EA041348B1 - COMPOSITIONS AND METHODS ASSOCIATED WITH PYRIDINOYLPIPERIDINE 5-HT1F AGONISTS - Google Patents

Description

Technical field

This invention relates to certain solvates and other pseudopolymorphic forms of 2,4,6-trifluoro-N-[6-(1-methylpiperidine-4-carbonyl)pyridin-2-yl]benzamide hemisuccinate salt useful for activating 5-HT _1f receptors u to treat or prevent migraines.

State of the art

Migraine is a common, often disabling, brain disorder that affects more than 10% of the adult population worldwide (Stovner LI et al., Cephalalgia 2007; 27:193-210). This disease is usually characterized by attacks of 1-3 days of severe headache associated with nausea, vomiting, photophobia and phonophobia (migraine without aura), and one-third of patients have symptoms of neurological aura (migraine with aura) (Goadsby PJ et al. , N Engl J Med 2002;346: 257-270).

The pathogenesis of migraine is not fully understood. As a rule, the main cause of migraine headache is vasodilation (Wolff's Headache and Other Head Pain. Ed Silberstein et al., Oxford University Press, 2001). Triptans, selective agonists of the 5-HT1B/1D receptor with reasonable efficacy against migraine, have been developed (Ferrari MD et al., Lancet 2001: 358; 1668-1675) based on the assumption that vasoconstriction in the skull, mediated by the 5- _HT1B receptor, is a prerequisite for efficacy against migraine (Humphrey PPA et al., Ann NY Acad Sci 1990; 600: 587-598). As a consequence, triptans also carry a risk of cardiac vasoconstriction (MaassenVanDenBrink A et al., Circulation 1998; 98: 25-30) and are contraindicated in patients with cardiovascular or cerebrovascular disease. In addition, many patients taking trypans report chest symptoms that may be similar to angina pectoris, causing anxiety and making diagnosis difficult (Welch KMA et al., Cephalalgia 2000; 20: 687-95; Visser WH, et al., Cephalalgia 1996; 16: 554-559). Thus, new treatments for migraine that exclude vasoconstrictor activity are needed.

In recent decades, it has become clear that vasodilation of the skull, if it occurs at all, during a migraine attack (Schoonman GG et al., Brain 2008; 131: 192-200) can only be a secondary phenomenon due to activation of the trigeminovascular system (Goadsby PJ et al ., N Engl J Med 2002;346: 257-270). Thus, vasoconstriction may not be necessary to treat migraine headaches. On the contrary, neural inhibition of the trigeminal pathway would provide a promising alternative mechanism for combating migraine without affecting the vessels. Indeed, LY334370, a neuroactive selective 5-HT1F receptor agonist that is not vasoconstrictor at clinically relevant concentrations, has proven effective in the acute treatment of migraine in an early proof-of-concept clinical study (Goldstein DJ et al., Lancet 2001; 358: 1230-4) . Unfortunately, clinical development of LY334370 was discontinued due to the safety hazard associated with this compound in long-term use in animals.

2,4,6-Trifluoro-M-[6-(1-methylpiperidin-4-ylcarbonyl)pyridin-2-yl]benzamide (Compound I) is a novel selective and highly potent 5-HT1F receptor agonist with Ki at the 5- Human HT _1f 2.21 nM and an affinity that is more than 450 times higher for 5-HT1F receptors than for other 5-HT1 receptor subtypes (Nelson DL et al., Cephalalgia 2009: 29; 122). US Pat. No. 7,423,050 and US Publication No. 20080300407 describe compound I and other pyridinoylpiperidine selective 5-HT1F agonists that are active in neurotransmitter preclinical models of migraine without causing vasoconstriction (i.e., anti-migraine neuroactive agents (NAANA)). The experiments described in the above publications show effective inhibition of cFos induction in the caudal nucleus of the trigeminal nerve and inhibition of dural plasma protein extravasation after electrical stimulation of the trigeminal ganglion. At concentrations up to 0.1 mM, compound I did not cause rabbit saphenous vein constriction in a surrogate assay of human coronary vasoconstriction capacity (Nelson DL et al., Cephalalgia 2009: 29; 122).

The crystallinity of medicinal substances affects, among other physical and mechanical properties, their solubility, dissolution rate, hardness, compressibility and melting point. Since these properties, in turn, can affect the production and applicability of a drug substance, there is a need in the field of chemistry and therapy for the identification of crystalline forms and drug substances, as well as methods for their preparation. The crystalline form of 2,4,6-trifluoro-N-[6-(1-methylpiperidine-4-carbonyl)pyridin-2yl]benzamide hemisuccinate salt is described and is referred to as Form A (See US Pat. No. 8,697,876).

In addition to the various solid crystalline forms commonly referred to as polymorphs, the drug substance can also exist in various pseudopolymorphic forms such as solvates and clathrates. The term solvate means a compound resulting from the association of one or more solvent molecules with a drug molecule. The term solvate includes hydrates, which refer to a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces, eg hemihydrate, monohydrate, dihydrate, trihydrate, tetrahydrate, etc. The term clathrate refers to a drug substance in the form of a crystal lattice that contains voids (eg, channels) in which guest molecules (eg, solvent or water) are trapped inside.

Polymorphic and pseudopolymorphic forms arise if a substance of the same composition crystallizes in different structural lattices, which causes different thermodynamic properties and stability characteristic of a particular polymorphic form. If two or more polymorphs can be obtained, it is desirable to have a method for obtaining both polymorphs in pure form. When deciding on the preference for one of the polymorphs, numerous properties of the polymorphs must be compared, and the preferred polymorph is selected based on many variable physical properties. It is possible that one polymorph may be preferred under certain circumstances if certain aspects such as ease of preparation, stability, etc. are important. In other situations, another polymorph may be preferred due to its higher or lower solubility and/or better pharmacokinetics. A particular crystalline form of a compound may have physical properties that differ from the physical properties of other polymorphic forms, and such properties may markedly affect the physicochemical and pharmaceutical processing of the compound, particularly in the preparation or use of the compound on an industrial scale.

There are stringent regulatory requirements for medicinal substances intended for pharmaceutical use, which require, among other things, exact knowledge of the polymorphic or pseudo-polymorphic form of the active pharmaceutical ingredient (API) in the dosage form. The importance of recognizing and controlling solid form change during drug development is recognized in the art. See, for example, the recent review by Newman and Wenslow (AAPS Open (2016)2:2). Accordingly, there is a need to define and control the characteristics of the polymorphic and/or pseudo-polymorphic form of the API in the dosage form, both to meet regulatory requirements and to ensure the quality and consistency of the finished dosage form.

This application describes the identification and characterization of newly identified pseudopolymorphic forms of the hemisuccinate salt of 2,4,6-trifluoro-N-[6-(1-methylpiperidin-4-carbonyl)pyridin2-yl]benzamide, as well as methods for controlling their content in solid dosage forms.

The essence of the invention

This invention relates to pseudo-polymorphic forms of 2,4,6trifluoro-N-[6-(1-methylpiperidine-4-carbonyl)pyridin-2-yl]benzamide hemisuccinate salt, also referred to herein as Compound I or lamitidan hemisuccinate. Pseudopolymorphic forms of the compound I described in this document, unexpectedly formed during the production of pharmaceutical products on an industrial scale. The pseudopolymorphic forms described herein are useful for activating 5-HT1F receptors and for treating or preventing migraine headache.

In various embodiments of this specification, Compound I is provided in the form of a solvate. In various embodiments, the solvate is a hydrate. In various embodiments, the hydrate is a dihydrate or a trihydrate. In various embodiments of this disclosure, a hydrate or dehydrated hydrate is provided having a powder x-ray diffraction (XRD) pattern substantially such as one of the patterns shown in FIG. 1.

In FIG. 1A is a XRD diagram of form D, dihydrate, also referred to as hydrate 1, obtained using Cu-Ka radiation. In various embodiments, the shape D TX pattern contains at least peaks at about 18.7, 26.5, 27.0, 27.5, and 27.8° 2θ, +/- 0.2°. In various embodiments, the Form D TX diagram contains one or more additional peaks shown in Table 2. In various embodiments of this specification, form D is provided, which has unit cell parameters at 100 Kelvin of about a = 25.08 A, b = 10.08 A, c = 20.84 A, α = 90°, β = 123.71, and angle γ = 90°.

In FIG. 1B is a diagram of the XRD form F, trihydrate. In various embodiments, the form F TX diagram contains the peaks shown in Table 1. 4.

In FIG. 1C is a plot of Form E, dehydrated Form D. In various embodiments, the PDP of Form E obtained using Cu-Ka radiation contains at least peaks at about 9.2 and 10.5° 2θ, +/- 0, 2°. In various embodiments, the form E PDP diagram contains the peaks shown in Table 1. 3.

Various embodiments of this disclosure provide compound I in the form of a dihydrate, form D, trihydrate, form F, or a dehydrated hydrate of form D, referred to herein as Form E. Various embodiments of this disclosure provide a composition comprising 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.

In various embodiments of this disclosure, compound I is provided in the form of a dihydrate form D characterized by a differential scanning calorimetry (DSC) thermogram having a wide endotherm starting at 53.1° C. (-158.2 J/g), a wide exotherm starting at 92.1°C (24.9 J/g), and a sharp endotherm starting at 197.9°C (-119.0 J/g). IN

- 2 041348 various embodiments, Form D shows a DSC thermogram substantially corresponding to FIG. 2.

In various embodiments of this description, compound I is provided in the form of a trihydrate form F characterized by a DSC thermogram having a wide endotherm starting at 71.2°C (-198.4 J/g), a flat endotherm (2 peaks) starting at 95 .7°C (-6.4 J/g), a gentle exotherm (2 peaks) at 103.4°C (26.9 J/g) and a sharp endotherm beginning at 197.8°C (-114.4 j/g). In various embodiments of this disclosure, compound I is provided in the form of a trihydrate form F having a DSC thermogram substantially corresponding to that of FIG. 3.

In various embodiments, the pseudopolymorphic form of compound I described herein can be identified based on a characteristic thermogravimetric curve, also referred to as thermogravimetric analysis (TGA). TGA is based on the continuous recording of the mass change of a material sample as a function of temperature and time combined.

In one embodiment of this description, Compound I is provided in the form of dihydrate form D, characterized by a TGA showing a loss of 7.5 wt.% in the range of 25-110 ° C, which corresponds to 2.0 mol. equiv. water, and the beginning of the destruction at about 200°C, essentially in accordance with Fig. 2.

In one embodiment of this description, Compound I is provided in the form of trihydrate form F, characterized by a TGA showing a loss of 11.4 wt.% in the range of 25-150°C, which corresponds to 3.1 mol.eq. water, and the beginning of the destruction at about 200°C, essentially in accordance with Fig. 3.

In various embodiments of this disclosure, Compound I is provided in the form of dihydrate Form D, characterized by a Cu-Ka XRD pattern that contains peaks at about 18.7, 26.5, 27.0, 27.5, and 27, 8° 2θ, +/- 0.2°, and a DSC thermogram showing broad endotherm onset at 53.1°C (-158.2 J/g), broad exotherm onset at 92.1°C (24.9 J /d) and the onset of a sharp endotherm at 197.9°C (-119.0 J/g).

In various embodiments of this specification, Compound I is provided in the form of dihydrate Form D having substantially the same X-ray diffraction pattern as in FIG. 1A and essentially the same DSC thermogram as in FIG. 2.

In various embodiments of this specification, Compound I is provided in the form of a dihydrate (Form D) obtained by a process comprising one of the following (1) a wet granulation process starting from Form A, (2) storing Form A at 25°C and relative humidity ( RH) 96%, (3) recrystallization from solvent/water mixtures with high water activity, (4) storage of amorphous compound I at 40°C and RH 75%, (5) suspension of amorphous compound I in solvent/water mixtures with high activity water, (6) obtaining a suspension of amorphous compound I in water at or above room temperature, (7) obtaining a suspension of form F in water at 37°C, (8) obtaining an alternative suspension of form F, for example, in a mixture of ethanol-water ( 50/50 v/v) at 20°C. Form A is the anhydrous solid crystalline form of compound I.

In various embodiments of this disclosure, Compound I is provided in the form of a trihydrate (Form F) prepared by a process comprising using amorphous Compound I as starting material and making a suspension in water at 5°C; or obtaining an alternative slurry starting from Form A seeded with Form F in water at 20°C, or in a mixture of ethanol/water (50:50) at 5°C.

According to the embodiments described herein, 2,4,6-trifluoro-K-[6-(1methylpiperidine-4-carbonyl)pyridin-2-yl]benzamide and its hemisuccinate salt, Compound I, can be prepared by methods described in the art. For example, as described in US 8697876 and US 7423050.

This specification also provides pharmaceutical compositions comprising Compound I in the form of a hydrate, such as a dihydrate or trihydrate, or in the form of a dehydrated hydrate, including mixtures thereof, and a pharmaceutically acceptable carrier. In various embodiments, the pharmaceutical composition comprises one or more of Form D, Form E, and Form F of Compound I. In various embodiments, the pharmaceutical composition comprises a mixture selected from the group consisting of a mixture of Forms A and D, a mixture of Forms A and E, a mixture forms D and E; and mixtures of forms A, D and E.

In various embodiments, the pharmaceutical composition is substantially free of impurities. In various embodiments, the pharmaceutical composition comprises Compound I Form D having a chemical purity of about 98%, about 99%, or about 99.9%, as determined by HPLC. In various embodiments, the pharmaceutical composition comprises Compound I Form F having a chemical purity of about 98%, about 99%, or about 99.9%, as determined by HPLC.

Also provided herein are methods for treating migraine in a mammal, comprising administering to a mammal in need of such treatment an effective amount of a Compound I pseudopolymorph described herein, or mixtures thereof. In various embodiments, the Compound I pseudopolymorph is selected from Form D, Form E, and Form F of Compound I and mixtures thereof, alone or in combination with Form A, as described herein. In various embodiments of any of the methods described herein, the compound I pseudopolymorph is selected from Form D, Form E, and Form F of Compound I, and mixtures thereof, including mixtures of one or more of Forms D, E, and

F with form A, as described in this document.

Brief description of graphic materials

Fig. 1A-G: X-ray powder diffraction (XRD) diagrams of various pseudopolymorphic forms of compound I (2,4,6-trifluoro-N-[6-(1-methylpiperidin-4carbonyl)pyridin-2-yl]benzamide hemisuccinate salt). A, form D (dihydrate); B, form F (trihydrate); C, form E (dehydrated form D); D, experimental and calculated XRD diagrams of a single crystal form D; E, partial section of XRD diffraction pattern (0-13°2θ), shape D (blue line), shape A (green), shape E (red); F, partial section of XRD diffraction pattern (13-19.5°2θ), shape D (blue line), shape A (green), shape E (red); G, partial section of XRD diffraction pattern (18.5-26°2θ), shape D (blue line), shape A (green), shape E (red).

Fig. 2: Thermogram of DSC and TGA analysis of Form D. Overlay DSC (blue line, heat flux (W/g), lower line and inset) and TGA (green, mass scale (%), upper line) results for Form D.

Fig. 3: DSC thermogram and TGA analysis of form F. Overlay DSC (blue line, heat flux (W/g), top line) and TGA (green, mass scale (%), bottom line) for form F.

Fig. 4A-B: A, HPLC line Form D having a chemical purity of 99.93%; B, HPLC line Form F having a chemical purity of 99.95%.

Fig. 5: ¹ H-NMR spectrum in solution state of dissolved form D or F of compound I.

Fig. 6: DSP isotherm plot for Form D showing 3 sorption/desorption cycles that are superimposed on each other.

Fig. 7: EAF isotherm plot for Form F showing 3 sorption/desorption cycles, and the desorption lines are topmost (red and blue) and substantially aligned with each other; the 2nd cycle desorption line is the second line from the top (pink), the sorption line (green) is built at RH 0 - ~70%; the sorption line in cycle 3 (magenta) was plotted at RH from 0 to ~40%.

Detailed description of the invention

Pyridinoylpiperidine compounds useful for activating the serotonin-1F (5HT _1F ) receptor and for treating or preventing migraine are described, for example, in US 7423050 and US 2010/0256187. Such compounds include 2,4,6-trifluoro-N-[6-(1-methylpiperidine-4carbonyl)pyridin-2-yl]benzamide hemisuccinate salt (Compound I) which has the structural formula below and may also be mentioned as lamitidan hemisuccinate.

0.5 but ₂ s^ _CO2H

Me

Compound I (2,4,6-τρπφτορ-Ν-[6-(1methylpiperidine-4-carbonyl)pyridin-2-yl]benzamide hemisuccinate salt)

Some polymorphic forms of compound I are also described in US 8697876. One of the described forms is a polymorph, referred to as form A. Form A is an anhydrous solid crystalline form of compound I. According to the embodiments described herein, 2,4, 6-trifluoro-N-[6-(1-methylpiperidin-4-carbonyl)pyridin-2-yl]benzamide, its hemisuccinate salt (Compound I), and the anhydrous solid crystalline form of Compound I, referred to as Form A, can be prepared by methods described in the art, for example, as described in the '876 patent. The '876 patent describes two additional VDP patterns, designated Form B and Form C. Additional characteristics of these forms are not disclosed. For ease of reference, this specification retains the nomenclature adopted in the '876 patent. Accordingly, the novel pseudopolymorphic forms of Compound I described herein are referred to as Form D, Form E, and Form F. Form D is also referred to as Hydrate 1 or dihydrate. Form E is also referred to as the dehydrated hydrate of Form D and may exist as a partially or fully dehydrated hydrate of Form D. Form F is also referred to as a trihydrate. The structure of Form F was determined based on the weight loss in the crystallization study.

Prior to this invention, it was known that Compound I could exist in the various pseudopolymorphic forms described herein. These pseudopolymorphic forms were discovered by chance in the process of obtaining a product for industrial pharmaceutical production. Given that the various regulatory authorities that oversee the approval and use of such pharmaceuticals require accurate knowledge, characterization, and control of the polymorphic form of the active ingredient in solid pharmaceutical dosage forms, there is a need in the art for crystallization and characterization. 041348 stick of these new polymorphic forms of compound I.

The terms polymorph, polymorph, polymorph form, pseudopolymorph, crystalline form, physical form or crystalline form of 2,4,6-trifluoro-K-[6-(1-methylpiperidine-4carbonyl)pyridin-2-yl]benzamide in this invention refer to to a crystalline modification of said compound, which can be characterized by analytical methods such as X-ray powder diffraction (XRD), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA) and gravimetric or dynamic vapor sorption (GSP; DSP).

The term hydrate in this context means a compound of this invention or a salt thereof, which additionally contains a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular bonds. Hydrates are formed when one or more water molecules combine with one molecule of substances in which water retains its H ₂ O molecular state, and such a combination can lead to the formation of one or more hydrates. In this context, the hydrate of Compound I is considered a pseudopolymorph, including the dehydrated hydrate described herein.

Pseudopolymorphs described in this document can be characterized by any methods, in accordance with the known prior art. For example, pseudopolymorphs can be characterized by X-ray powder diffraction (XRD), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), microscopy, and spectroscopy (eg, nuclear magnetic resonance (NMR)).

In various implementations, the characteristics of the pseudo-polymorphs are determined using the DRP. The relative intensity of the XRD peaks may vary depending on the sample preparation technique, sample fixing technique, and the specific instrument used. In addition, instrumental deviations and other factors can affect 2-theta values. Thus, the values of the peaks of the XRD can vary by plus or minus about 0.1, 0.2, 0.3 or 0.4°. For example, in some embodiments, the 2θ values of the form described herein may vary by plus or minus about 0.4°. In other embodiments, the 2θ values of the form described herein may vary plus or minus about 0.2°. In other embodiments, the 2θ values of the form described herein may vary plus or minus about 0.1°. Pharmaceutical compositions containing the pseudopolymorph described herein can be identified by comparing the powder x-ray diffraction patterns of these compositions with the x-ray powder diffraction pattern of the pure polymorph. It should be understood that pharmaceutical compositions containing a particular pseudopolymorph described herein may exhibit non-identical X-ray powder diffraction patterns compared to the pure polymorph's X-ray powder diffraction pattern.

The pseudopolymorphs described herein can also be identified from characteristic differential scanning calorimetry patterns, such as those shown in the figures. It is known that the observed temperatures for DSC depend on the rate of temperature change, as well as on the sample preparation technology and the specific instrument used. Thus, the values described herein in relation to DSC thermograms may vary by plus or minus about 4, 6, 8, or 10°C. For example, the values may vary by plus or minus about 6°C.

The pseudo-polymorphic forms of this invention may also exhibit different thermal properties than the amorphous material or other polymorphic form. Thermal properties can be measured in the laboratory using thermogravimetric analysis (TGA), which can be used to differentiate some polymorphs from others. In one aspect, the pseudo-olimorph can be characterized by thermogravimetric analysis.

The pseudopolymorphs of this invention can also be identified using gravimetric vapor sorption (GSP), which measures the rate and degree of absorption of the solvent by the sample. In one aspect, the pseudopolymorph can be characterized by gravimetric vapor sorption analysis.

Getting a polymorph

The crystallizing solvent is an important factor in determining which polymorph or pseudopolymorph of Compound I is formed. For example, solvents with low water activity, such as ethanol, preferentially form form A. The water content is also important because different polymorphs have different degrees of hydration. In mixtures of water and water-miscible solvents, the amount of water may vary from about 6.1 to about 95% by volume, preferably from about 10 to about 20% by volume, more preferably from about 5 to about 10% by volume, and most preferably about 5 to about 1% water. Forms D and F of Compound I are hydrates and therefore there is a minimum amount of water that must be present for Compound I to crystallize in any of these forms. In addition, the cooling rate and release temperature, as well as the amount of water, can play a role in determining which polymorph and/or hydrate forms, as described in more detail above.

- 5 041348

It has been found that starting from Form A or an amorphous form of Compound I, by adding only water or water/solvent mixtures, a conversion occurs from Form A or an amorphous form to one of the new pseudopolymorphic forms D, E or F. Form A is the dominant form in the absence of water (up to 10% by volume water; water activity approx. 0.6) or low water activity, e.g. in pure ethanol, at any temperature. At higher water activity, temperature and water content are decisive.

The conversion of form A to form D occurs as water is introduced, for example under conditions of high humidity or in solvent-water mixtures with high water activity. Form D is the most stable form at intermediate water activity and higher temperatures (ie, room temperature to about 40°C).

Various embodiments of this specification provide compound I in the form of dihydrate form D. An X-ray surface diffraction (XRD) analysis of a single crystal of compound I showed that it contained one molecule of compound I, two water molecules and half a succinate molecule. The X-ray powder diffraction modeled from this crystal structure corresponds to the XRD form D or Hydrate 1 shown in FIG. ID, confirming that Form D is the dihydrate of Compound I. The experimental X-ray diffraction pattern (RT) of the bulk sample is shown in red (upper line), and the graph calculated from the single crystal X-ray structure (100 K) is shown in black (lower line). Small differences in the position of the peak are due to changes in the crystal lattice depending on temperature and preferred orientation.

In various embodiments of this disclosure, a composition is provided comprising Form D or a mixture of Forms D and A.

Various embodiments of this disclosure provide Compound I in Form E, Dehydrated Form D. Form E can be prepared by heating Form D of Compound I to about 60°C and the conversion begins at about 40°C. As heating continues to a temperature of approximately 70-75° C. Form E is converted to Form A, the anhydrous form. Thus, form E can be considered as a metastable form. If Form E is cooled to about 35° C. or less after formation, it converts to Form D. In various embodiments of this specification, a composition is provided comprising Form E, or a mixture of Forms E and A, or a mixture of Forms E and D.

Form F is generally the most stable form at lower temperatures (eg, about 5 to about 20° C.) and very high water activity. But the composition of the initial mixture can also have its effect. While Form F is the stable form in pure water at 5°C, whether or not it is present in the initial mixture, at 20°C in water, Form F is the more stable form when using a mixture of Forms D and F. However, Form D is kinetically more stable when using a mixture of Forms A and D.

Thus Form F can be prepared by suspending amorphous compound I or Form A in pure water at 5° C. or by lyophilization of amorphous compound I from a mixture of tert-butanol/water (50/50, v/v). Form F can also be prepared at 5°C in ethanol/water (50/50, v/v) if Form F seeds are present in the feed mixture using Form A or Form D, but Form D is the stable form at 5°C in the case of using a mixture of Forms A and D.

At 20°C in water, Form F is more stable when starting from a mixture of Forms D and F. At 20°C in water, Form D is stable when using a mixture of Forms A and D.

The results obtained indicate that in pure water at 5°C, form F is the most stable form, but at 20°C, the presence of seed crystals of form F is necessary to effect conversion to the stable form F. Similarly, at 5°C, in the mixture ethanol/water 50/50 v/v Form F is a stable form when Form F is seeded in the feed mixture, but Form D is kinetically stable at 5°C using a mixture of Forms A and D. Based on the observed spontaneous crystallization of Form F at low temperatures and high water activity, Form F can be obtained in the composition of compound I, which is originally Form D or a mixture of Forms A and D. Accordingly, in various implementations of this description, a composition is provided containing Form F or a mixture of Forms D and F, or a mixture of Forms A, D and F .

Drying Form F in a vacuum oven at room temperature converts it to the amorphous Compound I. Form F converts to Form A by (a) heating, (b) exposure to 40° C./20% relative humidity, or (c) storage at very low humidity in a desiccator at room temperature. In addition, humidity cycling, as in the gravimetric vapor sorption experiment, results in the conversion of form F to form D.

In various embodiments of this specification, Compound I is provided in the form of a dihydrate Form D, obtained by processing Form A of Compound I in a wet granulation process using purified water as the granulation medium. In various embodiments, the wet granulation process includes a high shear mixing step (for example, in an apparatus such as Diosna® P 1/6 equipped with 1 and 4 L flasks), followed by gentle grinding (for example, in an apparatus such as Comil®, to break up granule lumps). In various embodiments, said method further includes the step of drying the granules (eg, using a Strea Pro® fluid bed dryer). In various embodiments, the granules are dried to a water content of not more than 4% w/w. (according to the results of measurements, for example, water balance).

In various embodiments, one or more excipients are added during the granulation process, either prior to granulation or after drying of the granules, as is known in the pharmaceutical art. In various embodiments, one or more adjuvants are selected from one or more of a bulking material (e.g., lactose, sucrose, glucose, mannitol, sorbitol, calcium phosphate, calcium carbonate, and cellulose, including microcrystalline cellulose), a binder in the form of a solution (e.g., gelatin, polyvinylpyrrolidone, cellulose derivatives such as hydroxypropylmethylcellulose, polyethylene glycol, sucrose and starch), dry binder (e.g. cellulose, methylcellulose, polyvinylpyrrolidone and polyethylene glycol), disintegrant (e.g. starch, cellulose, cross-linked polyvinylpyrrolidone, sodium starch glycolate and carboxymethyl cellulose, including cross-linked sodium carboxymethyl cellulose such as croscarmellose sodium), a wetting agent (eg sodium lauryl sulfate) and a lubricant (eg magnesium stearate, stearic acid, polyethylene glycol and sodium lauryl sulfate).

Pharmaceutical compositions

The invention also provides pharmaceutical compositions comprising one or more of Forms D, E or F of Compound I, alone or in admixture with Form A as described above, and a pharmaceutically acceptable carrier or excipient. The term pharmaceutically acceptable refers to those compounds, materials, compositions, carriers and/or dosage forms that are medically suitable for use in contact with body tissues in humans and animals without undue toxicity, irritation, allergic reaction, or other problems or complications, proportionately. with a reasonable benefit/risk ratio.

Pharmaceutically acceptable excipient means an excipient suitable for the preparation of a pharmaceutical composition that is generally safe, non-toxic and not biologically or otherwise unacceptable, and includes an excipient acceptable for veterinary use as well as pharmaceutical use in humans. Examples of pharmaceutically acceptable excipients are provided above in this document.

The pharmaceutical composition may be presented in bulk or unit dosage form. It is particularly advantageous to formulate the pharmaceutical compositions in unit dosage form for ease of administration and uniform dosing. The term unit dosage form in this context refers to physically discrete units suitable as single doses for subjects to be treated; each unit contains a certain amount of active compound, calculated to provide the desired therapeutic effect, in combination with the required pharmaceutical carrier. The characteristics of the unit dosage forms of this invention are dictated by and directly dependent on the unique characteristics of the active compound and the particular therapeutic effect to be achieved. The unit dosage form may be an ampoule, vial, suppository, dragee, tablet, capsule, IV sachet, or single pump on an aerosol inhaler.

In various embodiments, the chemical components of the pharmaceutical composition are substantially free of chemical impurities. The term chemical purity refers to the amount, usually expressed as a weight percent, of a particular compound in a compound sample. Unless otherwise indicated, the percentages given in this specification are percentages by weight (w/w). In various embodiments, the pharmaceutical composition contains a pseudopolymorphic form of Compound I that has a chemical purity greater than 98.0% as determined by HPLC. In various embodiments, the pseudopolymorph has a chemical purity of 99.0%. In various embodiments, the pseudopolymorph has a chemical purity of 99.5%. In various embodiments, the pseudopolymorph has a chemical purity of 99.9%.

The term suitable solvent refers to any solvent or mixture of solvents that is inert to the reaction and that sufficiently solubilizes the reactants and provides a medium in which the desired reaction will proceed.

The term suspension refers to a two-phase system consisting of a finely divided solid in amorphous form, crystalline form, or mixtures thereof, dispersed (suspended) in a liquid or dispersed medium, usually a solvent. The term suspension refers to a suspension formed by mixing a quantity of powder in a liquid in which the solid is only slightly soluble (or insoluble). Suspension refers to the preparation of a suspension.

The term amorphous in this context means essentially without a regularly repeating order of molecules or planes of external surfaces.

It should be understood that the height of the peaks in the X-ray powder diffraction pattern may differ and depend on variables such as temperature, crystal size, crystal habit, sample preparation, or sample height in the assay well.

It should also be understood that peak positions may vary when measured using different radiation sources.

The type of dosage form used to administer the polymorph used in the methods of this invention may be dictated by the type of pharmacokinetic profile that is desired to result from the given route of administration and the condition of the patient.

Dosage forms intended for oral, sublingual, nasal, or injection administration are prepared in a manner well known in the pharmaceutical art and contain at least one active compound (See, for example, REMINGTON'S PHARMACEUTICAL SCIENCES, ( ^16th ED. 1980)).

In general, this description provides a dosage form or pharmaceutical composition that contains at least one active ingredient, which is a pseudopolymorph of compound I described in this document. The proposed dosage forms and pharmaceutical compositions may additionally contain an additional active pharmaceutical ingredient (API). Dosage forms or pharmaceutical compositions typically contain an excipient, are diluted with an excipient, or are encapsulated in such a carrier, which may be in the form of a capsule, sachet, paper or other container. If the excipient serves as a diluent, it may be a solid, semi-solid or liquid material which acts as a vehicle, carrier or medium for the active ingredient. Thus, the dosage forms of this invention may be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing eg up to 10% by weight of the active compound, soft or hard gelatin capsules, gels, suppositories, sterile injectable solutions and sterile pre-packaged powders.

Upon receipt of the dosage form, it may be necessary to grind the active ingredient to obtain the appropriate particle size before combining with other ingredients. If the active ingredient is essentially insoluble, it is usually ground to a particle size of less than 200 mesh. If the active compound is substantially soluble in water, then the particle size is usually controlled by grinding to obtain a substantially uniform distribution in the dosage form, for example, about 40 mesh. In one embodiment of the present invention, the particle size range is from about 0.1 to about 100 microns.

Some examples of useful excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum arabic, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methylcellulose. Dosage forms may contain excipients such as lactose, sucrose, glucose, mannitol, sorbitol, calcium phosphate, calcium carbonate, and cellulose (including microcrystalline cellulose); lubricating agents such as talc, magnesium stearate and mineral oil; wetting agents; emulsifying and suspending agents; solution or dry binders such as gelatin, polyvinylpyrrolidone, cellulose, methylcellulose, cellulose derivatives (eg hydroxypropyl methylcellulose), polyethylene glycol, sucrose, starch and polyethylene glycol; disintegrants such as starch, cellulose, cross-linked polyvinylpyrrolidone, sodium starch glycolate and sodium carboxymethylcellulose (including cross-linked sodium carboxymethylcellulose such as croscarmellose sodium); preservatives such as methyl and propyl hydroxybenzoates; sweeteners; and flavoring agents.

The compounds of this invention can be formulated to provide fast, sustained or delayed release of the active ingredient after administration to a patient, using methods known in the art.

The following examples of dosage forms are illustrative only and are not intended to limit the scope of this invention. The term active ingredient refers to the pseudopolymorph described herein.

Although the active ingredient used in the methods described herein can be administered directly without any dosage form, the active agent is usually administered in the form of a pharmaceutical dosage form containing a pharmaceutically acceptable excipient and at least one active ingredient. . Such dosage forms can be administered by a variety of routes, including oral, buccal, rectal, intranasal, dermal, transdermal, subcutaneous, intravenous, intramuscular, and intranasal. The dosage forms used in the methods described herein are effective both in the form of injectable compositions and in the form of oral compositions.

Transdermal administration often requires a transdermal delivery device (patch). Such transdermal patches can be used to provide continuous or intermittent infusion of the polymorph of this invention in controlled amounts. The design and use of transdermal patches for the delivery of pharmaceutical agents are well known in the art. See, for example, US Pat. No. 5,023,252. Such patches can be designed for continuous, pulsed, or on-demand delivery of pharmaceuticals.

It is often desirable or necessary to directly or indirectly administer the pharmaceutical composition to the brain. Direct injection technologies typically involve placement of a drug delivery catheter into the recipient's ventricular system, bypassing the blood-brain barrier. One such implantable delivery system used to deliver biological factors to specific anatomical regions of the body is described in US Pat. No. 5,011,472, incorporated herein by reference. Delivery of hydrophilic drugs can be enhanced by intra-arterial infusion of hypertonic solutions, which can temporarily open the blood-brain barrier.

In various embodiments, a pharmaceutical dosage form is provided comprising at least one active ingredient as described above in a composition adapted for buccal and/or sublingual or nasal administration. This embodiment provides for the administration of the active ingredient in a manner that prevents gastric complications such as first pass metabolism in the gastric system and/or in the liver. Such a route of administration may also provide a reduction in absorption time, resulting in a faster onset of therapeutic effect.

In various embodiments of this description, a pharmaceutical composition is provided, containing a certain amount of the active ingredient, up to 500 mg per dose, which is administered once, twice or three times a day, and a pharmaceutically acceptable diluent or carrier.

In various embodiments of this description, a pharmaceutical composition for oral or rectal administration is provided, containing a certain amount of the active ingredient described herein, up to 500 mg per dose, which is administered once, twice or three times a day, and pharmaceutically acceptable diluent or carrier. In various embodiments of this description, a pharmaceutical composition is provided that contains a certain amount of the active ingredient described herein, and the specified amount is from 50 mg to 500 mg per dose. In various embodiments of this description, a pharmaceutical composition is provided that contains a certain amount of the active ingredient described herein, and the specified amount is from 50 mg to 400 mg per dose. In various embodiments of this description, a pharmaceutical composition is provided that contains a certain amount of the active ingredient described herein, and the specified amount is from 50 mg per dose. In various embodiments of this description, a pharmaceutical composition is provided that contains a certain amount of the active ingredient described herein, and the specified amount is from 100 mg per dose. In various embodiments of this description, a pharmaceutical composition is provided that contains a certain amount of the active ingredient described herein, and the specified amount is from 200 mg per dose. In various embodiments of this description, a pharmaceutical composition is provided that contains a certain amount of the active ingredient described herein, and the specified amount is from 400 mg per dose.

In various embodiments of this specification, there is provided a pharmaceutical composition containing the active ingredient described herein, wherein the administration is oral. In various embodiments of this description, a pharmaceutical composition is provided that contains a certain amount of the active ingredient described herein, and the administration is rectal.

In various embodiments of this description, a pharmaceutical composition for buccal, sublingual, nasal/intranasal, transdermal, subcutaneous, injection, intravenous or intramuscular administration is provided, which contains a certain amount of the active ingredient described herein, up to 200 mg per dose that is administered. once, twice or three times a day, and a pharmaceutically acceptable diluent or carrier.

In various embodiments of this description, a pharmaceutical composition is provided that contains the active ingredient described herein, the specified amount being from 2 to 100 mg per dose. In various embodiments, this invention relates to a pharmaceutical composition containing a certain amount of the active ingredient described in this document, and the specified amount is about 10, 15, 25, 30, 45, 50, 60, 75, 90

- 9 041348 or 100 mg per dose.

In various embodiments of this disclosure, a pharmaceutical composition is provided wherein administration is buccal. In various embodiments of this description, a pharmaceutical composition is provided, wherein the administration is sublingual. In various embodiments of this description, a pharmaceutical composition is provided, wherein the administration is nasal or intranasal. In various embodiments of this description, a pharmaceutical composition is provided, wherein the administration is transdermal. In various embodiments of this description, a pharmaceutical composition is provided, wherein the administration is subcutaneous. In various embodiments of this disclosure, a pharmaceutical composition is provided, wherein the administration is an injection. In various embodiments of this description, a pharmaceutical composition is provided, wherein the administration is intravenous. In various embodiments of this description, a pharmaceutical composition is provided, wherein the administration is intramuscular.

In various embodiments of this description, a pharmaceutical composition is provided, characterized in that the dose of the active ingredient described herein is administered once a day. In various embodiments of this description, a pharmaceutical composition is provided, characterized in that the dose of the active ingredient described herein is administered twice a day. In various embodiments of this description, a pharmaceutical composition is provided, characterized in that the dose of the active ingredient described herein is administered three times a day.

Application methods

Also provided herein are methods of treating migraine in a mammal comprising administering to a mammal in need of such treatment an effective amount of Compound I pseudopolymorph and mixtures thereof as described herein. In various embodiments, the Compound I pseudopolymorph is selected from Form D, Form E, and Form F of Compound I, and mixtures thereof, alone or in combination with Form A, as described herein. In various embodiments of any of the methods described herein, the pseudopolymorph of Compound I is selected from Form D, Form E, and Form F of Compound I, and mixtures thereof, including mixtures of one or more Forms D, E, and F with Form A, as described in this document. In various embodiments, the mammal is a human.

Various embodiments of this disclosure also provide methods for enhancing 5-HT1F receptor activation by administering an effective amount of Compound I pseudopolymorph and mixtures thereof, including mixtures with Form A as described herein, while preventing vasoconstriction, for the treatment of various disorders associated with reduced neurotransmission of serotonin in mammals. These disorders are migraine, generalized pain, trigeminal neuralgia, toothache or dysfunctional temporomandibular joint pain syndrome, anxiety, generalized anxiety disorder, panic disorder, depression, sleep disturbances, chronic fatigue syndrome, premenstrual syndrome, or late luteal phase syndrome. PTSD, memory loss, dementia including senile dementia, social phobia, autism, attention deficit hyperactivity disorder, disorganized conduct disorder, impulse control disorder, borderline personality disorder, obsessive-compulsive disorder, premature ejaculation, erectile dysfunction, bulimia, anorexia nervosa, alcoholism, tobacco abuse, mutism and trichotillomania. The pseudopolymorphs described herein are also useful as a prophylactic treatment for migraine.

In cases where disorders that can be treated with serotonin agonists are known according to an accepted and approved classification, their classification can be found in various sources. For example, the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV™) fourth edition (1994, American Psychiatric Association, Washington, DC) now provides a diagnostic tool for many of the disorders described in this document. In addition, many of the disorders described in this document are classified in the International Classification of Diseases, Tenth Revision (ICD-10). Those skilled in the art will appreciate that there are alternative nomenclatures, nosologies, and classification systems for the disorders described herein, including those described in DSM-IV and ICD-10, and that terminology and classification systems evolve with medical science. progress.

The use of a compound I pseudopolymorph selected from Forms D, E and Form F of Compound I, as well as mixtures thereof, including mixtures with Form A as described herein, to activate the 5-HT1F receptor, to inhibit neuronal peptide extravasation in general or in in particular by stimulating the trigeminal ganglion, and/or for the treatment of any of the disorders described above, are embodiments of the present invention.

The term "effective amount" means that amount of the pseudopolymorph described herein that can activate 5-HT _1F receptors and/or inhibit neuronal protein extravasation.

As used herein, treating or treating includes any effect, such as amelioration, reduction, modulation, or exclusion, that results in alleviation of a condition, disease, disorder, and the like. To treat or treat a disease state means the treatment of a disease state in a mammal, in particular a human, and includes: (a) suppression of an existing disease state, i.e. stopping its development or its clinical symptoms; and/or (c) alleviating the disease state, i. e. initiation of disease state regression.

In this context, prevention means preventing the development of the clinical symptoms of a disease state, i.e. delaying the onset of a disease in a subject who may be susceptible to or predisposed to the disease state but not yet experiencing or showing symptoms of the disease state.

Examples

The following examples are illustrative and should in no way be construed as limiting the scope of the present invention.

Example 1 Preparation of Form D (Hydrate 1)

Form D can be obtained, for example, by one of the following methods, including (1) a wet granulation process starting from form A, (2) storing form A at 25°C and 96% relative humidity (RH), (3) recrystallization from mixtures solvent/water with high water activity, (4) storing amorphous compound I at 40°C and 75% RH, (5) suspending amorphous compound I in solvent/water mixtures with high water activity, (6) preparing a suspension of amorphous compound I in water at or above room temperature, (7) obtaining a suspension of form F in water at 37°C, (8) obtaining an alternative suspension of form F, for example, in a mixture of ethanol-water (50/50 v/v) at 20 °C.

In a specific example, Hydrate 1 (Form D) was produced by a wet granulation process using a Diosna P 1/6 high shear granulator. 200 g of Form A of Compound I was mixed with water in an amount of from about 40 to 90% (w/v) in a 4 L flask. The initial dry mix of the mixture before adding liquid was maintained as a constant factor (2 min, impeller speed according to this run, chopper off). A spray rate (g*kg/min) of 20 to 60 was used at an impeller speed of 400-900 rpm, which corresponds to a tip speed of 4.6-10.3 m/s. When clinically acquired on the Roto RIO, the center point of this handpiece speed range corresponds to the handpiece speed on the Roto RIO (7.3 m/s). When manufactured on the PMA65, the corresponding tip speed is 9.8 m/s. The massaging time is from 0 to 2 minutes. The results of the experiment with varying the indicated parameters are given below; all these runs resulted in Hydrate 1 (Form D) as analyzed in the pre-drying step. Only in run 9 did the dehydrated hydrate (Form E) result from drying; the crystals obtained in all other runs, when dried, remained in the form of Hydrate 1.

Run Sprinkling rate (g*kg/min.) Impeller speed (rpm) Amount of water (%) Massaging time (min.). 1 20 400 87 2 2 60 400 87 0 3 40 650 66 1 4 40 650 66 1 5 60 900 45 0 6 40 650 66 1 7 20 400 45 0 8 60 400 45 2 9 20 900 45 2 10 20 900 87 0 AND 60 900 87 2

The granules were dried in a fluid bed system with the following settings: air supply volume: 60 m ³ /h.

air inlet temperature: 70°C product outlet temperature: 22 -> 34°C product temperature: 23 -> 50°C drying time and loss on drying (LOD):

min.; LOD = 13.2% 160 min. LOD = 5.1% 235 min; LOD = 4.9% 290 min; LOD = 4.3%

LOD was measured in a thermobalance, measuring the weight loss after 15 min at 70°C.

Granule samples were taken after the massaging time (wet granules) and during the

- 11 041348 drying (after 160 and 235 minutes). Samples were checked using XRD and TGA. All samples showed a XRD diagram corresponding to Hydrate 1 (Form D) obtained by suspending in water. The TGA data show the same weight loss for samples at 160 and 235 minutes for wet pellets taken after the massaging time.

In another specific example, Form D is prepared by suspending Form A as follows: A saturated solution of Compound I Form A (50 mg/mL) was prepared with sufficient solids for VRD, DSC, TGA and optical microscopy. The suspension was stirred for 4 hours and then the solid was isolated and analyzed. The solid was tested by XRD when wet and after drying, and by other methods only after drying. After suspension, a new form was found, named Hydrate 1 (Form D). This shape remained unchanged after drying the material.

In another specific example, form D was obtained in an expanded production by suspending an amorphous material in a mixture of MEK (methyl ethyl ketone) and water, 95/5 v/v, at 5°C. Suspension of Form A in water also produced Form D material, but the sample became sticky during recrystallization, which can cause mixing problems on a larger scale. In addition, a long mixing period was required for complete crystallization of the Form D material. Using an amorphous material as a starting material, a solvent/water mixture with high water activity, after stirring overnight at 5°C, a highly crystalline Form D material was obtained. The MEK/water mixture was chosen as the best solvent in terms of crystallinity and yield.

The amorphous substance was transferred to a glass reaction tube and weighed to obtain an initial mass of amorphous substance of 882 mg. The solid was cooled to 5° C. and 7.5 ml of pre-chilled MEK/water, 95/5 v/v was added to form a suspension. After approximately 10 minutes of agitation, the sample was seeded with the previously prepared Form D material. The sample was stirred at 5° C. (300 rpm) for 2 days. A small amount of the suspension was filtered off and dried in air for 10 min, then analyzed by XRD. The bulk sample was filtered through a nylon filter with a pore size of 0.22 μm and dried on the filter with suction for ~1 h. The filter cake was broken with a spatula and the powder was left to dry overnight at ambient conditions. The dried solid was weighed to give a yield of 843.3 mg.

Characterization

Scaling up form D gave a crystalline, coarse white powder that matched the reference diffraction pattern of form D. 1H NMR and KF (Karl Fischer) analysis confirmed that this form was the hemisuccinate salt dihydrate of compound I. The sample was chemically pure, according to HPLC, purity was 99.9%. Microscopy showed that the sample consisted of very small particles arranged in agglomerates, which were porous due to the presence of gaps between the small primary particles. Individual particles were irregularly shaped with a smooth surface.

Example 2: Get form F

Form F can be obtained, for example, starting from an amorphous compound I and receiving a suspension in water at 5°C; or an alternative suspension can be prepared starting from Form A seeded with Form F in water at 20°C or in a mixture of ethanol/water (50:50) at 5°C.

A. Zoom in

Amorphous samples of compound I were transferred to a glass reaction tube and weighed to obtain an initial mass of amorphous material of 913 mg. The solid was cooled to 5° C. and 12.5 ml of pre-chilled water was added to form a thick slurry. After approximately 10 minutes of agitation, the sample was seeded with ˜10 mg of the previously prepared Form F material. The sample was stirred at 5° C. (300 rpm) for 2 ^1/2 _days . A small amount of the suspension was filtered off and dried in air for 10 min, then analyzed by XRD. The bulk sample was filtered through a nylon filter with a pore size of 0.22 μm and dried on the filter with suction for ~1 h. The filter cake was broken with a spatula and the powder was left to dry overnight at ambient conditions. The dried solid was weighed to give a yield of 874.5 mg.

B. Characterization

Scaling up Form F gave a crystalline fine white powder that matched the reference diffraction pattern of Form F. 1H NMR and KF (Karl Fischer) analysis confirmed that this form was the unsolvated hemisuccinate salt trihydrate of Compound I. The sample was chemically pure by HPLC, the purity was 100%. The sample consisted of very small particles ordered in fragile agglomerates. The individual particles were irregularly shaped with a smooth surface, and few drusoid particles were observed.

Example 3: X-ray Powder Diffraction Analysis of Forms D and F

A. Bruker AXS C2 GADDS

X-ray powder diffraction (XRD) diffractograms were recorded on a diffractometer

- 12 041348

Bruker AXS C2 GADDS using Cu Ka radiation (40 kV, 40 mA), XYZ automatic platform, laser video microscope for automatic sample repositioning, and 2D Hi Star area detector. The X-ray optics consisted of a single multilayer Gobel mirror coupled to a collimator with a pinhole of 0.3 mm. Beam divergence, i.e. the effective size of the X-ray beam on the sample was about 4 mm. A θ-θ continuous scan mode was used with a sample-to-detector distance of 20 cm, resulting in an effective 2θ range of 3.2 to 29.7°. As a rule, the sample was exposed to the X-ray beam for 120 s. GADDS software for XP/2000 4.1.43 was used for data logging and data was analyzed and presented using Diffrac Plus EVA version 15.0.0.0.

For studies conducted under ambient conditions, the samples were obtained in the form of flat plates using the powder of the indicated form. About 1-2 mg of the sample was lightly pressed onto a glass slide to form a flat surface. For studies conducted under conditions other than ambient conditions, samples tested under conditions other than ambient conditions were placed on a silicon wafer with a layer of heat-conducting composition. The sample was then heated to the appropriate temperature at a rate of 10° C./min and then held isothermally for 1 min before data recording began.

B. Bruker AXS D8 Advance

XRD patterns were recorded on a Bruker D8 diffractometer using Cu Ka radiation (40 kV, 40 mA), a θ-2θ goniometer and V4 divergence and receiving slits, with a Ge monochromator and a Lynxeye detector. Diffrac Plus XRD Commander version 2.6.1 software was used for data logging and data was analyzed and presented using Diffrac Plus EVA version 15.0.0.0.

Samples were analyzed at ambient conditions in the form of flat plates using the powder of the indicated form. The sample was carefully placed in a recess cut in a polished silicon wafer with zero background (510). During the analysis, the sample was rotated in its own plane. Data acquisition details: Angular range: 2 to 42° 2θ; step size: 0.05° 2a; recording time: 0.5 s/step.

C. PANalytical Empyrean

XRD patterns were recorded on a PANalytical Empyrean diffractometer using Cu Ka radiation (45 kV, 40 mA) in transmission geometry. A 0.5° slit, a 4 mm mask, and a 0.04 rad Soller slit with a focusing mirror were used on the incident beam. A PIXcel3D detector mounted on a diffracted beam was equipped with a receiving slit and 0.04 rad Soller slits. X'Pert Data Collector software version 5.3 was used for data collection and data was analyzed and plotted using Diffrac Plus EVA version 15.0.0.0 or Highscore Plus version 4.5.

Samples were obtained and analyzed on a metal or 96-well Millipore plate in transmission mode. A plate with metal wells is made of an X-ray transparent film inserted between two metal sheets. Dry powder (about 5 mg) was lightly pressed into the assay wells. A Millipore plate was used to isolate and analyze solids from suspensions by adding a small amount of suspension directly to the plate before low vacuum filtration.

The metal plate scan mode used the gonioscan axis and the Millipore plate used a 2θ scan.

Data acquisition details: Angular range: 2.5 to 32.0° 2θ; step size: 0.0130° 2θ; recording time: total recording time 2.07 min. The longer method can also be used: angular range: 2.5 to 42.0° 2θ; step size: 0.0130° 2θ; recording time: total recording time 8.0 min.

Variable temperature PRT experiments (PTT-PT) were carried out on samples fixed on a metal sample holder (with a silicon insert) with a heat-conducting connection. The sample was then heated in air to the appropriate temperature at a rate of 5°C/min. The sample was analyzed at selected temperatures using the 8 minute method (described above).

D. Results for form D and form F.

The PDP diagram for Form D is shown in FIG. 1A; for form F - in fig. 1B. For Form D, XRP-PT showed a gradual conversion (40-60°C) to Form E upon heating, which was reversible as Form E converted back to Form D upon cooling to 35°C. Additional heating (80-95°C) caused form E to form A. For form F, XRD-PT showed a loss of crystallinity at 70°C, transformation to partially crystalline Form A at 75°C, but additional heating was required (up to 100°C). C) for complete crystallization into form A.

Example 4 Single Crystal X-Ray Diffraction (Single Crystal XRD)

The data were recorded on a Rigaku Oxford Diffraction Supernova Dual Source, Cu at Zero, Atlas CCD diffractometer with an Oxford Cryosystems Cobra cooling device. Data was collected using CuKa radiation. The structures were reconstructed using the SHELXTL programs (Sheldrick, 2013) and refined

- 13 041348 using the SHELXTL program from the Bruker AXS SHELXTL software package (version 6.10). Unless otherwise indicated, hydrogen atoms bonded to carbon atoms were placed based on geometric considerations and fitted with a variable isotropic displacement parameter. Hydrogen atoms bonded to a heteroatom were placed according to the results of Fourier synthesis difference minimization and fitting was performed with a free floating isotropic displacement parameter. The RD of a Form D single crystal is shown in FIG. 1D.

Table 1. Single crystal data for form D of compound I

Crystallizing solvent Crystallization method Empirical formula Formula mass Temperature

Wavelength

Crystal size

Crystal habit

Crystal system Space group Unit cell dimensions

Volume

Z

Density (calculated)

Absorption coefficient

F(000)

Water

Evaporation

C21H25F3N3O6

472.44

100(2)K

1.54178 A

0.200 x 0.150 x 0.100 mm clear block monoclinic

C2/s a = 25.0800(7) A b = 10.08215(13) A c = 20.8357(9) A

4382.4(3)A ³

1.432 t/ ^m3

1.048 mm' ¹

1976 a=90° β=123.714(4)' γ=90°

Table 2. List of PRD Form D peaks of Compound I

Form D Compounds I

Intensity

20°

20°

Intensity _

8.5 38.7 21.9 10.0 9.7 31.4 22.4 25.5 11.9 14.2 22.7 10.6 13.8 76.8 23.0 7.5 14.0 67.4 24.1 100.0 15.4 12.5 24.3 11.8 15.5 10.4 24.7 17.5 15.8 44.5 25.6 10.4 17.0 45.5 25.9 39.4 17.3 4.2 26.1 17.1 17.7 6.8 26.4 69.6 18.0 58.7 27.0 20.9 18.7 9.0 27.5 13.1 18.9 13.4 27.8 17.8 19.3 27.1 28.4 14.6 19.8 4.7 29.1 14.6 20.0 27.8 29.6 11.2 20.8 4.3 29.8 8.2 21.4 25.1 31.9 12.4 21.6 10.6

Characteristic peaks in the Form D X-ray diffraction pattern include peaks at about 18.7, 26.5, 27.0, 27.5, and 27.8° 2θ obtained with Cu-Ka radiation.

- 14 041348

Table 3. List of VRD peaks of form E of compound I

Form E Compounds I

20° Intensity (%) 20° Intensity (%) 8.4 100.0 19.7 14.8 9.2 9.5 20.2 19.5 9.7 28.4 20.5 27.7 9.8 69.1 20.7 8.1 10.5 15.5 21.1 15.2 I,9 12.0 21.5 20.6 12.1 37.5 22.0 13.9 12.5 8.4 22.3 11.0 13.9 48.6 22.6 25.0 14.2 89.3 22.9 8.1 15.4 17.5 23.5 I,4 15.6 8.4 24.3 43.3 15.9 33.4 24.5 52.0 16.3 26.2 24.8 I,7 16.4 23.9 25.5 13.1 16.8 19.5 26.0 23.0 16.9 20.3 26.7 64.3 17.0 19.8 27.1 14.2 17.5 6.4 27.7 11.3 17.8 7.2 28.0 11.9 18.1 33.5 28.5 23.6 18.3 57.6 29.3 10.8 18.8 6.7 29.9 16.9 19.0 10.1 30.5 8.7 19.4 15.7 32.2 12.3

The characteristic peaks of the Form E X-ray diffraction pattern include peaks at about 9.2 and 10.5°2θ obtained with Cu-Ka radiation.

Table 4. List of PRD peaks of form F of compound I

Form F Connections I

26° Intensity (%) 20° Intensity (%) 8.6 25.4 22.1 23.6 10.3 12.9 23.3 10.5 12.3 100.0 23.5 5.4 12.7 6.3 24.2 29.9 14.2 6.5 25.1 9.7 14.3 4.9 25.5 9.7 15.2 2.5 25.6 10.2 16.0 4.2 26.3 6.0 17.1 42.6 26.9 26.2 19.2 15.1 27.5 7.2 19.5 4.3 28.5 5.6 20.0 15.0 29.3 8.2 20.3 5.1 30.1 17.0 20.6 34.2 31.7 7.7 21.4 6.3 32.1 7.4 21.5 10.0

Data on the observed and characteristic peaks of form A of compound I, described in US patent 8697876 issued to Carniaux, are presented for reference in table. 5 and 6, respectively.

- 15 041348

Table 5. List of PRD peaks of form A of compound I

2Θ Intensity (%)

7.67±0.10 27 9.61±0.10 33 11.06±0.10 21 13.38±0.10 23 14.07±0.10 41 15.11±0.10 51 15.32±0.10 62 16.15±0.10 44 16.39±0.10 100 16.81±0.10 47 18.47±0.10 43 19.33±0.10 61 21.51±0.10 28 22.14±0.10 53 23.18±0.10 46 23.39±0.10 46 23.56±0.10 59 23.84±0.10 33 24.77±0.10 36 25.01±0.10 24 25.91±0.10 52 26.68±0.10 20 28.65±0.10 19 29.31±0.10 12

Table 6. List of characteristic peaks of VRD form A of compound I

2Θ Intensity(%) 15.32±0.10 16.39±0.10 19.33±0.10 22.14±0.10 23.56±0.10 25.91±0.10 62 100 61 53 59 52

Example 5 Comparative Analysis of Some PRD Peaks for Forms A, D and E

For comparison, in Fig. 1E-G are partial diagrams of Form D TX (blue line); form A (green); form E (red). For form A, a distinctive peak was noted at about (± 0.2° 2θ) 7.7° 2θ. Form D features peaks at about (±0.2° 2θ) 18.7° 2θ, 26.5° 2θ, 27.0° 2θ, 27.5° 2θ and 27.8° 2θ. For form E, distinctive peaks are noted at about (± 0.2° 2θ) 9.2° 2θ and 10.5° 2θ.

As can be seen from the data above, Forms D, E, and F of Compound I have unique PDD patterns that can be used to differentiate each of these forms from Form A of Compound I.

Example 6 Nuclear Magnetic Resonance (NMR)

NMR spectra were recorded on a Bruker 400 MHz instrument equipped with an automatic sampler and controlled from a DRX400 remote control. Automated experiments were performed with ICON-NMR version 4.0.7 running Topspin version 1.3 using standard Bruker loaded experiments. For custom spectroscopy, data were recorded using Topspin only. Samples were prepared in DMSO^6 unless otherwise noted. Offline analysis was performed using the ACD Spectrus Processor 2014 software.

As shown in FIG. 5, ¹ H-NMR spectrum in the state of solution of dissolved forms D or F corresponds to the hemisuccinate of compound I, crystallized from methyl ethyl ketone (present in the amount of 0.03 mol. equiv., 0.4 wt.%), showing 0.5 mol. equiv. succinic acid.

Example 7 Thermal Analysis (A) Differential Scanning Calorimetry (DSC)

DSC data were recorded on a TA Instruments Q2000 equipped with a 50 position autosampler. Heat capacity calibration was performed using sapphire, and certified indium was used for energy and temperature calibration. Typically, 0.5-3 mg of each sample in an aluminum crucible with a hole in the lid was heated at a rate of 10°C/min from 25 to 250°C. A flow of dry nitrogen was maintained over the sample at a rate of 50 ml/min.

Temperature modulated DSC was performed using an initial heating rate of 2°C/min and temperature modulation parameters of ±0.64°C (amplitude) every 60 s (period).

Advantage software for Q Series version 2.8.0.394 and Thermal Advantage version 5.5.3 were used to control the instrument, and data was analyzed using Universal Analysis version 4.5A.

(B) Thermogravimetric analysis (TGA)

TGA data was collected using a TA Instruments Q500 TGA equipped with a 16 position autosampler. Temperature calibration of the device was carried out using certified alumel and nickel. Typically, 5-10 mg of each sample was placed in a pre-tared aluminum DSC crucible and heated at a rate of 10°C/min from room temperature to

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350°C. A flow of nitrogen was maintained over the sample at a rate of 60 ml/min. Advantage software for Q Series version 2.5.0.256 and Thermal Advantage version 5.5.3 were used to control the instrument, and data was analyzed using Universal Analysis version 4.5A.

(C) DSC and TGA results for form D and form F

Superimposed DSC and TGA results for Form D are shown in FIG. 2, and for form F, in FIG. 3.

For form D, TGA showed a loss of 7.5 wt.% in the range of 25-110°C, which corresponds to 2.0 mol. equiv. water, with decomposition at about 200°C. DSC analysis showed the onset of a broad endotherm at 53.1 C (158.2 J/g), which corresponds to the loss of water, the onset of a broad exotherm at 92.1 C (-24.9 J/g) during recrystallization, and the onset of a sharp endotherm reflecting melting, at 197.9 C (-119.0 J/g).

For form F, TGA showed a loss of 11.4 wt.% in the range of 25-150°C, which corresponds to 3.1 mol. equiv. water, with decomposition at about 200°C. DSC analysis showed the beginning of a wide endotherm at 71.2°C (198.4 J/g), the beginning of a gentle endotherm (2 peaks) at 95.7°C (-6.4 J/g), the beginning of a gentle exotherm (2 peaks ) at 103.4°C (26.9 J/g) and the onset of an acute endotherm at 197.8°C (-114.4 J/g) reflecting melting.

Example 8 Microscopy

A. Polarized light microscopy (PLM)

A.1. Polarizing microscope Leica LM/DM

The samples were examined on a Leica LM/DM polarizing microscope with a digital video camera to obtain photographs. A small amount of each sample was placed on a glass slide, fixed in immersion oil and covered with a glass strip, the individual particles were separated as carefully as possible. The sample was viewed at appropriate magnification in partially polarized light coupled to a λ artificial color filter.

A. 2. Nikon LM/DM polarizing microscope

The samples were examined on a Nikon SMZ1500 polarizing microscope with a digital video camera connected to a DS camera control unit DS-L2 to take photographs. A small amount of each sample was placed on a glass slide, fixed in immersion oil, and the individual particles were separated as thoroughly as possible. The sample was viewed at appropriate magnification in partially polarized light coupled to a λ artificial color filter.

B. Scanning electron microscopy (SEM)

Data were recorded on a Phenom Pro scanning electron microscope. A small amount of the sample was fixed on an aluminum head using a conductive double-sided adhesive tape. A thin layer of gold was deposited using an ion sputtering device (20 mA, 120 s).

Example 9 Determination of water content by Karl Fischer (KF) titration

The water content of each sample was measured on a Metrohm 874 oven sampler at 150° C. with an 851 Titrano coulometer using Hydranal Coulomat AG oven reagent and a stream of nitrogen. The weighed solid samples were placed in a sealed sample vial. About 10 mg of sample was used for one titration and two measurements were taken. Data collection and analysis was performed using Tiamo version 2.2.

For form D, a loss of 7.6 wt % is set, which corresponds to 2.0 mol. equiv. water, confirming the dihydrate form. For form F, a loss of 11.6 wt.% is established, which corresponds to 3.2 mol. equiv. water, confirming the trihydrate form.

Example 10 Determination of Chemical Purity by HPLC

As shown in FIG. 4A, HPLC trace form D shows a chemical purity of 99.93%; and in FIG. 4B, HPLC trace of Form F shows a chemical purity of 99.95%.

Purity analysis was performed on an Agilent HP 1100 series system equipped with a diode array detector using ChemStation software version B.04.03, as detailed below:

Parameter Meaning Method type Reverse phase with gradient elution Getting a Sample 0.4 mg/ml in acetonitrile : water 1:1 Column Supelco Ascentis Express C18, 100 x 4.6 mm, 2.7 microns Column temperature (°C) 25 Sample injection (µl) 5 Wavelength, bandwidth (nm) 255, 90 Flow rate (ml/min.) 2 Phase A 0.1% TFA in water Phase B 0.085% TFA in acetonitrile Temporary scheme Time (min.) % Phase A % Phase B 0 95 5 6 5 95 6.2 95 5 8 95 5

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Example 11 Dynamic Vapor Sorption (DSP)

Sorption isotherms were obtained using an SMS DVS Intrinsic moisture uptake analyzer controlled by DVS Intrinsic control software version 1.0.1.2 (or version 1.0.1.3). The tool control system provided control of the sample temperature at the level of 25°С. Humidity was controlled by mixing dry and wet nitrogen streams at a total flow rate of 200 ml/min. Relative humidity was measured with a calibrated Rotronic probe (dynamic range 1.0-100% relative humidity) placed near the sample. The change in mass (mass relaxation) of the sample as a function of % RH was constantly monitored using a microbalance (accuracy ± 0.005 mg). Typically, 5-20 mg of sample was placed in a calibrated stainless steel sieve cuvette at ambient conditions. The sample was loaded and unloaded at 40% RH and 25°C (standard room conditions). The moisture uptake isotherm was recorded using the parameters below (2 scans correspond to 1 complete cycle). A standard isotherm was recorded at 25° C. at 10% RH intervals in the 0-90% RH range. Data analysis was performed using Microsoft Excel using the analytical package DVS version 6.3.

Parameter Meaning Adsorption - 1 scan 40-90 Desorption / adsorption - 2 scans 90 - 0, 0 - 40 Intervals (%RH) 10 Number of scans 2 Flow rate (ml/min.) 200 Temperature (°C) 25 Stability (°C/min.) 0.2 Sorption time (hours) 6 hour break

results

Form D showed a significant weight loss at the 10% RH step, but the weight increased again as soon as the humidity was raised to 20% RH. The residue after the EAF experiment was mainly form D, but some peaks corresponding to form F were observed, indicating that form D is not quite stable at low relative humidity.

Form F showed little weight change until the first 0% RH step when a loss of 9.6 wt.% (2.6 mol. eq. of water) was observed before the end of the experiment (Fig. 7). It is likely that if the sample is kept at 0% RH longer than the maximum step time of 6 hours, then all three moles of water will be lost. As moisture increased, the sample weight gradually increased to 70% RH, when a weight loss (typical of a crystallization event) was observed after weight growth. It then crystallized at the 70% RH stage when it had taken in enough water. The behavior in the second cycle was similar, but with an overall weight loss corresponding to the crystallized material being a dihydrate rather than a trihydrate starting material. This fact was confirmed by analysis of the residue after the EAF experiment (which was a crispy solid) which is mainly form D with a small amount of form F. The results obtained demonstrate that form F is unstable at low relative humidity.

Example 12 Thermodynamic Solubility in Water

Way. Solubility in water was determined by suspending a sufficient amount of the compound in water to obtain a maximum final concentration of >23 mg/ml of the original free form of the compound. The suspension was equilibrated at 37°C for 24 h, then the pH was measured. The suspension was then filtered through a glass fiber filter C. The filtrate was then diluted an appropriate number of times. For quantitative determination, HPLC was used against a standard solution of approximately 0.2 mg/mL in DMSO. Various volumes of standard, dilute, and undiluted sample solutions were injected. Solubility was calculated from peak areas determined by integrating the peak at the same retention time as the main peak of the introduced standard. The solubility given refers to the original free form of compound I.

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Claims (9)

Parameter Meaning Method type Reverse phase with gradient elution Column Phenomenex Luna, Cl8 (2) 5 µm, 50 x 4.6 mm Column temperature (°C) 25 Sample injection standard (µm) 1, 2, 3, 4, 5, 7 Experimental Sample Injection (µl) 1,2,3, 10, 15,20 Detection: wavelength, bandwidth (nm) 260, 90 Flow rate (ml/min.) 2 Phase A 0.1% ΤΦΚ in water Phase B 0.085% ΤΦΚ in acetonitrile Temporary scheme Time (min.) % Phase A % Phase B 0.0 95 5 1.0 80 20 2.3 5 95 s, s 5 95 3.5 95 5 4.4 95 5 results Suspension of form D in water at 37° C. did not change shape and measured thermodynamic solubility was 6.2-6.4 mg/mL (free form corrected for water and counterion in hemisuccinate dihydrate). No conversion to the trihydrate form F occurred at this temperature. The pH of the unfiltered saturated solution was 7.0. Suspension of form F in water at 37°C resulted in conversion to form D. Initially, the sample was highly soluble (kinetic solubility of form F -32 mg/ml), but over time, a solid corresponding to form D began to slowly precipitate. Thermodynamic solubility of this sample (form D) in water was measured after 24 h at 8.6 mg/mL (free form, corrected for water and counterion content in the hemihydrate dihydrate). It is not possible to measure the thermodynamic water solubility of form F at 37°C because form F is unstable under these conditions and converts to form D. The pH of the unfiltered saturated solution was 7.2. Although the present invention has been described in conjunction with its detailed description, the foregoing description is intended to illustrate and not limit the scope of the present invention, which should be determined by the scope of the appended claims. Other aspects, advantages and modifications are within the scope of the following claims. Those skilled in the art will appreciate that various changes in form and detail may be made to the invention without departing from the scope of the invention as defined by the appended claims. CLAIM 1. 2,4,6-Trifluoro-N-[6-(1-methylpiperidine-4-carbonyl)pyridin-2yl]benzamide hemisuccinate salt dihydrate (Form D), characterized by an X-ray diffraction pattern containing peaks at 18.7, 26 .5, 27.0, 27.5, and 27.8° 2θ, ± 0.2° 2θ, using Cu-Ka radiation. 2. The dihydrate according to claim 1, characterized in that the X-ray diffraction pattern contains one or more of the following additional peaks at 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, 26.4, 28.4, 29.1, 29.6, 3θ2° , using Cu-Ka radiation. 3. The dihydrate according to claim 1, additionally characterized by unit cell parameters at 100 K of about a = 25.08 A, b = 10.08 A, c = 20.84 A, α = 90°, β = 123.71 and angle γ = 90°. 4. The dihydrate according to claim 1, obtained by a method comprising wet granulation of amorphous 2,4,6-trifluoro-N-[6-(1-methylpiperidine-4-carbonyl)pyridin-2-yl]benzamide hemisuccinate. 5. Pharmaceutical composition containing the dihydrate according to any one of claims 1 to 4 and a pharmaceutically acceptable carrier. 6. Pharmaceutical composition according to claim 5, characterized in that said dihydrate is substantially free of impurities. 7. Pharmaceutical composition according to claim 6, characterized in that said dihydrate has a chemical purity of more than 98.0%, as determined by HPLC. 8. Pharmaceutical composition according to claim 5, additionally containing an anhydrous solid crystalline form of hemisuccinate salt of 2,4,6-trifluoro-N-[6-(1-methylpiperidine-4-carbonyl)pyridin-2yl]benzamide (Form A). 9. The use of a dihydrate according to any one of claims 1 to 4 for the treatment of migraine. -