WO2007052310A2 - Polymorphs of fexofenadine hydrochloride and process for their preparation - Google Patents
Polymorphs of fexofenadine hydrochloride and process for their preparation Download PDFInfo
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- WO2007052310A2 WO2007052310A2 PCT/IN2006/000436 IN2006000436W WO2007052310A2 WO 2007052310 A2 WO2007052310 A2 WO 2007052310A2 IN 2006000436 W IN2006000436 W IN 2006000436W WO 2007052310 A2 WO2007052310 A2 WO 2007052310A2
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- fexofenadine
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D211/20—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
- C07D211/22—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by oxygen atoms
Definitions
- the present invention provides two new polymorphs of Fexofenadine hhydrochloride 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.
- Chemically fexofenadine hydrochloride is 4-[4-[4-(hydroxydiphenylmethyl)-l- piperidinyl]-l-hydroxybutyl]- ⁇ , ⁇ - 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 2 - receptor antagonist devoid of any anticholingeric, antiserotoninergic and anti-adrenergic effects.
- 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-
- .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..
- Form IV is reported to undergo decomposition at 115-116.degree. C.
- 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)-l-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.
- 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,
- Form VI having a PXRD pattern with peaks at about 15.7, 16.1, 17.0, 17.3, 18.6,
- Form VIII having a PXRD pattern with peaks at about 8.5, 11.0, 11.4, 13.4, 13.8, 17.1,
- Form IX-cyclohexane solvate having a PXRD pattern with peaks of about 4.7, 9.3,
- Form X has a PXRD pattern with peaks at about 4.2, 8.0, 9.3, 14.2, 16.0, 16.8, 17.6,
- Form XI having a PXRD pattern with peaks at about 8.7, 14.5, 14.9, 16.6, 17.2, 18.3,
- 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,
- 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
- Fexofenadine is prepared by alkylation of a substitutd piperidine derivative such as diphenyl-4-piperidinemethanol with us- 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.
- the purity of staring material is critical for the production of acid addition salts.
- Fexofenadine Various alternatives are suggested towards this to give Fexofenadine hydrochloride.
- 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.
- object of the present invention is to provide new polymorph of fexofenadine hydrochloride of ICH grade having all unknown impurities less than 0.1%.
- 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.
- the present invention provides polymorph of Fexofenadine HCl (herein after designated as IXX and XX) wherein IXX is having X-ray powder diffraction pattern characterized by peaks at
- 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,
- Form XX is having melting range between 142-152 0 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:
- 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.
- 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):
- the invention is further characterized by the following XRD pattern expressed in terms of "2 Theta" XRD Data ( ⁇ 0.5°): Major signals:
- 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):
- the invention is further characterized by the following XRD pattern expressed in terms of "2 Theta" XRD Data ( ⁇ 0.5°) Major signals:
- 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 0 C until the solution got clear. Solution was stirred at 10-30 0 C, degassed under vacuum for lhr at 25-3O 0 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 0 C. Product was filtered and washed with methyl isobutyl ketone (100ml) at 0-5 0 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 0 C, then stirred for lhr. at 20-30 0 C, Mass was filtered and washed with water. Cake was dried under vacuum at 65-7O 0 C to yield 90 gm of the titled compound.
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Abstract
The invention discloses two new polymorphs of Fexofenadine hydrochloride and a process preparing the same. The forms are designated by us as IXX and XX. The forms are prepared by contacting fexofenadine base with hydrogen chloride gas in presence of organic solvent followed by crystallization.
Description
POLYMORPHS OF FEXOFENADINE HYDROCHLORIDE AND PROCESS FOR THEIR PREPARATION. FIELD OF INVENTION:
Particularly, the present invention provides two new polymorphs of Fexofenadine hhydrochloride 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]-α, α - 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 H2 - 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)-l-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.+-.Q.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 (' 13O) 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 us- 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 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° 2Θ 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° 2Θ values.
Form XX is having melting range between 142-1520C
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 Ci - 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, (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 "2 Theta" XRD Data (± 0.5°): Major signals:
All Signals:
The invention is further characterized by the following DSC pattern:
DSC
(25-2400C, 5.0°C/min.,N2 50.0 ml/min, peak ±5°C)
Main Signal
On set: 143.240C End set: 160.850C Peak: 154.980C Second signal On set: 41.450C End set: 62.10C Peak: 49.320C
Third signal
On set: 77.990C End set: 83.690C Peak: 80.650C
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 "2 Theta" XRD Data (± 0.5°) Major signals:
All Signals:
The invention is further characterized by the following DSC pattern:
DSC
(25-2400C, 5.0°C/min, N2 50.0 ml/min, peak ±5°C)
Main signal
On set: 29.27°C
End set: 52.070C
Peak: 39.020C
Second signal
On set: 139.310C
End set: 164.580C
Peak: 156.36°C
Note: 0-2 Small signals between 60-1300C.
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 0-100C until the solution got clear. Solution was stirred at 10-300C, degassed under vacuum for lhr at 25-3O0C, 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 0-50C. Product was filtered and washed with methyl isobutyl ketone (100ml) at 0-50C. 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 10-300C, then stirred for lhr. at 20-300C, Mass was filtered and washed with water. Cake was dried under vacuum at 65-7O0C to yield 90 gm of the titled compound.
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° 2Θ values.
2. Polymorphic Form IXX as claimed in claim 1 is having melting range between
145 and 155°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° 2Θ 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 , (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
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7671071B2 (en) | 2002-06-10 | 2010-03-02 | Teva Pharmaceutical Industries Ltd. | Polymorphic Form XVI of fexofenadine hydrochloride |
| CN104072402A (en) * | 2014-07-16 | 2014-10-01 | 昆山龙灯瑞迪制药有限公司 | Fexofenadine hydrochloride compound of novel crystal form and preparation method of fexofenadine hydrochloride compound |
| KR101513561B1 (en) * | 2013-03-06 | 2015-04-21 | 주식회사 파마코스텍 | A Novel Method for Preparing Fexofenadine HCl |
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| WO2001094313A2 (en) * | 2000-06-06 | 2001-12-13 | Geneva Pharmaceuticals, Inc. | Crystal modification of fexofenadine |
| WO2002066429A1 (en) * | 2001-02-23 | 2002-08-29 | Cilag Ag | Method for producing non-hydrated fexofenadine hydrochloride and a novel crystalline form obtained thereby |
| WO2002080857A2 (en) * | 2001-04-09 | 2002-10-17 | Teva Pharmaceutical Industries Ltd. | Polymorphs of fexofenadine hydrochloride |
| WO2003011295A1 (en) * | 2001-07-31 | 2003-02-13 | Texcontor Etablissement | Fexofenadine polymorph |
| US20040077683A1 (en) * | 2001-06-18 | 2004-04-22 | Reddy M. Satyanarayana | Novel crystalline forms of 4-[4-[4-(hydroxydiphenylmethyl)-1- piperidinyl]-1-hydroxybutyl]-$g(a)-dimethylbenzene acetic acid and its hydrochloride |
| WO2005019175A1 (en) * | 2003-08-26 | 2005-03-03 | Cipla Limited | Fexofenadine polymorphs and processes of preparing the same |
| WO2005102999A2 (en) * | 2004-04-26 | 2005-11-03 | Teva Pharmaceutical Industries Ltd. | Crystalline forms of fexofenadine hydrochloride and processes for their preparation |
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- 2006-11-01 WO PCT/IN2006/000436 patent/WO2007052310A2/en active Application Filing
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| US5738872A (en) * | 1995-02-28 | 1998-04-14 | Hoechst Marion Roussel, Inc. | Pharmaceutical composition for piperidinoalkanol compounds |
| WO2001094313A2 (en) * | 2000-06-06 | 2001-12-13 | Geneva Pharmaceuticals, Inc. | Crystal modification of fexofenadine |
| WO2002066429A1 (en) * | 2001-02-23 | 2002-08-29 | Cilag Ag | Method for producing non-hydrated fexofenadine hydrochloride and a novel crystalline form obtained thereby |
| WO2002080857A2 (en) * | 2001-04-09 | 2002-10-17 | Teva Pharmaceutical Industries Ltd. | Polymorphs of fexofenadine hydrochloride |
| US20040077683A1 (en) * | 2001-06-18 | 2004-04-22 | Reddy M. Satyanarayana | Novel crystalline forms of 4-[4-[4-(hydroxydiphenylmethyl)-1- piperidinyl]-1-hydroxybutyl]-$g(a)-dimethylbenzene acetic acid and its hydrochloride |
| WO2003011295A1 (en) * | 2001-07-31 | 2003-02-13 | Texcontor Etablissement | Fexofenadine polymorph |
| WO2005019175A1 (en) * | 2003-08-26 | 2005-03-03 | Cipla Limited | Fexofenadine polymorphs and processes of preparing the same |
| WO2005102999A2 (en) * | 2004-04-26 | 2005-11-03 | Teva Pharmaceutical Industries Ltd. | Crystalline forms of fexofenadine hydrochloride and processes for their preparation |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7671071B2 (en) | 2002-06-10 | 2010-03-02 | Teva Pharmaceutical Industries Ltd. | Polymorphic Form XVI of fexofenadine hydrochloride |
| KR101513561B1 (en) * | 2013-03-06 | 2015-04-21 | 주식회사 파마코스텍 | A Novel Method for Preparing Fexofenadine HCl |
| CN104072402A (en) * | 2014-07-16 | 2014-10-01 | 昆山龙灯瑞迪制药有限公司 | Fexofenadine hydrochloride compound of novel crystal form and preparation method of fexofenadine hydrochloride compound |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2007052310A3 (en) | 2007-07-12 |
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