphous Raltegravir in isopropyl ether; and b) isolating Raltegravir Form B.
According to the present invention, amorphous Raltegravir is suspended in isopropyl ether and stirred for 12-15 hrs at 25-30°C. The product is filtered to obtain Raltegravir Form B.
In another embodiment, the present invention provides amorphous Raltegravir potassium as shown in Figure 12. The amorphous form contains the water up to approximately 5.0 to 7.0 % by weight, preferably 6.0 to 7.0 % determined by the Karl-Fisher method. The DSC thermogram of amorphous Raltegravir potassium shows three characteristic peaks (Figure 13); first endothermal peak at an extrapolated onset temperature ranging from 30 to 130°C corresponding to the moisture loss, an exothermic peak at an extrapolated onset temperature ranging from 185 to 2550C, corresponding to the transition from amorphous phase to an crystalline anhydrous phase which is identified with a peak at 226.2°C, and a second endothermal peak at 272.20C (maxima), corresponding to the complete melting of the product. Amorphous Raltegravir potassium is further characterized by IR with absorption bands (cm"1) at 496, 571, 640, 830, 1218, 1280, 1510, 1639, 1680, and 3393 respectively; as depicted in Figure 14.
The present invention provides process for the preparation of amorphous Raltegravir potassium comprising the steps of: a) dissolving Raltegravir in a polar solvent; b) adding aqueous potassium hydroxide solution; c) removing the solvent; and d) isolating amorphous Raltegravir Potassium.
According to the present invention, Raltegravir is dissolved in a solvent group selected from ketones, nitriles, wherein the ketone is selected from acetone, MIBK or mixtures thereof, nitrile is acetonitrile. To this clear solution, potassium hydroxide solution is added and stirred at 25-30°C. The resulting clear solution is subjected to known distillation techniques such as vacuum distillation at 45-65°C preferably 50-60°C or spray drying in a Mini Spray Dryer (Model Buchi-290). Spray dryer is maintained in such a way that outlet temperature is 70-80°C with continuous purging of nitrogen to isolate amorphous Raltegravir potassium. The present invention provides process for the preparation of Raltegravir Potassium Form 1 comprising the steps of: a) dissolving Raltegravir in a solvent; b) adding alcoholic potassium hydroxide solution; and c) isolating Raltegravir Potassium Form 1.
According to the present invention, Raltegravir is dissolved in a solvent group selected from ketones, nitriles, wherein the ketone is selected from acetone, MIBK or mixtures thereof; nitrile is selected from acetonitrile and stirred for 10 min at 25-30°C. To this clear solution, methanolic potassium hydroxide solution is added. The solid obtained is filtered to get Raltegravir Potassium Form 1. The present invention provides alternative process for the preparation of Raltegravir Potassium Form 1 comprising the steps of: a) suspending amorphous Raltegravir potassium in solvent; b) heating the suspension to get a clear solution; c) cooling the reaction mass; and d) isolating Raltegravir Potassium Form 1.
According to the present invention, amorphous Raltegravir potassium is suspended in a solvent selected from alcohols, ketones, and nitroalkanes, wherein alcohol is selected from methanol, ethanol, isopropanol or mixtures thereof; ketone is selected from acetone,
MIBK or mixtures thereof, nitro-alkane is selected from nitro methane, nitro-ethane or mixtures thereof. The suspension is cleared at 25-30°C or subjected to heating at 60-75°C preferably 65-700C. The obtained filtrate is stirred at 25-30°C to precipitate out crystalline Raltegravir potassium Form 1.
The present invention provides alternative process for the preparation of Raltegravir Potassium Form 1 comprising the steps of: a) suspending amorphous Raltegravir potassium in solvent mixture; b) heating the suspension to get the clear solution; c) allowing the contents of step b) to evaporate slowly; and d) isolating Raltegravir potassium form 1.
According to the present invention, amorphous Raltegravir potassium salt is suspended in solvent selected from alcohols such as methanol, ketones such as acetone or mixtures thereof. The suspension is stirred at 25-3O0C to obtain clear solution which is subjected to slow evaporation to obtain Raltegravir potassium form 1.
In another embodiment, the present invention provides process for the preparation of Raltegravir Potassium Form 2 comprising the steps of: a) suspending amoiphous Raltegravir Potassium in chlorinated solvents; and b) isolating Raltegravir potassium Form 2.
According to the present invention, Raltegravir is suspended in chlorinated solvents such as dichloromethane and stirred at 25-30°C for 1-3 days, preferably 2 days. The resulting solid is filtered to obtain Raltegravir Potassium Form 2. In another embodiment, the present invention provides process for the preparation of Raltegravir Potassium Form 3 comprising the steps of: a) suspending Raltegravir in solvent or mixture of solvents; b) stirring the suspension to obtain a clear solution; c) adding alcoholic potassium hydroxide solution; d) adding isopropyl ether as anti-solvent; and e) isolating Raltegravir potassium Form 3.
According to the present invention, Raltegravir is suspended in a solvent selected from alcohols, ketones such as methanol, acetone or mixtures thereof. The suspension is stirred to get clear solution and to this clear mass, methanolic potassium hydroxide solution is added. Isopropyl ether is added to the solution as an anti-solvent to isolate crystalline Raltegravir Form 3.
In another embodiment, the present invention provides process for the preparation of
Raltegravir Potassium Form 3 comprising the steps of: a) suspending Raltegravir in a solvent or mixture of solvents; b) stirring the suspension to obtain a clear solution; c) adding alcoholic potassium hydroxide solution; and d) isolating Raltegravir potassium
Form 3.
According to the present invention, Raltegravir is suspended in a solvent selected from ester such as ethyl acetate. The suspension is stirred to get clear solution and to this clear mass, methanolic potassium hydroxide solution is added. The solid obtained is filtered to isolate Raltegravir Potassium Form 3.
Physical Stability
The physical stability of the amorphous and novel polymorphic form B of Raltegravir and amorphous form of Raltegravir potassium salt was determined by storing approximately 3.0 g of the sample at 40°C/75% Relative Humidity (RH). The samples were tested by PXRD after 15 days, 1 month and 2months and the observed results are shown in below table.
Figure imgf000014_0001
Figure imgf000015_0001
From indicative stability data it appears that the amorphous form of Raltegravir Potassium and Raltegravir anhydrate Form B are physically stable up to two months whereas amorphous Raltegravir is converting into a mixture of crystalline Form B and Form A.
INSTRUMENTATION
Powder X-ray Diffraction (PXRD)
The said polymorphs of the present invention are characterized by their X-ray powder diffraction pattern. Thus, the X-ray diffraction patterns of said polymorphs of the invention were measured on PANalytical, XΨert PRO powder diffractometer equipped with goniometer of θ/θ configuration and X'Celerator detector. The Cu-anode X-ray tube was operated at 4OkV and 3OmA. The experiments were conducted over the 2Θ range of 2.0°-50.0°, 0.030° step size and 50 seconds step time.
Differential Scanning Calorimetry (DSO
The DSC measurements were carried out on TA QlOOO of TA instruments. The experiments were performed at a heating rate of 10.0 °C/min over a temperature range of 30°C-300°C purging with nitrogen at a flow rate of 50ml/min. Standard aluminum crucibles covered by lids with three pin holes were used.
Thermo gravimetric Analysis (TGA)
TGA was recorded using the instrument TA Q5000 of TA instruments. The experiments were performed at a heating rate of 10.0 °C/min over a temperature range of 30°C-300°C purging with nitrogen at a flow rate of 25ml/min. Karl-Fisher
Water content was determined on Metrohm Karl-Fisher titrator (Model: 794 Basic Titrino) using pyridine free single solution (Merck, Mumbai) with sample mass between 450mg to 550mg.
Infrared spectroscopy
Fourier transform infrared (FT-IR) spectra were recorded with a Perkin-Elmer spectrum one spectrophotometer. The samples were prepared as 13mm thickness potassium bromide discs by triturating 1 to 2mg of sample with 300mg to 400mg of KBR by applying pressure of about 1000 lbs/sq inch. Then these discs were scanned in the spectral range of 4000 to 650 cm"1 with a resolution of 4 cm"1.
In the foregoing section embodiments are described by way of examples to illustrate the process of invention. However, these are not intended in any way to limit the scope of the present invention and several variants of these examples would be evident to person ordinary skilled in the art.
Example 1: Preparation of amorphous Raltegravir
Raltegravir (2g) was dissolved in acetone (20 ml) and stirred for 10-15 min at 25-300C. The clear solution was then distilled out completely under vacuum at 40-50°C. The solid isolated was identified as amorphous Raltegravir.
Example 2: Preparation of amorphous Raltegravir
Raltegravir (2g) was suspended in acetonitrile (20 ml) and stirred for 10-15 min at 25- 30°C. The clear solution was then distilled out completely under vacuum at 40-50°C. The solid isolated was identified as amorphous Raltegravir.
Example 3: Preparation of amorphous Raltegravir
Raltegravir (2g) was suspended in dichloromethane (20 ml) and stirred for 10-15 min at 25-3O0C. The clear solution was then distilled out completely under vacuum at 40-500C. The solid isolated was identified as amorphous Raltegravir. Example 4: Preparation of amorphous Raltegravir
Raltegravir (2g) was suspended in acetone (20 ml) and stirred at 25-30°C to get the clear solution. The resulting clear solution was subjected to spray drying in a Mini Spray Dryer (Model Buchi - 290) at the outlet temperature of 70-80°C with purging of nitrogen gas. The solid obtained was identified as amorphous Raltegravir.
Example 5: Preparation of Raltegravir Form A by Crystallization
Raltegravir Form B (1 g) is suspended in indicated solvents at the indicated volumes at 25-30°C and stir for 10 minutes. This slurry is heated for complete dissolution and allowed for crystallization at room temperature. The results obtained are displayed in the next table.
Figure imgf000017_0001
Example 6: Preparation of Raltegravir Form A
Ig of Raltegravir Form B is suspended in indicated solvents at the indicated volumes at 25-300C and stir for 10 minutes. This slurry is optionally heated for complete dissolution followed by addition of an antisolvent and stirred for crystallization at room temperature. The results obtained are displayed in the next table.
Figure imgf000017_0002
Figure imgf000018_0001
Example 7: Preparation of Raltegravir Form A
Raltegravir amorphous or Form B (Ig) was suspended in water (20 ml) and stirred for 12- 15 hrs at 25-300C. The solid obtained was filtered and identified as Form A of Raltegravir.
Example 8: Preparation of Raltegravir Form B by Crystallization
Ig of Raltegravir Form A is suspended in indicated solvents at the indicated volumes at 25-30°C and stir for 10 minutes. This slurry is heated for complete dissolution and allowed for crystallization at room temperature. The results obtained are displayed in the next table.
Figure imgf000018_0002
Example 9: Preparation of Raltegravir Form B
Raltegravir Form A (Ig) is suspended in indicated solvents at the indicated volumes at 25-30°C and stir for 10 minutes. This slurry is optionally heated for complete dissolution followed by addition of an antisolvent and stirred for crystallization at room temperature. The results obtained are displayed in the next table.
Figure imgf000018_0003
Figure imgf000019_0001
Example 10: Preparation of Raltegravir Form B
Raltegravir (Ig) was dissolved in acetonitrile (10 ml) and stirred for 15-30 min at 25- 30°C. The clear solution is then added to prechilled isopropyl ether (80 ml) at -30 to - 20°C. The solid precipitated was filtered and dried under vacuum at 40-500C for 4-5 hours. The solid obtained is identified as Form B of Raltegravir.
Example 11: Preparation of Raltegravir Form B
Raltegravir amorphous (Ig) was suspended in isopropyl ether (20 ml) and stirred for 12- 15 hrs at 25-30°C. The solid obtained was filtered and identified as Form B of Raltegravir.
Example 12: Preparation of amorphous Raltegravir Potassium salt
Raltegravir (5gm) was dissolved in acetonitrile (196 ml) and stirred for 10 min at 25- 30°C. To this clear solution 0.5N aqueous potassium hydroxide solution (22.3 ml) was added and stirred the mass for 15-20 min at 25-30°C. The resulting clear solution was then distilled out completely under vacuum at 50-60°C. The solid isolated was identified as amorphous Raltegravir Potassium salt.
Example 13: Preparation of amorphous Raltegravir Potassium salt
Raltegravir (5g) was dissolved in acetonitrile (196 ml) and stirred for 10 min at 25-30°C.
To this clear solution 0.5N aqueous potassium hydroxide solution (22.3 ml) was added and stirred the mass for 15-20 min at 25-300C. The resulting clear solution was subjected to spray drying in a Mini Spray Dryer (Model Buchi-290) at the outlet temperature of 80- 900C with purging of nitrogen gas. The solid obtained was identified as amorphous Raltegravir Potassium salt.
Example 14: Preparation of amorphous Raltegravir Potassium salt
Raltegravir (5g) was dissolved in acetone (196 ml) and stirred for 10 min at 25-30°C. To this clear solution 0.5N aqueous potassium hydroxide solution (22.3 ml) was added and stirred for 15-20 min at 25-300C. The resultant solution was subjected to spray drying in a Mini Spray Dryer (Model Buchi-290) at the outlet temperature of 70-80°C with purging of nitrogen gas. The solid obtained was identified as amorphous Raltegravir Potassium salt.
Example 15: Preparation of Raltegravir Potassium Form 1
Raltegravir (Ig) was dissolved in acetonitrile (40 ml) and stirred for 10 min at 25-30°C. To this clear solution 0.5N methanolic potassium hydroxide solution (4.5 ml) was added and stirred for 15-20 min at 25-300C. The solid obtained was filtered and identified as Form 1 of Raltegravir Potassium salt.
Example 16: Preparation of Raltegravir Potassium Form 1
Raltegravir (Ig) was dissolved in acetone (40 ml) and stirred for 10 min at 25-300C. To this clear solution 0.5N methanolic potassium hydroxide solution (4.5 ml) was added and stirred for 15-20 min at 25-300C. The solid obtained was filtered and identified as Form 1 of Raltegravir Potassium salt.
Example 17: Preparation of Raltegravir Potassium Form 1
Amorphous Raltegravir potassium salt (Ig) was suspended in nitro methane (12 ml) and heated at 65-7O0C to get the clear solution. The solution is then filtered through hyflo bed to remove any undissolved particulate. The clear filtrate was then stirred for 1 hr at 25- 3O0C during which the solid was precipitated out. The product obtained was filtered and identified as Form 1 of Raltegravir Potassium salt.
Example 18: Preparation of Raltegravir Potassium Form 1 Amorphous Raltegravir potassium salt (Ig) was suspended in 1 :1 mixture of methanol and acetone (40 ml) and stirred at 25-3O0C to get the clear solution. The solution is then filtered through hyflo bed to remove any undissolved particulate. The clear filtrate was then transferred to conical flask and allowed the solvent to evaporate slowly at 25-30°C. The solid obtained was identified as Form 1 of Raltegravir Potassium salt.
Example 19: Preparation of Raltegravir Potassium Form 2
Amorphous Raltegravir potassium salt (Ig) was suspended in dichloromethane (20 ml) and stirred at 25-30°C for 2 days. The resulting solid obtained was filtered and identified as Form 2 of Raltegravir Potassium salt.
Example 20: Preparation of Raltegravir Potassium Form 3
Raltegravir (5g) was suspended in 1 :1 mixture of methanol and acetone (40 ml) and stirred at 25-3O0C to get the clear solution. To this solution 0.5N methanolic potassium hydroxide solution (4.5 ml) was added and stirred for 15-20 min at 25-300C. To this clear solution IPE (160 ml) was added and stirred for 30 min at 25-300C. The solid obtained was filtered and identified as Form 3 of Raltegravir Potassium salt.
Example 21: Preparation of Raltegravir Potassium Form 3
Raltegravir (5g) was suspended in ethyl acetate (450 ml) and stirred at 25-300C to get the clear solution. To this solution 0.5N methanolic potassium hydroxide solution (2.3 ml) was added and stirred for 15-30 min at 25-300C. The solid obtained was filtered and identified as Form 3 of Raltegravir Potassium salt.

Claims

We Claim:
1. Amorphous Raltegravir.
2. A process for the preparation of amorphous Raltegravir comprising the steps of: a) dissolving Raltegravir in a solvent to form a clear solution;
b) removing the solvent; and
c) isolating amorphous Raltegravir.
3. Crystalline Raltegravir Form A.
4. The crystalline Raltegravir Form A according to claim 2, which is characterized by powder X-ray diffraction chromatogram having peaks at about 7.74, 8.03, 11.82,
15.10, 15.50, 16.08 ± 0.2Θ values.
5. A process for the preparation of crystalline Raltegravir Form A comprising the steps of:
a) suspending Raltegravir in a solvent;
b) heating the suspension to form clear solution; and
c) crystallizing the solution of step b) to isolate Raltegravir Form A.
6. A process for the preparation of crystalline Raltegravir Form A comprising the steps of:
a) suspending Raltegravir in a solvent;
b) heating the suspension to form clear solution;
c) adding anti-solvent; and
d) isolating Raltegravir Form A.
7. A process for the preparation of Raltegravir Form A comprising the steps of: a) suspending Raltegravir in a polar solvent; and b) isolating Raltegravir Form A.
8. Crystalline Raltegravir Form B.
9. The crystalline Raltegravir Form B according to claim 8, which is characterized by powder X-ray diffraction chromatogram having peaks at about 6.35, 8.25, 12.72, 19.88, 20.19, 21.63 ± 0.20 values.
10. A process for the preparation of crystalline Raltegravir Form B comprising the steps of:
a) suspending Raltegravir in a polar solvent or mixtures thereof; b) optionally heating the contents to form clear solution; and
c) cooling the solution to isolate Raltegravir Form B.
11. A process for the preparation of crystalline Raltegravir Form B comprising the steps of:
5 a) dissolving Raltegravir in a solvent;
b) adding isopropyl ether as anti-solvent; and
c) isolating Raltegravir Form B.
12. A process for the preparation of crystalline Raltegravir Form B comprising the steps of: a) suspending amorphous Raltegravir in isopropyl ether; and
0 b) isolating Raltegravir Form B.
13. A process for the preparation of amorphous Raltegravir potassium salt comprising the steps of:
a) dissolving Raltegravir in a polar solvent;
b) adding aqueous potassium hydroxide solution;
5 c) removing the solvent; and
d) isolating amorphous Raltegravir Potassium.
14. A process for the preparation of Raltegravir Potassium Form 1 comprising the steps of:
a) dissolving Raltegravir in a solvent;
>0 b) adding alcoholic potassium hydroxide solution; and
c) isolating Raltegravir Potassium Form 1.
15. A process for the preparation of Raltegravir Potassium Form 1 comprising the steps of:
a) suspending amorphous Raltegravir potassium in a solvent;
15 b) heating the suspension to get the clear solution;
c) cooling the reaction mass; and
d) isolating Raltegravir Potassium Form 1.
16. A process for the preparation of Raltegravir Potassium Form 1 comprising the steps of:
0 a) suspending amorphous Raltegravir potassium in solvent mixture;
b) heating the suspension to get the clear solution; c) allowing the contents of step b) to evaporate slowly; and
d) isolating Raltegravir potassium Form 1.
17. A process for the preparation of Raltegravir Potassium Form 2 comprising the steps of:
a) suspending amorphous Raltegravir in chlorinated solvents; and
b) isolating Raltegravir Potassium Form 2.
18. A process for the preparation of Raltegravir Potassium Form 3 comprising the steps of:
a) suspending Raltegravir in a solvent or mixture of solvents;
b) stirring the suspension to obtain a clear solution;
c) adding alcoholic potassium hydroxide solution;
d) adding isopropyl ether as anti-solvent; and
e) isolating Raltegravir Potassium Form 3.
19. A process for the preparation of Raltegravir Potassium Form 3 comprising the steps of:
a) suspending Raltegravir in a solvent or mixture of solvents;
b) stirring the suspension to obtain a clear solution;
c) adding alcoholic Potassium hydroxide solution; and
d) isolating Raltegravir Potassium Form 3.
PCT/IN2010/000490 2009-07-27 2010-07-26 Novel polymorphs of raltegravir WO2011024192A2 (en)

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WO2011123754A1 (en) 2010-04-01 2011-10-06 Teva Pharmaceutical Industries Ltd. Raltegravir salts and crystalline forms thereof
WO2012103105A1 (en) 2011-01-24 2012-08-02 Assia Chemical Industries Ltd. Processes for preparing raltegravir and intermediates in the processes
WO2012137142A1 (en) 2011-04-06 2012-10-11 Lupin Limited Novel salts of raltegravir
WO2012145446A1 (en) * 2011-04-22 2012-10-26 Merck Sharp & Dohme Corp. Taste-masked formulations of raltegravir
WO2013037731A1 (en) 2011-09-16 2013-03-21 Hexal Ag Novel polymorphic form of raltegravir potassium
US8742105B2 (en) 2009-06-02 2014-06-03 Hetero Research Foundation Polymorphs of raltegravir potassium
JP2015504913A (en) * 2012-01-25 2015-02-16 ルピン・リミテッドＬｕｐｉｎ Ｌｉｍｉｔｅｄ Stable amorphous raltegravir potassium premix and preparation method thereof
WO2015114608A1 (en) 2014-02-03 2015-08-06 Mylan Laboratories Ltd Processes for the preparation of intermediates of raltegravir
WO2018051239A1 (en) 2016-09-15 2018-03-22 Lupin Limited Process for the preparation of pure and stable crystalline raltegravir potassium form 3
US10391178B2 (en) * 2014-03-21 2019-08-27 Mylan Laboratories Limited Premix of crystalline raltegravir potassium salt and a process for the preparation thereof

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US8742105B2 (en) 2009-06-02 2014-06-03 Hetero Research Foundation Polymorphs of raltegravir potassium
EP2796458A1 (en) 2010-04-01 2014-10-29 Teva Pharmaceutical Industries Ltd. Crystalline raltegravir sodium salts
WO2011123754A1 (en) 2010-04-01 2011-10-06 Teva Pharmaceutical Industries Ltd. Raltegravir salts and crystalline forms thereof
US8722722B2 (en) 2010-04-01 2014-05-13 Teva Pharmaceutical Industries Ltd Raltegravir salts and crystalline forms thereof
WO2012103105A1 (en) 2011-01-24 2012-08-02 Assia Chemical Industries Ltd. Processes for preparing raltegravir and intermediates in the processes
WO2012137142A1 (en) 2011-04-06 2012-10-11 Lupin Limited Novel salts of raltegravir
US9163009B2 (en) 2011-04-06 2015-10-20 Lupin Limited Salts of raltegravir
WO2012145446A1 (en) * 2011-04-22 2012-10-26 Merck Sharp & Dohme Corp. Taste-masked formulations of raltegravir
WO2013037731A1 (en) 2011-09-16 2013-03-21 Hexal Ag Novel polymorphic form of raltegravir potassium
JP2015504913A (en) * 2012-01-25 2015-02-16 ルピン・リミテッドＬｕｐｉｎ Ｌｉｍｉｔｅｄ Stable amorphous raltegravir potassium premix and preparation method thereof
WO2015114608A1 (en) 2014-02-03 2015-08-06 Mylan Laboratories Ltd Processes for the preparation of intermediates of raltegravir
US10391178B2 (en) * 2014-03-21 2019-08-27 Mylan Laboratories Limited Premix of crystalline raltegravir potassium salt and a process for the preparation thereof
WO2018051239A1 (en) 2016-09-15 2018-03-22 Lupin Limited Process for the preparation of pure and stable crystalline raltegravir potassium form 3
US10752618B2 (en) 2016-09-15 2020-08-25 Lupin Limited Process for the preparation of pure and stable crystalline Raltegravir potassium form 3

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