Crystalline dihydrotetrabenazine and the method thereof

Abstract

Described herein are crystalline dihydrotetrabenazine, methods for obtaining such crystalline forms, pharmaceutical compositions comprising the crystalline dihydrotetrabenazine, as well as methods of using the crystalline dihydrotetrabenazine in the treatment of hyperkinetic disorders.

Description

[0001] Crystalline Dihydrotetrabenazine and the Method Thereof

[0002] TECHNICAL FIELD

[0003] The present disclosure relates to crystalline dihydrotetrabenazine. The present disclosure also relates to pharmaceutical compositions comprising the crystalline dihydrotetrabenazine, as well as methods of using the crystalline dihydrotetrabenazine in the treatment of hyperkinetic disorders, and methods for obtaining such crystalline forms.

[0004] CROSS REFERENCE TO RELATED APPLICATION

[0005] This application is entitled to priority to U.S. Provisional Patent Application No. 63 / 662,688, filed on June 21, 2024, the disclosure of which is incorporated herein by reference.

[0006] BACKGROUND

[0007] Dihydrotetrabenazines (HTBZs) are the active metabolites of tetrabenazine (TBZ, a racemate), also known as Ro 1-9569, a benzoquinolizine derivative with the chemical name l,3,4,6,7,l lb-hexahydro-9,10-dimethoxy-3-(2-methylpropyl)-2H- benzo[a]quinolizin-2-one (GB 789,789 and US 2,830,993), which is a vesicular monoamine transporter 2 (VMAT2) inhibitor and is therapeutically effective for the treatment of movement disorders including Huntington’s disease and tardive dyskinesia. HTBZs are also benzoquinolizine derivative with the chemical name 9,10-dimethoxy- 3-(2-methylpropyl)-2,3,4,6,7, 1 lb-hexahydro-lH-benzo[a]quinolizin-2-ol. There are four thermally stable stereoisomers of HTBZs (Scheme 1), among which (+)-alpha- dihydrotetrabenazine (abbreviated as (+)-a-HTBZ) and (+)-beta-dihydrotetrabenazine (abbreviated as (+)-P-HTBZ) are the ones with potent VMAT2 inhibition. The binding of HTBZs to VMAT2 is highly stereospecific; (+)-a-HTBZ [or (2R,3R,llbR)-HTBZ] exists higher Ki value of 3.96 nM, while (+)-P-HTBZ [or (2S,3R,llbR)-HTBZ] has slightly lower Ki value of 13.4 nM (Yao, Z., et al., Eur. J. Med. Chem. 2011, 46, 1841; Kilbourn, M. R., et al., Chirality 1997, 9, 59; Kilboum, M., et al., Eur. J. Pharmacol. 1995, 278, 249).

[0008] Scheme 1. Structures of the HTBZs, the metabolites of TBZ.

[0009] In addition, (+)-a-HTBZ and (+)-0-HTBZ exhibit negligible binding at various off-targets such as dopamine receptors, mitigating the risk of dopaminergic side effects associated with the administration of TBZ (WO 2005 / 077946). Other unwanted adverse effects like sedative effect could also be reduced. This stereospecific binding indicates that TBZ racemate and HTBZ stereoisomers may have different pharmacological and / or toxicological profiles, which remain to be determined. Therefore, it is highly desirable to develop a practical access to optically purify HTBZ stereoisomers to support the development of more potent and safer drugs for the treatment of hyperkinetic disorders (e.g. Huntington’s disease, tardive dyskinesia, Tourette’s syndrome, and tic).

[0010] It is well understood that the prediction of whether any given compound features crystalline polymorphism or amorphism is not possible. Hence, it is impossible to foresee the number and type of crystalline forms that exist for HTBZ, or the methods that is feasible for the preparation of any specific crystalline form. In addition, prediction of the properties of any unknown crystalline forms, and how they differ from the other crystalline form of the same compound, remains elusive (Joel Bernstein, Polymorphism in Molecular Crystals, Oxford University Press, New York, 2002). Therefore, it is definitely needed for a novel crystalline form of HTBZ for use in the preparation of drug products with improved properties. While crystalline forms of TBZ are reported in WO 2023 / 159040A1, WO 2012 / 081031 Al and WO 2015 / 175505 Al, and those of deutetrabenazine are reported in WO 2014 / 047167 Al and US9550780B2, no crystalline forms or polymorphs of HTBZs have been disclosed. In pharmaceutical industry, it is always essential to improve the fundamental properties of an active pharmaceutical ingredient (API), for example, solubility, bioavailability, powder flowability, crystallinity, hygroscopicity, and thermal stability. Among those, polymorph is one of the most critical keys for successful product development in API production and specifications. Crystalline API often is inevitable for the reason that it is naturally a more stable form of compounds. Finding the desired solid-state form takes a wide screening during the early stage of drug product development. However, the path toward manufacturing of desired API crystalline in a cost-efficient manner is complicated and unpredictable. It is often the case that the crystallization processes take long time, while API polymorphism creates additional hurdles for people with ordinary skilled in the arts. In addition, size and shape of the crystals obtained not only have significant influence on drug dissolution patterns, but also have a huge impact on subsequential drug product development processes, such as filling and setting specifications for a drug product.

[0011] It can be advantageous using (+)-HTBZs to improve efficacy and minimize side effects due to significantly stronger specific binding to VMAT2 of (+)-HTBZs, especially crystalline (+)-a-HTBZ, than for the currently approved drug product composed of racemate TBZ. The inventors of the present disclosure also demonstrated that it is novel to combine the use of (+)-a-HTBZ in certain crystalline form to develop pharmaceutical compositions that provides improved properties for the treatment of hyperkinetic disorders, and the manufacturing method thereof.

[0012] BRIEF SUMMARY

[0013] The present disclosure provides crystalline (+)-a-HTBZs, processes for preparing the crystalline (+)-a-HTBZs, pharmaceutical compositions comprising the crystalline (+)-a-HTBZ, and the use of the crystalline (+)-a-HTBZ for the treatment of hyperkinetic disorders.

[0014] The present disclosure further provides a pharmaceutical composition comprising crystalline (+)-a-HTBZ and at least one pharmaceutically acceptable excipient.

[0015] The present disclosure also provides a method of treating a hyperkinetic disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the crystalline (+)-a-HTBZ, or at least one of the above pharmaceutical compositions.

[0016] In some embodiments, the present disclosure provides a crystalline form of (+)- a-HTBZ, characterized in that the crystal form has an X-ray diffraction spectrum comprising peaks at diffraction 29 angels of 6.8±0.2°, 9.0±0.2°, 13.6±0.2°, 14.2±0.2°, and 18.7±0.2°.

[0017] In some embodiments, the crystalline form of (+)-a-HTBZ is Form 1.

[0018] In certain embodiments, the X-ray diffraction spectrum of (+)-a-HTBZ crystalline Form 1 comprises peaks at 29 angles of 6.8±9.2°, 8.9±9.2°, 11.3±0.2°, 14.2±0.2°, 15.8±0.2°, 17.9±9.2°, 18.9±9.2°, 18.7±9.2°, and 22.6±0.2°.

[0019] In certain embodiments, the X-ray diffraction spectrum of (+)-a-HTBZ crystalline Form 1 comprises peaks at 29 angles of 6.8±0.2°, 8.9±0.2°, 11.3±9.2°, 12.6±0.2°, 13.5±0.2°, 14.2±9.2°, 15.8±9.2°, 17.9±9.2°, 18.9±9.2°, 18.7±9.2°, and 22.6±0.2°.

[0020] In certain embodiments, the X-ray diffraction spectrum of (+)-a-HTBZ crystalline Form 1 comprises peaks at 29 angles of 6.8±9.2°, 8.9±9.2°, 11.3±9.2°, 12.6±0.2°, 13.5±0.2°, 14.2±9.2°, 15.8±0.2°, 17.0±0.2°, 18.0±0.2°, 18.7±9.2°, 21.1±0.2°, 21.3±0.2°, 22.6±9.2°, 23.1±9.2°, 23.6±9.2°, and 28.1±9.2°.

[0021] In certain embodiments, the X-ray diffraction spectrum of (+)-a-HTBZ crystalline Form 1 comprises the peaks as shown in Table 2 of the present disclosure.

[0022] In certain embodiments, (+)-a-HTBZ crystalline Form 1 has an X-ray powder diffraction spectrum represented by diffraction angle 29 angle substantially as shown in FIG. 5 A.

[0023] In some embodiments, the crystalline form of (+)-a-HTBZ is Form 2.

[0024] In certain embodiments, the X-ray diffraction spectrum of (+)-a-HTBZ crystalline Form 2 comprises peaks at 29 angles of 6.9±9.2°, 8.7±9.2°, 8.9±9.2°, 11.3±0.2°, 11.8±0.2°, 12.4±0.2°, 13.0±0.2°, 13.8±0.2°, 14.2±0.2°, 16.8±0.2°, and 18.7±0.2°.

[0025] In certain embodiments, the X-ray diffraction spectrum of (+)-a-HTBZ crystalline Form 2 comprises peaks at 29 angles of 6.2±9.2°, 6.9±9.2°, 8.7±9.2°, 8.9±9.2°, 11.3±0.2°, 11.8±0.2°, 12.4±0.2°, 13.0±0.2°, 13.8±0.2°, 14.2±0.2°, 14.7±0.2°, 15.8±0.2°, 16.8±0.2°, 18.7±0.2°, and 19.3±0.2°.

[0026] In certain embodiments, the X-ray diffraction spectrum of (+)-a-HTBZ crystalline Form 2 comprises peaks at 29 angles of 2.4±9.2°, 6.2±9.2°, 6.9±9.2°, 8.7±9.2°, 8.9±9.2°, 11.3±0.2°, 11.8±0.2°, 12.4±0.2°, 12.6±0.2°, 13.0±0.2°, 13.5±0.2°, 13.8±0.2°, 14.2±0.2°, 14.7±0.2°, 15.5±0.2°, 15.8±0.2°, 16.8±0.2°, 18.7±0.2°,

[0027] 19.3±0.2°, 29.9±9.2°, 21.1±0.2°, 21.3±0.2°, 21.9±0.2°, 22.1±0.2°, 22.7±9.2°,

[0028] 23.7±9.2°, and 24.8±9.2°.

[0029] In certain embodiments, the X-ray diffraction spectrum of (+)-a-HTBZ crystalline Form 2 comprises the peaks as shown in Table 3 of the present disclosure.

[0030] In certain embodiments, (+)-a-HTBZ crystalline Form 2 has an X-ray powder diffraction spectrum represented by diffraction angle 29 angle substantially as shown in FIG. 5B.

[0031] In some embodiments, the crystalline form of (+)-a-HTBZ is Form 3.

[0032] In certain embodiments, the X-ray diffraction spectrum of (+)-a-HTBZ crystalline Form 3 comprises peaks at 29 angles of 6.8±9.2°, 9.9±9.2°, 13.6±9.2°, 14.2±0.2°, and 18.7±0.2°. In certain embodiments, the X-ray diffraction spectrum of (+)-a-HTBZ crystalline Form 3 comprises the peaks as shown in Table 4 of the present disclosure.

[0033] In certain embodiments, (+)-a-HTBZ crystalline Form 3 has an X-ray powder diffraction spectrum represented by diffraction angle 29 angle substantially as shown in FIG. 5C.

[0034] In some embodiments, the crystalline form of (+)-a-HTBZ is Form 4.

[0035] In certain embodiments, the X-ray diffraction spectrum of (+)-a-HTBZ crystalline Form 4 comprises peaks at 29 angles of 6.8±9.2°, 9.9±9.2°, 11.3±0.2°, 14.2±0.2°, 15.8±0.2°, 17.0±0.2°, 18.7±0.2°, and 22.7±9.2°.

[0036] In certain embodiments, the X-ray diffraction spectrum of (+)-a-HTBZ crystalline Form 4 comprises peaks at 29 angles of 6.8±9.2°, 9.9±9.2°, 11.3±0.2°, 12.6±0.2°, 14.2±0.2°, 15.8±0.2°, 17.0±0.2°, 18.0±0.2°, 18.7±0.2°, and 22.7±9.2°.

[0037] In certain embodiments, the X-ray diffraction spectrum of (+)-a-HTBZ crystalline Form 4 comprises peaks at 29 angles of 6.1±9.2°, 6.8±9.2°, 9.9±9.2°, 11.3±0.2°, 12.6±0.2°, 13.5±0.2°, 14.2±0.2°, 15.8±0.2°, 17.0±0.2°, 18.0±0.2°, 18.5±0.2°, 18.7±0.2°, 19.8±0.2°, 21.3±0.2°, 22.1±0.2°, 22.7±9.2°, 23.6±9.2°, and 28.1±0.2°.

[0038] In certain embodiments, the X-ray diffraction spectrum of (+)-a-HTBZ crystalline Form 4 comprises the peaks as shown in Table 5 of the present disclosure.

[0039] In certain embodiments, (+)-a-HTBZ crystalline Form 4 has an X-ray powder diffraction spectrum represented by diffraction angle 29 angle substantially as shown in FIG. 5D.

[0040] In certain embodiments, (+)-a-HTBZ crystalline Form 1 has a differential scanning calorimetry scan spectrum comprising an endothermic peak at 98±5°C.

[0041] In certain embodiments, (+)-a-HTBZ crystalline Form 1 has a differential scanning calorimetry scan spectrum substantially as shown in FIG. 6A.

[0042] In certain embodiments, (+)-a-HTBZ crystalline Form 2 has a differential scanning calorimetry scan spectrum comprising an endothermic peak at 126±5°C.

[0043] In certain embodiments, (+)-a-HTBZ crystalline Form 2 has a differential scanning calorimetry scan spectrum substantially as shown in FIG. 6B.

[0044] In certain embodiments, (+)-a-HTBZ crystalline Form 3 has a differential scanning calorimetry scan spectrum comprising an endothermic peak at 113±5°C.

[0045] In certain embodiments, (+)-a-HTBZ crystalline Form 3 has a differential scanning calorimetry scan spectrum substantially as shown in FIG. 6C.

[0046] The present disclosure provides a method for preparing crystalline form of (+)- a-HTBZ, including Form 1, Form 2, Form 3, and Form 4.

[0047] In certain embodiment, the (+)-a-HTBZ crystalline form is Form 1, and the method comprises: a) dissolving (+)-a-HTBZ in di chloromethane at room temperature; b) concentrating and crushing / grinding to obtain (+)-a-HTBZ crystalline Form 1.

[0048] In certain embodiment, the (+)-a-HTBZ crystalline form is Form 2, and the method comprises: a) dissolving (+)-a-HTBZ in di chloromethane at room temperature; b) adding isopropyl ether as the anti-solvent to obtain (+)-a-HTBZ crystalline Form 2.

[0049] In certain embodiment, the (+)-a-HTBZ crystalline form is Form 3, and the method comprises: a) dissolving (+)-a-HTBZ in a solvent or a combination of solvents at various temperature; b) adding water as the anti-solvent to obtain (+)-a-HTBZ crystalline Form 3, or adding the dissolved (+)-a-HTBZ solution into water to obtain (+)-a-HTBZ crystalline Form 3.

[0050] In certain embodiments, the solvent in step (a) is any liquid substance capable of dissolving (+)-a-HTBZ. Preferably, the solvent is selected from the group consisting of isopropyl alcohol, methanol, ethanol, acetone, ethyl acetate, N-methyl-2- pyrrolidone, 2-pyrrolidone, N,N-dimethylformamide, tetraethylene glycol, dimethyl sulfoxide, benzyl alcohol, benzyl benzoate, dichloromethane, and combinations thereof.

[0051] In certain embodiment, the (+)-a-HTBZ crystalline form is Form 3, and the method comprises: a) dissolving (+)-a-HTBZ and one or more crystallization modifier in a solvent or a combination of solvents at various temperature; b) adding water as the anti-solvent to obtain (+)-a-HTBZ crystalline Form 3, or adding the dissolved (+)-a-HTBZ solution into water to obtain (+)-a-HTBZ crystalline Form 3.

[0052] In certain embodiments, the crystallization modifier in step (a) is any polysaccharide, polymer, and surfactant that could act as modifiers to affect either growth or nucleation of an API during crystallization process. Preferably, the crystallization modifier is selected from the group consisting of carboxymethyl cellulose (CMC), polyvinylpyrrolidone (PVP), hydroxypropyl-B-cyclodextrins (HPBCD), and combinations thereof.

[0053] In certain embodiments, the solvent in step (a) is any liquid substance capable of dissolving (+)-a-HTBZ. Preferably, the solvent is selected from the group consisting of isopropyl alcohol, methanol, ethanol, acetone, ethyl acetate, N-methyl-2- pyrrolidone, 2-pyrrolidone, N,N-dimethylformamide, tetraethylene glycol, dimethyl sulfoxide, benzyl alcohol, benzyl benzoate, dichloromethane, and combinations thereof. In certain embodiment, the (+)-a-HTBZ crystalline form is Form 4, and the method comprises: a) dissolving (+)-a-HTBZ in dichloromethane at room temperature; b) concentrating to obtain (+)-a-HTBZ crystalline Form 4.

[0054] The present disclosure further provides a pharmaceutical composition comprising the crystalline form of (+)-a-HTBZ described herein and at least one pharmaceutically acceptable excipient.

[0055] Crystalline (+)-a-HTBZ or the pharmaceutical formulation of the present disclosure can be formulated into a tablet, capsule, pill, granule, solution, suspension, syrup, emulsions, solutions, suspensions, creams, gels, hydrogels, pastes, ointments, dusting powders, dressings, elixirs, lotions, tinctures, pastes, foams, films, aerosols, irrigations, inhalant, sprays, suppositories, bandages, dermal patches, and injectable dosage forms (including injection solution, injection suspension emulsions, micelles, liposomes, microspheres, nanoparticles, sterile powder for injection, flowable or nonfl owable formulation for injection, viscous / concentrated or diluted formulation for injection or controlled delivery dosage forms).

[0056] The present disclosure also provides a method of treating a VMAT2-mediated movement disorder such as a hyperkinetic movement disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the crystalline form of (+)-a-HTBZ or the pharmaceutical composition of the present disclosure.

[0057] In some embodiments, the hyperkinetic movement disorder is selected from the group consisting of Huntington’s disease, tardive dyskinesia, Tourette’s syndrome, and tic.

[0058] Other features and advantages of the present disclosure are apparent from additional descriptions provided herein, including different examples. The provided examples illustrate different components and methodology useful in practicing the present invention. Such examples do not limit the claimed invention. Based on the present disclosure, the skilled artisan can identify and employ other components including other benzoquinolizine derivatives and methodology useful for practicing the present invention.

[0059] BRIEF DESCRIPTION OF THE DRAWINGS

[0060] The foregoing summary, as well as the following detailed description of the invention, will be better understood when read in conjunction with the appended drawings. It should be understood that the invention is not limited to the precise embodiments shown in the drawings.

[0061] FIG. 1 demonstrates crystalline (+)-a-HTBZ Form 1, 400X magnifications. FIG. 2 demonstrates crystalline (+)-a-HTBZ Form 2, 400X magnifications.

[0062] FIGs. 3A-3C demonstrate crystalline (+)-a-HTBZ Form 3:

[0063] 3A: crystalline (+)-a-HTBZ Form 3 obtained via feeding API stock solution (IPA) into anti-solvent (water), 100X magnifications;

[0064] 3B: crystalline (+)-a-HTBZ Form 3 obtained via feeding anti-solvent (water) into API stock solution (IPA), 100X magnifications; and.

[0065] 3C: Crystalline (+)-a-HTBZ Form 3 obtained via feeding API stock solution (IPA) into anti-solvent (water with (+)-a-HTBZ seeds), 100X magnifications.

[0066] FIGs. 4A-4D demonstrate crystalline (+)-a-HTBZ Form 3, obtained with polymer or surfactant crystallization modifiers:

[0067] 4A: crystalline (+)-a-HTBZ Form 3 obtained using 1% (w / v) HPMC as the modifier in aqueous anti-solvent, 100X magnifications;

[0068] 4B: crystalline (+)-a-HTBZ Form 3 obtained using 0.25% (w / v) CMC as the modifier in aqueous anti-solvent, 100X magnifications;

[0069] 4C: crystalline (+)-a-HTBZ Form 3 obtained using 1% (w / v) PVP KI 7 as the modifier in aqueous anti-solvent, 100X magnifications; and

[0070] 4D: crystalline (+)-a-HTBZ Form 3 obtained using 1% (w / v) HPBCD as the modifier in aqueous anti-solvent, 100X magnifications.

[0071] FIGs. 5A-5D demonstrate the XRPD patterns of different crystalline forms of (+)-a-

[0072] HTBZ:

[0073] 5A: XRPD of raw material crystalline (+)-a-HTBZ, Form 1;

[0074] 5B: XRPD of raw material crystalline (+)-a-HTBZ, Form 2;

[0075] 5C: XRPD of raw material crystalline (+)-a-HTBZ, Form 3; and

[0076] 5D: XRPD of raw material crystalline (+)-a-HTBZ, Form 4.

[0077] FIGs. 6A-6C demonstrate the differential scanning calorimetry (DSC) patterns of different crystalline forms of (+)-a-HTBZ:

[0078] 6A: DSC of raw material crystalline (+)-a-HTBZ, Form 1;

[0079] 6B: DSC of raw material crystalline (+)-a-HTBZ, Form 2; and

[0080] 6C: DSC of raw material crystalline (+)-a-HTBZ, Form 3.

[0081] DETAILED DESCRIPTION

[0082] Various publications, articles and patents are cited or described in the background and throughout the specification; each of these references is herein incorporated by reference in its entirety. Discussion of documents, acts, materials, devices, articles or the like which has been included in the present disclosure is for the purpose of providing context for the present disclosure. Such discussion is not an admission that any or all of these matters form part of the prior art with respect to any inventions disclosed or claimed.

[0083] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood to one of ordinary skill in the art to which the present disclosure pertains. Otherwise, certain terms used herein have the meanings as set forth in the specification. All patents, published patent applications and publications cited herein are incorporated by reference as if set forth fully herein.

[0084] The present disclosure, therefore, provides (+)-a-HTBZ in crystalline forms, processes for preparing the crystalline (+)-a-HTBZ, pharmaceutical compositions comprising the crystalline (+)-a-HTBZ, and the use of the crystalline (+)-a-HTBZ for the treatment of hyperkinetic disorders. Crystalline (+)-a-HTBZ can be the form of free base, salts, or hydrates, which have one or more desirable properties such as chemical purity, solubility, dissolution rate, crystal morphology, polymorphic stability, thermal stability, mechanical stability, storage stability, a low content of residual solvent, a low degree of hygroscopicity, and advantageous processing and handling characteristics such as flowability, wettability, compressibility and bulk density. Preferably, crystalline (+)-a-HTBZ is in the form of free base, wherein the nitrogen atoms are not protonated.

[0085] Different aspects of the present disclosure are described below in further detail by embodiments, without being limited thereto. Each aspect of the present disclosure may be described by one embodiment or by combining two or more of the embodiments.

[0086] Definitions

[0087] It must be noted that as used herein and in the appended claims, the singular forms “a,” “an,” and “the” include plural reference unless the context clearly dictates otherwise.

[0088] As used herein, the term “about” preceding a numerical value or a series of numerical values means ±10% of the numerical value unless otherwise indicated. For example, “about 100 mg” means 90 to 110 mg.

[0089] Unless otherwise indicated, the term “at least” preceding a series of elements is to be understood to refer to every element in the series. Those skilled in the art will recognize or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the present disclosure described herein. Such equivalents are intended to be encompassed by the present disclosure.

[0090] Throughout this specification and the claims which follow, unless the context requires otherwise, the word “comprise”, and variations such as “comprises” and “comprising”, will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integer or step. When used herein the term “comprising” can be substituted with the term “containing” or “including” or sometimes when used herein with the term “having.”

[0091] When used herein “consisting of’ excludes any element, step, or ingredient not specified in the claim element. When used herein, “consisting essentially of’ does not exclude materials or steps that do not materially affect the basic and novel characteristics of the claim. Any of the aforementioned terms of “comprising,” “containing,” “including,” and “having,” whenever used herein in the context of an aspect or embodiment of the present disclosure can be replaced with the term “consisting of’ or “consisting essentially of’ to vary scopes of the disclosure.

[0092] As used herein, the conjunctive term “and / or” between multiple recited elements is understood as encompassing both individual and combined options. For instance, where two elements are conjoined by “and / or,” a first option refers to the applicability of the first element without the second. A second option refers to the applicability of the second element without the first. A third option refers to the applicability of the first and second elements together. Any one of these options is understood to fall within the meaning, and therefore satisfy the requirement of the term “and / or” as used herein. Concurrent applicability of more than one of the options is also understood to fall within the meaning, and therefore satisfy the requirement of the term “and / or.”

[0093] As used herein, dihydrotetrabenazine (HTBZ) refers to all four thermally stable stereoisomers of HTBZ. (+)-dihydrotetrabenazine (abbreviated as (+)-HTBZ) refers to both (+)-alpha-dihydrotetrabenazine (abbreviated as (+)-a-HTBZ) and (+)-beta- dihydrotetrabenazine (abbreviated as (+)-0-HTBZ).

[0094] As used herein, the term “(+)-dihydrotetrabenazine or (+)-HTBZ free base” refers to the solid form of “(+)-dihydrotetrabenazine or (+)-HTBZ free base”, having a chemical structure, wherein the molecule is not associated with any acid molecule.

[0095] As used herein, the term “crystalline (+)-a-HTBZ” is interchangeable with the term “(+)-a-HTBZ crystal” and the term “crystallized (+)-a-HTBZ” and the term “crystal form of (+)-a-HTBZ” throughout this specification and the claims which follow, unless the context requires otherwise.

[0096] The term “hydrate” as used herein, refers to a crystalline solid where water is cooperated in or accommodated by the crystal structure [e.g., water is part of the crystal structure or entrapped into the crystal (water inclusions)]. Thereby, water can be present in a stoichiometric or non-stoichiometric amount.

[0097] The terms “physical form” and “solid form” are used interchangeably herein and refer to any crystalline and / or amorphous phase of a compound.

[0098] As used herein, X-ray diffraction [as known as powder X-ray diffraction (PXRD), X-ray powder diffraction (XRPD), or X-ray diffraction (XRD)] is a laboratory technique that reveals structural information, such as chemical composition, crystal structure, crystallite size, strain, preferred orientation, and layer thickness. The XRD can be used to analyze a wide range of materials, from powder to solids such as thin films and nanomaterials. The peaks in an X-ray diffractogram are caused at certain diffraction angles (Bragg angles) by constructive interference from X-rays scattered by parallel planes of atoms in solid material, which are distributed in an ordered and repetitive pattern in a long-range positional order. Such a solid material is classified as crystalline material. A solid form of a compound that is not crystalline is defined as an amorphous material. An amorphous compound possesses no long-range order and does not display a definitive X-ray diffraction pattern, (see “Fundamentals of Powder Diffraction and Structural Characterization of Materials” by Vitalij et al., Kluwer Academic Publishers, 2003, page 3). A good X-ray diffractogram with clear, sharp peaks with low background noise should be obtained to enable data analysis and interpretation.

[0099] The term “29” or “29 angle” or “2-Theta” used in the present disclosure refers to the diffraction angle, and 9 is the Bragg angle, and the unit of which is ° or degree. The error range of 29 is between ±0.1 and ±0.5, preferably between ±0.1 and ±0.3, and can be -0.34, -0.33, -0.32, 0.31, -0.30, -0.29, -0.28, -0.27, -0.26, -0.25, -0.24, -0.23, - 0.22, -0.21, -0.20, -0.19, -0.18, -0.17, -0.16, -0.15, -0.14, -0.13, -0.12, -0.11, -0.10, - 0.09, -0.08, -0.07, -0.06, -0.05, -0.04, -0.03, -0.02, -0.01, 0.00, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.20, 0.21, 0.22, 0.23, 0.24, 0.25, 0.26, 0.27, 0.28, 0.29, 0.30, 0.31, 0.32, 0.33, 0.34, and more preferably ±0.2.

[0100] As used herein, the term “substantially the same as shown” with reference to XRD or XRPD means that variabilities in peak positions and relative intensities of the peaks are to be considered. For example, a typical precision of the 2-Theta values is in the range of ±0.2° 2-Theta, preferably in the range of ±0.1° 2-Theta. In addition, one skilled in the art will appreciate that relative peak intensities will show inter-apparatus variability as well as variability due to degree of crystallinity, preferred orientation, sample preparation and other factors known to those skilled in the art.

[0101] The term “subject” or “patient” refers to an animal, in some embodiments a mammal, which is the object of treatment, observation or experiment. An animal may be a human, a non-human primate, a companion animal (e.g., dogs, cats, and the like), farm animal (e.g., cows, sheep, pigs, horses, and the like) or a laboratory animal (e.g., rats, mice, guinea pigs, and the like).

[0102] “Treatment” or “treating” refers to clinical intervention in an attempt to alter the natural course of the individual or cell being treated and can be performed during the course of clinical pathology. Desirable effects of treatment include, but are not limited to, preventing recurrence of disease, alleviation of symptoms, diminishing of any direct or indirect pathological consequences of the disease, preventing metastasis, decreasing the rate of disease progression, amelioration or palliation of the disease state, and remission or improved prognosis.

[0103] The term “effective amount” as used herein refers to that amount of the crystalline form of (+)-a-HTBZ or the pharmaceutical composition, which will accomplish the goal of the recited method, e.g., relieve to some extent one or more of the symptoms of the disease, condition or disorder being treated. The amount of the crystalline form of (+)-a-HTBZ or the pharmaceutical composition, which will be effective in the treatment, or inhibition of the disease or disorder can be determined by standard clinical techniques. In addition, in vitro assays may optionally be employed to help identify optimal dosage ranges. The precise dose to be employed in the methods will also depend on the route of administration, and the seriousness of the VMAT- mediated disorders, and should be decided according to the judgment of the practitioner and each patient’s circumstances. Effective doses can be extrapolated from doseresponse curves derived from in vitro or animal model test systems.

[0104] As used herein, the term “consisting essentially of’ with reference to the amount of the crystalline (+)-a-HTBZ in a composition means that slight variabilities in the amount are to be considered. This term is also to be understood herein in that such a composition comprises at least 75% by weight, preferably 80% by weight, more preferably 85% by weight, and most preferably 90% by weight of the crystalline (+)- a-HTBZ as defined above, based on the total weight of the composition.

[0105] A crystalline solid form of (+)-a-HTBZ herein can be referred to as being characterized by graphical data “as shown in” a figure. Such data include, for example, XRD or XRPD, differential scanning calorimetry, and thermogravimetric analysis. The person skilled in the art understands that factors such as variations in instrument type, response and variations in sample directionality, sample concentration, sample purity, sample history and sample preparation may lead to variations for such data when presented in graphical form, for example variations relating to the exact peak positions and intensities. However, a comparison of the graphical data in the figures herein with the graphical data generated for an unknown physical form and the confirmation that two sets of graphical data relate to the same crystal form is well within the knowledge of a person skilled in the art. Multiple polymorphs in a sample can also be determined by XRPD. All powder X-ray diffraction patterns were obtained by methods known in the art using a Bruker D2 Phaser XRPD analyzer A26-X1 -A2B0B2 AO (Ser No. : 209872, Germany) with Cu anode.

[0106] Measurement of thermal analysis are conducted for the purpose of evaluating the physical and chemical changes that may take place in a heated sample. Thermal reactions can be endothermic (e.g., melting, boiling, sublimation, vaporization, desolvation, solid-solid phase transitions, chemical degradation, etc.) or exothermic (e.g., crystallization, oxidative decomposition, etc.) in nature. Such methodology has gained widespread use in the pharmaceutical industry in characterization of polymorphism. Thermal measurements have proven to be useful in the characterization of polymorphic systems. The most commonly applied techniques are thermogravimetry analysis (TGA), differential thermal analysis (DTA), and differential scanning calorimetry (DSC).

[0107] DSC is a thermodynamic tool for direct assessment of the heat energy uptake occurring in a sample within a controlled increase or decrease temperature process. The calorimetry throughout the process is applied to monitor the changes of phase transitions of the sample. DSC curves presented herein were obtained by methods known in the art using Waters Q200. The weight of the samples was about 1 to about 5 mg. The samples were scanned up from 25°C to 200 °C at 5°C / min increment.

[0108] As used herein, a solvent is any liquid substance capable of dissolving (+)-a- HTBZ. As used herein, the term "anti-solvent" means a liquid in which a compound is poorly soluble. The addition of an anti-solvent to a solvent reduces the solubility of a compound. As used herein a mixture of solvents refers to a composition comprising more than one solvent.

[0109] As used herein, "concentrating" when referring to the preparation of crystalline (+)-a-HTBZ means any method that decreases its solubility or reduces the amount of solubilized (+)-a-HTBZ in a solvent.

[0110] The starting material used in the method for preparing the crystal forms described herein can be (+)-a-HTBZ in any form, and the specific forms include, but are not limited to, amorphous form, arbitrary crystal forms and the like.

[0111] According to an embodiment of the present disclosure, (+)-a-HTBZ can be obtained via reduction of (+)-TBZ with NaBH4, borane or L-selectride. In another embodiment, (+)-a-HTBZ can be prepared by asymmetric synthesis.

[0112] In some embodiments, crystalline (+)-a-HTBZ is prepared by anti-solvent precipitation, concentrating, temperature alteration, or solid-state crystallization. The different crystallization methods can be selected depending on the desired physiochemical properties of (+)-a-HTBZ or on the subsequent processes for preparation of the pharmaceutical compositions. The present disclosure describes practical, reproducible methods of the production of crystalline (+)-a-HTBZ. Such methods can be easily scaled up under various temperature control, including at room temperature. This process is fast and only small amount of solvent is required while the yield can be over 50%. More preferably, the yield can be over 90%.

[0113] The present disclosure provides crystalline (+)-a-HTBZs, processes for preparing the crystalline (+)-a-HTBZs, pharmaceutical compositions comprising the crystalline (+)-a-HTBZ, and the use of the crystalline (+)-a-HTBZ for the treatment of hyperkinetic disorders.

[0114] The present disclosure further provides a pharmaceutical composition comprising crystalline (+)-a-HTBZ and at least one pharmaceutically acceptable excipient.

[0115] The present disclosure also provides a method of treating a hyperkinetic disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the crystalline (+)-a-HTBZ, or at least one of the above pharmaceutical compositions.

[0116] In some embodiments, the present disclosure provides a crystalline form of (+)- a-HTBZ, characterized in that the crystal form has an X-ray diffraction spectrum comprising peaks at diffraction 29 angels of 6.8±0.2°, 9.0±0.2°, 13.6±0.2°, 14.2±0.2°, and 18.7±0.2°.

[0117] In some embodiments, the crystalline form of (+)-a-HTBZ is Form 1.

[0118] In certain embodiments, the X-ray diffraction spectrum of (+)-a-HTBZ crystalline Form 1 comprises peaks at 29 angles of 6.8±9.2°, 8.9±9.2°, 11.3±0.2°, 14.2±0.2°, 15.8±0.2°, 17.0±0.2°, 18.0±0.2°, 18.7±0.2°, and 22.6±9.2°.

[0119] In certain embodiments, the X-ray diffraction spectrum of (+)-a-HTBZ crystalline Form 1 comprises peaks at 29 angles of 6.8±9.2°, 8.9±9.2°, 11.3±0.2°, 12.6±0.2°, 13.5±0.2°, 14.2±0.2°, 15.8±0.2°, 17.0±0.2°, 18.0±0.2°, 18.7±0.2°, and 22.6±9.2°.

[0120] In certain embodiments, the X-ray diffraction spectrum of (+)-a-HTBZ crystalline Form 1 comprises peaks at 29 angles of 6.8±9.2°, 8.9±9.2°, 11.3±0.2°, 12.6±0.2°, 13.5±0.2°, 14.2±0.2°, 15.8±0.2°, 17.0±0.2°, 18.0±0.2°, 18.7±0.2°, 21.1±0.2°, 21.3±0.2°, 22.6±9.2°, 23.1±0.2°, 23.6±9.2°, and 28.1±0.2°.

[0121] In certain embodiments, the X-ray diffraction spectrum of (+)-a-HTBZ crystalline Form 1 comprises the peaks as shown in Table 2 of the present disclosure.

[0122] In certain embodiments, (+)-a-HTBZ crystalline Form 1 has an X-ray powder diffraction spectrum represented by diffraction angle 29 angle substantially as shown in FIG. 5 A.

[0123] In some embodiments, the crystalline form of (+)-a-HTBZ is Form 2.

[0124] In certain embodiments, the X-ray diffraction spectrum of (+)-a-HTBZ crystalline Form 2 comprises peaks at 29 angles of 6.9±9.2°, 8.7±9.2°, 8.9±9.2°, 11.3±0.2°, 11.8±0.2°, 12.4±0.2°, 13.0±0.2°, 13.8±0.2°, 14.2±0.2°, 16.8±0.2°, and 18.7±0.2°.

[0125] In certain embodiments, the X-ray diffraction spectrum of (+)-a-HTBZ crystalline Form 2 comprises peaks at 29 angles of 6.2±9.2°, 6.9±9.2°, 8.7±9.2°, 8.9±9.2°, 11.3±0.2°, 11.8±0.2°, 12.4±0.2°, 13.9±9.2°, 13.8±9.2°, 14.2±0.2°, 14.7±9.2°, 15.8±0.2°, 16.8±0.2°, 18.7±9.2°, and 19.3±9.2°.

[0126] In certain embodiments, the X-ray diffraction spectrum of (+)-a-HTBZ crystalline Form 2 comprises peaks at 29 angles of 2.4±0.2°, 6.2±0.2°, 7.0±0.2°, 8.7±9.2°, 9.9±9.2°, 11.3±0.2°, 11.8±9.2°, 12.4±9.2°, 12.6±9.2°, 13.9±9.2°, 13.5±9.2°, 13.8±0.2°, 14.2±0.2°, 14.7±9.2°, 15.5±0.2°, 15.8±9.2°, 16.8±9.2°, 18.7±9.2°,

[0127] 19.3±0.2°, 20.0±0.2°, 21.1±9.2°, 21.3±9.2°, 21.9±9.2°, 22.1±9.2°, 22.7±0.2°,

[0128] 23.7±9.2°, and 24.8±0.2°.

[0129] In certain embodiments, the X-ray diffraction spectrum of (+)-a-HTBZ crystalline Form 2 comprises the peaks as shown in Table 3 of the present disclosure.

[0130] In certain embodiments, (+)-a-HTBZ crystalline Form 2 has an X-ray powder diffraction spectrum represented by diffraction angle 29 angle substantially as shown in FIG. 5B.

[0131] In some embodiments, the crystalline form of (+)-a-HTBZ is Form 3.

[0132] In certain embodiments, the X-ray diffraction spectrum of (+)-a-HTBZ crystalline Form 3 comprises peaks at 29 angles of 6.8±9.2°, 9.9±9.2°, 13.6±9.2°, 14.2±0.2°, and 18.7±0.2°.

[0133] In certain embodiments, the X-ray diffraction spectrum of (+)-a-HTBZ crystalline Form 3 comprises the peaks as shown in Table 4 of the present disclosure.

[0134] In certain embodiments, (+)-a-HTBZ crystalline Form 3 has an X-ray powder diffraction spectrum represented by diffraction angle 29 angle substantially as shown in FIG. 5C.

[0135] In some embodiments, the crystalline form of (+)-a-HTBZ is Form 4.

[0136] In certain embodiments, the X-ray diffraction spectrum of (+)-a-HTBZ crystalline Form 4 comprises peaks at 29 angles of 6.8±9.2°, 9.9±9.2°, 11.3±0.2°, 14.2±0.2°, 15.8±0.2°, 17.0±0.2°, 18.7±0.2°, and 22.7±9.2°.

[0137] In certain embodiments, the X-ray diffraction spectrum of (+)-a-HTBZ crystalline Form 4 comprises peaks at 29 angles of 6.8±9.2°, 9.9±9.2°, 11.3±0.2°, 12.6±0.2°, 14.2±0.2°, 15.8±0.2°, 17.0±0.2°, 18.0±0.2°, 18.7±0.2°, and 22.7±9.2°.

[0138] In certain embodiments, the X-ray diffraction spectrum of (+)-a-HTBZ crystalline Form 4 comprises peaks at 29 angles of 6.1±9.2°, 6.8±9.2°, 9.9±9.2°, 11.3±0.2°, 12.6±0.2°, 13.5±0.2°, 14.2±0.2°, 15.8±0.2°, 17.0±0.2°, 18.0±0.2°, 18.5±0.2°, 18.7±0.2°, 19.8±0.2°, 21.3±0.2°, 22.1±0.2°, 22.7±9.2°, 23.6±9.2°, and 28.1±0.2°.

[0139] In certain embodiments, the X-ray diffraction spectrum of (+)-a-HTBZ crystalline Form 4 comprises the peaks as shown in Table 5 of the present disclosure.

[0140] In certain embodiments, (+)-a-HTBZ crystalline Form 4 has an X-ray powder diffraction spectrum represented by diffraction angle 29 angle substantially as shown in FIG. 5D. In certain embodiments, (+)-a-HTBZ crystalline Form 1 has a differential scanning calorimetry scan spectrum comprising an endothermic peak at 98±5°C.

[0141] In certain embodiments, (+)-a-HTBZ crystalline Form 1 has a differential scanning calorimetry scan spectrum substantially as shown in FIG. 6A.

[0142] In certain embodiments, (+)-a-HTBZ crystalline Form 2 has a differential scanning calorimetry scan spectrum comprising an endothermic peak at 126±5°C.

[0143] In certain embodiments, (+)-a-HTBZ crystalline Form 2 has a differential scanning calorimetry scan spectrum substantially as shown in FIG. 6B.

[0144] In certain embodiments, (+)-a-HTBZ crystalline Form 3 has a differential scanning calorimetry scan spectrum comprising an endothermic peak at 113±5°C.

[0145] In certain embodiments, (+)-a-HTBZ crystalline Form 3 has a differential scanning calorimetry scan spectrum substantially as shown in FIG. 6C.

[0146] The present disclosure provides a method for preparing crystalline form of (+)- a-HTBZ, including Form 1, Form 2, Form 3, and Form 4.

[0147] In certain embodiment, the (+)-a-HTBZ crystalline form is Form 1, and the method comprises: a) dissolving (+)-a-HTBZ in di chloromethane at room temperature; b) concentrating and crushing / grinding to obtain (+)-a-HTBZ crystalline Form 1.

[0148] In certain embodiment, the (+)-a-HTBZ crystalline form is Form 2, and the method comprises: a) dissolving (+)-a-HTBZ in di chloromethane at room temperature; b) adding isopropyl ether as the anti-solvent to obtain (+)-a-HTBZ crystalline Form 2.

[0149] In certain embodiment, the (+)-a-HTBZ crystalline form is Form 3, and the method comprises: a) dissolving (+)-a-HTBZ in a solvent or a combination of solvents at various temperature; b) adding water as the anti-solvent to obtain (+)-a-HTBZ crystalline Form 3, or adding the dissolved (+)-a-HTBZ solution into water to obtain (+)-a-HTBZ crystalline Form 3.

[0150] In certain embodiments, the solvent in step (a) is any liquid substance capable of dissolving (+)-a-HTBZ. Preferably, the solvent is selected from the group consisting of isopropyl alcohol, methanol, ethanol, acetone, ethyl acetate, N-methyl-2- pyrrolidone, 2-pyrrolidone, N,N-dimethylformamide, tetraethylene glycol, dimethyl sulfoxide, benzyl alcohol, benzyl benzoate, dichloromethane, and combinations thereof.

[0151] In certain embodiment, the (+)-a-HTBZ crystalline form is Form 3, and the method comprises: a) dissolving (+)-a-HTBZ and one or more crystallization modifier in a solvent or a combination of solvents at various temperature; b) adding water as the anti-solvent to obtain (+)-a-HTBZ crystalline Form 3, or adding the dissolved (+)-a-HTBZ solution into water to obtain (+)-a-HTBZ crystalline Form 3.

[0152] In certain embodiments, the crystallization modifier in step (a) is any polysaccharide, polymer, and surfactant that could act as modifiers to affect either growth or nucleation of an API during crystallization process. Preferably, the crystallization modifier is selected from the group consisting of carboxymethyl cellulose (CMC), polyvinylpyrrolidone (PVP), hydroxypropyl-B-cyclodextrins (HPBCD), and combinations thereof.

[0153] In certain embodiments, the solvent in step (a) is any liquid substance capable of dissolving (+)-a-HTBZ. Preferably, the solvent is selected from the group consisting of isopropyl alcohol, methanol, ethanol, acetone, ethyl acetate, N-methyl-2- pyrrolidone, 2-pyrrolidone, N,N-dimethylformamide, tetraethylene glycol, dimethyl sulfoxide, benzyl alcohol, benzyl benzoate, dichloromethane, and combinations thereof.

[0154] In certain embodiment, the (+)-a-HTBZ crystalline form is Form 4, and the method comprises: a) dissolving (+)-a-HTBZ in di chloromethane at room temperature; b) concentrating to obtain (+)-a-HTBZ crystalline Form 4.

[0155] The present disclosure further provides a pharmaceutical composition comprising the crystalline form of (+)-a-HTBZ of the present disclosure and at least one pharmaceutically acceptable excipient.

[0156] Oral Administration

[0157] Crystalline (+)-a-HTBZ or the pharmaceutical composition of the present disclosure can be administrated to a patient as in oral dosage forms. The pharmaceutical formulations described herein can be prepared in solid, semisolid, or liquid forms for oral administration, which includes buccal, lingual, and sublingual delivery. Suitable oral dosage forms encompass tablets, capsules, pills, troches, lozenges, pastilles, cachets, pellets, medicated chewing gum, granules, bulk powders, effervescent or non- effervescent powders or granules, solutions, emulsions, suspensions, wafers, sprinkles, elixirs, and syrups. When formulated into an oral formulation, the pharmaceutical formulation may further comprise suitable binders, fillers, diluents, disintegrants, wetting agents, lubricants, glidants, coloring agents, dye-migration inhibitors, sweetening agents, and flavoring agents and the like.

[0158] It is important to note that many carriers and excipients can serve multiple roles within the same formulation. The pharmaceutical compositions described herein may be available in various tablet forms, including compressed tablets, tablet triturates, chewable lozenges, rapidly dissolving tablets, multiple compressed tablets, enteric- coated tablets, sugar-coated tablets, and film-coated tablets. Enteric-coated tablets are designed with a protective coating that withstands stomach acid but dissolves in the intestine, ensuring that the active ingredients remain unaffected by the stomach’s acidic environment. Common enteric-coating materials include fatty acids, fats, phenylsalicylate, waxes, shellac, ammoniated shellac, and cellulose acetate phthalates. Sugar-coated tablets feature a sugar-based coating that helps mask undesirable tastes or odors while also offering protection against oxidation. Film-coated tablets are covered with a thin, water-soluble film, often made of materials such as hydroxyethylcellulose, sodium carboxymethylcellulose, polyethylene glycol 4000, and cellulose acetate phthalate. This film provides similar benefits to sugar coating. Multiple compressed tablets undergo more than one compression cycle, resulting in different forms such as layered tablets and press-coated or dry-coated tablets.

[0159] Tablet dosage forms can be formulated using the active ingredient in powdered, crystalline, or granular form, either alone or combined with one or more carriers or excipients. These may include binders, disintegrants, controlled-release polymers, lubricants, diluents, and colorants. Additionally, flavoring and sweetening agents play a crucial role in enhancing the palatability of chewable tablets and lozenges.

[0160] The compositions may include various excipients, such as binders (e.g., acacia, cornstarch, gelatin, carbomer, ethyl cellulose, guar gum, hydroxypropyl cellulose, hydroxypropyl methylcellulose, povidone), disintegrants (e.g., cornstarch, potato starch, alginic acid, silicon dioxide, croscarmellose sodium, crospovidone, guar gum, sodium starch glycolate), and buffering agents (e.g., Tris-HCl, acetate, phosphate) with varying pH and ionic strengths. Other optional components include additives to minimize adsorption to surfaces (e.g., albumin, gelatin), detergents (e.g., Tween 20, Tween 80, Pluronic F68, bile acid salts), surfactants (e.g., sodium lauryl sulfate), permeation enhancers, solubilizing agents (e.g., glycerol, polyethylene glycol), antioxidants (e.g., ascorbic acid, sodium metabisulfite, butylated hydroxyanisole), stabilizers (e.g., hydroxypropyl cellulose, hydroxypropyl methylcellulose), viscosity enhancers (e.g., carbomer, colloidal silicon dioxide, ethyl cellulose, guar gum), sweeteners (e.g., aspartame, citric acid), preservatives (e.g., thimerosal, benzyl alcohol, parabens), lubricants (e.g., stearic acid, magnesium stearate, polyethylene glycol, sodium lauryl sulfate), flow agents (e.g., colloidal silicon dioxide), plasticizers (e.g., diethyl phthalate, triethyl citrate), emulsifiers (e.g., carbomer, hydroxypropyl cellulose, sodium lauryl sulfate), polymer coatings (e.g., poloxamers), and film-forming or coating agents (e.g., ethyl cellulose, acrylates, polymethacrylates). Each of these excipients constitutes a separate embodiment of the present invention.

[0161] The pharmaceutical compositions described herein may also be formulated as liquid or semisolid dosage forms, including emulsions, solutions, suspensions, elixirs, and syrups. An emulsion consists of two phases, where one liquid is dispersed in small globules within another, which may be either oil-in-water or water-in-oil. Emulsions can incorporate pharmaceutically acceptable non-aqueous liquids or solvents, emulsifying agents, and preservatives. Suspensions may contain a pharmaceutically acceptable suspending agent along with a preservative. Elixirs are clear, sweetened hydroalcoholic solutions, while syrups consist of concentrated aqueous solutions of sugar, such as sucrose, and may also incorporate preservatives. In liquid dosage formulations, for instance, a polyethylene glycol-based solution can be diluted with a pharmaceutically acceptable liquid carrier, such as water, to facilitate accurate measurement for administration.

[0162] Topical Administration

[0163] Crystalline (+)-a-HTBZ or the pharmaceutical composition of the present disclosure described herein can also be administered topically to the skin, orifices, or mucosal surfaces. Routes of topical administration may include (intra)dermal, conjunctival, intracorneal, intraocular, ophthalmic, auricular, transdermal, nasal, vaginal, urethral, respiratory, and rectal delivery.

[0164] The pharmaceutical compositions described herein can be formulated in various dosage forms suitable for topical administration, enabling both local and systemic effects. These formulations may include emulsions, solutions, suspensions, creams, gels, hydrogels, ointments, dusting powders, dressings, elixirs, lotions, tinctures, pastes, foams, films, aerosols, irrigations, sprays, suppositories, bandages, and dermal patches. Additionally, advanced delivery systems such as liposomes, micelles, microspheres, nanoparticles, and their combinations may be incorporated to enhance drug absorption and therapeutic efficacy.

[0165] Topical formulations may incorporate a variety of pharmaceutically acceptable carriers and excipients to enhance stability, solubility, and delivery. These may include aqueous, water-miscible, or non-aqueous vehicles. The composition may also incorporate one or more preservatives, typically in concentrations ranging from approximately 0.01% to 2.0% by weight of the formulation. Suitable preservatives include phenoxyethanol, methyl paraben, propyl paraben, butyl paraben, and benzyl alcohol. The composition may optionally contain an antioxidant. Suitable antioxidants may include but are not limited to butylated hydroxyanisole (BHA), ascorbyl palmitate, butylated hydroxytoluene (BHT), tertiary butyl hydroquinone, propyl gallate, a- tocopherol, sodium metabisulfite, and other similar compounds. Additional components may consist of stabilizers, solubility enhancers, isotonic agents, buffering agents, antioxidants, and local anesthetics. The formulations may also include suspending and dispersing agents, wetting or emulsifying agents, complexing agents, sequestering or chelating agents, penetration enhancers, cryoprotectants, lyoprotectants, thickening agents, and inert gases, each selected to optimize therapeutic efficacy and formulation performance.

[0166] The pharmaceutical compositions described herein may be formulated as ointments, creams, or gels, utilizing a variety of suitable vehicles. Oleaginous or hydrocarbon bases may include, but not limited to, lard, benzoinated lard, olive oil, cottonseed oil, other vegetable oils, and white petrolatum. Emulsifiable or absorption bases, such as hydrophilic petrolatum, hydroxystearin sulfate, and anhydrous lanolin, enhance formulation versatility. Water-removable bases, such as hydrophilic ointments, and water-soluble bases, including polyethylene glycols of varying molecular weights, offer additional formulation options. Emulsion bases, categorized as water-in-oil (W / O) or oil-in-water (O / W) emulsions, may incorporate cetyl alcohol, glyceryl monostearate, lanolin, and stearic acid. While these vehicles provide emollient properties, the inclusion of antioxidants and preservatives is generally necessary to maintain stability and efficacy.

[0167] Gels are semisolid suspension systems, with single-phase gels characterized by the uniform dispersion of organic macromolecules within a liquid carrier. Suitable gelling agents include, but not limited to, crosslinked acrylic acid polymers, such as carbomers, carboxypolyalkylenes, and Carbopol®; hydrophilic polymers like polyethylene oxides, polyoxyethylene-polyoxypropylene copolymers, and polyvinyl alcohol; cellulosic polymers such as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate, and methylcellulose; as well as natural gums like tragacanth and xanthan gum, sodium alginate, and gelatin. To ensure uniform consistency, dispersing agents such as alcohol or glycerin may be incorporated, or the gelling agent may be processed through trituration, mechanical mixing, or stirring.

[0168] The composition may also be formulated as a cream, an emulsion composed of oleaginous substances and water as the carrier. This cream can exist as either a water- in-oil (w / o) emulsion, where the aqueous phase is dispersed within an oil phase, or an oil-in-water (o / w) emulsion, in which oil is distributed throughout an aqueous base.

[0169] The composition may also be formulated as an ointment, typically possessing greater viscosity than an oil-in-water (o / w) cream and potentially being free of water. Traditional ointment bases, serving as carriers, include hydrocarbons such as petrolatum and beeswax, vegetable oils like canola oil and olive oil, fatty alcohols including cholesterol, lanolin, wool alcohol, and stearyl alcohol, as well as polyethylene glycols (PEGs) and silicones. Depending on the formulation, active ingredients in ointments may be fully dissolved or present in full or partial suspension.

[0170] Pastes, may be another type of composition, which are distinguished by their high content of insoluble particulate solids, which can constitute up to 50% by weight. Common insoluble solids used in pastes include starch, zinc oxide, calcium carbonate, and talc.

[0171] Intranasal Administration

[0172] Crystalline (+)-a-HTBZ or the pharmaceutical composition of the present disclosure described herein may be administered intranasally or for respiratory tract delivery. These formulations can be provided as aerosols or solutions, delivered through a pressurized container, pump, spray, atomizer including electrohydrodynamic atomizers that generate fine mists, or nebulizers, with or without a suitable propellant. They may also be formulated as dry powders for insufflation, either alone or combined with an inert carrier such as lactose or phospholipids, as well as nasal drops. For intranasal administration, the powder formulation may incorporate bioadhesive agents like chitosan or cyclodextrin to enhance mucosal adhesion and absorption. In certain embodiments, the pharmaceutical formulation includes one or more excipients, such as water, EDTA, and sodium chloride. Additionally, in some cases, benzalkonium chloride may be incorporated into the formulation.

[0173] Inhalation Administration

[0174] Crystalline (+)-a-HTBZ or the pharmaceutical composition of the present disclosure described herein may be administered by inhalation or for respiratory tract delivery. The pharmaceutical composition may include a lubricating, emulsifying, and / or viscosity-enhancing compound. Suitable compounds may consist of carbomers, polymers, acacia, alginic acid, carboxymethyl cellulose, ethylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, methylcellulose, poloxamers, polyvinyl alcohol, lecithin, sodium alginate, tragacanth, guar gum, sodium hyaluronate, hyaluronic acid, xanthan gum, glycerin, vegetable glycerin, polyethylene glycol (PEG), and PEG 400. Additionally, the composition may contain a polysorbate or related surfactant, such as polyoxyethylene (20) sorbitan monolaurate (polysorbate 20), polyoxyethylene (20) sorbitan monooleate (polysorbate 80), polyoxyethylene (20) sorbitan monopalmitate (polysorbate 40), polyoxyethylene (20) sorbitan monostearate (polysorbate 60), sorbitan tri octadecanoate, polyglyceryl-3 stearate, polyglyceryl-3 palmitate, polyglyceryl-2 laurate, polyglyceryl-5 laurate, polyglyceryl-5 oleate, polyglyceryl-5 dioleate, polyglyceryl- 10 diisostearate, or combinations thereof. The pharmaceutical composition may contain a pH-adjusting agent, which can include sodium hydroxide, sodium bicarbonate, sodium carbonate, sodium citrate, benzoic acid, ascorbic acid, or combinations thereof. The pharmaceutical composition may include a preservative, such as ethylenediaminetetraacetic acid (EDTA), benzalkonium chloride, benzoic acid, sorbic acid, or a combination thereof.

[0175] Rectal Administration

[0176] Crystalline (+)-a-HTBZ or the pharmaceutical composition of the present disclosure described herein may be administered via rectal delivery. In one embodiment, the compositions may also include various excipients, such as binders, disintegrating agents, buffers, additives, detergents, protease inhibitors, surfactants, permeation enhancers, solubilizing agents, antioxidants, stabilizers, viscosity-enhancing agents, sweeteners, preservatives, lubricants, flow-aids, plasticizers, emulsifiers, polymer coatings, and film-forming agents. Examples of binders include acacia, cornstarch, gelatin, carbomer, ethyl cellulose, guar gum, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, and povidone. Disintegrating agents may include cornstarch, potato starch, alginic acid, silicon dioxide, croscarmellose sodium, crospovidone, guar gum, and sodium starch glycolate. Buffers of varying pH and ionic strength may consist of Tris-HCl, acetate, or phosphate. Surfactants like sodium lauryl sulfate and permeation enhancers may also be included. Solubilizing agents such as glycerol and polyethylene glycol are also suitable. Antioxidants may comprise ascorbic acid, sodium metabisulfite, and butylated hydroxyanisole. Stabilizers can include hydroxypropyl cellulose and hydroxypropyl methyl cellulose. Viscosity-enhancing agents may feature carbomer, colloidal silicon dioxide, ethyl cellulose, and guar gum.

[0177] Parenteral Administration

[0178] Crystalline (+)-a-HTBZ or the pharmaceutical composition of the present disclosure described herein can also be formulated in various dosage forms suitable for parenteral administration, including solutions, sterile powder for injection, concentrated solution for injection, suspensions, emulsions, micelles, liposomes, microspheres, nanoparticles, controlled delivery dosage forms and solid forms designed for dissolution or suspension in liquid prior to injection. These formulations can be prepared using conventional techniques well known to experts in pharmaceutical science.

[0179] Pharmaceutical compositions designed for parenteral administration may incorporate one or more pharmaceutically acceptable carriers and excipients. These may include aqueous, water-miscible, or non-aqueous vehicles, as well as antimicrobial agents or preservatives to prevent microbial growth. Additional components may consist of stabilizers, solubility enhancers, isotonic agents, buffering agents, antioxidants, local anesthetics, suspending and dispersing agents, wetting or emulsifying agents, complexing agents, sequestering or chelating agents, cryoprotectants, lyoprotectants, thickening agents, pH-adjusting agents, and inert gases.

[0180] Aqueous vehicles may include, but not limited to, water, saline, physiological saline, phosphate-buffered saline (PBS), sodium chloride injection, Ringer’s injection, isotonic dextrose injection, sterile water injection, and dextrose with lactated Ringer’s inj ection. Non-aqueous vehicles can consist of, but not limited to, fixed oils of vegetable origin, such as castor oil, corn oil, cottonseed oil, olive oil, peanut oil, peppermint oil, safflower oil, sesame oil, soybean oil, hydrogenated vegetable oils, hydrogenated soybean oil, and medium-chain triglycerides derived from coconut oil or palm seed oil. Water-miscible vehicles may include, but not limited to, ethanol, 1,3 -butanediol, liquid polyethylene glycol (e.g., polyethylene glycol 300 or polyethylene glycol 400), propylene glycol, glycerin, N-methyl-2-pyrrolidone, dimethylacetamide, and dim ethyl sulfoxi de .

[0181] The pharmaceutical compositions described herein can be formulated for either single-dose or multi-dose administration. Single-dose formulations are typically packaged in ampules, vials, or syringes. Multi-dose parenteral formulations must contain an antimicrobial agent at bacteriostatic or fungistatic concentrations to ensure preservation. All parenteral formulations must be sterile, in accordance with established pharmaceutical standards and practices.

[0182] The pharmaceutical compositions may be formulated as ready-to-use sterile solutions. Alternatively, they may be provided as sterile dry soluble products, such as lyophilized powders and hypodermic tablets, which require reconstitution with a suitable vehicle before use. In some formulations, ready-to-use sterile suspensions may be prepared. Additionally, sterile dry insoluble products can be supplied, necessitating reconstitution with a vehicle prior to administration. Certain compositions may also be formulated as ready-to-use sterile emulsions.

[0183] The pharmaceutical compositions can be formulated as a suspension, solid, semisolid, or thixotropic liquid for implantation as a depot. In some embodiments, the compositions are dispersed within a solid inner matrix, encased by an outer polymeric membrane that remains insoluble in bodily fluids while enabling controlled diffusion of the active ingredient.

[0184] In certain embodiment, a pharmaceutical composition comprises crystalline (+)- a-HTBZ, a biocompatible solvent, and one or more biodegradable polymer. The biocompatible copolymers of the present disclosure may be bioerodible, i.e., gradually decompose, dissolve, hydrolyze and / or erode in situ. Examples of bioerodible copolymers and / or co-oligomer include, but are not limited to, polylactides, polyglycolides, polycaprolactones, polyanhydrides, polyamines, polyurethanes, polyesteramides, polyorthoesters, polydioxanones, polyacetals, polyketals, polycarbonates, polyorthocarbonates, polyphosphazenes, poly(malic acid), poly(amino acids), polyvinylpyrrolidone, polyethylene glycol, polyhydroxycellulose, polysaccharides, chitin, chitosan, and mixtures thereof. The copolymer and / or cooligomer can be in linear, di-block, tri-block, branched or dendritic structure. In one embodiment, the copolymer is a block copolymer. The block copolymer is composed of one or more hydrophilic block(s) linked with one or more hydrophobic block(s). A hydrophilic block is composed of, but not limited to poly(malic acid), poly(amino acids), polyvinylpyrrolidone, and polyethylene glycol (PEG), or the combination thereof. A hydrophobic block is composed of, but not limited to polylactides (or polylactic acid, PLA), poly(lactide-coglycolide) or poly(lactic-co-glycolic acid) (PLGA or PLG), polycaprolactones (PCL), polyanhydrides, polyurethanes, polyesteramides, polyorthoesters, polydioxanones, polyacetals, polyketals, polycarbonates, polyorthocarbonates, polyphosphazenes, or the combination thereof. The biodegradable polymer can have one ester terminal functional group and one hydroxyl end group and can also be made to have one or two carboxyl terminal groups. The biodegradable polymer can be dissolved with biocompatible solvent selected from the group consisting of N-methyl-2-pyrrolidone, 2-pyrrolidone, N,N-dimethylformamide, dimethyl sulfoxide, benzyl alcohol, benzyl benzoate, triacetin, and combinations thereof.

[0185] The present disclosure further exemplified using a pharmaceutical composition comprising the different crystalline forms of (+)-a-HTBZ of the present disclosure and biodegradable polymers for controlled drug delivery via subcutaneous administration routs in rats. Significantly, formulations prepared with either crystalline (+)-(a)-HTBZ in Form 1 or in Form 3 demonstrated sustained release capability lasting for at least 35 days, whereas different total systemic exposure was found. This is the first time that different crystalline forms of (+)-a-HTBZ disclosed and demonstrated different bioavailability in animals.

[0186] As a whole, this present disclosure enabled the manufacturing of (+)-a-HTBZ in various crystalline forms, processes for preparing (+)-a-HTBZ in various crystalline forms, pharmaceutical compositions comprising (+)-a-HTBZ in various crystalline forms, and the use of the crystalline (+)-a-HTBZ for the treatment of hyperkinetic disorders.

[0187] Other features and advantages of the present invention are apparent from additional descriptions provided herein, including different examples. The provided examples illustrate different components and methodology useful in practicing the present invention. Such examples do not limit the claimed invention. Based on the present disclosure, the skilled artisan can identify and employ other components and methodology useful for practicing the present invention.

[0188] Methods of Use

[0189] The present disclosure also provides a method of treating a VMAT2-mediated movement disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the crystalline form of (+)-a-HTBZ or the pharmaceutical composition of the present disclosure.

[0190] In some embodiments, the VMAT2-mediated movement disorder is a hyperkinetic movement disorder.

[0191] In certain embodiments, the hyperkinetic movement disorder is selected from the group consisting of Huntington’s disease, tardive dyskinesia, Tourette’s syndrome, and tic.

[0192] In some embodiments, the subject is a patient suffering from a hyperkinetic movement disorder.

[0193] EXAMPLES

[0194] The following examples of the present disclosure are to further illustrate the nature of the disclosure. It should be understood that the following examples do not limit the disclosure and the scope of the disclosure is to be determined by the appended claims.

[0195] Example 1 : Synthesis of (+)-alpha-dihydrotetrabenazine

[0196] (2R,3R,llbT)-HTBZ or, (+)-a-HTBZ, was synthesized by reduction of (3R,llbR)-TBZ or, (+)-tetrabenazine, with borane as the stereo-selective reducing agent at -20°C. 3.2 mmol of (+)-TBZ was dissolved in 11 mL THF. 6.4 mmol of 2M borane-Me2S was then added dropwise into the mixture. The reaction was continued over 2 hours, followed by adding of 11 mL ammonia water. The whole mixture was then warmed up to 35°C and stirred overnight. Diluted the mixture with brine and then extracted with ether. The organic layer was washed with brine, followed by drying over Na2SO4 and concentrated under vacuum to obtain the crude product. [Yao et al., Preparation and evaluation of tetrabenazine enantiomers and all eight stereoisomers of dihydrotetrabenazine as VMAT2 inhibitors; European Journal of Medicinal Chemistry, 46 (2011) 1841-1848], The crude product was then purified following the crystallization procedures as disclosed in the present disclosure giving crystalline (+)- a-HTBZ.

[0197] Example 2: Crystallization of (+)-q-HTBZ Form 1 In one approach, the synthesized (+)-a-HTBZ as described in Example 1 was first dissolved in dichloromethane at room temperature, followed by concentrating from dichloromethane and then crushed to obtain crystalline (+)-a-HTBZ Form 1. Microscope image of crystalline (+)-a-HTBZ Form 1 was investigated as shown in FIG. 1.

[0198] Example 3: Crystallization of (+)-q-HTBZ Form 2

[0199] In another approach, the synthesized (+)-a-HTBZ was first dissolved in dichloromethane, followed by anti-solvent precipitation using isopropyl ether to obtain crystalline (+)-a-HTBZ Form 2. Microscope image of crystalline (+)-a-HTBZ Form 2 was also investigated as shown in FIG. 2.

[0200] Example 4: Crystallization of (+)-q-HTBZ Form 3

[0201] In addition to dichloromethane, a good solvent can also be selected from the group consisting of isopropyl alcohol, methanol, ethanol, acetone, ethyl acetate, N- methyl-2-pyrrolidone, 2-pyrrolidone, N,N-dimethylformamide, tetraethylene glycol, dimethyl sulfoxide, benzyl alcohol, benzyl benzoate, and combinations thereof to prepare API stock solution. The crystalline (+)-a-HTBZ can then be produced by either feeding the API stock solution into water or adding water into the API stock solution. In addition, via this approach, (+)-q-HTBZ crystalline morphology and size can be tailored by several factors, including but not limited to: concentration of API stock solution, types of solvent and anti-solvent used, feeding rate of the API stock solution, solvent to anti-solvent ratio, agitation speed, temperature, addition of crystallization modifier such as polysaccharide, polymer, or surfactant, and the employment of seeding procedure.

[0202] In one embodiment, (+)-a-HTBZ was dissolved in IPA as the API stock solution. Water was then added dropwise into the API stock solution as the anti-solvent with agitation at about 200-400 rpm and room temperature. Rectangular-shaped crystalline (+)-q-HTBZ could be obtained as shown in FIG. 3 A.

[0203] In another embodiment, (+)-a-HTBZ was dissolved in IPA as the API stock solution and added dropwise into water (anti -solvent) with agitation at about 200-400 rpm (room temperature). Cubic-shaped crystalline (+)-a-HTBZ could be obtained as shown in FIG. 3B.

[0204] In still another example, (+)-a-HTBZ was dissolved in IPA as the API stock solution. The anti-solvent was prepared by seeding crystalline (+)-a-HTBZ into water. API stock solution was then added dropwise into the seed containing anti-solvent with agitation at about 200-400 rpm (room temperature). Small, cubic-shaped crystalline (+)-q-HTBZ could be obtained as shown in FIG. 3C.

[0205] Example 5: Crystallization of (+)-oc-HTBZ Form 3, with Crystallization Modifier

[0206] Polysaccharide, polymer, and surfactant could act as modifiers to affect either growth or nucleation of an API during crystallization process. In one example, (+)-q- HTBZ was dissolved in acetone as the API stock solution. 1% (w / v) hydroxypropyl methylcellulose (HPMC, Mw 10,000) aqueous solution was adopted as the anti-solvent. API stock solution was added dropwise into the anti-solvent with agitation at about 200- 400rpm and room temperature. Cubic-shaped crystalline (+)-a-HTBZ was obtained as shown in FIG. 4A.

[0207] In another example, (+)-a-HTBZ was dissolved in acetone as the API stock solution. 0.25% (w / v) carboxymethyl cellulose (CMC, 50-100 cP) aqueous solution was adopted as the anti -solvent. API stock solution was added dropwise into the anti- solvent at about 200-400 rpm and room temperature. Cubic-shaped crystalline (+)-q- HTBZ could be obtained as shown in FIG. 4B.

[0208] In another example, (+)-a-HTBZ was dissolved in IPAas the API stock solution. 1% (w / v) polyvinylpyrrolidone (PVP) KI 7 aqueous solution was adopted as the antisolvent. API stock solution was added dropwise into the anti-solvent with agitation at about 200-400 rpm (room temperature). Cubic-shaped crystalline (+)-a-HTBZ could be obtained as shown in FIG. 4C.

[0209] In still another example, (+)-a-HTBZ was dissolved in IPA as the API stock solution. 1-2 g / mL hydroxypropyl-B-cyclodextrins (HPBCD) aqueous solution was adopted as the anti-solvent. Anti-solvent was added into API stock solution with agitation at about 200-400 rpm (room temperature). Cubic-shaped crystalline (+)-q- HTBZ could be obtained as shown in FIG. 4D.

[0210] Example 6: Crystallization of (+)-q-HTBZ Form 4

[0211] In another approach, the synthesized (+)-a-HTBZ as described in Example 1 was first dissolved in dichloromethane at room temperature, followed by concentrating from dichloromethane to obtain crystalline (+)-a-HTBZ Form 4.

[0212] Example 7: X-ray powder diffraction (XRPD) Analysis of Crystalline (+)-q-HTBZ Form 1, Form 2, Form 3, and Form 4 Crystallinity of (+)-a-HTBZ was investigated via XRPD analysis using Bruker D2 Phaser XRPD analyzer A26-X1-A2B0B2A0 (Ser No.: 209872, Germany) with Cu anode. Divergence and anti-scatter slit were set as 0.2 mm and 1.0 mm, respectively. About 10 mg of the sample was scanned from 3° to 45° at a step size of 0.02° per second. The parameters were tabulated in Table 1.

[0213] Table 1. Parameters of X-Ray Diffractometer.

[0214] Characteristic peaks of crystalline (+)-a-HTBZ Form 1 as prepared in example 2 are summarized in Table 2.

[0215] Table 2. List of Characteristic Peaks: Crystalline (+)-a-HTBZ, Form 1

[0216]

[0217] Characteristic peaks of crystalline (+)-a-HTBZ Form 2 as prepared in example 3 are summarized in Table 3.

[0218] Table 3. List of Characteristic Peaks: Crystalline (+)-a-HTBZ, Form 2

[0219]

[0220] Characteristic peaks of crystalline (+)-a-HTBZ Form 3 as prepared in examples 4 & 5 are summarized in Table 4.

[0221] Table 4. List of Characteristic Peaks: Crystalline (+)-a-HTBZ, Form 3

[0222] Characteristic peaks of crystalline (+)-a-HTBZ Form 4 as prepared in examples 6 are summarized in Table 5.

[0223] Table 5. List of Characteristic Peaks: Crystalline (+)-a-HTBZ, Form 4

[0224]

[0225] FIG. 5A, 5B, 5C, and 5D demonstrate the results that confirm the formation of crystalline (+)-a-HTBZ Form 1, Form 2, Form 3, and Form 4.

[0226] Example 8. Differential scanning calorimetry (DSC) analysis of (+)-a-HTBZ in different crystalline forms

[0227] Differential scanning calorimetry (DSC) is a thermodynamic tool for direct assessment of the heat energy uptake occurring in a sample within a controlled increase or decrease temperature process. The calorimetry throughout the process is applied to monitor the changes of phase transitions of the sample. DSC curves presented herein were obtained by methods known in the art using Waters Q200. The weight of the samples was about 1 to about 5 mg. The samples were scanned up from 25°C to 200 °C at 5°C / min increment. The present disclosure enables the production of crystalline (+)- a-HTBZ in various crystalline forms. DSC analysis of different crystalline forms of (+)-a-HTBZ were shown in FIGs. 6A-6C. All the DSC patterns showed distinct endothermic peaks at various temperature (melting temperature, Tm; Table 6). The sharp endothermic peak demonstrated that each crystalline form of (+)-a-HTBZ was in its pure crystalline form.

[0228] Table 6. Melting temperature (Tm) of different crystalline forms of (+)-a-HTBZ determining via differential scanning calorimetry. Example 9. Subcutaneously Administration of Sustained-Release, Crystalline (+)-(a)- HTBZ Formulations in Rats

[0229] In one embodiment, a 35-day PK study of sustained-release, polymeric depot (+)- (a)-HTBZ formulations composed of crystalline (+)-(a)-HTBZ in Form 1 or Form 3, biodegradable poly(lactic-co-glycolic acid), and N-Methyl-2-pyrrolidone (NMP) was conducted in Sprague Dawley (SD) rats. The formulation was subcutaneously administrated to SD rats (N=3) at a dose level of 100 mg / kg. Animals that received formulations containing (+)-(a)-HTBZ crystalline Formulations were dosed on Day 1, followed by blood sampling at 2, 6, 12, 24 hours and 4, 7, 14, 21, 28, 35 days postdosing. For each animal, plasma (+)-(a)-HTBZ concentration was measured via LC- MS. PK results were evaluated by plasma (+)-(a)-HTBZ level. Systemic exposure was determined by total area under the curve (AUC) of (+)-(a)-HTBZ plasma level measured in the animals versus time.

[0230] 35-Day duration PK parameters after administration of (+)-(a)-HTBZ crystalline- PLGA polymeric depot formulations were summarized in Table 7 below.

[0231] Table 7. PK parameters of polymeric formulations composed of crystalline (+)-a- HTBZ Form 1 and Form 3

[0232] As shown in Table 7, formulations prepared with either crystalline (+)-(a)-HTBZ in Form 1 or in Form 3 demonstrated sustained release capability lasting for at least 35 days. Surprisingly, significantly different total systemic exposure was found when different crystalline forms (+)-a-HTBZ were formulated in PLGA polymeric depot formulations dosed subcutaneously to SD rats. This is the first time that different crystalline forms of (+)-a-HTBZ disclosed and demonstrated different bioavailability in animals.

Claims

Claims1. A crystal form of (+)-alpha-dihydrotetrabenazine having an X-ray powder diffraction pattern comprising peaks at diffraction 29 angels of 6.8±0.2°, 9.0±0.2°, 13.6±0.2°, 14.2±0.2°, and 18.7±9.2°.

2. The crystal form of (+)-alpha-dihydrotetrabenazine according to claim 1, being Form 1 having an X-ray powder diffraction pattern comprising peaks at diffraction 29 angels of 6.8±9.2°, 8.9±9.2°, 11.3±0.2°, 14.2±0.2°, 15.8±0.2°, 17.0±0.2°, 18.0±0.2°, 18.7±0.2°, and 22.6±9.2°.

3. The crystal form of (+)-alpha-dihydrotetrabenazine according to claim 1 or 2, being Form 1 having an X-ray powder diffraction pattern substantially the same as shown in FIG. 5A.

4. The crystal form of (+)-alpha-dihydrotetrabenazine according to claim 1, being Form 2 having an X-ray powder diffraction pattern comprising peaks at diffraction 29 angels of 6.9±9.2°, 8.7±9.2°, 8.9±9.2°, 11.3±0.2°, 11.8±0.2°, 12.4±0.2°, 13.0±0.2°, 13.8±0.2°, 14.2±0.2°, 16.8±0.2°, and 18.7±9.2°.

5. The crystal form of (+)-alpha-dihydrotetrabenazine according to claim 1 or 4, being Form 2 having an X-ray powder diffraction pattern substantially the same as shown in FIG. 5B.

6. The crystal form of (+)-alpha-dihydrotetrabenazine according to claim 1, being Form 3 having an X-ray powder diffraction pattern comprising peaks at diffraction 29 angels of 6.8±9.2°, 9.9±9.2°, 13.6±0.2°, 14.2±0.2°, and 18.7±0.2°.

7. The crystal form of (+)-alpha-dihydrotetrabenazine according to claim 1 or 6, being Form 3 having an X-ray powder diffraction pattern substantially the same as shown in FIG. 5C.

8. The crystal form of (+)-alpha-dihydrotetrabenazine according to claim 1, being Form 4 having an X-ray powder diffraction pattern comprising peaks at diffraction 29 angels of 6.8±9.2°, 9.9±9.2°, 11.3±0.2°, 14.2±0.2°, 15.8±0.2°, 17.0±0.2°, 18.7±0.2°, and 22.7±9.2°.

9. The crystal form of (+)-alpha-dihydrotetrabenazine according to claim 1 or 8, being Form 4 having an X-ray powder diffraction pattern substantially the same as shown in FIG 5D.

19. A process of making a crystal form of (+)-alpha-dihydrotetrabenazine having an X- ray powder diffraction pattern comprising peaks at diffraction 29 angles of 6.8±9.2°, 9.9±9.2°, 13.6±9.2°, 14.2±0.2°, and 18.7±0.2°, comprising: allowing (+)-alpha- dihydrotetrabenazine to crystallize by anti-solvent precipitation, concentrating,temperature alteration, or solid-state crystallization.

11. The process according to claim 10, wherein the crystal form of (+)-alpha- dihydrotetrabenazine is Form 1 having an X-ray powder diffraction pattern comprising peaks at diffraction 29 angels of 6.8±0.2°, 8.9±0.2°, 11.3±0.2°, 14.2±0.2°, 15.8±0.2°, 17.0±0.2°, 18.0±0.2°, 18.7±0.2°, and 22.6±0.2°.

12. The process according to claim 10 or 11, wherein the crystal form of (+)-alpha- dihydrotetrabenazine is Form 1 having an X-ray powder diffraction pattern substantially the same as shown in FIG. 5A.

13. The process according to claim 10, wherein the crystal form of (+)-alpha- dihydrotetrabenazine is Form 2 having an X-ray powder diffraction pattern comprising peaks at diffraction 29 angels of 6.9±0.2°, 8.7±0.2°, 8.9±0.2°, 11 ,3±0.2°, 11.8±0.2°, 12.4±0.2°, 13.0±0.2°, 13.8±0.2°, 14.2±0.2°, 16.8±0.2°, and 18.7±0.2°.

14. The process according to claim 10 or 13, wherein the crystal form of (+)-alpha- dihydrotetrabenazine is Form 2 having an X-ray powder diffraction pattern substantially the same as shown in FIG. 5B.

15. The process according to claim 10, wherein the crystal form of (+)-alpha- dihydrotetrabenazine is Form 3 having an X-ray powder diffraction pattern comprising peaks at diffraction 29 angels of 6.8±0.2°, 9.0±0.2°, 13.6±0.2°, 14.2±0.2°, and 18.7±0.2°.

16. The process according to claim 10 or 15, wherein the crystal form of (+)-alpha- dihydrotetrabenazine is Form 3 having an X-ray powder diffraction pattern substantially the same as shown in FIG. 5C.

17. The process according to claim 10, wherein the crystal form of (+)-alpha- dihydrotetrabenazine is Form 4 having an X-ray powder diffraction pattern comprising peaks at diffraction 29 angels of 6.8±0.2°, 9.0±0.2°, 11.3±0.2°, 14.2±0.2°, 15.8±0.2°, 17.0±0.2°, 18.7±0.2°, and 22.7±0.2°.

18. The process according to claim 10 or 17, wherein the crystal form of (+)-alpha- dihydrotetrabenazine is Form 4 having an X-ray powder diffraction pattern substantially the same as shown in FIG. 5D.

19. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a crystalline form of (+)-alpha-dihydrotetrabenazine having an X-ray powder diffraction pattern comprising peaks at diffraction 29 angles of 6.8±0.2°, 9.0±0.2°, 13.6±0.2°, 14.2±0.2°, and 18.7±0.2°.

20. The pharmaceutical composition according to claim 19, wherein the crystal form of (+)-alpha-dihydrotetrabenazine is Form 1 having an X-ray powder diffractionpattern comprising peaks at diffraction 29 angels of 6.8±0.2°, 8.9±0.2°, 11.3±9.2°, 14.2±0.2°, 15.8±0.2°, 17.9±9.2°, 18.9±9.2°, 18.7±9.2°, and 22.6±0.2°.

21. The pharmaceutical composition according to claim 19 or 20, wherein the crystal form of (+)-alpha-dihydrotetrabenazine is Form 1 having an X-ray powder diffraction pattern substantially the same as shown in FIG. 5A.

22. The pharmaceutical composition according to claim 19, wherein the crystal form of (+)-alpha-dihydrotetrabenazine is Form 2 having an X-ray powder diffraction pattern comprising peaks at diffraction 29 angels of 6.9±0.2°, 8.7±0.2°, 8.9±0.2°, 11.3±0.2°, 11.8±0.2°, 12.4±0.2°, 13.0±0.2°, 13.8±0.2°, 14.2±0.2°, 16.8±0.2°, and 18.7±0.2°.

23. The pharmaceutical composition according to claim 19 or 22, wherein the crystal form of (+)-alpha-dihydrotetrabenazine is Form 2 having an X-ray powder diffraction pattern substantially the same as shown in FIG. 5B.

24. The pharmaceutical composition according to claim 19, wherein the crystal form of (+)-alpha-dihydrotetrabenazine is Form 3 having an X-ray powder diffraction pattern comprising peaks at diffraction 29 angels of 6.8±9.2°, 9.9±9.2°, 13.6±9.2°, 14.2±0.2°, and 18.7±9.2°.

25. The pharmaceutical composition according to claim 19 or 24, wherein the crystal form of (+)-alpha-dihydrotetrabenazine is Form 3 having an X-ray powder diffraction pattern substantially the same as shown in FIG. 5C.

26. The pharmaceutical composition according to claim 19, wherein the crystal form of (+)-alpha-dihydrotetrabenazine is Form 4 having an X-ray powder diffraction pattern comprising peaks at diffraction 29 angels of 6.8±9.2°, 9.9±9.2°, 11.3±0.2°, 14.2±0.2°, 15.8±0.2°, 17.0±0.2°, 18.7±9.2°, and 22.7±9.2.

27. The pharmaceutical composition according to claim 19 or 26, wherein the crystal form of (+)-alpha-dihydrotetrabenazine is Form 4 having an X-ray powder diffraction pattern substantially the same as shown in FIG. 5D.

28. A method of treating a VMAT2-mediated movement disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of crystalline (+)-alpha-dihydrotetrabenazine having an X-ray powder diffraction pattern comprising peaks at diffraction 29 angles of 6.8±9.2°, 9.9±9.2°, 13.6±0.2°, 14.2±9.2°, and 18.7±9.2°.

29. The method according to claim 28, wherein the VMAT2-mediated disorder is a hyperkinetic movement disorder selected from the group consisting of Huntington’s chorea, tardive dyskinesia, Tourette’s syndrome, and tic.

30. The method to claim 28 or 29, wherein the crystal form of (+)-alpha- dihydrotetrabenazine is Form 1 having an X-ray powder diffraction pattern comprising peaks at diffraction 29 angels of 6.8±0.2°, 8.9±0.2°, 11.3±9.2°, 14.2±0.2°, 15.8±0.2°, 17.9±9.2°, 18.9±9.2°, 18.7±9.2°, and 22.6±0.2°.

31. The method according to any one of claims 28-30, wherein the crystal form of (+)- alpha-dihydrotetrabenazine is Form 1 having an X-ray powder diffraction pattern substantially the same as shown in FIG. 5A.

32. The method according to claim 28 or 29, wherein the crystal form of (+)-alpha- dihydrotetrabenazine is Form 2 having an X-ray powder diffraction pattern comprising peaks at diffraction 29 angels of 6.9±0.2°, 8.7±0.2°, 8.9±0.2°, 11 ,3±0.2°, 11.8±0.2°, 12.4±0.2°, 13.0±0.2°, 13.8±0.2°, 14.2±0.2°, 16.8±0.2°, and 18.7±0.2°.

33. The method according to any one of claim 28, 29, and 32, wherein the crystal form of (+)-alpha-dihydrotetrabenazine is Form 2 having an X-ray powder diffraction pattern substantially the same as shown in FIG. 5B.

34. The method according to claim 28 or 29, wherein the crystal form of (+)-alpha- dihydrotetrabenazine is Form 3 having an X-ray powder diffraction pattern comprising peaks at diffraction 29 angels of 6.8±9.2°, 9.9±9.2°, 13.6±9.2°, 14.2±0.2°, and 18.7±9.2°.

35. The method according to any one of claims 28, 29, and 34, wherein the crystal form of (+)-alpha-dihydrotetrabenazine is Form 3 having an X-ray powder diffraction pattern substantially the same as shown in FIG. 5C.

36. The method according to claim 28 or 29, wherein the crystal form of (+)-alpha- dihydrotetrabenazine is Form 4 having an X-ray powder diffraction pattern comprising peaks at diffraction 29 angels of 6.8±9.2°, 9.9±9.2°, 11.3±0.2°, 14.2±0.2°, 15.8±0.2°, 17.0±0.2°, 18.7±9.2°, and 22.7±9.2.

37. The method according to any one of claims 28, 29, and 36, wherein the crystal form of (+)-alpha-dihydrotetrabenazine is Form 4 having an X-ray powder diffraction pattern substantially the same as shown in FIG. 5D.

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