This application claims priority to Indian patent applications numbered 2578/CHE/2010 filed on Sep 6, 2010 and 755/CHE/2011 filed on Mar 14, 2011 the contents of which are incorporated by reference in their entirety.

FIELD OF THE INVENTION:

The present invention relates to a novel pseudopolymorph of Adefovir dipivoxil, and process for the preparation thereof. The present invention specifically relates to Adefovir dipivoxil formic acid solvate.

BACKGROUND OF THE INVENTION:

Adefovir dipivoxil is a diester prodrug of adefovir. Adefovir is an orally-administered
nucleotide analog reverse transcriptase inhibitor (ntRTI) used for treatment of hepatitis B.

Adefovir dipivoxil (9-[2-[[bis[(pivaloyloxy)methoxy]phosphinyl]-
methoxy] ethyl]adenine) having Formula-I is more suitable for developing formulations and has been recommended as a drug.

Adefovir dipivoxil and processes for the preparation of the same is described in US 5663159.

United States patent US 6451340 discloses various crystalline salts of Adefovir dipivoxil. Fumaric acid, hemisulfate, hydrobromide, hydrochloride, nitrate, mesylate, ethyl sulfonate, P-naphthylene sulfonic acid, -naphthylene sulfonic acid, (S)-camphor sulfonic acid, succinic acid, maleic acid, ascorbic acid and nicotinic acid salts or complexes disclosed in the US 6451340.

United States patent publication US 20090247749 discloses novel salts and cocrystals of Adefovir dipivoxil. Cocrystals of Adefovir dipivoxil with Nicotimamide, salicylamide and saccharin salt of Adefovir dipivoxil are disclosed in the patent publication US '749. WO 2010062147 discloses Ethanolate solvate of Adefovir dipivoxil.

Active pharmaceutical ingredients (APIs) are frequently administered in the solid state as part of an approved dosage type (e.g., tablets, capsules, etc.). Solids provide a convenient, compact and generally a stable format to store an API or a drug product. APIs can exist in a variety of distinct solid forms (solvates or pseudopolymorphs, hydrates and polymorphs), where each form may display unique physicochemical properties such as hygroscopicity, morphology, solubility and bioavailability. Unfortunately, some potentially useful compounds with highly desirable molecular pharmacological properties may never realize their maximum potential. This is because of the physical properties of the bulk material which may provide unfavorable bioavailability, processing characteristics, and unacceptable shelf-life. Current approaches to changing properties of APIs include the utilization of ionic salts, solvates, hydrates, and polymorphs.

There is a need in the art to provide novel crystal forms of Adefovir dipivoxil with improved stability.

OBJECT AND SUMMARY OF THE INVENTION:

The principle object of the present invention is to provide a novel pseudopolymorph of Adefovir dipivoxil.

Another object of the present invention is to provide Adefovir dipivoxil formic acid solvate.

Another object of the present invention is to provide process for the preparation of Adefovir dipivoxil formic acid solvate.

BRIEF DESCRIPTION OF THE DRAWINGS:

Figure 1 illustrates Powder X-ray diffraction pattern of Adefovir dipivoxil formic acid
solvate.

Figure 2 illustrates DSC thermogram of Adefovir dipivoxil formic acid solvate.

Figure 3 illustrates TGA/DTA of Adefovir dipivoxil formic acid solvate.

Figure 4 illustrates Infrared spectrum of Adefovir dipivoxil formic acid solvate.

Figure 5 illustrates H-NMR spectrum of Adefovir dipivoxil formic acid solvate.

Figure 6 illustrates thermal ellipsoid plot of Adefovir Dipivoxil formic acid solvate with
atomic numbering scheme.

Figure 7 illustrates comparison of experimental and simulated (from single crystal data)
Powder X-ray diffraction patterns of Adefovir Dipivoxil Formic acid solvate.

DETAILED DESCRIPTION OF THE INVENTION:

The present invention relates to a novel pseudopolymorph of Adefovir dipivoxil. The present invention specifically relates to Adefovir dipivoxil formic acid solvate. The present invention further provides process for the preparation of Adefovir Dipivoxil formic acid solvate.

The main aspect of the present invention is to provide Adefovir Dipivoxil formic acid solvate.

In one more aspect, the present invention provides process for the preparation of Adefovir Dipivoxil formic acid solvate comprising the steps of:

a) dissolving Adefovir dipivoxil in formic acid;
b) adding ethereal solvent to the obtained solution; and
c) isolating Adefovir dipivoxil formic acid solvate.

In one embodiment of the present invention, the ethereal solvent used in step-b is selected from diethyl ether, diisopropyl ether, Methyl tert-butyl ether, preferably diisopropyl ether.

As per the present invention, Adefovir dipivoxil is dissolved in formic acid at a temperature 15-45 °C preferably 25-35 °C and to the obtained clear solution ethereal solvent is added. Ethereal solvent is selected from diethyl ether, diisopropyl ether, Methyl tert-butyl ether, preferably diisopropyl ether. The obtained solid is filtered, optionally washed with ethereal solvent and Adefovir dipivoxil formic acid solvate is isolated.
The physical stability of Adefovir dipivoxil formic acid solvate was monitored by subjecting approximately 1.0 g of the sample to different stress conditions; Drying, exposure to Relative Humidity, milling and Slurry conversion. The samples were tested by PXRD. The novel form is stable to drying at 40°C, 90 % relative humidity and slurry conditions as shown in the following Table 1.

Table 1

The physical stability and chemical stability of the Adefovir dipivoxil formic acid was monitored by storing the sample at both long term (25°C and 60% Relative Humidity) and accelerated stability (40°C and 75% Relative Humidity) conditions. The samples were tested by PXRD after 15 days, 1 month, 2 months and 3 months and the observed results were shown below (Table 2).
Table 2

The Adefovir dipivoxil formic acid solvate is stable under lab stress conditions (drying, humidity, milling and slurry) as mentioned in Table 1. From indicative stability data it appears that the formic acid solvate is physically and chemically stable up to three months as shown in Table 2.

The physical stability of Adefovir dipivoxil anhydrate Form I was monitored by subjecting approximately 1.0 g of the sample to different stress conditions; Drying,
milling and exposure to Relative Humidity (RH). The samples were tested by PXRD and results incorporated in Table 3.

Table 3

The solubility of Adefovir dipivoxil formic acid solvate and Adefovir dipivoxil Form I were determined in distilled water and at several pH (0.1N HC1, acetate buffer and phosphate buffer) at 25 °C and the results were incorporated in Table 4.

Table 4

Adefovir dipivoxil formic acid solvate is more stable to humidity & milling (Table 1) compared to the Adefovir dipivoxil anhydrate Form I (Table 3). The solubility data

incorporated in Table 4 shows that Adefovir dipivoxil Formic acid solvate has superior solubility over Adefovir dipivoxil anhydrate Form I.
Instrumentation

Powder X-ray Diffraction (PXRD)

The said formic acid solvate of the present invention is characterized by their X-ray powder diffraction pattern. Thus, the X-ray diffraction patterns of said polymorphs of the invention were measured on Bruker AXS D8 Discover powder X-ray diffractometer equipped with a goniometer of 0/20 configuration, Variol monochromator and Lynx-Eye detector. The Cu-anode X-ray tube was operated at 40kV and 30mA. The experiments were conducted over the 20 range of 2.0°-50.0°, 0.030° step size and 25 seconds step time.

Differential Scanning Calorimetry (DSC)

The DSC measurements were carried out on TA Q1000 of TA instruments. The experiments were performed at a heating rate of 10.0 °C/min over a temperature range of 30°C-200°C purging with nitrogen at a flow rate of 50ml/min. Standard aluminum crucibles covered by lids with three pin holes were used.

Thermo gravimetric Analysis (TGA)

TGA/DTA was recorded using the instrument TA Q5000 of TA instruments. The experiments were performed at a heating rate of 10.0 °C/min over a temperature range of 30°C-300°C purging with nitrogen at a flow rate of 25ml/min.

Infrared (IR) spectroscopy

Fourier transform infrared (FT-IR) spectra were recorded with a Perkin-Elmer spectrum one spectrometer. The samples were prepared as 1 mm thickness and 13 mm diameter KBr glassy discs by triturating 1 to 3 mg of sample with 300 mg to 400 mg of KBr and

applying pressure of about 1000 lbs/sq inch. Then these discs were scanned in the spectral range of 4000 to 650 cm"1 with a resolution of 4 cm-1.

Nuclear Magnetic Resonance (NMR) spectroscopy
The 1HNMR experiments were performed on Bruker 300MHz Avarice NMR spectrometer equipped with 5mm BBO probe in CDCl3. The data collected and processed by XWIN-NMR software.

Single crystal X-ray diffraction

Single crystal X-ray diffraction measurement for Adefovir dipivoxil formic acid solvate was made using Rigaku Mercury 375R/M CCD (XtaL LAB mini) diffractometer using Mo-Ka radiation (X=0.71073 A).

In one embodiment, Adefovir dipivoxil formic acid solvate is characterized by the Powder X-ray diffraction having peaks at about 14.08, 16.41, 19.42 and 23.34 (±) 0.2 20 values.

In another embodiment, Adefovir dipivoxil formic acid solvate is further characterized by the Powder X-ray diffraction having peaks at about 7.94, 14.08, 14.48, 16.41, 17.00 18.64, 19.42, 20.16, 20.97, 21.38, 22.45, 23.34, 23.87, 25.30 and 32.92 (±) 0.2 26 values.

In one more embodiment, Adefovir dipivoxil formic acid solvate is further characterized by the Powder X-ray diffraction as depicted in Figure 1.

In one more embodiment, Adefovir dipivoxil formic acid solvate is further characterized by DSC thermogram as depicted in Figure 2. In DSC thermogram, endothermic peak at 116.4 °C shows the melting point of Adefovir dipivoxil formic acid pseudopolymorph.

The Adefovir dipivoxil formic acid solvate is further characterized by TGA/DTA as depicted in Figure 3.

The Adefovir dipivoxil formic acid solvate is further characterized by Infrared spectrum as depicted in Figure 4.

The Adefovir dipivoxil formic acid solvate is further characterized by 'H-NMR spectrum as depicted in Figure 5.

The Adefovir dipivoxil formic acid solvate is characterized by single crystal X-ray diffraction as shown in Figure 6. The crystallographic data and atomic coordinates are incorporated respectively in Table 5 and

Table 6.

Table 5: Crystallographic Data of Adefovir Dipivoxil formic acid solvate from single crystal X-ray diffraction.

Table 6: Atomic coordinates of Adefovir Dipivoxil formic acid solvate obtained from single crystal X-ray diffraction.

The following examples are provided for illustrative purposes only and are not intended to limit the scope of the invention in any way

Experimental procedure:

Example -1

5g of Adefovir dipivoxil was dissolved in formic acid (5 mL) at room temperature and stirred for 20 minutes. To the resulting clear solution, 75 ml of diisopropyl ether was added dropwise over a period of 30 minutes under stirring and continued for 4 h. The solid obtained was filtered and washed with 10 mL of diisopropyl ether and dried to yield Adefovir dipivoxil formic acid solvate.

Example – 2

5g of Adefovir dipivoxil was dissolved in formic acid (5 mL) at room temperature and stirred for 20 minutes. To the resulting clear solution, 75 ml of Methyl tert-butyl ether was added dropwise over a period of 30 minutes under stirring and continued for 4 h. The solid obtained was filtered and washed with 10 mL of Methyl tert-butyl ether and dried to yield Adefovir dipivoxil formic acid solvate.

Example – 3

25g of Adefovir dipivoxil was dissolved in formic acid (25 mL) at room temperature and stirred for 20 minutes. To the resulting clear solution, 375 mL of diisopropyl ether was added dropwise over a period of 30 minutes under stirring and stirring was continued for 4 h. The solid obtained was filtered and washed with 50 mL (2 x 25 mL) of diisopropyl ether to yield 25g of crystalline Adefovir dipivoxil Formic acid solvate. This material was slurred in 125 mL of acetonitrile for 4 h. The material was filtered and dried at 40 °C u/v for 15h to yield 20g of Adefovir dipivoxil formic acid solvate.

Example – 4

50g of Adefovir dipivoxil was dissolved in formic acid (40 mL) at room temperature and stirred for 20 minutes. To the resulting clear solution, 500 mL of diisopropyl ether was added dropwise over a period of 30 minutes under stirring and stirring was continued for 3-4 h. The solid obtained was filtered and washed with 100 mL (2 x 50 mL) of diisopropyl ether to yield 50g of crystalline Adefovir dipivoxil Formic acid solvate. This
material was slurred in 100 mL of acetone for 2 h. The material was filtered and dried at 40 °C u/v for 15h to yield 47 g of Adefovir dipivoxil formic acid solvate.

Example – 5

100 mg of Adefovir dipivoxil formic acid solvate powder was dissolved in MeOH (2 mL) in a conical flask and allowed for slow evaporation at room temperature. Diffraction quality single crystals were obtained in about 2 days.

We claim:

1. Adefovir Dipivoxil formic acid solvate.

2. The Adefovir Dipivoxil formic acid solvate according to claim 1, characterized by the Powder X-ray diffraction having peaks at about 14.08, 16.41, 19.42 and 23.34 (±) 0.2 20 values.

3. The Adefovir Dipivoxil formic acid solvate according to claim 1, characterized by the Powder X-ray diffraction having peaks at about 7.94, 14.08, 14.48, 16.41, 17.00 18.64, 19.42, 20.16, 20.97, 21.38, 22.45, 23.34, 23.87, 25.30 and 32.92 (±) 0.2 20 values.

4. The Adefovir Dipivoxil formic acid solvate according to claim 1, characterized by the Powder X-ray diffraction as depicted in Figure 1.

5. The Adefovir Dipivoxil formic acid solvate according to claim 1, characterized by DSC thermogram as depicted in Figure 2.

6. The Adefovir Dipivoxil formic acid solvate according to claim 1, characterized by TGA/DTA as depicted in Figure 3.

7. A process for the preparation of Adefovir Dipivoxil formic acid solvate comprising the steps of:

a) dissolving Adefovir dipivoxil in formic acid;
b) adding ethereal solvent to the obtained solution; and
c) isolating Adefovir dipivoxil formic acid solvate.

8. The process according to claim 7, wherein the ethereal solvent is selected from
diethyl ether, diisopropyl ether or Methyl tert-butyl ether.