EP1453509A2 - Polymorphes a base fexofenadine - Google Patents

Polymorphes a base fexofenadine

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Publication number
EP1453509A2
EP1453509A2 EP02792238A EP02792238A EP1453509A2 EP 1453509 A2 EP1453509 A2 EP 1453509A2 EP 02792238 A EP02792238 A EP 02792238A EP 02792238 A EP02792238 A EP 02792238A EP 1453509 A2 EP1453509 A2 EP 1453509A2
Authority
EP
European Patent Office
Prior art keywords
fexofenadine base
fexofenadine
base
preparing
solution
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP02792238A
Other languages
German (de)
English (en)
Inventor
Barnaba Krochmal
Dov Diller
Ben-Zion Dolitzky
Judith Aronhime
Shlomit Wizel
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Teva Pharmaceutical Industries Ltd
Original Assignee
Teva Pharmaceutical Industries Ltd
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
Priority claimed from US10/118,807 external-priority patent/US20020177608A1/en
Priority claimed from US10/133,460 external-priority patent/US20030021849A1/en
Application filed by Teva Pharmaceutical Industries Ltd filed Critical Teva Pharmaceutical Industries Ltd
Publication of EP1453509A2 publication Critical patent/EP1453509A2/fr
Withdrawn legal-status Critical Current

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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

Definitions

  • the present invention relates to the solid state chemistry of fexofenadine base and its use as an active pharmaceutical agent.
  • fexofenadine can be prepared starting from ethyl ⁇ , ⁇ -dimethylphenyl acetate and 4-chlorobutyroyl chloride, which are reacted under Freidel-Crafts conditions. Chloride is displaced from the Freidel-Crafts product with ⁇ , ⁇ -diphenyl-4-piperidinemethanol to give 4- [4- [4- (hydroxydiphenylmethyl)- 1 -piperidinyl] - 1 -oxobutyl] - ⁇ , ⁇ -dimethylbenzeneacetate, which is isolated as its hydrochloride salt. The ketone is then reduced with PtO/H 2 and the ester group is hydrolyzed to yield fexofenadine base. Other methods of preparing fexofenadine are discussed in U.S. Patents Nos.
  • the present invention relates to the solid state physical properties of fexofenadine base prepared by any of these or other methods. These properties can be influenced by controlling the conditions under which fexofenadine base is obtained in solid form.
  • Solid state physical properties include, for example, the flowability of the milled solid. Flowability affects the ease with which the material is handled during processing into a pharmaceutical product. When particles of the powdered compound do not flow past each other easily, a formulation specialist must take that fact into account in developing a tablet or capsule formulation, which may necessitate the use of glidants such as colloidal silicon dioxide, talc, starch or tribasic calcium phosphate.
  • Another important solid state property of a pharmaceutical compound is its rate of dissolution in aqueous fluid.
  • the rate of dissolution of an active ingredient in a patient's stomach fluid can have therapeutic consequences since it imposes an upper limit on the rate at which an orally-administered active ingredient can reach the patient's bloodstream.
  • the rate of dissolution is also a consideration in formulating syrups, elixirs and other liquid medicaments.
  • the solid state form of a compound may also affect its behavior on compaction and its storage stability. These practical physical characteristics are influenced by the conformation and orientation of molecules in the unit cell, which defines a particular polymorphic form of a substance. The polymorphic form may give rise to thermal behavior different from that of the amorphous material or another polymorphic form.
  • Thermal behavior is measured in the laboratory by such techniques as capillary melting point, thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) and can be used to distinguish some polymorphic forms from others.
  • TGA thermogravimetric analysis
  • DSC differential scanning calorimetry
  • a particular polymorphic form may also give rise to distinct spectroscopic properties that may be detectable by powder X-ray crystallography, solid state 13 C NMR spectrometry and infrared spectrometry.
  • Form I is reported to have a capillary melting point range of 196-201 °C, a DSC endotherm with onset between 195- 199°C and a powder X-ray diffraction ("PXRD") pattern with d-spacings of 14.89, 11.85,
  • Form JJ is reported to have a capillary melting point range of 100-105 °C, a DSC endotherm with onset between 124-126°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 A.
  • Form JJI is reported to have a capillary melting point range of 166- 171 ° C, a DSC endotherm with onset at 166 ° 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 A.
  • Form JN is reported to undergo decomposition at 115-116°C.
  • a DSC endotherm with onset at 146°C is reported.
  • Form JN 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 A.
  • the "872 patent discusses methods of interconverting Forms I-IN.
  • Aqueous recrystallization of Form I can be used to produce Form JJ.
  • Water-minimizing recrystallization or azeotropic distillation of either Form JJ or Form IN can yield Form I.
  • Form JJJ is reported to be accessible by water minimizing recrystallization of Form II.
  • Crystal digestion of Form JJJ can be used to obtain Form I.
  • Forms II and IN can be obtained directly by sodium borohydride reduction of 4-[4-[4-(hydroxydiphenylmethyl)-l- piperidinyl]-l-oxobutyl]- ⁇ , ⁇ -dimethylbenzeneacetate as described in Examples 1 and 2.
  • amorphous fexofenadine hydrochloride can be prepared by lyophilizing or spray drying a solution of fexofenadine hydrochloride.
  • the product is characterized by its IR spectrum and a featureless PXRD pattern.
  • International Publication No. WO 01/94313 is also directed to polymorphs of fexofenadine hydrochloride.
  • the present invention provides new crystal forms of fexofenadine base, rather than fexofenadine hydrochloride, and processes for their preparation.
  • the present invention provides for a new crystalline form of fexofenadine base, which is characterized by a powder X-ray diffraction pattern with peaks at about 9.8, 11.6, 12.1, 13.5, 14.0, 18.0, 18.4 and 19.7 ⁇ 0.2 degrees two theta, and/or a differential scanning calorimetric thermogram with a major endothermic peak at about
  • the present invention provides a process for preparing fexofenadine base having at least one of the characteristics of Form I comprising the steps of preparing a solution of fexofenadine base in 1 -propanol, admixing the solution with water, ice or a mixture thereof to form a precipitate and separating the precipitate as fexofenadine base Form I.
  • the present invention provides for fexofenadine base which is characterized by a PXRD pattern with peaks at about 7.4, 9.7, 11.7, 12.1, 13.8, 14.4, 18.0, 18.5 and 19.7 ⁇ 0.2 degrees two theta and/or a differential scanning calorimetric thermogram with an endotherm at about 100°C, a maximum endotherm at about 223 °C and a minor endotherm at about 144°C, and two exotherms at about 146°C and about 182°C.
  • Said new crystalline form denotes Form II.
  • the present invention provides a process for preparing fexofenadine base having at least one of characteristics of Form II comprising the steps of preparing a solution of fexofenadine base in a mixture of water and 1 -propanol, wherein fexofenadine base precipitates from the solution, and separating the fexofenadine base.
  • the present invention provides for fexofenadine base which is characterized by a PXRD pattern with peaks at about 4.4, 10.3, 11.3, 16.3, 19.8 ⁇ 0.2 degrees 20 and a DSC thermogram with two exothermic peaks at about 107°C and about
  • the present invention provides a process for preparing fexofenadine base having at least one of characteristics of Form HI comprising the steps of slurrying fexofenadine base in methanol, heating the slurry and separating fexofenadine base Form HI as a solid.
  • the present invention provides for fexofenadine base characterized by a PXRD diffraction pattern with peaks at about 4.3, 8.7, 12.5, 13.1 and 13.6 ⁇ 0.2 degrees 20, which is further characterized by peaks at about 16.3, 16.7, 17.5, 18.1, 18.5, 19.6, 20.7, 21.8 and 22.6 ⁇ 0.2 degrees 20.
  • Said new crystalline form denotes Form IN.
  • the present invention provides a process for preparing fexofenadine base having one of characteristics of Form IN comprising the steps of preparing a solution of fexofenadine base in a mixture of a C, to a C 4 alcohol and water, with the proviso that the alcohol is not 1 -propanol, wherein fexofenadine base precipitates from the solution and separating the precipitate;
  • a process for preparing fexofenadine base having one of characteristics of Form IN comprising the steps of preparing a solution of a sodium or a potassium salt of fexofenadine in a mixture of a C, to a C 4 alcohol and water, with the proviso that the alcohol is not 1 -propanol and acidifying the solution to precipitate fexofenadine base.
  • methanol is used.
  • the present invention provides for fexofenadine base which is characterized by a PXRD pattern with peaks at about 17.2, 18.2, 18.8, 20.3 ⁇ 0.2 deg. 2 ⁇ and/or a DSC thermogram with an endotherm followed by an exotherm at about 200 °C, and an additional endotherm at about 226°C.
  • Said new crystalline form denotes Form N.
  • the present invention provides for fexofenadine base which is characterized by a PXRD pattern (Fig. 9) with peaks at about 3.9, 9.6, 11.8, 16.0 and 19.0 ⁇ 0.2 degrees 2 ⁇ , and/or a DSC thermogram (Fig. 10) with endotherms at about 140°C and 229°C, and an exotherm at about 160°C.
  • a PXRD pattern Fig. 9
  • Fig. 10 a DSC thermogram
  • the present invention provides processes for preparing fexofenadine base having at least one of characteristics of Form NI comprising the steps of slurrying fexofenadine base in methanol under suitable condition, separating a solid from the methanol and optionally repeating the slurry process.
  • the present invention provides for fexofenadine base, which is characterized by a PXRD pattern (Fig. 11) with peaks at about 3.9, 7.7, 10.6, 13.4, 14.5 and 19.2 ⁇ 0.2 degrees 29 and or a DSC thermogram (Fig. 12) with an endotherm at about 228 °C.
  • a PXRD pattern Fig. 11
  • Fig. 12 DSC thermogram
  • the present invention provides processes for preparing fexofenadine base having at least one of characteristics of Form Nil comprising carrying out an azeotropic distillation of fexofenadine base in toluene to remove water.
  • the present invention provides for pharmaceutical compositions of fexofenadine base and their methods of administration.
  • FIGURES Figure 1 is a PXRD pattern for fexofenadine Base Form I.
  • Figure 2 is a DSC thermogram for fexofenadine base Form I.
  • Figure 3 is a PXRD pattern for fexofenadine base Form II.
  • Figure 4 is a DSC thermogram for fexofenadine base Form IL
  • Figure 5 is a PXRD pattern for fexofenadine base Form HI.
  • Figure 6 is a DSC thermogram for fexofenadine base Form HI.
  • Figure 7 is a PXRD pattern for fexofenadine base Form V.
  • Figure 8 is a DSC thermogram for fexofenadine base Form V.
  • Figure 9 is a PXRD pattern for fexofenadine base Form VI.
  • Figure 10 is a DSC thermogram for fexofenadine base Form NI.
  • Figure 11 is a PXRD pattern for fexofenadine base Form NH.
  • Figure 12 is a DSC thermogram for fexofenadine base Form NH.
  • precipitation As used herein, precipitation (or “precipitate”) is used in the same way as crystallization (or “crystal”), and refers to obtaining a solid material from a solution.
  • Fexofenadine base Form X refers to a polymorph of fexofenadine base that one of skill in the art can identify as a distinct entity distinguishable from other polymorphs of fexofenadine base based on the characterization provided herein.
  • Form X having at least one of characteristics of Form X refers to a crystalline fexofenadine base polymorph that possesses one of the PXRD peaks, or endotherms and exotherms of a DSC thermogram provided herein.
  • a single or a combination of PXRD peaks which is not found in another polymorphic entity of fexofenadine base is enough to show at least one of the characteristics of Form X.
  • a single or a combination of endotherms and/or exotherms of a DSC thermogram may also serve the same purpose.
  • the present invention provides new crystal Form I of fexofenadine base (designated Form X in Provisional Appl. No. 60/336930, filed November 8, 2001, entitled "Crystal Forms X, XI, XH and XHI of Fexofenadine Hydrochloride, Compositions Containing the New Forms and Methods of Relieving Inflammation by Administering the
  • the fexofenadine base Form I has a PXRD pattern (Fig. 1) with characteristic peaks at about 9.8, 11.6, 12.1, 13.5, 14.0, 18.0, 18.4 and 19.7 ⁇ 0.2 degrees two theta.
  • Fexofenadine base Form I has a DSC profile (Fig. 2) characterized by a major endothermic peak at about 100°C and a minor endothermic peak at about 143 °C, and two exothermic peaks at about 155 °C and about 180°C.
  • the present invention provides for a process for preparing fexofenadine base having at least one of characteristics of Form I comprising the steps of preparing a solution of fexofenadine base in 1 -propanol, admixing the solution with water or ice or a mixture thereof to form a precipitate and separating the precipitate.
  • Fexofenadine base is added to 1 -propanol.
  • the temperature may be raised to further dissolve the fexofenadine base in 1 -propanol.
  • the temperature is raised to more than about 60 °C, more preferably about 80 °C.
  • temperatures may be adequate to dissolve the fexofenadine base in 1- propanol and that other temperatures may be used under other conditions.
  • the solution is poured into ice, water or a mixture thereof to cause precipitation of fexofenadine base Form I.
  • the water is kept at about room temperature.
  • the precipitated fexofenadine base Form I is separated from the solution.
  • the precipitate is separated with a filter.
  • the separated precipitate may be optionally dried under either ambient or reduced pressure. In a preferred embodiment, the precipitate is dried under a vacuum.
  • the present invention also provides fexofenadine base Form H (designated Form XI in Provisional Appl. No. 60/336,930, filed November 8, 2001, entitled "Crystal Forms X, XI, XH and XHI of Fexofenadine Hydrochloride, Compositions Containing the New
  • the fexofenadine base Form H has a powder X-ray diffraction pattern (Fig. 3) with peaks at about 7.4, 9.7, 11.7, 12.1, 13.8, 14.4, 18.0, 18.5 and 19.7 ⁇ 0.2 degrees two theta.
  • the fexofenadine base Form H also has a differential scanning calorimetric (DSC) thermogram (Fig.4) having an endotherm at about 100°C, a maximum endotherm at about 223 °C and aminor endotherm at about 144°C, and two exotherms at about 146°C and about 182°C.
  • DSC differential scanning calorimetric
  • Fexofenadine base Form H may be prepared by preparing a solution of fexofenadine base in a mixture of water and 1 -propanol, wherein fexofenadine base precipitates from the solution and separating the fexofenadine base.
  • a solution of fexofenadine base is prepared in a mixture of 1 -propanol and water.
  • the mixture of water and 1 -propanol is preferably from about a 4:1 ratio to about a 1 :1 ratio (vol/vol). Most preferably, the mixture is about a 3:1 ratio of water to 1 -propanol.
  • the mixture is heated to completely dissolve the fexofenadine base.
  • the temperature is raised to more than about 60 °C, more preferably to about 80 °C.
  • the solution is preferably cooled to about room temperature and left for a few days to crystallize.
  • Water is used for preparation of Form H as a co-solvent of the solution, rather than as an anti-solvent added to the solution as in preparation of Form I.
  • the crystals are separated, preferably by a filter, and optionally dried. To accelerate the drying process, the temperature may be raised or the pressure reduced.
  • the crystals are dried from about 55 °C to about 70 °C in a vacuum. A vacuum oven known in the art may be used. The product of this process is fexofenadine free base H.
  • the present invention provides for fexofenadine base Form HI.
  • Fexofenadine base Form HI is characterized by a PXRD pattern (Fig. 5) with peaks at about 4.4, 10.3, 11.3, 16.3, 19.8 ⁇ 0.2 degrees 29.
  • Fexofenadine free base Form HI is also characterized by a DSC thermogram (Fig. 6) with two broad exothermic peaks at about
  • the present invention provides a process for preparing fexofenadine base having at least one of characteristics of Form HI comprising the steps of slurrying fexofenadine base in methanol, heating the slurry and separating fexofenadine base Form HI as a solid.
  • Fexofenadine free base is slurried in methanol and heated for a sufficient amount of time at a suitable temperature to obtain a transition to Form HI.
  • the slurry is heated from about 5 minutes to about 50 hours at about reflux (65 °C), more preferably for less than about 1 hour.
  • the temperature is above about 45 °C, with reflux temperature being most preferred.
  • the slurry is then preferably cooled.
  • Form HI settles down, which is then separated by techniques well known in the art, such as filtration.
  • the fexofenadine base is optionally dried.
  • the temperature can be increased or the pressure reduced to accelerate the drying process.
  • the fexofenadine base is dried at about 60 °C overnight.
  • the product of this process is fexofenadine base Form HI.
  • the present invention also provides for fexofenadine base Form IN.
  • Fexofenadine base Form IN is characterized by a PXRD pattern with peaks at about 4.3, 8.7, 12.5, 13.1, 13.6, 16.3, 16.7, 17.5, 18.1, 18.5, 19.6, 20.7, 21.8 and 22.6 ⁇ 0.2 degrees 29. The most characteristic peaks are at about 4.3, 8.7, 12.5, 13.1 and 13.6 ⁇ 0.2 degrees 29.
  • Fexofenadine base Form IN can be prepared by a process comprising the steps of preparing a solution of fexofenadine base in a mixture of a C j to a C 4 alcohol and water, with the proviso that the alcohol is not 1 -propanol, wherein fexofenadine base precipitates from the solution and separating the precipitate.
  • a solution of fexofenadine base is prepared in a mixture of water and a lower alcohol, preferably methanol.
  • Fexofenadine base Form IN is then crystallized out of the solution.
  • the solution can be cooled for example to allow for precipitation.
  • a first solution of the sodium or potassium salt of fexofenadine base can be prepared, by using a suitable inorganic base such as potassium or sodium hydroxide. After obtaining a solution of the salt of fexofenadine, the solution is acidified to precipitate fexofenadine base.
  • Form IV is relatively stable during slurry for short amount of times.
  • Form IV can also be recrystallized from a mixture of an alcohol and a ketone, such as a methanohmethyl ethyl ketone ("MEK”) mixture.
  • MEK methanohmethyl ethyl ketone
  • the slurry is carried out at a temperature of from about 45 °C to about 65 °C, more preferably at about 50°C. Residual solvents can be removed by drying the precipitate.
  • the present invention provides for fexofenadine base Form V.
  • Fexofenadine base Form V is characterized by a PXRD diffraction pattern (Fig. 7) with peaks at about 13.2, 13.7, 14.4, 17.2, 18.2, 18.8, 20.3 ⁇ 0.2 degrees 29. The most characteristic peaks are at about 17.2, 18.2, 18.8, 20.3 ⁇ 0.2 degrees 29.
  • Fexofenadine base is also characterized by a DSC thermogram (Fig, 8) with an endotherm followed by an exotherm at about 200°C, and an additional endotherm at about 226°C.
  • the present invention provides a process for preparing fexofenadine base having at least one of characteristics of Form V comprising the steps of slurrying fexofenadine base in methyl ethyl ketone and separating fexofenadine base Form
  • Fexofenadine free base is slurried in methyl ethyl ketone and preferably heated to reflux. The slurry is then preferably cooled. Fexofenadine base Form V is then separated as a solid, preferably by filtration. The separated fexofenadine base is then optionally dried. The pressure is reduced or the temperature increased to accelerate the drying process. Preferably, fexofenadine base is dried at a temperature of about 65 °C in a vacuum. The product of this process is fexofenadine base Form V.
  • Fexofenadine Form VI is characterized by a PXRD pattern (Fig. 9) with peaks at about
  • the DSC profile of fexofenadine Form VI (Fig. 10) has an endotherm at about 140°C followed by an exotherm. In addition, the DSC profile has a sharp endothermic peak at about 229 °C.
  • Fexofenadine base Form VI can be prepared by slurry of fexofenadine base in methanol. Fexofenadine base is added to methanol and slurried for preferably a few hours.
  • a solid is then separated from the slurry by conventional techniques such as filtration.
  • the slurry process is repeated at least once, more preferably twice, by adding the separated solid to methanol and slurrying the solid.
  • a solid is separated for a final time. Before separation, the solid is preferably allowed to stand for a while.
  • the separated solid is then optionally dried, from about 40°C to about 70°C, more preferably about 60 °C.
  • the slurry of fexofenadine base in methanol in the process for preparation of From VI is carried out under suitable conditions, i.e., preferably not heated above room temperature to avoid a transition to Form HI.
  • suitable conditions i.e., preferably not heated above room temperature to avoid a transition to Form HI.
  • the transition depends on the temperature and the amount of time of heating, and that these variable can be ascertained in a routine fashion.
  • Form VI may also be obtained with slight heating, as long as the heating is not sufficient to induce a transition to Form HI.
  • heating is not applied at all, while in another the temperature is kept below about 30°C.
  • the starting material used for preparing either Form HI or Form VI is preferably not fexofenadine Form IV since it tends to show relative stability towards the slurry process when slurried for short periods of times.
  • Fexofenadine base Form VH is characterized by a PXRD pattern (Fig. 11) with peaks at about 3.9, 7.7, 10.6, 13.4, 14.5 and 19.2 ⁇ 0.2 degrees 29.
  • Fexofenadine base Form VH is also characterized by a DSC thermogram (Fig. 12) with an endotherm at about 228 °C.
  • the present invention also provides a process for preparing fexofenadine base having at least one of characteristics of Form VH comprising carrying out an azeotropic distillation of fexofenadine in toluene to remove water.
  • the water removed is traces of water present in the starting material.
  • a hydrate can also be used as a starting material, where the water of crystallization is removed as well.
  • fexofenadine base is added of toluene. The mixture is then distilled to remove the water.
  • the mixture is preferably allowed to cool.
  • the fexofenadine can then be separated by conventional techniques, preferably filtration.
  • the wet sample can then optionally be dried, preferably from a temperature of about 40 °C to about 70 °C, with about 60 °C being preferred.
  • the solid can be recrystallized from a suitable solvent such as a lower alcohol.
  • the starting material can be anhydrous fexofenadine base or any fexofenadine base hydrate or lower alcohol solvate.
  • the starting fexofenadine base can also be in an amorphous or any crystalline crystal form.
  • the starting material can also be that prepared by reducing a fexofenadine ketoacid with a catalytic reducing reagent or a transfer hydride such as sodium borohydride, BH 3 or lithium borohydride.
  • the process can be used as a purification method by using the desired form in an unacceptably pure state as starting material.
  • Hydrochloric acid used can be aqueous or non-aqueous.
  • the aqueous hydrochloric acid used is preferably concentrated and has a molarity of about 12 or a mass percentage of about 38%.
  • hydrochloric acid is used in a slight excess, more particularly from about a 1.01 to about a 1.20 molar equivalent of the free base.
  • the free base can be regenerated by treating the salt with a suitable dilute aqueous base solution, such as dilute aqueous sodium hydroxide, potassium carbonate, ammonia or sodium bicarbonate.
  • the conditions can also be changed to induce precipitation.
  • a preferred way of inducing precipitation is to reduce the solubility of the solvent.
  • the solubility of the solvent can be reduced, for example, by cooling the solvent.
  • an anti-solvent is added to a solution to decrease its solubility for a particular compound, thus resulting in precipitation.
  • an anti- solvent is added to an oily residue or a gummy material, wherein the low solubility of the anti-solvent for a particular compound results in precipitation of that compound.
  • Another manner to accelerate crystallization is by seeding with a crystal of the product or scratching the inner surface of the crystallization vessel with a glass rod. Other times, crystallization can occur spontaneously without any inducement.
  • the present invention covers both embodiments where precipitation is induced/accelerated or occurs spontaneously, except in the circumstance where the inducement/acceleration is critical for obtaining a particular polymorph, e.g., the process requires the use of a particular anti- solvent.
  • a separate precipitating step is not recited in the present invention to emphasize that precipitation can occur spontaneously, but such emphasis is not meant to change the scope of the present invention from one reciting a separate precipitating step.
  • fexofenadine As an antihistamine, fexofenadine is effective at relieving symptoms caused by airborne and contact inducers of histamine release. Such substances include pollen, spores, animal dander, cockroach dander, industrial chemicals, dust and dust mites.
  • Symptoms that can be alleviated by fexofenadine include bronchial spasms, sneezing, rhinorrhia, nasal congestion, lacrimation, redness, rash, urticaria and itch.
  • Fexofenadine base Forms I, H, HI, IV, V, VI and VH are useful for delivering fexofenadine to the gastrointestinal tract, mucus membranes, bloodstream and inflamed tissues of a patient suffering from inflammation caused by a histamine. They can be formulated into a variety of compositions for administration to humans and animals.
  • Pharmaceutical compositions of the present invention contain fexofenadine base Forms I, H, HI, IN, N, VI and VH, optionally in a mixture with other forms or amorphous fexofenadine and/or active ingredients such as pseudoephedrine. They can also be optionally mixed with pseudoephedrine.
  • the pharmaceutical compositions of the present invention can contain one or more excipients.
  • Excipients are added to the composition for a variety of purposes.
  • Diluents increase the bulk of a solid pharmaceutical composition and can make a pharmaceutical dosage form containing the composition easier for the patient and care giver to handle.
  • Diluents for solid compositions include, for example, microcrystalline cellulose (e.g. Avicel ® ), microfine cellulose, lactose, starch, pregelitinized starch, calcium carbonate, calcium sulfate, sugar, dextrates, dextrin, dextrose, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, kaolin, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, polymethacrylates (e.g.
  • Solid pharmaceutical compositions that are compacted into a dosage form like a tablet can include excipients whose functions include helping to bind the active ingredient and other excipients together after compression.
  • Binders for solid pharmaceutical compositions include acacia, alginic acid, carbomer (e.g. carbopol), carboxymethylcellulose sodium, dextrin, ethyl cellulose, gelatin, guar gum, hydrogenated vegetable oil, hydroxyethyl cellulose, hydroxypropyl cellulose (e.g. KJucel ® ), hydroxypropyl methyl cellulose (e.g.
  • Methocel ® liquid glucose, magnesium aluminum silicate, maltodextrin, methylcellulose, polymethacrylates, povidone (e.g. Kollidon ® , Plasdone ® ), pregelatinized starch, sodium alginate and starch.
  • povidone e.g. Kollidon ® , Plasdone ®
  • pregelatinized starch sodium alginate and starch.
  • the dissolution rate of a compacted solid pharmaceutical composition in the patient's stomach can be increased by the addition of a disintegrant to the composition.
  • Disintegrants include alginic acid, carboxymethylcellulose calcium, > carboxymethylcellulose sodium (e.g. Ac-Di-Sol ® , Primellose ® ), colloidal silicon dioxide, croscarmellose sodium, crospovidone (e.g. Kollidon ® , Polyplasdone ® ), guar gum, magnesium aluminum silicate, methyl cellulose, microcrystalline cellulose, polacrilin potassium, powdered cellulose, pregelatinized starch, sodium alginate, sodium starch glycolate (e.g. Explotab ® ) and starch. Glidants can be added to improve the flowability of non-compacted solid composition and improve the accuracy of dosing.
  • alginic acid e.g. Ac-Di-Sol ® , Primellose ®
  • colloidal silicon dioxide e.g. Kollidon ® , Polyplasdone ®
  • crospovidone e.g. Kollidon ® , Polyplasdone
  • Excipients that can function as glidants include colloidal silicon dixoide, magnesium trisilicate, powdered cellulose, starch, talc and tribasic calcium phosphate.
  • colloidal silicon dixoide magnesium trisilicate
  • powdered cellulose starch
  • talc tribasic calcium phosphate.
  • a lubricant can be added to the composition to reduce adhesion and ease release of the product form the dye.
  • Lubricants include magnesium stearate, calcium stearate, glyceryl monostearate, glyceryl palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil, mineral oil, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc and zinc stearate.
  • Flavoring agents and flavor enhancers make the dosage form more palatable to the patient.
  • Common flavoring agents and flavor enhancers for pharmaceutical products that can be included in the composition of the present invention include maltol, vanillin, ethyl vanillin, menthol, citric acid, fumaric acid, ethyl maltol, and tartaric acid.
  • Solid and liquid compositions can also be dyed using any pharmaceutically acceptable colorant to improve their appearance and/or facilitate patient identification of the product and unit dosage level.
  • liquid pharmaceutical compositions of the present invention fexofenadine base Forms I, H, HI, TV, V, VI and VH, and any other solid excipients are dissolved or suspended in a liquid carrier such as water, vegetable oil, alcohol, polyethylene glycol, propylene glycol or glycerin.
  • Liquid pharmaceutical compositions can contain emulsifying agents to disperse uniformly throughout the composition an active ingredient or other excipient that is not soluble in the Hquid carrier.
  • Emulsifying agents that can be useful in liquid compositions of the present invention include, for example, gelatin, egg yolk, casein, cholesterol, acacia, tragacanth, chondrus, pectin, methyl cellulose, carbomer, cetostearyl alcohol and cetyl alcohol.
  • Liquid pharmaceutical compositions of the present invention can also contain a viscosity enhancing agent to improve the mouth-feel of the product and/or coat the lining of the gastrointestinal tract.
  • a viscosity enhancing agent include acacia, alginic acid bentonite, carbomer, carboxymethylcellulose calcium or sodium, cetostearyl alcohol, methyl cellulose, ethylcellulose, gelatin guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, maltodextrin, polyvinyl alcohol, povidone, propylene carbonate, propylene glycol alginate, sodium alginate, sodium starch glycolate, starch tragacanth and xanthan gum.
  • Sweetening agents such as sorbitol, saccharin, sodium saccharin, sucrose, aspartame, fructose, mannitol and invert sugar can be added to improve the taste.
  • Preservatives and chelating agents such as alcohol, sodium benzoate, butylated hydroxy toluene, butylated hydroxyanisole and ethylenediamine tetraacetic acid can be added at levels safe for ingestion to improve storage stability.
  • a liquid composition according to the present invention can also contain a buffer such as guconic acid, lactic acid, citric acid or acetic acid, sodium guconate, sodium lactate, sodium citrate or sodium acetate.
  • a buffer such as guconic acid, lactic acid, citric acid or acetic acid, sodium guconate, sodium lactate, sodium citrate or sodium acetate.
  • the solid compositions of the present invention include powders, granulates, aggregates. and compacted compositions.
  • the dosages include dosages suitable for oral, buccal, rectal, parenteral (including subcutaneous, intramuscular, and intravenous), inhalant and ophthalmic administration. Although the most suitable route in any given case will depend on the nature and severity of the condition being treated, the most preferred route of the present invention is oral.
  • the dosages can be conveniently presented in unit dosage form and prepared by any of the methods well-known in the pharmaceutical arts.
  • Dosage forms include solid dosage forms like tablets, powders, capsules, suppositories, sachets, troches and losenges as well as liquid syrups, suspensions and elixirs.
  • a dosage form of the present invention is a capsule containing the composition, preferably a powdered or granulated solid composition of the invention, within either a hard or soft shell.
  • the shell can be made from gelatin and optionally contain a plasticizer such as glycerin and sorbitol, and an opacifying agent or colorant.
  • compositions and dosage forms can be formulated into compositions and dosage forms according to methods known in the art.
  • a composition for tableting or capsule filing can be prepared by wet granulation.
  • wet granulation some or all of the active ingredients and excipients in powder form are blended and then further mixed in the presence of a liquid, typically water, which causes the powders to clump up into granules.
  • a liquid typically water
  • the granulate is screened and/or milled, dried and then screened and/or milled to the desired particle size.
  • the granulate can then be tableted or other excipients can be added prior to tableting, such as a glidant and/or a lubricant.
  • a tableting composition can be prepared conventionally by dry blending.
  • the blended composition of the actives and excipients can be compacted into a slug or a sheet and then comminuted into compacted granules. The compacted granules can be compressed subsequently into a tablet.
  • a blended composition can be compressed directly into a compacted dosage form using direct compression techniques. Direct compression produces a more uniform tablet without granules.
  • Excipients that are particularly well-suited to direct compression tableting include microcrystalline cellulose, spray dried lactose, dicalcium phosphate dihydrate and colloidal silica.
  • a capsule filling of the present invention can comprise any of the aforementioned blends and granulates that were described with reference to tableting, only they are not subjected to a final tableting step.
  • Capsules, tablets and lozenges and other unit dosage forms preferably contain a dosage level of about 30 to about 180 mg of fexofenadine base. Other dosages may also be administered depending on the need.
  • a round standard aluminum sample holder with a round zero background quartz plate was used. Scans were performed over a range of 2 to 40 degrees two-theta, continuously, with a scan rate of 3 degrees/min.
  • the DSC thermogram was obtained using a DSC Mettler 821 Star.
  • the temperature range of scans was 30-350°C at a rate of 10°C/min.
  • the weight of the sample was 2-5 mg.
  • the sample was purged with nitrogen gas at a flow rate of 40 mL/min. Standard 40 ⁇ l aluminum crucibles having lids with three small holes were used.
  • Fexofenadine base (10 grams) was mixed with 1 -propanol (30 mL) and water (100 mL). The mixture was then heated to 80 °C. 1 -propanol (40 mL) was then added to the mixture to complete the dissolution. The solution was cooled to 25 °C with stirring for 2 days to precipitate crystals. The crystals were filtered and dried under vacuum at 62 °C to yield 6.5 grams of product. Subsequent PXRD analysis confirmed that the product was a new form of fexofenadine base, labeled Form H.
  • Fexofenadine base (80.2 grams) was slurried in methanol (400 mL) and heated at reflux for 20 minutes. The hot slurry was cooled to a temperature of 20 °C. A solid was then filtered after 0.5 hours and dried overnight at 60 °C. The yield of this process was 92%. Subsequent PXRD analysis confirmed the product was a new form of fexofenadine base, labeled Form HI.
  • Fexofenadine ketoacid was reduced with sodium borohydride in methanol-water in the presence of sodium hydroxide. After completion of the reduction, the fexofenadine so prepared was precipitated by acidification using acetic acid. The resulting precipitate was filtered and slurried three times in methanol at 50°C. The material was dried for 2 hours at 65 °C under vacuum.
  • Fexofenadine free base was prepared an in Example 8 except that it was slurried only once in methanol and recrystallized from MEK:methanol.
  • Fexofenadine free base (5 grams) was heated in boiling MEK:methanol 1 : 1 (300 ml), most of which dissolved. The mixture was filtered hot from undissolved material. The filtrate was left overnight at room temperature. A crystalline precipitate formed, which was cooled in an ice salt bath and filtered. The precipitate fexofenadine free base was dried for 1 hour under vacuum at
  • Fexofenadine free base (4.5 grams) was slurried in methyl ethyl ketone (70 mL) at reflux temperature for 2 hours. The hot slurry was then cooled to a temperature of 20 °C. A solid settled down which was then filtered after 0.5 hours and dried in a vacuum oven at 65 °C, first with a water aspirator and then with an oil vacuum pump. The yield of this process was 45%. Subsequent PXRD analysis confirmed the product was a new form of fexofenadine base, labeled Form V.
  • Fexofenadine base (50.3 grams) was slurried with 300ml methanol at room temperature ( ⁇ 25 °C) for 2.5 hours, followed by filtration. The filtered sample was slurried for a second time for 1.5 hours at room temperature with methanol, followed by filtration. The sample was slurried for a third time for 1.67 hours at room temperature with 300ml of methanol. The sample was left alone without stirring for 12 hours, then filtered, and dried at 60 °C overnight to yield 9.5 grams of fexofenadine free base From VI. Subsequent PXRD analysis confirmed the product of this process was a new form of fexofenadine free base, labeled Form VI.
  • Fexofenadine base (30.52 grams) was set up in a dean stark apparatus using toluene (200 ml) to remove water. After 6.5 hours, the apparatus was allowed to cool. After standing overnight, a gray solid was filtered (3.46 grams), which was shown to be form VH as a wet sample. The wet sample was initially highly soluble in methanol, but crystallized out of methanol overtime. The wet sample (4.28 grams) was dried in the oven at 60 °C degrees for 3 hours to yield 2.22 grams of fexofenadine base Form VH. Subsequent PXRD analysis confirmed the product of this process was a new form of fexofenadine free base, labeled Form VH.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
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Abstract

L'invention concerne de nouvelles formes cristallines à base fexofénadine et des procédés de préparation de celles-ci. Ces formes sont administrées à des êtres humains et à des animaux afin de soulager les symptômes entraînés par l'histamine. Cette invention concerne, en outre, des compositions pharmaceutiques de ces nouvelles formes cristallines.
EP02792238A 2001-11-08 2002-11-08 Polymorphes a base fexofenadine Withdrawn EP1453509A2 (fr)

Applications Claiming Priority (23)

Application Number Priority Date Filing Date Title
US33693001P 2001-11-08 2001-11-08
US336930P 2001-11-08
US33904101P 2001-12-07 2001-12-07
US339041P 2001-12-07
US34411401P 2001-12-28 2001-12-28
US344114P 2001-12-28
US36178002P 2002-03-04 2002-03-04
US361780P 2002-03-04
US36348202P 2002-03-11 2002-03-11
US363482P 2002-03-11
US10/118,807 US20020177608A1 (en) 2001-04-09 2002-04-08 Polymorphs of fexofenadine hydrochloride
US118807 2002-04-08
US10/133,460 US20030021849A1 (en) 2001-04-09 2002-04-26 Polymorphs of fexofenadine hydrochloride
US133460 2002-04-26
US38767002P 2002-06-10 2002-06-10
US39019802P 2002-06-19 2002-06-19
US390198P 2002-06-19
US40376502P 2002-08-15 2002-08-15
US403765P 2002-08-15
US40621402P 2002-08-27 2002-08-27
US406214P 2002-08-27
US387670P 2002-10-06
PCT/US2002/035996 WO2003039482A2 (fr) 2001-11-08 2002-11-08 Polymorphes a base fexofenadine

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GB0319935D0 (en) 2003-08-26 2003-09-24 Cipla Ltd Polymorphs
ITMI20041143A1 (it) * 2004-06-08 2004-09-08 Dipharma Spa Polimorfi di fexofenadina e procedimento per la loro preparazione
ITMI20041568A1 (it) * 2004-07-30 2004-10-30 Dipharma Spa "polimorfi di fexofenadina base"
JP2008514641A (ja) * 2004-09-28 2008-05-08 テバ ファーマシューティカル インダストリーズ リミティド 結晶形フェキソフェナジン、およびその調製方法
TWI665190B (zh) 2013-11-15 2019-07-11 阿克比治療有限公司 ｛［５－（３－氯苯基）－３－羥基吡啶－２－羰基］胺基｝乙酸之固體型式，其組合物及用途

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US4254129A (en) * 1979-04-10 1981-03-03 Richardson-Merrell Inc. Piperidine derivatives
JP3034047B2 (ja) * 1993-06-24 2000-04-17 オールバニー・モレキュラー・リサーチ・インコーポレイテッド ピペリジン誘導体及びそれらの製造法
US6147216A (en) * 1993-06-25 2000-11-14 Merrell Pharmaceuticals Inc. Intermediates useful for the preparation of antihistaminic piperidine derivatives
US6201124B1 (en) * 1995-12-21 2001-03-13 Albany Molecular Research, Inc. Process for production of piperidine derivatives

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AU2002357701A1 (en) 2003-05-19

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