FORM 2
THE PATENTS ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)

1. “CRYSTALLINE FORM OF RALTEGRAVIR POTASSIUM AND PROCESSES FOR ITS PREPARATION”

2.

1. (A) APOTEX PHARMACHEM INDIA PVT. LTD.
(B) INDIA.
(C) Plot No. 1A, Bommasandra Industrial Area, 4th Phase
Jigani Link Road, Bommasandra, BANGALORE - 560 099, INDIA

The following specification particularly describes the invention and the manner in which it is to be performed.

TECHNICAL FIELD
The invention provides a crystalline form of Raltegravir potassium and processes for its preparation. The crystalline Raltegravir potassium has a water content ranging from about 3.0% to about 5.0%.

BACKGROUND
Raltegravir potassium (1) is a human immunodeficiency virus integrase strand transfer inhibitor (HIV-1 INSTI) and is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection in treatment-experienced adult patients who have evidence of viral replication and HIV-1 strains resistant to multiple antiretroviral agents. The chemical name forRaltegravir potassium is 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. It is marketed in the USA under the brand name ISENTRESS?.

US 7,169,780 B2 discloses compounds of the formula:

and their pharmaceutically acceptable salts, wherein R1, R2, R3 and R4 are defined as in the specification, useful in the prevention and treatment of infection by HIV and in the prevention, delay in the onset, and treatment of AIDS.
US 7,754,731 B2 is directed to potassium salt of 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 (Raltegravir). The invention in particular is directed to crystalline potassium salts of Raltegravir. The potassium salt of Raltegravir is significantly more soluble in water compared to the free base. One crystalline form identified as Form 1, which is an anhydrous crystalline potassium salt of Raltegravir, has exhibited improved pharmacokinetics in animal models over the freebase. The other embodiments of the invention disclosed in this patent include a hydrated crystalline potassium salt of Raltegravir identified as Form 2 and an anhydrous crystalline potassium salt of Raltegravir identified as Form 3.
The publication, Journal of Medicinal Chemistry (2008), 51(18), 5843-5855 describes the preparation of potassium salt of Raltegravir by freeze-drying a solution of Raltegravir in acetonitrile and aqueous KOH, followed by crystallization of the freeze-dried material from ethanol. The Raltegravir potassium salt reported in this publication is characterized by mp 282oC.
The IP.com Journal (2010), 10(4A), 23 (IPCOM000194495D published on Mar. 28, 2010)describes an amorphous form of Raltegravir potassium.
Organic Process Research & Development Article ASAP (DOI:10.1021/op100257r) Publication Date (Web):November 16, 2010, reports the preparation of the potassium salt of Raltegravir by adding aqueous KOH to a solution of Raltegravir in ethanol : water (1:1 by volume) at 20oC followed by seeding at room temperature with Raltegravir potassium. The Raltegravir potassium salt reported in this publication is characterized by mp 274.2-275.2oC.
The PCT publication WO 2010/140156 A2 describes an amorphous form of Raltegravir potassium and a crystalline form of Raltegravir potassium designated as Form H1.
SUMMARY
The present invention relates to a crystalline form of Raltegravir potassium termed herein APO-I. Processes for preparing APO-I are also provided.
In illustrative embodiments of the present invention, there is provided APO-I form of Raltegravir potassium.
In illustrative embodiments of the present invention, there is provided an APO-I form of Raltegravir potassium, which has water content ranging from about 3.0% to about 5.0%, preferably approximately from about 3.5% to about 4.5%,.
In illustrative embodiments of the present invention, there is provided an APO-I form of Raltegravir potassium described herein having a powder X-ray diffraction (PXRD) pattern comprising peaks, in terms of degrees 2?, at approximately 7.9, 11.9, 14.8, 18.0, 19.6, 19.9, and 26.5.
In illustrative embodiments of the present invention, there is provided an APO-I form of Raltegravir potassium described herein having a powder X-ray diffraction pattern further comprising peaks, in terms of degrees 2?, at approximately 15.4, 17.4, 23.9, 25.9, and 26.2.
In illustrative embodiments of the present invention, there is provided an APO-I form of Raltegravir potassium described herein having a differential scanning calorimetry (DSC) thermogram comprising two endothermic peaks with peak onset temperatures of approximately 79.5oC and 225.9oC and peak maximum of approximately 104.5oC and 242.0oC; and a third sharp endotherm with peak onset temperature of approximately 275.4oC and peak maximum of approximately 280.3oC.
In illustrative embodiments of the present invention, there is provided an APO-I form of Raltegravir potassium described herein having a PXRD diffractogram substantially similar to a PXRD diffractogram as depicted in Figure 1.
In illustrative embodiments of the present invention, there is provided an APO-I form of Raltegravir potassium described herein having a DSC thermogram substantially similar to a DSC thermogram as depicted in Figure 2.
In illustrative embodiments of the present invention, there is provided a process for preparing APO-I comprising:
(a) mixing an aqueous solution of a potassium base with a mixture of Raltegravir and an organic solvent to form a basic solution of Raltegravir; optionally filtering and concentrating the solution;
(b) adding a ketonic solvent to the solution of step (a) to precipitate the Raltegravir potassium; and recovering the resulting solid.

Other aspects and features of the present invention will become apparent to those ordinarily skilled in the art upon review of the following description of specific embodiments of the invention in conjunction with the accompanying figures.

BRIEF DESCRIPTION OF THE DRAWINGS
In drawings which illustrate embodiments of the invention,
Figure 1 is the PXRD diffractogram of APO-I from Example 1.
Figure 2 is the DSC thermogram of APO-I from Example 1.
Figure 3 is the PXRD diffractogram of APO-I from Example 2.
Figure 4 is the DSC thermogram of APO-I from Example 2.
Figure 5 is the PXRD diffractogram of APO-I from Example 3.
Figure 6 is the DSC thermogram of APO-I from Example 3

DETAILED DESCRIPTION
When used in reference to a diffractogram, a spectrum and/or data presented in a graph, the term “substantially similar” means that the subject diffractogram, spectrum and/or data presented in a graph encompasses all diffractograms, spectra and/or data presented in graphs that vary within acceptable boundaries of experimentation that are known to a person of skill in the art. Such boundaries of experimentation will vary depending on the type of the subject diffractogram; spectrum and/or data presented in a graph, and are known to and understood by a person of skill in the art.
When used in reference to a peak in a powder X-ray diffraction (PXRD) diffractogram, the term “approximately” means that the peak may vary by ±0.2 degrees 2? of the subject value.
When used in reference to a peak in a differential scanning calorimetry (DSC) thermogram, the term “approximately” means that the peak may vary by ±5 degrees of subject value.
As used herein when referring to a diffractogram, spectrum and/or to data presented in a graph, the term “peak” refers to a feature that one skilled in the art would recognize as not attributing to background noise.
Depending on the nature of the methodology applied and the scale selected to display results obtained from an X-ray diffraction analysis, an intensity of a peak obtained may vary quite dramatically. For example, it is possible to obtain a relative peak intensity of 0.01% when analysing one sample of a substance, but another sample of the same substance may show a much different relative intensity for a peak at the same position. This may be due, in part, to the preferred orientation, of the sample and its deviation from the ideal random sample orientation, sample preparation and the methodology applied. Such variations are known and understood by a person of skill in the art.
In an illustrative embodiment, the present invention comprises a crystalline form of Raltegravir potassium which is a polymorphic form referred to herein as APO-I.
In illustrative embodiments of the present invention, there is provided an APO-I form of Raltegravir potassium, which has water content ranging from about 3.0% to about 5.0%, preferably from about 3.5% to about 4.5%.
Illustrative peaks, expressed in angle 2?, appearing in a typical PXRD for APO-I include peaks at approximately 7.9, 11.9, 14.8, 15.4, 17.4, 18.0, 19.6, 19.9, 23.9, 25.9, 26.2, and 26.5. Illustrative relative peak intensities of the aforementioned peaks appearing in a typical PXRD for APO-I, expressed in terms of percent, are illustrated below in Table 1.
Table 1: Relative Peak Intensities for APO-I
Angle 2? Relative Intensity %
7.9 100.0
11.9 64.6
14.8 3.1
15.4 2.0
17.4 1.7
18.0 4.5
19.6 2.4
19.9 4.0
23.9 2.9
25.9 2.3
26.2 3.0
26.5 3.5

An illustrative PXRD diffractogram of APO-I is given in Figure 1.
A typical DSC thermogram for APO-I comprises two endothermic peaks with peak onset temperatures of approximately 79.5oC and 225.9oC and peak maximum of approximately 104.5oC and 242.0oC; and a third sharp endotherm with peak onset temperature of approximately 275.4oC and peak maximum of approximately 280.3oC.
An illustrative DSC thermogram of APO-I is given in Figure 2.
In another illustrative embodiment, the present invention provides a process for preparing APO-I comprising:
(a) mixing an aqueous solution of a potassium base with a mixture of Raltegravir and an organic solvent to form a basic solution of Raltegravir; optionally filtering and concentrating the solution;
(b) adding a ketonic solvent to the solution of step (a) to precipitate the Raltegravir potassium; and recovering the resulting solid.

The organic solvent of the step (a) maybe selected from acetonitrile, propionitrile, 1-propanol, isopropanol, n-butanol, iso-butanol or t-butanol. The potassium base is potassium hydroxide or potassium alkoxide; preferably potassium hydroxide. The ketonic solvent of step (b) maybe selected from methyl isobutyl ketone (MIBK) or methyl ethyl ketone (MEK).
The processes of step (a) and step (b) may be carried out at room temperature.
The Raltegravir potassium isolated in step (b) may be dried under vacuum at about 40-45oC.
The following examples are illustrative of some of the embodiments of the invention described herein. These examples do not limit the spirit or scope of the invention in any way.

Examples
Powder X-ray Diffraction (PXRD) Analysis: The data were acquired on a PANanalytical X-pert Pro MPD diffractometer with fixed divergence slits and an X-Celerator RTMS detector. The diffractometer was configured in Bragg-Brentano geometry; data was collected over a 2? range of 5 to 35 using CuKa radiation at a power of 40mA and 45kV. CuKß radiation was removed using a divergent beam Nickel filter. A step size of 0.017 degrees was used. A step time of 20 seconds was used. Samples were rotated at 1Hz to reduce preferred orientation effects. The samples were prepared by the back-loading technique.
Differential Scanning Calorimetry (DSC) Analysis: The DSC thermograms were collected on a Mettler-Toledo 822e instrument. Samples (1 to 3 mg) were weighed into a 40µL aluminum pan and were crimped closed with an aluminium lid. The samples were analyzed under a flow of nitrogen (ca. 50 mL/min) at a scan rate of 10oC/minute, from 40 to 300oC.

Example 1 - Preparation of the crystalline form Raltegravir potassium (APO-I):
n-Butanol (15 mL) and Raltegravir (3 g) were charged at 20-25oC to a round bottomed flask. Aqueous KOH (0.567 g of KOH in 3 mL of water) was added to the suspension and stirred over a period of 1-2 hours. Methyl iso-butyl ketone (30 mL) was added to the resulting solution at 20-25oC and continued stirring for 2-3 hours. Raltegravir potassium was collected by filtration, washed with methyl isobutyl ketone (3 mL), and dried under vacuum at 40-45oC to provide crystalline form of Raltegravir potassium (APO-I). Yield: 2g (60%).
The APO-I has a water content of approximately 4.31% as determined according to Karl Fischer method. The APO-I product was subjected to PXRD analysis as well as DSC analysis. The results of the PXRD analysis and the DSC analysis are shown in Figures 1 and 2 respectively.

Example 2 - Preparation of the crystalline form Raltegravir potassium (APO-I):
Acetonitrile (50 mL) and Raltegravir (10g) were charged at 20-25oC to a round bottomed flask. Aqueous KOH (1.7g of KOH in 20 mL of water) was added to the suspension and stirred over a period of 30 min. The resulting solution was filtered through Celite® bed. The filtrate was concentrated to 15-20 mL under vacuum at 20-25oC. Methyl isobutyl ketone (100 mL) was added to the concentrated filtrate and stirred for 3-4 hours at 20-25oC. The resultant solid was collected by filtration, washed with methyl isobutyl ketone (10mL), dried under suction for 1hour, followed by drying at 40-45oC under vacuum to provide crystalline form of Raltegravir potassium (APO-I). Yield: 7.2 g (62%).
The APO-I has a water content of approximately 4.03% determined according to Karl Fischer method.
The APO-I product was subjected to PXRD analysis as well as DSC analysis. The results of the PXRD analysis and the DSC analysis are in Figures 3 and 4 respectively.

Example 3 - Preparation of the crystalline form Raltegravir potassium (APO-I):
Acetonitrile (25 mL) and Raltegravir (5 g) were charged at 20-25oC to a round bottomed flask. Aqueous KOH (0.83 g of KOH in 10 mL of water) was added. The mixture was stirred for 30 min, the resultant solution was filtered through Celite® bed, and the bed was washed with acetonitrile (2.5 mL). The filtrate was concentrated to 5-8.75 mL under vacuum at 20-25oC charged with methyl isobutyl ketone (50 mL) and the mixture was stirred for 1-2 hours. The solid was collected by filtration and washed with methyl isobutyl ketone and dried under vacuum for 2 hours at 40-45oC to provide crystalline form of Raltegravir potassium (APO-I). Yield: 3.5 g (70%).
The APO-I has a water content of approximately 4.47% determined according to Karl Fischer method.
The APO-I product was subjected to PXRD analysis as well as DSC analysis. The results of the PXRD analysis and the DSC analysis are shown in Figures 5 and 6 respectively.

We Claim:
1. APO-I crystalline form of Raltegravir potassium.

2. The APO-I crystalline form of Raltegravir potassium of claim 1 wherein the water content ranges from about 3.0% to about 5.0%

3. The APO-I crystalline form of Raltegravir potassium of claim 1 or 2 having a powder X-ray diffraction pattern comprising peaks, in terms of degrees 2?, at approximately 7.9, 11.9, 14.8, 18.0, 19.6, 19.9 and 26.5.

4. The APO-I crystalline form of Raltegravir potassium of claim 3 wherein the powder X-ray diffraction pattern further comprising peaks, in terms of degrees 2?, at approximately 15.4, 17.4, 23.9, 25.9 and 26.2.

5. The APO-I crystalline form of Raltegravir potassium of claim 4, having a DSC thermogram, comprising two endothermic peaks with peak onset temperatures of approximately 79.5oC and 225.9oC and peak maximum of approximately 104.5oC and 242.0oC; and a third sharp endotherm with peak onset temperature of approximately 275.4oC and peak maximum of approximately 280.3oC.

6. The APO-I crystalline form of Raltegravir potassium of claim 1 or 2 having a PXRD diffractogram substantially similar to a PXRD diffractogram as depicted in Figure 1.

7. A process for preparing APO-I crystalline form of Raltegravir potassium, comprising:
a. mixing an aqueous solution of potassium base with a mixture of Raltegravir and an organic solvent to form a basic solution of Raltegravir;
b. adding a ketonic solvent to the basic solution of Raltegravir thereby precipitating Raltegravir potassium; and
c. recovering precipitated Raltegravir potassium.

8. The process according to claim 7 wherein the basic solution of Raltegravir is filtered and concentrated prior to adding the ketonic solvent.

9. The process according to claim 7 or 8 wherein the organic solvent is selected from the group consisting of acetonitrile, propionitrile, 1-propanol, isopropanol, n-butanol, isobutanol and t-butanol.

10. The process according to any one of claims 7 to 9 wherein the ketonic solvent is selected from methyl isobutyl ketone or methyl ethyl ketone.

11. The process according to any one of claims 7 to 10 wherein the potassium base is potassium hydroxide or potassium alkoxide.

12. The process according to any one of claims 7 to 10 wherein the potassium base is potassium hydroxide.

Dated this 24th Day of February, 2011.