EA046754B1 - COMPOSITION RELATED TO PYRIDINOYLPIPERIDINE 5-HT1F AGONISTS - Google Patents

Description

Field of technology

This invention relates to a composition containing the dihydrate of the hemisuccinate salt of 2,4,6trifluoro-H-[6-(1-methylpiperidin-4-carbonyl)pyridin-2-yl|benzamide. useful for activating 5-HT _1f receptors and for the treatment or prevention of migraine.

State of the art

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

The pathogenesis of migraine is not fully understood. Typically, the main cause of migraine headaches is considered to be vasodilation (Wolff's Headache and Other Head Pain. Ed Silberstein et al., Oxford University Press, 2001). Triptans, selective 5-HTIB/ID receptor agonists with reasonable efficacy against migraine, have been developed (Ferrari MD et al., Lancet 2001: 358; 1668-1675) based on the assumption that 5-HT _1f receptor-mediated vasoconstriction in the skull is a prerequisite for effectiveness against migraine (Humphrey PPA et al., Ann NY Acad Sci 1990; 600: 587-598). As a consequence, triptans also carry a risk of causing 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, 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 avoid vasoconstrictor activity are needed.

In recent decades, it has become clear that cranial vasodilation, if it occurs at all, during a migraine attack (Schoonman GG et al., Brain 2008; 131: 192-200) may 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. In contrast, neural inhibition of the trigeminal pathway would provide a promising alternative mechanism for combating migraine that does not involve the blood vessels. Indeed, LY334370, a neuroactive selective 5-HT _1f receptor agonist with no vasoconstrictor effects at clinically relevant concentrations, proved effective in the acute treatment of migraine in an early proof-of-concept clinical trial (Goldstein DJ et al., Lancet 2001; 358: 1230-4 ). Unfortunately, clinical development of LY334370 was discontinued due to safety concerns associated with this compound in long-term use in animals.

2,4,6-Trifluoro-N-[6-(1-methylpiperidin-4-ylcarbonyl)pyridin-2-yl]benzamide (compound I) is a novel selective and highly potent 5-HT _1f receptor agonist with Ki at 5HT receptors human _{1f is} 2.21 nM and has an affinity that is more than 450 times higher for 5-HT _1f receptors than for other 5-HT ₁ receptor subtypes (Nelson DL et al., Cephalalgia 2009: 29; 122). US Patent No. 7,423,050 and US Publication No. 20080300407 describe Compound I and other pyridinoylpiperidine selective 5-HT _1f agonists that are active in neurotransmitter preclinical models of migraine without causing vasoconstriction (ie, neuroactive anti-migraine agents (NAANA)). The experiments described in the above publications show effective inhibition of cFos induction in the trigeminal nucleus caudalis and inhibition of dural extravasation of plasma protein 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 for human coronary vasoconstriction (Nelson DL et al., Cephalalgia 2009: 29; 122).

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

In addition to various solid crystalline forms, which are usually called polymorphs, a drug substance can also exist in various pseudo-polymorphic forms, such as solvates and clathrates. The term solvate means a compound obtained by 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, for example, hemihydrate, monohydrate, dihydrate, trihydrate, tetrahydrate, etc. The term clathrate refers to a drug substance in the form of a crystal lattice that contains voids (such as channels) in which guest molecules are located (on

- 1 046754 example, solvent or water) trapped inside.

Polymorphic and pseudo-polymorphic 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 produced, it is desirable to have a method for producing both polymorphs in pure form. When deciding whether one polymorph is preferable, multiple properties of the polymorphs must be compared, and the preferred polymorph is selected based on many physical property variables. It is possible that one polymorphic form may be preferred in certain circumstances if certain aspects such as ease of preparation, stability, etc. are important. In other situations, a different 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 significantly influence the physicochemical and pharmaceutical processing of the compound, particularly when preparing or using the compound on an industrial scale.

There are stringent regulatory requirements for medicinal substances intended for pharmaceutical use, which include, among other things, precise knowledge of the polymorphic or pseudo-polymorphic form of the active pharmaceutical ingredient (API) in the dosage form. The importance of recognizing and controlling changes in solid forms 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 determine and control the characteristics of the polymorphic and/or pseudo-polymorphic form of an API in a dosage form, both to satisfy 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-L-[6-(1-methylpiperidin-4-carbonyl)pyridin2-yl]benzamide, as well as methods for controlling their content in solids. dosage forms.

The essence of the invention

This invention relates to pseudo-polymorphic forms of 2,4,6trifluoro-L-[6-(1-methylpiperidin-4-carbonyl)pyridin-2-yl]benzamide hemisuccinate salt, also referred to herein as Compound I or lasmitidan hemisuccinate. The pseudopolymorphic forms of Compound I described herein are unexpectedly generated during the industrial production of pharmaceutical products. The pseudo-polymorphic forms described herein are useful for activating 5-HT _1F receptors and for treating or preventing migraine headaches.

Various embodiments of this disclosure provide Compound I in the form of a solvate. In various embodiments, the solvate is a hydrate. In various embodiments, the hydrate is a dihydrate or trihydrate. Various embodiments of this disclosure provide a hydrate or dehydrated hydrate having a powder x-ray diffraction (XRD) pattern substantially similar to one of those shown in FIG. 1.

In fig. 1A is a PRD diagram of Form D, dihydrate, also referred to as Hydrate 1, obtained using Cu-Ka radiation. In various embodiments, the Shape D PDP diagram contains at least peaks at about 18.7, 26.5, 27.0, 27.5, and 27.8 degrees 2θ, ±0.2 degrees. In various embodiments, the Form D PRD diagram contains one or more additional peaks presented in table. 2. In various embodiments of this description, form D is proposed, characterized by unit cell parameters at 100 Kelvin about a = 25.08 A, b = 10.08 A, c = 20.84 A, α = 90°, β = 123, 71, and angle γ=90°.

In fig. Figure 1B shows the PDP diagram of Form F, the trihydrate. In various embodiments, the Form F PRD diagram contains the peaks presented in Table. 4.

In fig. 1C shows the PDP diagram of Form E, dehydrated Form D. In various embodiments, the PDP diagram of Form E obtained using Cu-Ka radiation contains at least peaks at about 9.2 and 10.5 degrees 2θ, ±0.2 degrees . In various embodiments, the PRD diagram of Form E contains the peaks presented in Table. 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.

Various embodiments of this disclosure provide Compound I in the form of dihydrate form D, characterized by a differential scanning calorimetry (DSC) thermogram having a broad endotherm beginning at 53.1° C. (-158.2 J/g), a broad exotherm beginning at 92.1°C (24.9 J/g), and a sharp endotherm starting at 197.9°C (-119.0 J/g). IN

- 2 046754 various embodiments, Form D shows a DSC thermogram substantially corresponding to FIG. 2.

Various embodiments of this disclosure provide Compound I in the form of trihydrate form F, characterized by a DSC thermogram having a broad 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 flat exotherm (2 peaks) at 103.4°C (26.9 J/g), and a sharp endotherm starting at 197.8°C (-114. 4 J/g). Various embodiments of this disclosure provide Compound I in the form of trihydrate form F, exhibiting a DSC thermogram substantially consistent with that in FIG. 3.

In various embodiments, the pseudo-polymorphic 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 a continuous recording of the change in mass of a material sample as a function of temperature and time combined.

One embodiment of this disclosure provides Compound I in the form of dihydrate form D, characterized by TGA showing a loss of 7.5 wt.% in the range of 25-110°C, corresponding to 2.0 mol. equivalents of water, and the onset of destruction at about 200°C, essentially in accordance with FIG. 2.

One embodiment of this disclosure provides Compound I in the form of trihydrate form F, characterized by TGA showing a loss of 11.4 wt.% in the range of 25-150°C, corresponding to 3.1 mol. equivalents of water, and the onset of destruction at about 200°C, essentially in accordance with FIG. 3.

Various embodiments of this disclosure provide Compound I in the form of dihydrate form D, characterized by a Cu-Ka radiation PRD diagram that contains peaks at about 18.7, 26.5, 27.0, 27.5, and 27. 8 degrees 2θ, ±0.2 degrees, and a DSC thermogram having the beginning of a wide endotherm at 53.1°C (-158.2 J/g), the beginning of a wide ectotherm at 92.1°C (24.9 J/g ) and the beginning of a sharp endotherm at 197.9°C (-119.0 J/g).

Various embodiments of this disclosure provide Compound I in the form of dihydrate Form D having substantially the same X-ray diffraction pattern as in FIG. 1 A, and essentially the same DSC thermogram as in FIG. 2.

Various embodiments of this disclosure provide Compound I in a dihydrate form (Form D) prepared by a process comprising one of the following (1) a wet granulation process based on 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) preparing a suspension of amorphous compound I in water at or above room temperature, (7) preparing a suspension of Form F in water at 37°C, (8) preparing an alternative suspension of Form F, for example, in an ethanol-water mixture ( 50/50 v/v) at 20°C. Form A is the anhydrous solid crystalline form of Compound I.

Various embodiments of this disclosure provide Compound I in the form of a trihydrate (Form F) prepared by a process comprising using amorphous Compound I as a starting material and preparing a suspension in water at 5° C.; or preparing an alternative suspension 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.

In accordance with embodiments described herein, 2,4,6-trifluoro-N-[6-(1methylpiperidin-4-carbonyl)pyridin-2-yl]benzamide and its hemisuccinate salt, Compound I, can be prepared by methods such as: described in the art. For example, as described in US 8697876 and US 7423050.

Also provided herein are pharmaceutical compositions containing Compound I in the form of a hydrate, such as a dihydrate or trihydrate, or a dehydrated hydrate, including mixtures thereof, and a pharmaceutically acceptable carrier. In various embodiments, the pharmaceutical composition contains one or more of Form D, Form E, and Form F of Compound I. In various embodiments, the pharmaceutical composition contains 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 contains Form D of Compound I having a chemical purity of about 98%, about 99%, or about 99.9%, as determined by HPLC. In various embodiments, the pharmaceutical composition contains Form F of Compound I having a chemical purity of about 98%, about 99%, or about 99.9%, as determined by HPLC.

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 a pseudopolymorph of Compound I described herein, or mixtures thereof. In various versions

- 3 046754 lysis pseudo-polymorph of compound I 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 pseudo-polymorph 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.

Brief description of graphic materials

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

Fig. 2. DSC thermogram and TGA analysis of form D. Results of overlay of DSC (blue line, heat flux (W/g), bottom line and inset) and TGA (green, mass scale (%), top line) for form D.

Fig. 3. DSC thermogram and TGA analysis of Form F. Results of overlay of 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 of form D, having a chemical purity of 99.93%; B, HPLC line of Form F having a chemical purity of 99.95%.

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

Fig. 6. EAF isotherm plot for Form D showing 3 sorption/desorption cycles that are compatible with each other.

Fig. 7. DSP isotherm plot for Form F, showing 3 sorption/desorption cycles, and the desorption lines are uppermost (red and blue) and essentially compatible with each other; the desorption line of cycle 2 is the second line from the top (pink), the sorption line (green) is plotted at RH 0 - ~70%; the sorption line in cycle 3 (purple) was built at RH from 0 to ~40%.

Detailed Description of the Invention

Pyridinoylpiperidine compounds useful for activating the serotonin-lF receptor (5HT1F) and for treating or preventing migraine are described, for example, in US 7423050 and US 2010/0256187. Such compounds include 2,4,6-trifluoro-H-[6-(1-methylpiperidin-4carbonyl)pyridin-2-yl]benzamide hemisuccinate salt (Compound I), which has the structural formula shown below and may also be mentioned as lasmitidan hemisuccinate.

Compound I (hemisuccinate salt of 2,4,6-trifluoro-H-[6-(1-methylpiperidin-4-carbonyl)pyridin2-yl]benzamide).

Certain polymorphic forms of Compound I are also described in US Pat. No. 8,697,876. One of the described forms is a polymorph referred to as Form A. Form A is an anhydrous solid crystalline form of Compound I. In accordance with embodiments described herein, 2,4, 6-Trifluoro-H-[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 the following methods: , described in the art, for example, as described in the '876 patent. The '876 patent describes two additional PRD diagrams, designated Form B and Form C. Additional characteristics of these forms are not provided. For ease of reference, the nomenclature adopted in the '876 patent is retained in this specification. Accordingly, the new pseudopolymorphic forms of compound I described herein are designated Form D, Form E, and Form F. Form D is also designated hydrate 1 or dihydrate. Form E is also referred to as the dehydrated hydrate of Form D, and may exist as a partially or completely dehydrated hydrate of Form D. Form F is also referred to as the trihydrate. The structure of Form F was determined based on mass loss in a crystallization study.

Prior to this invention, it was known that Compound I can exist in various pseudopolymorphic forms described herein. These pseudo-polymorphic forms were discovered accidentally during the process of obtaining a product for industrial pharmaceutical production. Considering that the various regulatory authorities that monitor the approval and use of such pharmaceuticals require precise knowledge, characterization and control of the polymorphic form of the active ingredient in solid pharmaceutical drugs

- 4 046754 forms, there is a need in the art to crystallize and characterize these new polymorphic forms of compound I.

The terms polymorphic form, polymorph, polymorph form, pseudo-polymorph, crystalline form, physical form or crystalline form of 2,4,6-trifluoro-N-[6-(1-methylpiperidin-4carbonyl)pyridin-2-yl]benzamide in this The invention relates to a crystalline modification of the specified compound, which can be characterized by analytical methods such as powder x-ray diffraction (XRD), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA) and gravimetric or dynamic vapor sorption (GSV; DSP).

The term hydrate in this context means a compound of this invention or a salt thereof which further contains a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular bonds. Hydrates are formed when one or more molecules of water combine with one molecule of substances in which water retains its molecular state of H ₂ O, 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 pseudo-polymorph, including the dehydrated hydrate described herein.

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

In various embodiments, the characteristics of pseudo-polymorphs are determined using PRD. The relative intensity of the PRD peaks may vary depending on the sample preparation technology, sample mounting technique, and the specific instrument used. Additionally, instrumental biases and other factors may influence 2-theta values. Thus, the values of the PDP peaks can vary by plus or minus about 0.1, 0.2, 0.3 or 0.4 degrees. For example, in some embodiments, the 2θ values of a form described herein may vary by plus or minus about 0.4 degrees. In other embodiments, the 2θ values of the form described herein may vary by plus or minus about 0.2 degrees. In other embodiments, the 2θ values of the form described herein may vary by plus or minus about 0.1 degree. Pharmaceutical compositions containing the pseudo-polymorph described herein can be identified by comparing the X-ray powder diffraction patterns of the compositions with the X-ray powder diffraction pattern of the pure polymorph. It should be understood that pharmaceutical compositions containing a particular pseudo-polymorph described herein may exhibit non-identical powder X-ray diffraction patterns compared to the powder X-ray diffraction pattern of the pure polymorph.

The pseudo-polymorphs described herein can also be identified by characteristic differential scanning calorimetry patterns, such as those presented in the Figures. It is known that for DSC the observed temperatures 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, values can vary by plus or minus about 6°C.

The pseudo-polymorphic forms of this invention may also exhibit thermal properties that are different from those of 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-polymorph can be characterized using thermogravimetric analysis.

The pseudo-polymorphs of this invention can also be identified using gravimetric vapor sorption (GVA), which measures the rate and extent of solvent absorption by a sample. In one aspect, the pseudo-polymorph can be characterized using gravimetric vapor sorption analysis.

Obtaining a polymorph

The crystallizing solvent is an important factor in determining which polymorph or pseudo-polymorph of compound I is formed. For example, solvents with low water activity, such as ethanol, preferentially form Form A. 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% by volume to about 95% by volume, preferably from about 10% to about 20% by volume, more preferably from about 5% to about 10% by volume volume, and most preferably from about 5% to about 1% water. Forms D and F of Compound I are hydrates and, therefore, there is a minimum limit on the amount of water that must be present for Compound I to crystallize in either of these forms. In addition, the cooling rate and release temperature, as well as the amount of water

- 5 046754 may play a role in determining which polymorph and/or hydrate is formed, as described in more detail above.

It has been found that, based on Form A or the amorphous form of Compound I, upon addition of water alone or water/solvent mixtures, a conversion from Form A or the amorphous form to one of the new pseudo-polymorphic Forms D, E or F occurs. Form A is the dominant form in the absence of water (up to 10% by volume water; water activity approximately 0.6) or at low water activity, for example, in pure ethanol, at any temperature. At higher water activity, the determining factors are temperature and water content.

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 approximately 40°C).

Various embodiments of this disclosure provide Compound I in the form of dihydrate Form D. X-ray diffraction (XRD) analysis of a single crystal of Compound I revealed that it contains one molecule of Compound I, two molecules of water, and half a molecule of succinate. The X-ray powder diffraction pattern modeled based on this crystal structure corresponds to the PRD of Form D or Hydrate 1 shown in FIG. 1D, confirming that Form D is the dihydrate of compound I. The experimental x-ray diffraction pattern (room temperature) of the bulk sample is shown in red (top line) and the diagram calculated from the single crystal X-ray structure (100 K) is shown in black (bottom line). . The slight differences in peak position are due to changes in the crystal lattice depending on temperature and preferred orientation.

Various embodiments of this disclosure provide a composition containing Form D or a mixture of Forms D and A.

Various embodiments of this disclosure provide Compound I in Form E, a dehydrated Form D. Form E can be prepared by heating Form D of Compound I to about 60°C and the transformation begins at about 40°C. As heating continues to approximately 70-75°C, Form E converts to Form A, the anhydrous form. Thus, Form E can be considered a metastable form. Once Form E is formed, if it is cooled to about 35° C. or less, it becomes Form D. Various embodiments of this disclosure provide a composition 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°C to about 20°C) and very high water activity. But the composition of the initial mixture can also have its influence. While Form F is a stable form in pure water at 5°C, whether present in the original mixture or not, 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 the kinetically more stable form 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 lyophilizing amorphous compound I from a mixture of t-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 starting 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 B.

At 20°C in water, Form F is the more stable form when using a mixture of Forms D and F as the starting material. At 20°C in water, Form D is the stable form 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 for the transformation to stable form F to occur. Likewise, at 5°C in the mixture ethanol/water 50/50 v/v Form F is a stable form when seed crystals of Form F are present in the starting mixture, but Form D is kinetically stable at 5°C when using a mixture of Forms A and D. Based on the observed spontaneous crystallization of Form F at low temperatures and high water activities, Form F can be prepared in a composition of compound I that is initially Form D or a mixture of Forms A and D. Accordingly, various embodiments of this disclosure provide a composition 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 amorphous compound I. Form F converts to Form A (a) upon heating, (b) upon exposure to 40°C/20% relative humidity, or (c) upon storage at very low humidity in a desiccator at room temperature. In addition, cyclic changes in humidity, as in the gravimetric vapor sorption experiment, lead to the conversion of form F to form D.

Various embodiments of this disclosure provide Compound I in the form of dihydrate Form D obtained by treating Form A of Compound I in a wet granulation process

- 6 046754 roving using purified water as a medium for granulation. In various embodiments, the wet granulation process includes a high shear mixing step (for example, in an instrument such as a Diosna® P 1/6 equipped with 1 L and 4 L flasks), followed by gentle grinding (for example, in an instrument such as like Comil®, to break up granule clumps). In various embodiments, the 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 no more than 4% w/w. (based on measurement results, for example, water balance).

In various embodiments, one or more excipients are added during the granulation process, either before granulation or after drying of the granules, as known in the pharmaceutical art. In various embodiments, the one or more excipients are selected from one or more of a filler material (e.g., lactose, sucrose, glucose, mannitol, sorbitol, calcium phosphate, calcium carbonate, and cellulose, including microcrystalline cellulose), a solution binder (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 carboxymethylcellulose s, including cross-linked sodium carboxymethylcellulose 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 present invention also provides pharmaceutical compositions containing one or more of Forms D, E or F of Compound I, alone or in admixture with Form A 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 human and animal tissues without undue toxicity, irritation, allergic reaction or other problems or complications, in proportion 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 objectionable, and includes an excipient acceptable for veterinary use as well as for pharmaceutical use in humans. Examples of pharmaceutically acceptable excipients are presented above in this document.

The pharmaceutical composition may be presented in bulk or in unit dosage form. It is particularly advantageous to formulate pharmaceutical compositions in unit dosage form for ease of administration and uniformity of dosage. The term unit dosage form as used herein refers to physically discrete units suitable as single doses for the subjects to be treated; each unit contains a specified 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 depend on the unique characteristics of the active compound and the specific therapeutic effect to be achieved. The unit dosage form may be an ampoule, vial, suppository, dragee, tablet, capsule, IV pack, or a disposable aerosol inhaler pump.

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 percentage by weight, of a particular compound in a sample of the compound. Unless otherwise indicated, percentages stated herein are percentages by weight (w/w). In various embodiments, the pharmaceutical composition contains a pseudo-polymorphic form of Compound I that has a chemical purity of greater than 98.0% as determined by HPLC. In various embodiments, the pseudo-polymorph has a chemical purity of 99.0%. In various embodiments, the pseudo-polymorph 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, inert to the reaction, which sufficiently solubilizes the reactants and provides the environment in which the desired reaction will occur.

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 particulate medium, usually a solvent. The term suspension refers to sus

- 7 046754 pension formed by mixing a certain amount of powder in a liquid in which the solid is only slightly soluble (or insoluble). Suspending 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 peak heights in a powder X-ray diffraction pattern may vary 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 determined by the type of pharmacokinetic profile that is desired to be obtained from a given route of administration and the condition of the patient.

Dosage forms intended for oral, sublingual, nasal or injection administration are prepared by a method well known in the pharmaceutical field 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 that is a pseudopolymorph of Compound I described herein. 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 that acts as an excipient, carrier or vehicle for the active ingredient. Thus, the dosage forms of this invention can be in the form of tablets, pills, powders, lozenges, sachets, wafers, elixirs, suspensions, emulsions, solutions, syrups, aerosols (in the form of 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 packaged powders.

When preparing a dosage form, it may be necessary to grind the active ingredient to the appropriate particle size before combining with other ingredients. If the active ingredient is substantially insoluble, it is typically ground to a particle size of less than 200 mesh. If the active compound is substantially water soluble, the particle size is typically adjusted 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 microns to about 100 microns.

Some examples of suitable 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); lubricants such as talc, magnesium stearate and mineral oil; wetting agents; emulsifying and suspending agents; binders in solution or dry binders such as gelatin, polyvinylpyrrolidone, cellulose, methylcellulose, cellulose derivatives (eg hydroxypropylmethylcellulose), 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 rapid, sustained or sustained 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 typically 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

- 8 046754 small, transdermal, subcutaneous, intravenous, intramuscular and intranasal. The dosage forms used in the methods described herein are effective in both injectable and 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 may be designed for continuous, pulsed, or on-demand delivery of pharmaceuticals.

It is often desirable or necessary to administer a pharmaceutical composition directly or indirectly to the brain. Direct administration technologies typically involve inserting a catheter to deliver the drug 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 containing at least one active ingredient described above in a composition adapted for buccal and/or sublingual or nasal administration. This embodiment provides for administration of the active ingredient in a manner that prevents gastric complications such as first pass metabolism in the gastric system and/or the liver. This route of administration may also provide a reduction in absorption time, resulting in a more rapid onset of therapeutic effect.

Various embodiments of this disclosure provide a pharmaceutical composition containing an amount of active ingredient, up to 500 mg per dose, administered once, twice or thrice daily, and a pharmaceutically acceptable diluent or carrier.

Various embodiments of this disclosure provide a pharmaceutical composition for oral or rectal administration containing a specified amount of an active ingredient described herein, up to 500 mg per dose administered once, twice or three times daily, and a pharmaceutically acceptable diluent or carrier. Various embodiments of this disclosure provide a pharmaceutical composition containing a specified amount of an active ingredient described herein, the amount being between 50 mg and 500 mg per dose. In various embodiments, this disclosure provides a pharmaceutical composition containing a specified amount of an active ingredient described herein, the amount being from 50 mg to 400 mg per dose. In various embodiments, this disclosure provides a pharmaceutical composition containing a specified amount of an active ingredient described herein, the amount being 50 mg per dose. In various embodiments, this disclosure provides a pharmaceutical composition containing a specified amount of an active ingredient described herein, wherein the amount is from 100 mg per dose. In various embodiments, this disclosure provides a pharmaceutical composition containing a specified amount of an active ingredient described herein, wherein the amount is from 200 mg per dose. Various embodiments of this disclosure provide a pharmaceutical composition containing a specified amount of an active ingredient described herein, the amount being 400 mg per dose.

Various embodiments of this disclosure provide a pharmaceutical composition comprising an active ingredient described herein, administered orally. Various embodiments of this disclosure provide a pharmaceutical composition containing a predetermined amount of an active ingredient described herein for rectal administration.

Various embodiments of this disclosure provide a pharmaceutical composition for buccal, sublingual, nasal/intranasal, transdermal, subcutaneous, injection, intravenous, or intramuscular administration that contains a specified amount of an active ingredient described herein, up to 200 mg per dose administered once, twice or thrice daily, and a pharmaceutically acceptable diluent or carrier.

Various embodiments of this disclosure provide a pharmaceutical composition comprising an active ingredient described herein, the amount being from 2 mg to 100 mg per dose. In various embodiments, this invention provides a pharmaceutical composition containing a specified amount of an active ingredient described herein, wherein said amount is about 10, 15, 25, 30, 45, 50, 60, 75, 90

- 9 046754 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 disclosure, a pharmaceutical composition is provided, wherein administration is sublingual. In various embodiments of this disclosure, a pharmaceutical composition is provided, wherein administration is nasal or intranasal. In various embodiments of this disclosure, a pharmaceutical composition is provided, wherein administration is transdermal. In various embodiments of this disclosure, a pharmaceutical composition is provided, wherein administration is subcutaneous. In various embodiments of this disclosure, a pharmaceutical composition is provided, wherein the administration is by injection. In various embodiments of this disclosure, a pharmaceutical composition is provided, wherein administration is intravenous. In various embodiments of this disclosure, a pharmaceutical composition is provided, wherein administration is intramuscular.

Various embodiments of this disclosure provide a pharmaceutical composition characterized in that a dose of the active ingredient described herein is administered once daily. Various embodiments of this disclosure provide a pharmaceutical composition characterized in that a dose of the active ingredient described herein is administered twice daily. Various embodiments of this disclosure provide a pharmaceutical composition characterized in that a dose of the active ingredient described herein is administered three times daily.

Methods of application

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 a pseudopolymorph of Compound I, and mixtures thereof, as described herein. In various embodiments, the pseudo-polymorph of Compound I 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 pseudo-polymorph 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 herein also provide methods for enhancing activation of 5-HT _1F receptors by administering an effective amount of a pseudo-polymorph of Compound I and mixtures thereof, including mixtures with Form A, as described herein, while preventing vasoconstrictor effects, for the treatment of various disorders associated with decreased serotonin neurotransmission in mammals. These disorders include migraine, generalized pain, trigeminal neuralgia, dental pain or dysfunctional temporomandibular joint pain syndrome, anxiety, generalized anxiety disorder, panic disorder, depression, sleep disorders, chronic fatigue syndrome, premenstrual syndrome or late luteal phase syndrome. , post-traumatic stress disorder, memory loss, dementia, including senile dementia, social phobia, autism, attention deficit hyperactivity disorder, disorganized behavior disorder, impulse control disorder, borderline personality disorder, obsessive-compulsive disorder, premature ejaculation, erectile dysfunction, bulimia, anorexia nervosa, alcoholism, tobacco abuse, mutism and trichotillomania. The pseudo-polymorphs 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 current fourth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV!!!) (1994, American Psychiatric Association, Washington, DC) 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.

Use of a pseudo-polymorph of Compound I 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 particular through stimulation of 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 a pseudo-polymorph described herein that can activate 5-HT _1F receptors and/or inhibit extravasation

- 10 046754 neuronal protein.

As used herein, to treat or treatment includes any effect, such as attenuation, reduction, modulation or elimination, which results in the alleviation of a pathological condition, disease, disorder, etc. To treat or cure a disease state means treating a disease state in a mammal, particularly a human, and includes: (a) suppressing an existing disease state, i.e. stopping its development or its clinical symptoms; and/or (c) alleviation of a painful condition, i.e. initiation of regression of the disease state.

In this context, prevention means preventing the development of clinical symptoms of a disease state, i.e. delaying the onset of a disease in a subject who may be susceptible or predisposed to a given disease state, but is not yet experiencing or demonstrating 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 prepared, 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) preparing a suspension of Form F in water at 37°C, (8) preparing 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 prepared by a wet granulation method using a Diosna P 1/6 high shear granulator. 200 g of Form A of Compound I were mixed with about 40 to 90% (w/v) water in a 4 L flask. The initial dry mixing of the mixture before adding liquid was maintained as a constant factor (2 min, impeller speed according to this run, chopper off). Spray speed (g-kg/min) from 20 to 60 was used with an impeller speed of 400-900 rpm, which corresponds to a tip speed of 4.6-10.3 m/s. For clinical acquisition on the Roto P10, the center point of this tip speed range corresponds to the tip speed on the Roto P10 (7.3 m/s). When manufactured on PMA65, the corresponding tip speed is 9.8 m/s. Massaging time ranges from 0 to 2 minutes. The results of the experiment when varying the specified parameters are given below; all of these runs resulted in hydrate 1 (Form D) as analyzed in the pre-drying step. Only in the 9th run did dehydrated hydrate (form E) be obtained during drying; the crystals obtained in all other runs remained in the form of hydrate 1 when dried.

Run Spray speed (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 fluidized bed system at 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%

- 11 046754

235 min; LOD=4.9%

290 min.; LOD=4.3%

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

Granule samples were taken after the massaging time (wet granules) and during the drying stage (at 160 and 235 min). The samples were tested using PRD and TGA. All samples exhibited a PDP diagram corresponding to that of hydrate 1 (Form D) obtained by suspension in water. TGA data show similar mass loss for samples at 160 min and 235 min 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 Form A of Compound I (50 mg/ml) is prepared with sufficient solid remaining for PRD, DSC, TGA and optical microscopy. The suspension was stirred for 4 hours and then the solid was isolated and analyzed. The solid was tested using PRD in the wet state and after drying, and by other methods - only after drying. After suspension, a new form was discovered, called hydrate 1 (form D). This shape remained unchanged after the material dried.

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

The amorphous material was transferred to a glass reaction tube and weighed to obtain an initial mass of amorphous material of 882 mg. The solid was cooled to 5°C and 7.5 ml of pre-cooled MEK/water, 95/5 v/v was added to form a suspension. After approximately 10 minutes of stirring, the sample was seeded with the previously obtained Form D material. The sample was stirred at 5°C (300 rpm) for 2 _1/2 days. A small amount of the suspension was filtered and air-dried for 10 min, then analyzed by PRD. 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 hour. The filter cake was broken with a spatula and the powder was left to dry overnight under ambient conditions. The dried solid was weighed to give a yield of 843.3 mg.

Determination of characteristics. Zooming in on Form D produced 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 dihydrate hemisuccinate salt of Compound I. The sample was chemically pure, as determined by HPLC, purity was 99.9%. Microscopy showed that the sample consisted of very small particles arranged in agglomerates that were porous due to the presence of gaps between the small primary particles. The individual particles were irregular in shape with a smooth surface.

Example 2: Obtaining Form F.

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

A. Zooming in. Amorphous samples of Compound I were transferred to a glass reaction tube and weighed to give an initial mass of 913 mg of amorphous material. The solid was cooled to 5°C and 12.5 ml of pre-cooled water was added to obtain a thick suspension. After approximately 10 minutes of stirring, the sample was seeded with ~10 mg of the previously obtained 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 and air-dried for 10 min, then analyzed by PRD. 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 hour. The filter cake was broken with a spatula and the powder was left to dry overnight under ambient conditions. The dried solid was weighed to give a yield of 874.5 mg.

B. Determination of characteristics. Zooming in on Form F produced a crystalline, fine-grained 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 trihydrate of the hemisuccinate salt of Compound I. The sample was chemically pure, as determined by HPLC, purity was 100%. The sample consisted of very small particles ordered in fragile agglomerates. Individual particles were irregular in shape with a smooth surface, and few drusen-like particles were observed.

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

- 12 046754

A. Bruker AXS C2 GADDS.

Powder X-ray diffraction (XRD) patterns were recorded on a Bruker AXS C2 GADDS diffractometer using CuKa radiation (40 kV, 40 mA), an automatic XYZ platform, a laser video microscope for automatic sample repositioning, and a 2-dimensional HiStar area detector. The X-ray optics consisted of a single multilayer Gobel mirror coupled to a collimator with a 0.3 mm pinhole aperture. Beam divergence, i.e. The effective size of the X-ray beam on the sample was about 4 mm. A continuous θ-θ 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°. Typically, the sample was exposed to the X-ray beam for 120 s. GADDS software for XP/2000 4.1.43 was used for data acquisition, and data were analyzed and presented using Diffrac Plus EVA version 15.0.0.0.

For studies carried out under ambient conditions, samples were prepared in the form of flat plates using the specified powder form. About 1-2 mg of sample was lightly pressed onto a glass slide to obtain a flat surface. For studies conducted under non-ambient conditions, samples tested under non-ambient conditions were placed on a silicon wafer with a layer of thermally conductive composition. The sample was then heated to the appropriate temperature at a rate of 10°C/min and then kept isothermal for 1 min before data recording began.

B. Bruker AXS D8 Advance.

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

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

C. PANalytical Empyrean.

PXRD diffraction patterns were recorded on a PANalytical Empyrean diffractometer using CuKa 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. The 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 were analyzed and presented graphically using Diffrac Plus EVA version 15.0.0.0 or Highscore Plus version 4.5.

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

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

Acquisition details: Angular range: 2.5 to 32.0° 2θ; step size: 0.0130° 2θ; Recording time: total recording time 2.07 min. A 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 PRD (TDP-PT) experiments were carried out on samples mounted on a metal sample holder (with a silicon insert) with a thermally conductive connection. Then the sample was 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, PRD-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 the transformation of form E into form A. For form F, PRD-PT showed loss of crystallinity at 70°C, transformation into 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. X-ray diffraction of a single crystal (XRD of a single crystal).

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 from

- 13 046754 CuKa radiation. Structures were reconstructed using the SHELXTL programs (Sheldrick, 2013) and refined using the SHELXTL program from the Bruker AXS SHELXTL software package (version 6.10). Unless otherwise stated, hydrogen atoms bonded to carbon atoms were placed based on geometric considerations and fitted with a variable isotropic displacement parameter. The hydrogen atoms associated with the heteroatom were placed according to the results of minimizing the Fourier synthesis difference and the fitting was carried out with a free-floating isotropic bias parameter. The XRD of a single crystal of form D is shown in Fig. 1D.

Table 1

Single Crystal Data for Form D of Compound I

Crystallizing solvent Water Crystallization method Evaporation Empirical formula C21H25F3N3O6 Formula weight 472.44 Temperature 100(2) K Wavelength 1.54178 A Crystal size 0.200 x 0.150 x 0.100 mm Crystal habit colorless block Crystal system monoclinic Space group C2/s Unit cell dimensions a = 25.0800(7) A a=90° b = 10.08215(13)A β=123.714(4)° c = 20.83 57(9)A γ=90° Volume 4382.4(3)A ³ Z 8 Density (calculated) 1.432 t/m ³ Absorption coefficient 1.048 mm' ¹ F(000) 1976

table 2

List of PRD peaks of form D of compound I

Form D of Compound I

2Θ ° Intensity 2Θ ° Intensity (%)

8.5 38.7 21.9 10.0 9.7 31.4 22.4 25.5 I,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 AND 2 20.8 4.3 29.8 8.2 21.4 25.1 31.9 12.4 21.6 10.6

The characteristic peaks of the X-ray diffraction pattern of Form D include peaks at about 18.7, 26.5, 27.0, 27.5 and 27.8 degrees 2θ obtained using Cu-Ka radiation.

- 14 046754

Table 3

List of PRD peaks of form E of compound I

26° Form E of Compound I Intensity (%) Intensity (%) 20° 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 and about 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 11.7 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 from 17.8 7.2 28.0 I,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 Yu, 1 30.5 8.7 19.4 15.7 32.2 12.3

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

Table 4

List of PRD peaks of form F of compound I

Form F of Compound I

20° 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 046754

Table 5

List of PRD peaks of form A of compound I

2Θ Intensity (%) 7.67 ±0.10 9.61 ±0.10 11.06 ±0.10 13.38 ±0.10 14.07 ±0.10 15.11 ±0.10 15.32 ±0.10 16 .15 ±0.10 16.39 ±0.10 16.81 ±0.10 18.47 ±0.10 19.33 ±0.10 21.51 ±0.10 22.14 ±0.10 23, 18 ±0.10 23.39 ±0.10 23.56 ±0.10 23.84 ±0.10 24.77 ±0.10 25.01 ±0.10 25.91 ±0.10 26.68 ±0.10 28.65 ±0.10 29.31 ±0.10 27 33 21 23 41 51 62 44 100 47 43 61 28 53 46 46 59 33 36 24 52 20 19 12

Table 6

List of characteristic peaks of PRD form A of compound I

20 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 PDP peaks for forms A, D and E.

For comparison, in FIG. Figures 1E-G show partial diagrams of the Form D PDP (blue line); Form A (green); form E (red). For form A, a distinctive peak was noted at about (±0.2° 2θ) 7.7° 2θ. For form D, the distinctive peaks are 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 (±.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 PDP diagrams 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 console. Automated experiments were performed using ICON-NMR version 4.0.7 running Topspin version 1.3 using standard downloaded Bruker experiments. For custom spectroscopy, data were recorded using Topspin only. Samples were obtained in DMS(.)-s1 ₆ unless otherwise stated. Offline analysis was carried out using the ACD Spectrus Processor 2014 program.

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

Example 7. Thermal analysis.

(A) Differential scanning calorimetry (DSC).

DSC data were recorded on a TA Instruments Q2000 instrument 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 each

- 16 046754 One sample in an aluminum crucible with a hole in the lid was heated at a rate of 10°C/min from 25°C 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 were analyzed using Universal Analysis version 4.5A.

(B) Thermogravimetric analysis (TGA).

TGA data were collected using an Instruments Q500 TGA equipped with a 16-position autosampler. The 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 350°C. A nitrogen flow 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 were 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, corresponding to 2.0 mol. eq. 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. eq. water, with decomposition at about 200°C. DSC analysis showed the beginning of a broad endotherm at 71.2°C (-198.4 J/g), the beginning of a flat endotherm (2 peaks) at 95.7°C (-6.4 J/g), the beginning of a flat ectotherm (2 peak) at 103.4°C (26.9 J/g) and the beginning of an acute endotherm at 197.8°C (-114.4 J/g), reflecting melting.

Example 8. Microscopy.

A. Polarized light microscopy (PLM).

A.1. Leica LM/DM polarizing microscope.

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

A.2. Polarizing microscope Nikon LM/DM.

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

B. Scanning electron microscopy (SEM).

Data were recorded on a Phenom Pro scanning electron microscope. A small amount of sample was secured to an aluminum head using conductive double-sided tape. A thin layer of gold was deposited using an ion sputterer (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 sample processor at 150°C with an 851 Titrano coulometer using Hydranal Coulomat AG oven reagent and a nitrogen stream. Weighed solid samples were placed in a sealed sample vial. For one titration, approximately 10 mg of sample was used and double measurements were performed. Data collection and analysis were performed using Tiamo version 2.2.

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

Example 10 Determination of chemical purity using HPLC.

As shown in FIG. 4A, HPLC trace of 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 in the manner described in detail below.

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Parameter Meaning Method type Reversed phase with gradient elution Receiving 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 input (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

Example 11. Dynamic vapor sorption (VVA).

Sorption isotherms were obtained using a SMS DVS Intrinsic moisture absorption analyzer controlled by DVS Intrinsic control software version 1.0.1.2 (or version 1.0.1.3). The instrument control system ensured control of the sample temperature at 25°C. Humidity was controlled by mixing dry and wet nitrogen streams at a full flow rate of 200 mL/min. Relative humidity was measured with a calibrated Rotronic probe (dynamic range 1.0-100% RH) placed near the sample. The change in mass (mass relaxation) of the sample as a function of %RH was continuously monitored using a microbalance (accuracy ±0.005 mg). Typically, 5-20 mg of sample was placed in a tared stainless steel mesh cuvette under ambient conditions. The sample was loaded and unloaded at 40% RH and 25°C (standard room conditions). The moisture absorption isotherm was recorded using the parameters presented 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 carried out using Microsoft Excel using the DVS analytical package 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 significant weight loss at the 10% RH stage, but weight increased again as the humidity was increased to 20% RH. The residue from the EAF experiment was mainly Form D, but some peaks corresponding to Form F were observed, indicating that Form D is not completely stable at low relative humidity.

Form F showed little weight change until the first 0% RH step, where a loss of 9.6 wt% (2.6 mole water equivalent) was observed before the end of the experiment (Figure 7). It is likely that if the sample is kept at 0% RH for longer than the maximum step time of 6 hours, all three moles of water will be lost. With increasing humidity, the mass of the sample gradually increased to 70% RH, when, after the increase in mass, a loss of mass (typical of a crystallization event) was observed. It then crystallized at the 70% RH stage when it had collected enough water. The behavior in the second cycle was similar, but with an overall mass loss consistent with crystallized material being a dihydrate rather than a trihydrate starting material. This fact was confirmed by analysis of the residue from the chipboard experiment (which was a crispy solid) consisting mainly of 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. Water solubility 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 hours, then the pH was measured. Then sus

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Claims (4)

The mixture was filtered through a glass fiber filter C. The filtrate was then diluted by the appropriate amount. HPLC was used for quantitation against a standard solution of approximately 0.2 mg/mL in DMSO. Various volumes of standard, diluted, 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 injected standard. The solubility given refers to the original free form of compound I. Parameter Meaning Method type Reversed phase with gradient elution Column Phenomenex Luna, Cl8 (2) 5 µm, 50 x 4.6 mm Column Temperature (°C) 25 Standard sample input (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% TFA in water Phase B 0.085% TFA in acetonitrile Temporary scheme Time (min.) % Phase A % Phase B OD 95 5 1.0 80 20 2.3 5 95 3.3 5 95 3.5 95 5 4.4 95 5 Results. Suspension of Form D in water at 37°C did not result in a change in shape, and the measured thermodynamic solubility was 6.2-6.4 mg/ml (free form corrected for water and counterion content of hemisuccinate dihydrate). At this temperature there was no conversion to the trihydrate form F. The pH of the unfiltered saturated solution was 7.0. Suspending Form F in water at 37°C resulted in conversion to Form D. The sample was initially highly soluble (kinetic solubility of Form F ~32 mg/ml), but over time a solid corresponding to Form D slowly began to precipitate. Thermodynamic solubility of this sample (Form D) in water was measured after 24 hours at 8.6 mg/ml (free form, corrected for water and counterion content of hemihydrate dihydrate). It is not possible to measure the thermodynamic solubility in water 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 connection with its detailed description, the foregoing description is intended to illustrate and not to limit the scope of the present invention, which is to be determined by the scope of the appended claims. Other aspects, advantages and modifications are included 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. Pharmaceutical composition containing a single dose of 2,4,6-trifluoro-N-[6-(1-methylpiperidin-4-carbonyl)pyridin-2-yl]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 degrees ± 0.2 degrees 2Θ using Cu-Ka radiation, and a pharmaceutically acceptable carrier, wherein a single dose of the composition contains from 2 to 100 mg shape D. 2. The pharmaceutical composition according to claim 1, wherein a unit dose of the composition contains from 10, 15, 25, 30, 45, 50, 60, 75, 90 or 100 mg of Form D. 3. The pharmaceutical composition according to claim 1, wherein the x-ray diffraction pattern contains one or more of the following 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, 26.4, 28.4, 29.1, 29 ,6, 29.8 and 31.9 degrees 2Θ using Cu-Ka radiation. 4. Use of a pharmaceutical composition according to any one of claims 1-3 for the treatment of migraine. -