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WO2008040935A1 - New polymorphic forms of pregabalin - Google Patents

New polymorphic forms of pregabalin Download PDF

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Publication number
WO2008040935A1
WO2008040935A1 PCT/GB2007/003516 GB2007003516W WO2008040935A1 WO 2008040935 A1 WO2008040935 A1 WO 2008040935A1 GB 2007003516 W GB2007003516 W GB 2007003516W WO 2008040935 A1 WO2008040935 A1 WO 2008040935A1
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WO
WIPO (PCT)
Prior art keywords
pregabalin
polymorphic
polymorphic form
following
mixture
Prior art date
Application number
PCT/GB2007/003516
Other languages
French (fr)
Inventor
Maja Devcic
Miroslav Zegarac
Original Assignee
Pliva Hrvatska D.O.O.
Bucks, Teresa, Anne
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 Pliva Hrvatska D.O.O., Bucks, Teresa, Anne filed Critical Pliva Hrvatska D.O.O.
Publication of WO2008040935A1 publication Critical patent/WO2008040935A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C229/06—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton
    • C07C229/08—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to hydrogen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants

Definitions

  • the present invention is concerned with new polymorphic forms of pregabalin, processes of preparing the new polymorphic forms, pharmaceutical compositions containing the same, therapeutic uses thereof and methods of treatment employing the same.
  • Polymorphic forms of a drug substance can have different chemical and physical properties, including melting point, chemical reactivity, apparent solubility, dissolution rate, optical and mechanical properties, vapor pressure, and density. These properties can have a direct effect on the ability to process and/or manufacture a drug substance and a drug product, as well as on drug product stability, dissolution, and bioavailability. Thus, polymorphism can affect the quality, safety, and efficacy of a drug product.
  • Polymorphic forms as referred to herein can include crystalline and amorphous forms as well as solvate and hydrate forms, which can be further characterised as follows.
  • Crystalline forms have different arrangements and/or conformations of the molecules in the crystal lattice.
  • Amorphous forms consist of disordered arrangements of molecules that do not possess a distinguishable crystal lattice.
  • Solvates are crystal forms containing either stoichiometric or non- stoichiometric amounts of a solvent. If the incorporated solvent is water, the solvate is commonly known as a hydrate.
  • XRPD X-ray powder diffraction
  • microscopy e.g., thermal analysis (e.g., differential scanning calorimetry [DSC], thermal gravimetric analysis [TGA], and hot-stage microscopy), and spectroscopy (e.g., infrared [IR], Raman, solid-state nuclear magnetic resonance [ssNMR]) are also helpful to further characterise polymorphic forms.
  • thermal analysis e.g., differential scanning calorimetry [DSC], thermal gravimetric analysis [TGA], and hot-stage microscopy
  • spectroscopy e.g., infrared [IR], Raman, solid-state nuclear magnetic resonance [ssNMR]
  • Drug substance polymorphic forms can exhibit different chemical, physical and mechanical properties as referred to above, including aqueous solubility and dissolution rate, hygroscopicity, particle shape, density, flowability, and compactibility, which in turn may affect processing of the drug substance and/or manufacturing of the drug product.
  • Polymorphs can also exhibit different stabilities. The most stable polymorphic form of a drug substance is often chosen during drug development based on the minimal potential for conversion to another polymorphic form and on its greater chemical stability. However, a meta-stable form can alternatively be chosen for various reasons, including bioavailability enhancement.
  • Pregabalin, (3S)-3-(aminomethyl)-5-methyl-hexanoic acid can be represented by the following structural formula:
  • Pregabalin is an anticonvulsant and is, therefore, employed in an anti-seizure therapy for central nervous system disorders such as epilepsy, Huntington's chorea, cerebral ischemia, Parkinson's disease, tardive dyskinesia, and spasticity, and, possibly as an anti-depressant, anxiolytic, and antipsychotic activity.
  • EP641330 relates to novel compounds that are analogs of gamma aminobutyric acid (GABA), and methods for the synthesis of these compounds.
  • GABA gamma aminobutyric acid
  • WO2005/100580A1 provides methods for the conversion of 2 isobutyl- succinonitrile into (S)-3-cyano-5-methylhexanoic acid, which is a useful intermediate in the synthesis of (S)-3-(aminomethyl)-5-methylhexanoic acid (pregabalin).
  • this invention is the first to provide, describe and define polymorphic forms of pregabalin.
  • Polymorphic forms of pregabalin now provided by the present invention are hereinafter referred to as Form I, Form II, Form III and Form IV.
  • Form I according to the present invention is characterised as having one or more characteristic XRPD peaks selected from following (2 ⁇ ): 11.6 ⁇ 0.2, 13.3 ⁇ 0.2, 16.5 ⁇ 0.2, 20.0 ⁇ 0.2 and 23.4 ⁇ 0.2.
  • Form I can be further characterised by a typical DSC thermogram as shown in Figure 1.
  • Form I can be still further characterised by a typical TGA thermogram as shown in Figure 2.
  • Form Il characterised as having an X-ray powder diffraction pattern, or substantially the same X-ray powder diffraction pattern, as shown in Figure 3.
  • Form Il according to the present invention is further characterised as having one or more characteristic XRPD peaks selected from following (2 ⁇ ): 5.7 ⁇ 0.2, 11.3 ⁇ 0.2, 17.0 ⁇ 0.2 and 22.7 ⁇ 0.2.
  • Form Il according to the present invention is further characterised as having one or more other characteristic XRPD peaks selected from following (2 ⁇ ): 15.5 + 0.2, 17.8 ⁇ 0.2, 18.6 + 0.2 and 24.2 ⁇ 0.2.
  • Form III characterised as having one or more characteristic XRPD peaks selected from following (2 ⁇ ): 6.3 ⁇ 0.2, 12.6 ⁇ 0.2, 19.0 ⁇ 0.2, 20.8 ⁇ 0.2 and 27.0 ⁇ 0.2.
  • Form IV characterised as having one or more characteristic XRPD peaks selected from following (2 ⁇ ): 9.5 ⁇ 0.2, 12.3 ⁇ 0.2, 16.7 ⁇ 0.2, 19.1 ⁇ 0.2, 19.8 ⁇ 0.2.
  • Form IV according to the present invention is further characterised as having one or more other characteristic XRPD peaks selected from following (2 ⁇ ): 18.3 ⁇ 0.2, 18.4 ⁇ 0.2, 20.2 ⁇ 0.2, 22.2 ⁇ 0.2 and 23.2 ⁇ 0.2.
  • Form IV can be still further characterised by a typical DSC thermogram as shown in Figure 4. 2007/003516
  • Form IV can be still further characterised by a typical TGA thermogram as shown in Figure 5.
  • Pregabalin is an anticonvulsant and is thus useful in the anti-seizure therapy for central nervous system disorders such as epilepsy, Huntington's chorea, cerebral ischemia, Parkinson's disease, tardive dyskinesia, and spasticity, and, possibly as an anti-depressant, anxiolytic, and antipsychotic activity.
  • the present invention further provides, therefore, a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of Form I or of Form Il or of Form III or of Form IV or a mixture of any thereof according to the invention, together with a pharmaceutically acceptable carrier, diluent or excipients thereof.
  • Excipients are chosen according to the pharmaceutical form and the desired mode of administration.
  • the term "therapeutically effective amount” means an amount of one of said polymorphic forms of pregabalin according to the invention, which is capable of preventing, ameliorating or eliminating a disease state for which administration of anticonvulsant is indicated.
  • pharmaceutically acceptable it is meant that the carrier, diluent or excipient is compatible with pregabalin according to the invention, and not deleterious to a recipient thereof.
  • Form I or Form Il or Form III or Form IV or a mixture of any thereof according to the present invention is administered to animals and humans in unit forms of administration, mixed with conventional pharmaceutical carriers, for the prophylaxis or treatment of the above disorders or diseases.
  • the appropriate unit forms of administration include forms for oral administration, such as tablets, gelatin capsules, powders, granules and solutions or suspensions to be taken orally, forms for sublingual, buccal, intratracheal or intranasal administration, forms for subcutaneous, intramuscular 6 or intravenous administration and forms for rectal administration.
  • Form I or Form Il or Form 111 or Form IV or a mixture of any thereof according to the present invention can be used in creams, ointments or lotions.
  • the dose of Form I or of Form Il or of Form III or of Form IV or a mixture of any thereof according to the present invention can vary between 0.01 and 50 mg per kg of body weight per day.
  • Each unit dose can contain from 0.1 to 1000 mg, preferably 1 to 500 mg, of I or of Form Il or of Form III or of Form IV or a mixture of any thereof according to the present invention in combination with a pharmaceutical carrier.
  • This unit dose can be administered 1 to 5 times a day so as to administer a daily dosage of 0.5 to 5000 mg, preferably 1 to 2500 mg.
  • Form I or Form Il or Form III or Form IV or a mixture of any thereof according to the present invention is mixed with a pharmaceutical vehicle such as gelatin, starch, lactose, magnesium stearate, talc, gum arabic or the like.
  • a pharmaceutical vehicle such as gelatin, starch, lactose, magnesium stearate, talc, gum arabic or the like.
  • the tablets can be coated with sucrose, a cellulose derivative or other appropriate substances, or else they can be treated so as to have a prolonged or delayed activity and so as to release a predetermined amount of active principle continuously.
  • a preparation in the form of gelatin capsules can be obtained by mixing Form I or Form Il or Form III or Form IV or a mixture of any thereof according to the present invention with a diluent and pouring the resulting mixture into soft or hard gelatin capsules.
  • a preparation in the form of a syrup or elixir or for administration in the form of drops can contain Form I or Form Il or Form III or Form IV or a mixture of any thereof according to the present invention typically in conjunction with a sweetener, which is preferably calorie-free, optionally antiseptics such as methylparaben and propylparaben, as well as a flavoring and an appropriate colour.
  • a sweetener which is preferably calorie-free
  • optionally antiseptics such as methylparaben and propylparaben
  • Water-dispersible granules or powders can contain Form I or Form Il or Form III or Form IV or a mixture of any thereof according to the present invention mixed with dispersants or wetting agents, or suspending agents such as polyvinylpyrrolidone, as well as with sweeteners or taste correctors.
  • Rectal administration is effected using suppositories prepared with binders which melt at the rectal temperature, for example polyethylene glycols.
  • Parenteral administration is effected using aqueous suspensions, isotonic saline solutions or sterile and injectable solutions which contain pharmacologically compatible dispersants and/or wetting agents, for example propylene glycol or butylene glycol.
  • Form I or Form Il or Form III or Form IV or a mixture of any thereof according to the present invention can also be formulated as microcapsules, with one or more carriers or additives if appropriate.
  • the present invention further provides Form I or Form Il or Form III or Form IV or a mixture of any thereof substantially as hereinbefore described, for use in the manufacture of a medicament for the treatment of a disease state prevented, ameliorated or eliminated by the administration of anticonvulsant. More specifically, the present invention provides Form I or Form Il or Form III or Form IV or a mixture of any thereof substantially as hereinbefore described, for use in the manufacture of a medicament for anti-seizure therapy for central nervous system disorders such as epilepsy, Huntington's chorea, cerebral ischemia, Parkinson's disease, tardive dyskinesia, and spasticity, and, possibly as an anti-depressant, anxiolytic, and antipsychotic activity.
  • central nervous system disorders such as epilepsy, Huntington's chorea, cerebral ischemia, Parkinson's disease, tardive dyskinesia, and spasticity, and, possibly as an anti-depressant, anxiolytic, and antipsychotic activity.
  • the present invention also provides a method of treating a disease state prevented, ameliorated or eliminated by the administration of anticonvulsant in a patient in need of such treatment, which method comprises administering to the patient a therapeutically effective amount of Form I or of Form Il or of Form III or of Form IV or a mixture of any thereof substantially as hereinbefore described. More specifically, the present invention provides a method of treating central nervous system disorders such as epilepsy, Huntington's chorea, cerebral ischemia, Parkinson's disease, tardive dyskinesia, and spasticity in a patient in need of such treatment, which method comprises administering to the patient a therapeutically effective amount of Form I or of Form Il or of Form III or of Form IV or a mixture of any thereof substantially as hereinbefore described.
  • central nervous system disorders such as epilepsy, Huntington's chorea, cerebral ischemia, Parkinson's disease, tardive dyskinesia, and spasticity
  • Figure 1 shows a DSC pattern of Form I obtained by using MDSC TA instruments Q 1000 operating at heating rate of 10°C/min and in stream of nitrogen with flow of 50ml/min..
  • Figure 2 shows a TGA pattern of Form I obtained by using TGA 7 manufacturer Perkin Elmer, operating at heating rate of 10°C/min, and in stream of nitrogen with flow of 35 ml/min
  • Figure 3 shows an XRPD pattern of Form Il obtained by Philips X'Pert PRO diffractometer using CuKaI radiation
  • Figure 4 shows a DSC pattern of Form IV obtained by using MDSC TA instruments Q 1000 operating at heating rate of 10°C/min and in stream of nitrogen with flow of 50ml/min...
  • Figure 5 shows a TGA pattern of Form IV obtained by using TGA 7 manufacturer Perkin Elmer, operating at heating rate of 10°C/min, and in stream of nitrogen with flow of 35 ml/min.
  • pregabalin was dissolved in about 20 ml of 1-octanol and about 4 ml of water at about 90 0 C. The solution was left to evaporate at about
  • pregabalin About 10 mg was dissolved in about 4 ml of acetone and about 1 ml of water by heating. Solution was left to cool down to room temperature in an open flask. After solvents evaporated, crystals of pregabalin form Il were observed.
  • Example 3 About 10 mg of pregabalin was dissolved in about 4 ml of 1-octanol and about 1 ml of water by heating. The solution was left to cool down to room temperature. After about 24 hours crystals of pregabalin form III were observed.
  • Example 4 About 10 mg of pregabalin was dissolved in about 2 ml of methanol by heating. The solution was left to cool down to room temperature. After about 24 hours crystals of pregabalin form IV were observed.
  • Example 5
  • pregabalin About 10 mg was dissolved in about 3 ml of N, N- dimethylacetamide and about 1 ml of water by heating. The solution was left to cool down to room temperature. After about 24 hours single crystals of pregabalin form IV were observed.
  • pregabalin About 300 mg of pregabalin was dissolved in about 15 ml of acetone and about 7 ml of water at reflux conditions. The solution was slowly cooled yielding crystals of pregabalin form IV.

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Abstract

The present invention is concerned with new polymorphic forms of pregabalin, processes of preparing the new polymorphic form, pharmaceutical compositions containing the same, therapeutic uses thereof and methods of treatment employing the same.

Description

NEW POLYMORPHIC FORMS OF PREGABALIN
Field of invention
The present invention is concerned with new polymorphic forms of pregabalin, processes of preparing the new polymorphic forms, pharmaceutical compositions containing the same, therapeutic uses thereof and methods of treatment employing the same.
Background of the invention Polymorphic forms of a drug substance can have different chemical and physical properties, including melting point, chemical reactivity, apparent solubility, dissolution rate, optical and mechanical properties, vapor pressure, and density. These properties can have a direct effect on the ability to process and/or manufacture a drug substance and a drug product, as well as on drug product stability, dissolution, and bioavailability. Thus, polymorphism can affect the quality, safety, and efficacy of a drug product.
Polymorphic forms as referred to herein can include crystalline and amorphous forms as well as solvate and hydrate forms, which can be further characterised as follows.
(i) Crystalline forms have different arrangements and/or conformations of the molecules in the crystal lattice.
(ii) Amorphous forms consist of disordered arrangements of molecules that do not possess a distinguishable crystal lattice.
(iii) Solvates are crystal forms containing either stoichiometric or non- stoichiometric amounts of a solvent. If the incorporated solvent is water, the solvate is commonly known as a hydrate.
When a drug substance exists in polymorphic forms, it is said to exhibit polymorphism. There are a number of methods that can be used to characterise polymorphs of a drug substance. Demonstration of a non-equivalent structure by single crystal X-ray diffraction is currently regarded as the definitive evidence of polymorphism. X-ray powder diffraction hereinafter referred to as XRPD can also be used to support the existence of polymorphs. Other methods, including microscopy, thermal analysis (e.g., differential scanning calorimetry [DSC], thermal gravimetric analysis [TGA], and hot-stage microscopy), and spectroscopy (e.g., infrared [IR], Raman, solid-state nuclear magnetic resonance [ssNMR]) are also helpful to further characterise polymorphic forms.
Drug substance polymorphic forms can exhibit different chemical, physical and mechanical properties as referred to above, including aqueous solubility and dissolution rate, hygroscopicity, particle shape, density, flowability, and compactibility, which in turn may affect processing of the drug substance and/or manufacturing of the drug product. Polymorphs can also exhibit different stabilities. The most stable polymorphic form of a drug substance is often chosen during drug development based on the minimal potential for conversion to another polymorphic form and on its greater chemical stability. However, a meta-stable form can alternatively be chosen for various reasons, including bioavailability enhancement.
Pregabalin, (3S)-3-(aminomethyl)-5-methyl-hexanoic acid, can be represented by the following structural formula:
Figure imgf000003_0001
Pregabalin is an anticonvulsant and is, therefore, employed in an anti-seizure therapy for central nervous system disorders such as epilepsy, Huntington's chorea, cerebral ischemia, Parkinson's disease, tardive dyskinesia, and spasticity, and, possibly as an anti-depressant, anxiolytic, and antipsychotic activity.
There are only a few patents and applications concerning pregabalin. EP641330 relates to novel compounds that are analogs of gamma aminobutyric acid (GABA), and methods for the synthesis of these compounds. WO2005/100580A1 provides methods for the conversion of 2 isobutyl- succinonitrile into (S)-3-cyano-5-methylhexanoic acid, which is a useful intermediate in the synthesis of (S)-3-(aminomethyl)-5-methylhexanoic acid (pregabalin).
Therefore this invention is the first to provide, describe and define polymorphic forms of pregabalin. Polymorphic forms of pregabalin now provided by the present invention are hereinafter referred to as Form I, Form II, Form III and Form IV.
Description of the invention Form I according to the present invention is characterised as having one or more characteristic XRPD peaks selected from following (2Θ): 11.6 ± 0.2, 13.3 ± 0.2, 16.5 ± 0.2, 20.0 ± 0.2 and 23.4 ± 0.2.
Form I can be further characterised by a typical DSC thermogram as shown in Figure 1.
Form I can be still further characterised by a typical TGA thermogram as shown in Figure 2.
There is also provided by the present invention, therefore, Form Il characterised as having an X-ray powder diffraction pattern, or substantially the same X-ray powder diffraction pattern, as shown in Figure 3. 16
4
Form Il according to the present invention is further characterised as having one or more characteristic XRPD peaks selected from following (2Θ): 5.7 ± 0.2, 11.3 ± 0.2, 17.0 ± 0.2 and 22.7 ± 0.2. Form Il according to the present invention is further characterised as having one or more other characteristic XRPD peaks selected from following (2Θ): 15.5 + 0.2, 17.8 ± 0.2, 18.6 + 0.2 and 24.2 ± 0.2.
There is also provided by the present invention, therefore, Form III characterised as having one or more characteristic XRPD peaks selected from following (2Θ): 6.3 ± 0.2, 12.6 ± 0.2, 19.0 ± 0.2, 20.8 ± 0.2 and 27.0 ± 0.2.
There is also provided by the present invention, therefore, Form IV characterised as having one or more characteristic XRPD peaks selected from following (2Θ): 9.5 ± 0.2, 12.3 ± 0.2, 16.7 ± 0.2, 19.1 ± 0.2, 19.8 ± 0.2. Form IV according to the present invention is further characterised as having one or more other characteristic XRPD peaks selected from following (2Θ): 18.3 ± 0.2, 18.4 ± 0.2, 20.2 ± 0.2, 22.2 ± 0.2 and 23.2 ± 0.2.
Further characterising data for Form IV according to the present invention, as obtained by X-ray single crystal analysis at temperature of 22°C (295K), is crystal structure data collected on Kappa CCD Bruker-Nonius FR591 d iff racto meter with CuKa radiation using rotating anode.
Crystal structure data at temperature of 22°C (295K):
Crystal system, space group: orthorhombic, P 2i 2i 2i
Unit cell dimensions: a = 6.48±0.01 A a = 90.0 ° b = 7.86+0.01 A β = 90.0 ° c = 18.62±0.01 A Y = 90.0 °
Volume: 948±2 A3
Z, Calculated density: 4, 1.12+0.02 g cm"3
Form IV can be still further characterised by a typical DSC thermogram as shown in Figure 4. 2007/003516
5
Form IV can be still further characterised by a typical TGA thermogram as shown in Figure 5.
Pregabalin is an anticonvulsant and is thus useful in the anti-seizure therapy for central nervous system disorders such as epilepsy, Huntington's chorea, cerebral ischemia, Parkinson's disease, tardive dyskinesia, and spasticity, and, possibly as an anti-depressant, anxiolytic, and antipsychotic activity.
The present invention further provides, therefore, a pharmaceutical composition comprising a therapeutically effective amount of Form I or of Form Il or of Form III or of Form IV or a mixture of any thereof according to the invention, together with a pharmaceutically acceptable carrier, diluent or excipients thereof.
Excipients are chosen according to the pharmaceutical form and the desired mode of administration.
As used herein, the term "therapeutically effective amount" means an amount of one of said polymorphic forms of pregabalin according to the invention, which is capable of preventing, ameliorating or eliminating a disease state for which administration of anticonvulsant is indicated.
By "pharmaceutically acceptable" it is meant that the carrier, diluent or excipient is compatible with pregabalin according to the invention, and not deleterious to a recipient thereof.
In the pharmaceutical compositions of the present invention for oral, sublingual, subcutaneous, intramuscular, intravenous, topical, intratracheal, intranasal, transdermal or rectal administration, Form I or Form Il or Form III or Form IV or a mixture of any thereof according to the present invention is administered to animals and humans in unit forms of administration, mixed with conventional pharmaceutical carriers, for the prophylaxis or treatment of the above disorders or diseases. The appropriate unit forms of administration include forms for oral administration, such as tablets, gelatin capsules, powders, granules and solutions or suspensions to be taken orally, forms for sublingual, buccal, intratracheal or intranasal administration, forms for subcutaneous, intramuscular 6 or intravenous administration and forms for rectal administration. For topical application, Form I or Form Il or Form 111 or Form IV or a mixture of any thereof according to the present invention can be used in creams, ointments or lotions.
To achieve the desired prophylactic or therapeutic effect, the dose of Form I or of Form Il or of Form III or of Form IV or a mixture of any thereof according to the present invention can vary between 0.01 and 50 mg per kg of body weight per day. Each unit dose can contain from 0.1 to 1000 mg, preferably 1 to 500 mg, of I or of Form Il or of Form III or of Form IV or a mixture of any thereof according to the present invention in combination with a pharmaceutical carrier. This unit dose can be administered 1 to 5 times a day so as to administer a daily dosage of 0.5 to 5000 mg, preferably 1 to 2500 mg.
When a solid composition in the form of tablets is prepared, Form I or Form Il or Form III or Form IV or a mixture of any thereof according to the present invention is mixed with a pharmaceutical vehicle such as gelatin, starch, lactose, magnesium stearate, talc, gum arabic or the like. The tablets can be coated with sucrose, a cellulose derivative or other appropriate substances, or else they can be treated so as to have a prolonged or delayed activity and so as to release a predetermined amount of active principle continuously.
A preparation in the form of gelatin capsules can be obtained by mixing Form I or Form Il or Form III or Form IV or a mixture of any thereof according to the present invention with a diluent and pouring the resulting mixture into soft or hard gelatin capsules.
A preparation in the form of a syrup or elixir or for administration in the form of drops can contain Form I or Form Il or Form III or Form IV or a mixture of any thereof according to the present invention typically in conjunction with a sweetener, which is preferably calorie-free, optionally antiseptics such as methylparaben and propylparaben, as well as a flavoring and an appropriate colour. Water-dispersible granules or powders can contain Form I or Form Il or Form III or Form IV or a mixture of any thereof according to the present invention mixed with dispersants or wetting agents, or suspending agents such as polyvinylpyrrolidone, as well as with sweeteners or taste correctors.
Rectal administration is effected using suppositories prepared with binders which melt at the rectal temperature, for example polyethylene glycols.
Parenteral administration is effected using aqueous suspensions, isotonic saline solutions or sterile and injectable solutions which contain pharmacologically compatible dispersants and/or wetting agents, for example propylene glycol or butylene glycol.
Form I or Form Il or Form III or Form IV or a mixture of any thereof according to the present invention can also be formulated as microcapsules, with one or more carriers or additives if appropriate.
There is also provided by the present invention Form I or Form Il or Form III or Form IV or a mixture of any thereof substantially as hereinbefore described for use in therapy.
The present invention further provides Form I or Form Il or Form III or Form IV or a mixture of any thereof substantially as hereinbefore described, for use in the manufacture of a medicament for the treatment of a disease state prevented, ameliorated or eliminated by the administration of anticonvulsant. More specifically, the present invention provides Form I or Form Il or Form III or Form IV or a mixture of any thereof substantially as hereinbefore described, for use in the manufacture of a medicament for anti-seizure therapy for central nervous system disorders such as epilepsy, Huntington's chorea, cerebral ischemia, Parkinson's disease, tardive dyskinesia, and spasticity, and, possibly as an anti-depressant, anxiolytic, and antipsychotic activity..
The present invention also provides a method of treating a disease state prevented, ameliorated or eliminated by the administration of anticonvulsant in a patient in need of such treatment, which method comprises administering to the patient a therapeutically effective amount of Form I or of Form Il or of Form III or of Form IV or a mixture of any thereof substantially as hereinbefore described. More specifically, the present invention provides a method of treating central nervous system disorders such as epilepsy, Huntington's chorea, cerebral ischemia, Parkinson's disease, tardive dyskinesia, and spasticity in a patient in need of such treatment, which method comprises administering to the patient a therapeutically effective amount of Form I or of Form Il or of Form III or of Form IV or a mixture of any thereof substantially as hereinbefore described.
The present invention can be further illustrated by the following Figures and non-limiting Examples.
Brief description of drawings Figure 1 shows a DSC pattern of Form I obtained by using MDSC TA instruments Q 1000 operating at heating rate of 10°C/min and in stream of nitrogen with flow of 50ml/min..
Figure 2 shows a TGA pattern of Form I obtained by using TGA 7 manufacturer Perkin Elmer, operating at heating rate of 10°C/min, and in stream of nitrogen with flow of 35 ml/min
Figure 3 shows an XRPD pattern of Form Il obtained by Philips X'Pert PRO diffractometer using CuKaI radiation
Figure 4 shows a DSC pattern of Form IV obtained by using MDSC TA instruments Q 1000 operating at heating rate of 10°C/min and in stream of nitrogen with flow of 50ml/min...
Figure 5 shows a TGA pattern of Form IV obtained by using TGA 7 manufacturer Perkin Elmer, operating at heating rate of 10°C/min, and in stream of nitrogen with flow of 35 ml/min. Examples
The following examples are for the purpose of illustration of the invention only and are not intended in any way to limit the scope of the present invention. It will thus be readily apparent to one skilled in the art that varying substitutions and modifications may be made to the invention disclosed herein without departing from the scope and spirit of the invention. Thus, it should be understood that although the present invention has been specifically disclosed by preferred embodiments and optional features, modification and variation of the concepts herein disclosed may be resorted to by those skilled in the art, and that such modifications and variations are considered to be falling within the scope of the invention.
Example 1
About 300 mg of pregabalin was dissolved in about 20 ml of 1-octanol and about 4 ml of water at about 900C. The solution was left to evaporate at about
900C. After about 15 minutes crystallization took place. The suspension was cooled to room temperature, and then filtered yielding pregabalin form I.
Example 2
About 10 mg of pregabalin was dissolved in about 4 ml of acetone and about 1 ml of water by heating. Solution was left to cool down to room temperature in an open flask. After solvents evaporated, crystals of pregabalin form Il were observed.
Example 3 About 10 mg of pregabalin was dissolved in about 4 ml of 1-octanol and about 1 ml of water by heating. The solution was left to cool down to room temperature. After about 24 hours crystals of pregabalin form III were observed.
Example 4 About 10 mg of pregabalin was dissolved in about 2 ml of methanol by heating. The solution was left to cool down to room temperature. After about 24 hours crystals of pregabalin form IV were observed. Example 5
About 10 mg of pregabalin was dissolved in about 5 ml of ethanol by heating.
Solution was left to cool down to room temperature. After about 24 hours crystals of pregabalin form IV were observed.
Example 6
About 10 mg of pregabalin was dissolved in about 3 ml of N, N- dimethylacetamide and about 1 ml of water by heating. The solution was left to cool down to room temperature. After about 24 hours single crystals of pregabalin form IV were observed.
Example 7
About 300 mg of pregabalin was dissolved in about 15 ml of acetone and about 7 ml of water at reflux conditions. The solution was slowly cooled yielding crystals of pregabalin form IV.

Claims

Claims:
1. A pregabalin polymorphic Form I characterised as having one or more characteristic XRPD peaks selected from following (2Θ): 11.6 ± 0.2, 13.3 ± 0.2, 16.5 ± 0.2, 20.0 ± 0.2, 23.4 ± 0.2 and 28.5 ± 0.2.
2. A pregabalin polymorphic Form I characterised by a typical DSC thermogram as shown in Figure 1.
3. A pregabalin polymorphic Form I characterised by a typical TGA thermogram as shown in Figure 2.
4. A pregabalin polymorphic Form Il characterised as having an XRPD pattern, or substantially the same XRPD pattern, as shown in Figure 3.
5. A pregabalin polymorphic Form Il characterised as having one or more characteristic XRPD peaks selected from following (2Θ): 5.7 ± 0.2, 11.3 ± 0.2, 17.0 ± 0.2 and 22.7 ± 0.2.
6. A pregabalin polymorphic Form Il as claimed in claim 5 having one or more other characteristic XRPD peaks selected from following (2Θ): 15.5 ±
0.2, 17.8 ± 0.2, 18.6 ± 0.2, 24.2 ± 0.2 and 28.5 ± 0.2.
7. A pregabalin polymorphic Form III characterised as having one or more characteristic XRPD peaks selected from following (2Θ): 6.3 ± 0.2, 12.6 ± 0.2, 19.0 ± 0.2, 20.8 ± 0.2, 27.0 ± 0.2.
8. A pregabalin polymorphic Form IV characterised as having one or more characteristic XRPD peaks selected from following (2Θ): 9.5 ± 0.2, 12.3 ± 0.2, 16.7 ± 0.2, 19.1 ± 0.2 and 19.8 ± 0.2
9. A pregabalin polymorphic Form IV as claimed in claim 8 having one or more other characteristic XRPD peaks selected from following (2Θ): 18.3 ± 0.2, 18.4 ± 0.2, 20.2 ± 0.2, 22.2 ± 0.2, 23.2 ± 0.2.
10. A pregabalin polymorphic Form IV characterised by a typical DSC thermogram as shown in Figure 4.
11. A pregabalin polymorphic Form IV characterised by a typical TGA thermogram as shown in Figure 5.
12. A pregabalin polymorphic Form IV having following crystal structure properties: a) Crystal system, space group: orthorhombic, P 2i 2i 2i b) Unit cell dimensions: a = 6.48±0.01 A a = 90.0 ° b = 7.86±0.01 A β = 90.0 ° c = 18.62±0.01 A Y = 90.0 ° c) Volume: 948±2 A3 d) Z. Calculated density: 4, 1.12±0.02 g cm"3
13. A pharmaceutical composition comprising a therapeutically effective dose of Form I or of Form Il or of Form III or of Form IV or a mixture of any thereof according to claims 1 to 12, together with a pharmaceutically acceptable carrier, diluent or excipient therefor.
14. Form I or Form Il or Form III or Form IV or a mixture of any thereof according to claims 1 to 12 for use in therapy.
15. Form I or Form Il or Form III or Form IV or a mixture of any thereof according to claims 1 to 12 for use in the manufacture of a medicament for the treatment of a disease state prevented, ameliorated or eliminated by the administration of anticonvulsant.
16. A method of treating a disease state prevented, ameliorated or eliminated by the administration of anticonvulsant in a patient in need of such treatment, which method comprises administering to the patient a therapeutically effective amount of Form I or of Form Il or of Form III or of Form IV or a mixture of any thereof according to any of claims 1 to 12.
PCT/GB2007/003516 2006-10-07 2007-09-18 New polymorphic forms of pregabalin WO2008040935A1 (en)

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US7586005B2 (en) 2005-09-19 2009-09-08 Teva Pharmaceutical Industries Ltd. Asymmetric synthesis of (S)-(+)-3-(aminomethyl)-5-methylhexanoic acid
US7619112B2 (en) 2005-05-10 2009-11-17 Teva Pharmaceutical Industries Ltd. Optical resolution of 3-carbamoylmethyl-5-methyl hexanoic acid

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CN1827590A (en) * 2006-04-14 2006-09-06 北京润德康医药技术有限公司 Novel pregabalin crystalline form, its preparing process and pharmaceutical compositions thereof
WO2006108151A1 (en) * 2005-04-06 2006-10-12 Teva Pharmaceutical Industries Ltd. Crystalline forms of pregabalin
US20060270871A1 (en) * 2005-05-30 2006-11-30 Khanduri Chandra H Polymorphic form i of pregabalin and processes for its preparation
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CN1634869A (en) * 2004-12-06 2005-07-06 北京阜康仁生物制药科技有限公司 Novel pregabalin crystalline form and its preparing process
WO2006108151A1 (en) * 2005-04-06 2006-10-12 Teva Pharmaceutical Industries Ltd. Crystalline forms of pregabalin
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US7619112B2 (en) 2005-05-10 2009-11-17 Teva Pharmaceutical Industries Ltd. Optical resolution of 3-carbamoylmethyl-5-methyl hexanoic acid
US7678938B2 (en) 2005-05-10 2010-03-16 Teva Pharmaceutical Industries Ltd. Optical resolution of 3-carbamoylmethyl-5-methyl hexanoic acid
US7586005B2 (en) 2005-09-19 2009-09-08 Teva Pharmaceutical Industries Ltd. Asymmetric synthesis of (S)-(+)-3-(aminomethyl)-5-methylhexanoic acid
US7851651B2 (en) 2005-09-19 2010-12-14 Teva Pharmaceutical Industries Ltd. Asymmetric synthesis of (S)-(+)-3-(aminomethyl)-5-methylhexanoic acid
US7923575B2 (en) 2005-09-19 2011-04-12 Teva Pharmaceutical Industries Limited Asymmetric synthesis of (S)-(+)-3-(aminomethyl)-5-methylhexanoic acid

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