FIELD OF THE INVENTION

The present invention relates to novel solvates of Darunavir of Formula I.

BACKGROUND OF THE INVENTION

Darunavir is a potent HIV protease inhibitor, which is chemically known as [(lS,2R)-3-[[(4-Aminophenyl)sulfonyl](2-methylpropyl)amino]-2-hydroxy-l-(phenylmethyl) propyl]carbamic acid, (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl ester, represented by Formula I.

Darunavir is a new generation of non-peptide protease inhibitor (PI). It is exceeding potent and has shown impressive broad-spectrum activity against highly cross-resistant HIV mutants. Darunavir is being marketed under the brand name Prezista® as an oral tablet and oral suspension in the form of monoethanolate solvate.

Prezista® must be co-administered with Ritonavir to exert its therapeutic effect. Failure to correctly co-administer Prezista® with Ritonavir will result in plasma levels of Darunavir that will be insufficient to achieve the desired antiviral effect and will alter some drug interactions.

Darunavir is generically disclosed in US Patent US 5,843,946, specifically disclosed in US patent US 6,248,775. However, in these patents, there is no specific example for preparing Darunavir.

US 7,700,645 discloses several pseudopolymorphs of Darunavir, including the ethanolate, hydrate, methanolate, acetonate, dichloromethanoate, ethyl acetate, 1- methoxy-2-propanolate, anisolate, tetrahydrofuranate, isopropanolate and mesylate solvates; US 2011/0313035 discloses Darunavir C5.8 alcohol solvate, wherein C5.8 alcohol solvate is selected from 2-methyl-2-butanol and n-pentanol; US 2012/0035142 discloses Darunavir dimethylsulfoxide solvate, Tetrahydrofuran solvate.

New polymorphic forms and solvates of a pharmaceutically useful compound or salts thereof can also provide an opportunity to improve the performance characteristics of a pharmaceutical product and new solvates of Darunavir that may have advantageous physico-chemical and biokinetic properties such as suitable solubility in neutral, acidic or alkaline water medium, solubility in technologically important organic solvents, water/lipid partition coefficient, electrochargeability, thermal stability, water and oxygen inertness, hygroscopicity, crystal shape, particle size and surface, dissolution profile, compatibility with excipients and combined active ingredients or special properties for final dosage form design.

Journal of Organic Chemistry 2004, 69, 7822-7829 discloses a process for preparing amorphous Darunavir, by purifying Darunavir by column chromatography.

European Journal of Pharmaceutical Sciences 2009, 38,489-497 discloses processes for the preparation of amorphous Darunavir.

- by melting Darunavir hydrate or ethanolate on a Kofler hot bar and cooling
- by dissolving Darunavir ethanolate in MDC and spray drying

The prior-art processes involve the use of chromatographic and spray drying techniques. Hence, there is a need in the art to develop an improved process for the preparation of amorphous Darunavir.

The present inventors have found that Darunavir ethanolate is hygroscopic and converts to Darunavir hydrate at moderate or high relative humidity at 25°C. Further, the isolation of Darunavir ethanolate involves special precautions during isolation, drying and powder processing, which is onerous during the large scale manufacturing of Darunavir ethanolate.

In view of the above, the present inventors have now developed novel solvates of Darunavir, which are stable solvates and does not require laborious isolation. Further, the present inventors developed an improved process for the preparation of amorphous Darunavir from Darunavir or its solvates thereof.

OBJECTIVE OF THE INVENTION

The main objective of the present invention is to provide novel solvates of Darunavir, which are stable.

Yet another objective of the present invention is to provide pharmaceutical compositions comprising Darunavir solvate and use thereof in treating retroviral infections and, in particular, HIV infection

Yet another objective of the present invention is to provide a process for preparing amorphous Darunavir, which is simple and industrially applicable.

SUMMARY OF THE INVENTION

The present invention relates to novel solvates of Darunavir, wherein the solvate is glycol or glycol ethers. Preferred glycol is ethylene glycol, propylene glycol (1,2-propanediol), trimethylene glycol (1,3-propanediol) and glycol ether is 2-methoxyethanol.

In another aspect of the present invention is to provide a process for the preparation of novel solvates of Darunavir, which comprises:

a) treating Darunavir with glycol or glycol ethers, optionally in presence of a solvent; and
b) isolating Darunavir solvate.

wherein glycol is selected from group comprising of ethylene glycol, propylene glycol, trimethylene glycol; glycol ether is selected from group comprising 2-methoxyethanol.

In another aspect of the present invention is to provide an improved process for the preparation of Darunavir in amorphous form, which comprises:

a) treating Darunavir or its solvates thereof in water and/or water miscible solvent; and
b) isolating amorphous Darunavir.

In another aspect of the present invention is to provide pharmaceutical compositions comprising Darunavir solvate and use thereof in treating retroviral infections and, in particular, HIV infection

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 - Powder X-ray diffraction pattern of Darunavir trimethylene glycol solvate. Figure 2 - Powder X-ray diffraction pattern of Darunavir ethylene glycol solvate. Figure 3 - Powder X-ray diffraction pattern of Darunavir propylene glycol solvate. Figure 4 - DSC of Darunavir propylene glycol solvate.

Figure 5 - Powder X-ray diffraction pattern of Darunavir methoxyethanol solvate. Figure 6 - Powder X-ray diffraction pattern of amorphous Darunavir. Figure 7 - Powder X-ray diffraction pattern of Darunavir ethanolate solvate. Figure 8 - DSC of Darunavir ethanolate solvate.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to novel solvates of Darunavir, wherein the solvate is glycol or glycol ethers. The preferred glycol's are selected from the group comprising ethylene glycol, propylene glycol (1,2-propanediol), trimethylene glycol (1,3-propanediol) and glycol ether is selected from the group comprising 2-methoxyethanol.

Another aspect of the present invention is to provide a process for the preparation of Darunavir glycol solvate, by treating Darunavir with glycol, optionally in presence of a solvent, selected from methyl tert-butylether or diisopropylether and isolating Darunavir glycol solvate, wherein glycol is selected from the group comprising ethylene glycol, propylene glycol, trimethylene glycol.

Another aspect of the present invention is to provide a process for the preparation of Darunavir 2-methoxyethanol solvate, by treating Darunavir with 2-methoxyethanol, optionally in presence of a solvent, selected from methyl tert-butylether or diisopropylether and isolating Darunavir 2-methoxyethanol solvate.

In another aspect of the present invention the ratio of Darunavir to glycol or glycol ether is about 1:1.

The present inventors have compared the hygroscopicity of Darunavir propylene glycolate of the present invention with Darunavir ethanolate under the conditions of hygroscopic testing (at 25°C ± 2°C and 80% RH ± 2°C for 24 h). The results obtained are as tabulated:

In both the cases the solvent is replaced correspondingly with water. However, the content of solvent replaced in Darunavir propylene glycolate is very low when compared with solvent replaced in Darunavir ethanolate. Hence, Darunavir propylene glycolate is less hygroscopic and stable when compared to Darunavir ethanolate.

The present inventors have also studied the stability of Darunavir propylene glycolate at 40°C and 75% RH for 3 months and found that the product complies with the initial results and found to be stable.

In another aspect of the present invention the isolation of Darunavir glycol or glycol ether solvates is carried out by way of cooling, anti solvent technique, evaporation of solvent, filtration techniques etc.,.

Another aspect of the present invention is to provide a process for preparing Darunavir in amorphous form, by treating Darunavir or its solvate thereof in water and/or water miscible solvent selected from methanol, ethanol, isopropanol, acetone, at a temperature ranging from 5-40°C, preferably at 25-30°C and isolating amorphous Darunavir, wherein solvate is selected from ethanolate, ethylene glycol solvate, propylene glycol solvate, trimethylene glycol solvate, 2-methoxyethanol solvate.

The isolated amorphous Darunavir is dried at a temperature 55-60°C using different methods, such as under atmospheric pressure, under reduced pressure, by circulation drying, flow drying or fluidized bed drying till water content is less than 1.2 %.

In another aspect of the present invention is to provide pharmaceutical composition comprising Darunavir glycol or glycol ether solvate and one or more pharmaceutically acceptable excipients.

In another aspect of the present invention is to provide pharmaceutical composition comprising Darunavir propylene glycol solvate and one or more pharmaceutically acceptable excipients.

In another aspect of the present invention is to provide an oral pharmaceutical composition in a solid oral dosage form, such as a tablet, which is optionally film coated.

In another aspect, the present invention is to provide an oral pharmaceutical composition comprising Darunavir propylene glycol solvate and one or more pharmaceutically acceptable excipients, wherein the composition is substantially free of co-processed spray-dried mixture of microcrystalline cellulose and colloidal silicon dioxide.

The oral pharmaceutical composition of Darunavir propylene glycol solvate may be prepared by direct compression, wet granulation or roll compaction. Specifically, the oral pharmaceutical composition of Darunavir solvate is prepared by direct compression.

The oral pharmaceutical composition may contain one or more additional excipients such as diluents, binders, disintegrants and lubricants. Exemplary diluents include lactose, sucrose, glucose, mannitol, sorbitol, calcium carbonate, microcrystalline cellulose such as Prosolv.RTM., magnesium stearate and mixtures thereof. Specifically, the diluent is Prosolv.RTM. Exemplary binders are selected from L-hydroxy propyl cellulose, polyvinyl pyrrolidine, hydroxylpropyl methyl cellulose, hydroxylethyl cellulose and pre-gelatinized starch. Exemplary disintegrants are selected from croscarmellose sodium, crospovidone, sodium starch glycolate and low substituted hydroxylpropyl cellulose. In a specific embodiment, the disintegrant is low substituted hydroxylpropyl cellulose and crospovidone. Exemplary lubricants are selected from sodium stearyl fumarate, magnesium stearate, zinc stearate, calcium stearate, stearic acid, talc, glyceryl behenate and colloidal silicon dioxide. A specific lubricant is selected from magnesium stearate, zinc stearate, calcium stearate and colloidal silicon dioxide.

In another aspect of the present invention also provide a method of preventing the development of drug resistance of HIV in an HIV-infected mammal by administration of a drug resistance-inhibiting effective amount of Darunavir propylene glycol solvate.

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

EXAMPLE 1

Preparation of Darunavir

To the mixture of Diamino alcohol monohydrochloride (5 g), methylene chloride (50 ml), DM water (15 ml), 10 %w/w aqueous sodium hydroxide solution (5 ml) was added to adjust the pH to 10 at 20-30°C. The organic layer was separated and washed with DM water (10 ml). Methylene chloride extract was dried over anhydrous sodium sulphate and 1 -[[[(3R,3aS,6aR)-hexahydroruro[2,3-b]furan-3-yloxy]carbonyl]oxy]-2,5-pyrrolidine-dione (3.17 g) was added and cooled to 5-10°C. Thereafter, triethylamine (1.18 g) was added and the temperature of reaction mass was raised to 25-30°C and stirred at this temperature for 3 h. The reaction mass was washed with 7% w/w aqueous sodium bicarbonate solution (20 ml), followed by DM water (2x15 ml) and then concentrated under reduced pressure at 30-40°C to obtain Darunavir as viscuous oily mass. Yield: 8 g (Viscous oily mass)

EXAMPLE 2

Preparation of amorphous Darunavir

Darunavir (3 g) was dissolved in methanol (4 ml) at 45-50°C and diluted with DM water (20 ml). Thereafter, the mass was concentrated at 40-50°C under reduced pressure to a volume of -18 ml, which was cooled to 25-30°C and stirred at this temperature for 15 h. The obtained solid was filtered, washed with DM water and dried at 55-60°C under reduced pressure to obtain amorphous Darunavir.

Yield: 2.2 g
Water content (by Karl-Fisher): 0.71%

EXAMPLE 3

Preparation of Darunavir Propylene glycol solvate

Triethylamine (70.90g) was added to methylene chloride (750ml) solution of Diamino alcohol monohydrochloride (150g) and l-[[[(3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yloxy] carbonyl]oxy]-2,5-pyrrolidinedione (90.30g) at -25°C to -15°C and stirred for 2 h. The reaction mass was treated with monomethylamine (solution in methanol, ~20%w/w, 6.0g) for 30 min. The reaction mass was sequentially washed with ~7%w/w aqueous sodium bicarbonate solution (300 ml), -2% w/w aqueous hydrochloric acid (2 x 300 ml), ~7%w/w aqueous sodium bicarbonate solution (300 ml) and water (300 ml) at 5-25°C. Thereafter, methylene chloride solution was treated with carbon (7.50 g) and concentrated under reduced pressure at 30-40°C. The residue was dissolved in a mixture of propylene glycol (300 ml) and methyl tert-butyl ether (300 ml) and stirred at 25-30°C for 12 h. The resulting slurry was cooled to 2-5°C and stirred at this temperature for 2 h. The product was filtered, washed with methyl tert-butyl ether (150 ml) and dried at 50-55°C under reduced pressure to obtain Darunavir propylene glycolate.

Yield: 172 g
Chromatographic purity (by HPLC): 99.84%
DSC: Single endotherm peak at 94.93°C
Propylene glycol content: 11.48 % w/w

EXAMPLE 4

Preparation of Darunavir Ethanolate

Triethylamine (56.70g) was added to the mixture of diamino alcohol monohydrochloride (120g), l-[[[(3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yloxy] carbonyl]oxy]-2,5-pyrrolidinedione (73.80g) and methylene chloride (600ml) at -25°C to -15°C and stirred for 2 h. The reaction mass was treated with monomethyl amine (solution in methanol, ~20%w/w, 4.70g) for 30 min. The reaction mass was sequentially washed with ~7%w/w aqueous sodium bicarbonate solution (240 ml), -2% w/w aqueous hydrochloric acid (2 x 240 ml), ~7%w/w aqueous sodium bicarbonate solution (240 ml) and water (240 ml) at 5-25°C. Thereafter, methylene chloride solution was treated with carbon (6.0 g) and concentrated under reduced pressure at 30-40°C. The residue was stirred with ethanol (600 ml) at 50-55°C for 30 min. The resulting slurry was cooled to 25-30°C and stirred at this temperature for 1 h. The product was filtered, washed with ethanol (120 ml) and dried at 40-50°C under reduced pressure to obtain Darunavir ethanolate. Yield: 133 g

Chromatographic purity (by HPLC): 99.86% DSC: Single endotherm peak at 104.97°C Ethanol content: 7.40 % w/w

EXAMPLE 5

Preparation of Darunavir Ethylene glycol solvate

Ethylene glycol (30 ml) was added to Darunavir (10 g) at 30-40°C and stirred at 45-50°C under reduced pressure for 20 minutes. The resulting solution was cooled to 25-30°C and stirred at this temperature for 5 h. The separated product was filtered, washed with ethylene glycol (6 ml) and dried at 45-50°C under reduced pressure to obtain Darunavir ethylene glycol solvate. Yield: 6.2 g

EXAMPLE 6

Preparation of Darunavir Propylene glycol solvate

Propylene glycol (24 ml) was added to Darunavir (8 g) at 30-40°C and stirred at 45-50°C under reduced pressure for 20 minutes. The resulting solution was cooled to 25-30°C and stirred at this temperature for 5 h. The separated product was filtered, washed with propylene glycol (5 ml) and dried at 45-50°C under reduced pressure to obtain Darunavir propylene glycol solvate. Yield: 4.9 g

EXAMPLE 7

Preparation of Darunavir Trimethylene glycol solvate

Trimethylene glycol (24 ml) was added to Darunavir (8 g) at 30-40°C and stirred at 45-50°C under reduced pressure for 20 minutes. The resulting solution was cooled to 25-30°C and stirred at this temperature for 5 h. The separated product was filtered, washed with trimethylene glycol (5 ml) and dried at 45-50°C under reduced pressure to obtain Darunavir trimethylene glycol solvate. Yield: 4.8 g

EXAMPLE 8

Preparation of Darunavir 2-Methoxyethanol solvate

2-Methoxyethanol (24 ml) was added to Darunavir (8 g) at 30-40°C and stirred at 45-50°C under reduced pressure for 20 minutes. The resulting solution was cooled to 25-30°C and stirred at this temperature for 5 h. The separated product was filtered, washed with 2-methoxyethanol (5 ml) and dried at 45-50°C under reduced pressure to obtain Darunavir 2-methoxyethanol solvate. Yield: 4.8

EXAMPLE 9

Preparation of amorphous Darunavir

Darunavir ethylene glycol solvate (3 g) was suspended in DM water (30 ml) at 25-30°C and stirred at this temperature for 15 h. The slurry was filtered, washed with DM water (6 ml) and dried at 55-60°C under reduced pressure to obtain amorphous Darunavir. Yield: 1.7 g Water content: 0.63%

EXAMPLE 10

Preparation of amorphous Darunavir

Darunavir propylene glycol solvate (2 g) was suspended in DM water (20 ml) at 25- 30°C and stirred at this temperature for 15 h. The slurry was filtered, washed with DM water (4 ml) and dried at 55-60°C under reduced pressure to obtain amorphous Darunavir.
Yield: 1.6 g
Water content: 1.0%

EXAMPLE 11

Preparation of amorphous Darunavir

Darunavir trimethylene glycol solvate (2 g) was suspended in DM water (20 ml) at 25- 30°C and stirred at this temperature for 15 h. The slurry was filtered, washed with DM water (4 ml) and dried at 55-60°C under reduced pressure to obtain amorphous

Darunavir.
Yield: 1.2 g
Water content: 1.1%.

EXAMPLE 12

Preparation of amorphous Darunavir

Darunavir 2-methoxyethanol solvate (2 g) was suspended in DM water (20 ml) at 25- 30°C and stirred at this temperature for 15 h. The slurry was filtered, washed with DM water (4 ml) and dried at 55-60°C under reduced pressure to obtain amorphous Darunavir.

Yield: 1.6 g
Water content: 0.69%

EXAMPLE 13

Preparation of amorphous Darunavir

Darunavir ethanolate (3 g) was suspended in DM water (30 ml) at 25-30°C and stirred at this temperature for 15 h. The slurry was filtered, washed with DM water (6 ml) and dried at 55-60°C under reduced pressure to produce amorphous Darunavir.

Yield: 2.4 g
Water content: 0.67%

EXAMPLE 14

Preparation of amorphous Darunavir Darunavir (2 g) was stirred in a mixture of methanol (2 ml) and DM water (18 ml) at 25-30°C for 15 h. The obtained solid was filtered, washed with D M water and dried at 55-60°C under reduced pressure to obtain amorphous Darunavir.

Yield: 1.6 g
Water content: 0.26%

EXAMPLE 15
Preparation of Tablet dosage form of Darunavir

We Claim:

1) Novel solvates of Darunavir, wherein the solvate is a glycol or glycol ether.

2) The Darunavir glycol solvate according to claim 1, wherein the glycol solvate or glycol ether solvate is selected from ethylene glycol, propylene glycol, trimethylene glycol and 2-methoxyethanol solvate.

3) A process for the preparation of Darunavir solvate as defined in claim 1, which comprises:

a) treating Darunavir with glycol or glycol ether, optionally in presence of a solvent; and

b) isolating Darunavir solvate.

wherein glycol is selected from ethylene glycol, propylene glycol, trimethylene glycol and glycol ether is 2-methoxyethanol.

4) The process according to claims 3, wherein the solvent is selected from the group comprising methyl tert-butylether and diisopropylether.

5) An improved process for the preparation of Darunavir in amorphous form, which comprises:

a) treating Darunavir or its solvates thereof in water and/or water miscible solvent; and

b) isolating amorphous Darunavir.

6) The process according to claim 5, wherein Darunavir solvate is selected from ethanolate, ethylene glycol solvate, propylene glycol solvate, trimethylene glycol solvate and 2-methoxyethanol solvate.

7) The process according to claim 5, wherein water miscible solvent is selected from the group comprising of methanol, ethanol, isopropanol, acetone.

8) A pharmaceutical composition comprising Darunavir glycol or glycol ether solvate and one or more pharmaceutical acceptable excipients.

9) A pharmaceutical composition according to claim 8, wherein Darunavir glycol is propylene glycol solvate and one or more pharmaceutically acceptable excipients in a solid dosage form.

10) A method of treating retroviral infections or inhibiting retrovirus protease activity comprising administering to a subject in need thereof an effective amount of a composition comprising Darunavir propylene glycolate solvate.