This invention relates to polymorphs of fexofenadine hydrochloride and process for their
preparation.
FIELD OF INVENTION:
Particularly, the present invention provides two new polymorphs of Fexofenadine
hydrochloride hereby designated by us as form IXX and form XX and process of
preparation of these two forms. More particularly, the present invention provides a
process for converting Fexofenadine base to its novel polymorphs as hydrochloride.
BACKGROUND OF THE INVENTION:
Chemically fexofenadine hydrochloride is 4-[4-[4-(hydroxydiphenylmethyl)-l-
piperidinyl]-l-hydroxybutyl]-a, a - dimethybenzene acetic acid hydrochloride. It is
also known as terfenadine carboxylic acid metabolite.
Fexofenadine is non-sedating anti-histamine. It is reported to be a specific H? - receptor
antagonist devoid of any anticholingeric, antiserotoninergic and anti-adrenergic effects.
It lacks the cardiac side effects seen with terfenadine.
The relevant patents known to the inventor are enumerated below.
US 5,738,872; US 5,932,247 and US 5,855,912 disclose four crystalline forms of
Fexofenadine designated as I to IV. According to these patents Forms II and IV are
hydrated and Forms I and III are anhydrous. Form I is reported to have a capillary
melting point range of 196-201.degree. C, a DSC endotherm with onset between 195-
199.degree. C. and a powder X-ray diffraction ("PXRD") pattern with d-spacings of
14.89, 11.85, 7.30, 6.28, 5.91, 5.55, 5.05, 4.96, 4.85, 4.57, 4.45, 3.94, 3.89, 3.84, 3.78,
3.72, 3.63, 3.07, 3.04, 2.45 .ANG.. Form II is reported to have a capillary melting point
range of 100-105.degree. C, a DSC endotherm with onset between 124-126.degree. C.
and a PXRD pattern with d-spacings of 7.8, 6.4, 5.2, 4.9, 4.7, 4.4, 4.2, 4.1, 3.7, 3.6, 3.5
.ANG.. Form III is reported to have a capillary melting point range of 166-171.degree.
C, a DSC endotherm with onset at 166.degree. C. and a PXRD pattern with d-spacings of 8.95, 4.99, 4.88, 4.75, 4.57, 4.47, 4.46, 3.67, 3.65 .ANG.. In Example 2, Form IV is reported to undergo decomposition at 115-116.degree. C. In the general written description, a DSC endotherm with onset at 146.degree. C. is reported. Form IV is reported as having a PXRD pattern with d-spacings of 10.38, 6.97, 6.41, 5.55, 5.32, 5.23, 5.11, 4.98, 4.64, 4.32, 4.28, 4.12, 4.02, 3.83, 3.65, 3.51, 3.46 and 2.83 .ANG.. The '872 patent discusses methods of interconverting Forms I-IV. Aqueous recrystallization of Form I can be used to produce Form II. Water-minimizing recrystallization or azeotropic distillation of either Form II or Form IV can yield Form I. Form III is reported to be accessible by water minimizing recrystallization of Form II. Crystal digestion of Form III can be used to obtain Form I. Forms II and IV can be obtained directly by sodium borohydride reduction of 4-[4-[4-(hydroxydiphenylmethyl)-1 -piperidinyl]-l -oxobutyl]-.alpha.,.alpha-dimethylbenzeneacetate as described in Examples 1 and 2.
WO 95/31437 has disclosed four polymorphic forms, two as anhydrous and two as hydrates. The patent also describes a process for preparing these forms. These forms can be inter-converted to one another, but to get anhydrous forms Fexofenadine base has to be converted first to hydrated Fexofenadine hydrochloride which is further dehydrated by various processes to give anhydrous Fexofenadine hydrochloride resulting in more number of steps making the process low yielding, complex and uneconomical, generating the acidic effluents. In general, the process advocates subjecting hydrated form to an azeotropic distillation or to water minimizing crystallization.
WO 02/ 080857 discloses a number of polymorphic forms (V-XV) of Fexofenadine hydrochloride prepared in various ways. But in all processes Fexofenadine hydrochloride is prepared first by wet crystallization using hydrochloric acid,
generating aqueous effluent, which is further recrystallised in various solvents such as
saturated hydrocarbons with C5 to C12 to give desired polymorphic forms.
Form V, having a PXRD pattern with peaks at about 15.9, 16.8, 17.2, 20.9, 21.5,
21.8.+-.0.2 degrees two theta
Form VI, having a PXRD pattern with peaks at about 15.7, 16.1, 17.0, 17.3, 18.6,
18.8.+-.0.2 degrees two theta.
Form VIII having a PXRD pattern with peaks at about 8.5, 11.0, 11.4, 13.4, 13.8, 17.1,
20.0, 21.5.+-.0.2 degrees two theta.
Form IX-cyclohexane solvate, having a PXRD pattern with peaks of about 4.7, 9.3,
17.4,18.2,19.4,19.6,21.6 and 24.0.+-.0.2 degrees two theta.
Form X has a PXRD pattern with peaks at about 4.2, 8.0, 9.3, 14.2, 16.0, 16.8, 17.6,
18.8,20.0, 20.6, 21.7, 22.9, 23.8, 24.2 and 25.4.+-.0.2 degrees two theta.
Form XI, having a PXRD pattern with peaks at about 8.7, 14.5, 14.9, 16.6, 17.2, 18.3,
19.5, 21.2, 22.1 and 23.3.+-.0.2 degrees two theta.
XII, having a PXRD peaks at about 5.2, 7.9, 8.1, 12.1, 18.5, 19.0.+-.0.2 degrees two
theta.
Form XIII, having a PXRD pattern with peaks at about 5.5, 6.8, 16.0, 16.3.+-.0.2
degrees two theta.
Form XIV is characterized by a PXRD diffraction pattern with peaks at about 5.4, 5.7,
10.9, 11.4,11.6.+-.0.2 degrees two theta.
Form XV produces a PXRD pattern with peaks at about 5.5, 5.8, 16.4, 16.9, 18.4.+-.0.2
degrees two theta.
WO 02/102777 discloses form X of Fexofenadine hydrochloride that has purity of more
than 99.5 %, yield of more than 92% of theoretical value, contains less than 0.1% meta
isomer and which is prepared following a lengthy and tedious procedure resulting in
yield losses.
Fexofenadine was disclosed first time in US Patent Nos. US 4,254,129 ('129) and US
4,254,130 ('130) as one of the substituted piperidine derivative. In accordance with
'129 and '130, Fexofenadine is prepared by alkylation of a substitutd piperidine
derivative such as diphenyl-4-piperidinemethanol with xa- halo alkyl substituted phenyl
ketone.
WO 03/039482 A2 provides novel crystalline forms of fexofenadine base and a process
for their preparation as well as a composition containing the said forms.
US 4,285,957 and 4,285,958 relates to 1-piperidine-alkylene ketones. The compounds
of these patents are prepared adopting the processes disclosed in '129 and '130. The
free base Fexofenadine is converted to its acid addition salts by treating the base, in a
conventional manner, with a respective pharmaceutically acceptable organic or
inorganic acid. However, the purity of staring material is critical for the production of
acid addition salts.
US 5,578,610 teach using purified starting material in order to get desired isomer of
Fexofenadine. Various alternatives are suggested towards this to give Fexofenadine
hydrochloride.
The processes disclosed above suffer from one or the other problems. To quote a few,
the final product contains meta isomer, the yield is low, the processes are uneconomical
and hazardous to environment.
BRIEF DESCRIPTION OF THE DRAWING
Fig I: Infra red spectrum of polymorphic form IXX
Fig II: X-ray spectrum of polymorphic form IXX
Fig III: DSC pattern of polymorphic form IXX
Fig IV: Infra red spectrum of polymorphic form XX
Fig V: X-ray spectrum of polymorphic form XX
Fig VI: DSC pattern of polymorphic form XX SUMMARY OF THE INVENTION
The main object of the present invention is to provide new polymorphs of fexofenadine
hydrochloride hereby designated by us as form IXX and form XX.
Other object of the present invention is to provide new polymorph of fexofenadine
hydrochloride of ICH grade having all unknown impurities less than 0.1%.
Further, the present invention is intended to provide a process for preparing new
polymorphs in high purity and high yield.
Another object of the present invention is to provide a process that is advantageous to
operate, eco-friendly, commercially viable and cost-effective.
Yet other object of the present invention is to provide a process for converting
fexofenadine base to its polymorphs as hydrochloride.
Still another object of the present invention is to provide a process for preparing novel
crystalline forms avoiding use of corrosive reactants posing problems for effluent
treatment.
STATEMENT OF INVENTION:
Accordingly the present invention provides polymorph of Fexofenadine HC1 (herein
after designated as IXX and XX) wherein IXX is having X-ray powder diffraction
pattern characterized by peaks at
4.68, 9.32, 9.56, 15.08, 17.08, 17.9, 18.54, 19.28, 19.74, 21.02, 23.96 ± 0.5° 26 values.
Form IXX is having melting range between 145 and 155°C
Crystalline Fexofenadine form XX according to claim 10 having an X-ray powder
diffraction pattern characterized by peaks at
11.18, 11.14, 13.56, 13.84, 16.18, 17.04, 18.28, 18.84,20.08,21.4,21.96,23.48,23.84,
24.72 ± 0.5° 26 values.
Form XX is having melting range between 142-152°C
Crystalline Fexofenadine form IXX according to claim 1 characterized by an infra red spectroscopy having absorption bands (± 2cm-1) at: 3394, 2665, 1718, 1448, 1152, 750, 704
Crystalline Fexofenadine form XX according to claim 10 characterized by an infra red
spectroscopy having absorption bands (± 2cm-1) at:
3394, 2712, 1719, 1448, 1261, 1152, 750, 707
In accordance with other aspect of this invention there is provided a process for
preparing Fexofenadine hydrochloride in polymorphic form comprising of the
following steps:
(i) optionally purifying fexofenadine base in C1 - C4 aliphatic alkanols, (ii) contacting the Fexofenadine base or optionally purified as obtained in step (i) with hydrogen chloride gas in presence of ethereal organic solvents such as herein described (iii)crystallizating by contacting with antisolvent selected from aliphatic ketones,
followed by, isolation and drying to get polymorphs IX, (iv) converting to form XX by stirring in demineralized water and recovering by filtration anf drying if so desired. Suitable ethereal solvents may be such as tetrahydrofuran, isopropyl ether, methyl-t-butyl ether.
Ketonic solvents used may be such as methyl isobutyl ketone, acetone or a mixture of two or more solvents. More preferred solvents being tetrahydrofuran, methyl isobutyl ketone
and methyl-t-butyl ether or a mixture of these. The most preferred solvents being tetrahydrofuran and methyl isobutyl ketone or a mixture of these.
Characterization data of polymorphic form IXX of Fexofenadine hydrochloride
Polymorphic form IXX may be characterized by following data: Melting Range (MR): 145-155°C
The invention is further characterized by the following IR pattern: Infra Red Spectrum (± 2 cm-1): 3394, 2665, 1718, 1448, 1152, 750, 704
The invention is further characterized by the following XRD pattern expressed in terms of "2Theta" XRD Data (± 0.5°): Major signals:

(Table Removed)

The invention is further characterized by the following DSC pattern:
DSC
(25-240°C, 5.0°C/min.,N2 50.0 ml/min, peak ±5°C)
Main Signal
On set: 143.24°C End set: 160.85°C Peak: 154.98°C Second signal On set:41.45°C End set:62.1°C Peak: 49.32°C
Third signal
On set: 77.99°C End set: 83.69°C Peak: 80.65°C
Characterization data of polymorphic form XX of Fexofenadine hydrochloride
Polymorphic form XX may be characterized by following data: Melting Range (MR): 142-152°C
The invention is further characterized by the following IR pattern: Infra Red Spectrum (± 2 cm-1):
3394, 2712, 1719, 1448, 1261, 1152, 750, 707
The invention is further characterized by the following XRD pattern expressed in terms of"2Theta" XRD Data (± 0.5°) Major signals:

(Table Removed)
The invention is further characterized by the following DSC pattern:
DSC
(25-240°C, 5.0°C/min, N2 50.0 ml/min, peak ±5°C)
Main signal
On set: 29.27°C
End set: 52.07°C
Peak: 39.02°C
Second signal
Onset: 139.31°C
End set: 164.58°C
Peak: 156.36°C
Note: 0-2 Small signals between 60-130°C.
The invention can further be described by taking following examples which may not be
considered limiting to the invention.
Example 1: Preparation of polymorphic form IXX of Fexofenadine hydrochloride
Fexofenadine base [prepared through US 4,254,129 upon recrystallization in methanol followed by washing with isopropyl alcohol] was added to tetrahydrofuran (250ml). HCl gas was purged to the mass at 0-10°C until the solution got clear. Solution was stirred at 10-30°C, degassed under vacuum for lhr at 25-30°C, made the volume with tetrahydrofuran and charcoalized. Methyl isobutyl ketone (900 ml) was slowly added to the filtrate and was stirred to get crystallization at 0-5°C. Product was filtered and washed with methyl isobutyl ketone (100ml) at 0-5°C. Upon drying 92 gm of the titled compound was obtained.
Example 2: Preparation of polymorphic form XX of Fexofenadine hydrochloride

Compound (100 gm) from example 1 was added to DM water (1 lit) at 10-30°C, then stirred for lhr. at 20-30°C, Mass was filtered and washed with water. Cake was dried under vacuum at 65-70°C to yield 90 gm of the titled compound.

We Claims :-
1. Polymorph of Fexofenadine HCl (herein after designated as IXX and XX) wherein
IXX is having X-ray powder diffraction pattern characterized by peaks at
4.68, 9.32, 9.56, 15.08, 17.08, 17.9, 18.54, 19.28, 19.74, 21.02, 23.96 ± 0.5° 2values.
2. Polymorphic Form-IXX as claimed in claim 1 is having melting range between 145 and l55°C.
3. Polymorphic Form IXX as claimed in claim 1 is characterized by an infra red spectroscopy having absorption bands (± 2cm-1) at:
3394, 2665, 1718, 1448, 1152, 750, 704
4. Polymorphic Form XX as claimed in claim 1 having an X-ray powder diffraction
pattern characterized by peaks at
11.18, 11.14, 13.56, 13.84, 16.18, 17.04, 18.28, 18.84, 20.08, 21.4, 21.96, 23.48, 23.84,24.72 ± 0.5° 29 values.
5. Polymorphic Form XX as claimed in claim 1 characterized by an infra red
spectroscopy having absorption bands (± 2cm-1) at:
3394, 2712, 1719, 1448, 1261, 1152, 750, 707
6. Polymorphic Form XX as claimed in claim 1 is having melting range between
142- 152°C
7. A process for preparing Fexofenadine hydrochloride in polymorphic form
comprising of the following steps:
(i) optionally purifying fexofenadine base in C1- C4 aliphatic alkanols,
(ii) contacting the Fexofenadine base or optionally purified as obtained in step
(i) with hydrogen chloride gas in presence of ethereal organic solvents such
as herein described, (iii) crystallizating by contacting with antisolvent selected from aliphatic
ketones, followed by, isolation and drying to get polymorphs IX, followed
by (iv) converting to form XX by stirring in demineralized water and recovering by
filtration and drying if so desired.
8. A process as claimed in claim 7 wherein ethereal solvent used is tetrahydrofuran, isopropyl ether, methyl-t-butyl ether.
9. A process as claimed in claim 7 wherein Ketonic solvent used is selected from methyl isobutyl ketone, acetone or a mixture of two or more solvents preferred solvents being tetrahydrofuran, methyl isobutyl ketone and methyl-t-butyl ether the most preferred being tetrahydrofuran and methyl isobutyl ketone or a mixture of these.
10. Polymorph of Fexofenadine HCl (herein after designated as IXX and XX) and a
process therefore such as herein substantially described.