FORM 2
THE PATENT ACT, 1970
(39 OF 1970)
AND
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
1. TITLE OF THE INVENTION:
PROCESS FOR THE PURIFICATION OF POSACONAZOLE
2. APPLICANT:
a. NAME: INDOCO REMEDIES LIMITED
b. NATIONALITY: INDIAN
c. ADDRESS: Indoco House,166 C.S.T. Road, Santacruz East, Mumbai - 400 098, Maharashtra, India
3. PREAMBLE TO THE DESCRIPTION:
The following specification particularly describes the invention and the manner in which it is to be performed.

FIELD OF INVENTION:
The present invention relates to an improved process for purification of posaconazole.
The present invention also relates to a novel crystalline Form-/> of posaconazole and a process of preparation thereof.
BACKGROUND OF THE INVENTION:
The compound 4-[4-[4-[4-[[(3R,5R)-5-(2,4-difluorophenyl) tetrahydro-5-(lH-l,2,4-triazol-l-ylmethyl)-3-furanyl]methoxy]phenyl]-l-piperazinyl]phenyl]-2-[(lS,2S)-l-ethyl-2-hydroxy -propyl]-2,4-dihydro-3H-l,2,4-triazol-3-one of Formula I having an international non-proprietary name posaconazole is a triazole class antifungal drug used for the treatment of invasive fungal infections.

The drug posaconazole is marketed as oral suspension and tablet in the United States, the European Union, and in other countries under the trade name Noxafil.
International Publication Number WO95/17407 and W096/38443 discloses several substituted tetrahydrofuran antifungal compounds, including posaconazole.
According to one process, posaconazole is prepared by the condensation of toluene-4-sulfonic acid (-)-(5R-cis)-5-(2,4-difluorophenyl)-5-[ 1 ,2,4]triazol- 1 -

yl)methyl tetrahydro-3-furanmethyl ester with N-protected triazolone derivative in the presence of a strong base in an aprotic solvent to give a compound, which is then deprotected using hydrochloric acid in methanol followed by N-alkylation with brosylated (2S,3R) alcohol in the presence of cesium carbonate in an aprotic solvent to give hydroxy protected posaconazole, and is then deprotected to give posaconazole.
The major drawback of the above said process is necessity of laborious purification methods such as column chromatography which is a time consuming and tedious process; especially for large quantities hence it is not suitable for large scale production and further results in low yields of posaconazole.
There arises need of a purification process for posaconazole which is easy to implement on industrial scale production with minimum yield loss.
Further the synthetic procedures disclosed in International Publication Numbers WO95/17407 and W096/38443 produce the compound of formula I as an amorphous solid.
Three polymorphic forms of posaconazole designated as Form-I, Form-II and Form-Ill are described and characterized in WO99/18097. As per the disclosure crystalline Form-I is more stable and Form-II and Form-Ill were found to be unstable under the conditions investigated, so that crystalline Form-I was considered to be useful in the development of a pharmaceutical product.
Polymorphs are, by definition, crystals of the same molecule having different physical properties as a result of the order of the molecules in the crystal lattice. The polymorphic behavior of drugs can be of crucial importance in pharmacy and pharmacology. There may be several different crystalline forms for the same molecule with distinct crystal structures and distinct and varying physical properties like melting point, XRPD pattern, IR spectrum and solubility profile. The polymorphs may have distinct advantageous physical properties which can have a direct effect on the ability to process and manufacture the drug product,

like flowability, solubility, storage stability and dissolution properties, which can have a direct effect on drug product stability, solubility, dissolution, and bioavailability.
International patent publication WO2009/147075 discloses crystalline Form-Y of posaconazole and method of their preparation by thermal treatment of Form-II (monohydrate) or Form-Ill.
WO2010/000668 discloses crystalline polymorphic Form-IV of posaconazole and method for preparation of posaconazole Form-IV.
Another international publication WO2011/158248 discloses crystalline posaconazole Form-V and method of preparation thereof.
Another international publication WO2015/092595 discloses crystalline posaconazole hydrate Form-A prepared from crystalline Form-I.
The differences in physical properties exhibited by polymorphs affect pharmaceutical parameters such as storage stability, compressibility and density, and dissolution rates. Differences in stability can result from changes in chemical reactivity or mechanical changes viz. tablets crumble on storage as a kinetically favored polymorph converts to thermodynamically more stable polymorph. The finding of new forms of Posaconazole provides a new opportunity to improve the synthesis process of the pharmaceutical active ingredient (API), resulting in a form of Posaconazole with improved characteristics, for example, in terms of fluidity and solubility, the need of which is felt in the state of the art.
There is a need of an improved process for purification of posaconazole and develop stable polymorphic forms of posaconazole which have properties that make them suitable for bulk preparation and handling as well as for preparing of pharmaceutical compositions on a commercial scale which has advantageous properties for the preparation and storage thereof.

Thus it becomes objective of the present invention is to provide a purification process of Posaconazole.
Another objective of the present invention is to provide a process for the purification of crude posaconazole.
Yet another objective of the present invention is to provide a new crystalline form
of Posaconazole.
Yet another objective of the present invention is to provide process for the
preparation of the new polymorph.
Yet another objective of the present invention is to provide a process for the
preparation of Form-I using new Form-ir.
SUMMARY OF THE PRESENT INVENTION:
Accordingly the present invention provides a process for the purification of posaconazole.
According to primary object of the invention, there is provided a process for the purification of crude posaconazole to get the compound pure crystalline posaconazole of Formula I which comprises;
a) suspending crude posaconazole in a solvent, said solvent being in an amount sufficient to achieve dissolution to get clear solution in hot condition;
b) treating with activated charcoal and filtering hot;
c) adding an amount of anti-solvent at hot condition just sufficient to initiate crystallization, whereby less than 5% of said posaconazole crystallizes;
d) stirring and cooling the reaction mass to crystallise out solid completely;
e) isolating the compound pure crystalline posaconazole of Formula I.
In another aspect of the present invention, there is provided novel crystalline Form-ir of posaconazole.

According to object of the present invention, there is provided a novel crystalline Form-zr of posaconazole characterized by peaks in the powder x-ray diffraction spectrum having 29 angle positions at about 3.2, 6.3, 9.4, 15.8, 17.0, 23.8 and 24.9 ±0.2 degrees.
In another aspect of the present invention polymorph crystalline Form-ir of posaconazole is further charecterised by peaks in the powder x-ray diffraction spectrum having 29 angle positions at about 7.6, 8.6, 12.8, 14.6, 15.2, 18.6, 20.9, 22.8, 23.0, 26.3, and 28.0 ± 0.2 degrees.
In another aspect of the present invention crystalline Form-ir of posaconazole can be characterized by an attenuated total reflectance infrared spectrum comprising absorption bands at wave numbers of about 1665 cm-1, 1651 cm-1 and 1499 cm-having typical precision of the wavenumber values is in the range of ± 2 cm-1.
In another aspect of the present invention provides a process for the preparation of posaconazole crystalline Form-ir, which comprises;
a) providing a suspension of posaconazole in suitable solvent;
b) heating the suspension obtained in step (a) to get a clear solution;
c) charging anti-solvent to the solution obtained in step (b);
d) cooling the reaction mass obtained; and
e) Isolating posaconazole crystalline Form-ir.
BRIEF DESCRIPTION OF THE DRAWINGS:
Figure 1: X-ray powder diffraction pattern of crystalline Form-z> of posaconazole.
Figure 2: Infrared spectrum of crystalline Form-ir of posaconazole.
Figure 3: Differential scanning calorimetric curve of crystalline Form-ir of posaconazole.

Figure 4: Thermo gravimetric analysis of crystalline Form-ir of posaconazole.
These and the other objects of the present invention will be apparent from the following detailed description.
DETAILED DESCRIPTION OF THE INVENTION:
The present invention relates to purification process of crude posaconazole to isolate crystalline pure posaconazole having HPLC purity meeting the ICH guidelines.
In an embodiment of the present invention, there is provided a process for the purification of crude posaconazole to get the compound pure crystalline posaconazole of Formula I which comprises;
1. suspending crude posaconazole in a solvent, said solvent being in an amount sufficient to achieve dissolution to get clear solution in hot condition;
2. treating with activated charcoal and filtering hot;
3. adding an amount of anti-solvent at hot condition just sufficient to initiate crystallization, whereby less than 5% of said posaconazole crystallizes;
4. stirring and cooling the reaction mass to crystallise out solid completely;
5. isolating the compound pure crystalline posaconazole of Formula I.
In an embodiment of the present invention the solvent used for getting the clear solution in step (a) is selected from the group of acetone, methanol, isopropyl alcohol, dichloromethane, acetonitrile and N,N-dimethylformamide. The preferred temperature for dissolving the crude posaconazole to get clear solution is in the range of 30°C to 70°C. The anti-solvent used for initiating crystallization for the precipitation of solid is selected from the group of solvent cyclohexane, toluene, xylene, diisopropyl ether, ethyl acetate and water. The Anti-solvent is the

solvents in which posaconazole is insoluble or has low solubility and it is sufficient enough to precipitate the compound posaconazole.
In an embodiment of the present invention, the purification process can be repeated following the above process to get the HPLC purity of pure crystalline posaconazole more than 99.70%, preferably the HPLC purity of more than 99.80% and most preferably the HPLC purity of more than 99.90%.
The present invention further relates to crystalline Form-ir of posaconazole, the compound of Formula I.
In an embodiment of the present invention, crystalline Form-ir of posaconazole is characterized by a powder X-ray diffraction pattern having characteristic peaks, in terms of 20 angle positions at about 3.2, 6.3, 9.4, 15.8, 17.0, 23.8 and 24.9 ± 0.2 degrees.
In further embodiment of the present invention, the powder X-ray diffraction pattern of crystalline Form-ir further includes characteristic peaks, in terms of 20, angle positions at about 7.6, 8.6, 12.8, 14.6, 15.2, 18.6, 20.9, 22.8, 23.0, 26.3, and 28.0 ± 0.2 degrees.
In an embodiment of the present invention, crystalline Form-ir of posaconazole is characterized by a powder X-ray diffraction pattern substantially as shown in FIG. 1. The relative intensities of the peaks can vary, depending upon the sample preparation technique, the sample mounting procedure and the particular instrument employed. Moreover, instrument variation and other factors can affect the 2-theta values. Therefore, the XRPD peak assignments can vary by about ± 0.2 degrees.
The X-ray powder diffractogram (XRPD) was obtained by using an X'Pert PRO PANalytical tool, equipped with X'Celerator detector and X-ray tube (Cu LFF PW3373/00 DK312503) with 40mA current intensity and 40kV voltage. The sample is arranged on a support and analyzed using the following parameters:

• Scanning range (°): 3.0010-39.9997
• Step size (°): 0.0167
• Scanning mode: continuous - Count time (s): 12.700
• Soller slit (rad): 0.04
• divergent slit: 1/4
• Antiscatter slit: 1/2°
In an embodiment of the present invention, crystalline Form-ir of posaconazole is characterized by an infrared spectrum in KBr comprising absorption bands at wave numbers of about 1665 cm-1, 1651 cm-1 and 1499 cm-1 having typical precision of the wave number values is in the range of ± 2 cm-1.
In an embodiment of the present invention, crystalline Form-ir of posaconazole is characterized by an infrared spectrum in KBr comprising absorption bands at wave numbers of about 3395 cm-1, 3134 cm-1, 3062 cm-1, 2969 cm-1, 2865 cm-1, 2835 cm-1, 1692 cm-1, 1665 cm-1, 1651 cm-1, 1616 cm-1, 1550 cm-1, 1514 cm-1, 1499 cm-1, 1453 cm-1, 1422 cm-1, 1396 cm-1, 1273 cm-1, 1239 cm-1, 1135 cm-1, 1072 cm-1, 1050 cm-1, 946 cm-1, 823 cm-1, 786 cm-1. The typical precision of the wave number values is in the range of ± 2 cm-1.
In an embodiment of the present invention, crystalline Form-ir of posaconazole is characterized and identified by its infrared (IR) absorption spectrum as provided in FIG. 2.
In an embodiment of the present invention, crystalline Form-ir of posaconazole can also be identified by its characteristic differential calorimeter scanning (DSC) trace as provided in FIG. 3.
In an embodiment of the present invention, crystalline Form-ir of posaconazole is identified by a DSC trace showing endotherm peaks at about 95.3°C, peak at about 136.6°C and melting endotherm peak at about 168.1°C. For DSC it is known that the temperatures observed will depend upon the rate of temperature change as well as sample preparation technique and the particular instrument

employed. Thus, the values reported herein relating to DSC thermograms can vary by about ± 4°C.
The DSC analyses were obtained by the use of a differential scanning calorimeter DSC Q 1000. The samples have been loaded on aluminum crucibles and heated to 400°C at a heating rate of 10°C/min.
In an embodiment of the present invention, crystalline Form-ir of posaconazole can also be identified by its characteristic TGA thermogram as provided in FIG. 4.
The TGA analysis shows a weight loss at about 100°C. Furthermore, there is a continuous weight loss observed passing from about 350°C to about 450°C. The events characteristic of the measured weight loss are best noticed on the DTG curve, which is set forth on the same graph.
In an embodiment of the present invention, relates to a process for the preparation of crystalline Form-ir of posaconazole, the compound of Formula I, which comprises the steps of:
a) providing a suspension of posaconazole in suitable solvent;
b) heating the suspension obtained in step (a) to get a clear solution;
c) charging anti-solvent to the solution obtained in step (b);
d) cooling the reaction mass obtained; and
e) Isolating posaconazole crystalline Form-ir.
In an embodiment of the present invention, the suitable solvent used in step (a) is N,N-dimethylformamide. The reaction is heated to a preferred temperature in the range of 60°C to 65°C. The anti-solvent as used in step (c) is diisopropyl ether. The preferred ratio of the first solvent to anti-solvent is 1:3 v/v. The reaction mass is gradually cooled to preferred temperature in the range of 20°C to 30°C and maintained under stirring for one hour.

The compound posaconazole used for the preparation of crystalline Form-ir can be of any forms as described in the state of the art referred to in the preceding description or can be freshly prepared.
In an embodiment of the present invention, the crystalline Form-ir can be converted to crystalline Form-I.
The crystalline Form-ir of Posaconazole can find application in pharmaceutical compositions. The pharmaceutical composition comprising the crystalline Form-ir may contain additives, inert diluents, binders, and the like. Any conventional technique can be used for preparing pharmaceutical formulations in accordance with the present invention.
The present invention is further illustrated in detail with reference to the following examples. It is desired that the examples be considered in all respects as illustrative only and non restrictive to the invention.
Examples:
Example 1: Preparation of crystalline Form-ir:
Charged benzyl-posaconazole (100 gm), methanol (900 ml), cone, hydrochloric acid (100 ml) and of 10% palladium carbon (10 gm) in an autoclave at 25 °C to 30°C. Flushed the autoclave with nitrogen and applied heating and raised the temperature of the reaction mass to 45°C - 50°C. Purged the reaction mass with 6.0 kg hydrogen and maintained under stirring. Continued maintaining the reaction mass under hydrogen pressure till no further consumption of hydrogen observed. Checked for the completion of the reaction on HPLC. After completion of the reaction applied cooling and cooled the reaction mass to 25°C - 30°C. Filter the reaction mass through hyflow bed and washed with methanol (100 ml). Adjust the pH of filtrate to 8-10 with of aqueous ammonia. Heated the reaction mass to 60°C - 65°C, slowly charged water (600 ml) and stirred for one hour. Cooled the reaction mass to 25°C to 30°C and filtered. Wash the solid with water

(200 ml). Charged the wet cake and water (500 ml) in a flask and heated to 50°C - 55°C. Maintained for one hour and applied cooling. Cooled the reaction mass to 25°C to 30°C and filtered. Wash the solid with water (200 ml) to get Crude Posaconazole having HPLC purity of 93.0% - 97.0%.
Charged the wet solid mass in flask and added DMF (600ml). Heated the reaction mass to get clear solution. Charcoalised the reaction mass maintaining at 60°C - 65°C for one hour. Filtered the reaction mass through hyflo bed and washed the hyflo bed with DMF (100 ml) Heated the filtrate under stirring to 60°C - 65°C and charged slowly diisopropyl ether (2.0 lit). Maintained the reaction mass further for one hour. Cooled gradually the precipitated solid to 25°C to 30°C and stirred for one hour. Filtered the solid mass and washed with diisopropyl ether (100 ml). Dried the product at 60°C - 65°C till constant weight to get the compound posaconazole crystalline Form-ir.
Yield =55-60 gm.
HPLC Purity = 99.80%
Example 2: Preparation of crystalline Form-ir:
In a dry flask charged posaconazole Form-I (5.0 gm) and of N,N-dimethylformamide (35 ml) maintaining temperature at 25°C - 30°C. Raised the temperature of the reaction mass slowly to 60°C - 65 °C and maintained the reaction mass for one hour. Charged second solvent diisopropyl ether (100 ml) in the reaction mass. Stirred the reaction mass further for one hour. Cooled the reaction mass gradually to 25 °C - 30°C. Stirred the reaction mass for one hour and filtered the solid. Washed the wet cake with diisopropyl ether (5 ml) and dried product at 60°C - 65°C till constant weight.
Yield = 3.9-4.1 gm

Example 3: Process for purification of crude Posaconazole:
Charged crude posaconazole (10 gm) in flask containing N,N-dimethylformamide (60 ml). Heated the reaction mass to get clear solution. Charcoalised the reaction mass maintaining at 60°C - 65°C for one hour. Filtered the reaction mass through hyflo bed and washed the bed with N,N-dimethylformamide (10 ml). Heated the filtrate under stirring to 60°C - 65°C and charged slowly anti solvent diisopropyl ether (200 ml). Maintained the reaction mass further for one hour. Cooled gradually the precipitated solid to 25°C to 30°C and stirred for one hour. Filtered the solid mass and washed with diisopropyl ether (10 ml). Dried the product at 60°C - 65°C till constant weight to get pure crystalline posaconazole.
Yield = 6.5 - 7.0 gm. HPLC Purity = 99.80%
Example 4: Preparation of Crystalline Form-I:
In a flask charged posaconazole crystalline Form-ir (10 gm) and methanol (100 ml) at 25°C -30°C. Raised the temperature of the reaction mass to 60°C - 65°C. To the clear solution charged activated charcoal (1.0 gm). Maintained the reaction mass at 60°C - 65°C for one hour. Filtered the reaction mass through hyflo bed and washed the hyflo bed with methanol (10 ml). Heated the filtrate under stirring to 60°C - 65°C and charged slowly water (100 ml), in the reaction mass. Cooled gradually the precipitated solid to 25°C to 30°C and stirred for one hour. Filtered the solid mass and washed with water (10 ml). Dried the product at 60°C - 65 °C till constant weight.
Yield = 8.5 - 9.0 gm.

Claims:
1. A process for the purification of posaconazole the compound of Formula I

which comprises the steps of;
a) suspending crude posaconazole in a solvent, said solvent being in
an amount sufficient to achieve dissolution to get clear solution at
a temperature;
b) treating with activated charcoal and filtering hot;
c) adding an amount of anti-solvent at hot condition just sufficient to
initiate crystallization, whereby less than 5% of said posaconazole
crystallizes;
d) stirring and cooling the reaction mass to crystallise out solid completely;
e) isolating the compound pure crystalline posaconazole of Formula I.
2. The process as claimed in claim 1, wherein in step (a) the solvent used for
suspending crude posaconazole is selected from the group of acetone,
methanol, isopropyl alcohol, dichloromethane, acetonitrile and N,N-
dimethylformamide.
3. The process as claimed in claim 1, wherein in step (a) to step (c) the
temperature ranges from 30°C to 70°C.
4. The process as claimed in claim 1, wherein in step (c) the anti-solvent
used for initiating the crystallization is selected from the group of
cyclohexane, toluene, xylene, diisopropyl ether, ethyl acetate and water.

5. A crystalline polymorph Form-ir of posaconazole having a powder X-ray diffraction pattern comprising characteristic peaks in terms of 20 angle positions at about 3.2, 6.3, 9.4, 15.8, 17.0, 23.8 and 24.9 ± 0.2 degrees.
6. The polymorph crystalline Form-ir of posaconazole as claimed in claim 5, is further charecterised by peaks in the powder x-ray diffraction spectrum having 29 angle positions at about 7.6, 8.6, 12.8, 14.6, 15.2, 18.6, 20.9, 22.8, 23.0, 26.3, and 28.0 ± 0.2 degrees.
7. The polymorph crystalline Form-ir of posaconazole as claimed in claim 5 having a powder X-ray diffraction pattern substantially as shown in FIG. 1.
8. The polymorph crystalline Form-ir of posaconazole as claimed in claim 5, which is characterized by an attenuated total reflectance infrared spectrum comprising absorption bands at wave numbers of about 1665 cm-1, 1651 cm-1and 1499 cm- having typical precision of the wave number values is in the range of ± 2 cm-1 substantially as shown in FIG. 2.
9. The polymorph crystalline Form-ir of posaconazole as claimed in claim 5, which is identified by a DSC trace showing endotherm peaks at about 95.3°C, peak at about 136.6°C and melting endotherm peak at about 168.1°C substantially as shown in FIG. 3.
10. A process for the preparation of polymorph crystalline Form-ir of posaconazole which comprises the steps of;

a) providing a suspension of posaconazole in suitable solvent;
b) heating the suspension obtained in step (a) to get a clear solution;
c) charging anti solvent to the solution obtained in step (b);
d) cooling the reaction mass obtained; and
e) Isolating posaconazole crystalline Form-ir.
11. The process as claimed in claim 12, wherein the suitable solvent used in
step (a) is N,N-dimethylformamide.

12. The process as claimed in claim 12, wherein the anti-solvent used in step (c) is diisopropyl ether.