Composition and method related to pyridinoyl-piperidine 5-ht1f agonist

Abstract

To provide a new pseudo-polymorph of the hemisuccinate of 2,4,6-trifluoro-N-[6-(1-methyl-piperidine-4-carbonyl)-pyridine-2-yl]-benzamide.SOLUTION: Provided is a pharmaceutical composition used for treating migraine in a mammal, containing a composition that contains (a) a dihydrate crystalline form (Form D) of the hemisuccinate of 2,4,6-trifluoro-N-[6-(1-methyl-piperidine-4-carbonyl)-pyridine-2-yl]-benzamide characterized by an X-ray diffraction containing a specific peak when using Cu-Kα radiation, (b) an anhydrous solid crystalline form (Form A) of the hemisuccinate of 2,4,6-trifluoro-N-[6-(1-methyl-piperidine-4-carbonyl)-pyridine-2-yl]-benzamide characterized by an X-ray diffraction containing a specific peak when using Cu-Kα radiation, and (c) a pharmaceutically acceptable carrier.SELECTED DRAWING: Figure 1A

Description

[Technical field]

[0001] The present invention relates to 5-HT 1F To activate receptors and to treat or prevent migraines 2,4,6-trifluoro-N-[6-(1-methyl-piperidine Certain hemisuccinate salts of (4-carbonyl)-pyridin-2-yl)-benzamide This invention relates to solvates and other pseudopolymorphic forms of the compound. [Background technology]

[0002] Migraine is a common and significantly disabling brain disorder that affects 10% of adults worldwide. More than 20% of people are affected (Stovner LI et al., Cephalalgia 2 007;27:193-210). The disease is characterized by nausea, vomiting, photophobia, and phonophobia ( Severe headache attacks lasting 1-3 days, accompanied by migraine without aura, and in one third of patients In some cases, migraine headaches are typically characterized by a neurological aura (Goadsby PJ et al., N Engl J Med2002;346:257-270). The pathogenesis of migraine is incompletely understood. Traditionally, vasodilation has been thought to cause headache in migraine. It was thought to be crucial in causing Wolff's Headache. and Other Head Pain.Ed Silberstein et al ., Oxford University Press, 2001). Triptan (Fer), a selective 5-HT1B / 1D receptor agonist with pain efficacy rari MD et al., Lancet2001:358;1668-1675) 5-HT 1BReceptor-mediated cranial vasoconstriction is a prerequisite for antimigraine efficacy. It was developed based on the assumption that Acad Sci 1990;600:587-598). As a result, triptans There is also a risk of coronary vasoconstriction (Maassen Van Den Brink A et al., Circulation1998;98:25-30), cardiovascular disease In addition, many patients taking triptans have Patients report chest symptoms that can mimic angina, causing anxiety and diagnostic confusion. (Welch KMA et al., Cephaloalgia 2000;2 0:687-95, Visser WH,et al.,Cephalalgia199 6;16:554-559). Therefore, novel migraine treatments without vasoconstrictor activity are promising. It is said that this is the case.

[0003] In recent decades, cranial vasodilation during migraine attacks has been reported (Schoonman G G et al.,Brain2008;131:192-200), trigeminovascular system It has become clear that this may just be a secondary phenomenon caused by activation (Goadsb y PJ et al.,N Engl J Med2002;346:257-270 ). Therefore, vasoconstriction may not be necessary to treat migraine headaches. Thus, neuroinhibition of the trigeminal pathway offers an attractive alternative nonvascular antimigraine mechanism. Indeed, there are neuroactive compounds that have no vasoconstrictor activity at clinically relevant concentrations. Selective 5-HT 1F Receptor agonist LY334370 demonstrates early clinical proof of concept Trials have shown it to be effective in treating episodic migraines (Goldstein DJ et al., Lancet 2001;358:1230-4). Unfortunately, Clinical development of LY334370 will support compound-specific safety studies of long-term exposure in animals. It had to be stopped due to concerns.

[0004] 2,4,6-Trifluoro-N-[6-(1-methyl-piperidin-4-yl)carbonyl

[0011] -pyridin-2-yl-benzamide (compound I) is a novel, selective and highly potent 5-HT 1F Receptor agonist, 2.21 nM human 5-HT 1F Receptor Ki , and 5-HT1 receptor subtypes rather than other 5-HT1 receptor subtypes. 1F 4 for receptors It has a 50-fold higher affinity (Nelson DL et al., Cephalosporin, ia2009:29;122). U.S. Patent No. 7,423,050 and U.S. Patent Publication No. No. 2008 / 0300407, which is a study of neurally mediated pre-migraine therapy without causing vasoconstriction. Compound I, and other selective pyridinoylpiperidine 5- HT 1F Agonists (i.e., neutrally active antimigraine agents (NAANAs)) are described. The experiments in the publications referenced above demonstrate a strong induction of c-Fos in the trigeminal nucleus caudalis. have demonstrated inhibition of dural plasma protein extravasation following electrical stimulation of the trigeminal ganglion and inhibition of endothelial cell death. At concentrations up to 0.1 mM, Compound I did not constrict rabbit saphenous veins and did not constrict human coronary arteries. This is a surrogate assay for vasoconstrictor susceptibility (Nelson DL et al. .,Cephalalgia2009:29;122).

[0005] The degree of crystallinity of drugs affects their solubility, dissolution rate, among other physical and mechanical properties. These properties then affect the drug's manufacturing and The identification of the crystalline form of the drug and the method of manufacturing the drug may affect its usefulness. There is a need in the chemical and therapeutic arts to provide 2,4,6-trifluoro-N -[6-(1-methyl-piperidine-4-carbonyl)-pyridin-2-yl]-benz A crystalline form of the hemisuccinate salt of the amide has been characterized and is designated Form A. ,697,876.

[0006] In addition to different solid crystalline forms, commonly referred to as polymorphs, drugs may also exist as solvates and clathrates. The term solvate refers to a compound that is a mixture of two or more compounds, each of which may exist in different pseudopolymorphic forms, such as The term "solvate" includes compounds formed by the association of one or more solvent molecules with a drug molecule. The term refers to stoichiometric or nonstoichiometric amounts of molecules bound by noncovalent intermolecular forces. Hydrates refer to water, e.g., hemihydrate, monohydrate, dihydrate, trihydrate, tetrahydrate, etc. The term inclusion compound refers to a compound that contains a guest molecule (e.g., a solvent or water) trapped inside. ) refers to a drug in the form of a crystal lattice that contains spaces (e.g., channels) with

[0007] Polymorphs and pseudopolymorphs are substances of the same composition that crystallize in different lattice arrangements, resulting in This occurs when different chemical structures, which are related to different thermodynamic properties and stabilities, are inherent to a particular polymorphic form. If more than one polymorphic substance can be produced, how can each polymorph be made into a pure form? In determining which polymorph is preferred, a number of properties of the polymorphs must be compared. The polymorphs must be compared and the preferred polymorph selected based on a number of physical property variables. Certain aspects such as ease of preparation, stability, etc. are deemed important. It is quite possible that in some circumstances one polymorphic form may be preferred. In other situations, different drugs may be required for more or less solubility and / or better pharmacokinetics. A particular crystalline form of a compound may be preferred over a particular crystalline form of another polymorphic form. These properties may differ from those of the original state, especially when the compound is produced on a commercial scale. significantly affect the physicochemical and pharmaceutical processing of the compound when it is prepared or used in There are times when this happens.

[0008] In particular, the identification of polymorphic or pseudopolymorphic forms of the active pharmaceutical ingredient ("API") in the dosage form. There are strict regulatory requirements for drugs intended for medical use that require extensive knowledge. The importance of recognizing and controlling solid morphological changes during synthesis is recognized in the art. For example, see the recent review by Newman and Wenslow (AAPS O Therefore, the regulatory requirements are met and the final Polymorphic and / or pseudopolymorphic forms in the dosage form to ensure dosage form quality and consistency There is a need for characterization and control of the morphology of APIs.

[0009] This application relates to 2,4,6-trifluoro-N-[6-(1-methyl-piperidine-4-carboxylate] Newly discovered hemisuccinate salt of (carboxy)-pyridin-2-yl)-benzamide Identifying and characterizing pseudopolymorphic forms and how to account for their presence in solid dosage forms This section explains how to control the Summary of the Invention

[0010] The present invention relates to compound I or lasmitidan hemisuccinic acid. 2,4,6-Trifluoro-N-[6-(1-methyl-piperidine) Pseudopolymorphism of the hemisuccinate salt of (4-carbonyl)-pyridin-2-yl)-benzamide The pseudopolymorphic forms of Compound I described herein are suitable for commercial scale pharmaceutical manufacture. The pseudopolymorphic form described herein is a 5-HT 1F Receiving It is useful for invigorating the body and for treating or preventing migraines.

[0011] In an embodiment, the present disclosure provides Compound I in the form of a solvate. In embodiments, the solvate is a hydrate. In embodiments, the hydrate is a dihydrate or a trihydrate. In an embodiment, the present disclosure provides a method for manufacturing a semiconductor device substantially similar to the one shown in FIG. The present invention provides a hydrate or dehydrate characterized by an X-ray powder diffraction (XRPD) pattern of

[0012] FIG. 1A shows the dihydrate form D, also called hydrate 1, using Cu-Kα radiation. In an embodiment, the XRPD pattern for Form D is: At least about 18.7, 26.5, 27.0, 27.5, and 27.8 degrees 2θ, ±0. In an embodiment, the XRPD pattern of Form D is shown in Table 2. In an embodiment, the present disclosure provides a method for determining the peak intensity at 100 Kelvin. Approximately a=25.08Å, b=10.08Å, c=20.84Å, α=90°, β=123. Form D is characterized by having unit cell parameters of 71 and γ angle=90°. do.

[0013] FIG. 1B shows the XRPD pattern of Form F, which is a trihydrate. The XRPD pattern of F contains the peaks shown in Table 4.

[0014] FIG. 1C shows the XRPD pattern of Form E, which is the dehydrated form D. , the XRPD pattern for form E using Cu-Kα radiation shows at least about 9. 2 degrees and 10.5 degrees 2θ±0.2 degrees. The XRPD pattern of contains the peaks shown in Table 3.

[0015] In embodiments, the present disclosure provides a dihydrate, Form D, a trihydrate, Form F, or Compound I is provided in the form of a dehydrated hydrate of Form D, designated Form E in the embodiment. In some embodiments, the present disclosure relates to a mixture of Form A and Form D, or a mixture of Form A and Form E. or a mixture of Form D and Form E, or a mixture of Form A, Form D and Form E. A composition is provided.

[0016] In embodiments, the present disclosure provides a broad endothermic onset at 53.1° C. (−158.2 J / g). Then, a broad exotherm of 92.1℃ (24.9J / g) started, followed by a rapid exotherm of 197.9℃ (-119.0J / g). The differential scanning calorimetry (DSC) thermogram has a sharp endothermic onset at 100° C. / g. In an embodiment providing compound I in the dihydrate form of Form D, Form D is , exhibiting a DSC thermogram substantially in accordance with FIG.

[0017] In embodiments, the present disclosure provides a broad endothermic onset at 71.2° C. (−198.4 J / g). and a shallow endothermic (two peaks) onset at 95.7°C (-6.4 J / g) and a rapid endothermic (two peaks) onset at 103.4°C (2 6.9 J / g) and a shallow exotherm (two peaks) at 197.8 °C (-114.4 J / g). The trihydrate form F is characterized by a DSC thermogram having a sharp endothermic onset and Compound I is provided. In an embodiment, the present disclosure provides a method for preparing a compound substantially in accordance with that shown in FIG. Compound I in the form of trihydrate form F, characterized by a DSC thermogram

[0018] In embodiments, the pseudopolymorphic forms of Compound I described herein may be characterized by thermogravimetric analysis (TGA The thermogravimetric analysis (TGA) is a method to identify the composition of a sample based on its characteristic thermogravimetric curve, also known as the thermogravimetric curve. The method is based on the continuous recording of the change in mass of a material sample as a function of the combination of

[0019] In an embodiment, the present disclosure provides a method for producing a 7.5% by weight 25-110° C. solubility-in-water emulsion substantially in accordance with FIG. The TGA shows a loss of 2.0 molar equivalents of water, with decomposition beginning at approximately 200°C. Compound I is provided in the form of dihydrate form D, which is characteristic of

[0020] In an embodiment, the present disclosure provides a method for producing a 11.4 weight percent 25-150° C. refrigerant substantially in accordance with FIG. %, reflecting 3.1 molar equivalents of water, with decomposition beginning at approximately 200° C. Compound I is provided in the form of the characterized trihydrate form F.

[0021] In embodiments, the present disclosure provides a method for the treatment of pulmonary circulation comprising administering to a subject a dose of about 18.7, 26.5, 27.0, 27.5, and 27 XRPD pattern using Cu-Kα radiation with peaks at 0.8 degrees 2θ, ±0.2 degrees The onset of the broad endotherm at 53.1°C (-158.2 J / g) was followed by a peak at 92.1°C (24.9 A broad endothermic onset at 197.9 °C (-119.0 J / g) and a sharp endothermic Compound I in the form of dihydrate form D, characterized by a DSC thermogram with a thermal onset provide.

[0022] In an embodiment, the present disclosure provides an X-ray diffraction pattern substantially similar to that shown in FIG. 1A. and a DSC thermogram substantially similar to that shown in FIG. Compound I in the form of product form D is provided.

[0023] In an embodiment, the present disclosure provides a method for producing a granulated product comprising the steps of: (1) a wet granulation method starting with Form A; Storage of A at 25°C and 96% relative humidity (RH); (3) Solvent / water mixtures at high water activity (4) storage of amorphous Compound I at 40° C. and 75% RH; (5) high Slurries of amorphous Compound I in solvent / water mixtures at low water activity, (6) in water at room temperature or above forming a slurry of amorphous Compound I; (7) forming a slurry of Form F in water at 37° C. (8) preparing a competitive slurry of Form F at 20° C., e.g., ethanol-water (50:1); 50(v / v)) Compound I is provided in the form of a dihydrate (Form D). Form A is an anhydrous solid crystalline form of Compound I. It is.

[0024] In an embodiment, the present disclosure provides a method for preparing a crystalline compound I by slurrying the compound in water at 5° C. or in water at 20°C or in ethanol:water (50:50) at 5°C. forming a competitive slurry starting with Form A seeded with Form F in Compound I in the form of a trihydrate (form F) thus prepared is provided.

[0025] According to embodiments described herein, 2,4,6-trifluoro-N-[6-(1-methylphenyl)- ethyl-piperidine-4-carbonyl)-pyridin-2-yl]-benzamide, and Compound I, the hemisuccinate salt, can be prepared by methods described in the art. For example, US 8,697,876 and US 7,423,050 is explained in.

[0026] The present disclosure relates to hydrated forms such as the dihydrate or trihydrate, or mixtures thereof. A pharmaceutical composition comprising Compound I in the form of a dehydrated hydrate containing the compound and a pharma- ceutical acceptable carrier. In an embodiment, the pharmaceutical composition comprises Form D, Form E, and In an embodiment, the pharmaceutical composition comprises one or more of Form A and Form D. mixtures of Form A and Form E, mixtures of Form D and Form E, and mixtures of Form A and Form D. and Form E.

[0027] In an embodiment, the pharmaceutical composition is substantially free of impurities. The drug composition has an affinity for about 98%, about 99%, or about 99.9% as determined by HPLC. In an embodiment, the pharmaceutical composition comprises Form D of Compound I having a chemical purity as determined by HPLC. Compounds having a chemical purity of about 98%, about 99%, or about 99.9%, as determined by Contains form F of substance I.

[0028] The present disclosure provides a method of treating migraine in a mammal in need of such treatment. The mammal is administered an effective amount of a pseudopolymorph of Compound I described herein or a mixture thereof. In an embodiment, the pseudopolymorph of Compound I is a compound as described herein. As described above, Forms D, E, and F of Compound I and mixtures thereof can be isolated individually. alone or in combination with Form A. Any of the methods described herein In an embodiment, the pseudopolymorph of Compound I is a pseudopolymorph of Compound I as described herein. Form D, Form E, and Form F, and one or more of Form D, Form E, and Form F Form A is selected from the above and mixtures thereof, including mixtures with Form A. [Brief description of the drawings]

[0029] [Figure 1A] X-ray powder diffraction patterns (XRPD) of various pseudopolymorphic forms of compound I (2,4,6-trifluoro-N-[6-(1-methyl-piperidine-4-carbonyl)-pyridin-2-yl]-benzamide hemisuccinate salt). (A) Form D (dihydrate). [Figure 1B] X-ray powder diffraction patterns (XRPD) of various pseudopolymorphic forms of compound I (2,4,6-trifluoro-N-[6-(1-methyl-piperidine-4-carbonyl)-pyridin-2-yl]-benzamide hemisuccinate salt). (B) Form F (trihydrate). [Figure 1C] X-ray powder diffraction patterns (XRPD) of various pseudopolymorphic forms of compound I (2,4,6-trifluoro-N-[6-(1-methyl-piperidine-4-carbonyl)-pyridin-2-yl]-benzamide hemisuccinate salt). (C) Form E (dehydrated form D). [Figure 1D] X-ray powder diffraction patterns (XRPD) of various pseudopolymorphic forms of compound I (2,4,6-trifluoro-N-[6-(1-methyl-piperidine-4-carbonyl)-pyridin-2-yl]-benzamide hemisuccinate salt). (D) Experimental and calculated single crystal XRPD patterns of form D. [Figure 1E]X-ray powder diffraction patterns (XRPD) of various pseudopolymorphic forms of compound I (2,4,6-trifluoro-N-[6-(1-methyl-piperidine-4-carbonyl)-pyridin-2-yl]-benzamide hemisuccinate salt). (E) Partial cross-sections (0-13° 2θ) of the XRPD diffraction patterns, form D (blue lines), form A (green), and form E (red). [Figure 1F] X-ray powder diffraction patterns (XRPD) of various pseudopolymorphic forms of compound I (2,4,6-trifluoro-N-[6-(1-methyl-piperidine-4-carbonyl)-pyridin-2-yl]-benzamide hemisuccinate salt). (F) Partial cross-sections (13-19.5° 2θ) of the XRPD diffraction patterns of form D (blue lines), form A (green), and form E (red). [Figure 1G] X-ray powder diffraction patterns (XRPD) of various pseudopolymorphic forms of compound I (2,4,6-trifluoro-N-[6-(1-methyl-piperidine-4-carbonyl)-pyridin-2-yl]-benzamide hemisuccinate salt). (G) Partial cross-sections (18.5-26° 2θ) of the XRPD diffraction patterns of form D (blue lines), form A (green), and form E (red). [Diagram 2] DSC thermogram and TGA analysis of Form D. Overlay of DSC (blue line, heat flow (W / g), lower trace and inset) and TGA (green, weight (%) scale, upper trace) results for Form D. [Diagram 3] DSC thermogram and TGA analysis of Form F. Overlay of DSC (blue line, heat flow (W / g), upper trace) and TGA (green, weight (%) scale, lower trace) results for Form F. [Figure 4A] (A) HPLC trace of Form D having a chemical purity of 99.93%. [Figure 4B] (B) HPLC trace of form F showing chemical purity of 99.95%. [Diagram 5] Solution-state 1H-NMR spectra of dissolved Form D or Form F of Compound I [Figure 6]DVS isotherms for Form D showing three adsorption / desorption cycles, all superimposable. [Figure 7] DVS isotherm for form F showing three cycles of adsorption / desorption, where cycle 1 adsorption and desorption lines are at the top (red and blue) and are essentially superimposable, cycle 2 desorption line is the second line from the top (pink) adsorption line (green) plotted from 0-70% RH, and cycle 3 adsorption (turquoise) plotted from 0-40% RH. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0030] Serotonin-1F (5-HT 1F ) receptors and to treat migraines Pyridinoylpiperidine compounds useful for the treatment or prevention of osteoarthritis are described, for example, in US Pat. 0 and US2010 / 0256187. Such compounds include 2, 4,6-Trifluoro-N-[6-(1-methyl-piperidine-4-carbonyl)-pyridine and the hemisuccinate salt of [diphenyl-2-yl]-benzamide ("Compound I"), which is It has the structural formula shown below and is also known as rasmitidan hemisuccinate. be. [ka]

[0031] Certain polymorphic forms of Compound I are also described in US 8,697,876. One of the forms described is a polymorph designated Form A. Form A is a polymorph of Compound I. In accordance with the embodiments described herein, 2,4,6-trifluoroacetamide is an anhydrous solid crystalline form. r-N-[6-(1-methyl-piperidine-4-carbonyl)-pyridin-2-yl]- Benzamide, its hemi-succinate salt (Compound I), and anhydrous solid crystalline forms of Compound I has been described in the art, for example, as described in the '876 patent. The '876 patent names Form B and Form C. Two additional XRPD patterns are described. Further characterization of their morphology is For ease of reference, this disclosure is incorporated herein by reference in its entirety. Thus, the novel pseudopolymorphic forms of Compound I described herein inherit the same molecular structure. are referred to as Form D, Form E, and Form F. Form D is also known as the monohydrate or dihydrate. Form E is also called a dehydrated hydrate of Form D, and is a partially or completely dehydrated form of Form D. Form F may exist as a dehydrated hydrate. Form F is also called a trihydrate. The structure of was determined based on weight loss from crystallization studies.

[0032] Prior to this disclosure, it was not known that Compound I exists in the different pseudopolymorphic forms described herein. These pseudopolymorphic forms have not been known to be capable of being used in commercial scale pharmaceuticals. It was discovered by chance during the process of manufacturing a product. Regulatory authorities overseeing the approval and use of pharmaceuticals must determine the definitive existence of polymorphic forms of active ingredients in solid pharmaceutical dosage forms. Given that these new polymorphic forms require extensive knowledge, characterization, and control, There is a need in the art for crystallization and characterization of Compound I.

[0033] In the present invention, 2,4,6-trifluoro-N-[6-(1-methyl-piperidine-4 Polymorphic forms of [-carbonyl]-pyridin-2-yl-benzamide hic form), polymorph, polymorph form, pseudopolymorph, The term "crystalline form, physical form or polymorph" refers to a crystal form, physical form or polymorphism, determined by X-ray powder diffraction pattern (XRPD) analysis. By analytical methods such as differential scanning calorimetry (DSC), thermogravimetric analysis (TGA) and Can be characterized by gravimetric vapor sorption (GVS) or isotropic vapor sorption (DVS) Refers to a crystalline modification of this compound.

[0034] As used herein, the term "hydrate" refers to a compound that is bound by non-covalent intermolecular forces. means a compound of the present invention or a salt thereof further comprising a stoichiometric or non-stoichiometric amount of water. A hydrate is a substance that contains one or more water molecules and one molecule of water that retains its molecular state as H2O. and such combination may form one or more hydrates. As used herein, a hydrate of Compound I can be used in the deprotection process described herein. It is considered a "pseudopolymorph" that includes hydrates.

[0035] The pseudopolymorphs described herein may be characterized by any methodology known in the art. For example, pseudopolymorphism can be identified by X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), and SC), thermogravimetric analysis (TGA), microscopy, and spectroscopy (e.g., nuclear magnetic resonance (NM) R)).

[0036] In an embodiment, the pseudopolymorph is characterized by XRPD. The intensity of the contrast can vary depending on the sample preparation technique, sample mounting procedure, and particular instrument employed. Moreover, instrument variation and other factors can affect 2-theta values. Therefore, XRPD peak assignments are subject to a margin of error of approximately 0.1, 0.2, 0. For example, in some embodiments, the present invention The 2-theta values ​​of the embodiments described herein may vary by approximately plus or minus 0.4 degrees. In embodiments, the 2-theta values ​​of the embodiments described herein vary by about plus or minus 0.2 degrees. In yet other embodiments, the 2-θ values ​​of the embodiments described herein may be The pseudopolymorphs described herein may vary in magnitude by about minus 0.1 degrees. This was confirmed by comparing the X-ray powder diffraction pattern of the composition with that of the pure polymorph. Pharmaceutical compositions containing the specific pseudopolymorphs described herein can be identified as pure. exhibit a non-identical X-ray powder diffraction pattern compared to the X-ray powder diffraction pattern of the corresponding polymorph. It will be recognized that there is.

[0037] The pseudopolymorphs described herein also have characteristic Differential Calorimeter Scans (DS Scans) as shown in the Figures. C) The DSC trace can also be used to identify the temperature. It is known that the rate of change in temperature will depend on the sample preparation technique and the particular instrument employed. Therefore, the values ​​reported here for the DSC thermograms are The value can vary by about minus 4, 6, 8 or 10 degrees Celsius. For example, the value can vary by plus or minus 4, 6, 8 or 10 degrees Celsius. It can vary by about minus 6 degrees Celsius.

[0038] The pseudopolymorphic forms of the present invention also exhibit thermal behavior that differs from that of the amorphous material or other polymorphic forms. Thermal behavior is used to distinguish some polymorphs from others. This can be measured in the laboratory by thermogravimetric analysis (TGA), which may be used in a laboratory setting. In some cases, pseudopolymorphs can be characterized by thermogravimetric analysis.

[0039] The pseudopolymorphs according to the present invention can be analyzed by gravimetric vapor sorption, which measures the rate and amount of solvent absorption by a sample. In one embodiment, the pseudopolymorphs can also be identified by gravimetric vapor absorption spectroscopy (GVS). It can be characterized by the analysis of the

[0040] polymorphism The crystallization solvent plays a key role in determining which polymorph or pseudopolymorph of Compound I will form. For example, solvents with low water activity, e.g., ethanol, give mainly Form A. Water content is also important, as different polymorphic forms have different levels of hydration. In the mixture of water and a water-miscible solvent, the amount of water is about 6.1% by volume to about 95% by volume, preferably More preferably, the amount of the mixture is about 10% by volume to about 20% by volume, more preferably about 5% by volume to about 10% by volume, and most preferably about 10% by volume to about 20% by volume. or about 5% to about 1% water. Forms D and F of Compound I are hydrated. Therefore, Compound I exists to crystallize as any of these forms. In addition, there is a minimum threshold of water that must be cooled and the isolation temperature and amount of water. As will be described in more detail below, this will determine which polymorphic forms and / or hydrates are formed. can play a role in determining

[0041] Starting with either Form A or the amorphous form of Compound I, the compound is dissolved in water alone or in water / water. The addition of solvent mixtures resulted in the conversion of form A or the amorphous form to novel pseudopolymorphic forms D, E, or F. Form A is a non-hydrogen-soluble form of water at any temperature. In the presence (up to 10% water by volume; water activity of approximately 0.6) or at low water activity, e.g. At higher water activities, the temperature and water The molar content is crucial.

[0042] The conversion of form A to form D can occur when water is absorbed, for example, through high humidity conditions or high water activity. Form D occurs as water is introduced into a solvent-water mixture with a medium water activity. and is the most stable form at higher temperatures (i.e., room temperature to approximately 40°C).

[0043] In an embodiment, the present disclosure provides Compound I in the form of dihydrate form D. Compound I Surface X-ray diffraction (SXRD) analysis of the single crystals showed that the single crystals consisted of one molecule of compound I, two molecules of It is shown to contain water and half a molecule of succinate. The pattern is consistent with the XRPD for Form D, or hydrate 1, shown in FIG. 1D. Therefore, we confirm that Form D is the dihydrate of Compound I. Experimental patterns from bulk samples The reversal (RT) is in red (top trace) and is calculated from the single crystal X-ray structure (100 K). The resulting pattern is shown in black (bottom trace). The slight differences in peak positions are due to This is due to changes in the lattice due to temperature and preferred orientation.

[0044] In embodiments, the present disclosure comprises Form D or a mixture of Form D and Form A. A composition is provided.

[0045] In an embodiment, the present disclosure provides Compound I as Form E (dehydrated Form D). Form E is obtained by heating Form D of Compound I to approximately 60° C., with conversion starting at approximately 40° C. If heating continues beyond about 70-75°C, Form E converts to Form A, which is an anhydrous form. Therefore, Form E is considered a metastable form. If Form E is cooled to below about 35° C. after its formation, Form E can be In embodiments, the present disclosure relates to Form E, or a mixture of Form E and Form A. The present invention provides a composition comprising a mixture of Forms E and D, or a mixture of Forms E and D.

[0046] Form F generally thrives at lower temperatures (e.g., approximately 5°C to 20°C) and very high moisture content. It is the most stable form in activity. However, the composition of the starting mixture also has an effect. Form F is the stable form in pure water at 5°C, regardless of whether it is present in the starting mixture. However, in water at 20°C, when a mixture of Form D and Form F is used, Form F is more However, when a mixture of Form A and Form D is used, Form D is the kinetically more stable form.

[0047] Thus, Form F can be obtained by slurrying amorphous Compound I or Form A in water alone at 5° C. or by dissolving amorphous Compound I in t-butanol:water (50:50 (v / v) ) mixture by lyophilization. Form F can be produced by lyophilizing Form A or If Form F species are present in the starting mixture with either Form D, It can also be produced in a 50:50 (v / v) mixture at 5°C, but a mixture of Forms A and D may result. When the mixture is used, Form D is the stable form at 5°C.

[0048] In water at 20°C, when a mixture of Form D and Form F is used as the starting material, Form F is , which is the more stable form. In water at 20°C, when using a mixture of Form A and Form D, , Form D is a stable form.

[0049] These results show that form F is the most stable form in pure water at 5°C, but at 20°C, form F is the most stable form. This shows that a species of form F must be present to allow the transformation to the stable form F. Similarly, at 5°C in 50:50 ethanol:water (v / v), form F species was found in the starting mixture. When present in the pharmaceutical composition, Form F is the stable form, but when a mixture of Forms A and D is used, Form D is kinetically stable at 5°C. Form F at low temperatures and high water activity Based on the observed spontaneous crystallization of Form F, it is believed that Form F was initially Form D or Form A. It may be formed in formulations of compound I in a mixture with form D. In an embodiment, the present disclosure relates to Form F, or a mixture of Form D and Form F, or Form A and Form A composition comprising a mixture of Form D and Form F is provided.

[0050] Drying Form F in a vacuum oven at room temperature results in the conversion to amorphous Compound I. Form F undergoes conversion (a) upon heating and (b) upon exposure to 40°C / 20% relative humidity. or (c) upon storage in a desiccator at room temperature with very low humidity, it transforms to form A. In addition, cycling humidity, such as in gravimetric vapor sorption experiments, can convert Form F to This results in conversion to form D.

[0051] In embodiments, the present disclosure provides a method for granulating Form A of Compound I using purified water as a granulation medium. Compound I in the form of dihydrate form D is produced by subjecting the compound I to a granulation process according to the formula In embodiments, the wet granulation process includes a high shear mixing step (e.g., 1 L and 4 L bowls). (such as the Diosna® P1 / 6 equipped with a suction cup) followed by gentle and grinding (e.g., grinding the granules in a device such as Comil®). In embodiments, the process comprises subjecting the granules to a process (e.g., Strea Pro® flow purifier). In an embodiment, the granules further comprise a step of drying the granules (using a moving bed dryer). Dried to a moisture content of less than w / w (e.g., as measured by moisture balance) can be.

[0052] In an embodiment, one or more excipients may be added during the granulation process according to knowledge in the pharmaceutical art. In one embodiment, the additive is added either before granulation or after the granules are dried. The above excipients may be filler materials (e.g., lactose, sucrose, glucose, mannitol, etc.) Contains calcium phosphate, calcium carbonate, and microcrystalline cellulose. cellulose), liquid binders (e.g., gelatin, polyvinylpyrrolidone, hydroxypropyl cellulose derivatives such as propyl methylcellulose, polyethylene glycol, sucrose and starch), dry binders (e.g., cellulose, methylcellulose, polyvinyl chloride, pyrrolidone, and polyethylene glycol), disintegrants (e.g., starch, cellulose cross-linked polyvinylpyrrolidone, sodium starch glycolate, and croscarmellose Carboxymethylcellulose, including cross-linked sodium carboxymethylcellulose, such as sodium carboxymethylcellulose sodium dimethylcellulose), a wetting agent (e.g., sodium lauryl sulfate), and Lubricants (e.g., magnesium stearate, stearic acid, polyethylene glycol, and sodium lauryl sulfate).

[0053] Pharmaceutical Compositions The present disclosure relates to the compound, either alone or in admixture with Form A as described above. one or more of forms D, E, or F of I and a pharma- ceutically acceptable carrier or excipient. The term "pharmaceutical acceptable" means a pharmaceutical composition comprising a compound selected from the group consisting of phenylalanine, ... Within the scope of scientific judgment, the risk of excessive toxicity, irritation, or allergy is considered to be commensurate with a reasonable benefit / risk ratio. Used in contact with human and animal tissues without reactions or other problems or complications "Drugs that are suitable for administering to a patient in need of treatment" refers to compounds, materials, compositions, carriers, and / or dosage forms that are suitable for administering to a patient in need of treatment.

[0054] A "pharmaceutical acceptable excipient" is generally a substance that is safe, non-toxic, and biologically and otherwise compatible with the intended use. and It also includes excipients that are acceptable for veterinary as well as human pharmaceutical use. Examples of possible excipients are provided below.

[0055] The pharmaceutical compositions can be provided in bulk or in dosage unit form. It is particularly advantageous to formulate the pharmaceutical compositions in dosage unit form for purposes of uniformity of dosage. The term "dosage unit form" as used herein refers to a dosage unit that is refers to physically discrete units suitable as unit dosages for a given subject, each unit being , a predetermined amount of active agent calculated to produce the desired therapeutic effect together with the required pharmaceutical carrier. The details of the dosage unit forms of the present invention are based on the unique characteristics of the active compound. and is determined by and directly dependent on the specific therapeutic effect to be achieved. Unit forms include ampoules, vials, suppositories, dragees, tablets, capsules, and intravenous bags. , or a single pump of an aerosol inhaler.

[0056] In embodiments, the chemical components of the pharmaceutical composition are substantially free of chemical impurities. The term "chemical purity" refers to the amount of a particular compound in a sample of the compound, usually given as a percentage by weight. Unless otherwise stated, percentages stated throughout this specification are weight / weight. In an embodiment, the pharmaceutical composition is a pharmaceutical composition comprising a pharmaceutical composition having a glycerol content as determined by HPLC. In some embodiments, the compound is a pseudopolymorph of Compound I having a chemical purity of greater than 98.0%. In embodiments, the pseudo-polymorph has a chemical purity of 99.0%. 5% chemical purity. In an embodiment, the pseudopolymorph has a chemical purity of 99.9%. .

[0057] The term "suitable solvent" refers to a solvent that sufficiently solubilizes the reactants to effect the desired reaction therein. Any solvent or mixture of solvents that is inert to the ongoing reaction, providing a medium through which the Point.

[0058] The term "suspension" refers to non-volatile organic compounds dispersed (suspended) in a liquid or dispersion medium, usually a solvent. "Slurry" refers to a two-phase system consisting of finely divided solids in crystalline or crystal form, or a mixture thereof. The term "liquid" refers to a quantity of powder mixed with a liquid in which the solid is slightly soluble. This refers to the suspension that is formed when the material is only slightly dissolved (or not soluble). "Conducting" refers to creating a slurry.

[0059] The term "amorphous" as used herein refers to a material that is made up of regularly repeating molecules or This means that there is essentially no external surface configuration.

[0060] Peak heights in powder X-ray diffraction patterns can vary and are influenced by temperature in the analytical wells, This will depend on variables such as crystal size, crystal habit, sample preparation, or sample height. It is intended to be understood.

[0061] It is also understood that peak locations may differ when measuring with different radiation sources. It is intended to

[0062] The type of formulation used to administer the polymorph employed in the methods of the present invention will depend on the route of administration and The type of pharmacokinetic profile desired may be determined by the dosage and patient condition.

[0063] Formulations suitable for oral, sublingual, nasal or injectable administration are widely known in the pharmaceutical art. The pharmaceutical composition is prepared in a known manner and contains at least one active compound. 'S PHARMACEUTICAL SCIENCES,(16th ed.1980 ) for more information.

[0064] In general, the present disclosure provides at least one compound that is a pseudopolymorph of Compound I as described herein. The formulation or pharmaceutical composition is provided containing the active ingredient. The formulation and pharmaceutical composition may further comprise an additional active pharmaceutical ingredient. It may further comprise an active pharmaceutical ingredient (API). A formulation or pharmaceutical composition typically comprises an excipient. containing, diluted with excipients, or in the form of a capsule, sachet, paper or other container When the excipient serves as a diluent, it is encapsulated within such a carrier, which may be in the form of a diluent. An excipient is a solid, semi-solid, or liquid that acts as a vehicle, carrier, or medium for an active ingredient. The formulation may be in the form of a tablet, pill, powder, lozenge, or liquid. tablets, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols formulations (as solids or in a liquid medium), e.g. Ointments, soft and hard gelatin capsules, gels, suppositories, sterile injectable solutions, and The pharmaceutical composition may be in the form of a sterile packaged powder.

[0065] In preparing the formulation, the active ingredient is milled to provide an appropriate particle size before being combined with other ingredients. If the active ingredient is substantially insoluble, it may be necessary to provide If the active ingredient is substantially water soluble, the particle size is usually Milling to provide a substantially uniform distribution in the formulation, e.g., by milling through about 40 mesh. In one embodiment of the present invention, the particle size range is about 0.1 μm to about 100 μm. be.

[0066] Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, and the like. titol, mannitol, starch, gum arabic, calcium phosphate, alginate, Lagacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, The formulation contains cellulose, water, syrup, and methylcellulose. , sucrose, glucose, mannitol, sorbitol, calcium phosphate, calcium carbonate fillers such as cellulose (including microcrystalline cellulose); talc, stearyl alcohol, and cellulose acetate; Lubricating agents such as magnesium phosphate, mineral oil; wetting agents; emulsifying and suspending agents; gelatin, polysaccharides, etc. Vinylpyrrolidone, cellulose, methylcellulose, cellulose derivatives (e.g., hydroxy dimethyl cellulose), polyethylene glycol, sucrose, starch, and and polyethylene glycol; starch, cellulose , cross-linked polyvinylpyrrolidone, sodium starch glycolate, and carboxymethylcellulose. Sodium cellulose (cross-linked carboxymethylcellulose such as croscarmellose sodium) Disintegrants such as sodium ethylcellulose; methylhydroxybenzoates and It may also contain preservatives such as propylhydroxybenzoate; sweeteners; and flavoring agents. .

[0067] The compounds of the invention can be administered to patients by employing procedures known in the art. They can be formulated to provide quick, sustained, or delayed release of the active ingredient after administration. This can be done.

[0068] The following formulation examples are illustrative only and are not intended to limit the scope of the present invention. The term "active ingredient" refers to the pseudopolymorphs described herein.

[0069] Administering the active ingredient directly without any formulation in the methods described herein Although it is possible to use a pharmaceutical composition, the active ingredient is usually mixed with at least one pharma- ceutical acceptable excipient. The formulation is administered orally, bucally, or intramuscularly. By various routes including enteral, intranasal, intradermal, transdermal, subcutaneous, intravenous, intramuscular, and intranasal. The formulations employed in the methods described herein can be administered by injection. It is effective as both a dietary and oral composition.

[0070] For transdermal administration, a transdermal delivery device ("patch") is often required. Such transdermal patches provide continuous or discontinuous infusion of the polymorph of the present invention in controlled amounts. The construction and use of transdermal patches for the delivery of pharmaceutical agents is It is well known in the art. See, e.g., U.S. Pat. No. 5,023,252. Such patches may provide continuous, pulsatile, or on-demand delivery of pharmaceutical agents. can be built for.

[0071] It is often desirable to introduce a pharmaceutical composition into the brain, either directly or indirectly. Direct techniques usually involve the use of the host's ventricular system to bypass the blood-brain barrier. This involves the placement of a drug delivery catheter into a specific anatomical area of ​​the body. One such implantable delivery system used for transport of a child is described in detail in US Pat. No. 5,011,472, incorporated herein by reference. Drug delivery is enhanced by intra-arterial infusion of hypertonic solutions, which can transiently open the blood-brain barrier. This may be done.

[0072] In embodiments, formulations adapted for buccal and / or sublingual administration, or nasal administration. In accordance with another embodiment, there is provided a pharmaceutical formulation comprising at least one active ingredient as described above in a gastric A way to avoid gastric complications such as first-pass metabolism through the liver and / or the This route of administration provides for the administration of active ingredients in a short absorption time and a longer therapeutic benefit. It may also provide a faster start.

[0073] In embodiments, the present disclosure provides a maximum of 100 mg / dose administered once, twice, or three times daily. Contains an amount of active ingredient in the range of up to 500 mg and a pharma- ceutically acceptable diluent or carrier. The present invention provides a pharmaceutical composition.

[0074] In embodiments, the present disclosure provides up to 5 per dose administered once, twice or three times daily. 00mg range of active ingredient as described herein and a pharma- ceutical acceptable diluent or and a carrier. In an embodiment, the present invention provides a pharmaceutical composition for oral or rectal administration. The disclosure provides pharmaceutical compositions comprising the active ingredients in amounts described herein, the amounts being per dose. In embodiments, the present disclosure provides a method for administering a therapeutically effective amount of a medicament in an amount described herein. A pharmaceutical composition is provided comprising an active ingredient, the amount of which is between 50 mg and 400 mg per dose. In one embodiment, the present disclosure provides a pharmaceutical composition comprising an active ingredient in an amount as described herein, The amount is 50 mg per dose. In embodiments, the present disclosure provides and the amount is 100 mg per dose. In accordance with the present disclosure, there is provided a pharmaceutical composition comprising an active ingredient in an amount as described herein, the amount being 1 In embodiments, the present disclosure provides a method for administering active ingredients in the amounts described herein. A pharmaceutical composition is provided containing the active ingredient in an amount of 400 mg per dose.

[0075] In embodiments, the present disclosure provides pharmaceutical compositions comprising the active ingredients described herein. In embodiments, the present disclosure provides a method for administering a pharmaceutical composition comprising administering an amount of active ingredient as described herein. and administration is rectal.

[0076] In embodiments, the present disclosure provides up to 100 mg / dose administered once, twice, or three times daily. An amount ranging from about 200 mg of the active ingredient described herein and a pharma- ceutical acceptable diluent. or a carrier, buccal, sublingual, nasal / intranasal, transdermal, subcutaneous, injectable, intravenous or intramuscular A pharmaceutical composition for internal administration is provided.

[0077] In embodiments, the present disclosure provides pharmaceutical compositions comprising the active ingredients described herein. In an embodiment, the present invention relates to a method for treating a pulmonary artery disease, the amount being 2 to 100 mg per dose. For pharmaceutical compositions containing the indicated amounts of active ingredient, the amounts are about 10, 15, 25, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 250, 260, 270, 2 30, 45, 50, 60, 75, 90, or 100 mg.

[0078] In embodiments, the present disclosure provides pharmaceutical compositions in which administration is buccal. In an embodiment, the present disclosure provides a pharmaceutical composition for administration sublingually. In an embodiment, the present disclosure provides a pharmaceutical composition, the administration of which is intranasal or intranasal. In an embodiment, the present disclosure provides a pharmaceutical composition in which administration is subcutaneous. In an embodiment, the present disclosure provides a pharmaceutical composition for administration by injection. In embodiments, the present disclosure provides pharmaceutical compositions, wherein administration is intravenous. In some embodiments, the present disclosure provides pharmaceutical compositions, wherein the administration is intramuscular.

[0079] In embodiments, the present disclosure provides that the doses of active ingredients described herein are administered once daily. In embodiments, the present disclosure provides pharmaceutical compositions comprising the effective doses described herein. In an embodiment, the present disclosure provides a pharmaceutical composition in which the ingredients are administered twice daily. A pharmaceutical composition is provided in which the active ingredient is administered three times a day in the dosages described herein.

[0080] How to use The present disclosure provides a method of treating migraine in a mammal in need of such treatment. In a mammal, an effective amount of a pseudopolymorph of Compound I and mixtures thereof, as described herein, is administered to the mammal. In an embodiment, the pseudopolymorph of Compound I is As described herein, Forms D, E, and F of Compound I, as well as their alone or in combination with Form A. In any of the embodiments of the present invention, the pseudopolymorph of Compound I is as described herein: Form D, Form E, and Form F of Compound I, including mixtures of one or more of Forms D, E, and F. and Form F, and mixtures thereof. In an embodiment, the mammal is a human. be.

[0081] In embodiments, the present disclosure provides a method for treating a rheumatoid arthritis associated with decreased neurotransmission of serotonin in a mammal. Effective amounts of the compounds described herein, including in admixture with Form A, for treating various disorders. By administering pseudopolymorphs of Compound I and their mixtures, vasoconstrictor activity is avoided. While 5-HT 1F Methods for increasing receptor activation are also provided. These include migraine, generalized pain, trigeminal neuralgia, toothache or temporomandibular joint dysfunction pain, anxiety, Generalized anxiety disorder, panic disorder, depression, sleep disorder, chronic fatigue syndrome, premenstrual syndrome or Late luteal phase syndrome, post-traumatic syndrome, memory loss, dementia including age-related dementia, social phobia, Autism, Attention Deficit Hyperactivity Disorder, Disruptive Behavior Disorder, Impulse Control Disorder, Borderline Personality Disorder , obsessive-compulsive disorder, premature ejaculation, erectile dysfunction, overeating, anorexia nervosa, alcoholism, tobacco The pseudopolymorphs described herein are useful for the prophylactic treatment of migraine headaches. It is also useful as a

[0082] Established and accepted classification of disorders that can be treated with serotonin agonists Thus, when known, their classification can be found in various sources. For example, Currently, Diagnostic and Statistical Manual of Mental Disorders (DSM-IV (trademark)) (1994, America a Psychiatric Association,Washington,D. The fourth edition of the American College of Cardiology (Academic Press) provides diagnostic tools to identify many of the disorders described herein. In addition, the International Classification of Diseases, 10th Revision (ICD-10) provides a definition of the disorders described herein. The DSM-IV and ICD-14 provide classifications for many of the types of harm that can occur. Alternative nomenclature for the disorders described herein, including those described in 10; that there is a nomenclature and classification system, and that terminology and classification systems are in tune with the progress of medical science; You will realize that you evolve along the way.

[0083] 5-HT 1F Nitric oxide, due to stimulation of the trigeminal neuralgia in general or in particular, for the activation of receptors For the inhibition of extravasation of neuronal peptides and / or for the treatment of any of the above-mentioned disorders. Forms D, E, and F of Compound I as described herein for the treatment of any of the above conditions. Use of Selected Pseudopolymorphs of Compound I and Mixtures Thereof, Including Mixtures with Form A are all embodiments of the present invention.

[0084] The term "effective amount" refers to 5-HT 1F Able to activate receptors and / or The pseudomonas described herein can inhibit neuronal protein extravasation. It means the amount of polymorphism.

[0085] As used herein, "treating" or "treatment and treatment" refers to a condition, disease, Any effect that results in the improvement of a disorder, such as reducing, mitigating, modulating, or eliminating "Treating" or "treatment and management" of a disease condition refers to administering to a mammal, particularly a human, means to treat a medical condition in a medical facility, including (a) to inhibit an existing medical condition, i.e., to prevent its onset or (c) to arrest the clinical symptoms, i.e., This includes causing regression of the disease.

[0086] As used herein, "preventing" refers to preventing or preventing an individual from being exposed to a condition. may be susceptible to illness but have not yet experienced or shown symptoms of the condition. Inducing clinical symptoms of a condition in a subject without causing the onset of the disease, i.e. This means inhibiting the onset of the disease. EXAMPLES

[0087] The following examples are illustrative and should not be construed as limiting the scope of the invention in any way. You shouldn't.

[0088] Example 1: Preparation of Form D (Hydrate 1) Form D can be prepared, for example, by (1) wet granulation starting with Form A; (2) at 25° C. and 96% phase (3) Storage of Form A at High Humidity (RH); and (4) Reconstitution from Solvent / Water Mixtures with High Water Activity. (4) storage of amorphous Compound I at 40°C and 75% RH; (5) storage of amorphous Compound I at high water activity Slurry of amorphous compound I in solvent / water mixtures with (6) Slurry of amorphous compound I in water above room temperature (7) forming a slurry of Form F in water at 37° C. (8) Form F, e.g., a competitive slurry of ethanol-water (50:50 (v / v)) for 20 The compound can be prepared by any one of the above methods, including forming the compound at 30° C. Cut.

[0089] In a specific example, hydrate 1 (form D) is granulated using a Diosna P1 / 6 high shear granulator. It was produced through a wet granulation process using approximately 40-90% (w / v) in a 4 L bowl. 200 g of Compound I Form A was mixed with water at 100° C. The initial dry mix of the formulation prior to fluid addition was , maintained as a steady state factor (2 min, impeller speed with associated trial, chopper off) The impeller speed was 400-900 rpm, which corresponds to a tip speed of 4.6-10.3 m / s. The Roto P10 was used with a spray rate of 20 to 60 g kg / min. In production, the center of this tip speed range is the tip speed for the Roto P10 (7. When manufactured with PMA65, the corresponding tip speed is 9.8 m / s. The kneading time was 0 to 2 minutes. The results of the experiment with these parameters are shown below. All of these trials produced hydrate 1 (form D) as analyzed during the pre-drying step. Only trial 9 produced a dehydrated hydrate (form E) upon drying, whereas all other trials The crystals produced by this procedure remained as hydrate 1 upon drying. [Table 1] The granules were dried into a fluid bed system with the following settings: Intake volume: 60m 3 / time ●Intake temperature: 70℃ ●Outlet product temperature: 22→34℃ ●Product temperature: 23→50℃ Drying time and loss on drying (LOD): ○70 minutes LOD=13.2% ○160 minutes LOD=5.1% ○235 minutes LOD=4.9% ○290 minutes LOD=4.3% The LOD was determined on a thermobalance by measuring the weight loss after 15 min at 70°C.

[0090] Granule samples were analyzed after kneading time (wet granules) and during the drying process (160 and 235 min). Samples were examined by XRPD and TGA. All samples were water-stained. The XRPD pattern was consistent with that of hydrate 1 (form D) obtained by HPLC. The TGA data show similar weight losses for the samples after 160 and 235 minutes. The higher weight loss for the wet granules was observed in the wet granules taken at the end of the kneading period. The formula for granules is presented.

[0091] In another specific example, Form D can be prepared by slurrying Form A as follows: A saturated solution (50 mg / ml) of Compound III Form A was analyzed by XRPD, DSC, T The slurry was stirred for 4 hours with sufficient solid residue for GA and optical microscopy. The solid was then isolated and analyzed. The solid was analyzed "wet", after drying by XRPD, and by other techniques. After the slurry was dried, a new form called "hydrate 1" (form D) was found. The morphology remained the same after the material was dried.

[0092] In another specific example, Form D is dissolved in MEK (methyl ethyl ketone) / water 95 / at 5° C. The amorphous material is prepared from a scale-up production by slurrying in 5 (v / v). Slurrying Form A in water also produces Form D material, but the sample becomes viscous during recrystallization. This can cause problems with mixing on a large scale. was required to completely crystallize the Form D material. High water activity solvent / water mixtures When amorphous material was used as the input material, highly crystalline zeolites were obtained after stirring overnight at 5 °C. The material was of the form D. MEK / water was found to be the best solvent for crystallinity and yield. Selected.

[0093] The amorphous material was transferred to a glass reaction tube and weighed to give a starting amount of 882 mg of amorphous material. The solid was cooled to 5°C and 7.5 ml of pre-chilled MEK:water 95:5 (v / v) was added. After stirring for approximately 10 minutes, the sample was mixed with the previously prepared Form D material. The samples were stirred at 5°C (300 rpm) for 2 1 / 2 days. A small amount of the suspension was filtered and air-dried for 10 min before analysis. The bulk sample was filtered using a 0.22 μm filter. The mixture was filtered through a nylon filter and dried on the filter under suction for about 1 hour. The powder was crushed in a mortar and the powder was allowed to dry overnight at ambient conditions. The dried solid was weighed and A yield of 843.3 mg was obtained.

[0094] Characterization The scale-up of Form D shows a crystalline coarse crystalline structure consistent with the reference diffractogram of Form D. A pale white powder was produced. 1 H NMR and KF analyses confirmed that this form is a hemisymmetric derivative of compound I. The sample was chemically pure and was identified as the dihydrate of the succinate salt by HPLC. The purity was 99.9%. Microscopic examination showed that the sample was filled with small particles due to the interstices between the small primary particles. They found that the material is composed of very small particles arranged in aggregates that are highly porous. The particles were irregularly shaped with smooth surfaces.

[0095] Example 2: Preparation of Form F Form F can be prepared, for example, by starting with amorphous Compound I and forming a slurry in water at 5° C. or in water at 20° C. or in ethanol at 5° C. Form A was seeded with Form F in water (50:50) to form a starting competitive slurry. It is possible.

[0096] A. Scale-up An amorphous sample of Compound I was transferred to a glass reaction tube and weighed to yield 913 mg. A starting mass of amorphous material was obtained. The solid was cooled to 5° C. and 12.5 ml of pre-chilled water was added. After stirring for approximately 10 minutes, the sample was added with approximately 10 mg of pre-prepared The samples were stirred at 5°C (300 rpm) for 2.5 days. A small amount of the suspension was filtered and air-dried for 10 min before analysis by XRPD. The mixture was filtered through a 0.22 μm nylon filter and dried on the filter under suction for approximately 1 hour. The cake was crushed with a spatula and the powder was allowed to dry overnight at ambient conditions. was weighed, giving a yield of 874.5 mg.

[0097] B. Characterization. Scale-up of Form F shows crystals that match the reference diffractogram of Form F. The result was a fine white powder of good quality. 1 H NMR and KF analysis confirmed that this form is the same as compound I. The compound was confirmed to be the nonsolvated trihydrate of the hemisuccinate salt. The sample was chemically pure and 100% pure by HPLC. The sample contained non- It always consisted of small particles. The individual particles were irregularly shaped with smooth surfaces. There were some particles covered with fine crystals.

[0098] Example 3: X-ray powder diffraction analysis of forms D and F A.Bruker AXS C2 GADDS X-ray powder diffraction (XRPD) patterns were obtained using Cu Kα radiation (40 kV, 40 mA) Moving XYZ stage, laser video microscope and HiStar2 for automated sample positioning Collection was performed on a Bruker AXS C2 GADDS diffractometer using a primary area detector. The X-ray optics consisted of a single Gobel multilayer mirror coupled with a 0.3 mm pinhole collimator. The beam divergence, i.e., the effective diameter of the X-ray beam on the sample, was approximately 4 mm. The θ-θ continuous scanning mode was adopted with a sample-detector distance of 20 cm, which is 3.2°~ This gives an effective 2θ range of 29.7°. Typically, the sample is exposed to the X-ray beam for 120 seconds. The software used to collect the data was XP / 2000 4.1.43 The GADDS is for Diffrac Plus EVA v15.0.0. 0 was used for analysis and presentation.

[0099] For tests carried out under ambient conditions, samples were prepared as flat plates using the powder form shown. Approximately 1-2 mg of the sample was lightly pressed onto a glass slide to obtain a flat surface. For tests conducted under non-ambient conditions, the samples tested under non-ambient conditions were thermally conductive. The compound was used to mount the sample on a silicon wafer. The sample was then heated to the appropriate temperature at 10°C / min. After heating, the sample was held isothermal for 1 min before data collection began.

[0100] B. Bruker AXS D8 Advance XRPD patterns were obtained using Cu Kα radiation (40 kV, 40 mA) and θ-2θ goniometer. A Bruker D8 diffractometer with V4 and receiving slit diffusion, Ge The data was collected using a monochromator and a Lynxeye detector. The software is Diffrac Plus XRD Commander version 2.6.1. The data was analyzed using Diffrac Plus EVA version 15.0.0.0 presented.

[0101] Using the powder morphology shown, samples were run under ambient conditions as flat specimens. The nanoparticles were statically inserted into cavities cut into a polished zero-background (510) silicon wafer. The samples were rotated in their own plane during the analysis. The details of the data collection are as follows: This is the case. Angle range: 2-42°2θ, step size: 0.05°2θ, acquisition time: 0.5 sec / s Tep.

[0102] C.PANalytical Empyrean XRPD patterns were recorded using Cu Kα radiation (45 kV, 40 mA) in transmission geometry. ) on a PANalytical Empyrean diffractometer equipped with a focusing mirror. A 0.5° slit, 4mm mask and 0.04rad Soller slit were used. The PIXcel3D detector was placed on the diffracted beam and the receiving slip was The 0.04rad Soller slit was attached to the 100-mm square tube. The software is X'Pert Data Collector version 5.3, which collects data. Diffrac Plus EVA version 15.0.0.0 or Highscore The data were analyzed and presented using Plus version 4.5.

[0103] Samples were prepared and plated in either a Millipore 96-well plate in metal or transmission mode. The metal well plate is an X-ray transparent filter sandwiched between two metal plates. Dry powder (approximately 5 mg) was gently pressed into the well for analysis. Using a pore plate, a small amount of suspension was added directly to the plate and then incubated under light vacuum. The solids were isolated from the suspension by filtration and analyzed.

[0104] The scanning mode for the metal plate was the gonio-scan axis, whereas the Millipore plate was the 2θ Scanning was used.

[0105] The details of data collection are as follows: Angle range: 2.5 to 32.0° 2θ, step Size: 0.0130° 2θ, Collection time: 2.07 min total collection time. Longer methods also used Angular range: 2.5 to 42.0°2θ, step size: 0.0130°2θ, collected Time: 8.0 minutes total collection time.

[0106] Variable temperature XRPD (VT-XRPD) experiments have been performed on thermally conductive compounds (e.g. silicon insulators) The sample was mounted on a metal sample holder (with a sintered insert). The sample was then placed in air. The samples were heated in air at 5°C / min to the appropriate temperature. Samples were then stored at the selected temperature using the 8 minute method. analyzed (as described above).

[0107] Results for Forms D and F. The XRPD for Form D is shown in FIG. 1A and For Form D, VT-XRPD shows that upon heating, Form E is converted to Form F. It was shown that upon cooling to 35°C, form E gradually transformed into form A (40-60°C). Further heating (80-95°C) converted form E to form A. For Form F, VT-XRPD showed a loss of crystallinity at 70°C and a loss of crystallinity by 75°C. It showed partial conversion to crystalline form A, but further heating was required to completely crystallize to form A. (up to 100C).

[0108] Example 4: Single Crystal X-Ray Diffraction (SCXRD) Data were collected using an Oxford Cryosystems Cobra-equipped R igaku Oxford Diffraction Supernova Dual S The data were collected on a Cu at Zero Atlas CCD diffractometer. The structure was determined using SHELXTL (Sheldrick, 2006). 13) program was used to solve the problem, and the Bruker AXS SHELXTL suite (V6 The sequences were refined with the SHELXTL program as part of .10). Unless otherwise stated, The hydrogen atoms bonded to the carbon are geometrically arranged and have the riding isotropic displacement parameters The hydrogen atoms bonded to the heteroatoms were located in the difference Fourier synthesis. The SCXRD of form D was calculated using the isotropic displacement parameters and was refined freely. Shown in D. [Table 2] [Table 3]

[0109] Representative peaks in the X-ray diffraction pattern for Form D using Cu-Kα radiation Includes peaks at approximately 18.7, 26.5, 27.0, 27.5 and 27.8 degrees 2θ . [Table 4]

[0110] Representative peaks in the X-ray diffraction pattern for Form E using Cu-Kα radiation Includes peaks at approximately 9.2 and 10.5 degrees 2θ. [Table 5]

[0111] The observed compound I form A reported in US 8,697,876 to Carniaux Data for selected and representative peaks are shown in Tables 5 and 6, respectively, and the reference Presented for. [Table 6] [Table 7]

[0112] Example 5: Comparative Analysis of Selected XRPD Peaks for Forms A, D, and E For comparison, Figures 1E to 1G show the results for Form D (blue line), Form A (green line), and Form E (red line). ) for Form A. The partial XRPD pattern for Form A is approximately (±0.2° 2θ) 7. A characteristic peak is seen at 7° 2θ. For form D, the peak is approximately (±0.2° 2θ) 1 8.7°2θ, 26.5°2θ, 27.0°2θ, 27.5°2θ and 27.8°2θ For Form E, a peak at approximately (±0.2° 2θ) 9.2° is characteristic. Characteristic peaks are seen at 2θ and 10.5° 2θ.

[0113] As evidenced by the data presented above, Forms D, E, and F of Compound I are each In addition, there are unique features that can be used to distinguish each of these forms from Form A of Compound I. It has a specific XRPD pattern.

[0114] Example 6: Nuclear Magnetic Resonance (NMR) Bruke equipped with an autosampler and controlled by a DRX400 console NMR spectra were collected on a 400 MHz instrument. Automated experiments were performed using standard Bruker Loading experiments using Topspin version 1.3 run on ICON-NMR version 4.0 For non-routine spectroscopy, data were collected using Topspin alone. Unless otherwise stated, samples were prepared in DMSO-d6. Offline analysis was performed using CD Spectrus Processor 2014. Ta.

[0115] As shown in Figure 5, the solution state of dissolution forms D and F 1 The H-NMR spectrum shows that methyl This was consistent with the hemisuccinate salt of compound I crystallized from ethyl ketone (0.03 molar equivalents, 0 0.4% by weight), representing 0.5 molar equivalents of succinic acid.

[0116] Example 7: Thermal Analysis (A) Differential scanning calorimetry (DSC) DSC data was collected using a TA Instruments 50-series autosampler. The data was collected on a Q2000. Heat capacity calibration was performed using sapphire, and energy Calibration for temperature was performed using certified indium. Typically, a pinhole 0.5-3 mg of each sample was heated in an aluminum pan from 25°C to 250°C at 10°C / min. A purge of dry nitrogen at 50 ml / min was maintained over the sample.

[0117] The controlled temperature DSC uses a base heating rate of 2°C / min and a temperature gradient of ±0.64°C ( The temperature control parameters were adjusted to (amplitude).

[0118] The device control software is Advantage for Q Series version 2.8.0.3 94 and Thermal Advantage version 5.5.3. The data is from UniStation. The analysis was performed using Versal Analysis No. 4.5A.

[0119] (B) Thermogravimetric analysis (TGA) TGA data was obtained using a TA Instruments 16-position autosampler. Collected on a Q500 TGA. The instrument was temperature calibrated using certified Alumel and Nickel. Typically, 5-10 mg of each sample was placed on a pre-tared aluminum DSC pan. The sample was heated from ambient temperature to 350°C at a rate of 10°C / min. A nitrogen gas flow of 60 ml / min was applied to the sample. The instrument control software is Advantage for Q Series 2. 5.0.256 and Thermal Advantage 5.5.3. The data were analyzed using Universal Analysis version 4.5A.

[0120] (C) DSC and TGA results for Forms D and F. An overlay of the DSC and TGA results for Form D is shown in Figure 2 and for Form F in Figure 3. As shown in.

[0121] For Form D, TGA shows decomposition near 200° C., equivalent to 2.0 molar equivalents of water. DSC analysis showed a loss of 7.5% by weight from 25 to 110°C. 58.2 J / g), which is due to the onset of a broad endotherm at 92.1 C during water loss and recrystallization. (-24.9J / g) and a broad exotherm at 197.9C (-119.0J / g). The onset of the endotherm was abrupt, reflecting the melting of the

[0122] For form F, TGA showed a loss of 11.4 wt% from 25 to 150°C, a loss of 3.1 molar fraction. The decomposition temperature was about 200°C. A broad endotherm begins at 95.7C (-6.4J / g), followed by a shallow endotherm (two peaks) at 95.7C (-6.4J / g). onset, a shallow endotherm (2 peaks) at 103.4C (26.9J / g) and 197. It shows a sharp endothermic onset at 8C (-114.4 J / g), reflecting melting.

[0123] Example 8: Microscopy A. Polarized Light Microscope (PLM) A.1.Leica LM / DM Polarizing Microscope A Leica LM / DM polarizing microscope equipped with a digital video camera for image capture. The samples were examined. A small amount of each sample was placed on a glass slide, mounted in oil, and covered with a coverslip. The sample was covered with a glass to separate the individual particles as much as possible. Observations were made at appropriate magnification and with partial polarized light.

[0124] A.2. Nikon LM / DM Polarizing Microscope Connect a digital video camera to the DS Camera controller DS-L2 for image capture The samples were examined under a Nikon SMZ1500 polarizing microscope. A small amount of each sample was placed on a glass slide. The sample was placed on a plate and mounted by oil immersion to separate the individual particles as much as possible. The microscope was connected to a filter and observed at appropriate magnification and partial polarized light.

[0125] B. Scanning Electron Microscope (SEM) Data were collected on a Phenom Pro scanning electron microscope. A small amount of the sample was placed on an aluminum stub using a sputter coater (20 mA, 1 A thin layer of gold was applied using a 200 s UV light irradiator.

[0126] Example 9: Determination of Water by Karl Fischer Titration (KF) The moisture content of each sample was determined using Hydranal Coulomat AG oven reagent and Using a nitrogen purge, the 851 Titrano Coulometer was used for 150 The solid samples were weighed and measured at 100°C in a Metrohm874 oven sample processor. Approximately 10 mg of sample was used per titration and duplicate measurements were performed. Data collection and analysis was performed using Tiamo version 2.2.

[0127] For Form D, a loss of 7.6 wt.%, corresponding to 2.0 molar equivalents of water, was detected. Therefore, it was determined to be a dihydrate form. For Form F, the amount of water was 3.2 molar equivalents. A loss of 11.6% by weight was detected, thus confirming the trihydrate form.

[0128] Example 10: Chemical Purity Determination by HPLC As shown in FIG. 4A, the HPLC trace of Form D showed a chemical purity of 99.93%. In FIG. 4B, the HPLC trace of Form F showed a chemical purity of 99.95%.

[0129] Purity analysis was performed using an Agilent HP1100 series detector equipped with a diode array detector. On this system, using ChemStation software version B.04.03, The method was carried out as detailed in . [Table 8]

[0130] Example 11: Dynamic Vapor Sorption (DVS) Adsorption isotherms were performed using DVS Intrinsic Control software version 1.0. SMS DVS Intri controlled by version 1.2 (or version 1.0.1.3) The moisture sorption data were obtained using an NSIC moisture sorption analyzer. The sample temperature was kept at 25°C by instrument control. Humidity was controlled by mixing dry and wet nitrogen flows with a total flow rate of 200 ml / min. The relative humidity was controlled by a calibrated Rotronic probe ( The weight of the sample as a function of %RH was measured using a dynamic range of 1.0 to 100%RH. The change (mass relaxation) was constantly monitored by a microbalance (precision ±0.005 mg). To measure the temperature, 5–20 mg of sample was weighed in a tared mesh stainless steel basket under ambient conditions. The samples were loaded and unloaded at 40% RH and 25°C (typical room conditions). Moisture sorption isotherms were performed as outlined below (two scans for one complete cycle). The standard isotherm is a 25°C curve at 10% RH intervals over the range 0-90% RH. Data analysis was performed using DVS Analysis Suite version 6.3. The study was carried out using Microsoft Excel. [Table 9]

[0131] result. Form D showed a large weight loss during the 10% RH step, but as the humidity was increased to 20% RH The residue from the DVS experiment was primarily Form D, with some Form Several peaks consistent with Form F were observed, and Form D was not completely stable at low relative humidity. This shows that

[0132] Form F lost 9.6 wt. % (2.6 molar equivalents of water) before the experiment timed out. When observed, it showed little change in mass up to the first 0% RH step (Figure 7). If the sample is held at 0% RH for longer than the maximum step time of 6 hours, 3 moles of water are completely dissolved. As humidity increases, weight gain will be followed by a crystallization event. When there was a typical weight loss, the sample steadily gained weight up to 70% RH. When sufficient water was obtained, crystallization occurred in the 70% RH step. The behavior in the second cycle was similar. The results were similar, but with an overall weight loss, and the crystallized material was a dihydrate rather than a trihydrate. This was consistent with the residue from the DVS experiment (which was The results were confirmed by analysis of the granules, which were mostly Form D. Some of the syrup was form F. These results indicate that form F is not stable at low relative humidity. It shows.

[0133] Example 12: Thermodynamic Solubility in Water Methods. Solubility in water was determined to obtain a maximum final concentration of 23 mg / ml or greater of the parent free form of the compound. The compound was suspended in water for 24 hours at 37°C. After equilibration, the pH was measured and the suspension was then filtered through a glass fiber C filter. The filtrate was then diluted by an appropriate factor. Quantification was performed at approximately 0.2 mg / ml in DMSO. The standard solutions were analyzed by HPLC. Different volumes of standards, diluted and undiluted samples were analyzed. The solution was injected. The integral of the peak observed at the same retention time as the main peak in the standard injection was The solubility was calculated using the peak areas determined by the method described above. The solubility quoted is This concerns the parent "free type." [Table 10]

[0134] result Slurrying form D in water at 37°C does not result in a change in form, and the thermodynamic solubility is 6. Measured at 2-6.4 mg / ml (free form, versus water and hemisuccinate dihydrate) (corrected for ion content). Conversion to trihydrate form F did not occur at this temperature. Filtration The pH of the unsaturated solution was 7.0.

[0135] Slurrying form F in water at 37°C resulted in conversion to form D. Initially the sample was very Form F was soluble at 100°C (dynamic solubility of Form F is approximately 32 mg / ml), but over time it became consistent with Form D. The thermodynamic water solubility of this sample (Form D) was determined after 24 hours. Measured at 8.6 mg / ml (free form, water and hemisuccinate dihydrate counterions) Form F is stable under these conditions when it is converted to form D. Since there is no available data, it is not possible to determine the thermodynamic aqueous solubility value of Form F at 37°C. The pH of the unfiltered saturated solution was 7.2.

[0136] Although the present invention has been described in conjunction with the detailed description thereof, the above description is not intended to be limiting of the present invention. The scope of the invention is intended to be illustrative and is defined by the appended claims. Other aspects, advantages, and modifications are within the scope of the following claims, which do not limit the scope of the invention. Without departing from the scope of the invention as encompassed by the appended claims, It will be understood by those skilled in the art that various changes in form and details may be made. It will be.

Claims

1. (a) X-ray diffraction of 18.7±0.2 degrees 2θ, 26.5 ±0.2 degrees 2θ, 27.0±0.2 degrees 2θ, 27.5±0.2 degrees 2θ, and 27.8± 2,4,6-trifluoro-N-[6-( 1-Methyl-piperidine-4-carbonyl)-pyridin-2-yl]-benzamide A crystalline form of the mycosuccinate dihydrate (Form D); (b) X-ray diffraction of 15.3±0.2 degrees 2θ, 16.4 ±0.2 degrees 2θ, 19.3±0.2 degrees 2θ, 22.1±0.2 degrees 2θ, 23.6±0.2 2,4,6-trimethylsilyl 2,4,6-tetramethylsilyl ...tetramethylsilyl 2 Trifluoro-N-[6-(1-methyl-piperidine-4-carbonyl)-pyridine-2- an anhydrous solid crystalline form of the hemisuccinate salt of [(2-methyl-2-yl)-benzamide (Form A); and (c) a pharma- ceutically acceptable carrier; and A composition comprising:

2. The X-ray diffraction of Form D using Cu-Kα radiation is 8.5, 9.7, 11. ９，１３．８，１４．０，１５．４，１５．５，１５．８，１７．０，１７．３，１７． ７，１８．０，１８．９，１９．３，１９．８，２０．０，２０．８，２１．４，２１． ６，２１．９，２２．４，２２．７，２３．０，２４．１，２４．３，２４．７，２５． 6, 25.9, 26.1, 28.4, 29.1, 29.6, 29.8 or 31.9 degrees 2 θ, ±0.2 degrees 2θ.

3. The form D has a=25.08 Å, b=10.08 Å, and c=20.8 Å at 100 Kelvin. 4 Å, α=90°, β=123.71, and γ angle=90°. The composition of claim 1 further characterized by:

4. The Form D is an amorphous 2,4,6-trifluoro-N-[6-(1-methyl-piperidinyl) Wet synthesis of hemisuccinic acid of (4-diphenyl-4-carbonyl)-pyridin-2-yl)-benzamide The composition of claim 1 produced by a process comprising the steps of:

5. 10. The composition of claim 1, wherein said Form D is substantially free of impurities.

6. 6. The method of claim 5, wherein the Form D has a chemical purity of greater than 98.0% by HPLC. Composition of.

7. A pharmaceutical composition for use in treating migraine in a mammal comprising the composition of claim 1. Pharmaceutical composition.

8. The pharmaceutical composition of claim 7, wherein the mammal is a human.

9. When Cu-Kα radiation was used, the X-ray diffraction was 18.7±0.2 degrees 2θ, 26.5±0. .2 degrees 2θ, 27.0±0.2 degrees 2θ, 27.5±0.2 degrees 2θ, and 27.8±0. 2,4,6-trifluoro-N-[6-(1- Hemicopolysaccharide of methyl-piperidine-4-carbonyl-pyridin-2-yl-benzamide A crystalline form of the citrate dihydrate (Form D) for use in treating migraine in a mammal. A pharmaceutical composition that can be used.

10. The pharmaceutical composition of claim 9, wherein the mammal is a human.

11. The X-ray diffraction of Form D using Cu-Kα radiation is 8.5, 9.7, 11. ９，１３．８，１４．０，１５．４，１５．５，１５．８，１７．０，１７．３，１７． ７，１８．０，１８．９，１９．３，１９．８，２０．０，２０．８，２１．４，２１． ６，２１．９，２２．４，２２．７，２３．０，２４．１，２４．３，２４．７，２５． 6, 25.9, 26.1, 28.4, 29.1, 29.6, 29.8 or 31.9 degrees 2 10. The pharmaceutical composition of claim 9, comprising one or more additional peaks at θ, ±0.2 degrees 2θ.

12. The form D has a=25.08 Å, b=10.08 Å, and c=20.8 Å at 100 Kelvin. 4 Å, α=90°, β=123.71, and γ angle=90°. The pharmaceutical composition of claim 9 further characterized by:

13. The Form D is an amorphous 2,4,6-trifluoro-N-[6-(1-methyl-piperidinyl) Wet synthesis of hemisuccinic acid of (4-diphenyl-4-carbonyl)-pyridin-2-yl)-benzamide 10. The pharmaceutical composition of claim 9 produced by a method comprising the steps of:

14. 10. The pharmaceutical composition of claim 9, wherein said Form D is substantially free of impurities.

15. 15. The method of claim 14, wherein said Form D has a chemical purity of greater than 98.0% by HPLC. The pharmaceutical composition described above.

16. The pharmaceutical composition of claim 9 , wherein the composition further comprises a pharma- ceutically acceptable carrier.

17. The composition further has an X-ray diffraction of 15.3±0.2 using Cu-Kα radiation. degrees 2θ, 16.4±0.2 degrees 2θ, 19.3±0.2 degrees 2θ, 22.1±0.2 degrees 2θ, It is characterized by including peaks at 23.6±0.2 degrees 2θ and 25.9±0.2 degrees 2θ. 2,4,6-trifluoro-N-[6-(1-methyl-piperidine-4-carbonyl) The anhydrous solid crystalline form of the hemisuccinate salt of -pyridin-2-yl-benzamide (Form A) The pharmaceutical composition of claim 9 .

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