DESC:FORM 2

THE PATENTS ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003

COMPLETE SPECIFICATION
(Section 10 and Rule 13)

NOVEL CRYSTALLINE FORM OF LENACAPAVIR SODIUM AND PROCESSES FOR ITS PREPARATION

AUROBINDO PHARMA LTD HAVING CORPORATE OFFICE AT
GALAXY, FLOORS: 22-24,
PLOT No.1, SURVEY No.83/1,
HYDERABAD KNOWLEDGE CITY,
RAIDURG PANMAKTHA,
RANGA REDDY DISTRICT,
HYDERABAD – 500 032,
TELANGANA, INDIA
AN INDIAN ORGANIZATION

The following specification particularly describes and ascertains the nature of this invention and the manner in which the same is to be performed:

FIELD OF THE INVENTION
The present invention relates to a novel crystalline form of Lenacapavir Sodium and a process for its preparation.

BACKGROUND OF THE INVENTION
Lenacapavir sodium, chemically known as Sodium (4-chloro-7-(2-((S)-1-(2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclo-propa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)-6-(3-methyl-3-(methylsulfonyl)but-1-yn-1-yl)pyridin-3-yl)-1-(2,2,2-trifluoro-ethyl)-1H-indazol3-yl)(methylsulfonyl)amide (compound of Formula 1), which is a human immunodeficiency virus type 1 (HIV-1) capsid inhibitor and approved for treating HIV-1 infection.

Formula 1

Lenacapavir along with its sodium salt (1) was disclosed in US 10,071,985. US ‘985 generally covers amorphous form of Lenacapavir or its sodium salt. No other polymorphs were discussed in US ‘985.
US 11,267,799 disclosed crystalline forms of Lenacapavir sodium salt namely Form I, Form II and Form III characterized by their physiochemical properties including their crystallization process. US ‘799 further discloses different solvates of Lenacapavir such as ethanol, isopropanol, acetone and MIBK etc,. US ‘799 further discusses the use of these forms in the treatment of HIV virus.

Considering the importance of Lenacapavir sodium and its use in HIV treatment, nevertheless, besides the known forms of Lenacapavir sodium, there is still the need for a polymorph, which is stable as an API and during formulation and reproducible. The crystallization process of Lenacapavir Sodium involves the use of reagents that are less expensive and/or easier to handle and require smaller amounts to provide a higher yield of product with higher purity.

In view of the above, our inventors have developed Crystalline Form LEA-1 of Lenacapavir sodium. The novel crystalline Form LEA-1 of Lenacapavir sodium is highly pure, stable as itself and in formulation and it is reproducible.

Our inventors also developed a process for the preparation of crystalline Form LEA-1 of Lenacapavir sodium.

OBJECTIVE OF THE INVENTION
The main objective of the present invention is to provide a novel crystalline form of Lenacapavir sodium (1).

Another objective of the present invention is to provide a process for the preparation of a novel crystalline form of Lenacapavir sodium (1).

SUMMARY OF THE INVENTION
The present invention provides a novel crystalline form of Lenacapavir sodium, herein designated as Form LEA-1, wherein the crystalline Form LEA-1 has PXRD peaks, in terms of 2? ± 0.2°, selected from 4.6° and 6.3°.

The present invention further provides a novel crystalline Form LEA-1 of Lenacapavir sodium characterized by a DSC thermogram having an endothermic peak at about 206.3° C.
The present invention further provides a novel crystalline Form LEA-1 of Lenacapavir sodium characterized by weight loss, as measured by thermogravimetric analysis (TGA) of about 1% when heated above 200ºC.

The present invention also provides a process for the preparation of a novel crystalline Form LEA-1 of Lenacapavir sodium, comprising:
a) providing Lenacapavir sodium,
b) dissolving in a first solvent,
c) optionally adding a second solvent,
d) isolating the crystalline Form LEA-1 of Lenacapavir sodium.

BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1: PXRD pattern of crystalline Form LEA-1 of Lenacapavir sodium.
Figure 2: DSC pattern of crystalline Form LEA-1 of Lenacapavir sodium.
Figure 3: TGA of crystalline Form LEA-1 of Lenacapavir sodium.

DETAILED DESCRIPTION OF THE INVENTION
The present invention provides a crystalline Form LEA-1 of Lenacapavir sodium characterized by its PXRD, DSC & TGA patterns.

The X-ray powder diffraction pattern was measured on Bruker D8 advance-Eco with lynex detector equipped with Cu source (?=1.58Å). Before analysis small quantity of sample was gently grounded using Motor-pastel to prepare uniform sample. Grounded sample placed directly on low background silicon holder with cavity and pressed with glass slide to make flat surface.
Scanning parameters:
Scan type: Continuous scan
Scan range: 3-40 deg.
Time/step: 0.8 sec
Step size: 0.05°
Divergence slit: V20
Rotation: 30 rpm

In a preferred embodiment, the present invention provides a novel crystalline Form LEA-1 of Lenacapavir sodium characterized by its powder X-ray diffraction (PXRD) pattern having peaks at 4.6 and 6.3 ± 0.2° 2?.

The crystalline Form LEA-1 of Lenacapavir sodium is further characterized by its PXRD pattern having additional peaks at 14.0, 16.4, 17.2, 18.4, 21.0, 22.4, 24.6, 25.3 and 27.5 ± 0.2° 2?, wherein PXRD pattern is characterized as shown in Fig-1.

In another preferred embodiment, the crystalline Form LEA-1 of Lenacapavir sodium characterized by a DSC thermogram having an endothermic peak at about 206.3° C, wherein DSC is characterized as shown in Fig-2.

In yet another preferred embodiment, the crystalline form LEA-1 of Lenacapavir sodium characterized by weight loss, as measured by thermogravimetric analysis (TGA) of about 1% when heated above 200ºC, wherein thermogravimetric analysis (TGA) is characterized as shown in Fig-3.

In yet another preferred embodiment, the present invention also provides a process for the preparation of a novel crystalline Form LEA-1 of Lenacapavir sodium. The process comprises dissolving Lenacapavir sodium in a first solvent followed by optionally adding a second solvent and isolating the crystalline Form LEA-1 of Lenacapavir sodium.

In a preferred embodiment, the process optionally involves the addition of crystalline Form LEA-1 of Lenacapavir sodium seed crystal.
In a preferred embodiment, the Lenacapavir sodium used in the preparation of crystalline Form LEA-1 is either amorphous or crystalline form.

The first or second solvent as used in the above process comprises water, methanol, ethanol, isopropyl alcohol, acetone, ethyl acetate, isopropyl acetate, butyl acetate, toluene, xylene, chlorobenzene; or n-hexane and n-heptane or mixture thereof.

The novel crystalline Form LEA-1 of Lenacapavir sodium is stable when exposed to 20% RH to 100% RH for 7days at RT. Further, the novel crystalline Form LEA-1 of Lenacapavir sodium is also found to be stable for a period of at least 12, 18, or 24 months at RT under ambient conditions. The novel crystalline Form LEA-1 of Lenacapavir sodium is reproducible after storage at the above conditions.

In yet another preferred embodiment, the present invention also provides a pharmaceutical composition comprising a novel crystalline Form LEA-1 of Lenacapavir sodium and a pharmaceutical acceptable excipient.

In yet another preferred embodiment, the present invention further provides a method of treating or preventing a human immunodeficiency virus (HIV) infection comprising administering a therapeutically effective amount of a novel crystalline Form LEA-1 of Lenacapavir sodium of the present invention to a subject in need thereof.

The Lenacapavir used in the present invention may be produced by prior-art procedure available in the literature.

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.
EXAMPLES:
Example 1: Preparation of crystalline Form LEA-1 of Lenacapavir sodium.
Lenacapavir Sodium 100.0mg was dissolved in acetone (0.5ml). Chlorobenzene (0.5ml) was added at room temperature. The reaction mass was stirred for 20-24hr’s at room temperature for slow solvent evaporation. The solid obtained was dried at 50°C under vacuum for 4-5hr’s to give > 95% of crystalline Form LEA-1 of Lenacapavir sodium. The obtained material was analyzed by PXRD pattern as described in Fig.1.
Example 2: Preparation of crystalline Form LEA-1 of Lenacapavir sodium.
Lenacapavir Sodium 1000.0mg (amorphous) was dissolved in acetone (2.0 ml). Chlorobenzene (2.0 ml) was added at room temperature. The reaction mass was stirred for 20-24hr’s at room temperature for slow solvent evaporation. The obtained solid was dried at 55°C under vacuum for 20-24hr’s to give > 95% of crystalline Form LEA-1 of Lenacapavir sodium. The obtained material was analyzed by PXRD pattern as described in Fig.1.
Example 3: Preparation of crystalline Form LEA-1 of Lenacapavir sodium.
Lenacapavir Sodium 500.0mg was dissolved in ethyl acetate (1.0ml) at 50°C. This solution was charged to toluene (6.0ml) with crystalline Form LEA1 seed 25mg at room temperature. Reaction mass was stirred for 20-24hr’s at room temperature, filtered and washed with toluene (2.5ml). The obtained solid was dried at 50°C under vacuum for 20-24hr’s. The obtained material was analyzed by PXRD pattern as described in Fig.1.

Example 4: Preparation of crystalline Form LEA-1 of Lenacapavir sodium.
Lenacapavir Sodium 500.0mg and 25mg crystalline Form LEA1 seed was slurried in toluene (1.0 ml) at room temperature. Reaction mass was stirred for 20-24hr’s at room temperature. Reaction mass was filtered and washed with toluene 2.5ml. The obtained solid was dried at 50°C under vacuum for 20-24hr’s. The obtained material was analyzed by PXRD pattern as described in Fig.1. ,CLAIMS:WE CLAIM:
1. A novel crystalline form LEA-1 of Lenacapavir sodium, wherein the crystalline Form LEA-1 has PXRD peaks, in terms of 2? ± 0.2°, selected from 4.6° and 6.3°.

2. The crystalline form as claimed in claim 1, wherein the form is further characterized by its PXRD pattern having additional peaks at 14.0, 16.4, 17.2, 18.4, 21.0, 22.4, 24.6, 25.3 and 27.5 ± 0.2° 2?.

3. The crystalline form as claimed in claim 1, wherein PXRD pattern is characterized as shown in Fig-1.

4. A novel crystalline Form LEA-1 of Lenacapavir sodium characterized by a DSC thermogram having an endothermic peak at about 206.3° C.

5. The crystalline form as claimed in claim 4, wherein DSC is characterized as shown in Fig-2.

6. A novel crystalline Form LEA-1 of Lenacapavir sodium characterized by weight loss, as measured by thermogravimetric analysis (TGA) of about 1% when heated above 200ºC.

7. The crystalline form as claimed in claim 6, wherein thermogravimetric analysis (TGA) is characterized as shown in Fig-3.

8. A process for the preparation of a novel crystalline Form LEA-1 of Lenacapavir sodium, comprising:
a) providing Lenacapavir sodium,
b) dissolving in a first solvent,
c) optionally adding a second solvent,
d) isolating the crystalline Form LEA-1 of Lenacapavir sodium.

9. The process as claimed in claim 8, wherein the first or second solvent is selected from water, methanol, ethanol, isopropyl alcohol, acetone, ethyl acetate, isopropyl acetate, butyl acetate, toluene, xylene, chlorobenzene; or n-hexane and n-heptane or mixture thereof.