Compositions and methods relating to pyridinoylpiperidine 5-HT1F agonists

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 is directed to the use of 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 [Background technology]

[0002] Migraine is a common and significantly disabling brain disorder that affects 10% of adults worldwide. Over 20% of people are affected (Stovner LI et al., Cephalalgia 007;27:193-210). The disease is characterized by nausea, vomiting, photophobia, and phonophobia ( Attacks of severe headache lasting 1 to 3 days, accompanied by migraine without aura, and in one-third of patients It is typically characterized by a neurological aura (migraine with 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 extremely important in causing Wolff's Headache and Other Head Pain.Ed Silberstein et al ., Oxford University Press, 2001). Established anti-hemiphasic Triptans (Fer), selective 5-HT1B / 1D receptor agonists 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 are contraindicated in patients with cerebrovascular disease. Patients report chest symptoms that can mimic angina, causing anxiety and diagnostic confusion. (Welch KMA et al., Cephalalgia 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 (Schoonman G G et al.,Brain2008;131:192-200), trigeminovascular system It has become clear that this may simply be a secondary phenomenon of activation (Goadsb y PJ et al.,N Engl J Med2002;346:257-270 ). Therefore, vasoconstriction may not be necessary to treat migraine headaches. Neuroinhibition of the trigeminal pathway offers an attractive alternative non-vascular anti-migraine 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 Studies 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 involve compound-specific safety studies for 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] [I]-pyridin-2-yl-benzamide (compound I) is a novel, selective and highly potent 5-HT 1F receptor agonist, with a human 5-HT 1F Receptor Ki , and 5-HT1 receptors than to other 5-HT1 receptor subtypes 1F 4 for receptors It has over 50 times higher affinity (Nelson DL et al., Cephalalg ia2009:29;122). U.S. Patent No. 7,423,050 and U.S. Patent Publication No. No. 2008 / 0300407, which is a neurologically mediated precursor to migraine headache without causing vasoconstriction. Compound I, and other selective pyridinoylpiperidine 5- HT 1F Agonists (i.e., neutrally active antimigraine drugs (NAANAs)) are described. The experiments in the above-referenced publications demonstrate a strong c-Fos induction in the trigeminal nucleus caudalis. have demonstrated inhibition of dural plasma protein extravasation after electrical stimulation of the trigeminal ganglion and 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 crystallinity of drugs affects their solubility, dissolution rate, among other physical and mechanical properties. These properties then affect the manufacturing and The identification of the crystalline form of a 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. US8 See, 697,876.

[0006] In addition to different solid crystalline forms, generally referred to as polymorphs, drugs may also exist as solvates and clathrates. The term solvate refers to a compound that is a compound of formula (I) and a compound of formula (II). The term "solvate" encompasses compounds formed by the association of one or more solvent molecules with a drug molecule. The term refers to stoichiometric or non-stoichiometric groups bound by non-covalent intermolecular forces. Hydrates refer to water, including 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 containing 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 thermodynamic properties and stabilities inherent to a particular polymorphic form are produced. If more than one polymorphic substance can be produced, how can each polymorph be obtained in pure form? In determining which polymorph is preferred, many properties of the polymorphs must be compared. The polymorphs must be compared and the preferred polymorph must be selected based on many physical property variables. Certain aspects such as ease of preparation, stability, etc. are considered important. It is quite possible that in some circumstances one polymorphic form may be preferred. In other situations, different drugs may be used 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 prepared or used in This sometimes 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 state morphology changes during synthesis is recognized in the art. For example, a recent review by Newman and Wenslow (AAPS O Therefore, it is necessary to meet the regulatory requirements and to Polymorphic forms and / or pseudopolymorphs in the dosage form to ensure dosage form quality and consistency There is a need for characterization and control of the form of APIs.

[0009] This application relates to 2,4,6-trifluoro-N-[6-(1-methyl-piperidine-4-carboxylate] Newly discovered hemisuccinate salt of [(carbonyl)-pyridin-2-yl]-benzamide Identification and characterization of pseudopolymorphic forms and how their presence in solid dosage forms Explain how to control it. Summary of the Invention

[0010] The present invention relates to Compound I or lasmitidan hemisuccinate. 2,4,6-trifluoro-N-[6-(1-methyl-piperidine)- ... Pseudopolymorphs 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 manufacturing. The pseudopolymorphic forms described herein are 5-HT 1F Receiving It is useful for revitalizing the body and for treating or preventing migraines.

[0011] In embodiments, 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 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 referred to as 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 embodiments, the present disclosure provides a method for measuring the temperature at 100 Kelvin. Approximately a=25.08Å, b=10.08Å, c=20.84Å, α=90°, β=123. 71, and γ angle=90°. do.

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

[0014] Figure 1C shows the XRPD pattern of Form E, which is the dehydrated form D. , the XRPD pattern for Form E using Cu-Kα radiation is at least about 9. In an embodiment, Form E comprises peaks at 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 present specification. 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). and a broad exotherm of 92.1°C (24.9 J / g) followed by a 197.9°C (-119.0 J / g) A differential scanning calorimetry (DSC) thermogram was characterized, having a sharp endothermic onset at 1000 kJ / g. In embodiments 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 peak at 103.4°C (2 A shallow exotherm (two peaks) at 197.8°C (-114.4J / g) and a of trihydrate form F characterized by a DSC thermogram having a sharp endothermic onset and Compound I is provided. In an embodiment, the present disclosure provides 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 TGA is a method for identifying compounds based on their characteristic thermogravimetric curves, also known as thermogravimetric curves. The method is based on the continuous recording of the mass change 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 wt. % cellulose acetate solution at 25 to 110° C., 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 the compound I.

[0020] In an embodiment, the present disclosure provides a method for producing a 11.4 wt. %, 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 treating rhodium in a range of about 18.7, 26.5, 27.0, 27.5, and 27 XRPD patterns using Cu-Kα radiation including peaks at 0.8 degrees 2θ, ±0.2 degrees The onset of the broad endotherm was at 53.1°C (-158.2 J / g), 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. 2. Compound I is provided in the form of Product Form D.

[0023] In embodiments, the present disclosure provides a method for producing a granulated product comprising: (1) a wet granulation process starting with Form A; (2) a wet granulation process starting with Form A; A storage 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. (7) forming a slurry of amorphous Compound I in water at 37°C; (8) Form F in a competitive slurry 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. is.

[0024] In embodiments, the present disclosure provides a method for preparing a compound I by starting with amorphous Compound I and slurried 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 the trihydrate (Form F) thus prepared is provided.

[0025] According to embodiments described herein, 2,4,6-trifluoro-N-[6-(1-methylphenyl)-2,4,6-trifluoro-N-(2 ... (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. and a pharmaceutically acceptable carrier. In embodiments, the pharmaceutical composition comprises Form D, Form E, and Form E of Compound I. In an embodiment, the pharmaceutical composition comprises one or more of Form A and Form D. a mixture of Form A and Form E, a mixture of Form D and Form E, and a mixture of Form A and Form D and Form E.

[0027] In embodiments, the pharmaceutical composition is substantially free of impurities. The drug composition may have an HPLC purity of about 98%, about 99%, or about 99.9%. In an embodiment, the pharmaceutical composition comprises Form D of Compound I having 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 for treating migraine in a mammal, comprising administering to the mammal in need of such treatment administering to the mammal an effective amount of a pseudopolymorph of Compound I described herein or a mixture thereof; In embodiments, the pseudopolymorph of Compound I is a compound selected from the group consisting of methyl, ... As described above, Forms D, E, and F of Compound I, and mixtures thereof, can be isolated. alone or in combination with Form A. Any of the methods described herein In embodiments, the pseudopolymorph of Compound I is a polymorph 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 and mixtures thereof, including mixtures of the above with Form A. [Brief explanation 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 (hemisuccinate salt of 2,4,6-trifluoro-N-[6-(1-methyl-piperidine-4-carbonyl)-pyridin-2-yl]-benzamide). (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). (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 pattern 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 line), 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 for Form D (blue line), 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 for Form D (blue line), Form A (green), and Form E (red). [Figure 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. [Figure 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 showing a chemical purity of 99.93%. [Figure 4B] (B) HPLC trace of form F showing chemical purity of 99.95%. [Figure 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 cycles of adsorption / desorption, all superimposable. [Figure 7] DVS isotherm for Form F showing three cycles of adsorption / desorption, with cycle 1 adsorption and desorption lines at the top (red and blue) and essentially superimposable, cycle 2 desorption line (green) the second line from the top (pink) plotted from 0 to 70% RH, and cycle 3 adsorption (turquoise) plotted from 0 to 40% RH. DETAILED DESCRIPTION OF THE INVENTION

[0030] Serotonin-1F (5-HT 1F ) receptors and to treat migraines Pyridinoylpiperidine compounds useful for the treatment or prevention of rheumatoid arthritis are described, for example, in US Pat. No. 7,423,055. 0 and US2010 / 0256187. Such compounds include 2, 4,6-Trifluoro-N-[6-(1-methyl-piperidine-4-carbonyl)-pyridine and the hemisuccinate salt of [dibenzo-2-yl]-benzamide ("Compound I"), which is It has the structural formula shown below and is sometimes called rasmitidane hemisuccinate. be. [ka]

[0031] Certain polymorphic forms of Compound I are also described in US Pat. No. 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 embodiments described herein, 2,4,6-trifluoromethyl- ... 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 are described in the art, for example, as described in the '876 patent. The '876 patent designates Form B and Form C. Two additional XRPD patterns are described. Further characterization of their forms is For ease of reference, this disclosure incorporates the principles established in the '876 patent. Thus, the novel pseudopolymorphic forms of Compound I described herein inherit the same molecular structure. Forms D, E, and F 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 are not known to be capable of being used in commercial pharmaceuticals. It was discovered by chance during the manufacturing process of the product. The regulatory authorities overseeing the approval and use of pharmaceuticals must be able to determine the definitive identity of polymorphic forms of active ingredients in solid pharmaceutical dosage forms. These new polymorphic forms are expected to be of significant value given the extensive knowledge, characterization, and control required. There is a need in the art for the 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 or physical form that is formed by X-ray powder diffraction pattern (XRPD). 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) This refers to a crystalline modification of this compound.

[0034] As used herein, the term "hydrate" refers to a compound 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 in which one or more molecules of water and one molecule of water retain their molecular state as H2O. and such combination may form one or more hydrates. As used herein, a hydrate of Compound I can be obtained by the deprotection process described herein. It is considered a "pseudopolymorph" including hydrated forms.

[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), SC), thermogravimetric analysis (TGA), microscopy, and spectroscopy (e.g., nuclear magnetic resonance (NM) spectroscopy). R)).

[0036] In embodiments, the pseudopolymorph is characterized by XRPD. The intensity of the contrast can vary depending on the sample preparation technique, sample mounting procedure, and the particular instrument employed. Furthermore, instrument variation and other factors can affect 2-theta values. Therefore, XRPD peak assignments are subject to a tolerance 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 plus or minus approximately 0.4 degrees. In embodiments, the 2-theta values ​​of the embodiments described herein vary by approximately plus or minus 0.2 degrees. In yet other embodiments, the 2-theta 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. exhibiting 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) as shown in the figures. C) It can also be identified by the trace. For DSC, the observed temperature is 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 plus or minus about 4, 6, 8, or 10°C. It can vary by about 6°C (minus 6°C).

[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 conjunction with a thermogravimetric analyzer. In some cases, pseudopolymorphs can be characterized by thermogravimetric analysis.

[0039] Pseudopolymorphs according to the present invention can be characterized 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 (GVS). It can be characterized by a wear analysis.

[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, such as ethanol, give primarily Form A. Water content is also important, as different polymorphic forms have varying levels of hydration. In the mixture of the water-miscible solvent and the water-miscible solvent, the amount of water is about 6.1% by volume to about 95% by volume, preferably More preferably, about 10% to about 20% by volume, more preferably about 5% to about 10% by volume, and most preferably about 10% to about 20% by volume. Forms D and F of Compound I can be converted into hydrated forms by the addition of about 5% to about 1% water. Therefore, Compound I does not exist to crystallize as any of these forms. In addition, there is a minimum threshold of water that must be present. This will determine which polymorphic forms and / or hydrates are formed, as will be described in more detail below. It can play a role in determining

[0041] Starting with either Form A or the amorphous form of Compound I, water alone or water / solution The addition of solvent mixtures can convert form A or the amorphous form into novel pseudopolymorphic forms D, E, or F. Form A is a non-ionic surfactant that can be used in 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 occurs when water is released, 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 embodiments, 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 compound I, and 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 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 includes Form D or a mixture of Form D and Form A. A composition is provided.

[0045] In embodiments, 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 above approximately 70-75°C, Form E converts to Form A, 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 provides Form E, or a mixture of Form E and Form A. The present invention provides a composition comprising a mixture of Form E and Form D, or a mixture of Form E and Form 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 terms of activity. However, the composition of the starting mixture also has an effect. Form F is a stable form in pure water at 5°C, regardless of whether it is present in the starting mixture. However, when using a mixture of Form D and Form F in water at 20°C, 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) Form F can be produced by lyophilizing a mixture of 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 Form A and Form D may occur. 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 In water at 20°C, when a mixture of Form A and Form D is used, , 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 exist to allow the transformation to stable form F. Similarly, at 5°C in 50:50 ethanol:water (v / v), the Form F species was found in the starting mixture. Form F is a stable form when present in the pharmaceutical composition, but mixtures of Form A and Form D are used. Form D is kinetically stable at 5°C. Form F at low temperatures and high water activities Based on the observed spontaneous crystallization of Form F, it is possible 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 some embodiments, the present disclosure relates to Form F, or a mixture of Form D and Form F, or Form A and Form F. 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 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 a transformation into 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 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 hose) followed by gentle and milling (e.g., grinding granules in a device such as Comil®). In embodiments, the process involves dissolving the granules in a solution (e.g., a Strea Pro® solution). 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 or equal to 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 arts. In some embodiments, 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 cellulose, sorbitol, calcium phosphate, calcium carbonate, and microcrystalline cellulose. cellulose), liquid binders (e.g., gelatin, polyvinylpyrrolidone, hydroxypropyl cellulose derivatives such as propylmethylcellulose, polyethylene glycol, sucrose and starch), dry binders (e.g., cellulose, methylcellulose, polyvinyl 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 Composition The present disclosure provides 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 pharmaceutically acceptable carrier or excipient. The term "pharmaceutically acceptable" means a pharmaceutical composition that is acceptable to a person of sound medical standing. within the scope of scientific judgment, and commensurate with a reasonable benefit / risk ratio, Used in contact with human and animal tissues without reactions or other problems or complications "Drugs" refers to compounds, materials, compositions, carriers, and / or dosage forms that are suitable for administering a drug to a patient.

[0054] A "pharmaceutically acceptable excipient" is generally safe, non-toxic, and biologically and otherwise compatible. 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. and uniformity of dosage, it is especially advantageous to formulate pharmaceutical compositions in dosage unit form. The term "dosage unit form" as used herein refers to a dosage unit 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 contain the unique characteristics of the active compound. and is determined by and directly depends on the specific therapeutic effect to be achieved. Unit forms include ampoules, vials, suppositories, dragees, tablets, capsules, and intravenous bags. , or the 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 containing 100% EDTA as determined by HPLC. In embodiments, the compound I 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 Point.

[0058] The term "suspension" refers to non-aqueous substances 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 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 forms when the material is only liquid (or not soluble). "Conducting" refers to creating a slurry.

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

[0060] Peak heights in powder X-ray diffraction patterns may vary and may be affected by temperature, 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 positions 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 depends on the route of administration and The type of pharmacokinetic profile desired may be determined by the patient's condition and the type of drug to be administered.

[0063] Formulations suitable for oral, sublingual, nasal or injectable administration are widely known in the pharmaceutical arts. and containing at least one active compound. 'S PHARMACEUTICAL SCIENCES,(16th ed.1980 ) for more information.

[0064] In general, the present disclosure provides a method for producing at least one compound that is a pseudopolymorph of Compound I as described herein. The formulations and pharmaceutical compositions are provided as formulations or pharmaceutical compositions containing the active ingredient. Formulations or pharmaceutical compositions typically contain excipients. 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 non-solid substance 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 other liquid material. tablets, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols formulations (as solids or in liquid media), e.g. containing up to 10% by weight of the active compound 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 a formulation, the active ingredient is milled to provide the appropriate particle size before being combined with other ingredients. If the active ingredient is substantially insoluble, it may be necessary to provide a If the active ingredient is substantially water soluble, the particle size is usually less than 1 / 2 mesh. Milling to provide a substantially uniform distribution in the formulation, e.g., 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 sodium, and cellulose (including microcrystalline cellulose); talc, stearyl Lubricants such as magnesium phosphate, mineral oil; wetting agents; emulsifying and suspending agents; gelatin, polysorbate Vinylpyrrolidone, cellulose, methylcellulose, cellulose derivatives (e.g., hydroxy propyl methylcellulose), polyethylene glycol, sucrose, starch, and and liquid or dry binders such as polyethylene glycol; starch, cellulose , cross-linked polyvinylpyrrolidone, sodium starch glycolate, and carboxymethyl Sodium methylcellulose (cross-linked carboxymethylcellulose such as croscarmellose sodium) Disintegrants such as sodium methylcellulose; methylhydroxybenzoates and May contain preservatives such as propylhydroxybenzoate; sweeteners; and flavoring agents. .

[0067] The compounds of the present invention can be administered to patients by employing procedures known in the art. They may be formulated to provide rapid, 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 containing a pharmaceutical acceptable excipient, the active ingredient is usually mixed with at least one 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 steroid and oral composition.

[0070] For transdermal administration, transdermal delivery devices ("patches") are often required. Such transdermal patches provide continuous or discontinuous infusion of the polymorphs 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, for example, 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 pharmaceutical compositions into the brain, either directly or indirectly. Direct techniques typically involve 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 by reference and is described in U.S. Patent No. 5,011,472, which is incorporated herein by reference. Drug delivery is enhanced by intra-arterial infusion of hypertonic solutions, which can temporarily open the blood-brain barrier. This may be done.

[0072] In embodiments, formulations adapted for buccal and / or sublingual administration, or nasal administration In one embodiment, a pharmaceutical formulation is provided comprising at least one active ingredient as described above. A way to avoid gastric complications such as first-pass metabolism by the system and / or through the liver This route of administration provides for the administration of the active ingredient 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 / kg of niacin per dose administered once, twice, or three times daily. Contains an amount of active ingredient in the range of 500 mg or less and a pharmaceutically acceptable diluent or carrier. The present invention provides a pharmaceutical composition.

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

[0076] In embodiments, the present disclosure provides up to 100 mg of niacin per dose administered once, twice, or three times daily. an amount in the range of 200 mg or greater of the active ingredient described herein and a pharmaceutically 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 provides a method for treating a pulmonary arthritis with a steroid hormone, the amount of which is 2 to 100 mg per dose. For pharmaceutical compositions containing the specified amount of active ingredient, the amount may be about 10, 15, 25, or 30, 45, 50, 60, 75, 90, or 100 mg.

[0078] In embodiments, the present disclosure provides pharmaceutical compositions wherein administration is buccal. In embodiments, the present disclosure provides pharmaceutical compositions for sublingual administration. In an embodiment, the present disclosure provides a pharmaceutical composition for administration by nasal or intranasal administration. In embodiments, the present disclosure provides pharmaceutical compositions in which administration is transdermal. In embodiments, the present disclosure provides a pharmaceutical composition for administration by injection. In embodiments, the present disclosure provides pharmaceutical compositions wherein the administration is intravenous. In some embodiments, the present disclosure provides pharmaceutical compositions for administration intramuscularly.

[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. The present invention provides a pharmaceutical composition in which the active ingredient is administered in the dosages described herein three times a day.

[0080] How to use The present disclosure provides a method for treating migraine in a mammal, comprising administering to the mammal in need of such treatment administering to a mammal an effective amount of a pseudopolymorph of Compound I and mixtures thereof, as described herein, In embodiments, 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 embodiment of the present invention, the pseudopolymorph of Compound I is Form D, Form E, and Form F of Compound I, including mixtures of one or more of Forms D, E, and F. 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. an effective amount of the compounds described herein, including in admixture with Form A, for treating various disorders; Avoidance of vasoconstrictor activity by administering pseudopolymorphs of Compound I and their mixtures 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 migraines. It is also useful as a

[0082] There are established and accepted categories 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 CDC provides diagnostic tools for identifying many of the disorders described herein. Additionally, the International Classification of Diseases, 10th Revision (ICD-10) provides a list of the disorders described herein. Those skilled in the art will recognize that DSM-IV and ICD- Alternative nomenclatures 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 line with the progress of medical science; You will realize that you are evolving with every step.

[0083] 5-HT 1F Nitric oxide, due to stimulation of the trigeminal neuralgia in general or in particular, for the activation of receptors for inhibiting extravasation of neuronal peptides and / or for treating any of the above-mentioned disorders. Forms D, E, and F of Compound I as described herein for the treatment of any of 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 can activate receptors and / or The pseudomimetic 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, for example, a disorder, such as a reduction, mitigation, adjustment, or elimination "Treating" or "treatment and management" of a disease condition refers to the treatment of a mammal, particularly a human. means the treatment of a medical condition in a patient, including (a) the suppression of an existing medical condition, i.e., the prevention or mitigation of its onset or (c) to arrest the clinical symptoms, and / or (d) to alleviate the disease state, i.e., This includes causing regression of the condition.

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

[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 low 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. Slurries of amorphous Compound I in solvent / water mixtures containing (6) 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 and forming the compound at 20° 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 method using approximately 40-90% (w / v) of the amount in a 4 L bowl. 200 g of Compound I Form A was mixed with water at 100°C. The initial dry mixing of the formulation before adding fluid was , maintained as a steady state factor (2 min, impeller speed with associated trial, chopper off) Impeller speeds of 400 to 900 rpm correspond to tip speeds of 4.6 to 10.3 m / s. The spray rate (g × kg / min) was 20-60 at 100°C. In production, the center point of this tip speed range is the tip speed at 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, while all other trials The crystals formed 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 minutes at 70°C.

[0090] Granule samples were collected after the kneading time (wet granules) and during the drying process (160 and 235 min). The samples were analyzed by XRPD and TGA. All samples were analyzed by water staining. 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. Formula granules are 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 obtained. The morphology remained the same after the material dried.

[0092] In another specific example, Form D can be prepared by dissolving Form D in MEK (methyl ethyl ketone) / water 95 / 5 at 5°C. It is prepared from a scaled-up production by slurrying amorphous material in 5 (v / v). Slurrying Form A in water also produces Form D material, but the sample remains viscous during recrystallization. This can cause problems with large-scale mixing. was required to completely crystallize the Form D material. When amorphous material was used as the input material, highly crystalline ... The material was obtained in 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 sample was stirred at 5°C (300 rpm) for 2.5 days. Before analysis, a small amount of the suspension was filtered and air-dried for 10 minutes. The cake was filtered through a nylon filter and dried on the filter under suction for about 1 hour. The powder was crushed in a granular crusher and 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 exhibits a crystalline coarse crystalline structure consistent with the reference diffractogram of Form D. A pale white powder was produced. 1 H NMR and KF analysis confirmed that this form is a hemispherical form 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 revealed that the sample was void due to the small interparticle spaces. They found that the particles consist 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 obtained, for example, by starting with amorphous Compound I and forming a slurry in water at 5°C. Alternatively, in water at 20°C or in ethanol at 5°C: Form A 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 the previously prepared The samples were stirred at 5°C (300 rpm) for 2.5 days. Before analysis by XRPD, a small amount of the suspension was filtered and air-dried for 10 minutes. The mixture was filtered through a 0.22 μm nylon filter and dried on the filter under vacuum for about 1 hour. The cake was crushed with a spatula and the powder was allowed to dry overnight at ambient conditions. was weighed to give a yield of 874.5 mg.

[0097] B. Characterization. Scale-up of Form F is consistent with the reference diffractogram of Form F. A fine white powder of good quality was produced. 1 H NMR and KF analysis confirmed that this form is the same as compound I The sample was confirmed to be the non-solvated trihydrate of the hemisuccinate salt. 100% pure by HPLC. The sample contained non- It always consisted of small particles, each irregularly shaped with a smooth surface. 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 HiStar2D 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 employed with a sample-detector distance of 20 cm, which corresponds to 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 for data collection was XP / 2000 4.1.43 The data is from Diffrac Plus EVA v15.0.0. 0 was used for analysis and presentation.

[0099] For tests carried out under ambient conditions, the samples are prepared as flat plates using the powder in the form shown. Approximately 1 to 2 mg of 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 sample was mounted on a silicon wafer using a compound. The sample was then heated to the appropriate temperature at a rate of 10°C / min. After heating, the sample was held isothermal for 1 minute 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 divergence was used. 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 ion beam was statically inserted into cavities cut into a polished zero-background (510) silicon wafer. The sample was rotated in its own plane during the analysis. Data collection details are as follows: This is the case. Angle range: 2 to 42° 2θ, step size: 0.05° 2θ, acquisition time: 0.5 seconds / step Tep.

[0102] C.PANalytical Empyrean XRPD patterns were obtained using Cu Kα radiation (45 kV, 40 mA) in transmission geometry. ) was collected on a PANalytical Empyrean diffractometer equipped with a focusing mirror. A 0.5° slit, 4 mm mask, and 0.04 rad Soller slit were used. The PIXcel3D detector was placed on the diffracted beam and the receiving slit was The specimen was fitted with a 0.04 rad Soller slit. The software is X'Pert Data Collector version 5.3, which collects data. Diffrac Plus EVA version 15.0.0.0 or Highscore Analysis and presentation were carried out using Plus version 4.5.

[0103] Samples were prepared and plated in either metal or transmission mode in Millipore 96-well plates. The metal well plate was 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 vacuumed under a gentle vacuum. The solid was isolated from the suspension by filtration and analyzed.

[0104] The scanning mode for the metal plate was the gonio scanning axis, while 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 minutes total collection time. Longer methods also used. Angle range: 2.5 to 42.0°2θ, step size: 0.0130°2θ, collection Time: 8.0 minutes total collection time.

[0106] Variable temperature XRPD (VT-XRPD) experiments have been performed on thermally conductive compounds (silicon insulators) The sample was mounted on a metal sample holder (with a support). The samples were heated in air at 5°C / min to the appropriate temperature. Samples were then analyzed 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 Figure 1A, and Form F. For Form F, see Figure 1B. For Form D, VT-XRPD shows that upon heating, Form E is converted. It shows a gradual transformation (40-60°C) from Form E to Form B upon cooling to 35°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 complete 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 obtained using an Oxford Cryosystems Cobra cryocooler equipped R igaku Oxford Diffraction Supernova Dual S The data were collected on a source, Cu at Zero, Atlas CCD diffractometer. The structure was acquired using CuKα radiation. 13) program, and the Bruker AXS SHELXTL suite (V6 Refinements were performed with the SHELXTL program as part of .10). Unless otherwise stated, The hydrogen atoms bonded to the carbon atoms are geometrically arranged and have a riding isotropic displacement parameter The hydrogen atoms bonded to the heteroatoms were located in the differential Fourier synthesis. The SCXRD of Form D was shown in Figure 1. Shown in D. [Table 2] [Table 3]

[0109] Representative peaks in the X-ray diffraction pattern for Form D were obtained 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 were obtained using Cu-Kα radiation. It contains peaks at about 9.2 and 10.5 degrees 2θ. [Table 5]

[0111] The observed compound I form A reported in US Pat. No. 8,697,876 to Carniaux Data for selected and representative peaks are shown in Tables 5 and 6, respectively, and for 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-1G show the results for Form D (blue line), Form A (green line), and Form E (red line). ) for Form A, approximately (±0.2° 2θ) 7. A characteristic peak is observed at 7° 2θ. For Form D, the peak is approximately (±0.2° 2θ) 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 observed at 2θ and 10.5° 2θ.

[0113] As evidenced by the data presented above, Forms D, E, and F of Compound I are each and (iii) a unique compound that can be used to distinguish each of these forms from Form A of Compound I. It has a particular 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 were performed using Topspin version 1.3 with 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 were obtained using a TA Instruments 5000 series autosampler. The data was collected on a Q2000. Calibration for heat capacity was performed using sapphire, and the energy Calibration for temperature was performed using certified indium. Typically, a pinhole 0.5 to 3 mg of each sample was placed in an aluminum pan and heated from 25°C to 250°C at a rate of 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 ±0.64°C ( The temperature control parameters were adjusted as follows:

[0118] The device control software is Advantage for Q Series version 2.8.0.3 94 and Thermal Advantage 5.5.3. The data is from Uniform The analysis was performed using Versal Analysis 4.5A.

[0119] (B) Thermogravimetric analysis (TGA) TGA data was obtained using a TA Instruments 16-position autosampler. The data were 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 Form D and Form F. The overlay of DSC and TGA results for Form D is shown in Figure 2, and for Form F in Figure 3. Shown below.

[0121] For Form D, TGA showed decomposition at around 200°C, corresponding to 2.0 molar equivalents of water. DSC analysis showed a loss of 7.5 wt% from 25 to 110°C. 58.2 J / g), which is due to the onset of a broad endotherm at 92.1 C upon water loss and recrystallization. A broad exothermic onset of (-24.9J / g) and 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% between 25 and 150°C, a loss of 3.1 molar mass. The DSC analysis showed that the amount of water decomposed at around 71.2°C (approximately 198.4°C). A broad endotherm begins at 95.7C (-6.4J / g) and a shallow endotherm (two peaks) at 95.7C (-6.4J / g). onset, onset of a shallow endotherm (two peaks) at 103.4 C (26.9 J / g) and 197. It shows a sharp endothermic onset at 8°C (-114.4 J / g), reflecting melting.

[0123] Example 8: Microscopy A. Polarized Light Microscope (PLM) A.1.Leica LM / DM polarizing microscope Leica LM / DM polarizing microscope equipped with a digital video camera for image capture The samples were tested. A small amount of each sample was placed on a glass slide, mounted in oil, and covered with a cover glass. The sample was then 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 control unit 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 in oil immersion to separate individual particles as much as possible. The specimen was observed at appropriate magnification and partially polarized light in conjunction with a filter.

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

[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 851 Titrano Coulometer and a nitrogen purge, the The solid sample was weighed and measured in a Metrohm 874 oven sample processor at ℃. 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. % was detected, corresponding to 2.0 molar equivalents of water. 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 Figure 4A, the HPLC trace of Form D showed a chemical purity of 99.93%. In Figure 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 using the method detailed in

[2004] . [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 data were obtained using an NSIC moisture sorption analyzer. The sample temperature was maintained at 25°C by instrument control. Humidity was controlled by mixing dry and wet nitrogen streams at 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 over a dynamic range of 1.0 to 100%RH. The change (mass relaxation) was constantly monitored by a microbalance (accuracy ±0.005 mg). To measure the sample weight, 5–20 mg was placed in a tared mesh stainless steel basket under ambient conditions. The samples were subjected to loading and unloading 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 shown in 25°C 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 significant weight loss during the 10% RH step, but decreased as humidity increased to 20% RH. The residue from the DVS experiment was primarily Form D, but Form D was also present. 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, there was 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, the 3 moles of water are completely dissolved. As humidity increases, weight gain may follow (due to crystallization events). 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 It was confirmed by analysis that it was primarily 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. Aqueous solubility 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 the appropriate factor. Quantification was performed at approximately 0.2 mg / ml in DMSO. The standard solutions were analyzed by HPLC. Different volumes of the standard, diluted and undiluted samples were analyzed. The solution was injected. The peak observed at the same retention time as the main peak in the standard injection was integrated. The solubility was calculated using the peak areas determined by the method described above. The quoted solubility is This is about the parent's "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, 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 in water (dynamic solubility of about 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 counterion) 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] While the present invention has been described in conjunction with the detailed description thereof, the above description is not intended to be limiting. 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 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. When using Cu-Kα radiation, X-ray diffraction is 8.6, 10.3, 12.3, 17.1, 19.2, 20.0, 20.6, 21.5, 22.1, 23.3, 24.2, 25.6, 26.9, and 30.1±0.2° 1. A pharmaceutical composition comprising the trihydrate of 2,4,6-trifluoro-N-[6-(1-methyl-piperidine-4-carbonyl)-pyridin-2-yl]-benzamide hemisuccinate salt (Form F), characterized by X-ray diffraction peaks at 18.7±0.2 degrees two-theta, 26.5±0.2 degrees two-theta, 27.0±0.2 degrees two-theta, 27.5±0.2 degrees two-theta, and 27.8±0.2 degrees two-theta using Cu-Kα radiation; and a pharmaceutically acceptable carrier, wherein the pharmaceutical composition comprises the dihydrate of 2,4,6-trifluoro-N-[6-(1-methyl-piperidine-4-carbonyl)-pyridin-2-yl]-benzamide hemisuccinate salt (Form D), characterized by X-ray diffraction peaks at 18.7±0.2 degrees two-theta, 26.5±0.2 degrees two-theta, 27.0±0.2 degrees two-theta, 27.5±0.2 degrees two-theta, and 27.8±0.2 degrees two-theta using Cu-Kα radiation.

2. The pharmaceutical composition of claim 1, wherein the X-ray diffraction of the trihydrate (Form F) contains one or more additional peaks at 8.6, 10.3, 12.3, 12.7, 14.2, 14.3, 15.2, 16.0, 17.1, 19.2, 19.5, 20.0, 20.3, 20.6, 21.4, 21.5, 22.1, 23.3, 23.5, 24.2, 25.1, 25.5, 25.6, 26.3, 26.9, 27.5, 28.5, 29.3, 30.1, 31.7, or 32.1 degrees 2θ (±0.2 degrees 2θ) using Cu-Kα radiation.

3. 10. The pharmaceutical composition of claim 1, wherein the trihydrate (Form F) is further characterized in that it has a DSC thermogram with a broad endothermic onset at 71.2°C (-198.4 J / g), a shallow endothermic (two peaks) onset at 95.7°C (-6.4 J / g), a shallow exothermic (two peaks) at 103.4°C (26.9 J / g), and a sharp endothermic onset at 197.8°C (-114.4 J / g).

4. 10. A pharmaceutical composition for use in a method for treating migraine in a mammal in need thereof, comprising an effective amount of the trihydrate of claim 1.

5. The pharmaceutical composition of claim 4, wherein the mammal is a human.

6. 10. The composition of claim 1, wherein the X-ray diffraction of Form D is characterized by one or more additional peaks at 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 two-theta (±0.2 degrees two-theta) using Cu-Kα radiation.

7. 10. The composition of claim 1, wherein Form D is characterized by unit cell parameters at 100 Kelvin of a=25.08 Å, b=10.08 Å, c=20.84 Å, α=90°, β=123.71, and γ angle=90°.

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