STABLE POLYMORPHIC FORM OF PALIPERIDONE AND PROCESS FOR ITS PREPARATION
FIELD OF INVENTION
The present invention relates to stable polymorphic form of paliperidone and process for its preparation. The chemical name of Paliperidone(I) is 3-[2-[4-(6-fluoro-l,2-benzisoxazol-3-yI)-l-piperidinyl]ethyl]-6,7,8s9-tetrahydro-9-hydroxy-2-methyI-4H-pyrido[l,2-a]pyrimidin-4-one.
Paliperidone is useful as anti-psychotic agent in the treatment of psychotic disorders. Paliperidone is introduced by Janssen Pharmaceutica N.V.
BACKGROUND OF INVENTION
Paliperidone is reported for the first time in US 5,158,952 (1992) and its equivalent patent EP 0368 388 (1992). Accordingly, 3-[2-chloroethyl)-6,7.8,9 tetrahydro-9-hydroxy-2-methyl-4H-pyrido[l,2-a]pyrimidin-4-one of formula- II,

11
is reacted with 6-fluofo-3-(4-piperidinyl)-l,2-benzisoxazole monohydrochloride of formula-Ill.

in the presence of diisopropyl amine in methanol medium to yield paliperidone of formula-I. The crude paliperidone obtained from the reaction is twice purified by column chromatography, and the resulting residue is crystallized from acetone and recrystallized from 2-propanoI.
It is known that pharmaceutical substances can exhibit polymorphism. Polymorphism is commonly defined as the ability of any substance to have two or more different crystal structures. Pharmaceutical substances may also encapsulate water or solvent molecules when crystallized. These solvates or hydrates are referred to as pseudo polymorphs. It is also possible that the drug substance can exist in amorphous form.
A particular polymorphic form may give rise to distinct properties that may be detectable by X-Ray powder diffraction (XRPD), Differential scanning calorimetry (DSC), Infrared spectroscopy (IR), and Thermo gravimetric analysis (TGA) etc. Different polymorphs differ in their physical properties such as melting point, solubility, etc.
Polymorphism of active pharmaceutical ingredients is becoming an increasingly important issue in the contemporary drug development. Polymorphic form of an active pharmaceutical ingredient (API) might influence its kinetic solubilization and thus affect the release of API
from the finished dose of a drug. This is especially in case for solid dosages like tablets.
I
The release process of API from dosage form is crucial for drug bioavailability and therapeutic action. Due to higher activity of new generation of API's and lower doses of API in drugs the study of polymorphic forms of API's in finished doses have become recently a tough task.
Polymorphic forms of paliperidone are reported in PCT application WO 2008/021342. The authors disclosed six polymorphic forms of paliperidone along with an amorphous form and process for their preparation in the patent application. The polymorphic forms of paliperidone were isolated by recrystllizing crude paliperidone from suitable solvent or a mixture of solvents and exchanging frorii one Form to another Form by slurry of paliperidone in a suitable solvent at different temperatures.

When we repeated the above processes in our laboratory the following shortcomings were observed. Paliperidone crude product having purity 90-95% was not crystallized out from the solution even at lower temperatures. Paliperidone contains > 97% purity was crystallized from solution of different solvents and resulted only one polymorphic Form. Purity and stability of polymorphic forms of paliperidone were not mentioned in this patent application and the polymorphic forms described in this patent application were found to be meta stable.
SUMMARY OF THE INVENTION
Accordingly the main objective of the present invention is to provide stable crystalline form of paliperidone designated by us as polymorphic Form-a, process for its preparation and pharmaceutical compositions containing this crystalline form.
Another objective of the present invention is to provide novel process for the preparation of stable crystalline form of paliperidone.
This polymorph form Form-a of paliperidone is characterized by Infrared absorption bands in the IR spectra in potassium bromide, Differential Scanning Calorimetry data (DSC), the peaks appearing in powder X-ray diffraction pattern pCRD).
This form is found to be stable, reproducible, and suitable for pharmaceutical preparations.
DESCRIPTION OF THE INVENTION
According to one aspect of the present invention there is provided a stable crystalline form of paliperidone, designated as Form-a, characterized by an X-ray powder diffraction pattern as given in Table 1 below.



IR spectrum (KBr) of Form-a paliperidone has characteristic bands at 605, 649, 699, 759, 797, 819, 870, 955, 995, 1130, 1184, 1270, 1339, 1414, 1535, 1630, 2784, 2934, 3044, and 3293cm"'. DSC data shows that Form-a paliperidone has onset temperature 177.8°C, peak temperature 181.3°C, end set temperature 183.0°C, Form-a paliperidone has a melting range of 170.0X10 175.0.
According to another aspect of the present invention there is provided a process for the preparation of Form-a of paliperidone. Thus, paliperidone of formula I prepared according to the process disclosed in our pending patent application, which involves the coupling reaction of formula-II and formula-Ill in N,N-dimmethylformamide in the presence of alkali metal carbonte, hydroxide, or alkoxide.
Paliperidone crystallized directly from the above reaction mixture is filtered. The resulting solid is dissolved in a suitable solvent, and the Form-a of paliperidone is crystallized from the solution by techniques such as cooling or partial removal of solvent. The suitable solvent is selected from a group consisting of lower aliphatic alcohols such as methanol, ethanol, propanol, isopropanol, n-butanol, etc.; ketones such as acetone, methyl isobutyl ketone, etc.; esters such as ethyl acetate, methyl acetate etc.; ethers such as tetrahydrofuran; amides such as N,N-dimethylformamide, N,N-dimethylacetamide, etc.; nitriles such as acetonitrile. Anti solvents used in the crystallization are selected from hexane, heptane, cyclohexane, ethyl acetate, tert-butyl methyl ether, diethyl ether, and water.

Alternatively Form-a of paliperidone can be isolated by suitable chemical method by
choosing inorganic acids such as hydrochloric acid, hydrobromic acid, sulphuric acid etc,
organic acids such as acetic acid, oxalic acid, p-toluene sulphonic acid, methane sulphonic
acid etc. preferably inorganic acids, more preferably hydrochloric acid. The chemical method
comprises dissolution of technical grade paliperidone in aqueous mineral acid such as
hydrochloric acid, adjustment of pH to 3.5-6.5, preferably 4.5-6.5, more preferably 6.0-6.5
using an organic base such as ammonia or an inorganic base such as sodium bicarbonate,
isolation of pure paliperidone acid addition salt by filtration, suspension of the salt in water,
adjustment of pH of suspension to 8.5-9.0 with an inorganic base such as potassium
carbonate or an organic base such as ammonia, filtration of resultant solid and drying after
i washing with an alcoholic solvent.
DESCRIPTION OF FIGURES
FIG.l is an infrared absorption spectrum of polymorphic Form-a of paliperidone.
FIG2 is a differential scanning calorimetric thermogram of polymorphic Form-a of paliperidone.
FIG.3 is a powder XRD of polymorphic Form-a of paliperidone. FIG.4 is crystal morphology 6f polymorphic Form-a of paliperidone.
X-ray powder diffraction spectra were measured on a Siemens D5000 x-ray powder diffractometer having a copper-Ka radiation (1.5406A).
The details of the process of the invention in the examples given below which are provided by way of illustration only and therefore should not be construed to limit the scope of the invention.

Example 1
Charged 3-[2-chloroethyl)-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido[l,2-
a]pyrimidin-4-one (50g), N,N-dimethyl formamide (300ml), potassium iodide (33.66g), potassium carbonate (56.06g) and 6-fluoro-3-(4-piperidinyl)-1.2-benzisoxazole monohydrochloride (52.03g) were charged in IL 3NRB flask, reaction mass was stirred for 18h at 60-65°C. after maintenance reaction mass was cooled to room temperature, filtered the solid and washed with N,N-dimethyI formamide (lOOml). Resulting solid was leached twice with demineralized water (2x500ml) followed by methanol (250ml), dried at 70-75°C for Ih to yield paliperidone crude product.
Above crude product was dissolved in methanol (3000ml) at 60-65 , cooled to room temperature stirred for 2.5h. TThe resulting cream coloured solid was filtered off and dried at TO-TSX for 4h to afford 30g of Form-a of paliperidone. Purity by HPLC: 99.82%; melting point: 171.8- 173.7°C; DSC (peak max): 180.9°C
Example 2
Above paliperidone crude product (Ig) obtained from example Iwas heated with ethyl acetate
(150ml) to reflux temperature and the insoluble solid was filtrated out. After filtration the
filtrate was stirred at room temperature (25-30°C) for Ih. The resulting cream coloured solid
II was filtered off and dried at 70-75°C for 4h to afford 0.75g of Form-a of paliperidone
Purity by HPLC: 99.78%; melting point: 170.0-174.0X; DSC (peak max): 179.rC
Example 3
3-[2-Chloroethyl)-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido[l,2-a]pyrimidin-4-one (lOOg), N,N-dimethyl formaniide (600ml), potassium iodide (67.08g), potassium carbonate (lllJOg) and 6-fluoro-3-(4-[piperidinyl)-l,2-benzisoxazole monohydrochloride (103.68g) were charged in 2L 3NRB flask, reaction mass was stirred for 18h at 60-65°C. after maintenance reaction mass was cooled to room temperature, filtered the solid and washed with N,N-dimethyl formamide (200ml). Resulting solid was leached twice with

demineralized water (2x500ml) followed by methanol (500ml), dried at 70-75C for Ih to yield paliperidone crude product.
Above crude product was decolorized by adding charcoal to the reaction mass in methanol at 65-70'C and filtered. Filtrate was evaporated under reduced pressure, leached the resulting solid with methanol at 25-30°C and filtered. The solid obtained above was dissolved in 10% aq. hydrochloric acid and pH of the solution was adjusted to 6.0-6.5 by the addition of aq ammonia solution and the resulting paliperidone hydrochloride salt was filtered off, washed with methanol.
The above paliperidone hydrochloride salt was suspended in demineralized water, pH of the solution was adjusted to 8.5 - 9.0 by adding 10% aq potassium carbonate solution and filtered. Resulting paliperidone base was leached with methanol at 25-30°C, filtered and dried at 70-75°C for 4h to afforded: 60g of Form-a of paliperidone Purity by HPLC: 99.89%; melting point: 170.0-174.0°C; DSC (peak max): 178.8°C
Example 4
The product of example 3 was used for stability studies and results are tabulated in Table-2


The results indicate that Form-a of paliperidone of this invention is very stable at 30°C and at 45''C over a period of time and is useful for pharmaceutical applications since crystal morphology and flow properties remained unchanged.
Refer to the figures 1,2,3 and 4 to the product of example 3
ADVANTAGES OF PRESENT INVENTION
1. The crystalline form of paliperidone designated by us as Form-a, which is stable, reproducible, and usefiil for the treatment of psychotic disorders.
2. The processes for the preparation of the stable crystalline form, namely Form-a of paliperidone are simple and easy to adopt on a commercial scale.
3. The crystal Form-a of paliperidone of this invention is thermodynamically stable, the crystal morphology and flow properties remaining essentially unchanged over a period of time.
4. The crystal Form-a of paliperidone of this invention is suitable for pharmaceutical applications.

WE CLAIM:
l.The present invention relates to stable crystalline polymorphic form namely Form-a of Paliperidone of formula-I and process for their preparation.

2. Polymorphic Form-a of paliperidone of formula-I as defined in claim 1 characterized
by absorption bands observed in IR spectrum (KBr) at 605, 649, 699, 759,797, 819,
870, 955, 995, 1130, 1184, 1270, ,1339, 1414, 1535, 1630, 2784, 2934, 3044, and
3293cm"^ and as further characterized by an IR absorption spectrum (KBr) given in
figure 1.
3. Polymorphic Form-a of paliperidone of formula-I as defined in claim 1 characterized
by DSC data shows onset temperature 177.8°C, peak temperature 181.3°C, end set
temperature 183.0°C. And as further characterized by DSC thermogram given in figure2.
4. Polymorphic Form-a of paliperidone of formula-I as defined in claim 1 characterized
by peak patterns appearing in X-ray powder diffraction pattern expressed as 29 at about
8.05, 10.24, 13.72, 14.46, 14.92, 18.60, 19.20, 20.64, 24.98, 27.90, and 31.16, and as
further characterized by an X-ray powder diffraction pattern given in figure3.
5. Crystal morphology of Polymoiphic Form-a of paliperidone of formula-l as defined in
claim 1 is disclosed in figure 4.

6. A process for the preparation of polymorphic Form-a of paliperidone as defined in claim 1, which comprises:
(i) coupling of 3-[2-chloroethyl)-6,7.8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido[l,2-a]pyriinidin-4-one of formula- II,

with 6-fluoro-3-(4-piperidinyl)-l,2-benzisoxazoIe monohydrochloride of formula- III

in N,N-dimmethylformamide' in the presence of base at elevated temperatures;
(ii) filtering paliperidone, crystallized directly from the above reaction mixture;
(iii) leaching the solid obtained from step-(ii) with demineralized water twice followed by methanol;
(iv) recrystallization of compound obtained from step-(iii) in a suitable solvent or a mixture of solvents at 0-30°C;
OR
(v) Optionally isolated by a suitable chemical method to afford polymorphic Form-a of
paliperidone
7: A process according to claim 6, wherein step-(i) the base is selected from alkali metal
carbonate, hydroxide, alkoxide, or organic bases such as tertiary and secondary amines.
i| preferably alkali metal carbonates, more preferably potassium carbonate.

8. A process according to claim 6, wherein step- (i) temperature range of reaction mass is 50 - I00°C preferably 60-65°.
9. A process according to claim 6, wherein step- (iv) suitable solvent for recrystallization is selected from a group consisting of lower aliphatic alcohols such as methanol, ethanol, propanol, isopropanol, n-tiutanol, etc.; ketones such as acetone, methyl isobutyl ketone,

etc.; esters such as ethyl acetate, methyl acetate etc.; ethers such as tetrahydrofuran; amides such as N,N-dimmethylformamide, N,N-dimethyl acetamide, etc.; nitriles such as acetonitrile and sulfoxides such as dimethyl sulfoxide etc; aromatic hydrocarbons such as benzene, toluene, xylene etc; halogenated solvents such as dichloro methane, chloroform, carbon tetrachloride, etc. Suitable anti solvents used in the crystallization are selected from hexane, heptane, cyclohexane, ethyl acetate, tert-butyl methyl ether, diethyl ether, and water, etc;
10. The process according to claims 6, wherein step- (v) the chemical method used for
isolation of paliperidone Form-a comprises: dissolution of technical grade paliperidone in
aqueous mineral acid such as hydrochloric acid, adjustment of pH to 3.5-6.5, preferably
4.5-6.5, more preferably 6.0-6.5 using an organic base such as ammonia or an inorganic base such as sodium bicarbonate, isolation of pure paliperidone acid addition salt by filtration, suspension of the salt in water, adjustment of pH of suspension to 8.5-9.0 with an inorganic base such as potassium carbonate or an organic base such as ammonia, filtration of resultant solid and drying after washing with an alcoholic solvent.
11. The polymorphic Form-a of paliperidone as defined in claim I as a stable crystalline
form with stability characteristics essentially as mentioned in TabIe-2

12. The polymorphic Form-a of paliperidone as defined in claim las a stable crystalline form, suitable for pharmaceutical formulations and is prepared essentially as per
examples l-3>