WO2000071124A1 - Amorphous form of fexofenadine hydrochloride - Google Patents

Amorphous form of fexofenadine hydrochloride Download PDF

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Publication number
WO2000071124A1
WO2000071124A1 PCT/IB2000/000708 IB0000708W WO0071124A1 WO 2000071124 A1 WO2000071124 A1 WO 2000071124A1 IB 0000708 W IB0000708 W IB 0000708W WO 0071124 A1 WO0071124 A1 WO 0071124A1
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Prior art keywords
fexofenadine hydrochloride
amorphous form
solvent
fexofenadine
amorphous
Prior art date
Application number
PCT/IB2000/000708
Other languages
French (fr)
Inventor
Naresh Kumar
Chandras Has Khanduri
Mukesh Sharma
Original Assignee
Ranbaxy Laboratories Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Ranbaxy Laboratories Limited filed Critical Ranbaxy Laboratories Limited
Priority to AU46040/00A priority Critical patent/AU4604000A/en
Priority to EP00927651A priority patent/EP1185266A4/en
Publication of WO2000071124A1 publication Critical patent/WO2000071124A1/en

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Classifications

    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine

Definitions

  • This invention relates to an amorphous form of fexofenadine hydro- chloride, to a process for the preparation thereof, and to a composition containing it.
  • fexofenadine is 4-[4-[4-hdroxydiphenylmethyl)-1-piperidin- yl]-hydroxybutyl]- ⁇ , ⁇ -dimethylbenzene acetic acid also known as terfenadine carboxylic acid metabolite having the Formula I.
  • Fexofenadine hydrochloride (Terfenadine carboxylic acid hydrochlor- ide) is an effective antihistamine which avoids adverse effects associated with the administration of terfenadine including abnormal heart rhythms in some patients with liver disease or who also take the antifungal drug ketoconazole or the antibiotic erythromycin.
  • polymorphism we mean to include different physical forms, crystal forms, crystalline/liquid crystalline/non- crystalline (amorphous) forms. This has especially become very interesting after observing that many antibiotics, antibacterials tranquiiizers etc, exhibit polymorphism and some/one of the polymorphic forms of a given drug exhibit superior bio-availability and consequently show much higher activity compared to other polymorphs. It has also been disclosed that the amorphous forms in a number of drugs exhibit different dissolution characteristics and in some cases different bioavailability patterns compared to the crystalline form [Konne T., Chem. Pharm.
  • EP 490648 and EP 022527 also deal with the subject of polymorphism in drugs.
  • PCT patent application WO 95/31437 discloses fexofenadine hydrochloride in various new crystalline forms designated Form I, Form II and Form IV and methods for their preparation.
  • the first object of the present invention is to provide fexofenadine hydrochloride in an amorphous form.
  • the amorphous form of fexofenadine hydrochloride is prepared by an efficient process which uses conditions which are convenient to operate on a commercial scale and operationally safe.
  • the second object of the present invention is to provide a process for the preparation of fexofenadine hydrochloride in an amorphous form which comprises dissolving crystalline fexofenadine hydrochloride in a suitable solvent or dissolving fexofenadine base in a suitable solvent and adding a suitable solvent containing hydrogen chloride and recovering amorphous form of fexofenadine hydrochloride from the solution thereof by spray drying or freeze drying technique.
  • a pharmaceutical composition comprising fexofenadine hydrochloride in an amorphous form with one or more pharmaceutical carriers and/or excipients.
  • fexofenadine hydrochloride is recovered from the solution in an amorphous form using a freeze drying technique.
  • the freeze dryer (Model : Virtis Genesis SQ Freeze - Dryer), which is used, operates on the principle of lyophilization, i.e., a process of stabilizing initially wet materials (aqueous solution or suspensions) by freezing them, then subliming the ice while simultaneously desorbing some of the bound moisture (primary drying). Following disappearance of the ice, desorp- tion may be prolonged (secondary drying). This process is preferably conducted under vacuum.
  • fexofenadine hydrochloride is recovered from the solution in an amorphous form using a spray drying technique.
  • the Mini-Spray Dryer (Model : Buchi 190, Switzerland) which is used, operates on the principle of nozzle spraying in a parallel - flow, i.e., the sprayed product and the drying gas flow in the same direction.
  • the drying gas can be air or inert gases such as nitrogen, argon and carbon dioxide. Nitrogen is preferred in this case.
  • suitable solvent means lower alkanol or combination of lower alkanol, ester, ketone, chlorinated solvent and mixture (s) thereof.
  • Lower alkanol includes those primary, secondary and tertiary alcohols having from one to six carbon atoms.
  • Suitable lower alkanol solvents include methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, amyl alcohol and t-butanol.
  • ketone or ester includes solvents having from one to ten carbon atoms such as acetone, methyl ethyl ketone, 2-butanone, 4- methylpentan-2-one, ethyl acetate or n-butylacetate.
  • suitable chlorinated solvents include dichloromethane, chloroform or carbon tetrachloride. Mixture of these solvents are also contemplated.
  • Amorphous fexofenadine hydrochloride prepared according to the process of the present invention may be characterized by its infra-red spectrum in KBr disc ( Figure 1 ) and by its X-ray powder diffraction pattern
  • Fexofenadine hydrochloride crystalline (124g, 0.231 moles) was dissolved in methanol (300ml) at 25-30 s C. The clear solution so obtained was subjected to spray drying in a Mini-Spray Dryer (Buchi Model 190) and fexofenadine hydrochloride in an amorphous form was isolated (114g).
  • X-ray powder diffraction pattern ( Figure 2) shows a plain halo thus demonstrating the amorphous nature of the product. Infrared spectrum in KBr ( Figure 1 ) is different than the one obtained for crystalline form of fexofenadine hydrochloride ( Figure 3).
  • Example 1 The process of Example 1 was repeated with fexofenadine hydrochloride (10g, 0.0186moles) using ethylacetate (20ml) and methanol
  • Example 1 The process of Example 1 was repeated with fexofenadine hydrochloride (10g, 0.0186 moles) using acetone (20ml) and methanol (20ml) instead of methanol to give amorphous fexofenadine hydrochloride (8.9g).
  • IR (KBr) spectrum and x-ray crystallography examination confirmed the amorphous nature of the product.
  • Fexofenadine (15gm, 0.0299 moles) was suspended in methanol (60 ml) and to it was added isopropanol containing equivalent molar hydrogen chloride to get a clear solution.
  • the clear solution was subjected to spray drying in a mini spray dryer (Buchi Model 190) and fexofenadine hydrochloride in an amorphous form was isolated (14.9g).
  • IR (KBr) and x-ray crystallography revealed that the product was amorphous.

Abstract

This invention relates to an amorphous form of fexofenadine hydrochloride, to a process for the preparation thereof, and to a composition containing it.

Description

AMORPHOUS FORM OF FEXOFENADINE HYDROCHLORIDE
FIELD OF THE INVENTION
This invention relates to an amorphous form of fexofenadine hydro- chloride, to a process for the preparation thereof, and to a composition containing it.
BACKGROUND OF THE INVENTION
Chemically, fexofenadine is 4-[4-[4-hdroxydiphenylmethyl)-1-piperidin- yl]-hydroxybutyl]-α, α-dimethylbenzene acetic acid also known as terfenadine carboxylic acid metabolite having the Formula I.
Figure imgf000002_0001
Formula I
Fexofenadine hydrochloride (Terfenadine carboxylic acid hydrochlor- ide) is an effective antihistamine which avoids adverse effects associated with the administration of terfenadine including abnormal heart rhythms in some patients with liver disease or who also take the antifungal drug ketoconazole or the antibiotic erythromycin.
The pharmaceutical industry has, of late, conducted studies on polymorphism in drugs and the difference in the activity of different polymorphic forms of a given drug. By the term polymorphism we mean to include different physical forms, crystal forms, crystalline/liquid crystalline/non- crystalline (amorphous) forms. This has especially become very interesting after observing that many antibiotics, antibacterials tranquiiizers etc, exhibit polymorphism and some/one of the polymorphic forms of a given drug exhibit superior bio-availability and consequently show much higher activity compared to other polymorphs. It has also been disclosed that the amorphous forms in a number of drugs exhibit different dissolution characteristics and in some cases different bioavailability patterns compared to the crystalline form [Konne T., Chem. Pharm. Bull. 38, 2003 (1990)]. For some therapeutic indications one bioavailability pattern may be favoured over another. Cefurox- ime axetil is a good example of an amorphous form exhibiting higher bioavailability than the crystalline form. Sertraline, Frentizole, Sulphathiazole, Indo- methacine, etc., are some of the important examples of pharmaceuticals which exhibit polymorphism. A number of patents have been granted pertain- ing to these new forms of old drugs. To cite a few, US Patent No. 5,248,699 discloses five polymorphic forms of sertraline hydrochloride while EP 014490 describes four polymorphic forms of Frentizole. EP 490648 and EP 022527 also deal with the subject of polymorphism in drugs. PCT patent application WO 95/31437 discloses fexofenadine hydrochloride in various new crystalline forms designated Form I, Form II and Form IV and methods for their preparation.
SUMMARY OF THE INVENTION
The first object of the present invention is to provide fexofenadine hydrochloride in an amorphous form. The amorphous form of fexofenadine hydrochloride is prepared by an efficient process which uses conditions which are convenient to operate on a commercial scale and operationally safe.
The second object of the present invention is to provide a process for the preparation of fexofenadine hydrochloride in an amorphous form which comprises dissolving crystalline fexofenadine hydrochloride in a suitable solvent or dissolving fexofenadine base in a suitable solvent and adding a suitable solvent containing hydrogen chloride and recovering amorphous form of fexofenadine hydrochloride from the solution thereof by spray drying or freeze drying technique.
In yet another aspect of this invention, there is provided a pharmaceutical composition comprising fexofenadine hydrochloride in an amorphous form with one or more pharmaceutical carriers and/or excipients.
DETAILED DESCRIPTION OF THE INVENTION
In a preferred embodiment of the invention, fexofenadine hydrochloride is recovered from the solution in an amorphous form using a freeze drying technique. The freeze dryer (Model : Virtis Genesis SQ Freeze - Dryer), which is used, operates on the principle of lyophilization, i.e., a process of stabilizing initially wet materials (aqueous solution or suspensions) by freezing them, then subliming the ice while simultaneously desorbing some of the bound moisture (primary drying). Following disappearance of the ice, desorp- tion may be prolonged (secondary drying). This process is preferably conducted under vacuum.
In a more preferred embodiment of the invention, fexofenadine hydrochloride is recovered from the solution in an amorphous form using a spray drying technique. The Mini-Spray Dryer (Model : Buchi 190, Switzerland) which is used, operates on the principle of nozzle spraying in a parallel - flow, i.e., the sprayed product and the drying gas flow in the same direction. The drying gas can be air or inert gases such as nitrogen, argon and carbon dioxide. Nitrogen is preferred in this case.
The term "suitable solvent" means lower alkanol or combination of lower alkanol, ester, ketone, chlorinated solvent and mixture (s) thereof. Lower alkanol includes those primary, secondary and tertiary alcohols having from one to six carbon atoms. Suitable lower alkanol solvents include methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, amyl alcohol and t-butanol. The term ketone or ester includes solvents having from one to ten carbon atoms such as acetone, methyl ethyl ketone, 2-butanone, 4- methylpentan-2-one, ethyl acetate or n-butylacetate. The suitable chlorinated solvents include dichloromethane, chloroform or carbon tetrachloride. Mixture of these solvents are also contemplated.
Amorphous fexofenadine hydrochloride prepared according to the process of the present invention may be characterized by its infra-red spectrum in KBr disc (Figure 1 ) and by its X-ray powder diffraction pattern
(Figure 2). The infra red spectrum in KBr (Figure 1 ) obtained for the samples prepared by the process of the present invention is different than infra red spectrum in KBr for crystalline form (Figure 3) of fexofenadine hydrochloride obtained per WO patent application (WO 95/31437). X-ray powder diffraction patterns gave a plain halo (Figure 2) and show no peaks which are characteristic of a crystalline fexofenadine hydrochloride (Figure 4) thus demonstrating the amorphous nature of the product.
The present invention is illustrated by the following examples which are not intended to limit the effective scope of the claims.
Preparation of amorphous fexofenadine hydrochloride by Spray Drying using crystalline fexofenadine hydrochloride
EXAMPLE 1
Fexofenadine hydrochloride crystalline (124g, 0.231 moles) was dissolved in methanol (300ml) at 25-30sC. The clear solution so obtained was subjected to spray drying in a Mini-Spray Dryer (Buchi Model 190) and fexofenadine hydrochloride in an amorphous form was isolated (114g). X-ray powder diffraction pattern (Figure 2) shows a plain halo thus demonstrating the amorphous nature of the product. Infrared spectrum in KBr (Figure 1 ) is different than the one obtained for crystalline form of fexofenadine hydrochloride (Figure 3).
EXAMPLE 2
The process of Example 1 was repeated with fexofenadine hydrochloride (10g, 0.0186moles) using ethylacetate (20ml) and methanol
(20ml) instead of methanol to give amorphous fexofenadine hydrochloride
(9.2g). IR (KBr) spectrum and x-ray crystallography confirmed that the material was amorphous in nature.
EXAMPLE 3
The process of Example 1 was repeated with fexofenadine hydrochloride (10g, 0.0186 moles) using acetone (20ml) and methanol (20ml) instead of methanol to give amorphous fexofenadine hydrochloride (8.9g). IR (KBr) spectrum and x-ray crystallography examination confirmed the amorphous nature of the product.
Preparation of amorphous fexofenadine hydrochloride by spray drying using fexofenadine base.
EXAMPLE 4
Fexofenadine (15gm, 0.0299 moles) was suspended in methanol (60 ml) and to it was added isopropanol containing equivalent molar hydrogen chloride to get a clear solution. The clear solution was subjected to spray drying in a mini spray dryer (Buchi Model 190) and fexofenadine hydrochloride in an amorphous form was isolated (14.9g). IR (KBr) and x-ray crystallography revealed that the product was amorphous.
EXAMPLE 5
The process of Example 4 was repeated with fexofenadine (10g,
0.0199 moles) using methanol (40ml) and to it was added methanol containing equimolar hydrogen chloride to give amorphous fexofenadine hydrochloride (9.5g). IR (KBr) spectrum and x-ray crystallography examina- tion confirmed the amorphous nature of the product.

Claims

WE CLAIM :
1. Fexofenadine hydrochloride in an amorphous form.
2. A pharmaceutical composition containing a therapeutically effective amount of the amorphous form of claim 1 together with one or more pharmaceutical carriers or excipients.
3. A process for the preparation of fexofenadine hydrochloride in an amorphous form which comprises dissolving crystalline fexofenadine hydrochloride in a suitable solvent or dissolving fexofenadine base in a suitable solvent and adding a suitable solvent containing hydrogen chloride and recovering fexofenadine hydrochloride from said solution by spray drying or freeze drying technique.
4. The process of claim 3, wherein suitable solvent is selected from the group consisting of lower alkanol, ester, ketone, chlorinated solvent and mixtures thereof.
5. The process of claim 4, wherein lower alkanol includes primary, secondary and tertiary alcohols having from one to six carbon atoms.
6. The process of claim 5, wherein said lower alkanol is selected from the group consisting of methanol, ethanol, n-propanol, isopropanol or n-butanol and mixtures thereof.
7. The process of claim 6, wherein the solvent is methanol, ethanol or isopropanol.
8. The process of claim 4, wherein the ester solvent is selected from ethyl acetate or n-butyl acetate.
9. The process of claim 4, wherein the ketone solvent is acetone, methylethyl ketone, 2-butanone, 4-methylpentan-2-one.
10. The process of claim 4, wherein the chlorinated solvent is chloroform, dichloromethane or carbontetrachloride.
11. The process of claim 3, wherein fexofenadine hydrochloride in an amorphous form is isolated from said solution by spray drying.
12. The process of claim 3, wherein the spray drying is effected in the presence of an inert gas.
13. The process of claim 3, wherein fexofenadine hydrochloride in an amorphous form is isolated from said solution by freeze drying.
PCT/IB2000/000708 1999-05-25 2000-05-25 Amorphous form of fexofenadine hydrochloride WO2000071124A1 (en)

Priority Applications (2)

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AU46040/00A AU4604000A (en) 1999-05-25 2000-05-25 Amorphous form of fexofenadine hydrochloride
EP00927651A EP1185266A4 (en) 1999-05-25 2000-05-25 Amorphous form of fexofenadine hydrochloride

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IN776/DEL/99 1999-05-25

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Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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
CN100390145C (en) * 2001-06-18 2008-05-28 雷迪实验室有限公司 Novel crystalline forms of 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-a, a-dimethylbenzene acetic acid and its hydrochloride
US7589128B2 (en) 2004-06-01 2009-09-15 Teva Gyógyszergyár Zártkörüen Müködö Részvénytársaság Process for preparation of amorphous form of a drug
EP2105134A1 (en) 2008-03-24 2009-09-30 Ranbaxy Laboratories Limited Stable amorphous fexofenadine hydrochloride
US7671071B2 (en) 2002-06-10 2010-03-02 Teva Pharmaceutical Industries Ltd. Polymorphic Form XVI of fexofenadine hydrochloride
KR101014010B1 (en) * 2010-12-30 2011-02-14 주식회사 한국에너지관리 Apparatus for mixing air bubble into water
WO2011158262A1 (en) 2010-06-15 2011-12-22 Chemelectiva S.R.L. Polymorphic form of fexofenadine hydrochloride, intermediates and process for its preparation

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Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001094313A3 (en) * 2000-06-06 2002-04-04 Novartis Ag Crystal modification of fexofenadine
WO2001094313A2 (en) * 2000-06-06 2001-12-13 Geneva Pharmaceuticals, Inc. Crystal modification of fexofenadine
US6613906B1 (en) 2000-06-06 2003-09-02 Geneva Pharmaceuticals, Inc. Crystal modification
CH695216A5 (en) * 2001-02-23 2006-01-31 Cilag Ag A method for manufacturing a non-hydrated salt of a piperidine derivative and a novel crystalline form thus obtainable of such a salt.
WO2002066429A1 (en) 2001-02-23 2002-08-29 Cilag Ag Method for producing non-hydrated fexofenadine hydrochloride and a novel crystalline form obtained thereby
US7759364B2 (en) 2001-02-23 2010-07-20 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
WO2002080857A3 (en) * 2001-04-09 2003-12-18 Teva Pharma Polymorphs of fexofenadine hydrochloride
CN100390145C (en) * 2001-06-18 2008-05-28 雷迪实验室有限公司 Novel crystalline forms of 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-a, a-dimethylbenzene acetic acid and its hydrochloride
EP2261209A1 (en) 2001-06-18 2010-12-15 Dr. Reddy's Laboratories Ltd. Novel crystalline forms of 4-[4-[4- hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-alpha, alpha-dimethylbenene acetic acid and its hydrochloride
US7671071B2 (en) 2002-06-10 2010-03-02 Teva Pharmaceutical Industries Ltd. Polymorphic Form XVI of fexofenadine hydrochloride
US7589128B2 (en) 2004-06-01 2009-09-15 Teva Gyógyszergyár Zártkörüen Müködö Részvénytársaság Process for preparation of amorphous form of a drug
EP2105134A1 (en) 2008-03-24 2009-09-30 Ranbaxy Laboratories Limited Stable amorphous fexofenadine hydrochloride
WO2011158262A1 (en) 2010-06-15 2011-12-22 Chemelectiva S.R.L. Polymorphic form of fexofenadine hydrochloride, intermediates and process for its preparation
KR101014010B1 (en) * 2010-12-30 2011-02-14 주식회사 한국에너지관리 Apparatus for mixing air bubble into water

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