Polymorphs of the hydrochloride of PN6047

Abstract

To provide a stable crystal form of 4 - [(3-carbamoylphenyl) [1 - (1, 3-thiazol-5-ylmethyl) piperidin-4-ylidene] methyl] - N, N-dimethylbenzamide (PN6047).SOLUTION: To provide a hydrochloride of PN6047, and a HCl2 type and a HCl3 type of PN6047 which are crystalline forms thereof. Also provided are pharmaceutical compositions comprising such polymorphs, processes for the preparation of these polymorphs, and the use of these polymorphs in the treatment or prevention of diseases mediated by agonism of the δ - opioid receptor, particularly in the treatment or prevention of pain.SELECTED DRAWING: None

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority from Swedish Patent Application No. 2050910-5, filed July 17, 2020, the contents of which are incorporated herein by reference in their entirety.

[0002] The present invention relates to the hydrochloride salt of 4-[(3-carbamoylphenyl)[1-(1,3-thiazol-5-ylmethyl)piperidin-4-ylidene]methyl]-N,N-dimethylbenzamide (PN6047) and its crystalline forms, more specifically Form HCl 2 and Form HCl 3 of PN6047. The present invention further relates to pharmaceutical compositions containing such polymorphs, processes for preparing these polymorphs, and the use of these polymorphs in the treatment or prevention of diseases mediated by agonism of the δ-opioid receptor, particularly the treatment or prevention of pain. [Background technology]

[0003] The compound 4-[(3-carbamoylphenyl)[1-(1,3-thiazol-5-ylmethyl)piperidin-4-ylidene]methyl]-N,N-dimethylbenzamide (PN6047, structure shown below) is disclosed in WO2016 / 099393. It is a highly potent δ-opioid receptor agonist and maintains analgesic efficacy even with continuous administration. In contrast to existing analgesics that only provide moderate analgesic effects, PN6047 has the potential to provide sustained analgesia in painful conditions with a reduced risk of undesirable side effects such as respiratory depression and constipation.

[0004] [ka]

[0005] When used in pharmaceutical formulations, it is desirable for the pharmaceutical active ingredient (API) to be in a highly crystalline form. Amorphous (i.e., non-crystalline) materials may contain a large amount of residual solvents, which is not desirable. Furthermore, amorphous materials have lower chemical and physical stability compared to crystalline materials, so they decompose faster and may spontaneously form crystals with variable crystallinity. As a result, the dissolution rate becomes non-reproducible, and the storage and handling of the material may become difficult. Therefore, a crystalline form of PN6047 with improved properties regarding stability, large-scale processing, and solubility is needed. Specifically, it is an object of the present invention to provide a stable crystalline form of PN6047 that exhibits high solubility, contains a low level of residual solvents, has high chemical stability and low hygroscopicity, and can be obtained with high crystallinity.

Brief Description of the Drawings

[0006] [Figure 1] Shows the X-ray powder diffraction pattern (diffractogram) of the HCl2 form. [Figure 2] Shows the X-ray powder diffraction pattern of the HCl3 form. [Figure 3] Shows the temperature profile of the thermocycling experiment. [Figure 4] Shows the differential scanning calorimetry (DSC) thermogram of the HCl2 form. [Figure 5] Shows the DSC thermogram of the HCl3 form. [Figure 6] Shows the thermogravimetric analysis (TGA) and heat flow thermogram of the HCl2 form. [Figure 7] Shows the TGA and heat flow thermogram of the HCl3 form. [Figure 8] Shows the dynamic vapor sorption (DVS) isotherm plot of the HCl2 form. [Figure 9] Shows the DVS isotherm plot of the HCl3 form.

Modes for Carrying Out the Invention

[0007] It has been discovered that the hydrochloride (HCl) salt of PN6047 has certain advantages over the free base compound, including improved solubility in water at room temperature and enhanced bioavailability. It has further been discovered that the HCl salt of PN6047 can exist in various crystalline forms, or polymorphs. Some of these crystalline forms exhibit good solubility, good chemical and physical stability (including dissolution stability), and low hygroscopicity, and are therefore useful in pharmaceutical compositions of PN6047. Thus, in a first aspect, the present invention relates to an HCl salt of PN6047. In some embodiments, the HCl salt is a crystalline salt.

[0008] In some embodiments, the present invention provides a crystalline HCl salt of PN6047 that is stable at temperatures of 25° C. and up to 60% relative humidity (RH). In some embodiments, the present invention provides a crystalline HCl salt of PN6047 that is stable at temperatures of 40° C. and up to 75% relative humidity. Such crystalline HCl salts may be stable under these conditions for periods of at least 1 day, 1 week, 1 month, 3 months, 6 months, 1 year, 2 years, 3 years, or longer.

[0009] In one embodiment, the crystalline HCl salt of PN6047 is Form HCl2. This form can be prepared by crystallization from certain organic solvents, such as 2-propanol, acetone, acetonitrile, ethanol, ethyl acetate, or tetrahydrofuran. In one embodiment, Form HCl2 has an X-ray powder diffraction (XRPD) pattern obtained using CuKα1 radiation with peaks at °2θ values ​​of at least 16.5±0.2, 23.3±0.2, and 23.5±0.2. In some embodiments, Form HCl2 has an XRPD pattern obtained using CuKα1 radiation with peaks at °2θ values ​​of at least 16.5±0.2, 23.3±0.2, and 23.5±0.2, and more particularly at one or more of 14.3±0.2, 16.1±0.2, 16.3±0.2, and 20.2±0.2. In some embodiments, Form HCl2 has an XRPD pattern obtained using CuKα1 radiation with peaks at °2θ values ​​of at least 14.3±0.2, 16.1±0.2, 16.3±0.2, 16.5±0.2, 20.2±0.2, 23.3±0.2, and 23.5±0.2. In some embodiments, Form HCl2 has an XRPD pattern obtained using CuKα1 radiation with peaks at °2θ values ​​of at least 14.3±0.2, 16.1±0.2, 16.3±0.2, 16.5±0.2, 20.2±0.2, 23.3±0.2, and 23.5±0.2, and more particularly 15.2±0.2, 18.5±0.2, 19.4±0.2, 20.4±0.2, 24.0±0.2, 24.8±0.2, and 26.9±0.2. In some embodiments, Form HCl2 has an XRPD pattern, obtained using CuKα1 radiation, with peaks at °2θ values ​​of at least 14.3±0.2, 15.2±0.2, 16.1±0.2, 16.3±0.2, 16.5±0.2, 18.5±0.2, 19.4±0.2, 20.2±0.2, 20.4±0.2, 23.3±0.2, 23.5±0.2, 24.0±0.2, 24.8±0.2, and 26.9±0.2. In certain embodiments, the present invention relates to Form HCl2 having an XRPD pattern, obtained using CuKα1 radiation, substantially as shown in FIG.

[0010] In other embodiments, the crystalline HCl salt of PN6047 is Form HCl3. This form can be isolated by evaporation of water from aqueous solution, crystallization from acetonitrile, or by exposing the amorphous HCl salt of PN6047 to 40°C / 75% RH. Form HCl3 is believed to be a hydrate. In one embodiment, Form HCl3 has an XRPD pattern obtained using CuKα radiation with peaks at °2θ values ​​of at least 12.8±0.2, 19.1±0.2, and 23.9±0.2. In some embodiments, Form HCl3 has an XRPD pattern obtained using CuKα radiation with peaks at °2θ values ​​of at least 12.8±0.2, 19.1±0.2, and 23.9±0.2, and in particular one or more of 10.0±0.2, 25.3±0.2, and 26.3±0.2. In some embodiments, Form HCl 3 has an XRPD pattern obtained using CuKa radiation with peaks at °2θ values ​​of at least 10.0±0.2, 12.8±0.2, 19.1±0.2, 23.9±0.2, 25.3±0.2, and 26.3±0.2. In some embodiments, Form HCl 3 has an XRPD pattern obtained using CuKa radiation with peaks at °2θ values ​​of at least 10.0±0.2, 12.8±0.2, 19.1±0.2, 23.9±0.2, 25.3±0.2, and 26.3±0.2, and in particular one or more of 14.5±0.2, 16.2±0.2, 18.3±0.2, 20.8±0.2, 27.4±0.2, and 29.7±0.2. In some embodiments, Form HCl 3 has an XRPD pattern, obtained using CuKa radiation, with peaks at °2θ values ​​of at least 10.0±0.2, 12.8±0.2, 14.5±0.2, 16.2±0.2, 18.3±0.2, 19.1±0.2, 20.8±0.2, 23.9±0.2, 25.3±0.2, and 26.3±0.2, 27.4±0.2, and 29.7±0.2. In certain embodiments, the present invention relates to Form HCl 3 having an XRPD pattern, obtained using CuKa radiation, substantially as shown in FIG.

[0011] Form HCl2 may be a hydrate or anhydrous. Its water absorption rate at 25°C / 80% RH is approximately 2.2%, indicating moderate hygroscopicity. This moderate hygroscopicity is considered advantageous because the crystalline water content remains fairly constant even when humidity is varied within the normal relative humidity range of approximately 30% to approximately 70% RH. At high relative humidity (e.g., above 85% RH), Form HCl2 has been observed to absorb water and transform into Form HCl3, which is believed to be a hydrate. This transformation is not reversible; drying Form HCl3 does not result in Form HCl2, but rather in the low-crystalline phase Form HCl3. However, Form HCl2 is believed to be stable under conditions up to 85% RH. Stability studies have shown that Form HCl2 is chemically stable in saline for up to one week and physically stable for at least four weeks at 25°C / 60% RH, 40°C / 75% RH, and 60°C / 38% RH.

[0012] The solubility of the two crystalline HCl salts of PN6047 was found to be significantly higher than that of the free base. For example, the free base is practically insoluble in water at pH 7 (<1 mg / mL), whereas the HCl2 and HCl3 forms are highly soluble in water at the same pH (>100 mg / mL). The increased solubility of the HCl salt allows for continued investigation of the compound at higher concentrations, which is advantageous, for example, for toxicology studies. Surprisingly, it was further discovered that the HCl salt of PN6047 has significantly greater bioavailability than the free base. Specifically, the maximum bioavailability (tested in rats) of the HCl2 form of PN6047 was 35% (50 mg / kg oral), while the maximum bioavailability of the free base was only 8% (3 mg / kg oral). It is expected that the increased bioavailability of the HCl salt (and therefore increased exposure) may improve the efficacy of PN6047 in treating pain and other indications described herein. Potentially, the increased bioavailability may allow the HCl salt to be administered at substantially lower doses than the free base. The unexpected increased bioavailability of the HCl salt may further enable the use of sustained release formulations of this compound.

[0013] In another aspect, the present invention relates to pharmaceutical compositions comprising a therapeutically effective amount of the crystalline HCl salt of PN6047 disclosed herein in association with one or more pharmaceutically acceptable excipients. Excipients may include, for example, fillers, binders, disintegrants, glidants, and lubricants. In some embodiments, the crystalline HCl salt of PN6047 is Form HCl2. In some embodiments, the crystalline HCl salt of PN6047 is Form HCl3.

[0014] In some embodiments, the pharmaceutical composition comprises Form HCl 2 or Form HCl 3 having a polymorphic purity of at least about 90%. In some embodiments, the polymorphic purity is at least about 95%. In some embodiments, the polymorphic purity is at least about 98%. For example, the polymorphic purity is at least about 98.5%, e.g., at least about 99%, e.g., at least about 99.5%, e.g., at least about 99.8%, or e.g., at least about 99.9%. In some embodiments, the pharmaceutical composition comprises Form HCl 2 and is substantially free of other crystalline HCl salts of PN6047. For example, in some embodiments, the pharmaceutical composition comprising Form HCl 2 is substantially free of Form HCl 3 of PN6047. In some embodiments, Form HCl 2 comprises less than about 15% by weight of Form HCl 3 or any other crystalline HCl salt of PN6047. For example, Form HCl 2 contains less than about 14% by weight, about 13% by weight, about 12% by weight, about 11% by weight, about 10% by weight, about 9% by weight, about 8% by weight, about 7% by weight, about 6% by weight, about 5% by weight, about 4% by weight, about 3% by weight, about 2% by weight, about 1% by weight or less of Form HCl 3 or any other crystalline HCl salt of PN6047.

[0015] In some embodiments, the pharmaceutical compositions comprise Form HCl 3 and are substantially free of other crystalline HCl salts of PN6047. For example, in some embodiments, the pharmaceutical compositions comprising Form HCl 3 are substantially free of Form HCl 2 of PN6047. In some embodiments, Form HCl 3 contains less than about 15% by weight of Form HCl 2 or any other crystalline HCl salt of PN6047. For example, Form HCl 3 contains less than about 14%, about 13%, about 12%, about 11%, about 10%, about 9%, about 8%, about 7%, about 6%, about 5%, about 4%, about 3%, about 2%, about 1% or less by weight of Form HCl 2 or other crystalline HCl salts of PN6047.

[0016] In some embodiments, the pharmaceutical composition comprises from about 0.5 to about 99.5% by weight of the crystalline HCl salt of PN6047 disclosed herein. For example, the composition may comprise from about 0.5% to about 20%, about 20% to about 40%, about 40% to about 60%, about 60% to about 80%, or about 80% to 99.5% by weight of the crystalline HCl salt of PN6047 disclosed herein. In some embodiments, the composition comprises about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 77%, about 80%, about 85%, about 90%, or about 95% by weight of the crystalline HCl salt of PN6047 disclosed herein.

[0017] In some embodiments, the pharmaceutical composition comprises a filler. Examples of suitable fillers include, but are not limited to, dicalcium phosphate dihydrate, calcium sulfate, lactose (e.g., lactose monohydrate), sucrose, mannitol, sorbitol, cellulose, microcrystalline cellulose, dry starch, hydrolyzed starch, and pregelatinized starch.

[0018] In some embodiments, the pharmaceutical composition comprises a binder.Examples of suitable binders include but are not limited to starch, pregelatinized starch, gelatin, sugars (such as sucrose, glucose, dextrose, lactose and sorbitol), polyethylene glycol, wax, natural and synthetic gums (such as gum acacia and gum tragacanth), sodium alginate, cellulose derivatives (such as hydroxypropylmethylcellulose (or hypromellose), hydroxypropylcellulose and ethylcellulose), and synthetic polymers (such as acrylic acid copolymers and methacrylic acid copolymers, methacrylic acid copolymers, methyl methacrylate copolymers, aminoalkyl methacrylate copolymers, polyacrylic acid / polymethacrylic acid copolymers and polyvinylpyrrolidone (povidone)).

[0019] In some embodiments, the pharmaceutical composition comprises a disintegrant. Examples of suitable disintegrants include, but are not limited to, dry starch, modified starch (such as (partially) pregelatinized starch, sodium starch glycolate and sodium carboxymethyl starch), alginic acid, cellulose derivatives (such as sodium carboxymethylcellulose, hydroxypropylcellulose and low-substituted hydroxypropylcellulose (L-HPC)) and cross-linked polymers (such as carmellose, croscarmellose sodium, carmellose calcium and cross-linked PVP (crospovidone)).

[0020] In some embodiments, the pharmaceutical composition comprises a glidant or lubricant. Examples of suitable glidants and lubricants include, but are not limited to, talc, magnesium stearate, calcium stearate, sodium stearyl fumarate, stearic acid, glyceryl behenate, colloidal anhydrous silica, aqueous silicon dioxide, synthetic magnesium silicate, finely divided silicon oxide, starch, sodium lauryl sulfate, boric acid, magnesium oxide, waxes (such as carnauba wax), hydrogenated oils, polyethylene glycol, sodium benzoate, polyethylene glycol, and mineral oil.

[0021] In general, pharmaceutical compositions may be prepared in a conventional manner using conventional excipients. In some embodiments, the components of the composition are mixed to form a homogeneous mixture, which is then formulated into tablets or capsules. The homogeneous mixture of ingredients may be compressed into tablets using conventional techniques, such as a rotary tablet press. Alternatively, the mixture may be moistened by adding a liquid such as water and / or a suitable organic solvent (e.g., ethanol or isopropanol), and then granulated and dried. The resulting granules may then be compressed into tablets using conventional techniques. Tablets may be coated with one or more coating layers. The coating layer may comprise, for example, a polysaccharide (such as sugar or starch), a cellulose-based polymer, a polyvinyl-based polymer, an acrylate copolymer, or a mixture thereof. The one or more coating layers may provide a modified release of the active ingredient, such as delayed, extended, slow, controlled, or sustained release of the active ingredient.

[0022] Capsules (such as hard gelatin capsules) may contain a powder mixture of the ingredients, or small multiparticulates (such as granules, extruded pellets, or minitablets), or a liquid or semi-solid formulation of the ingredients. For soft gelatin capsules, the crystalline HCl salt of PN6047 may be mixed with, for example, vegetable oil or polyethylene glycol.

[0023] Formulations for use in nasal administration or oral inhalation (e.g., nebulized solutions) may comprise an aqueous solution of the crystalline HCl salt of PN6047 with a suitable preservative, such as, for example, benzalkonium chloride. Formulations for use in topical administration (e.g., ointments or creams) may comprise the crystalline HCl salt of PN6047 mixed with, for example, an oil or wax and a suitable preservative.

[0024] In another aspect, the present invention relates to the crystalline HCl salt of PN6047 disclosed herein for use in therapy. The crystalline HCl salt of PN6047 disclosed herein is useful for the treatment or prevention of pain, including, but not limited to, acute pain, chronic pain, neuropathic pain, cancer pain, visceral pain, diabetic pain, and pain caused by diseases or conditions such as rheumatoid arthritis, osteoarthritis, fibrositis, migraine, and opioid-induced hyperalgesia (OIH). Additionally, they may be used as an analgesic, for example, during general anesthesia and monitored anesthesia care.

[0025] The crystalline HCl salt of PN6047 disclosed herein is further useful for treating or preventing various psychiatric disorders, such as depression, anxiety, and substance use disorders (including abuse or addiction to alcohol, nicotine, opioids, and other drugs). Additionally, they are useful for treating withdrawal and abstinence symptoms resulting from chronic use of opioids and other drugs that produce negative emotional states, including hypersensitivity to emotional and painful stimuli. Other diseases and conditions that can be treated or prevented with the crystalline HCl salt of PN6047 disclosed herein include neurodegenerative disorders (including stroke, Alzheimer's disease, and Parkinson's disease), cardiovascular disease (including ischemic heart disease), epilepsy, urinary incontinence, sensory hypersensitivity (including chronic cough and pruritus), pulmonary edema, various gastrointestinal disorders (including irritable bowel syndrome and irritable bowel disease), spinal cord injury, and disorders of the sympathetic nervous system (such as hypertension).

[0026] The crystalline HCl salt of PN6047 disclosed herein may further be used as an immunomodulator, particularly in the treatment of autoimmune diseases such as rheumatoid arthritis and osteoarthritis, skin engraftment, and organ transplantation. They are also useful in diseases in which opioid receptor degeneration or dysfunction is present or indicated.

[0027] Thus, in one embodiment, the present invention relates to the crystalline HCl salt of PN6047 disclosed herein for use in the treatment or prevention of diseases or conditions such as those listed above.

[0028] In another embodiment, the present invention relates to the use of the crystalline HCl salt of PN6047 disclosed herein in the manufacture of a medicament for the treatment or prevention of a disease or disorder such as those listed above.

[0029] In yet another embodiment, the present invention relates to a method for the treatment or prevention of a disease or disorder in a warm-blooded animal, such as those listed above, comprising the step of administering to a warm-blooded animal in need of such treatment or prevention a therapeutically effective amount of the crystalline HCl salt of PN6047 as disclosed herein.

[0030] In some embodiments, the crystalline HCl salt of PN6047 disclosed herein may be administered in combination with at least one other therapeutically active agent, e.g., one, two, three, or more other therapeutically active agents. The crystalline HCl salt of PN6047 and the at least one other therapeutically active agent may be administered simultaneously, sequentially, or separately. Therapeutically active agents suitable for combination with the crystalline HCl salt of PN6047 include, but are not limited to, known active agents useful in the treatment of any of the aforementioned diseases, disorders, and conditions.

[0031] In one embodiment, the crystalline HCl salt of PN6047 disclosed herein is administered in combination with one or more other analgesics. Combinations of various analgesics (with different properties) are often used to achieve a balance of effects necessary to maintain an anesthetic state (e.g., amnesia, analgesia, muscle relaxation, and sedation). The one or more other analgesics may be, for example, anesthetics, hypnotics, anxiolytics, neuromuscular blockers, neuropeptide receptor blockers, or opioids. Specific examples of such compounds include, but are not limited to, tricyclic antidepressants, gabapentinoids, CGRP receptor antagonists, benzodiazepines, and ketamine.

[0032] In another embodiment, the crystalline HCl salt of PN6047 disclosed herein is administered in combination with one or more other compounds useful for treating or preventing pain. Examples of such compounds include, but are not limited to, opioid receptor agonists and antagonists, cannabinoids, alpha-2 adrenergic receptor agonists, purinergic receptor antagonists, transient receptor potential channel blockers, sodium channel blockers, calcium channel blockers, and potassium channel blockers.

[0033] In another aspect, the present invention relates to processes for preparing Form HCl2 and Form HCl3 of PN6047. In some embodiments, Form HCl2 can be formed by direct crystallization from a suitable solvent. In some embodiments, the solvent is 2-propanol, acetone, acetonitrile, ethanol, ethyl acetate, or tetrahydrofuran. In a preferred embodiment, the solvent is 2-propanol. In some embodiments, Form HCl3 can be formed by direct crystallization from a suitable solvent or by evaporating the solvent from a solution. In some embodiments, the solvent is water or acetonitrile.

[0034] In some embodiments, the process for preparing the HCl2 form of PN6047 comprises: a) preparing a solution or suspension of the HCl salt of PN6047 in a suitable solvent; b) maintaining stirring until a solid is obtained or the conversion to the HCl2 form is complete; c) recovering the solid material obtained in step b); d) drying the solid under vacuum.

[0035] When the free base is used as the starting material, the HCl2 form of PN6047 may further be obtained. In some embodiments, therefore, the process for preparing the HCl2 form of PN6047 comprises: a) preparing a solution or suspension of the free base of PN6047 in a suitable solvent; b) adding an HCl solution to the solution or suspension of step a) to achieve a free base to HCl ratio of about 1:1; c) maintaining stirring until a solid is obtained or the conversion to the HCl2 form is complete; d) recovering the solid material obtained in step c); e) drying the solid under vacuum.

[0036] The free base of PN6047 used in step a) may be crystalline or amorphous.

[0037] As used herein, the term "polymorph" refers to crystals of the same molecule that have different physical properties as a result of the molecular order in the crystal lattice. Polymorphs of a compound have one or more distinct chemical, physical, mechanical, electrical, thermodynamic, and / or biological properties. Differences in the physical properties exhibited by polymorphs can affect pharmaceutical parameters such as storage stability, compressibility, density (important in formulations and product manufacturing), dissolution rate (a key factor in determining bioavailability), solubility, melting point, chemical stability, physical stability, powder flowability, water absorption, compaction, and particle morphology. Differences in stability can result from changes in chemical reactivity (e.g., differential oxidation, such that a dosage form discolors more rapidly when composed of one polymorph than when composed of another), or mechanical changes (e.g., crystalline changes upon storage due to conversion of a kinetically favorable polymorph to a thermodynamically more stable polymorph), or both (e.g., one polymorph is more hygroscopic than another). As a result of differences in solubility / dissolution, some transitions affect efficacy and / or toxicity. In addition, the physical properties of the crystal may be important in processing; for example, a polymorph may be more prone to forming solvates or may have impurities that are difficult to remove by filtration and washing (i.e., the particle shape and size distribution may be different for one polymorph compared to another). "Polymorph" does not include amorphous forms of a compound.

[0038] As used herein, the term "amorphous" refers to a non-crystalline form of a compound, which may be a solid state form of the compound or a solubilized form of the compound. For example, "amorphous" refers to a compound that does not contain a regularly repeating arrangement of molecules or geometrical surfaces.

[0039] As used herein, the term "anhydrate" or "anhydrous form" refers to a polymorph of PN6047 (i.e., crystalline HCl salt) having 1% or less water by weight, e.g., 0.5% or less, 0.25% or less, or 0.1% or less water by weight.

[0040] As used herein, the term "hydrate" refers to a polymorph of PN6047 in which the crystal lattice contains water of crystallization.

[0041] The term "non-stoichiometric hydrate" refers to a polymorph of PN6047 that contains water but whose crystal structure does not change significantly with variations in water content. In some embodiments, a non-stoichiometric hydrate can refer to a crystalline HCl salt of PN6047 that has channels or networks throughout its crystal structure through which water molecules can diffuse. During drying of a non-stoichiometric hydrate, a significant proportion of the water can be removed without significantly disturbing the crystalline network, and the crystal can then be rehydrated to yield the original non-stoichiometric hydrate crystal form. Unlike stoichiometric hydrates, the dehydration and rehydration of non-stoichiometric hydrates does not involve a phase transition, so all hydration states of non-stoichiometric hydrates represent the same crystal form. In some embodiments, non-stoichiometric hydrates can have up to about 20% water by weight, such as about 20%, about 19%, about 18%, about 17%, about 16%, about 15%, about 14%, about 13%, about 12%, about 11%, about 10%, about 9%, about 8%, about 7%, about 6%, about 5%, about 4%, about 3%, about 2%, or about 1% water by weight. In some embodiments, the non-stoichiometric hydrate can have between about 1% and about 20% water by weight, e.g., between about 1% and about 5%, about 1% and about 10%, about 1% and about 15%, about 2% and about 5%, about 2% and about 10%, about 2% and about 15%, about 2% and about 20%, about 5% and about 10%, about 5% and about 15%, about 5% and about 20%, about 10% and about 15%, about 10% and about 20%, or about 15% and about 20% water by weight.

[0042] In some embodiments, the weight percent of water in a crystalline form, such as a non-stoichiometric hydrate, is determined by Karl Fischer titration. In some embodiments, the crystalline form is dried prior to Karl Fischer titration.

[0043] As used herein, the term "polymorphic purity," when used in reference to a composition containing a polymorph of PN6047, means the ratio of one particular polymorph to another polymorph or amorphous form of PN6047 in the referenced composition. For example, a composition containing Form HCl2 with a polymorphic purity of 90% would contain 90 parts by weight of Form HCl2 and 10 parts by weight of other crystalline and / or amorphous forms of PN6047.

[0044] As used herein, the term "effective amount" or "therapeutically effective amount" refers to the amount of the crystalline HCl salt of PN6047 sufficient, following administration to a subject, to alleviate to some extent one or more of the symptoms of the disease or disorder being treated. This can result in a reduction and / or alleviation of the signs, symptoms, or causes of the disease, or any other desired change in a biological system. For example, an "effective amount" in therapeutic applications is the amount of PN6047 disclosed herein required to produce a clinically significant reduction in disease symptoms. An appropriate "effective" amount for any individual case can be determined using any suitable technique, such as a dose escalation study.

[0045] As used herein, the terms "treatment," "treat," and "treating," as used herein, refer to reversing, alleviating, delaying the onset of, or inhibiting the progression of a disease or disorder, or one or more symptoms thereof. In some embodiments, treatment may occur after one or more symptoms have developed. In other embodiments, treatment may occur in the absence of symptoms. For example, treatment may occur in susceptible individuals (e.g., in light of a history of symptoms and / or in light of genetic or other susceptibility factors) before symptoms develop. Additionally, treatment may continue after symptoms have subsided, for example, to prevent or delay recurrence.

[0046] As used herein, the term "pharmaceutically acceptable" refers to compounds, materials, compositions, and / or dosage forms that are suitable for human pharmaceutical use and are generally safe, non-toxic, and biologically or otherwise undesirable.

[0047] As used herein, a compound or composition is "substantially free" of one or more other components if the compound or composition does not contain significant amounts of such other components. Such components may include starting materials, residual solvent, or any other impurities that may result from the preparation and / or isolation of the compounds and compositions provided herein. In some embodiments, the polymorphic forms provided herein are substantially free of other polymorphic forms. In some embodiments, a particular polymorphic form of PN6047 (i.e., the crystalline HCl salt) is "substantially free" of other polymorphic forms when it constitutes at least about 95% by weight of the PN6047 present. In some embodiments, a particular polymorphic form of PN6047 is "substantially free" of other polymorphic forms when it constitutes at least about 97%, about 98%, about 99%, or about 99.5% by weight of the PN6047 present.

[0048] As used herein, a compound is "substantially present" as a given polymorph when at least about 50% by weight of the compound is in that polymorph, e.g., at least about 60%, at least about 70%, at least about 80%, or at least about 90% by weight of the compound is in that polymorph. In some embodiments, at least about 95% by weight of the compound is in that polymorph, e.g., at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 99.5% by weight of the compound.

[0049] As used herein, the term "stable" means that the polymorph does not change over time in one or more of the following: polymorph form (e.g., increase or decrease in a particular form), appearance, pH, percentage of impurities, activity (measured by in vitro assay), or osmolality. In some embodiments, the polymorphs provided herein are stable for at least 1, 2, 3, or 4 weeks. For example, the polymorph does not change over time in one or more of the following: polymorph form (e.g., increase or decrease in a particular form), appearance, pH, percentage of impurities, activity (measured by in vitro assay), or osmolality. In some embodiments, the polymorphs provided herein are stable for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months. For example, the polymorph does not exhibit a change in one or more of the following over a period of at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months: polymorph form (e.g., an increase or decrease in a particular form), appearance, pH, percent impurities, activity (as measured by in vitro assay), or osmolality. In the above, the phrase "do not exhibit a change" refers to a measured change of less than 5% (e.g., less than 4%, less than 3%, less than 2%, less than 1%) for any of the above parameters over the relevant period of time.

[0050] The crystallinity of a polymorph of PN6047 can be measured, for example, by X-ray powder diffractometry (XRPD) or differential scanning calorimetry (DSC). When reference is made herein to a crystalline compound, the crystallinity is preferably greater than about 70%, e.g., greater than about 80%, particularly greater than about 90%, and more particularly greater than about 95%. In some embodiments, the crystallinity is greater than about 98%. In some embodiments, the crystallinity is greater than about 99%. Percent crystallinity refers to the weight percent of the total sample mass that is crystalline.

[0051] As used herein, the term "about" refers to a value or parameter herein, including (and describing) embodiments directed to that value or parameter itself. For example, a statement referring to "about 20" includes the statement "20." Numerical ranges include the numbers defining the range. Generally, the term "about" refers to the indicated value of a variable, and refers to all values ​​of the variable that are within experimental error of the indicated value (e.g., within a 95% confidence interval of the mean) or within 10% of the indicated value, whichever is greater.

[0052] The present invention is described by the following examples, which are not intended to be limiting in any way. All citations and references mentioned herein are incorporated by reference in their entirety.

[0053] Abbreviation h time min TFE 2,2,2-trifluoroethanol THF tetrahydrofuran rpm Revolutions per minute

[0054] Experimental Method The amorphous HCl salt of PN6047 was prepared by lyophilizing a mixture of PN6047 free base and aqueous HCl. 500.5 mg of free base was dissolved in 5 mL of 1:1 TFE / water (v / v). To this solution, 1.2 mL of 1 M aqueous HCl was added to achieve a 1:1 free base:HCl ratio. The solution was liquid-dosed into 11 HPLC vials, frozen in liquid nitrogen, and placed under deep vacuum using a lyophilizer (Alpha 2-4 LD, Christ). After lyophilization, the material was confirmed to be amorphous by HT-XRPD. The material was then dried under deep vacuum (1 mbar) at 80°C for 3 days to remove any residual solvent. 1H NMR analysis confirmed the formation of the HCl salt after lyophilization and the chemical integrity of PN6047.

[0055] X-ray powder diffraction (XRPD) analysis High-throughput X-ray powder diffraction (HT-XRPD) patterns were acquired using a Crystallics T2 high-throughput XRPD setup. Plates were mounted on a Bruker General Area Detector Diffraction System (GADDS) equipped with a VÅNTEC-500 gas area detector corrected for intensity and geometric variations. Calibration of measurement accuracy (peak positions) was performed using a NIST SRM1976 standard (Corundum). Data collection was performed at room temperature using monochromated CuKα radiation over the 2θ range of 1.5° to 41.5°. Diffraction patterns for each well were collected over two 2θ ranges (1.5° ≤ 2θ ≤ 21.5° for the first frame, and 19.5° ≤ 2θ ≤ 41.5° for the second frame) with an exposure time of 45 seconds for each frame. No background subtraction or curve smoothing was applied to the XRPD patterns.

[0056] High-resolution X-ray powder diffraction (HR-XRPD) data were collected at room temperature on a D8 Advance diffractometer using CuKα radiation (1.54056 Å) with a germanium monochromator. Diffraction data were collected over the 2θ range of 1.5–41.5°2θ. Detector scans were performed on a solid-state LynxEye detector at a scan speed of 0.016° / step and 4 s / step. Samples were measured in 8 mm long glass capillaries with an outer diameter of 0.4 mm.

[0057] It is known in the art that X-ray powder diffraction patterns may be obtained with one or more measurement errors depending on the measurement conditions (such as the instrument, sample preparation, and the machine used). In particular, it is generally known that intensities in an XRPD pattern may vary depending on the measurement conditions and sample preparation. For example, those skilled in the art of XRPD will understand that the relative intensities of peaks may vary depending on the orientation of the sample under test and the type and settings of the instrument used. Those skilled in the art will also understand that the position of reflections may be affected by the exact height at which the sample is placed in the diffractometer and the zero calibration of the diffractometer. The surface flatness of the sample may also have some effect. Therefore, those skilled in the art will recognize that the diffraction patterns presented herein should not be construed as absolute, and that any crystalline form that provides a powder diffraction pattern substantially identical to that disclosed herein is within the scope of the present disclosure (for further information, see "Introduction to X-ray Powder Diffractionometry" by R. Jenkins and R. L. Snyder, John Wiley & Sons, 1996).

[0058] Thermogravimetric analysis (TGA) Analyses were performed on a TGA / DSC 3+STARe system (Mettler Toledo GmbH, Switzerland). The TGA / DSC 3+ was temperature calibrated with indium and aluminum. Samples (approximately 2 mg) were weighed into 100 μL aluminum crucibles and sealed. A pinhole was drilled in the seal, and the crucibles were heated in the TGA from 25 to 300 °C at a heating rate of 10 °C / min, unless otherwise specified. Dry N2 gas was used for purging.

[0059] Differential Scanning Calorimetry (DSC) Analyses were performed on a heat flux DSC3+STARe system (Mettler-Toledo GmbH, Switzerland). The DSC3+ was calibrated for temperature and enthalpy with small pieces of indium (mp = 156.6 °C, δHf = 28.45 J / g) and zinc (mp = 419.6 °C, δHf = 107.5 J / g). Samples (approximately 2 mg) were placed in standard 40 μL aluminum pans, sealed with a pinhole, and heated in the DSC at a heating rate of 10 °C / min from 25 °C to 300 °C, unless otherwise specified. Dry N2 gas was used at a flow rate of 50 ml / min to purge the DSC instrument during measurements.

[0060] Dynamic Vapor Sorption (DVS) Analysis was performed using a DVS-1 system from Surface Measurement Systems (London, UK). Weight balance for each step was a minimum of 1 h and a maximum of 6 h, with dm / dt < 0.002. Samples were subjected to adsorption-desorption-adsorption cycles of 40 → 95 → 0 → 45% RH at a constant temperature of 25 °C. One cycle consisted of 20 steps, each acquired at 10% RH between 0 and 90% RH. Samples were then analyzed by HT-XRPD. [Example]

[0061] Example 1 Preparation of HCl2 and HCl3 A slurry of the amorphous HCl salt of PN6047 was prepared in neat solvent as shown in Table 1 below. Approximately 45 mg of amorphous salt was mixed with the solvent at room temperature. The mixture was then placed in a Crystal16® apparatus and subjected to the temperature profile shown in Figure 3. After the temperature profile, the solid was separated from the liquid by centrifugation. This solid phase was dried at ambient temperature and under deep vacuum (5 mbar) and analyzed by HT-XRPD before and after exposure to accelerated aging conditions (AAC; 40°C / 75% RH for 3 days). Additionally, the liquid phase was dried under deep vacuum (5 mbar) and the recovered solid was analyzed by HT-XRPD.

[0062] [Table 1]

[0063] The XRPD peaks of Form HCl2 are listed below in Table 2. The HR-diffractogram of Form HCl2 is shown in Figure 2.

[0064] [Table 2-1]

[0065] [Table 2-2]

[0066] The XRPD peaks of Form HCl3 are listed below in Table 3. The HT-diffractogram of Form HCl3 is shown in Figure 3.

[0067] [Table 3]

[0068] Example 2 Differential scanning calorimetry (DSC) analysis Form HCl2 displayed a broad endothermic event between approximately 25 and approximately 100 °C due to the loss of water. A subsequent endothermic event was observed at approximately 228 °C (onset 222.0 °C, end 231.5 °C, peak 227.9 °C), which may be due to the melting of the anhydrous HCl salt. The DSC thermogram is shown in Figure 4.

[0069] Form HCl3 exhibited a broad endothermic event between approximately 70 and approximately 150 °C due to the loss of water, which was attributed to the dehydration of Form HCl3. A subsequent endothermic event was observed at approximately 167 °C (onset 159.8 °C, end 175.2 °C, peak 166.9 °C), which may be due to the melting of the anhydrous HCl salt. The DSC thermogram is shown in Figure 5.

[0070] Example 3 thermogravimetric analysis The HCl2 sample exhibited a 2.5% mass loss between approximately 30°C and approximately 160°C. This mass loss was most likely due to the removal of water. Thermal decomposition of the sample began at approximately 220°C. The TGA and heat flow thermograms are shown in Figure 6.

[0071] The HCl3-form sample exhibited a 5.1% mass loss between approximately 30°C and approximately 160°C. This mass loss was attributed to the removal of moisture. Thermal decomposition of the sample began at approximately 220°C. The TGA and heat flow thermograms are shown in Figure 7.

[0072] Example 4 Dynamic Vapor Sorption (DVS) Analysis DVS measurements were performed to determine the hygroscopicity of Form HCl2 and Form HCl3. The DVS isotherm plot for Form HCl2 is shown in Figure 8. The material initially absorbed water gradually as the relative humidity (RH) was increased to approximately 90% RH. The mass change was approximately 3.3%, corresponding to approximately one molecule of water per molecule of PN6047. At 25°C / 80% RH, the water absorption rate was approximately 2.2%, making the material moderately hygroscopic (according to the European Pharmacopoeia classification). From 90% to 95% RH, the mass increased significantly from 3.3 to 10.0%, corresponding to approximately two additional molecules of water per molecule of PN6047. The material was then gradually dried from 95% to 0% RH in 10% RH increments. The mass change during drying was different from the initial mass gain during hydration. Finally, from 0 to 40% RH, water absorption proceeded similarly to the dehydration process described above. After the DVS cycle, analysis by HT-XRPD confirmed that conversion of HCl2 to HCl3 had occurred, possibly by incorporating two additional water molecules.

[0073] The DVS isotherm plot for Form HCl3 is shown in Figure 9. The material gradually absorbed water as the relative humidity (RH) was increased up to 95% RH. The water absorption at 25 °C / 80% RH was approximately 8.0%, making the material moderately hygroscopic (according to the European Pharmacopoeia classification). The material was then gradually dried from 95 to 0% RH in 10% RH increments. The mass change upon drying was nearly identical to the initial mass gain upon hydration. Finally, from 0 to 40% RH, water absorption proceeded similarly to the dehydration process described above. After the DVS cycle, the material was analyzed by HT-XRPD, which showed that Form HCl3 was still present.

[0074] To further understand the hygroscopic nature of the HCl2 form, a sample of the material was incubated at 85% RH and room temperature for 2 days, after which the material was analyzed by XRPD, which confirmed that conversion to HCl3 had occurred.

[0075] A sample of Form HCl3 was further incubated at 50°C / 1 mbar for 2 days to determine whether conversion to Form HCl2 occurred. However, this material was recovered as a partially crystalline phase of Form HCl3, and the additional diffraction peaks could not be associated with any of the Form HCl.

[0076] Example 5 Large-scale preparation of HCl2 In scale-up experiments, HCl Form 2 was prepared from 2-propanol as outlined in Table 4 below. In one experiment, 2-propanol was added to the amorphous HCl salt of PN6047. The suspension was stirred at 50°C for 1 hour. In two other experiments, the crystalline free base was suspended in 2-propanol and stirred at 1000 rpm using a magnetic stir bar. To these suspensions, a 37% HCl solution was added to achieve a 1:1 ratio of free base:HCl. The suspension was then stirred at elevated temperature.

[0077] [Table 4]

[0078] After confirming complete conversion to the HCl2 form by HT-XRPD, the suspension was centrifuged and the liquid phase was removed from the solid phase using a pipette. The solid phase was dried at 50 °C for 18 h, and the resulting solid was analyzed by XRPD.

[0079] Example 6 Stability test of HCl type 2 Solution Stability Test Experiments were performed in saline (0.9% NaCl in water). Two stock solutions of HCl2 in saline were prepared: 10 mg / mL and 100 mg / mL. The 10 mg / mL stock solution was prepared by dissolving 56 mg of material in 5 mL of saline. The 100 mg / mL stock solution was prepared by dissolving 196.2 mg of material in 1.75 mL of saline. For each experiment involving 10 mg / mL, 0.5 mL of stock solution was transferred to an HPLC vial, and for each experiment involving 100 mg / mL, 0.15 mL of stock solution was transferred. The HPLC vials were sealed with screw caps, placed in a Crystal16™ instrument, and incubated at various temperatures.

[0080] After the incubation period, the sample was diluted with 1:1 (v / v) acetonitrile / water and measured by LCMS to determine the API peak area. The experimental details and results are shown in Table 5.

[0081] [Table 5]

[0082] Solid Stability Test The solid state stability of Form HCl2 was determined by incubating approximately 18 mg samples under different conditions (temperature and relative humidity). After 1 and 4 weeks, the samples were analyzed to determine the polymorph by XRPD, mass loss upon heating by TGA, and API purity by LCMS. Experimental details and results are listed in Table 6.

[0083] [Table 6]

[0084] Example 7 Bioavailability Testing Male Wistar rats were used. Six groups of four animals each were used. Two groups received a single intravenous dose of 1 mg / kg of the free base or HCl2 salt, one group received a single oral dose of 3 mg / kg of the free base, and three groups received a single oral dose of 3, 10, or 50 mg / kg of the HCl2 salt. Blood samples were collected at 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours after intravenous administration and at 0.083, 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours after oral administration. Samples were analyzed using an LC / MS / MS system. Bioavailability (Fab) is shown in Table 7 and was calculated as follows:

[0085]

number

[0086] [Table 7]

Claims

1. HCl salt of PN6047.

2. Crystalline HCl salt of PN6047.

3. 3. The crystalline HCl salt of claim 2, wherein the salt is stable at a temperature of 25°C and a relative humidity of 60%.

4. 3. The crystalline HCl salt of claim 2, wherein the salt is stable at a temperature of 40° C. and a relative humidity of 75%.

5. The crystalline HCl salt of any one of claims 2 to 4, wherein the salt is anhydrous.

6. 3. The crystalline HCl salt of claim 2, which is Form HCl2 having an XRPD pattern obtained using CuKα1 radiation with peaks at °2θ values ​​of at least 16.5±0.2, 23.3±0.2, and 23.5±0.

2.

7. 7. The crystalline salt of claim 6, wherein Form HCl2 has an XRPD pattern, obtained using CuKα1 radiation, with peaks at °2θ values ​​of at least 16.5±0.2, 23.3±0.2, and 23.5±0.2, and one or more of 14.3±0.2, 16.1±0.2, 16.3±0.2, and 20.2±0.

2.

8. 7. The crystalline salt of claim 6, wherein Form HCl2 has an XRPD pattern obtained using CuKα1 radiation substantially as shown in Figure 1.

9. 9. The crystalline salt of claim 2, wherein Form HCl2 has a DSC curve that includes an endotherm at about 228°C.

10. 3. The crystalline salt of claim 2, which is Form HCl3 having an XRPD pattern obtained using CuKα radiation with peaks at °2θ values ​​of at least 12.8±0.2, 19.1±0.2, and 23.9±0.

2.

11. 11. The crystalline salt of claim 10, wherein Form HCl3 has an XRPD pattern, obtained using CuKα radiation, with peaks at °2θ values ​​of at least 12.8±0.2, 19.1±0.2, and 23.9±0.2, and one or more of 10.0±0.2, 25.3±0.2, and 26.3±0.

2.

12. 11. The crystalline salt of claim 10, wherein Form HCl3 has an XRPD pattern obtained using CuKα radiation substantially as shown in Figure 2.

13. 13. The crystalline salt of any one of claims 2 and 10 to 12, wherein Form HCl3 has a DSC curve that includes an endotherm at about 167°C.

14. 14. The crystalline HCl salt of any one of claims 2 to 13, having a crystallinity greater than about 99%.

15. A pharmaceutical composition comprising a therapeutically effective amount of the crystalline HCl salt of PN6047 according to any one of claims 2 to 14, in association with one or more pharmaceutically acceptable excipients.

16. 16. The pharmaceutical composition of claim 15, wherein the HCl salt of PN6047 is Form HCl2 having a polymorphic purity of at least about 90%.

17. 17. The pharmaceutical composition of claim 16, wherein Form HCl2 is substantially free of Form HCl3.

18. 15. The crystalline HCl salt of PN6047 according to any one of claims 2 to 14 for use in therapy.

19. 15. The crystalline HCl salt of PN6047 according to any one of claims 2 to 14 for use in the treatment or prevention of pain.

20. 20. The crystalline HCl salt of PN6047 for use according to claim 19, wherein the pain is acute pain, chronic pain, neuropathic pain, cancer pain, visceral pain, diabetic pain, or pain caused by a disease or condition such as rheumatoid arthritis, osteoarthritis, fibrositis, migraine, and opioid-induced hyperalgesia (OIH).

21. 1. A process for preparing PN6047 HCl2 form, comprising: a) preparing a solution or suspension of the HCl salt of PN6047 in a suitable solvent; b) maintaining stirring until a solid is obtained or the conversion to the HCl2 form is complete; c) recovering the solid material obtained in step b); d) drying the solid under vacuum.

22. 1. A process for preparing PN6047 HCl2 form, comprising: a) preparing a solution or suspension of the free base of PN6047 in a suitable solvent; b) adding an HCl solution to the solution or suspension of step a) to achieve a free base to HCl ratio of about 1:1; c) maintaining stirring until a solid is obtained or the conversion to the HCl2 form is complete; d) recovering the solid material obtained in step c); e) drying the solid under vacuum.

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