CLIAMS:Claim 1. A process for the preparation of lopinavir : oxalic acid co-crystal comprising crystallization of lopinavir and oxalic acid in a suitable solvent.
Claim 2. The process of claim 1, wherein ratio of lopinavir and oxalic acid is 1:0.5 to 1:2.
Claim 3. The process of claim 2, wherein ratio of lopinavir and oxalic acid is 1:1.
Claim 4. The process of claim 1, wherein the solvent is selected from acetonitrile, C1-C4 alcohol, C2-C6 ether and mixtures thereof.
Claim 5. The process of claim 4, wherein C1-C4 alcohol is selected from methanol, ethanol, isopropanol, n-butanol.
Claim 6. The process of claim 4, wherein C2-C6 ether is selected from diethyl ether, diisopropyl ether, methyl t-butyl ether (MTBE).
Claim 7. The process of claim 4, wherein the solvent is selected from acetonitrile and mixture of methanol and methyl t-butyl ether (MTBE).
Claim 8. The process of claim 1, wherein the quantity of solvent is 1 to 5 times of lopinavir.
Claim 9. The process of claim 1, wherein lopinavir : oxalic acid co-crystal is isolated by filtration, concentration and evaporation etc.
Claim 10. The lopinavir: oxalic acid co-crystal obtained by the process of claim 1.
,TagSPECI:FIELD OF THE INVENTION
The present invention relates to lopinavir : oxalic acid co-crystal and process for its preparation.

BACKGROUND OF THE INVENTION
Lopinavir is an antiretroviral of the protease inhibitor class. It is used against HIV infections as a fixed-dose combination with another protease inhibitor, ritonavir, under the trade names Kaletra. It was first approved by the US FDA on Sept 15, 2000. It is chemically known as (2S)-N-[(2S,4S,5S)-5-[2-(2,6-dimethylphenoxy)acetamido]-4-hydroxy-1,6-diphenylhexan-2-yl]-3-methyl-2-(2-oxo-1,3-diazinan-1-yl)butanamide.

It is known that crystalline polymorphs typically have different solubilities from one another, such that a more thermodynamically stable polymorph is less soluble than a less thermodynamically stable polymorph. Pharmaceutical polymorphs can also differ in properties such as shelf-life, bioavailability, morphology, vapour pressure, density, colour, and compressibility. Accordingly, variation of the crystalline state of an API is one of many ways in which to modulate the physical properties thereof.

Obtaining suitable crystalline forms of a drug is a necessary stage for many orally available drugs. Suitable crystalline forms possess the desired properties of a particular drug. Such suitable crystalline forms may be obtained by forming a co-crystal between the drug and a coformer.

“Co-crystal” means a crystalline material comprised of two or more unique solids at room temperature, each containing distinctive physical characteristics, such as structure, melting point and heats of fusion. The co-crystals comprise a co-crystal former H-bonded to an API.

Following are the advantages of the co-crystals:
i. increase or decrease the dissolution rate of API-containing pharmaceutical compositions in water,
ii. increased stability,
iii. improved processability, or preparation of pharmaceutical formulations
iv. increase or decrease the bioavailability of orally-administered compositions, and provide a more rapid or more delayed onset to therapeutic effect.

Lopinavir is a BCS Class II antiretroviral drug which possesses low oral bioavailability due to its poor aqueous solubility and extensive metabolism by the liver microsomal enzymes.

Lopinavir exhibits polymorphism. It shows different physical forms such as amorphous and various crystalline forms which exist in different solvation and hydration states.

The patent US 5914332 disclose amorphous lopinavir.

The patent US 6864369 discloses various crystalline forms of lopinavir such as Type I hydrated, Type I higher hydrated, Type II solvated, Type III solvated, Type III desolvated crystal forms.

The patent US 6608198 disclose Type IV non solvated crystal form of lopinavir.

The patent US 8445506 discloses lopinavir cyclohexane solvate and lopinavir desolvated crystalline form H1.

SUMMARY OF THE INVENTION
The present invention relates to lopinavir : oxalic acid co-crystal.

The present invention further provides process for the preparation of lopinavir : oxalic acid co-crystal comprising crystallization of lopinavir and oxalic acid in a suitable solvent.

BRIEF DESCRIPTION OF DRAWINGS
Figure 1— XRPD diffractogram for lopinavir : oxalic acid co-crystal.
Figure 2—DSC thermogram for lopinavir : oxalic acid co-crystal.
Figure 3—TGA thermogram for lopinavir : oxalic acid co-crystal.
Figure 4—IR spectrum for lopinavir : oxalic acid co-crystal.

DETAILED DESCRIPTION OF THE INVENTION
In one embodiment there is provided lopinavir : oxalic acid co-crystal.

In another embodiment there is provided a monohydrate form of lopinavir: oxalic acid co-crystal.

Lopinavir : oxalic acid co-crystal of the present invention can be characterized by X-ray crystallography, IR spectroscopy, thermogravimetric analysis (TGA), and differential scanning calorimetry (DSC).

In another embodiment there is provided lopinavir : oxalic acid co-crystal wherein said lopinavir: oxalic acid co-crystal is characterized by a powder X-ray diffraction pattern comprising peaks at about 9.6, 12.4 and 16.6 degrees 2-theta.

The characteristic peaks found in XRPD of crystalline lopinavir : oxalic acid co-crystal are given in the following table.
Peaks in the XRPD of crystalline lopinavir : oxalic acid co-crystal:
Positiondegree2? (±0.2) d-spacing I/I0(%) Positiondegree2? (±0.2) d-spacing I/I0(%)
9.6 9.184 100 17.4 5.086 43
10.1 8.705 54 19.1 4.633 42
12.4 7.130 91 19.4 4.562 42
12.7 6.943 39 19.6 4.520 77
13.2 6.692 48 20.2 4.383 37
13.3 6.610 55 22.8 3.888 41
15.7 5.611 67 23.7 3.738 33
16.6 5.326 78 24.2 3.674 38
17.1 5.170 57 25.3 3.513 33

The XRPD of crystalline lopinavir : oxalic acid co-crystal is as shown in figure 1.

In another embodiment there is provided lopinavir : oxalic acid co-crystal wherein said lopinavir: oxalic acid co-crystal is characterized by endotherm peak at about 108 °C in differential scanning calorimetry (DSC).

The DSC of lopinavir : oxalic acid co-crystal is shown in figure 2.

In another embodiment there is provided lopinavir : oxalic acid co-crystal wherein said lopinavir: oxalic acid co-crystal is characterized by thermogravimetric analysis showing Delta Y of 2.45 % which corresponds to the loss of one water molecule.

The TGA of lopinavir : oxalic acid co-crystal is shown in figure 3.

In yet another embodiment there is provided lopinavir : oxalic acid co-crystal wherein said lopinavir: oxalic acid co-crystal is characterized by an IR spectrum comprising peaks at about 1755 and 1542 cm-1.

The IR spectrum of lopinavir : oxalic acid co-crystal is as shown in figure 4.

In another embodiment there is provided process for the preparation of lopinavir : oxalic acid co-crystal comprising crystallization of lopinavir and oxalic acid in a suitable solvent.

Lopinavir used in the present invention may be amorphous or crystalline form such as anhydrous, hydrated, solvated or desolvated etc.

The ratio of lopinavir and oxalic acid is 1:0.5 to 1:2, preferably 1:1.

The solvent is selected from acetonitrile, C1-C4 alcohol, C2-C6 ether and mixtures thereof.

The C1-C4 alcohol is selected from methanol, ethanol, isopropanol, n-butanol.

The C2-C6 ether is selected from diethyl ether, diisopropyl ether, methyl t-butyl ether (MTBE).
The preferred solvent is selected from acetonitrile and mixture of methanol and methyl t-butyl ether (MTBE).

The quantity of solvent is 1 to 5 times of lopinavir.

The crystallization was carried out by warming the mixture of lopinavir and oxalic acid at a temperature in the range 20-50 °C, preferably the temperature is between 25-35 °C.
The solution allowed to cool to 0-20 °C, more preferably to 5-15 °C.

Optionally, seeding with lopinavir : oxalic acid co-crystal can be carried out.

Lopinavir : oxalic acid co-crystal can be isolated by methods known in the literature such as filtration, concentration and evaporation etc.

Experimental:
The X-ray powder diffraction spectrum (XRPD) was recorded at room temperature using PANalytical X’Pert PRO diffractogram with Cu Ka radiation (? = 1.54060 Å), running at 45 kV and 40 mA.

Differential scanning calorimetry (DSC) was done using Diamond DSC Perkin Elmer instrument. The scans were recorded between 50 and 300 °C at a constant heating rate of 10°C/min.

Thermogravimetric analysis (TGA) was done using Pyris-1 TGA Perkin Elmer instrument. The scans were recorded between 20 and 300 °C at a constant heating rate of 10°C/min.

FTIR spectrum was obtained using a Perkin Elmer Precisely Spectrum 400 instrument using KBr pellet method.

The present invention is described in the following examples, however it should be noted that the scope of present invention is not limited by the examples.

Example 1
Preparation of lopinavir : oxalic acid co-crystal
Lopinavir (100 g, 0.159 mol) was dissolved in acetonitrile (100 mL) at 30 °C and oxalic acid dihydrate (20.034 g, 0.159 mol) was added at the same temperature. The mixture was stirred for 5 hours at the same temperature. The resulting suspension was cooled to 15 °C and the solid was filtered, washed with acetonitrile (25 ml) and dried under vacuum at 45 °C for 4 hours. Yield: 83 g, melting point: 107.9-108.7°C.

Example 2
Preparation of lopinavir : oxalic acid co-crystal
Lopinavir (20 g, 0.032 mol) was dissolved in acetonitrile (20 mL) at 30 °C and oxalic acid dihydrate (4.032 g, 0.032 mol) was added at the same temperature. The mixture was stirred for 4 hours at the same temperature. Lopinavir : oxalic acid co-crystal seed was added and stirred for an hour. The solid was filtered, washed with acetonitrile (5 ml) and dried under vacuum at 45 °C for 4 hours. Yield: 14.2 g, melting point: 109.1-110.6 °C.

Example 3
Preparation of lopinavir : oxalic acid co-crystal
Lopinavir (20 g, 0.032 mol) was dissolved in methanol (10 mL) at 30 °C and oxalic acid dihydrate (4.032 g, 0.032 mol) was added at the same temperature. Methyl t-butyl ether (MTBE) (20 mL) was added. The mixture was stirred for 1 hour at the same temperature. The solid was filtered, washed with MTBE (10 ml) and dried under vacuum at 45 °C for 4 hours. Yield: 4.5 g, melting point: 110.3-111.2 °C.

Example 4
Solubility studies:
The lopinavir : oxalic acid co-crystal of the present invention has higher solubility compared to amorphous lopinavir at 37 °C.
Medium Form Solubility (µg/mL)
Water Amorphous lopinavir 0.004
lopinavir : oxalic acid co-crystal 0.01
0.1N HCl Amorphous lopinavir 0.004
lopinavir : oxalic acid co-crystal 0.012