FIELD OF THE INVENTION

The present invention relates to solid premix composition comprising Raltegravir potassium of Formula (I) and at least one carrier.

BACKGROUND OF THE INVENTION

Raltegravir potassium is chemically known as N-[(4-fluorophenyl)methyl]-l,6-dihydro-5-hydroxy-1 -methyl-2-[ 1 -methyl-1 -[[(5-methyl-1,3,4-oxadiazol-2-yl)carbonyl]amino]ethyl]-6-oxo-4-pyrimidine carboxamide mono potassium.

Raltegravir is an antiretroviral drug used to treat HIV infection. Raltegravir targets integrase, an HIV enzyme that integrates the viral genetic material into human chromosomes, a critical step in the pathogenesis of HIV. Raltegravir potassium is marketed under the trade name Isentress™.

Raltegravir and its pharmaceutically acceptable salts are disclosed in US 7,169,780.

US 7,754,731 discloses polymorphic forms of Raltegravir potassium namely anhydrous crystalline Raltegravir potassium (Form 1 and Form 3); hydrated crystalline Raltegravir potassium (Form 2) and amorphous Raltegravir potassium.

US '731 also discloses a process for the preparation of amorphous Raltegravir potassium by adding aqueous KOH to a solution of Raltegravir in acetonitrile and the resulting solution has frozen in a -78°C bath and then freeze dried.

WO 2010/140156 A2 discloses a process for the preparation of amorphous Raltegravir potassium by dissolving Raltegravir potassium in water and the resulting solution is freeze dried at-180°C.

WO ' 156 also further discloses a process for the preparation of amorphous Raltegravir potassium by stirring Raltegravir potassium Form 1 in water and removing water to obtain a solid and the resulting solid is stirred in Heptane and filtered.

WO 2011/024192 A2 discloses a process for the preparation of amorphous Raltegravir potassium by dissolving Raltegravir in acetonitrile followed by adding aqueous KOH and distilled out the solvent and isolated.

WO '192 also discloses an another variant process for the preparation of amorphous Raltegravir potassium by dissolving Raltegravir in acetonitrile or acetone followed by adding aqueous potassium hydroxide and spray dried in mini spray dryer.
IP.com Journal (2010), 10(4B), 23 (IPCOM000194495D) discloses a process for the preparation of amorphous form of Raltegravir potassium by dissolving Raltegravir potassium in water and spray dried.

It has been disclosed that amorphous forms of a number of drugs exhibit different dissolution characteristics and in some cases different bioavailability patterns compared to the corresponding crystalline forms [Konne T., Chem. Pharm. Bull., 38, 2003 (1990)]. For some therapeutic indications one bioavailability pattern may be favored over another.

The amorphous form of Raltegravir potassium obtained by above prior-art processes is hygroscopic therefore its usage in solid formulations is inefficient and requires special care in handling and storage, which adversely affect the efficiency of the production process.

Hence, there is a need to develop a stable amorphous form of Raltegravir potassium which is non-hygroscopic upon exposure to atmosphere.

The present invention is specifically directed towards stable solid premix composition comprising Raltegravir potassium of Formula (I) and at least one carrier.

The present invention is also directed to stable and non-hygroscopic amorphous form of Raltegravir potassium, which is easy to handle, good dissolution rate and good storage stability.

OBJECTIVE OF THE INVENTION

The main objective of the present invention is to provide solid premix composition comprising Raltegravir potassium and at least one pharmaceutically acceptable carrier.

Another objective of the present invention is to provide stable and non-hygroscopic amorphous Raltegravir potassium.

SUMMARY OF THE INVENTION

In one aspect, the present patent application provides solid premix composition comprising Raltegravir potassium and at least one pharmaceutically acceptable carrier.

In another aspect, the present invention relates to a solid premix composition wherein Raltegravir potassium is characterized by its X-ray powder diffraction (XRD) pattern, as well as using thermal techniques such as Differential Scanning Calorimetry (DSC).

In another embodiment the invention includes stable amorphous Raltegravir potassium and a process for the preparation thereof.

In an aspect, the present invention includes compositions and/or formulations comprising stable amorphous form of Raltegravir potassium.

Another embodiment of the present invention provides a process for the preparation of solid premix composition comprising Raltegravir potassium and a pharmaceutically acceptable carrier comprising the steps of:

a) providing a solution or dispersion comprising Raltegravir potassium and a pharmaceutically acceptable carrier in a solvent;

b) removing the solvent(s) to form a solid premix.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 Illustrates the X-ray powder diffraction pattern of solid premix composition comprising Raltegravir potassium and a pharmaceutically acceptable carrier prepared according to the Example-1.

Figure 2 Illustrates the Differential Scanning Calorimetry (DSC) of solid premix composition comprising Raltegravir potassium and a pharmaceutically acceptable carrier prepared according to the Example-1.

Figure 3 Illustrates the X-ray powder diffraction pattern of solid premix composition comprising Raltegravir potassium and a pharmaceutically acceptable carrier prepared according to the Example-2.

Figure 4 Illustrates the Differential Scanning Calorimetry (DSC) of solid premix composition comprising Raltegravir potassium and a pharmaceutically acceptable carrier prepared according to the Example-2.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a process for the preparation of solid premix composition comprising Raltegravir potassium and a pharmaceutically acceptable carrier comprising the steps of:

(a) providing a solution or dispersion comprising Raltegravir potassium and one or more pharmaceutically acceptable carriers in a solvent;

(b) removing the solvent(s) to form a solid premix.

In another embodiment, Raltegravir potassium present in solid premix composition prepared according to the present invention is stable amorphous Raltegravir potassium.

The solution or dispersion of Raltegravir potassium in step (a) may be provided either by dissolving Raltegravir potassium in a suitable organic solvent(s) or it may be provided directly from a reaction mixture containing it that is obtained during the course of its manufacture.

Suitable solvents may be selected from the group selected from, but not limited to, water; various classes of solvents, such as for example, alcoholic solvents, ketones, esters, ethers, halogenated solvents, hydrocarbons, nitriles, water aprotic polar solvents or mixtures thereof. Alcohol solvents such as for example methanol, ethanol, denatured spirit, n-propanol, isopropanol, n-butanol, isobutanol, and t-butanol; ketonic solvents
such as acetone, propanone, and 2-butanone; halogenated solvents, such as dichloromethane, 1,2-dichloroethane, chloroform, and carbontetrachloride; ester solvents, such as ethyl acetate, n-propyl acetate, isopropylacetate and n-butyl acetate and the like; ether solvents such as for example dimethylether, diethylether, methyltertiarybutylether, ethylmethylether, diisopropylether, tetrahydrofuran, and dioxane. The hydrocarbon may be any solvent from this class such as for example toluene, xylene, cyclohexane, n-hexane, and n-heptane. The nitrile solvents may include acetonitrile, and propionitrile; aprotic polar solvents, such as N,N-dimethylformide (DMF), Dimethylsulfoxide (DMSO), and N,N-dimethylacetamide (DMA) or mixtures thereof.

Pharmaceutically acceptable carriers according to the present invention may be added to a reaction mixture containing Raltegravir potassium dissolved or dispersed in the said mixture(s) or the mixtures can be obtained separately by dissolving Raltegravir potassium and one or more pharmaceutically acceptable carriers in a solvent.

Suitable pharmaceutically acceptable carriers used in the present invention includes, but are not limited to, hydrophilic carriers like polymers of N-vinyl pyrrolidone commonly known as polyvinylpyrrolidine and its derivatives ("PVP" or "povidone"), copovidone, crospovidone, gums, cellulose derivatives (including hydroxy! propyl methyl cellulose, hydroxyl methyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose and the like), cyclodextrins, gelatin, , sugars, polyhydric alcohols, polyethylene glycol, polyethylene oxides, polyoxyalkylene derivatives, methacrylic acid copolymers, polyvinyl alcohol, and propylene glycol derivatives, hydrophobic carriers such as hypromellose phthalate, methacrylic acid copolymers and the like or combinations thereof.

The use of mixtures of more than one of the pharmaceutical carriers to provide desired release profiles or for the enhancement of stability is within the scope of this invention.

Useful pyrrolidones are homopolymers or copolymers of N-vinyl pyrrolidone. Such polymers are known to form complexes with a variety of compounds. The water-soluble forms of N-vinyl pyrrolidone are available in a variety of viscosity and molecular weight grades and may be chosen from but not limited to PVP K-12, PVP K-15, PVP K-17, PVP K-25, PVP K-30, PVP K-90, PVP K-120 and the like. Any of the above mentioned pharmaceutically acceptable carriers could be chosen or their mixtures or their mixtures with any of the excipients mentioned above.

The dissolution temperature for providing the solution or dispersion of Raltegravir potassium, optionally along with one or more pharmaceutically acceptable carriers between 40°C to 130°C or reflux temperature of the solvents used or any other suitable temperature.

The solvent(s) may be removed from the solution or dispersion by techniques known in art which includes, but are not limited to, distillation, evaporation, oven drying, tray drying, rotational drying (such as the Buchi Rotavapor), spray drying, freeze-drying, fluid bed drying, flash drying, spin flash drying and Ultrafilm agitated thin film dryer-vertical (ATFD-V) and the like.

The solvent(s) may be removed from the solution or dispersion optionally under reduced pressure of less than about 100 mbar or less than about 60 mbar or less than about 30 mbar or less than about 10 mbar or less than about 1 mbar or any other suitable pressure.

Suitable temperature that may be used for said removal of solvent(s) between 40°C to 130°C or any other suitable temperature.

The resulting product after removal of solvent(s) may be further dried in conventional manner at a suitable temperature optionally under reduced pressure. Preferably, drying temperature may vary from about 30°C to 125°C and in presence or absence of inert atmosphere. Other conventional drying methods known in the art may also be used.

Raltegravir potassium that is used as the input in the process of the present application may be of any form known in the art. Any form of Raltegravir potassium or its precursor intermediate can also be used as starting material for the preparation of amorphous Raltegravir potassium by following the processes according to the present invention.

In another embodiment, Solid premix composition according to the present invention comprising Raltegravir potassium and a pharmaceutically acceptable carrier may be subjected to particle size reduction by ball milling, roller milling, micronizing, hammer milling, jet milling, grinding and the like, to get the desired particle size.

In another embodiment, the solid premix composition comprising Raltegravir potassium and a pharmaceutically acceptable carrier may be formulated into a suitable dosage form including solid dosage form for oral administration such as capsules, tablets, pills, powders or granules or the like, liquid dosage form such as suspensions or the like.

In an embodiment according to the present invention, the solid premix composition is mixed with one or more pharmaceutically acceptable excipients.

The present invention further provides solid premix composition comprising Raltegravir potassium and a pharmaceutically acceptable carrier for use in the manufacture of a medicament for the treatment of HIV infection.

The following examples are provided to illustrate the invention and are merely for illustrative purpose only and should not be construed to limit the scope of the invention.

EXAMPLE-1;

Preparation of solid premix composition comprising Raltegravir potassium and a pharmaceutically acceptable carrier:

Raltegravir potassium (5g) was dissolved in 60ml of DM water at 60°C, which was mixed with the solution of PVP (Kollidon K-30) (5g in 60ml DM water). The resulting solution was filtered and made particle free. The filtrate was concentrated at 60-65°C under reduced pressure to produce the solid. The solid obtained was further dried under vacuum oven at about 60°C for 16hrs to afford desired solid amorphous product.

EXAMPLE-2:

Preparation of solid premix composition comprising Raltegravir potassium and a pharmaceutically acceptable carrier:

Raltegravir potassium (5g) was dissolved in 60ml of water at 60°C, which was mixed with the solution of PVP (Kollidon K-30) (5g in 60ml DM water). The resulting solution was filtered and made particle free. The clear solution was further lyophilized at -65°C for approximately 16hrs.

WE CLAIM

1. A solid premix composition comprising Raltegravir potassium and at least one pharmaceutically acceptable carrier.

2. The solid premix composition of claim I, wherein the pharmaceutically acceptable carrier is selected from hydrophilic carriers, hydrophobic carriers and combinations thereof.

3. The solid premix composition of claim 1, wherein the pharmaceutically acceptable carrier is selected from polyvinylpyrrolidone and its derivatives, copovidone, crospovidone, gums, cellulose derivatives, cyclodextrins, gelatin, sugars, polyhydric alcohols, polyethylene glycol, polyethylene oxides, polyoxyalkylene derivatives, methacrylic acid copolymers, polyvinyl alcohol, propylene glycol derivatives, hypromellose phthalate and combinations thereof.

4. The solid premix composition of claim 1, wherein Raltegravir potassium is characterized by its X-ray powder diffraction (XRD) pattern as shown in Figure 1 and Figure 3; and Differential Scanning Calorimetry (DSC) as shown in Figure 2 and Figure
4.

5. The solid premix composition of claim 1, wherein Raltegravir potassium is present in stable amorphous form.

6. A process for the preparation of solid premix composition comprising Raltegravir potassium and a pharmaceutically acceptable carrier comprising the steps of:

(a) providing a solution or dispersion comprising Raltegravir potassium and one or more pharmaceutically acceptable carriers in a solvent;

(b) removing the solvent(s) to form the solid premix.

7. The process of claim 6, wherein the solution or dispersion is provided either by dissolving Raltegravir potassium and pharmaceutically acceptable carrier in a suitable solvent(s) or adding pharmaceutically acceptable carrier in a reaction mixture comprising Raltegravir potassium obtained during the course of its manufacture.

8. The process of claim 6, wherein the solvent(s) is selected from water, alcoholic solvents, ketones, esters, ethers, halogenated solvents, hydrocarbons, nitriles, aprotic polar solvents or mixtures thereof.

9. The process of claim 8, wherein the alcoholic solvent is selected from methanol, ethanol, denatured spirit, n-propanol, isopropanol, n-butanol, isobutanol, and t-butanol and mixtures thereof; ketone is selected from acetone, propanone, and 2-butanone and mixtures thereof, and halogenated solvent is selected from dichloromethane, 1,2-dichloroethane, chloroform and mixtures thereof.

10. The process of claim 8, wherein the ester is selected from ethyl acetate, n-propyl acetate, isopropylacetate and n-butyl acetate and mixture thereof; ether is selected from dimethylether, diethylether, methyltertiarybutylether, ethylmethylether, diisopropylether, tetrahydrofuran, and dioxane and mixture thereof; hydrocarbon is selected from toluene, xylene, cyclohexane, n-hexane, and n-heptane and mixture thereof; nitrile is selected from acetonitrile, propionitrile and mixture thereof; and aprotic polar solvent is selected from N,N-dimethylformide (DMF), Dimethylsulfoxide (DMSO), and N,N-dimethylacetamide (DMA) or mixtures thereof.