FORM 2
THE PATENTS ACT, 1970
(39 OF 1970)
AND
The Patents Rules, 2003
COMPLETE SPECIFICATION
[See section 10 and rule 13]
1. TITLE OF THE INVENTION:
"AN IMPROVED PROCESS FOR THE PREPARATION OF CRYSTALLINE CHOLINE FENOFIBRATE AND A NOVEL POLYMORPH THEREOF "
2. APPLICANT(S):
(a) NAME: HARMAN FINOCHEM LIMITED
(b) NATIONALITY: Indian Company incorporated under the
Companies Act, 1956
(c) ADDRESS: 107, Vinay Bhavya Complex, 159-A, C.S.T. Road,
Kalina, Mumbai-400098, Maharashtra, India
3. PREAMBLE TO THE DESCRIPTION:
The following specification particularly describes this invention and the manner in which it is to be performed:

Title:
An improved process for the preparation of crystalline choline fenofibrate and a novel polymorph thereof
Field of invention:
The present invention relates to a chemical process for the synthesis of choline fenofibrate, a lipid-regulating agent used in the treatment of adult endogenous hyperlipidemias, hypercholesterolemias and hypertriglyceridemias. In another aspect it relates to a novel crystalline morph of choline fenofibrate, more particularly Form B of choline fenofibrate.
Background of the invention:
The term "fibrates" denotes a family of compounds which have hypocholesterolemic and hypolipidemic properties. A well known member of this family i.e. fenofibrate is administered orally and metabolized in the body to fenofibric acid which is in fact the active ingredient of fenofibrate. One of the challenges associated with the fenofibrate, is that this compound is hydrophobic and poorly soluble in water; as a consequences bioavailability of the compound can be low.
U.S. Pat. No. 4072705 and its subsequent divisional applications US4179515 and US4235896 described the preparation of fenofibric acid and acid addition salt of amine containing analogs. Further, the choline fenofibrate (Formula 1) has been first reported in US7259186 exhibiting fairly improved bioavailability.


According to the synthesis process disclosed in US' 186; fenofibric acid was reacted with choline chloride or choline hydroxide in a suitable solvent at the temperature 55°C or 65°C respectively, as shown below,

A : IP A, choline hydroxide in methanol, 65°C
B : Sodium carbonate. Methanol, Choline chloride, 55°C
However, during procedure B sodium chloride is formed as a side product and precipitates out from the reaction mixture which has to be filtered off. As sodium chloride being partially soluble in methanol passes alongwith the choline fenofibrate and thereby contaminating the final product.
US7714163 has described a one pot preparation of choline fenofibrate (Formula I), which comprises reacting (4-chlorophenyl)(4-hydroxyphenyI)methanone and isopropyl-2-bromo-2-methylpropanoate in presence of potassium carbonate at 155°C. The reaction mixture was then added with propanol, heated to 80-90°C and filtered. The filtrate obtained was charged with aq. solution of choline hydroxide and the reaction mixture was refluxed to give choline fenofibrate. However, the choline being heat sensitive (as reported in Canadian patent no. 555201), may get decomposed on heating the reaction mass at the reflux

temperature of propanol resulting in lower yield of product. Also the process is cumbersome and not feasible for industrial production.
The application WO2010086700 has claimed a process for the preparation of choline fenofibrate and a new crystalline polymorphic Form A which shows x-ray powder diffraction pattern having characteristic peaks expressed as 28 values at about 9.61, 15.96, 19.27, 24.89 ±0.2° 20.
In recent years, the use of choline fenofibrate has achieved great pharmacological significance, but in spite of the importance considerable difficulty has existed in preparing this compound in highly purified form with a high yield. Also there is not much discloser in the prior art about the polymorphism of choline fenofibrate. In pharmaceuticals, while using a substance as a solid preparation it is important that the presence or absence of polymorphism is confirmed in advance and a technique of selectively producing a desired polymorph is developed.
Thus, there is a great need for developing an alternative, relatively simple, economical and commercially feasible process for the synthesis of crystalline forms of choline fenofibrate with the commercially acceptable yield and purity.
In the present invention a new polymorphic form of choline fenofibrate has now been discovered and characterized by various techniques, designated as Form B. The present invention also provides an improved process for the preparation of crystalline choline fenofibrate in a high yield and purity.

Objects of the invention:
An object of the present invention is to provide an improved process for the preparation of crystalline choline fenofibrate (Formula I) in an industrially easy and reproducible manner, in a high yield and a pharmaceutically pure form.
Another object of the present invention is to provide a novel polymorph of choline fenofibrate (Formula I) designated as Form B.
Summery of the invention:
In one aspect, the present invention relates to an improved process for the preparation of choline fenofibrate (Formula 1) which is cost effective and industrially practicable.
The process comprises steps of, (a) hydrolyzing the choline chloride in an organic solvent at ambient temperature, leaving choline base free in the solution; (b) reacting the choline free base and fenofibric acid in presence of the same organic solvent at the same temperature to form a crystalline choline fenofibrate.
In another aspect, the present invention also relates to a novel crystalline form of choline fenofibrate designated as Form B. The crystalline Form B is characterized by using different analytical tools including X-ray Powder Diffraction Pattern, Differentia] Scanning Calorimetry (DSC) and Infra-red Spectroscopy.
Brief description of drawings:
FIG. 1 represents the X-ray Powder Diffraction pattern (XRPD) of crystalline
choline fenofibrate Form B of the present invention.
FIG. 2 represents the Differential Scanning Calorimetry (DSC) thermogram of
crystalline choline fenofibrate Form B of the present invention.
FIG. 3 represents the FTIR spectrum of crystalline choline fenofibrate Form B of
the p resent invention.

Detailed description of the invention:
The present invention provides an improved process for the preparation of choline fenofibrate (Formula I) in a high yield and a high purity using single organic solvent throughout the procedure. It also relates to a novel crystalline form of choline fenofibrate.

The process for the preparation of crystalline choline fenofibrate comprises the steps of,
(a) hydrolyzing the choline chloride in an organic solvent at ambient temperature, leaving choline base free in the solution;
(b) reacting the choline free base and fenofibric acid in presence of the same organic solvent at the same temperature.
In one of the embodiment of the present invention, (a) a solution of choline chloride in an organic solvent is treated with hydrolyzing agent at ambient temperature, preferably at 26- 28°C and the reaction mixture is stirred for 1-2 hrs. The reaction mixture is filtered and washed with the organic solvent to remove impurities or side products generated during hydrolysis leaving choline base free in the solution;
(b) the solution of choline free base in the organic solvent is reacted with fenofibric acid at the same temperature, preferably at 26- 28°C with the continuous stirring for 2 hrs. The product thus precipitated is filtered off and washed 2-3

times with the organic solvent and dried in oven below 60°C to obtain a crystalline choline fenofibrate (Formula I) having HPLC purity above 99.9%.
As used herein, ambient temperature means a temperature from about 25°C to 35°C. The organic solvent used in the reactions is selected from the group of ethyl acetate, acetone, methyl ethyl ketone and acetonitrile, more preferably ethyl acetate. The use of a single organic solvent throughout the procedure renders the process simple, economical and feasible for commercial scale production with a high yield and purity of product.
The hydrolyzing agent used for leaving choline base free in solution is selected from sodium carbonate or potassium carbonate, more preferably potassium carbonate.
The reaction process of the present invention can be schematically represented as,

The crystalline choline fenofibrate prepared by above process is analyzed and characterized by various techniques and found to have a novel crystalline form.
In accordance with another embodiment, the present invention also relates to a new crystalline form of choline fenofibrate which has been analyzed, characterized and differentiated by X-ray Diffractogram, Differential Scanning Calorimetry Thermogram and Infrared Spectrum techniques and designated as Form B.

The present invention provides a crystalline Form B of choline fenofibrate characterized by having a XRPD pattern depicted in Figure I, with the peaks at °20 positions (± 0.2° 26) and d-values as listed in Table ]. The X-ray powder diffraction pattern has been measured on XRD-6000-SHIMADZU, 40KV/30mA diffractometer equipped with scintillation detector using Cu-Kα radiations.
Table 1: XRPD values of Form B

Peak listing (°28) d-values (A°) Relative intensity (Count)
7.95 11.10 33
15.90 5.56 100
16.62 5.32 31
17.35 5.1 16
19.08 4.64 24
19.33 4.58 62
22.10 4.01 46
22.63 3.92 13
23.96 3.71 29
28.42 3.13 18
28.79 3.09 11
31.49 2.83 24
Choline fenofibrate crystalline Form B of the present invention is further characterized by having a differential scanning calorimetry (DSC), thermogram exhibiting two significant exothermic peaks, one at 175.77°C and other at 184.10°C as depicted in Figure II.

Choline fenofibrate crystalline Form B of the present invention is furthermore characterized by a FTIR spectrum having characteristic absorptions at about 3459.67, 2990.09, and 2609.22, ± 2 cm-1 as depicted in Figure HI. The Fourier transform (FT) IR spectrum has been measured in a KBr disk using a JASCO FT/1R-4100 spectrometer with the resolution of 4 cm-1 from 4000 cm-1 to 600 cm-1.
The following examples will further illustrate the preparation of crystalline choline fenofibrate, but are not intended to limit the scope of the invention as defined hereinabove or as claimed.
Example:
In 250 ml RBF, a solution of choline chloride 25 gm (0.18 moles) in ethyl acetate
100ml was charged with the potassium carbonate 23 gm (0.16 moles) and the
reaction mixture was stirred for 1 hr at 26-28°C. The inorganic salt formed in the
reaction mixture was filtered out and washed with ethyl acetate (75 ml). The
filtrate was diluted with ethyl acetate 25 ml followed by addition of fenofibric acid
50 gm (0.157moles). The reaction was maintained at 26-28°C for 2 hrs. The
precipitate formed was filtered off and washed twice with 25 ml ethyl acetate each
time. The wet product was oven dried at 50- 55°C to obtain 60 gm of choline
fenofibrate in the form of a white crystalline solid,
Yield~91%
Chromatographic purity (by HPLC): 99.96%
XRPD, DSC and FTIR analysis data of final product obtained from the example
(see Figures 1, II and III) confirmed that the product formed is a novel polymorph
of choline fenofibrate. The novel polymorph, crystalline Form B, is substantially
pure polymorphically with no levels of other form detected.
It will be appreciated that the invention may be modified within the scope of the
appended claims.

We claim,
1. A novel crystalline Form B of choline fenofibrate, characterized by a X-ray powder diffraction pattern (XRPD) having peaks at 7.95, 15.90, 16.62, 17.35, 19.08, 19.33, 22.10, 22.63, 23.96, 28.42, 28.79 and 31.49 ± 0.2° 29.
2. The choline fenofibrate Form B of claim 1, characterized by having a X-ray powder diffraction pattern as shown in Fig. I.
3. The choline fenofibrate Form B of claim 1, wherein said Form B is further characterized by a DSC thermogram exhibiting two significant exothermic peaks one at 175.77°C and other at 184.10oC.
4. The choline fenofibrate Form B of claim 1, characterized by having a DSC thermogram as shown in Fig. II.
5. The choline fenofibrate Form B of claim 1, wherein said Form B is further characterized by a FTIR spectrum having characteristic absorptions at about 3459.67, 2990.09, and 2609.22, ± 2 cm-1.
6. The choline fenofibrate Form B of claim 1, characterized by having a FTIR spectrum as shown in Fig. III.
7. A method of making crystalline choline fenofibrate using single organic solvent, comprising,

(a) hydrolyzing the choline chloride in an organic solvent at ambient temperature, leaving choline base free in solution; and
(b) reacting the choline free base and fenofibric acid in presence of the same organic solvent at the same temperature.

8. The process according to claim 7, wherein the organic solvent used in the reaction is selected from the group of ethyl acetate, acetone, methyl ethyl ketone and acetonitrile, more preferably ethyl acetate.
9. The process according to claim 7, wherein the reaction is optimally carried at the temperature range of 25-35°C, preferably at 26-28°C.

10. The process as claimed in any of the claims 7 to 10, wherein the purity of crystalline choline fenofibrate produced is above 99.90% by HPLC.