DESC:The following specification describes the invention and the manner in which it is to be performed:

INTRODUCTION

Aspects of the present application relate to improved process for the preparation of amorphous Raltegravir potassium and Raltegravir potassium Form-3.

Raltegravir is an antiretroviral drug 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 chemically described as N-[(4-Fluorophenyl)methyl]-1,6-dihydro-5-hydroxy-1-methyl-2-[1-methyl-1-[[(5-methyl-1,3,4-oxadiazol-2-yl)carbonyl]amino]ethyl]-6-oxo-4-pyrimidinecarboxamide monopotassium salt and it has the structure of Formula (I). Raltegravir potassium salt is marketed under the brand name Isentress®.

(I)
Raltegravir and it's pharmaceutically acceptable salts are disclosed in US 7,169,780. US 7,754,731 describes the 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). US 7,754,731 describes the preparation of form-3 of Raltegravir potassium by crystallization of amorphous Raltegravir potassium from ethanol.

International Application Publication No. WO 2010/140156 A2 describes amorphous form and crystalline form H1 of Raltegravir potassium. The amorphous form is obtained by freeze drying the aqueous solution of Raltegravir potassium at -180°C. International Application Publication No. 2011/024192 A2 describes 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.

International Application Publication No. 2011/024192 A2 describes 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.

Though, there are processes available in the literature for the preparation of amorphous Raltegravir potassium and Raltegravir potassium Form-3. Still there remains a need for the simple and cost effective process for the preparation of amorphous Raltegravir potassium and Raltegravir potassium Form-3.

SUMMARY

In an aspect, the application provides a process for the preparation of amorphous Raltegravir potassium, comprising the steps of;

a) providing a solution of Raltegravir potassium in water;
b) removing the water from the solution as obtained in step a), by spray drying; and
c) isolating the amorphous Raltegravir potassium.
In another aspect, the application provides a process for the preparation of Raltegravir potassium Form-3, comprising the steps of;
a) providing a solution or suspension of Raltegravir in ethanol;
b) adding aqueous potassium hydroxide solution to the solution or suspension as obtained in step a);
c) optionally adding the seed material; and
d) isolating Raltegravir potassium Form-3.
In another aspect, the application provides a pharmaceutical composition comprising the amorphous Raltegravir potassium or Raltegravir potassium Form-3 together with one or more pharmaceutically acceptable excipients.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 illustrates an X-ray powder diffraction pattern of amorphous Raltegravir potassium obtained according to the procedure of example-1.
Figure 2 illustrates an X-ray powder diffraction pattern of Raltegravir potassium Form-3 obtained according to the procedure of example-2.

DETAILED DESCRIPTION

In an aspect, the application provides a process for the preparation of amorphous Raltegravir potassium, comprising the steps of;
a) providing a solution of Raltegravir potassium in water;
b) removing the water from the solution as obtained in step a), by spray drying; and
c) isolating the amorphous Raltegravir potassium.

In embodiments of step a), Raltegravir potassium can be dissolved in water to provide a solution. In embodiments, a solution of Raltegravir potassium can be prepared at any suitable temperatures, such as from about room temperature to about the boiling point of water. Mixing may be used to reduce the time required for the dissolution process. In embodiments, a solution of Raltegravir potassium may be filtered to make it clear, free of undissolved particles. In embodiments, the obtained solution may be optionally treated with a decolorizing agent or an adsorbent material, such as carbon and/or hydrose, to remove colored components, etc., before filtration.

In embodiments of step b), the clear solution of Raltegravir potassium as obtained in step a) is subjected to spray drying. Spray drying is maintained in such a way that outlet temperature is 50 to 80°C with continuous purging of nitrogen to isolate amorphous Raltegravir potassium.

In embodiments of step c), amorphous Raltegravir potassium that is isolated can be dried at suitable temperatures such as room temperature to about 120°C under atmospheric or reduced pressures, for about 10 minutes to about 50 hours, or longer, using any types of drying equipment, such as a tray dryer, vacuum oven, fluidized bed dryer, spin flash dryer, flash dryer, or the like.
In another aspect, the application provides a process for the preparation of Raltegravir potassium Form-3, comprising the steps of;
a) providing a solution or suspension of Raltegravir in ethanol;
b) adding aqueous potassium hydroxide solution to the solution or suspension as obtained in step a);
c) optionally adding the seed material; and
d) isolating Raltegravir potassium Form-3.
In embodiments of step a), Raltegravir can be dissolved in ethanol to provide a solution. In embodiments, a solution of Raltegravir can be prepared at any suitable temperatures, such as from about room temperature to about the reflux temperature of the solvent. Raltegravir solution can also be obtained directly from reaction mixtures in the final stage of process for preparing Raltegravir. Mixing may be used to reduce the time required for the dissolution process. In embodiments, a solution of Raltegravir may be filtered to make it clear, free of undissolved particles. In embodiments, the obtained solution may be optionally treated with a decolorizing agent or an adsorbent material, such as carbon and/or hydrose, to remove colored components, etc., before filtration. In embodiments of step a), the suspension of raltegravir in ethanol can also be used in place of the solution as discussed above.

In embodiments of step b), an aqueous solution of potassium hydroxide may be added to the solution or suspension of raltegravir in ethanol as obtained in step a) to obtain Raltegravir potassium. The aqueous solution of potassium hydroxide may be added drop wise or in one lot at a temperature ranging from about -10 to 50°C, preferably at the temperature about 0 to 20°C.
In embodiments of step c), optionally the seed material may be added to the slurry or suspension obtained in step b). The seed material used in the step b) is Raltegravir potassium Form-3. The seed material may be added either in solid form or by making slurry in ethanol. The seed material may be required to reproduce consistently Raltegravir potassium Form-3. A sufficient quantity of the seed material may be used to get Raltegravir potassium Form-3 consistently. The Raltegravir potassium Form-3 which is used as a seed material can be obtained by the procedures known in the art.

In embodiments, the slurry comprising precipitated Raltegravir potassium Form-3 can be maintained at any suitable temperatures, such as at a temperature ranging from about -10 to 50°C, preferably at the temperature about 0 to 20°C. In general, yields of the crystalline product will be improved by maintaining the reaction mass at lower temperatures that are above the freezing point of the solvents and/or by increasing the solute content of the solution. In embodiments, the slurry comprising precipitated Raltegravir potassium Form-3 can be maintained for about 10 minutes to about 10 hours, or longer.

In embodiments of step d), Raltegravir potassium Form-3 can be isolated by using any techniques, such as decantation, filtration by gravity or suction, centrifugation, or the solvent can be evaporated from the mass to obtain the desired product, and optionally the solid can be washed with a solvent, such as the solvent used for the crystallization to reduce the amount of entrained impurities in the product. In embodiments, Raltegravir potassium Form-3 can be isolated by filtration.

In embodiments of step d), Raltegravir potassium Form-3 that is isolated can be dried at suitable temperatures such as room temperature to about 120°C under atmospheric or reduced pressures, for about 10 minutes to about 50 hours, or longer, using any types of drying equipment, such as a tray dryer, vacuum oven, air oven, fluidized bed dryer, spin flash dryer, flash dryer, or the like.

In embodiments, Raltegravir potassium or Raltegravir which is used as the starting material for the preparation of amorphous Raltegravir potassium or Raltegravir potassium Form-3 as described in the present application can be prepared by the procedure as described in the art. In embodiments, Raltegravir potassium or Raltegravir which is used as the starting material for the preparation of amorphous Raltegravir potassium or Raltegravir potassium Form-3 as described in the present application can be in any known or unknown crystalline form, anhydrous form, hydrated form, solvate or amorphous form.
X-ray powder diffraction patterns described herein were generated using a PAnalytical X Pert Pro powder X-ray diffractometer, with a copper K-alpha radiation source. Generally, a diffraction angle (2?) in powder X-ray diffractometry may have an error in the range of ±0.2°. Therefore, the aforementioned diffraction angle values should be understood as including values in the range of about ± 0.2°. Accordingly, the present invention includes not only crystals whose peak diffraction angles in powder X-ray diffractometry completely coincide with each other, but also crystals whose peak diffraction angles coincide with each other with an error of about ± 0.2°. Therefore, in the present specification, the phrase "having a diffraction peak at a diffraction angle (2?) ±0.2° of 8.2°" means "having a diffraction peak at a diffraction angle (2?) of 8.0° to 8.4°. Although the intensities of peaks in the x-ray powder diffraction patterns of different batches of a compound may vary slightly, the peak relationships and the peak locations are characteristic for a specific polymorphic form. The relative intensities of the PXRD peaks can vary somewhat, depending on factors such as the sample preparation technique, crystal size distribution, various filters used, the sample mounting procedure, and the particular instrument employed. Moreover, instrumental variation and other factors can slightly affect the 2-theta values. Therefore, the term "substantially" in the context of PXRD is meant to encompass that peak assignments can vary by plus or minus about 0.2°. Moreover, new peaks may be observed or existing peaks may disappear, depending on the type of the machine or the settings (for example, whether a filter is used or not).
In embodiments, amorphous Raltegravir potassium or Raltegravir potassium Form-3 as described in this application may be optionally milled to get desired particle sizes. Milling or micronization may be performed before drying, or after the completion of drying of the product. Techniques that may be used for particle size reduction include, without limitation, ball, roller and hammer mills, and jet mills.
In an aspect of the application, amorphous Raltegravir potassium or Raltegravir potassium Form-3 prepared according to the processes of the present application can be substantially pure having a chemical purity greater than about 99%, or greater than about 99.5%, or greater than about 99.9%, by weight, as determined using high performance liquid chromatography (HPLC). Amorphous Raltegravir potassium or Raltegravir potassium Form-3 produced by the method of present invention can be chemically pure having purity greater than about 99.5% and containing no single impurity in amounts greater than about 0.15%, by HPLC. Amorphous Raltegravir potassium or Raltegravir potassium Form-3 produced by the methods of present invention can be chemically pure having purity greater than about 99.8% and containing no single impurity in amounts greater than about 0.1%, by HPLC.
In an aspect of the application, amorphous Raltegravir potassium or Raltegravir potassium Form-3 as obtained by the methods of the present application can be further purified by using techniques known in the art to enhance its chemical purity. In embodiments, optionally a decolorizing agent may be used to remove the colored impurities or any other impurities to enhance its chemical purity.
In an aspect of the application, Raltegravir potassium Form-3 is stable for more than six months at all three ICH specified conditions with two packaging options, Option-1 and Option-2A. The three ICH specified conditions are 2°C to 8°C; 25°C / 60 ± 5 % relative humidity and 40°C / 75 ± 5 % relative humidity.
Option-1 packing procedure: Take clear polyethylene bag flush with nitrogen, place the sample in it, tie it properly with thread by twisting after removing the air as far as possible and keep it in a black polyethylene bag and seal it. Keep the above in triple laminated bag along with silica gel pouch and seal it with multi sealer and label it properly. Finally keep the packed sample in HDPE container and store.
Option-2A packing procedure: Take clear polyethylene bag flush with nitrogen, place the sample in it and tie it properly with thread. Keep it in a black polyethylene bag along with silica gel pouch and fill it with nitrogen and seal it. Keep the above in triple laminated bag along with silica gel pouch and seal it with VNS sealer. Keep this again in triple laminated bag along with silica gel pouch, seal it with VNS sealer and label it properly. Finally, keep the packed sample in HDPE container and store.
An aspect of the present application provides a pharmaceutical composition containing a therapeutically effective amount of amorphous Raltegravir potassium or Raltegravir potassium Form-3 as described herein in the present application, together with one or more pharmaceutically acceptable excipients. Pharmaceutically acceptable excipients that are useful in the present application include, but are not limited to, any one or more of: diluents such as starches, pregelatinized starches, powdered cellulose, microcrystalline cellulose, dicalcium phosphate, tricalcium phosphate, mannitol, sorbitol, sugar, or the like; binders such as acacia, guar gum, tragacanth, gelatin, polyvinylpyrrolidones, hydroxypropyl celluloses, hydroxypropyl methylcelluloses, pregelatinized starches, or the like; disintegrants such as starches, sodium starch glycolate, pregelatinized starches, crospovidones, croscarmellose sodium, colloidal silicon dioxide, or the like; lubricants such as stearic acid, magnesium stearate, zinc stearate, or the like; glidants such as colloidal silicon dioxide or the like; solubility or wetting enhancers such as anionic, cationic, and neutral surfactants; complex forming agents such as various grades of cyclodextrins and resins; and release rate controlling agents such as hydroxypropyl celluloses, hydroxymethyl celluloses, hydroxypropyl methylcelluloses, ethylcelluloses, methylcelluloses, various grades of methyl methacrylates, waxes, or the like. Other pharmaceutically acceptable excipients that are useful include, but are not limited to, film-formers, plasticizers, colorants, flavoring agents, sweeteners, viscosity enhancers, preservatives, antioxidants, or the like.

DEFINITIONS
The following abbreviations and acronyms are used herein and have the indicated definitions:
A “decolorizing agent” removes colored impurities by adsorption on the surface of the “decolorizing agent” particles. Examples of a “decolorizing agent” include, decolorizing carbon, activated alumina, activated clay, or silica gel.
Certain specific aspects and embodiments of the present application will be explained in greater detail with reference to the following examples, which are provided only for purposes of illustration and should not be construed as limiting the scope of the application in any manner. Variations of the described procedures, as will be apparent to those skilled in the art, are intended to be within the scope of the present application.

Examples
Example-1: Preparation of amorphous Raltegravir potassium
Raltegravir potassium (50 g) and water (1250 mL) were charged into a flask at 26°C and stirred to get a solution. The obtained solution was filtered to obtain a clear solution. The resulting clear solution was subjected to spray drying in a Mini Spray Dryer (Model Buchi-290) at the outlet temperature of 60°C with purging of nitrogen gas. The solid product was obtained as amorphous Raltegravir potassium. The material was kept for drying at 110°C for 7 hours. The PXRD pattern of the obtained product was substantially according to Figure-1.

Example-2: Preparation of Raltegravir potassium Form-3
Raltegravir (5 g) and ethanol (100 mL) were charged into the easy max reactor and stirred for 10 minutes to get a suspension at 0-5°C. 25% aqueous potassium hydroxide solution (3 mL) was added to the reactor and maintained for 30 minutes at 0-5°C. Raltegravir potassium Form-3 (0.5 g) as seed material was added to the reactor and stirred for 30 minutes at the same temperature. The precipitated product was collected by filtration and dried at 40°C for 40 minutes. Yield: 3.98 g;
The PXRD pattern of the obtained product was substantially according to Figure-2.

,CLAIMS:We claim

1. A process for the preparation of amorphous Raltegravir potassium, comprising the steps of
a. providing a solution of Raltegravir potassium in water;
b. removing the water from the solution as obtained in step a), by spray drying; and
c. isolating the amorphous Raltegravir potassium.

2. A process of claim 1, wherein the out let temperature of spray dryer is maintained at 50°C and above.

3. A process of claim 1, wherein spray drying is carried out under nitrogen atmosphere.

4. A process for the preparation of Raltegravir potassium Form-3, comprising the steps of
a. providing a solution or suspension of Raltegravir in ethanol;
b. adding aqueous potassium hydroxide solution to the solution or suspension as obtained in step a;
c. optionally adding the seed material; and
d. isolating Raltegravir potassium Form-3.

5. A process of claim 4, wherein solution or suspension of Raltegravir of step a is obtained directly from reaction mixtures in the final stage of process for preparing Raltegravir.

6. A process of claim 4, wherein aqueous potassium hydroxide solution is added drop wise or in one lot.

7. A process of claim 4, wherein aqueous potassium hydroxide solution is added at a temperature about 0 to 20°C.

8. A process of claim 4, wherein seed material is added either in solid form or by making slurry in ethanol.