EA043769B1 - VALBENAZINE SALT AND THEIR POLYMORPHS - Google Patents

Description

Link to related application

This application claims benefit from U.S. Provisional Patent Application No. 62/249,074, filed October 30, 2015, the entire contents of which are incorporated herein by reference.

Field of technology to which the present invention relates

Provided herein are (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11bhexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl salts (S)-2-amino-3-methylbutyric acid ester in amorphous and crystalline forms, methods for their preparation and their pharmaceutical compositions. In addition, methods are provided for their use to treat, prevent, or reduce the intensity of one or more symptoms of neurological disorders and diseases, including hyperkinetic movement disorders or diseases.

BACKGROUND OF THE INVENTION

Hyperkinetic disorders are characterized by excessive, pathological involuntary movements. These neurological disorders include tremor, dystonia, ballismus, tics, akathisia, stereotypies, chorea, myoclonus and athetosis. Although the pathophysiology of these movement disorders is poorly understood, dysregulation of neurotransmitters in the basal ganglia is thought to play an important role (Kenney et.al., Expert Review Neurotherapeutics, 2005, 6, 7-17). Long-term use and high dosage of typical antipsychotics or centrally acting antiemetics blocking dopamine receptors makes patients predisposed to the occurrence of tardive syndromes. Tardive dyskinesia, one subtype of the latter symptoms, is characterized by rapid, repetitive, stereotyped, involuntary movements of the face, limbs, or trunk (Muller, Expert Opin. Investig. Drugs, 2015, 24, 737-742).

Reversible inhibition of the vesicular monoamine transporter 2 (VMAT2) system by 3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-2- it, also known as tetrabenazine (TBZ), improves the treatment of various hyperkinetic movement disorders. However, the disadvantages of this treatment include inconsistent response, the need for frequent dosing due to the rapid metabolism of TBZ, and side effects. Side effects associated with TBZ include sedation, depression, akathisia, and parkinsonism.

TBZ, which contains two chiral centers and is a racemic mixture of two stereoisomers, is rapidly and extensively metabolized in vivo to its reduced form, 3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro- 2H-pyrido[2,1-a]isoquinolin-2-ol, also known as dihydrotetrabenazine (DHTBZ). DHTBZ is believed to exist as four distinct isomers: (±) alpha-DHTBZ and (±) beta-DHTBZ, 2R,3R,11bR or (+) alpha-DHTBZ is believed to represent the absolute configuration of the active metabolite (Kilbourn et al., Chirality, 1997, 9, 59-62). Tetrabenazine has orphan drug designation in the United States and is approved in some European countries. Its use also provides an opportunity for the treatment of chorea in patients with Huntington's disease. However, tetrabenazine is rapidly metabolized and must be administered frequently throughout the day (Muller, Expert Opin. Investig. Drugs, 2015, 24, 737-742). Therefore, there is an unmet need in the art to develop effective therapeutic agents for the treatment of hyperkinetic movement disorders, including tardive dyskinesia.

Valbenazine, (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1a]isoquinolin-2-yl ester (S )-2-amino-3-methylbutyric acid, a purified prodrug of the (+)-a-isomer of dihydrotetrabenazine, has recently demonstrated significant improvement in the treatment of hyperkinetic movement disorders, including symptoms of tardive dyskinesia, with an improved pharmacokinetic and tolerability profile.

Brief Disclosure of the Present Invention

Provided herein are pharmaceutically acceptable salts of (2R,3R,11bR)-3-isobutyl9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-2 -yl ester of (S)-2-amino-3methylbutyric acid according to the formula

or their isotopic variant, or their solvate.

Provided herein is a crystalline form of di(4-methylbenzenesulfonate) (S)-(2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H- nirido[2,1-a]isoquinolin-2-yl2-amino-3-methylbutanoate according to formula I

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(I), or an isotopic variant thereof, or a solvate thereof.

Also provided herein are Forms I, II, III, IV, V and VI of di(4-methylbenzenesulfonate) (S)-(2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3 ,4,6,7,11b-hexahydro-Spirido[2,1-a]isoquinolin-2-yl-2-amino-3-methylbutanoate (formula I), or an isotopic variant thereof, or a solvate thereof.

Provided herein is a method for preparing a crystalline form of di(4-methylbenzenesulfonate) (S)-(2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro- 1Hpyrido[2,1-a]isoquinolin-2-yl-2-amino-3-methylbutanoate (formula I) or an isotopic variant thereof; or a pharmaceutically acceptable salt or solvate thereof comprising dissolving di(4-methylbenzenesulfonate) (S)-(2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b- hexahydro-1Hpyrido[2,1-a]isoquinolin-2-yl-2-amino-3-methylbutanoate (formula I) in a solvent at the first temperature.

Provided herein is a pharmaceutical composition containing a crystalline form of di(4-methylbenzenesulfonate) (S)-(2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11bhexahydro- 1H-pyrido[2,1-a]isoquinolin-2-yl-2-amino-3-methylbutanoate (formula I), or an isotopic variant thereof, or a solvate thereof.

Provided herein is a method of treating, preventing, or reducing one or more symptoms of a hyperkinetic disorder comprising administering to a subject a pharmaceutically acceptable salt of (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6, 7,11bhexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester of (8)-2-amino-3-methylbutyric acid, or an isotopic variant thereof, or a solvate thereof.

Provided herein is a method of treating, preventing, or ameliorating one or more symptoms of a hyperkinetic disorder comprising administering to a subject a crystalline form of di(4-methylbenzenesulfonate) (S)-(2R,3R,11bR)-3-isobutyl-9,10dumethoxy-2 ,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-yl-2-amino-3-methylbutanoate (formula I), or an isotopic variant thereof, or a solvate thereof.

Brief description of the figures

In fig. 1 shows an illustrative X-ray powder diffraction (XRP) pattern of a sample of di(4-methylbenzenesulfonate) (S)-(2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b- hexahydro-1Hpyrido[2,1-a]isoquinolin-2-yl-2-amino-3-methylbutanoate (formula I) in crystalline form I.

In fig. 2 shows an illustrative thermogravimetric analysis (TGA) thermogram (dashed line) and differential scanning calorimetry (DSC) diffractogram (solid line) of a sample of formula I in crystalline form I.

In fig. 3 depicts an exemplary gravimetric vapor sorption (GVS) of a sample of formula I in crystalline form I.

In fig. 4 shows scanning electron microscope (SEM) photographs of sample particles according to Formula I in Form I at a magnification of 500 (A); 2000 (B) and 5000 (C).

In fig. 5 shows an exemplary X-ray powder diffraction (XRP) pattern of a sample of formula I in crystalline form II.

In fig. 6 shows an exemplary differential scanning calorimetry (DSC) diffraction pattern (upper panel) and thermogravimetric analysis (TGA) thermogram (lower panel) of a sample of formula I in crystalline form II.

In fig. 7 depicts an exemplary gravimetric vapor sorption (GVS) of a sample of formula I in crystalline form II.

In fig. 8 shows an exemplary X-ray powder diffraction (XRP) pattern of a sample of formula I in crystalline form III.

In fig. 9 shows an exemplary thermogravimetric analysis (TGA) thermogram (upper graph) and a differential scanning calorimetry (DSC) diffraction pattern (lower graph) of a sample of formula I in crystalline form III.

In fig. 10 depicts an exemplary X-ray powder diffraction (XRP) pattern of a sample of formula I in crystalline form IV.

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In fig. 11 depicts an exemplary thermogravimetric analysis (TGA) thermogram (dashed line) and differential scanning calorimetry (DSC) diffractogram (solid line) of a sample of formula I in crystalline form IV.

In fig. 12 depicts an exemplary gravimetric vapor sorption (GVS) of a sample of formula I in crystalline form IV.

In fig. 13 shows an exemplary X-ray powder diffraction (XRP) pattern of a sample of formula I in crystalline form V.

In fig. 14 shows an exemplary thermogravimetric analysis (TGA) thermogram (dashed line) and differential scanning calorimetry (DSC) diffractogram (solid line) of a sample of formula I in crystalline form V.

In fig. 15 depicts an exemplary gravimetric vapor sorption (GVS) of a sample of formula I in crystalline form V.

In fig. 16 depicts an exemplary X-ray powder diffraction (XRP) pattern of a sample of formula I in crystalline form VI.

In fig. 17 shows an exemplary thermogravimetric analysis (TGA) thermogram (solid line) and a differential scanning calorimetry (DSC) diffractogram (dashed line) of a sample of formula I in crystalline form VI.

In fig. 18 depicts an exemplary gravimetric vapor sorption (GVS) of a sample of formula I in crystalline form VI.

In fig. 19 depicts an exemplary X-ray powder diffraction (XRP) pattern of a sample of Formula I in amorphous form.

In fig. 20 shows an exemplary X-ray powder diffraction (XRP) pattern of a sample of (S)-(2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido [2,1a]isoquinolin-2-yl-2-amino-3-methylbutanoate (formula II) in crystalline form I.

In fig. 21 shows an exemplary differential scanning calorimetry (DSC) diffraction pattern (upper panel) and thermogravimetric analysis (TGA) thermogram (lower panel) of a Formula II sample in crystalline form I.

In fig. 22 depicts an exemplary gravimetric vapor sorption (GVS) of a sample of formula II in crystalline form I.

In fig. 23 depicts an exemplary X-ray powder diffraction (XRP) pattern of a sample of Formula II in crystalline Form II.

In fig. 24 shows an exemplary differential scanning calorimetry (DSC) diffraction pattern (upper panel) and a thermogravimetric analysis (TGA) thermogram (lower panel) of a sample of Formula II in crystalline form II.

In fig. 25 depicts an exemplary gravimetric vapor sorption (GVS) of a sample of formula II in crystalline form II.

In fig. 26 depicts an exemplary X-ray powder diffraction (XRP) pattern of a Formula II sample in amorphous form.

The dotted and solid lines in the figures are used for the sole purpose of distinguishing the graphs and are not intended to indicate signal intensity.

Detailed Disclosure of the Present Invention

Definitions.

To assist in understanding the disclosure provided herein, a number of terms are defined below.

In general, the nomenclature used herein and the laboratory procedures described herein in organic chemistry, medicinal chemistry and pharmacology are well known and widely used in the art. Unless otherwise specified, all technical and scientific terms used herein generally have the same meaning as commonly known to one skilled in the art to which the present invention pertains.

The term subject refers to an animal, including, without limitation, a primate (eg, human), cow, pig, sheep, goat, horse, dog, cat, rabbit, rat or mouse. The terms subject and patient are used interchangeably herein, referring, for example, to a mammalian subject, such as a human subject, in one embodiment, a human.

As used herein, isotopically enriched refers to an atom having an isotopic composition different from the natural isotopic composition of the atom. Isotopically enriched can also refer to a compound containing at least one atom having an isotopic composition different from that atom's natural isotopic composition.

With respect to the compounds provided herein, if a particular atomic position is designated as containing deuterium or D, it is understood that the deuterium content at that position is substantially greater than the natural deuterium content, which is approximately 0.015%. A position designated as containing deuterium typically has a minimum isotopic enrichment ratio of, in particular embodiments, at least 1000 (15% deuterium incorporation), at least 2000 (30% deuterium incorporation), or at least 3000 (45% deuterium penetration), at least 3500 (52.5% deuterium penetration), at least 4000 (60% deuterium penetration), at least 4500 (67.5% deuterium penetration), at least 5000 (75% deuterium penetration), at least 5500 (82.5% deuterium penetration), at least 6000 (90% deuterium penetration), at least 6333.3 (95% deuterium penetration), at least 6466.7 ( 97% deuterium incorporation), at least 6600 (99% deuterium incorporation) or at least 6633.3 (99.5% deuterium incorporation) at each designated deuterium position.

The isotopic enrichment of the compounds provided herein can be determined using conventional analytical techniques known to one of ordinary skill in the art, including mass spectrometry, nuclear magnetic resonance spectroscopy, and crystallography.

Isotope enrichment (eg, deuteration) of pharmaceuticals to improve pharmacokinetics (PK), pharmacodynamics (PD), and toxicity profiles has been demonstrated previously with certain drug classes. See, for example, Lijinsky et. al., Food Cosmet. Toxicol., 20:393 (1982); Lijinsky et. al., J. Nat. Cancer Inst. 69:1127 (1982); Mangold et. al., Mutation Res., 308:33 (1994); Gordon et. al., Drug Metab. Dispos., 15:589 (1987); Zello et. al., Metabolism, 43:487 (1994); Gately et. al., J. Nucl. Med., 27:388 (1986); Wade D., Chem. Biol. Interact., 117:191 (1999).

Isotope enrichment of a drug can be used, for example, to (1) reduce or eliminate unwanted metabolites;

(2) increasing the half-life of the parent drug;

(3) reducing the number of doses required to achieve the desired effect;

(4) reducing the dose required to achieve the desired effect;

(5) increasing the formation of active metabolites, if they are formed at all; and/or (6) reducing the production of harmful metabolites in specific tissues and/or creating a more effective drug and/or a safer drug for combination therapy, whether combination therapy is planned or not.

Replacing an atom with one of its isotopes will often result in a change in the rate of a chemical reaction. This phenomenon is known as the kinetic isotope effect (KIE). For example, if a C-H bond is broken during the rate-determining step of a chemical reaction (i.e., the highest transition state energy step), replacing that hydrogen atom with deuterium will cause the reaction rate to decrease and the process will slow down. This phenomenon is known as the deuterium kinetic isotope effect (DKIE). (See, for example, Foster et al., Adv. Drug Res., vol. 14, p. 1-36 (1985); Kushner et al., Can. J. Physiol. Pharmacol., vol. 77, p. 79-88 (1999)).

The DKIE value can be expressed as the ratio between the rates of a given reaction in which the C-H bond is broken and the same reaction in which hydrogen is replaced by deuterium. DKIE can range from about 1 (no isotope effect) to very large values such as 50 or more, meaning the reaction can be 50 times slower or more when hydrogen is replaced by deuterium. High DKIE values may be due in part to a phenomenon known as the tunneling effect, which is a consequence of the uncertainty principle. It is believed that the tunneling effect is due to the low mass of the hydrogen atom and occurs because transition states in which the proton is involved can sometimes form in the absence of the necessary activation energy. Since deuterium has more mass than hydrogen, it is statistically much less likely to be affected by this phenomenon.

Tritium (T) is a radioactive isotope of hydrogen used in research, fusion reactors, neutron generators, and radiopharmaceuticals. Tritium is a hydrogen atom that contains 2 neutrons in the nucleus and has an atomic mass close to 3. It occurs naturally in the environment in very low concentrations, most often occurring as T ₂ O. Tritium decays slowly (half-life=12 ,3 years) and emits a low-energy beta particle that cannot penetrate the outer layer of human skin. Internal exposure is the main potential hazard associated with this isotope, but it must be ingested in large quantities to pose a significant health risk. Compared to deuterium, smaller amounts of tritium must be consumed before it reaches dangerous levels. Substituting tritium (T) for hydrogen results in an even stronger bond than with deuterium and results in numerically larger isotope effects. Likewise, substitution of isotopes of other elements, including but not limited to ¹³ C or ¹⁴ C for carbon, ³³ S, ³⁴ S, or ³⁶ S for sulfur, ¹⁵ N for nitrogen, and ¹⁷ O or ¹⁸ O for oxygen, can result in a similar kinetic isotope effect.

For example, DKIE has been used to reduce the hepatotoxicity of halothane, presumably by limiting the production of reactive molecules such as trifluoroacetyl chloride. However, this method may not be applicable to all classes of drugs. For example, implementing

- 4 043769 deuterium depletion can lead to metabolic switching. The concept of metabolic switching posits that xenogens sequestered by phase I enzymes can bind transiently and rebind in multiple conformations prior to chemical reaction (e.g., oxidation). This hypothesis is supported by the relatively large size of binding pockets in many phase I enzymes and the promiscuous nature of many metabolic reactions. Metabolic switching can potentially result in different ratios of known metabolites as well as completely new metabolites. This new metabolic profile may provide greater or less toxicity.

The animal's body expresses a variety of enzymes to eliminate foreign substances, such as therapeutic agents, from its circulatory system. Examples of such enzymes include enzymes of the cytochrome P450 (CYP) family, esterases, proteases, reductases, dehydrogenases and monoamine oxidases, to react and convert these foreign substances into more polar intermediates or metabolites for renal excretion. Some of the most common metabolic reactions of pharmaceutical compounds involve the oxidation of a carbon-hydrogen (C-H) bond to either a carbon-oxygen (C-O) or a carbon-carbon (C-C) pi bond. The resulting metabolites may be stable or unstable under physiological conditions and may exhibit significantly different pharmacokinetic, pharmacodynamic, and acute and long-term toxicity profiles relative to the parent compounds. For many drugs, such oxidation reactions are rapid. Consequently, these drugs often require the administration of multiple or high daily doses.

Therefore, isotopic enrichment at certain positions of a compound provided herein may produce a detectable KIE that will affect the pharmacokinetic, pharmacological and/or toxicological profiles of the compound provided herein compared to a similar compound having a naturally occurring isotopic composition.

The term isotopic variant refers to a therapeutic agent that contains an unnatural isotope ratio on one or more of the atoms that make up the therapeutic agent. In certain embodiments, the isotopic variant of the therapeutic agent contains unnatural ratios of one or more isotopes, including without limitation the following: hydrogen (1H), deuterium ( ^2H ), tritium ( ^3H ), carbon-11 ( ^PS ), carbon-12 ( ¹² C), carbon-13 ( ¹³ C), carbon-14 ( ¹⁴ C), nitrogen-13 ( ¹³ N), nitrogen-14 ( ¹⁴ N), nitrogen-15 ( ¹⁵ N), oxygen-14 ( ¹⁴ O ), oxygen-15 ( ¹⁵ O), oxygen-16 ( ¹⁶ O), oxygen-17 ( ¹⁷ O), oxygen-18 ( ¹⁸ O), fluorine-17 ( ¹⁷ F), fluorine-18 ( ¹⁸ F), phosphorus-31 ( ³¹ R), phosphorus-32 ( ³² R), phosphorus-33 ( ³³ R), sulfur-32 ( ³² S), cepa-33 ( ³³ S), cepa-34 ( ³⁴ S), sulfur- 35 ( ³⁵ S), cepa-36 ( ³⁶ S), chlorine-35 ( ³⁵ Cl), chlorine-36 ( ³⁶ Cl), chlorine-37 ( ³⁷ Cl), bromine-79 ( ⁷⁹ Br), bromine-81 ( ⁸¹ Br), iodine 123 ( ¹²³ I), iodine-125 ( ¹²⁵ I), iodine-127 ( ¹²⁷ I), iodine-129 ( ¹²⁹ I) and iodine-131 ( ¹³¹ I). In certain embodiments, the isotopic variant of the therapeutic agent contains unnatural ratios of one or more isotopes, including without limitation the following: hydrogen (1H), deuterium ( ^2H ), tritium ( ^3H ), carbon-11 ( ^PS ), carbon-12 ( ¹² C), carbon-13 ( ¹³ C), carbon-14 ( ¹⁴ C), nitrogen-13 ( ¹³ N), nitrogen-14 ( ¹⁴ N), nitrogen-15 ( ¹⁵ N), oxygen-14 ( ¹⁴ O ), oxygen-15 ( ¹⁵ O), oxygen-16 ( ¹⁶ O), oxygen-17 ( ¹⁷ O), oxygen-18 ( ¹⁸ O), fluorine-17 ( ¹⁷ F), fluorine-18 ( ¹⁸ F), phosphorus-31 ( ³¹ R), phosphorus-32 ( ³² R), phosphorus-33 ( ³³ R), sulfur-32 ( ³² S), cepa-33 ( ³³ S), cepa-34 ( ³⁴ S), sulfur- 35 ( ³⁵ S), cepa-36 ( ³⁶ S), chlorine-35 ( ³⁵ Cl), chlorine-36 ( ³⁶ Cl), chlorine-37 ( ³⁷ Cl), bromine-79 ( ⁷⁹ Br), bromine-81 ( ⁸¹ Br), iodine 123 ( ¹²³ I), iodine-125 ( ¹²⁵ I), iodine-127 ( ¹²⁷ I), iodine-129 ( ¹²⁹ I) and iodine-131 ( ¹³¹ I).

It will be understood that in a therapeutic agent, any hydrogen may be, for example, ² H, or any carbon may be, for example, ¹³ C, or any nitrogen may be, for example, ¹⁵ N, or any oxygen may be, for example, 15 N. , ¹⁸ O if appropriate, in accordance with the judgment of one of those skilled in the art. In certain embodiments, the isotopic variant of the therapeutic agent contains non-naturally occurring ratios of deuterium (D).

The terms treat, treat, and treat are intended to include alleviating or eliminating a disorder, disease, or condition, or one or more symptoms associated with the disorder, disease, or condition; or alleviating or eliminating the cause(s) of the disorder, disease, or condition itself.

The terms prevent, prevention and prophylaxis are intended to include a method of delaying and/or preventing the onset of a disorder, disease or condition and/or its associated symptoms;

preventing the subject from developing a disorder, disease or condition; or reducing the subject's risk of developing a disorder, disease or condition.

As used herein, unless otherwise noted, the terms manage, manage and manage refer to preventing or slowing the progression, spread or

- 5 043769 worsening of a disease or disorder or one or more of its symptoms. Often, the beneficial effects that a subject receives from a prophylactic and/or therapeutic agent do not result in a cure for the disease or disorder. In this regard, the term management includes treating a subject who has suffered from a particular disease in an attempt to prevent or minimize recurrence of the disease.

As used herein, reduction in the intensity of symptoms of a particular disorder by administration of a particular pharmaceutical composition refers to any reduction, whether permanent or temporary, long-term or short-term, that can be attributed to or associated with the administration of the composition.

It is intended that the term disorder as used herein is generally synonymous with and is used interchangeably with the terms disease, syndrome and condition (as in the phrase medical condition), as they all reflect a pathological condition of a human or animal body or one of its parts that impairs normal functioning, usually manifested by distinctive signs and symptoms.

The term therapeutically effective amount is meant to include an amount of a compound that, when administered, is sufficient to prevent the development or alleviate to some extent one or more symptoms of the disorder, disease or condition being treated. The term therapeutically effective amount also refers to an amount of a compound that is sufficient to produce a biological or medical response in a biological molecule (e.g., protein, enzyme, RNA or DNA), cell, tissue, system, animal or human that is sought by a researcher, veterinarian , general practitioner or clinician.

As used herein, unless otherwise indicated, the term prophylactically effective amount of a compound is an amount sufficient to prevent a disease or disorder or prevent its recurrence. A prophylactically effective amount of a compound means an amount of a therapeutic agent, alone or in combination with one or more other agents, that provides a prophylactic benefit in preventing a disease.

The term prophylactically effective amount may include an amount that improves overall prophylaxis or enhances the prophylactic effectiveness of another prophylactic agent.

The term pharmaceutically acceptable carrier, pharmaceutically acceptable excipient, physiologically acceptable carrier or physiologically acceptable excipient refers to a pharmaceutically acceptable material, composition or carrier medium, such as a liquid or solid excipient, diluent, solvent or encapsulating material. In one embodiment, each component is pharmaceutically acceptable in the sense that it is compatible with the other ingredients of the pharmaceutical composition and suitable for use in contact with tissue or organ of humans and animals without excessive toxicity, irritation, allergic reaction, immunogenicity or other problems or complications. , commensurate with a reasonable risk/benefit ratio. See, Remington: The Science and Practice of Pharmacy, 22nd ed.; Pharmaceutical Press: 2012; Handbook of Pharmaceutical Excipients, 7th ed.; Rowe et al., eds.; The Pharmaceutical Press: 2012; Handbook of Pharmaceutical Additives, 3rd ed.; Ash and Ash Eds.; Gower Publishing Company: 2007; Pharmaceutical Preformulation and Formulation, 2nd ed.; Gibson Ed.; CRC Press LLC: Boca Raton, FL, 2009.

As used in this specification and the accompanying claims, the singular form includes both the plural and singular entities, unless the context clearly dictates otherwise.

The term approximately means the acceptable error for a particular value, as determined by one of ordinary skill in the art, which depends in part on how the specified value is measured or determined. In certain embodiments, the term approximately means within 1, 2, 3, or 4 standard deviations. In certain embodiments, the term approximately means within 30, 25, 20, 15, 10, 9, 8, 7, 6, 5, 4, 3, 2, 1, 0.5, or 0.05% of a given value or range . In certain embodiments, approximately with respect to X-ray powder diffraction peaks in degrees, 2-theta means within ±0.2°.

The terms active ingredient and active substance refer to a compound that is administered, alone or in combination with one or more pharmaceutically acceptable excipients, to a subject for the treatment, prevention or amelioration of one or more symptoms of a disorder, disease or condition. As used herein, the term active ingredient and active substance may be an optically active isomer or isotopic variant of a compound described herein.

The term antisolvent refers to a liquid that is added to a solvent to reduce the solubility of a compound in that solvent, in some cases causing the compound to precipitate.

The terms drug, therapeutic agent, and chemotherapeutic agent refer to a compound or pharmaceutical composition thereof that is administered to a subject to treat, prevent, or reduce the intensity of one or more symptoms of a disorder, disease, or condition.

The term solvate refers to a complex or aggregate formed by one or more molecules of a solute, such as a compound provided herein, and one or more molecules of a solvent that is present in a stoichiometric or non-stoichiometric amount. Suitable solvents include, but are not limited to, water, methanol, ethanol, n-propanol, isopropanol, and acetic acid. In certain embodiments, the solvent is pharmaceutically acceptable. In one embodiment, the complex or aggregate is in crystalline form. In another embodiment, the complex or aggregate is in non-crystalline form. If the solvent is water, the solvate is a hydrate. Examples of hydrates include, but are not limited to, hemihydrate, monohydrate, dihydrate, trihydrate, tetrahydrate and pentahydrate.

The term crystalline form of a compound can refer to any crystalline form of a compound as a free acid, a free base compound, an acid addition salt of a compound, a base addition salt of a compound, a complex of a compound, a solvate (including a hydrate) of a compound, or a co-crystal of a compound. . The term solid form of a compound may refer to any crystalline form of a compound or any amorphous form of a compound as a free acid, a free base compound, an acid addition salt of a compound, a base addition salt of a compound, a complex of a compound, a solvate (including hydrate ) compounds or coprecipitation of compounds. In many cases, the terms crystalline form and solid form may refer to forms that are pharmaceutically acceptable, including, for example, pharmaceutically acceptable addition salt forms, pharmaceutically acceptable complexes, pharmaceutically acceptable solvates, pharmaceutically acceptable cocrystals, and pharmaceutically acceptable coprecipitates.

The term stereotyped refers to repetitive behavior that occurs repeatedly with minor changes or less frequently as a complex series of movements.

The term hyperkinetic disorder or hyperkinetic movement disorder or hyperkinesia refers to disorders or diseases characterized by excessive, abnormal, involuntary movements. These disorders include, but are not limited to, Huntington's disease, tardive dyskinesia, Tourette's syndrome, dystonia, hemiballismus, chorea, senile chorea or tics.

The term neurological disorder or neurological disease includes, without limitation, hyperkinetic disorder, bipolar disorder, major depressive disorder, anxiety disorder, attention deficit hyperactivity disorder, dementia, depression, insomnia, psychosis, post-traumatic stress disorder, substance abuse, levodopa-induced dyskinesia in Parkinson's disease, movement disorders or oppositional defiant disorder.

The term tardive syndrome includes the limitations of tardive dyskinesia, tardive dystonia, tardive akathisia, tardive tics, myoclonus, tremor, and abrupt withdrawal syndrome.

The term VMAT2 refers to human vesicular monoamine transporter isoform 2, an integral membrane protein that transports monoamines, particularly neurotransmitters such as dopamine, norepinephrine, serotonin and histamine, from the cell cytosol into synaptic vesicles.

The term VMAT2-mediated disorder refers to a disorder that is characterized by abnormal VMAT2 activity or VMAT2 activity that, when modulated, results in a decrease in the intensity of other abnormal biological processes. VMAT2-mediated disorder may be mediated in whole or in part by modulation of VMAT2. In particular, a VMAT2-mediated disorder is a disorder in which inhibition of VMAT2 results in some effect on the underlying disorder, eg, administration of a VMAT2 inhibitor results in some improvement in at least some treated patients.

The term VMAT2 inhibitor, VMAT2 inhibit or VMAT2 inhibition refers to the ability of a compound disclosed herein to alter the function of VMAT2. A VMAT2 inhibitor can block or reduce the activity of VMAT2 by forming a reversible or irreversible covalent bond between the inhibitor and VMAT2 or by forming a non-covalently linked complex. Such inhibition may only occur in specific cell types or may be due to a specific biological phenomenon. The terms VMAT2 inhibitor, VMAT2 inhibit, or VMAT2 inhibition also refer to altering the function of VMAT2 by reducing the likelihood of complex formation between VMAT2 and a natural substrate. In some embodiments, VMAT2 modulation can be assessed using a method

- 7 043769 described in international patent publication WO 2005/077946; WO 2008/058261; European patent EP 1716145; Kilbourn et al., European Journal of Pharmacology, 1995, (278), 249-252; Lee et al.

J. Med. Chem., 1996, (39), 191-196; Scherman et al., Journal of Neurochemistry, 1988, 50(4), 1131-36; Kilbourn et al., Synapse 2002, 43(3), 188-194; Kilbourn et al., European Journal of Pharmacology, 1997, 331(2-3),

161-68; and Erickson et al., Journal of Molecular Neuroscience, 1995, 6(4), 277-87.

A pharmaceutically acceptable salt refers to any salt of a compound provided herein that retains its biological properties and is not toxic or otherwise undesirable for pharmaceutical use. Such salts can be prepared from a variety of organic and inorganic counterions well known in the art. Such salts include, without limitation, the following:

(1) acid addition salts formed with organic or inorganic acids such as hydrochloric, hydrobromic, sulfuric, nitric, phosphoric, sulfamic, acetic, trifluoroacetic, trichloroacetic, propionic, caproic, cyclopentylpropionic, glycolic, glutaric, pyruvic, lactic , malonic, succinic, sorbic, ascorbic, malic, maleic, fumaric, tartaric, citric, benzoic, 3-(4-hydroxybenzoyl)benzoic, picric, cinnamic, almond, phthalic, lauric, methanesulfonic, ethanesulfonic, 1,2-ethanedisulfonic, 2-hydroxyethanesulfonic, benzenesulfonic, 4-chlorobenzenesulfonic, 2-naphthalene sulfonic, 4-toluenesulfonic, camphor, camphorsulfonic, 4-methylbicyclo[2.2.2]-oct-2-en-1-carboxylic, glucoheptonic, 3-phenylpropionic, trimethylacetic, tert -butylacetic acid, lauryl sulfuric acid, gluconic acid, benzoic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, cyclohexylsulfamic acid, quinic acid, muconic acid, etc. acids; or (2) salts formed when the acid proton present in the parent compound is either (a) replaced by a metal ion, such as an alkali metal ion, an alkaline earth metal ion, or an aluminum ion, or by alkali metal or alkaline earth metal hydroxides, such as sodium hydroxide, potassium hydroxide, calcium, magnesium, aluminum, lithium, zinc and barium, ammonia, or (b) is in coordinate relationship with an organic base such as aliphatic, alicyclic or aromatic organic amines such as ammonia, methylamine, dimethylamine, diethylamine, picoline, ethanolamine, diethanolamine, triethanolamine, ethylenediamine, lysine, arginine, ornithine, choline, N,N'-dibenzylethylene-diamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, N-methylglucamine piperazine, tris(hydroxymethyl)-aminomethane, tetramethylammonium hydroxide, etc. .

Pharmaceutically acceptable salts, by way of example and without limitation, further include sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium and the like salts, and, if the compound contains a basic functional group, salts of non-toxic organic or inorganic acids such as hydrohalides, e.g. hydrochloride and hydrobromide, sulfate, phosphate, sulfamate, nitrate, acetate, trifluoroacetate, trichloroacetate, propionate, hexanoate, cyclopentylpropionate, glycolate, glutarate, pyruvate, lactate, malonate, succinate, sorbate, ascorbate, malate, maleate, fumarate, tartrate , citrate, benzoate, 3-(4-hydroxybenzoyl)benzoate, picrate, cinnamate, mandelate, phthalate, laurate, methanesulfonate (mesylate), ethanesulfonate, 1,2-ethanedisulfonate, 2-hydroxyethanesulfonate, benzenesulfonate (besylate), 4-chlorobenzenesulfonate, 2-naphthalene sulfonate, 4-toluene sulfonate, camphorate, camphor sulfonate, 4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylate, glucoheptonate, 3-phenylpropionate, trimethyl acetate, tert-butyl acetate, lauryl sulfate, gluconate, benzoate, glutamate , hydroxynaphthoate, salicylate, stearate, cyclohexylsulfamate, quinnate, muconate, etc.

The term amino acid refers to naturally occurring and synthetic α, β, γ or δ amino acids and includes, without limitation, amino acids found in proteins, i.e. glycine, alanine, valine, leucine, isoleucine, methionine, phenylalanine, tryptophan, proline, serine, threonine, cysteine, tyrosine, asparagine, glutamine, aspartate, glutamate, lysine, arginine and histidine. In one embodiment, the amino acid is in the L configuration. Alternatively, the amino acid may be a derivative of alanyl, valinyl, leucinyl, isoleucinyl, prolinyl, phenylalaninyl, tryptophanyl, methioninyl, glycinyl, serinyl, threoninyl, cysteinyl, tyrosinyl, asparaginyl, glutaminyl, aspartoyl, glutaroyl, lysinyl, argininyl, histidinyl, β -alanila, β-valinyl, β-leucinyl, β-isoleucinyl, β-prolinyl, β-phenylalaninyl, β-tryptophanyl, β-methioninyl, β-glycinyl, β-serinyl, β-threoninyl, β-cysteinyl, β-tyrosinyl, β- asparaginyl, β-glutaminyl, β-aspartoyl, β-glutaroyl, β-lysinyl, β-argininyl or β-histidinyl.

Solid forms.

In one embodiment, provided herein are pharmaceutically acceptable salts of (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1a ]isoquinolin-2-yl ester of (S)-2-amino-3-methylbutyric acid or their isotopic variant. (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester (S )-2-amino-3-methylbutyric acid is characterized by a structure according to the formula

- 8 043769

O^O\/^nh ₂

Compound (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1a]isoquinolin-2-yl ether(S) -2-amino-3-methylbutyric acid, also known as valbenazine, can be obtained in accordance with US Pat. No. 8,039,627 and 8,357,697, the entire disclosure of each of which is incorporated herein by reference.

Valbenazine ditosylate.

In another embodiment, provided herein is a crystalline form of di(4-methylbenzenesulfonate) (S)-(2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b- hexahydro1H-pyrido[2,1-a]isoquinolin-2-yl-2-amino-3-methylbutanoate, or an isotopic variant thereof, or a solvate thereof according to formula I

I o.

(I)

The crystalline forms shown herein (e.g., according to Formula I) can be characterized using a number of methods known to one skilled in the art, including the following: single crystal X-ray diffractometry, X-ray powder diffraction (XRPD), microscopy (e.g., scanning electron microscopy (SEM), thermal analysis (e.g. differential scanning calorimetry (DSC), thermal gravimetric analysis (TGA) and high temperature microscopy, and spectroscopy (e.g. infrared, Raman spectroscopy, solid-state nuclear magnetic resonance). Particle size and particle distribution size can be determined using conventional techniques such as laser light scattering techniques.The purity of the crystalline forms provided herein can be determined using standard analytical techniques such as thin layer chromatography (TLC), gel electrophoresis, gas chromatography, high performance liquid chromatography ( HPLC) and mass spectrometry (MS).

Form I of valbenazine ditosylate.

In another embodiment, provided herein is a crystalline form of di(4-methylbenzenesulfonate) (S)-(2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b- hexahydro1H-pyrido[2,1-a]isoquinolin-2-yl-2-amino-3-methylbutanoate (formula I), or an isotopic variant thereof, or a solvate thereof, the crystalline form being Form I.

In various embodiments, crystalline Form I of di(4-methylbenzenesulfonate) (S)-(2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H -pyrido[2,1-a]isoquinolin-2-yl-2amino-3-methyl butanoate (formula I) is characterized by an X-ray diffraction pattern. In some embodiments, the x-ray diffraction pattern of Form I of di(4-methylbenzenesulfonate) (S)-(2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro- 1H-pyrido[2,1-a]isoquinolin-2-yl2-amino-3-methylbutanoate (Formula I) includes XRP diffraction peaks at 2-theta angles of approximately 6.3, 17.9 and 19.7 °. In some embodiments, X-ray powder diffraction pattern of Form I of di(4-methylbenzenesulfonate) (S)-(2R,3R,11bR)-3-isobutyl9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H -pyrido[2,1-a]isoquinolin-2-yl-2-amino-3-methyl butanoate (Formula I) includes an XRP diffraction peak at 2-theta angles of approximately 6.3, 17.9, or 19 .7°. In another embodiment, crystalline Form I of di(4methylbenzenesulfonate) (S)-(2R,3R,11R)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1Hpyrido[2 ,1-a]isoquinolin-2-yl-2-amino-3-methyl butanoate (Formula I) includes an XRP diffraction peak at 2-theta angles of approximately 6.3 and 19.7°. In another embodiment, crystalline Form I of di(4-methylbenzenesulfonate) (S)-(2R,3R,11bR)-3-isobutyl-9,10dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido [2,1-a]isoquinolin-2-yl-2-amino-3-methyl butanoate (Formula I) includes an XRP diffraction peak at 2-theta angles of approximately 6.3°.

- 9 043769

In certain embodiments, crystalline Form I of di(4methylbenzenesulfonate) (S)-(2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1Hpyrido[2 ,1-a]isoquinolin-2-yl-2-amino-3-methyl butanoate (Formula I) has an x-ray diffraction pattern essentially as shown in FIG. 1.

In some embodiments, crystalline Form I is characterized by one or more characteristic XRP diffraction peaks at 2-theta angles of about 6.3° and about 19.7°. In certain embodiments, crystalline Form I is characterized by one or more characteristic XRP diffraction peaks at 2-theta angles of about 6.3°, about 17.9°, and about 19.7°. In some embodiments, crystalline Form I is characterized by one or more characteristic XRP diffraction peaks at 2-theta angles of about 6.3°, about 17.9°, about 19.7°, and about 22.7°. In certain embodiments, crystalline Form I is characterized by one or more characteristic XRP diffraction peaks at 2-theta angles of about 6.3°, about 15.6°, about 17.9°, about 19.7°, and about 22.7 °. In some embodiments, crystalline Form I is characterized by one or more characteristic XRP diffraction peaks at 2-theta angles of about 6.3°, about 15.6°, about 16.6°, about 17.9°, about 19.7 ° and approximately 22.7°.

In various embodiments, crystalline Form I is characterized by an endothermic differential scanning calorimetry (DSC) thermogram. In some embodiments, crystalline Form I is characterized by a DSC thermogram comprising an endothermic event with an onset temperature of approximately 240°C and a peak at approximately 243°C. According to another embodiment, crystalline Form I is characterized by a DSC thermogram substantially as shown in FIG. 2. In another embodiment, crystalline Form I is characterized by a thermal gravimetric analysis (TGA) plot containing a mass loss of less than about 0.4% when heated from about 25°C to about 140°C. In another embodiment, crystalline Form I is characterized by a TGA plot substantially as shown in FIG. 2.

In various embodiments, crystalline Form I is characterized by a gravimetric vapor sorption (GVS) plot. In some embodiments, crystalline Form I exhibits a weight increase of about 1% when subjected to an increase in relative humidity from about 0% to about 95% relative humidity. In certain embodiments, the mass increased by adsorption is lost when the relative humidity (RH) is reduced back to approximately 0% RH. In another embodiment, crystalline Form I exhibits a gravimetric vapor sorption plot substantially as shown in FIG. 3. In another embodiment, crystalline Form I is stable when exposed to approximately 25° C. and approximately 60% relative humidity. In another embodiment, crystalline Form I is stable when exposed to about 25° C. and about 60% relative humidity for about 24 months. Additionally, in another embodiment, crystalline Form I is stable when exposed to about 25° C. and about 60% relative humidity for about 3 months. In another embodiment, crystalline Form I is stable when exposed to approximately 25° C. and approximately 92% relative humidity. In another embodiment, crystalline Form I is stable when exposed to about 40° C. and about 75% relative humidity. In another embodiment, crystalline Form I is stable when exposed to about 40° C. and about 75% relative humidity for about 6 months. In another embodiment, crystalline Form I is stable when exposed to about 40° C. and about 75% relative humidity for about 3 months.

In certain embodiments, the crystalline form of Formula I in Form I may contain no less than about 95%, no less than about 97%, no less than about 98%, no less than about 99%, or no less than about 99.5% by weight of the salt according to Formula I. The crystalline form may also contain no less than about 90%, no less than about 95%, no less than about 98%, no less than about 99%, or no less than 99.5% by weight crystalline Form I.

In certain embodiments, Crystalline Form I has a water solubility of about 17.58, about 18.58, about 19.58, about 26.75, about 26.87, about 26.96, about 27.06, about 10 043769 exactly 27.75, approximately 27.87, approximately 27.97, approximately 28.06, approximately 28.75, approximately 28.87, approximately 28.97, approximately 29.06, approximately 27.45, approximately 28, 45, approximately 29.45, approximately 30.61, approximately 31.61, approximately 32.61, approximately 32.17, approximately 32.98, approximately 33.17, approximately 33.98, approximately 34.17, approximately 34, 35, approximately 34.98, approximately 35.35, approximately 36.35 mg/ml. In certain embodiments, crystalline Form I has a water solubility of about 31.61 and about 33.17 at a pH of about 1.2; about 28.45 and about 27.97 at a pH of about 3; about 28.06 and about 27.77 at a pH of about 4; about 18.58 and about 27.87 at a pH of about 5; about 33.98 and about 35.35 at a pH of about 6.8.

In certain embodiments, crystalline Form I may contain no more than about 0.1%, no more than about 0.11%, no more than about 0.12%, no more than about 0.13%, no more than about 0 .14%, no more than about 0.15%, no more than about 0.16%, no more than about 0.17%, no more than about 0.18%, no more than about 0.19%, not more than about 0.2%, no more than about 0.21%, no more than about 0.22%, no more than about 0.23%, no more than about 0.24%, no more than about 0, 25%, not more than about 0.26%, not more than about 0.27%, not more than about 0.28%, not more than about 0.29%, not more than about 0.3%, not more no more than about 0.31%, no more than about 0.32%, no more than about 0.33%, no more than about 0.34%, no more than about 0.35%, no more than about 0.36 %, not more than about 0.37%, not more than about 0.38%, not more than about 0.39%, not more than about 0.4%, not more than about 0.5%, not more than about 0.6%, not more than about 0.7%, not more than about 0.8%, not more than about 0.9%, not more than about 1%, not more than about 2%, not more than about 3%, no more than about 4%, or no more than about 5% water by weight.

In certain embodiments, Form I can be characterized by particle size analysis. In certain embodiments, the Form I sample comprises particles characterized by a diamond-shaped crystal morphology. In another embodiment, the sample of Form I contains particles measuring about 100 μm, about 90 μm, about 80 μm, about 70 μm, about 60 μm, about 50 μm, about 40 μm, about 30 μm, about 20 μm, about 10 μm , approximately 5 µm in length. In some embodiments, the Form I sample contains particles that are about 70 μm, about 60 μm, about 40 μm, about 20 μm, about 10 μm in length. In other embodiments, the Form I sample contains particles measuring approximately 69.39 μm, approximately 56.22 μm, approximately 34.72 μm, approximately 17.84 μm, and approximately 10.29 μm in length.

Form II of valbenazine ditosylate.

In another embodiment, a crystalline form of di(4-methylbenzenesulfonate) (S)-(2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1Hpyrido is provided [2,1-a]isoquinolin-2-yl-2-amino-3-methylbutanoate (formula I), or an isotopic variant thereof, or a solvate thereof, the crystalline form being Form II.

In various embodiments, crystalline Form II of di(4-methylbenzenesulfonate) (S)-(2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1Hpyrido [2,1-a]isoquinolin-2-yl-2-amino-3-methyl butanoate (formula I) is characterized by an x-ray diffraction pattern. In some embodiments, the X-ray diffraction pattern of Form II di(4-methylbenzenesulfonate) (S)-(2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11bhexahydro-1H- pyrido[2,1-a]isoquinolin-2-yl-2-amino-3-methylbutanoate (Formula I) includes XRP diffraction peaks at 2-theta angles of approximately 5.7, 15.3 and 22.5 °. In some embodiments, X-ray powder diffraction pattern of Form II di(4-methylbenzenesulfonate) (S)-(2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro -1Hpyrido[2,1-a]isoquinolin-2-yl-2-amino-3-methyl butanoate (Formula I) includes an XRP diffraction peak at 2-theta angles of approximately 5.7, 15.3, or 22 ,5°. In other embodiments, powder X-ray diffraction pattern of Form II di(4-methylbenzenesulfonate) (S)-(2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro -1H-pyrido[2,1-a]isoquinolin-2-yl2-amino-3-methylbutanoate (Formula I) includes an XRP diffraction peak at 2-theta angles of approximately 5.7 and 15.3°. In some embodiments, X-ray powder diffraction pattern of Form II di(4-methylbenzenesulfonate) (S)-(2R,3R,11bR)-3-isobutyl9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H α-pyrido[2,1-a]isoquinolin-2-yl-2-amino-3-methylbutanoate (Formula I) includes an XRP diffraction peak at 2-theta angles of approximately 5.7°.

- 11 043769

In certain embodiments, crystalline Form II of di(4-methylbenzenesulfonate) (S)-(2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1Hpyrido [2,1-a]isoquinolin-2-yl-2-amino-3-methylbutanoate (Formula I) has an X-ray diffraction pattern essentially as shown in FIG. 5.

In some embodiments, crystalline Form II is characterized by one or more characteristic XRP diffraction peaks at 2-theta angles of approximately 5.7 and 15.3 degrees. In certain embodiments, crystalline Form II is characterized by one or more characteristic XRP diffraction peaks at 2-theta angles of about 5.7°, about 15.3°, and about 22.5°. In some embodiments, crystalline Form II is characterized by one or more characteristic XRP diffraction peaks at 2-theta angles of about 5.7°, about 14.2°, about 15.3°, and about 22.5°. In other embodiments, crystalline Form II is characterized by one or more characteristic XRP diffraction peaks at 2-theta angles of about 5.7°, about 14.2°, about 15.3°, about 15.9°, and about 22.5 °. In other embodiments, crystalline Form II is characterized by one or more characteristic XRP diffraction peaks at 2-theta angles of about 5.7°, about 14.2°, about 15.3°, about 15.9°, about 18.6 ° and approximately 22.5°.

In various embodiments, crystalline Form II is characterized by an endothermic differential scanning calorimetry (DSC) thermogram. In some embodiments, crystalline Form II is characterized by a DSC thermogram comprising an endothermic event with an onset temperature of approximately 143°C and a peak at approximately 155°C; and another endothermic event with an onset temperature of approximately 232°C and a peak at approximately 235°C.

According to another embodiment, crystalline Form II is characterized by a DSC thermogram substantially as shown in FIG. 6. In another embodiment, crystalline Form II is characterized by a thermal gravimetric analysis (TGA) plot containing a mass loss of approximately 2.2% when heated from about 25°C to about 140°C.

In another embodiment, crystalline Form II is characterized by a TGA plot substantially as shown in FIG. 6.

In various embodiments, crystalline Form II is characterized by a gravimetric vapor sorption (GVS) graph. In some embodiments, crystalline Form II exhibits a weight increase of about 0.5% when subjected to an increase in relative humidity from about 0% to about 95% relative humidity. In certain embodiments, the mass increased by adsorption is lost when the relative humidity (RH) is reduced back to approximately 0% RH. In another embodiment, crystalline Form II exhibits a gravimetric vapor sorption plot substantially as shown in FIG. 7. In certain embodiments, Form II is substantially non-hygroscopic. In certain embodiments, the XRPD diffraction pattern of the Form II material remains substantially unchanged after adsorption/desorption analysis. In certain embodiments, Form II is moisture stable. In another embodiment, crystalline Form II has a water solubility of approximately 18.5 mg/ml at pH 5.1.

In certain embodiments, Form II can be characterized by particle size analysis. In certain embodiments, the Form II sample comprises particles characterized by a birefringent lamellar morphology. In another embodiment, the Form II sample contains particles measuring about 100 μm, about 90 μm, about 80 μm, about 70 μm, about 60 μm, about 50 μm, about 40 μm, about 30 μm, about 20 μm, about 10 μm , approximately 5 µm in length. In some embodiments, the Form II sample contains particles that are about 100 μm, about 70 μm, about 60 μm, about 40 μm, about 20 μm, about 10 μm in length. In another embodiment, the sample of Form II contains particles that are approximately 100 μm in length.

In certain embodiments, the crystalline form of Formula I in Form II may contain no less than about 95%, no less than about 97%, no less than about 98%, no less than about 99%, or no less than about 99.5% by weight of the salt according to Formula I. The crystalline form may also contain no less than about 90%, no less than about 95%, no less than about 98%, no less than about 99%, or no less than 99.5% by weight crystalline forms II.

- 12 043769

Form III of valbenazine ditosylate.

In another embodiment, a crystalline form of di(4-methylbenzenesulfonate) (S)-(2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1Hpyrido is provided [2,1-a]isoquinolin-2-yl-2-amino-3-methylbutanoate (formula I), or an isotopic variant thereof, or a solvate thereof, the crystalline form being Form III.

In various embodiments, crystalline Form III of di(4-methylbenzenesulfonate) (S)-(2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1Hpyrido [2,1-a]isoquinolin-2-yl-2-amino-3-methyl butanoate (formula I) is characterized by an x-ray diffraction pattern. In some embodiments, the X-ray diffraction pattern of Form III of di(4-methylbenzenesulfonate) (S)-(2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11bhexahydro-1H- pyrido[2,1-a]isoquinolin-2-yl-2-amino-3-methylbutanoate (Formula I) includes XRP diffraction peak at 2-theta angles of approximately 6.3, 18.3, 18.9 , 19.8 and 20.4°. In another embodiment, X-ray diffraction pattern of Form III of di(4-methylbenzenesulfonate) (S)-(2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro- 1Hpyrido[2,1-a]isoquinolin-2-yl-2-amino-3-methyl butanoate (Formula I) includes an XRP diffraction peak at 2-theta angles of approximately 6.3, 18.3, 18. 9, 19.8 or 20.4°. In some embodiments, the X-ray diffraction pattern of Form III of di(4-methylbenzenesulfonate) (S)-(2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro- 1Hpyrido[2,1-a]isoquinolin-2-yl-2-amino-3-methylbutanoate (Formula I) includes XRP diffraction peaks at 2-theta angles of approximately 6.3, 18.3 and 19.8 °. In other embodiments, the X-ray diffraction pattern of Form III of di(4-methylbenzenesulfonate) (S)-(2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro- 1H-pyrido[2,1-a]isoquinolin-2-yl2-amino-3-methylbutanoate (Formula I) includes an XRP diffraction peak at 2-theta angles of approximately 6.3°. In certain embodiments, crystalline Form III of di(4-methylbenzenesulfonate) (S)-(2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11bhexahydro-1H-pyrido [2,1-a]isoquinolin-2-yl-2-amino-3-methylbutanoate (Formula I) has an X-ray diffraction pattern essentially as shown in FIG. 8.

In some embodiments, crystalline Form III is characterized by one or more characteristic XRP diffraction peaks at 2-theta angles of about 6.3° and about 19.8°. In certain embodiments, crystalline Form III is characterized by one or more characteristic XRP diffraction peaks at 2-theta angles of about 6.3°, about 18.3°, and about 19.8°. In other embodiments, crystalline Form III is characterized by one or more characteristic XRP diffraction peaks at 2-theta angles of about 6.3°, about 18.3°, about 19.8°, and about 20.4°. In some embodiments, crystalline Form III is characterized by one or more characteristic XRP diffraction peaks at 2-theta angles of about 6.3°, about 18.3°, about 18.9°, about 19.8°, and about 20.4 °. In other embodiments, crystalline Form III is characterized by one or more characteristic XRP diffraction peaks at 2-theta angles of about 6.3°, about 15.3°, about 18.3°, about 18.9°, about 19.8 ° and approximately 20.4°. In some embodiments, crystalline Form III is characterized by one or more characteristic XRP diffraction peaks at 2-theta angles of about 6.3°, about 15.3°, about 18.3°, about 18.9°, about 19.8 °, approximately 20.4° and approximately 24.1°.

In various embodiments, crystalline Form III is characterized by an endothermic differential scanning calorimetry (DSC) thermogram. In some embodiments, crystalline Form III is characterized by a DSC thermogram containing endothermic events with peak temperatures of about 93°C, 158°C, and about 230°C.

According to another embodiment, crystalline Form III is characterized by a DSC thermogram substantially as shown in FIG. 9. In another embodiment, crystalline Form III is characterized by a thermal gravimetric analysis (TGA) plot containing two mass losses of about 2.7% and about 8.86% when heated from about 25°C to about 140°C. In another embodiment, crystalline Form III exhibits a TGA plot substantially as shown in FIG. 9.

In certain embodiments, Form III can be characterized by particle size analysis. In certain embodiments, the Form III sample comprises particles characterized by a birefringent lamellar morphology. In another embodiment, the sample of Form III contains particles of approximately 100 μm, approximately 90 μm, approximately 80 μm, approximately 70 μm, approximately

- 13 043769 µm, approximately 50 µm, approximately 40 µm, approximately 30 µm, approximately µm, approximately 10 µm, approximately 5 µm in length. In some embodiments, the Form III sample contains particles that are about 100 μm, about μm, about 60 μm, about 40 μm, about 20 μm, about 10 μm in length.

In certain embodiments, the crystalline form of Formula I in Form III may contain no less than about 95%, no less than about 97%, no less than about 98%, no less than about 99%, or no less than about 99.5% by weight of the salt according to Formula I. The crystalline form may also contain no less than about 90%, no less than about 95%, no less than about 98%, no less than about 99%, or no less than 99.5% by weight crystalline forms III.

Form IV of valbenazine ditosylate.

In another embodiment, a crystalline form of di(4-methylbenzenesulfonate) (S)-(2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1Hpyrido is provided [2,1-a]isoquinolin-2-yl-2-amino-3-methylbutanoate (formula I), or an isotopic variant thereof, or a solvate thereof; wherein the crystalline form is Form IV.

In various embodiments, crystalline Form IV of di(4-methylbenzenesulfonate) (S)-(2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1Hpyrido [2,1-a]isoquinolin-2-yl-2-amino-3-methyl butanoate (formula I) is characterized by an x-ray diffraction pattern. In some embodiments, the X-ray diffraction pattern of Form IV of di(4-methylbenzenesulfonate) (S)-(2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11bhexahydro-1H- pyrido[2,1-a]isoquinolin-2-yl-2-amino-3-methylbutanoate (Formula I) includes XRP diffraction peak at 2-theta angles of approximately 6.2, 10.4, 17.9 , 19.2, 19.9 and 20.2°. In some embodiments, X-ray powder diffraction pattern of Form IV of di(4-methylbenzenesulfonate) (S)-(2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11bhexahydro-1H -pyrido[2,1-a]isoquinolin-2-yl-2-amino-3-methylbutanoate (Formula I) includes an XRP diffraction peak at 2-theta angles of approximately 6.2, 10.4, 17. 9, 19.2, 19.9 or 20.2°. In other embodiments, powder X-ray diffraction pattern of Form IV of di(4-methylbenzenesulfonate) (S)-(2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro -1Hpyrido[2,1-a]isoquinolin-2-yl-2-amino-3-methylbutanoate (Formula I) includes an XRP diffraction peak at 2-theta angles of approximately 6.2° and approximately 20.2° . In some embodiments, X-ray powder diffraction pattern of Form IV of di(4-methylbenzenesulfonate) (S)-(2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro -1Hpyrido[2,1-a]isoquinolin-2-yl-2-amino-3-methylbutanoate (Formula I) includes an XRP diffraction peak at 2-theta angles of approximately 6.2°. In certain embodiments, crystalline Form IV of di(4-methylbenzenesulfonate) (S)-(2R,3R,11bR)-3-isobutyl-9,10dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido [2,1-a]isoquinolin-2-yl-2-amino-3-methylbutanoate (Formula I) has an X-ray diffraction pattern essentially as shown in FIG. 10.

In some embodiments, crystalline Form IV is characterized by one or more characteristic XRP diffraction peaks at 2-theta angles of about 6.2° and about 20.2°. In certain embodiments, crystalline Form IV is characterized by one or more characteristic XRP diffraction peaks at 2-theta angles of about 6.2°, about 10.4°, and about 20.2°. In other embodiments, crystalline Form IV is characterized by one or more characteristic XRP diffraction peaks at 2-theta angles of about 6.2°, about 10.4°, about 17.9°, and about 20.2°. In some embodiments, crystalline Form IV is characterized by one or more characteristic XRP diffraction peaks at 2-theta angles of about 6.2°, about 10.4°, about 17.9°, about 19.2°, and about 20.2 °. In other embodiments, crystalline Form IV is characterized by one or more characteristic XRP diffraction peaks at 2-theta angles of about 6.2°, about 10.4°, about 17.9°, about 19.2°, about 19.9 ° and approximately 20.2°.

In various embodiments, crystalline Form IV is characterized by an endothermic differential scanning calorimetry (DSC) thermogram. In some embodiments, crystalline Form IV is characterized by a DSC thermogram containing endothermic events with peak temperatures of approximately 128°C, 159°C, and approximately 237°C.

In another embodiment, crystalline Form IV is characterized by a DSC thermogram substantially as shown in FIG. 11. In another embodiment, crystalline Form IV is characterized by a thermal gravimetric analysis (TGA) plot comprising

- 14 043769 weight loss of approximately 3.3% when heated from approximately 25°C to approximately 140°C. In another embodiment, crystalline Form IV is characterized by a TGA plot substantially as shown in FIG. eleven.

In various embodiments, crystalline Form IV is characterized by a gravimetric vapor sorption (GVS) graph. In some embodiments, crystalline Form IV exhibits a weight increase of about 3.4% when subjected to an increase in relative humidity from about 0% to about 95% relative humidity. In some embodiments, crystalline Form IV exhibits a weight increase of about 1.6% when subjected to an increase in relative humidity from about 40% to about 95% relative humidity. In certain embodiments, the mass increased by adsorption is lost when the relative humidity (RH) is reduced back to approximately 0% RH. In certain embodiments, a 1.8% weight loss occurs when the relative humidity is reduced to a range of from about 40 to 0% RH. In another embodiment, crystalline Form IV exhibits a gravimetric vapor sorption plot substantially as shown in FIG. 12. In certain embodiments, the XRPD diffraction pattern of the Form IV material remains substantially unchanged after adsorption/desorption analysis. In certain embodiments, Form IV is moisture stable. In certain embodiments, Form IV is substantially stable. In another embodiment, Form IV is converted to Form I upon exposure to a solvent system containing, for example, acetonitrile/water mixtures at 30°C for about 2 days. In another embodiment, Form IV is converted to Form I by resuspending a sample of Form IV at room temperature in acetonitrile. In another embodiment, Form IV is converted to Form I when heated at approximately 230°C.

In certain embodiments, Form IV can be characterized by particle size analysis. In another embodiment, the Form IV sample contains particles measuring about 100 μm, about 90 μm, about 80 μm, about 70 μm, about 60 μm, about 50 μm, about 40 μm, about 30 μm, about 20 μm, about 10 μm , approximately 5 µm in length. In some embodiments, the Form IV sample contains particles that are about 100 μm, about 70 μm, about 60 μm, about 40 μm, about 20 μm, about 10 μm in length.

In certain embodiments, the crystalline form of Formula I in Form IV may contain no less than about 95%, no less than about 97%, no less than about 98%, no less than about 99%, or no less than about 99.5% by weight of the salt according to Formula I. The crystalline form may also contain no less than about 90%, no less than about 95%, no less than about 98%, no less than about 99%, or no less than 99.5% by weight crystalline Form IV.

Form V of valbenazine ditosylate.

In another embodiment, a crystalline form of di(4-methylbenzenesulfonate) (S)-(2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1Hpyrido is provided [2,1-a]isoquinolin-2-yl-2-amino-3-methylbutanoate (formula I), or an isotopic variant thereof, or a solvate thereof, the crystalline form being Form V.

In various embodiments, crystalline Form V of di(4-methylbenzenesulfonate) (S)-(2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1Hpyrido [2,1-a]isoquinolin-2-yl-2-amino-3-methyl butanoate (formula I) is characterized by an x-ray diffraction pattern. In some embodiments, the X-ray diffraction pattern of di(4-methylbenzenesulfonate) Form V (S)-(2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11bhexahydro-1H- pyrido[2,1-a]isoquinolin-2-yl-2-amino-3-methylbutanoate (Formula I) includes an XRP diffraction peak at 2-theta angles of approximately 6.7, 7.9, 10.7 , 12.8, 17.1 and 23.7°. In some embodiments, X-ray powder diffraction pattern of di(4-methylbenzenesulfonate) Form V (S)-(2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11bhexahydro-1H -pyrido[2,1-a]isoquinolin-2-yl-2-amino-3-methylbutanoate (Formula I) includes an XRP diffraction peak at 2-theta angles of approximately 6.7, 7.9, 10. 7, 12.8, 17.1 or 23.7°. In certain embodiments, X-ray powder diffraction pattern of di(4-methylbenzenesulfonate) Form V (S)-(2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11bhexahydro-1H α-pyrido[2,1-a]isoquinolin-2-yl-2-amino-3-methyl butanoate (Formula I) includes an XRP diffraction peak at 2-theta angles of approximately 6.7 and 7.9°. In some embodiments, a powder X-ray diffraction pattern of di(4-methylbenzenesulfonate) Form V (S)-(2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro -1Hpyrido[2,1-a]isoquinolin-2-yl-2-amino-3-methylbutanoate (formula I) includes diffraction

- 15 043769 XRP peak at 2-theta angles of approximately 6.7°. In certain embodiments, crystalline Form V of di(4-methylbenzenesulfonate) (S)-(2R,3R,11bR)-3-isobutyl-9,10dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido [2,1-a]isoquinolin-2-yl-2-amino-3-methylbutanoate (Formula I) has an X-ray diffraction pattern essentially as shown in FIG. 13.

In some embodiments, crystalline Form V is characterized by one or more characteristic XRP diffraction peaks at 2-theta angles of about 6.7° and about 7.9°. In certain embodiments, crystalline Form V is characterized by one or more characteristic XRP diffraction peaks at 2-theta angles of about 6.7°, about 7.9°, and about 23.7°. In some embodiments, crystalline Form V is characterized by one or more characteristic XRP diffraction peaks at 2-theta angles of about 6.7°, about 7.9°, about 17.1°, and about 23.7°. In other embodiments, crystalline Form V is characterized by one or more characteristic XRP diffraction peaks at 2-theta angles of about 6.7°, about 7.9°, about 15.8°, about 17.1°, and about 23.7 °. In some embodiments, crystalline Form V is characterized by one or more characteristic XRP diffraction peaks at 2-theta angles of about 6.7°, about 7.9°, about 15.8°, about 17.1°, about 21.5 ° and approximately 23.7°. In certain embodiments, crystalline Form V is characterized by one or more characteristic XRP diffraction peaks at 2-theta angles of about 6.7°, about 7.9°, about 15.8°, about 16.0°, about 17.1 °, approximately 21.5° and approximately 23.7°. In other embodiments, crystalline Form V is characterized by one or more characteristic XRP diffraction peaks at 2-theta angles of about 6.7°, about 7.9°, about 10.7°, about 15.8°, about 16.0 °, approximately 17.1°, approximately 21.5° and approximately 23.7°. In some embodiments, crystalline Form V is characterized by one or more characteristic XRP diffraction peaks at 2-theta angles of about 6.7°, about 7.9°, about 10.7°, about 12.8°, about 15.8 °, approximately 16.0°, approximately 17.1°, approximately 21.5° and approximately 23.7°.

In various embodiments, crystalline Form V is characterized by an endothermic differential scanning calorimetry (DSC) thermogram. In some embodiments, crystalline Form V is characterized by a DSC thermogram containing endothermic events with peak temperatures of approximately 113°C and approximately 181°C.

According to another embodiment, crystalline Form V is characterized by a DSC thermogram substantially as shown in FIG. 14. In another embodiment, crystalline Form V is characterized by a thermal gravimetric analysis (TGA) plot containing a mass loss of approximately 4.1% when heated from about 25°C to about 140°C. In another embodiment, crystalline Form V is characterized by a TGA plot substantially as shown in FIG. 14.

In various embodiments, crystalline Form V is characterized by a gravimetric vapor sorption (GVS) graph. In some embodiments, crystalline Form V exhibits a weight increase of about 1% when subjected to an increase in relative humidity from about 10% to about 95% relative humidity. In certain embodiments, the mass increased by adsorption is lost when the relative humidity (RH) is reduced back to approximately 0% RH. In certain embodiments, a 1.2% weight loss occurs when the relative humidity is reduced from about 20 to 0% RH. In another embodiment, crystalline Form V exhibits a gravimetric vapor sorption plot substantially as shown in FIG. 15. In certain embodiments, the XRPD diffraction pattern of the Form V material remains substantially unchanged after adsorption/desorption analysis. In certain embodiments, Form V is substantially stable. In another embodiment, Form V is converted to Form VI when heated from about 110°C to about 140°C.

In certain embodiments, Form V can be characterized by particle size analysis. In another embodiment, the Form V sample contains particles measuring about 100 μm, about 90 μm, about 80 μm, about 70 μm, about 60 μm, about 50 μm, about 40 μm, about 30 μm, about 20 μm, about 10 μm , approximately 5 µm in length. In some embodiments, the Form V sample contains particles that are about 100 μm, about 70 μm, about 60 μm, about 40 μm, about 20 μm, about 10 μm in length.

In certain embodiments, the crystalline form of Formula I in Form V may contain no less than about 95%, no less than about 97%, no less than about 98%, no less than about 99%, or no less than about 99.5% by weight of the salt according to Formula I. The crystalline form may also contain no less than about 90%, no less than about 95%, no less than about 98%, no less than about 99%, or no less than 99.5% by weight crystalline V shape.

Form VI of valbenazine ditosylate.

In another embodiment, a crystalline form of di(4-methylbenzenesulfonate) (S)-(2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1Hpyrido is provided [2,1-a]isoquinolin-2-yl-2-amino-3-methylbutanoate (formula I), or an isotopic variant thereof, or a solvate thereof, the crystalline form being Form VI.

In various embodiments, crystalline Form VI of di(4-methylbenzenesulfonate) (S)-(2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1Hpyrido [2,1-a]isoquinolin-2-yl-2-amino-3-methyl butanoate (formula I) is characterized by an x-ray diffraction pattern. In some embodiments, the X-ray diffraction pattern of Form VI of di(4-methylbenzenesulfonate) (S)-(2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11bhexahydro-1H- pyrido[2,1-a]isoquinolin-2-yl-2-amino-3-methylbutanoate (Formula I) includes XRP diffraction peak at 2-theta angles of approximately 6.8, 8.0, 16.3 and 17.5°. In some embodiments, a powder X-ray diffraction pattern of Form VI of di(4-methylbenzenesulfonate) (S)-(2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro -1Hpyrido[2,1-a]isoquinolin-2-yl-2-amino-3-methyl butanoate (Formula I) includes an XRP diffraction peak at 2-theta angles of approximately 6.8, 8.0, 16 .3 or 17.5°. In certain embodiments, a powder X-ray diffraction pattern of Form VI of di(4-methylbenzenesulfonate) (S)-(2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro -1Hpyrido[2,1-a]isoquinolin-2-yl-2-amino-3-methylbutanoate (Formula I) includes an XRP diffraction peak at 2-theta angles of approximately 6.8° and 8.0°. In other embodiments, the X-ray powder diffraction pattern of Form VI of di(4-methylbenzenesulfonate) (S)(2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro- 1H-pyrido[2,1-a]isoquinolin-2-yl-2amino-3-methylbutanoate (Formula I) includes an XRP diffraction peak at 2-theta angles of approximately 6.8°. In certain embodiments, crystalline Form VI of di(4-methylbenzenesulfonate) (S)-(2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11bhexahydro-1H-pyrido [2,1-a]isoquinolin-2-yl-2-amino-3-methylbutanoate (Formula I) has an X-ray diffraction pattern essentially as shown in FIG. 16.

In some embodiments, crystalline Form VI is characterized by one or more characteristic XRP diffraction peaks at 2-theta angles of about 6.8° and about 8.0°. In certain embodiments, crystalline Form VI is characterized by one or more characteristic XRP diffraction peaks at 2-theta angles of about 6.8°, about 5.4°, and about 8.0°. In other embodiments, crystalline Form VI is characterized by one or more characteristic XRP diffraction peaks at 2-theta angles of about 6.8°, about 5.4°, and about 8.0° and about 17.5°. In other embodiments, crystalline Form VI is characterized by one or more characteristic XRP diffraction peaks at 2-theta angles of about 6.8°, about 5.4° and about 8.0°, about 16.3° and about 17.5 °. In other embodiments, crystalline Form VI is characterized by one or more characteristic XRP diffraction peaks at 2-theta angles of about 6.8°, about 5.4°, about 8.0°, about 16.3°, about 17.5 ° and approximately 18.7°.

In various embodiments, crystalline Form VI is characterized by an endothermic differential scanning calorimetry (DSC) thermogram. In some embodiments, crystalline Form VI is characterized by a DSC thermogram containing endothermic events with peak temperatures of approximately 175°C and approximately 238°C.

In another embodiment, crystalline Form VI is characterized by a DSC thermogram substantially as shown in FIG. 17. In another embodiment, crystalline Form VI is characterized by a thermal gravimetric analysis (TGA) plot containing a mass loss of approximately 1% when heated from about 25°C to about 140°C. In another embodiment, crystalline Form V is characterized by a TGA plot substantially as shown in FIG. 17.

- 17 043769

In various embodiments, crystalline Form VI is characterized by a gravimetric vapor sorption (GVS) graph. In some embodiments, crystalline Form VI exhibits a weight increase of about 3.1% when subjected to an increase in relative humidity from about 0% to about 90% relative humidity. In some embodiments, crystalline Form VI exhibits a weight increase of about 0.5% when subjected to an increase in relative humidity from about 40% to about 80% relative humidity. In some embodiments, crystalline Form VI exhibits a weight increase of about 3.1% when subjected to an increase in relative humidity from about 80% to about 90% relative humidity. In certain embodiments, the mass increased by adsorption is not lost when the relative humidity (RH) is reduced back to approximately 0% RH. In certain embodiments, a 1.2% weight loss occurs when the relative humidity is reduced from about 90 to 15% RH. In certain embodiments, a 2.0% weight loss occurs when the relative humidity is reduced from about 15 to 0% RH. In another embodiment, crystalline Form VI exhibits a gravimetric vapor sorption plot substantially as shown in FIG. 18. In certain embodiments, the XRPD diffraction pattern of the Form VI material changes substantially after adsorption/desorption analysis. In another embodiment, Form VI is converted to Form V when subjected to a gravimetric vapor sorption assay.

In certain embodiments, Form VI can be characterized by particle size analysis. In another embodiment, the Form VI sample contains particles measuring about 100 μm, about 90 μm, about 80 μm, about 70 μm, about 60 μm, about 50 μm, about 40 μm, about 30 μm, about 20 μm, about 10 μm , approximately 5 µm in length. In some embodiments, the Form VI sample contains particles that are about 100 μm, about 70 μm, about 60 μm, about 40 μm, about 20 μm, about 10 μm in length.

In certain embodiments, the crystalline form of Formula I in Form VI may contain no less than about 95%, no less than about 97%, no less than about 98%, no less than about 99%, or no less than about 99.5% by weight of the salt according to Formula I. The crystalline form may also contain no less than about 90%, no less than about 95%, no less than about 98%, no less than about 99%, or no less than 99.5% by weight crystalline Form VI.

In another embodiment, the crystalline form of di(4-methylbenzenesulfonate) (S)-(2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H- pyrido[2,1-a]isoquinolin-2-yl2-amino-3-methylbutanoate (Formula I), or an isotopic variant thereof, or a solvate thereof is amorphous. Amorphous forms are characterized by a powder X-ray diffraction pattern essentially as shown in FIG. 19, which lacks characteristic XRP diffraction peaks for Form I and/or Forms II-VI particles. In one embodiment, the amorphous form of Formula I may contain no less than about 95%, no less than about 97%, no less than about 98%, no less than about 99%, or no less than about 99.5% by weight acid according to Formula I. The amorphous form may also contain not less than about 90%, not less than about 95%, not less than about 98%, not less than about 99%, or not less than 99.5% by weight of the amorphous form according to the formula I.

Valbenazine dihydrochloride.

Provided herein is the crystalline form of (S)-(2R,3R,11bR)3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1- a]isoquinolin-2-yl-2-amino-3methylbutanoate, or an isotopic variant thereof, or a solvate thereof according to formula II

I

(II) .

Form I of valbenazine dihydrochloride.

In another embodiment, a crystalline form of (S)-(2R,3R,11BR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11B-hexahydro-1H-pyrido[2, 1-a]isoquinolin-2-yl- 18 043769

2-amino-3-methylbutanoate (formula II), or an isotopic variant thereof, or a solvate thereof, the crystalline form being Form I.

In various embodiments, crystalline Form I of (S)-(2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2, 1-a]isoquinolin-2-yl2-amino-3-methylbutanoate (formula II) is characterized by an x-ray diffraction pattern. In some embodiments, an X-ray diffraction pattern of Form I dihydrochloride (S)-(2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2 ,1-a]isoquinolin-2-yl2-amino-3-methylbutanoate (Formula II) includes XRP diffraction peaks at 2-theta angles of approximately 7.2, 9.2 and 18.0°. In some embodiments, the X-ray powder diffraction pattern of Form I dihydrochloride (S)-(2R,3R,11bR)-3-isobutyl-9,10-dimethoxy2,3,4,6,7,11b-hexahydro-1H-pyrido[2, 1-a]isoquinolin-2-yl-2-amino-3-methylbutanoate (Formula II) includes an XRP diffraction peak at 2-theta angles of approximately 7.2, 9.2, or 18.0°. In certain embodiments, the X-ray powder diffraction pattern of Form I dihydrochloride (S)-(2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1Hpyrido[2, 1-a]isoquinolin-2-yl-2-amino-3-methylbutanoate (Formula II) includes an XRP diffraction peak at 2-theta angles of approximately 7.2 and 9.2°. In other embodiments, X-ray powder diffraction pattern of Form I dihydrochloride (S)-(2R,3R,11bR)-3-isobutyl-9,10dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2, 1-a]isoquinolin-2-yl-2-amino-3-methylbutanoate (Formula II) includes an XRP diffraction peak at 2-theta angles of approximately 7.2°. In certain embodiments, crystalline Form I of (S)-(2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2, 1-a]isoquinolin-2-yl2-amino-3-methylbutanoate (Formula II) has an X-ray diffraction pattern essentially as shown in FIG. 20.

In some embodiments, crystalline Form I of Formula II is characterized by one or more characteristic XRP diffraction peaks at 2-theta angles of about 7.2° and about 9.2°. In certain embodiments, crystalline Form I of Formula II is characterized by one or more characteristic XRP diffraction peaks at 2-theta angles of about 7.2°, about 9.2°, and about 18.0°. In some embodiments, crystalline Form I of Formula II is characterized by one or more characteristic XRP diffraction peaks at 2-theta angles of about 7.2°, about 9.2°, about 18.0°, and about 20.8°. In other embodiments, crystalline Form I of Formula II is characterized by one or more characteristic XRP diffraction peaks at 2-theta angles of about 7.2°, about 9.2°, about 18.0°, about 20.8°, and about 25.9°. In certain embodiments, crystalline Form I of Formula II is characterized by one or more characteristic XRP diffraction peaks at 2-theta angles of about 7.2°, about 9.2°, about 18.0°, about 20.8°, about 22.5° and approximately 25.9°. In some embodiments, crystalline Form I of Formula II is characterized by one or more characteristic XRP diffraction peaks at 2-theta angles of about 7.2°, about 9.2°, about 12.7°, about 18.0°, about 20.8°, approximately 22.5° and approximately 25.9°. In other embodiments, crystalline Form I of Formula II is characterized by one or more characteristic XRP diffraction peaks at 2-theta angles of about 7.2°, about 9.2°, about 12.7°, about 18.0°, about 20.8°, approximately 22.5°, approximately 24.0° and approximately 25.9°.

In various embodiments, crystalline Form I of Formula II is characterized by an endothermic differential scanning calorimetry (DSC) thermogram. In some embodiments, crystalline Form I is characterized by a DSC thermogram comprising an endothermic event with an onset temperature of approximately 240°C and a peak at approximately 250°C.

According to another embodiment, crystalline Form I according to Formula II is characterized by a DSC thermogram essentially as shown in FIG. 21. In another embodiment, crystalline Form I of Formula II is characterized by a thermal gravimetric analysis (TGA) plot substantially as shown in FIG. 21.

In various embodiments, crystalline Form I of Formula II is characterized by a gravimetric vapor sorption (GVS) plot. In some embodiments, crystalline Form I exhibits a weight increase of about 14% when subjected to an increase in relative humidity from about 0% to about 90% relative humidity. In another embodiment, crystalline Form I of Formula II exhibits a gravimetric vapor sorption graph substantially as shown in

- 19 043769 fig. 22. In certain embodiments, the XRPD diffraction pattern of Form I of Formula II is substantially altered after adsorption/desorption analysis. In another embodiment, Form I of Formula II is converted to Form II when stored at approximately 25° C. and approximately 92% relative humidity for approximately 7 days. In another embodiment, Form I of Formula II is converted to Form II when stored at approximately 40°C and approximately 75% relative humidity for approximately 7 days. According to another embodiment, crystalline form I according to formula II has a solubility in water greater than 90 mg/ml at pH 4.1.

In certain embodiments, Form I of Formula II can be characterized by particle size analysis. In certain embodiments, the Form II sample comprises particles characterized by a birefringent lamellar morphology. In another embodiment, a sample of Form I of Formula II contains particles measuring approximately 100 μm, approximately 90 μm, approximately 80 μm, approximately 70 μm, approximately 60 μm, approximately 50 μm, approximately 40 μm, approximately 30 μm, approximately 20 μm, approximately 10 µm, approximately 5 µm in length. In some embodiments, a sample of Form I of Formula II contains particles that are about 100 μm, about 70 μm, about 60 μm, about 40 μm, about 20 μm, about 10 μm in length. In another embodiment, a sample of Form I of Formula II contains particles that are approximately 150 μm in length.

In certain embodiments, the crystalline form of Formula II in Form I may contain no less than about 95%, no less than about 97%, no less than about 98%, no less than about 99%, or no less than about 99.5% by weight of salt according to formula II. The crystalline form may also contain no less than about 90%, no less than about 95%, no less than about 98%, no less than about 99%, or no less than 99.5% by weight of crystalline Form I.

Form II of valbenazine dihydrochloride.

In another embodiment, a crystalline form of (S)-(2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2, 1-a]isoquinolin-2-yl2-amino-3-methylbutanoate (formula II), or an isotopic variant thereof, or a solvate thereof, the crystalline form being Form II.

In various embodiments, crystalline Form II of (S)-(2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2, 1-a]isoquinolin-2-yl2-amino-3-methylbutanoate (formula II) is characterized by an x-ray diffraction pattern. In some embodiments, the X-ray diffraction pattern of Form II dihydrochloride (S)-(2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2 ,1-a]isoquinolin-2-yl2-amino-3-methylbutanoate (Formula II) includes XRP diffraction peaks at 2-theta angles of approximately 4.8, 13.3 and 24.9°. In some embodiments, a Form II powder X-ray diffraction pattern of (S)-(2R,3R,11bR)-3-isobutyl-9,10dimethoxy-2,3,4,6,7D1b-hexahydro-III-pyrido[2D-a] dihydrochloride Isoquinolin-2-yl-2-amino-3-methylbutanoate (Formula II) includes an XRP diffraction peak at 2-theta angles of approximately 4.8, 13.3, or 24.9°. In certain embodiments, a Form II powder X-ray diffraction pattern of (S)-(2R,3RD1bR)-3-isobutyl-9D0-dimethoxy-2,3,4,6,7D1b-hexahydro1H-pyrido[2,1-a]isoquinoline-dihydrochloride 2-yl-2-amino-3-methylbutanoate (Formula II) includes an XRP diffraction peak at 2-theta angles of approximately 4.8°. In certain embodiments, crystalline Form II of (S)-(2R,3RD1bR)-3-isobugyl-9D0-dimethoxy2,3,4,6,7D1b-hexahydro-III-pyrido[2D-a]isoquinolin-2-yl-dihydrochloride 2-amino-3-methylbutanoate (Formula II) has an x-ray diffraction pattern essentially as shown in FIG. 23.

In some embodiments, crystalline Form II of Formula II is characterized by one or more characteristic XRP diffraction peaks at 2-theta angles of about 4.8° and about 24.9°. In certain embodiments, crystalline Form II of Formula II is characterized by one or more characteristic XRP diffraction peaks at 2-theta angles of about 4.8°, about 13.3°, and about 24.9°. In some embodiments, crystalline Form II of Formula II is characterized by one or more characteristic XRP diffraction peaks at 2-theta angles of about 4.8°, about 13.3°, about 14.1°, and about 24.9°. In other embodiments, crystalline Form II of Formula II is characterized by one or more characteristic XRP diffraction peaks at 2-theta angles of about 4.3°, about 4.8°, about 13.3°, about 14.1°, and about 24.9°. In some embodiments, crystalline Form II of Formula II is characterized by one or more

- 20 043769 how many characteristic diffraction peaks of XRP at 2-theta angles of approximately 4.3°, approximately 4.8°, approximately 13.3°, approximately 14.1°, approximately 18.4° and approximately 24.9° . In other embodiments, crystalline Form II of Formula II is characterized by one or more characteristic XRP diffraction peaks at 2-theta angles of about 4.3°, about 4.8°, about 8.7°, about 13.3°, about 14.1°, approximately 18.4° and approximately 24.9°. In other embodiments, crystalline Form II of Formula II is characterized by one or more characteristic XRP diffraction peaks at 2-theta angles of about 4.3°, about 4.8°, about 8.4°, about 8.7°, about 13.3°, approximately 14.1°, approximately 18.4° and approximately 24.9°. In other embodiments, crystalline Form II of Formula II is characterized by one or more characteristic XRP diffraction peaks at 2-theta angles of about 4.3°, about 4.8°, about 8.4°, about 8.7°, about 13.3°, approximately 14.1°, approximately 14.6°, approximately 18.4° and approximately 24.9°.

In various embodiments, crystalline Form II of Formula II is characterized by an endothermic differential scanning calorimetry (DSC) thermogram. In some embodiments, crystalline Form II is characterized by a DSC thermogram comprising an endothermic event with an onset temperature of approximately 80°C and a peak at approximately 106°C.

According to another embodiment, crystalline Form II according to Formula II is characterized by a DSC thermogram substantially as shown in FIG. 24. In another embodiment, crystalline Form II of Formula II is characterized by a thermal gravimetric analysis (TGA) plot containing a mass loss of approximately 10% when heated from about 25°C to about 100°C. In another embodiment, crystalline Form II of Formula II is characterized by a TGA plot substantially as shown in FIG. 24.

In various embodiments, crystalline Form II of Formula II is characterized by a gravimetric vapor sorption (GVS) graph. In some embodiments, crystalline Form II exhibits a weight loss of approximately 12% when subjected to a reduction in relative humidity from about 75% to about 0% relative humidity. In another embodiment, crystalline Form II according to Formula II exhibits a gravimetric vapor sorption plot substantially as shown in FIG. 25. In certain embodiments, Form II is substantially stable. In another embodiment, Form II is converted to Form I when heated. In yet another embodiment, Form II of Formula II is converted to an amorphous material when heated at temperatures above about 160°C. According to another embodiment, crystalline form II according to formula II has a solubility in water greater than 67 mg/ml at pH 4.1.

In certain embodiments, Form II of Formula II can be characterized by particle size analysis. In another embodiment, a sample of Form II according to Formula II contains particles of about 100 μm, about 90 μm, about 80 μm, about 70 μm, about 60 μm, about 50 μm, about 40 μm, about 30 μm, about 20 μm, approximately 10 µm, approximately 5 µm in length. In some embodiments, the Form II sample of Formula II contains particles that are about 100 μm, about 70 μm, about 60 μm, about 40 μm, about 20 μm, about 10 μm in length.

In certain embodiments, the crystalline form of Formula II in Form II may contain no less than about 95%, no less than about 97%, no less than about 98%, no less than about 99%, or no less than about 99.5% by weight of salt according to formula II. The crystalline form may also contain no less than about 90%, no less than about 95%, no less than about 98%, no less than about 99%, or no less than 99.5% by weight of crystalline Form II.

In another embodiment, the crystalline form of (S)-(2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1 -a]isoquinolin-2-yl2-amino-3-methylbutanoate (formula II), or an isotopic variant thereof, or a solvate thereof is amorphous. Amorphous forms are characterized by a powder X-ray diffraction pattern essentially as shown in FIG. 26, which lacks characteristic XRP diffraction peaks for Form I and/or Form II particles according to Formula II. In one embodiment, the amorphous form of Formula II may contain no less than about 95%, no less than about 97%, no less than about 98%, no less than about 99%, or no less than about 99.5% by weight salt according to formula II. The amorphous form may also contain

- 21 043769 not less than about 90%, not less than about 95%, not less than about 98%, not less than about 99% or not less than 99.5% by weight of the amorphous form according to formula II.

It should be understood that the numerical values of the peaks of X-ray powder diffraction patterns may vary slightly between instruments or between samples, and therefore the values given should not be interpreted as absolute, but with an acceptable variability, such as 0.2°, as defined herein.

Method of receipt.

In addition, methods are provided for preparing salts according to formula I and/or formula II in amorphous form or crystalline form. The methods include the step of contacting a salt according to formula I and/or formula II with a solvent, in which the salt particles according to formula I and/or formula II are in amorphous form or crystalline form (for example, form I, II, III, IV, V or VI) according to formula I and/or formula II can be formed from solution or converted from one solid form to another. The method may further include an isolation step in which the compounds can be isolated using a conventional method such as filtration and centrifugation followed by washing with a solvent and then drying (eg, vacuum oven drying, air drying or desiccator drying).

Suitable solvents for use in preparing the compounds in amorphous form or crystalline form include, but are not limited to, hydrocarbons, including petroleum ether, pentane, hexane(s), heptane, octane, isooctane, cyclopentane, cyclohexane, methylcyclohexane, benzene, toluene, xylene, tetralin and kumen; chlorinated hydrocarbons including dichloromethane (DCM), 1,2-dichloroethane, 1,1-dichloroethene, 1,2-dichloroethene, chloroform, trichloroethane, trichloroethane, carbon tetrachloride, chlorobenzene and trifluoromethylbenzene; alcohols including methanol, ethanol, isopropanol (IPA), 1-propanol, 1-butanol, 2-butanol, tert-butanol, 3-methyl-1-butanol, 1-pentanol, 2-methoxyethanol, 2-ethoxyethanol and ethylene glycol; ethers including diethyl ether, diisopropyl ether, methyl tert-butyl ether (MTBE), diphenyl ether, 1,2-dimethoxyethane, bi(2-methoxyethyl) ether, 1,1-dimethoxymethane, 2,2-dimethoxypropane and anisole ; ketones, including acetone, butanone, methyl ethyl ketone (MEK), methyl isopropyl ketone, methyl butyl ketone and methyl isobutyl ketone (MIBK); esters including methyl acetate, ethyl formate, ethyl acetate, propyl acetate, isopropyl acetate, isobutyl acetate and butyl acetate; carbonates, including ethylene carbonate and propylene carbonate; amides including formamide, N,N-dimethylformamide (DMF) and N,N-dimethylacetamide; nitriles, including acetonitrile (ACN); sulfoxides such as dimethyl sulfoxide (DMSO); sulfones such as sulfolane; nitro compounds such as nitromethane and nitrobenzene; heterocycles such as N-methylpyrrolidone, 2-methyltetrahydrofuran, tetrahydrofuran (THF), dioxane and pyridine; carboxylic acids such as acetic acid, trichloroacetic acid and trifluoroacetic acid; phosphoramides such as hexamethylphosphoramide; carbon sulfide; water; and mixtures thereof.

The salt compounds of Formula I and/or Formula II in crystalline form can be prepared from a solution or thick suspension of the salt of Formula I and/or Formula II in a solvent using conventional methods including, but not limited to, cooling, quenching, solvent evaporation, or addition of an antisolvent.

According to one embodiment, a method for obtaining a crystalline form of a salt according to Formula I and/or Formula II involves the following steps:

(a) obtaining a solution of an acid according to formula I and/or formula II in a solvent at a first temperature; and (b) obtaining a crystalline compound at a second temperature.

To accelerate the formation of crystalline material according to Formula I and/or Formula II, the method may also include a seeding step by seeding the solution with crystals of Form I before or during step (b). The method may further include an isolation step, as described herein.

The solution can be prepared from any salt forms of Formula I and/or Formula II, including but not limited to oils, semi-solid forms, solid forms (such as amorphous form or Form I, II, III, IV, V or VI of Formula I and/or formula II), or mixtures thereof. The solution according to step (a) can be obtained as a saturated or near-saturated solution at the first temperature. A saturated or near-saturated solution can be prepared by dissolving a sufficient amount of a salt of Formula I and/or Formula II in a solvent at a temperature that is higher than the first temperature so that when the solution cools to the first temperature, a saturated or near-saturated solution is obtained. A sufficient amount of salt according to Formula I and/or Formula II can be assessed based on the solubility of the compounds according to Formula I and/or Formula II in the solvent at the first temperature, which can be determined using a method known to one skilled in the art.

The first temperature may be in the range from room temperature to about the boiling point of the solvent, for example from about 20°C to about 200°C, from

- 22 043769 approximately 20°C to approximately 150°C or from approximately 20°C to approximately 100°C. The second temperature may range from -100°C to about 100°C, from about -50°C to about 50°C, from about -10°C to about 30°C, from about 20°C to about 200°C, from about 20°C to about 150°C or from about 20°C to about 100°C. The first temperature may be higher or lower than the second temperature, or the same as the second temperature. To maximize the yield and efficiency of the process, the second temperature is typically set to be lower than the first temperature.

In one embodiment, crystalline compounds of Formula I and/or Formula II are formed by heating a solvent from a solution at a second temperature. Solvent evaporation can be facilitated by applying heat and/or vacuum to the solution. In one embodiment, the solvent is acetonitrile, dichloromethane, DMF, 1,4-dioxane, methanol, 2-methoxyethanol, MIBK, acetone, 1-butanol, MTBE, DMSO, ethanol, ethyl acetate, isobutyl acetate, isopropyl acetate, 1-propanol, IPA, MEK, THF, water or a mixture of these.

According to another embodiment, crystalline compounds according to Formula I and/or Formula II are formed by cooling the solution to a second temperature. In this case, the second temperature is set to be lower than the first temperature. In one embodiment, the solvent is acetonitrile, DMF, 1,4-dioxane, methanol, ethanol, 2-methoxyethanol, 1-butanol, 1-propanol, IPA, MIBK, MEK, THF, acetone, or a mixture thereof. In one embodiment, the solvent is acetonitrile, water, 1-propanol, and mixtures thereof. In another embodiment, the solvent is acetonitrile, water, and mixtures thereof. In another embodiment, the solvent is 1-propanol, water, and mixtures thereof. In another embodiment, the solvent is 1-propanol.

In one embodiment, Form I of Formula I is formed by cooling the solution to a second temperature. In this case, the second temperature is set to be lower than the first temperature. In one embodiment, the solvent is acetonitrile/water (1% v/v), acetonitrile/water (2% v/v), acetonitrile/water (3% v/v). In one embodiment, the solvent is acetonitrile/water (3% v/v).

In another embodiment, crystalline compounds of Formula I and/or Formula II are formed by adding an antisolvent to a solution at a second temperature.

Suitable antisolvents include, but are not limited to, hydrocarbons including petroleum ether, pentane, hexane(s), heptane, octane, isooctane, cyclopentane, cyclohexane, methylcyclohexane, benzene, toluene, xylene, tetralin and cumene; chlorinated hydrocarbons including dichloromethane (DCM), 1,2-dichloroethane, 1,1-dichloroethene, 1,2-dichloroethene, chloroform, trichloroethane, trichloroethane, carbon tetrachloride, chlorobenzene and trifluoromethylbenzene; alcohols including methanol, ethanol, isopropanol (IPA), 1-propanol, 1-butanol, 2-butanol, tert-butanol, 3-methyl-1-butanol, 1-pentanol, 2-methoxyethanol, 2-ethoxyethanol and ethylene glycol; ethers including diethyl ether, diisopropyl ether, methyl tert-butyl ether (MTBE), diphenyl ether, 1,2-dimethoxyethane, bi(2-methoxyethyl) ether, 1,1-dimethoxymethane, 2,2-dimethoxypropane and anisole ; ketones, including acetone, butanone, methyl ethyl ketone (MEK), methyl isopropyl ketone, methyl butyl ketone and methyl isobutyl ketone (MIBK); esters including methyl acetate, ethyl formate, ethyl acetate, propyl acetate, isopropyl acetate, isobutyl acetate and butyl acetate; carbonates, including ethylene carbonate and propylene carbonate; amides including formamide, N,N-dimethylformamide (DMF) and N,N-dimethylacetamide; nitriles, including acetonitrile (ACN); sulfoxides such as dimethyl sulfoxide (DMSO); sulfones such as sulfolane; nitro compounds such as nitromethane and nitrobenzene; heterocycles such as N-methylpyrrolidone, 2-methyltetrahydrofuran, tetrahydrofuran (THF), dioxane and pyridine; carboxylic acids such as acetic acid, trichloroacetic acid and trifluoroacetic acid; phosphoramides such as hexamethylphosphoramide; carbon sulfide; water; and mixtures thereof.

If two solvents are used as a solvent/antisolvent pair, the compound of Formula I and/or Formula II has a higher solubility in the solvent than in the antisolvent. Optionally, the solvent and antisolvent in a solvent/antisolvent pair are at least partially miscible. In one embodiment, the solvent is acetonitrile, methanol, ethanol, 1-propanol, water, or a mixture thereof; and the antisolvent is hexane(s), heptanes, diethyl ether, ethyl acetate, THF, isopropanol, and mixtures thereof. In another embodiment, crystalline compounds of Formula I and/or Formula II are formed by adding a solution to an antisolvent at a second temperature. In one embodiment, the solvent is acetonitrile, methanol, ethanol, 1-propanol, water, or a mixture thereof; and the antisolvent is hexane(s), heptanes, diethyl ether, ethyl acetate, THF, isopropanol, and mixtures thereof.

According to another embodiment, a method for preparing crystalline compounds according to Formula I and/or Formula II involves the following steps:

- 23 043769 (a) obtaining a thick suspension of a compound according to formula I and/or formula II in a solvent at a first temperature; and (b) obtaining crystalline compounds according to Formula I and/or Formula II by subjecting the thick suspension to a second temperature.

The thick suspension can be prepared from any form of the compounds of Formula I and/or Formula II, including, but not limited to, oily, semi-solid, solid forms (such as amorphous form or Form I, II, III, IV, V or VI of Formula I and/or formula II) or mixtures thereof. The method may further include a seeding step and/or an isolation step, as described herein.

The first and second temperatures and solvent are as defined herein. In one embodiment, the solvent is acetonitrile, methanol, ethanol, 1-propanol, water, or a mixture thereof.

According to another embodiment, a method for preparing crystalline compounds according to Formula I and/or Formula II involves the following steps:

(a) obtaining a solution of compounds according to formula I and/or formula II in a solvent at a first temperature;

(b) obtaining a thick suspension by cooling the solution to a second temperature; and (c) obtaining crystalline compounds according to Formula I and/or Formula II by subjecting the thick suspension to one or more heating and cooling cycles.

The method may further include a seeding step and/or an isolation step, as described herein.

The first and second temperatures and solvent are as defined herein. In one embodiment, the solvent is acetonitrile, methanol, ethanol, 1-propanol, 1,4-dioxane, water, or a mixture thereof. In one embodiment, the solvent is water. The heating and cooling cycle can be carried out in a temperature range from about -50°C to about 120°C, from about -50°C to about 100°C, from about -20°C to about 80°C, from about 0°C to about 80°C, from about 10°C to about 80°C, from about 20°C to about 80°C, from about 20°C to about 60°C, or from about 20°C to about 50°C.

In one embodiment, Form II of Formula I can be prepared from a solution or thick suspension of a compound of Formula I in a solvent using conventional methods including, but not limited to, cooling, quenching, solvent evaporation, or addition of an antisolvent.

According to one embodiment, a method for producing Form II according to Formula I involves the following steps:

(a) obtaining a thick suspension of the compound according to formula I in a solvent at a first temperature; and (b) obtaining crystalline Form II at a second temperature.

To accelerate the formation of Form II particles, the method may also include a seeding step by seeding the solution with Form II crystals, before or during step (b). The method may further include an isolation step, as described herein.

The solution can be prepared from any form of the compound of Formula I, including, but not limited to, oily, semi-solid, solid forms (such as amorphous form or Form I, II, III, IV, V or VI of Formula I) or mixtures thereof. The solution according to step (a) can be obtained as a saturated or near-saturated solution at the first temperature. A saturated or near-saturated solution can be prepared by dissolving a sufficient amount of a compound of Formula I in a solvent at a temperature that is higher than the first temperature so that when the solution cools to the first temperature, a saturated or near-saturated solution is obtained. A sufficient amount of a compound of Formula I can be assessed based on the solubility of the Form II particles in the solvent at the first temperature, which can be determined using a method known to one skilled in the art. In one embodiment, the solvent is acetonitrile, water, or a mixture thereof. In one embodiment, the solvent is water.

In one embodiment, Form III of Formula I can be prepared from a solution or thick suspension of a compound of Formula I in a solvent using conventional methods including, but not limited to, cooling, quenching, solvent evaporation, or addition of an antisolvent.

According to another embodiment, a method for obtaining crystalline Form III according to Formula I involves the following steps:

(a) preparing a solution of a compound of formula I in a solvent at a first temperature;

(b) obtaining a thick suspension by cooling the solution to a second temperature; And

- 24 043769 (c) obtaining crystalline Form III according to Formula I by subjecting the thick suspension to one or more heating and cooling cycles.

The method may further include a seeding step and/or an isolation step, as described herein.

The first and second temperatures and solvent are as defined herein. In one embodiment, the solvent is acetonitrile, methanol, ethanol, 1-propanol, 1,4-dioxane, water, or a mixture thereof. In one embodiment, the solvent is a 1,4-dioxane/water mixture. In one embodiment, the solvent is water. The heating and cooling cycle can be carried out in a temperature range from about -50°C to about 120°C, from about -50°C to about 100°C, from about -20°C to about 80°C, from about 0°C to about 80°C, from about 10°C to about 80°C, from about 20°C to about 80°C, from about 20°C to about 60°C, or from about 20°C to about 50°C.

In one embodiment, Form IV of Formula I can be prepared from a solution or thick suspension of a compound of Formula I in a solvent using conventional methods including, but not limited to, refrigeration, quenching, solvent evaporation, or addition of an antisolvent.

According to one embodiment, a method for preparing crystalline Form IV according to Formula I involves the following steps:

(a) preparing a solution of a compound of formula I in a solvent at a first temperature; and (b) obtaining a crystalline compound at a second temperature.

To accelerate the formation of crystalline material according to Formula I, the method may also include a seeding step by seeding the solution with crystals of Form IV before or during step (b). The method may further include an isolation step, as described herein.

The solution can be prepared from any salt forms of Formula I and/or Formula II, including but not limited to oily, semi-solid, solid forms (such as amorphous form or Form I, II, III, IV, V or VI of Formula I and/or Formula II) or mixtures thereof. The solution according to step (a) can be obtained as a saturated or near-saturated solution at the first temperature. A saturated or near-saturated solution can be prepared by dissolving a sufficient amount of a salt according to Formula I and/or Formula II in a solvent at a temperature that is higher than the first temperature so that when the solution cools to the first temperature, a saturated or near-saturated solution is obtained. A sufficient amount of salt according to Formula I and/or Formula II can be assessed based on the solubility of the compounds of Formula I and/or Formula II in the solvent at the first temperature, which can be determined using a method known to one skilled in the art.

The first temperature may be in the range from room temperature to about the boiling point of the solvent, for example from about 20°C to about 200°C, from about 20°C to about 150°C, or from about 20°C to about 100°C. The second temperature may be in the range of -100 to 100°C, from about -50°C to about 50°C, from about -10°C to about 30°C, 20°C to about 200°C, from about 20 °C to about 150°C or from about 20°C to about 100°C. The first temperature may be higher or lower than the second temperature, or the same as the second temperature. To maximize the yield and efficiency of the process, the second temperature is typically set to be lower than the first temperature.

In one embodiment, Form IV of Formula I is formed by cooling the solution to a second temperature. In this case, the second temperature is set to be lower than the first temperature. In one embodiment, the solvent is acetonitrile/water. In one embodiment, the solvent is acetonitrile/water (4% v/v). In one embodiment, the solvent is acetonitrile/water (10% v/v).

In one embodiment, Form V of Formula I can be prepared from a solution or thick suspension of a compound of Formula I in a solvent using conventional methods including, but not limited to, cooling, quenching, solvent evaporation, or addition of an antisolvent.

According to one embodiment, a method for producing Form V according to Formula I involves the following steps:

(a) obtaining a thick suspension of the compound according to formula I in a solvent at a first temperature; and (b) obtaining crystalline Form V at a first temperature.

- 25 043769

To accelerate the formation of Form V particles, the method may also include a seeding step by seeding the solution with Form V crystals before or during step (b). The method may further include an isolation step, as described herein.

A thick suspension can be prepared from any form of a compound of Formula I, including, without limitation, oily, semi-solid, solid forms (such as an amorphous form or Form I, II, III, IV, V or VI of Formula I), or mixtures thereof. The solution according to step (a) can be obtained as a saturated or near-saturated solution at the first temperature. A saturated or near-saturated solution can be prepared by dissolving a sufficient amount of a compound of Formula I in a solvent at a temperature that is higher than the first temperature so that when the solution cools to the first temperature, a saturated or near-saturated solution is obtained. A sufficient amount of a compound of Formula I can be assessed based on the solubility of the Form V particles in the solvent at the first temperature, which can be determined using a method known to one skilled in the art. In one embodiment, the solvent is acetonitrile, water, or a mixture thereof. In one embodiment, the solvent is water.

In one embodiment, Form VI of Formula I can be prepared from a solution or thick suspension of a compound of Formula I in a solvent using conventional methods including, but not limited to, cooling, quenching, solvent evaporation, or adding an antisolvent.

According to one embodiment, a method for producing Form VI according to Formula I involves the following steps:

(a) obtaining a thick suspension of the compound according to formula I in a solvent at a first temperature; and (b) obtaining crystalline Form VI at the first temperature.

To accelerate the formation of Form VI particles, the method may also include a seeding step by seeding the solution with Form VI crystals before or during step (b). The method may further include an isolation step, as described herein.

A thick suspension can be prepared from any form of a compound of Formula I, including, without limitation, oily, semi-solid, solid forms (such as an amorphous form or Form I, II, III, IV, V or VI of Formula I), or mixtures thereof. The solution according to step (a) can be obtained as a saturated or near-saturated solution at the first temperature. A saturated or near-saturated solution can be prepared by dissolving a sufficient amount of a compound of Formula I in a solvent at a temperature that is higher than the first temperature so that when the solution cools to the first temperature, a saturated or near-saturated solution is obtained. A sufficient amount of a compound of Formula I can be assessed based on the solubility of the Form VI particles in the solvent at the first temperature, which can be determined using a method known to one skilled in the art. In one embodiment, the solvent is acetonitrile, water, or a mixture thereof. In one embodiment, the solvent is water.

Amorphous compounds of Formula I and/or Formula II can be prepared from a solution or thick suspension of a compound of Formula I in a solvent using conventional methods including, but not limited to, cooling, quenching, solvent evaporation, or addition of an antisolvent.

According to one embodiment, a method for preparing amorphous compounds according to Formula I and/or Formula II involves the following steps:

(a) preparing a solution of a compound according to Formula I and/or Formula II in a solvent at a first temperature;

(b) cooling the solution to a second temperature; and (c) preparing amorphous compounds at a second temperature.

The method may also include an isolation step, as described herein.

The solution can be prepared from any form of the compound of Formula I and/or Formula II, including, without limitation, oily, semi-solid, solid forms (such as amorphous form or Form I, II, III, IV, V or VI) or mixtures thereof. The solution according to step (a) can be obtained as a saturated or near-saturated solution at the first temperature. A saturated or near-saturated solution can be prepared by dissolving a sufficient amount of a compound of Formula I and/or Formula II in a solvent at a temperature that is higher than the first temperature so that when the solution cools to the first temperature, a saturated or near-saturated solution is obtained. A sufficient amount of a compound according to Formula I and/or Formula II can be assessed based on the solubility of the amorphous compounds in the solvent at the first temperature, which can be determined using a method known to one skilled in the art.

In another embodiment, amorphous compounds are formed by cooling the solution to a second temperature. In one embodiment, the solvent is

- 26 043769 alcohol, water or a mixture thereof. In one embodiment, the solvent is tert-butyl alcohol, water, or a mixture thereof.

In another embodiment, amorphous compounds are formed by adding a solution to an antisolvent at a second temperature. Antisolvents are as defined herein.

According to another embodiment, a method for preparing amorphous compounds of a compound according to Formula I and/or Formula II involves the following steps:

(a) obtaining a thick suspension of the compound according to formula I in a solvent at a first temperature; and (b) obtaining amorphous particles through phase transformation at a second temperature.

A thick suspension can be prepared from any form of a compound of Formula I and/or Formula II, including, without limitation, oily, semi-solid, solid forms (such as an amorphous form or Form I, II, III, IV, V or VI) or mixtures thereof. The first and second temperatures and solvent are as defined herein.

Other methods of formation may also be applicable to obtain a compound according to Formula I and/or Formula II in amorphous form or crystalline Form I, II, III, IV, V or VI according to Formula I and/or crystalline Form I or II according to Formula II, including spray drying, roll drying, lyophilization and melt crystallization.

Pharmaceutical compositions.

Further provided herein is a pharmaceutical composition comprising di(4-methylbenzenesulfonate) (S)-(2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b- hexahydro-1Hpyrido[2,1-a]isoquinolin-2-yl-2-amino-3-methylbutanoate (formula I) in amorphous form or crystalline form I, II, III, IV, V or VI, or a suitable hydrate thereof or solvate, as an active pharmaceutical ingredient, in combination with one or more pharmaceutically acceptable carriers or excipients.

Further provided herein is a pharmaceutical composition comprising (S)-(2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H- pyrido[2,1a]isoquinolin-2-yl-2-amino-3-methylbutanoate (formula II) in amorphous form or crystalline form I or II, or a suitable hydrate or solvate thereof, as an active pharmaceutical ingredient, in combination with one or several pharmaceutically acceptable carriers or excipients.

The choice of excipient depends largely on factors such as the specific route of administration, the effect of the excipient on the solubility and stability of the active ingredient, and the nature of the dosage form.

The pharmaceutical compositions provided herein may be provided in unit dosage forms or in multi-dose dosage forms. As used herein, unit dosage forms refer to physically discrete units suitable for administration to a subject, such as a human or animal, and individually packaged as is known in the art. Each unit dose contains a predetermined amount of active ingredient(s) sufficient to obtain the desired therapeutic effect, in association with the necessary pharmaceutical carriers or excipients. Examples of unit dosage forms include ampoules, syringes, and individually packaged tablets and capsules. Unit dosage forms can be administered in fractions or multiples thereof. A multi-dose dosage form is a plurality of identical unit dosage forms packaged in a single container for administration as a separate unit dosage form. Examples of multi-dose forms include vials, tablet or capsule bottles, or pint or gallon bottles.

Particles of the compounds provided herein according to Formula I and/or Formula II can be administered alone or in combination with one or more other compounds provided herein, one or more other active ingredients. The pharmaceutical compositions provided herein can be formulated into various dosage forms for oral, parenteral and topical administration. The pharmaceutical compositions can also be formulated as a modified release dosage form, including delayed, extended, sustained release, delayed, pulsatile, controlled, accelerated and rapid, targeted, programmed release and gastric retention dosage forms. These dosage forms can be prepared in accordance with conventional methods and techniques known to those skilled in the art (see, Remington: The Science and Practice of Pharmacy, earlier; Modified-Release Drug Delivery Technology, Rathbone et al., eds., Drugs and the Pharmaceutical Science, Marcel Dekker, Inc.: New York, NY, 2002, vol. 126).

The pharmaceutical compositions provided herein can be administered once or multiple times over time. It should be understood that the exact dosage and duration of treatment may vary depending on the age, body weight and condition of the patient being treated, and can be determined empirically using known test protocols or by extrapolation from in vivo or in vitro testing or diagnostic tests. data. In addition, it should be understood that for any particular individual, specific dosage regimens must be adjusted over time in accordance with individual needs and the professional judgment of the person administering or supervising the administration of the formulations.

Oral administration.

The pharmaceutical compositions provided herein can be prepared in solid, semi-solid or liquid dosage forms for oral administration. As used herein, oral administration also includes buccal, lingual and sublingual administration. Suitable oral dosage forms include, but are not limited to, tablets, capsules, pills, lozenges, lozenges, lozenges, starch capsules, pellets, medicinal chewing gum, granules, bulk powders, effervescent or non-effervescent powders or granules, solutions, emulsions, suspensions, solutions, wafers, coated capsules, elixirs and syrups. In addition to the active ingredient(s), pharmaceutical compositions may contain one or more pharmaceutically acceptable carriers or excipients, including, without limitation, binders, fillers, diluents, disintegrants, wetting agents, lubricants, glidants, coloring agents, dye mobility inhibitors, sweeteners and flavoring agents.

Binders or granulating agents impart integrity to the tablet so that the tablet remains intact after compression. Suitable binders or granulating agents include, but are not limited to, starches such as corn starch, potato starch, and pregelatinized starch (eg, STARCH 1500); gelatin; sugars such as sucrose, glucose, dextrose, molasses and lactose; natural and synthetic gums such as gum acacia, alginic acid, alginates, Irish moss extract, panwar gum, ghatti gum, plantain mucilage, carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone (PVP), veegum, larch arabogalactan, powdered tragacanth and guar gum ; celluloses such as ethylcellulose, cellulose acetate, calcium carboxymethylcellulose, sodium carboxymethylcellulose, methylcellulose, hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC); microcrystalline celluloses such as AVICEL-PH-101, AVICEL-PH-103, AVICEL RC-581, AVICEL-PH-105 (FMC Corp., Marcus Hook, PA); and mixtures thereof. Suitable fillers include, but are not limited to, talc, calcium carbonate, microcrystalline cellulose, powdered cellulose, dexrates, kaolin, mannitol, silicic acid, sorbitol, starch, pregelatinized starch, and mixtures thereof. The binder or excipient may comprise from about 50% to about 99% by weight of the pharmaceutical compositions provided herein.

Suitable diluents include, but are not limited to, dicalcium phosphate, calcium sulfate, lactose, sorbitol, sucrose, inositol, cellulose, kaolin, mannitol, sodium chloride, dry starch and powdered sugar. Certain diluents, such as mannitol, lactose, sorbitol, sucrose and inositol, if present in sufficient quantities, may impart properties to some compressed tablets that disintegrate in the mouth when chewed. Such compressed tablets can be used as chewable tablets.

Suitable leavening agents include, but are not limited to, agar; bentonite; celluloses such as methylcellulose and carboxymethylcellulose; wood products; natural sponges; cation exchange resins; alginic acid; gums such as guar gum and wigum HV; citrus pulp; cross-linked celluloses such as croscarmellose; cross-linked polymers such as crospovidone; cross-linked starches; calcium carbonate; microcrystalline cellulose such as sodium starch glycolate; polacriline potassium; starches such as corn starch, potato starch, cassava starch and pregelatinized starch; clay; levelers; and mixtures thereof. The amount of disintegrant in the pharmaceutical compositions provided herein varies depending on the type of formulation and will be understood by those of ordinary skill in the art. Pharmaceutical compositions provided herein may contain from about 0.5% to about 15%, or from about 1% to about 5%, by weight of a disintegrant.

Suitable lubricants include, but are not limited to, calcium stearate; magnesium stearate; mineral oil; clarified mineral oil; glycerin, sorbitol; mannitol; glycols such as glyceryl behenate and polyethylene glycol (PEG); stearic acid; sodium lauryl sulfate; talc; hydrogenated vegetable oil, including peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil and soybean oil; zinc stearate; ethyl oleate; ethyl laurate; agar; starch; lycopodium; silica or silica gels such as AEROSIL® 200 (W.R. Grace Co., Baltimore, MD) and CAB-O-SIL® (Cabot Co. of Boston, MA); and mixtures thereof. The pharmaceutical compositions provided herein may contain from about 0.1% to about 5% by weight of lubricant.

Suitable glidants include colloidal silica, CAB-O-SIL® (Cabot Co. of Boston, MA), and asbestos-free talc. Colorants include any of the approved, certified, water-soluble FD&C dyes and water-insoluble FD&C dyes suspended in alumina hydrate, as well as paint varnishes and mixtures thereof. A paint varnish is a combination obtained by adsorption of a water-soluble dye in an aqueous heavy metal oxide, resulting in an insoluble form of the dye. Flavoring agents include natural flavoring agents extracted from plants such as fruits and synthetic mixtures of compounds that produce a pleasant taste, such as peppermint and methyl salicylate. Sweeteners include sucrose, lactose, mannitol, syrups, glycerin and artificial sweeteners such as saccharin and aspartame. Suitable emulsifiers include gelatin, gum acacia, tragacanth, bentonite and surfactants such as polyoxyethylene sorbitan monooleate (TWEEN® 20), polyoxyethylene sorbitan monooleate 80 (TWEEN® 80) and triethanol aminooleate. Suspending and dispersing agents include sodium carboxymethylcellulose, pectin, tragacanth, veegum, gum acacia, sodium carboxymethylcellulose, hydroxypropylmethylcellulose and polyvinylpyrrolidone. Preservatives include glycerin, methyl and propyl paraben, benzoic acid, sodium benzoate and alcohol. Wetting agents include propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate and polyoxyethylene lauryl ether. Solvents include glycerin, sorbitol, ethyl alcohol and syrup. Examples of water-insoluble liquids used in emulsions include mineral oil and cottonseed oil. Organic acids include citric acid and tartaric acid. Sources of silica include sodium bicarbonate and sodium carbonate.

It should be understood that many carriers and excipients can serve multiple functions, even within the same formulation. The pharmaceutical compositions provided herein may be provided in the form of compressed tablets, crushed tablets, chewable lozenges, instant tablets, multiple compressed tablets or enteric-coated tablets, sugar-coated tablets or film-coated tablets. Enteric-coated tablets are compressed tablets coated with substances that are resistant to stomach acid but dissolve or disintegrate in the intestine, thereby protecting the active ingredients from the acidic environment of the stomach. Enteric coatings include, but are not limited to, fatty acids, fats, phenyl salicylate, waxes, shellac, ammonia-rich shellac, and cellulose acetate phthalates. Sugar-coated tablets are compressed tablets surrounded by a sugar coating, which can be effective in masking unpleasant tastes or odors and in protecting the tablets from oxidation. Film-coated tablets are compressed tablets that are coated with a thin layer or film of water-soluble material. Film coatings include, but are not limited to, hydroxyethylcellulose, sodium carboxymethylcellulose, polyethylene glycol 4000, and cellulose acetate phthalate. The film coating imparts the same general characteristics as the sugar coating. Multiple compressed tablets are compressed tablets produced by more than one compression cycle, including multilayer tablets and press-coated or dry-coated tablets.

Tablet dosage forms can be prepared from the active ingredient in powder, crystalline or granular forms, alone or in combination with one or more carriers or excipients described herein, including binders, disintegrants, controlled release polymers, lubricants, thinners and/or coloring agents. Flavorings and sweeteners are particularly useful in the formation of chewable tablets and lozenges.

The pharmaceutical compositions provided herein can be prepared in the form of soft or hard capsules, which can be prepared from gelatin, methylcellulose, starch or calcium alginate. A hard gelatin capsule, also known as a dry fill capsule (DFC), consists of two sections, with one sliding over the other, thereby completely surrounding the active ingredient. A soft elastic capsule (SEC) is a soft spherical shell, such as a gelatin shell, which is plasticized by adding glycerin, sorbitol or a similar polyhydric alcohol. Soft gelatin shells may contain a preservative to prevent the growth of microorganisms. Suitable preservatives are those described herein, including methyl and propyl parabens and sorbic acid. The liquid, semi-solid and solid dosage forms provided herein may be encapsulated in a capsule. Suitable liquid and semi-solid dosage forms include solutions and suspensions in propylene carbonate, vegetable oils or triglycerides. Capsules containing

- 29 043769 such solutions can be prepared as described in US Pat. Nos. 4,328,245, 4,409,239 and 4,410,545. Capsules can also be coated, as is known to those skilled in the art, to modify or maintain dissolution of the active ingredient.

The pharmaceutical compositions provided herein can be prepared in liquid and semi-solid dosage forms, including emulsions, solutions, suspensions, elixirs and syrups. An emulsion is a two-phase system in which one liquid is completely dispersed in the form of small globules in another liquid, which may be oil-in-water or water-in-oil. Emulsions may include pharmaceutically acceptable non-aqueous liquids or a solvent, an emulsifier and a preservative. Suspensions may include a pharmaceutically acceptable suspending agent and a preservative. Aqueous alcohol solutions may include a pharmaceutically acceptable acetal, such as a lower alkyl aldehyde di(lower alkyl)acetal (the term lower means alkyl having 1-6 carbon atoms), such as acetaldehyde diethyl acetal; and a water-miscible solvent characterized by one or more hydroxyl groups, such as propylene glycol and ethanol. Elixirs are clear, sweetened and aqueous-alcoholic solutions. Syrups are concentrated aqueous solutions of sugar, such as sucrose, and may also contain a preservative. For a liquid dosage form, for example, a solution in polyethylene glycol can be diluted with a sufficient amount of a pharmaceutically acceptable liquid carrier, for example water, suitably measured for administration.

Other useful liquid and semi-solid dosage forms include, but are not limited to, those containing the active ingredient(s) provided herein and dialkylated mono- or polyalkylene glycol, including 1,2-dimethoxymethane, diglyme, triglyme , tetraglyme, polyethylene glycol dimethyl ether-350, polyethylene glycol dimethyl ether-550, polyethylene glycol dimethyl ether-750, where the numbers 350, 550 and 750 refer to the approximate average molecular weight of polyethylene glycol. These formulations may further contain one or more antioxidants, such as butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), propyl gallate, vitamin E, hydroquinone, hydroxycoumarins, ethanolamine, lecithin, cephalin, ascorbic acid, malic acid, sorbitol, phosphoric acid, bisulfite, sodium metabisulfite, thiodipropionic acid and its esters, and dithiocarbamates.

The pharmaceutical compositions provided herein for oral administration can also be obtained in the forms of liposomes, micelles, microspheres or nanosystems. Micellar dosage forms can be prepared as described in US Pat. No. 6,350,458.

The pharmaceutical compositions provided herein can be obtained in the form of non-effervescent or effervescent granules and powders, which can be dissolved to obtain a liquid dosage form. Pharmaceutically acceptable carriers and excipients used in non-effervescent granules or powders may include diluents, sweeteners and wetting agents. Pharmaceutically acceptable carriers and excipients used in the effervescent granules or powders may include organic acids and a source of carbon dioxide.

Coloring and flavoring agents can be used in all of the above dosage forms. The pharmaceutical compositions provided herein can be formulated in immediate or modified release dosage forms, including delayed, sustained, pulsatile, controlled, targeted and programmed release forms.

The pharmaceutical compositions provided herein can be formulated with other active ingredients that do not impair the desired therapeutic effect, or with substances that complement the desired effect, such as antacids, proton pump inhibitors and H ₂ receptor antagonists.

The pharmaceutical compositions provided herein can be administered parenterally by injection, infusion or implantation for local or systemic administration. Parenteral administration as used herein includes intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular, intrasynovial, and subcutaneous.

Parenteral administration.

The pharmaceutical compositions provided herein can be formulated into any dosage forms that are suitable for parenteral administration, including solutions, suspensions, emulsions, micelles, liposomes, microspheres, nanosystems, and solid forms suitable for preparing solutions or suspensions in liquid before injection. Such dosage forms can be prepared according to conventional methods known to those skilled in the art of pharmacy (see Remington: The Science and Practice of Pharmacy, earlier).

Pharmaceutical compositions for parenteral administration may include one or more pharmaceutically acceptable carriers and excipients, including, but not limited to, aqueous carrier vehicles, water-miscible carrier vehicles, non-aqueous carrier vehicles

- 30 043769 media, antimicrobial agents or preservatives against the growth of microorganisms, stabilizers, solubility enhancers, isotonic agents, buffer agents, antioxidants, local anesthetics, suspending and dispersing agents, wetting or emulsifying agents, complexing agents, sequestering or chelating agents, cryoprotectants, lyoprotectants, adjusting thickeners, pH agents and inert gases.

Suitable aqueous carrier media include, but are not limited to, water, aqueous sodium chloride, saline or sodium phosphate buffered saline (PBS), sodium chloride injection, Ringer's injection, isotonic dextrose injection, sterile water for injection, injection dextrose and lactated Ringer's solution. Non-aqueous carrier vehicles include, but are not limited to, vegetable fatty oils, 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 triglycerides medium chain coconut oil, and palm seed oil. Water miscible carrier media include, but are not limited to, ethanol, 1,3-butanediol, liquid polyethylene glycol (eg, polyethylene glycol 300 and polyethylene glycol 400), propylene glycol, glycerin, K-methyl-2-pyrrolidone, dimethyl acetamide, and dimethyl sulfoxide.

Suitable antimicrobial agents or preservatives include, but are not limited to, phenols, cresols, mercuric compounds, benzyl alcohol, chlorobutanol, methyl and propyl p-hydroxybenzenes, thimerosal, benzalkonium chloride, benzethonium chloride, methyl and propyl parabens, and sorbic acid. Suitable isotonic agents include, but are not limited to, sodium chloride, glycerin, and dextrose. Suitable buffering agents include, but are not limited to, phosphate and citrate. Suitable antioxidants are those described herein, including sodium bisulfite and sodium metabisulfite. Suitable local anesthetics include, but are not limited to, procaine hydrochloride. Suitable suspending and dispersing agents are those described herein, including sodium carboxymethylcellulose, hydroxypropylmethylcellulose and polyvinylpyrrolidone. Suitable emulsifying agents include those described herein, including polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monooleate 80 and triethanol aminooleate. Suitable sequestering or chelating agents include, but are not limited to, EDTA. Suitable pH adjusting agents include, but are not limited to, sodium hydroxide, hydrochloric acid, citric acid and lactic acid. Suitable complexing agents include, but are not limited to, cyclodextrins, including alpha-cyclodextrin, beta-cyclodextrin, hydroxypropyl-beta-cyclodextrin, sulfobutyl ether-betacyclodextrin, and sulfobutyl ether-7-beta-cyclodextrin (CAPTISOL®, CyDex, Lenexa, KS).

The pharmaceutical compositions provided herein can be formulated for single or multiple dosage administration. Single-dose formulations are packaged in an ampoule, vial or syringe. Parenteral multiple-dose formulations must contain the antimicrobial agent at bacteriostatic or fungistatic concentrations. All parenteral formulations must be sterile as is known and practiced in the art.

In one embodiment, the pharmaceutical compositions are provided in the form of ready-to-use sterile solutions. In another embodiment, the pharmaceutical compositions are provided as sterile dry soluble products, including lyophilized powders and subcutaneous tablets, to be reconstituted with a vehicle prior to use. According to yet another embodiment, the pharmaceutical compositions are provided in the form of ready-to-use sterile suspensions. In another embodiment, the pharmaceutical compositions are provided as sterile, dry, insoluble products to be reconstituted with a vehicle prior to use. According to yet another embodiment, the pharmaceutical compositions are provided in the form of ready-to-use sterile emulsions.

The pharmaceutical compositions provided herein can be formulated in immediate or modified release dosage forms, including delayed, sustained, pulsatile, controlled, targeted and programmed release forms.

Pharmaceutical compositions can be formulated as a suspension, solid, semi-solid or thixotropic liquid for administration as an implantable depot. In one embodiment, the pharmaceutical compositions provided herein are dispersed in a solid internal matrix surrounded by an outer polymeric membrane that is insoluble in body fluids but allows the active ingredient in the pharmaceutical compositions to diffuse through it.

Suitable internal matrices include polymethyl methacrylate, polybutyl methacrylate, plasticized or unplasticized polyvinyl chloride, plasticized nylon, plasticized polyethylene terephthalate, natural rubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene, ethylene-vinyl acetate copolymers, silicone rubber. uchuks, polydimethylsiloxanes, copolymers of silicone and carbonate , hydrophilic polymers such as acrylic acid methacrylic acid ester hydrogels, collagen, cross-linked polyvinyl alcohol and cross-linked, partially hydrolyzed polyvinyl acetate.

Suitable outer polymer membranes include polyethylene, polypropylene, ethylene-propylene copolymers, ethylene-ethyl acrylate copolymers, ethylene-vinyl acetate copolymers, silicone rubbers, polydimethylsiloxanes, neoprene rubber, chlorinated polyethylene, polyvinyl chloride; copolymers of vinyl chloride with vinyl acetate, vinylidene chloride, ethylene and propylene; ionomer polyethylene terephthalate, butyl rubber, epichlorohydrin rubbers, ethylene-vinyl alcohol copolymer, ethylene-vinyl acetate-vinyl alcohol terpolymer, and ethylene-vinyloxyethanol copolymer.

Local administration.

Pharmaceutical compositions provided herein can be administered topically to the skin, orifices, or mucosa. Topical administration as used herein includes (intra)dermal, conjunctival, intracorneal, intraocular, ophthalmic, auricular, transdermal, nasal, vaginal, urethral, respiratory, and rectal.

The pharmaceutical compositions provided herein may be formulated into any dosage form that is suitable for topical administration to achieve local or systemic effect, including emulsions, solutions, suspensions, creams, gels, hydrogels, ointments, powders, dressings, elixirs, lotions, suspensions , tinctures, pastes, foams, films, aerosols, rinses, sprays, suppositories, bandages, skin patches. The topical formulation of the pharmaceutical compositions provided herein may also contain liposomes, micelles, microspheres, nanosystems, and mixtures thereof.

Pharmaceutically acceptable carriers and excipients suitable for use in the topical formulations provided herein include, but are not limited to, aqueous carrier vehicles, water miscible carrier vehicles, non-aqueous carrier vehicles, antimicrobial agents or preservatives against the growth of microorganisms, stabilizers, solubility enhancers , isotonic agents, buffering agents, antioxidants, local anesthetics, suspending and dispersing agents, wetting or emulsifying agents, complexing agents, sequestering or chelating agents, penetration enhancers, cryoprotectants, lyoprotectants, thickeners and inert gases.

Pharmaceutical compositions can also be administered topically by electroporation, iontophoresis, phonophoresis, sonophoresis, and microneedle or needleless injections such as POWDERJECT™ (Chiron Corp., Emeryville, CA) and BIOJECT™ (Bioject Medical Technologies Inc., Tualatin, CA) OR).

The pharmaceutical compositions provided herein can be obtained in the forms of ointments, creams and gels. Suitable carrier media for ointments include oily or hydrocarbon bases, including such as tallow, benzoinylated tallow, olive oil, cottonseed oil and other oils, white petrolatum; emulsifiable or absorbable bases such as hydrophilic petrolatum, hydroxystearine sulfate and anhydrous lanolin; water-removable bases such as hydrophilic ointment; water-soluble ointment bases, including polyethylene glycols of various molecular weights; emulsion bases, or water-in-oil (W/O) or oil-in-water (O/W) emulsions, including cetyl alcohol, glyceryl monostearate, lanolin, and stearic acid (see, Remington: The Science and Practice of Pharmacy, above). These carrier media provide a softener, but typically require the addition of antioxidants and preservatives.

A suitable cream base may be an oil-in-water or water-in-oil type. The cream carrier media can be water washable and contain an oil phase, an emulsifier and an aqueous phase. The oil phase is also called the internal phase, which typically consists of petrolatum and a fatty alcohol such as cetyl alcohol or stearyl alcohol. The aqueous phase is typically, although not necessarily, larger in volume than the oil phase and typically contains a humectant. The emulsifier in the cream can be a nonionic, anionic, cationic or amphoteric surfactant.

Gels are semi-solid suspension-type systems.

Single-phase gels contain organic macromolecules distributed substantially uniformly in a liquid carrier. Suitable gelling agents include cross-linked acrylic acid polymers such as carbomers, carboxypolyalkylenes, Carbopol®; hydrophilic polymers such as polyethylene oxides, polyoxyethylene-polyoxypropylene copolymers and polyvinyl alcohol; cellulose polymers such as hydroxypropylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose phthalate and methylcellulose; gums such as tra- 32 043769 gum and xanthan gum; sodium alginate; and gelatin. In order to obtain a homogeneous gel, dispersing agents such as alcohol or glycerin can be added, or the gelling agent can be dispersed by trituration, mechanical mixing and/or stirring.

The pharmaceutical compositions provided herein may be administered rectally, urethrally, vaginally or perivaginally, in the forms of suppositories, pessaries, probes, poultices or cataplasms, pastes, powders, dressings, creams, patches, contraceptives, ointments, solutions, emulsions, suspensions, tampons, gels, foams, sprays or enemas. These dosage forms can be manufactured using conventional methods, as described in Remington: The Science and Practice of Pharmacy, previously.

Rectal, urethral and vaginal suppositories are solid forms for insertion into the orifices of the body that are solid at normal temperatures but melt or soften at body temperature, releasing the active ingredient(s) into the orifices. Pharmaceutically acceptable carriers used in rectal and vaginal suppositories include carrier vehicles such as stiffening agents that provide a melting point near body temperature when formulated with the pharmaceutical compositions provided herein; and antioxidants as described herein, including sodium bisulfite and sodium metabisulfite. Suitable carrier media include, without limitation, cocoa butter (theobromine oil), glycerol-gelatin, carbowax (polyoxyethylene glycol), spermaceti, paraffin, white and yellow wax, and suitable mixtures of mono-, di- and triglycerides of fatty acids, hydrogels such as polyvinyl alcohol, hydroxyethyl methacrylate, polyacrylic acid; glycerinized gelatin. Combinations of different carrier media can be used. Rectal and vaginal suppositories can be produced by compression or injection molding. The usual weight of a rectal and vaginal suppository is approximately 2-3 g.

The pharmaceutical compositions provided herein can be administered ophthalmically in the forms of solutions, suspensions, ointments, emulsions, gel-forming solutions, powder solutions, gels, ophthalmic inserts and implants.

The pharmaceutical compositions provided herein can be administered intranasally or by inhalation into the respiratory tract. The pharmaceutical compositions can be formulated as an aerosol or solution for delivery using a pressurized container, pump, spray, atomizer, such as an electrohydrodynamic mist atomizer, or nebulizer, alone or in combination with a suitable propellant such as 1 ,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane. The pharmaceutical compositions can also be prepared as a dry powder for insufflation, alone or in combination with an inert carrier such as lactose or phospholipids; and in the form of nasal drops. For intranasal use, the powder may contain a bioadhesive agent including chitosan or cyclodextrin.

Solutions or suspensions for use in a pressurized container, pump, spray, atomizer, or nebulizer may be formulated to contain ethanol, aqueous ethanol, or a suitable alternative agent for dispersing, solubilizing, or sustained release of the active ingredient provided herein, the propellant. solvent; and/or a surfactant such as sorbitol trioleate, oleic acid or oligolactic acid.

The pharmaceutical compositions provided herein can be micronized to a size suitable for delivery by inhalation, such as 50 microns or less or 10 microns or less. Particles of these sizes can be produced using a grinding method known to those skilled in the art, such as spiral jet milling, fluid bed jet milling, supercritical fluid nanoparticle processing, high pressure homogenization, or spray drying.

Capsules, blisters and cartridges for use in an inhaler or insufflator can be formulated to contain a powder mixture of the pharmaceutical compositions provided herein; a suitable powder base such as lactose or starch; and a processing property modifier such as l-leucine, mannitol or magnesium stearate.

Lactose can be anhydrous or in the form of a monohydrate. Other suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose and trehalose. The pharmaceutical compositions provided herein for administration by inhalation or intranasal administration may further contain a suitable flavoring agent such as menthol and levomenthol, or sweeteners such as saccharin or sodium saccharin.

Pharmaceutical compositions provided herein for topical administration can be formulated for immediate release or modified release, including delayed, sustained, pulsatile, controlled, targeted and programmed release.

- 33 043769

Modified release.

The pharmaceutical compositions provided herein can be formulated as a modified release dosage form. As used herein, the term modified release refers to a dosage form in which the rate or site of release of the active ingredient(s) is different from that of an immediate release dosage form when administered by the same route. Modified release dosage forms include delayed, extended, extended release, delayed, pulsatile or pulsed, controlled, accelerated and rapid, targeted, programmed release and gastric retention dosage forms. Pharmaceutical compositions in modified release dosage forms can be prepared using a variety of modified release devices and methods known to those skilled in the art, including, without limitation, matrix controlled release devices, osmotic controlled release devices, multiparticulate controlled release devices, ion exchange resins, enteric coatings, multilayer coatings, microspheres, liposomes and combinations thereof. The release rate of the active ingredient(s) can also be modified by changing particle sizes and polymorphism of the active ingredient(s).

Examples of modified release include, but are not limited to, those described in US Pat. No.: 3,845,770; 3916899; 3536809; 3598123; 4008719; 5674533; 5059595; 5591767; 5120548; 5073543; 5639476; 5354556; 5639480; 5733566; 5739108; 5891474; 5922356; 5972891; 5980945; 5993855; 6045830; 6087324; 6113943; 6197350; 6248363; 6264970; 6267981; 6376461; 6419961; 6589548; 6613358 and 6699500.

Matrix devices for controlled release.

The pharmaceutical compositions provided herein in modified release dosage form can be manufactured using a controlled release matrix device known to those skilled in the art (see, Takada et. al., in Encyclopedia of Controlled Drug Delivery, vol. 2, Mathiowitz ed., Wiley, 1999).

In one embodiment, the pharmaceutical compositions provided herein in a modified release dosage form are formulated using a degradable matrix device that is water-swellable, degradable, or soluble polymers, including synthetic polymers and naturally occurring polymers and derivatives such as polysaccharides and proteins.

Materials useful in forming the erodible matrix include, but are not limited to, chitin, chitosan, dextran and pullulan; agar, gum arabic, karaya gum, locust bean gum, tragacanth, carrageenan, ghatti gum, guar gum, xanthan gum and scleroglucan; starches such as dextrin and maltodextrin; hydrophilic colloids such as pectin; phosphatides such as lecithin; alginates; propylene glycol alginate; gelatin; collagen; and celluloses such as ethylcellulose (EC), methylethylcellulose (MEC), carboxymethylcellulose (CMC), CMEC, hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC), cellulose acetate (CA), cellulose propionate (CP), cellulose butyrate (CB), cellulose acetate butyrate (CAB), CAP, CAT, hydroxypropyl methylcellulose (HPMC), HPMCP, HPMCAS, hydroxypropyl methylcellulose trimellitate acetate (HPMCAT) and ethylhydroxyethylcellulose (EHEC); polyvinylpyrrolidone; polyvinyl alcohol; polyvinyl acetate; glycerol fatty acid esters; polyacrylamide; polyacrylic acid; ethacrylic acid or methacrylic acid copolymers (EUDRAGIT®, Rohm America, Inc., Piscataway, NJ); poly(2-hydroxyethyl methacrylate); polylactides; copolymers of L-glutamic acid and ethyl-glutamate; degradable copolymers of lactic acid and glycolic acid; poly-D-(-)-3-hydroxybutyric acid; and other acrylic acid derivatives such as homopolymers and copolymers of butyl methacrylate, methyl methacrylate, ethyl methacrylate, ethyl acrylate, (2-dimethylaminoethyl) methacrylate and (trimethylaminoethyl) methacrylate chloride.

In another embodiment, pharmaceutical compositions are formulated using a non-degradable matrix device. The active ingredient(s) are dissolved or dispersed in an inert matrix and are initially released by diffusion through the inert matrix administered once. Materials suitable for use as an indestructible matrix device include, but are not limited to, insoluble plastics such as polyethylene, polypropylene, polyisoprene, polyisobutylene, polybutadiene, polymethyl methacrylate, polybutyl methacrylate, chlorinated polyethylene, polyvinyl chloride, methyl acrylate-methyl methacrylate copolymers, ethylene-vinyl acetate copolymers , ethylene-propylene copolymers, ethylene-ethyl acrylate copolymers, vinyl chloride-vinyl acetate copolymers, vinylidene chloride, ethylene-propylene, ionomer polyethylene terephthalate, butyl rubber, epichlorohydrin rubbers, ethylene-vinyl alcohol copolymer, ethylene-vinyl acetate-vinyl alcohol terpolymer, and copolymer of ethylene and vinyloxyethanol, polyvinyl chloride, plasticized nylon, plasticized polyethylene terephthalate, natural rubber, silicone rubbers, polydimethylsiloxanes, silicone carbonate copolymers; And

- 34 043769 hydrophilic polymers such as ethylcellulose, cellulose acetate, crospovidone and cross-linked, partially hydrolyzed polyvinyl acetate; and fatty compounds such as carnauba wax, microcrystalline wax and triglycerides.

In a controlled release matrix system, the desired release kinetics can be controlled, for example, by the type of polymer used, the viscosity of the polymer, the particle size of the polymer and/or active ingredient(s), the ratio of active ingredient(s) to polymer, and other excipients in the compositions.

The pharmaceutical compositions provided herein in modified release dosage form can be prepared by methods known to those skilled in the art, including direct compression, dry or wet granulation followed by compression, and melt granulation followed by compression.

Osmotic devices for controlled release.

The pharmaceutical compositions provided herein in a modified release dosage form can be prepared using an osmotic controlled release device, including a single chamber system, a dual chamber system, asymmetric membrane technology (AMT), and an extrusion core system (ECS). Typically, such devices contain at least two components:

(a) a core that contains the active ingredient(s); and (b) a semi-permeable membrane with at least one inlet that encapsulates the core.

The semi-permeable membrane controls the flow of water to the core from the aqueous medium used so that the drug is released by extrusion through the inlet(s).

In addition to the active ingredient(s), the core of the osmotic device optionally includes an osmotic agent that provides a driving force to transport water from the medium used to the core of the device. One class of osmotic agents are water-swellable hydrophilic polymers, also called osmopolymers and hydrogels, including but not limited to hydrophilic vinyl and acrylic polymers, polysaccharides such as calcium alginate, polyethylene oxide (PEO), polyethylene glycol (PEG), polypropylene glycol (PPG), poly(2-hydroxyethyl methacrylate), poly(acrylic) acid, poly(methacrylic) acid, polyvinylpyrrolidone (PVP), cross-linked PVP, polyvinyl alcohol (PVA), PVA/PVP copolymers, PVA/PVP copolymers with hydrophobic monomers such as methyl methacrylate and vinyl acetate, hydrophilic polyurethanes containing large blocks of PEO, croscarmellose sodium, carrageenan, hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC), carboxymethylcellulose (CMC) and carboxyethylcellulose (CEC), sodium alginate, polycarbophil, gelatin, xanthan gum and sodium starch glycolate.

Another class of osmotic agents are osmogens, which are capable of drawing water under the influence of an osmotic pressure gradient across the barrier of the surrounding coating. Suitable osmogens include, but are not limited to, inorganic salts such as magnesium sulfate, magnesium chloride, calcium chloride, sodium chloride, lithium chloride, potassium sulfate, potassium phosphates, sodium carbonate, sodium sulfite, lithium sulfate, potassium chloride and sodium sulfate; sugars such as dextrose, fructose, glucose, inositol, lactose, maltose, mannitol, raffinose, sorbitol, sucrose, trehalose and xylitol; organic acids such as ascorbic acid, benzoic acid, fumaric acid, citric acid, maleic acid, sebacic acid, sorbic acid, adipic acid, edetic acid, glutamic acid, p-toluenesulfonic acid, succinic acid and tartaric acid; urea; and mixtures thereof.

Osmotic agents with different dissolution rates can be used to influence the rate of initial delivery of the active ingredient(s) from the dosage form. For example, amorphous sugars such as Mannogeme EZ (SPI Pharma, Lewes, DE) can be used to provide accelerated delivery within the first couple of hours, immediately producing the desired therapeutic effect, and to gradually and continuously release the remaining amount to maintain the desired level therapeutic or prophylactic effect over a long period of time. In such a case, the active ingredient(s) are released at such a rate as to replace the amount of active ingredient metabolized and excreted.

The core may also include a wide variety of other excipients and carriers, as described herein, to enhance the activity of the dosage form or to aid stability or processing.

Materials useful in forming a semipermeable membrane include various classes of acrylic, vinyl, ether, polyamide, polyester, and cellulose derivatives that are water-permeable and insoluble in water at physiologically relevant pH values or that are capable of becoming water-insoluble by chemical change , such as the formation of cross-links. Examples of suitable polymers applicable

- 35 043769 in shell formation, include plasticized, unplasticized and reinforced cellulose acetate (CA), cellulose diacetate, cellulose triacetate, CA propionate, cellulose nitrate, cellulose butyrate acetate (CAB), ethyl carbamate CA, CAP, methyl carbamate CA, succinate CA, trimellitate cellulose acetate (CAT), dimethylaminoacetate CA, ethyl carbonate CA, chloroacetate CA, ethyl oxalate CA, methyl sulfonate CA, butyl sulfonate CA, p-toluene sulfonate CA, agaracetate, amylose triacetate, beta-glucan acetate, beta-glucan triacetate, acetaldehyde dimethyl acetate, triacetate carob gum, hydroxylated ethylene vinyl acetate, EC, PEG, PPG, PEG/PPG copolymers, PVP, HEC, HPC, CMC, CMEC, HPMC, HPMCAS, HPMCAS, HPMCAT, poly(acrylic) acids and their esters, and poly(methacrylic) acids and their esters and copolymers, starch, dextran, dextrin, chitosan, collagen, gelatin, polyalkenes, polyethers, polysulfones, polyethersulfones, polystyrenes, polyvinyl halides, polyvinyl esters and ethers, natural waxes and synthetic waxes.

The semi-permeable membrane may also be a hydrophobic microporous membrane in which the pores are substantially filled with gas and are not wetted by an aqueous medium, but are permeable to water vapor, as disclosed in US Pat. No. 5,798,119. Such hydrophobic but water vapor-permeable membranes are typically , consist of hydrophobic polymers such as polyalkenes, polyethylene, polypropylene, polytetrafluoroethylene, polyacrylic acid derivatives, polyethers, polysulfones, polyethersulfones, polystyrenes, polyvinyl halides, polyvinylidene fluoride, polyvinyl esters and ethers, natural waxes and synthetic waxes.

The entry hole(s) in the semipermeable membrane can be created after coating by mechanical or laser drilling. The inlet(s) can also be formed in situ by eroding a plug of water-soluble material or by rupturing a thinner portion of the membrane by pressing into the core. In addition, inlets can be created during the coating process, as in the case of asymmetric membrane shells of the type described in US Pat. Nos. 5,612,059 and 5,698,220.

The total amount of active ingredient(s) released and the rate of release can be substantially modulated by the thickness and porosity of the semi-permeable membrane, the composition of the core and the number, size and position of the inlets.

Pharmaceutical compositions in osmotically controlled release dosage form may further contain additional conventional excipients as described herein to aid the activity or processing of the formulation.

Osmotically controlled release dosage forms can be prepared according to conventional methods and techniques known to those skilled in the art (see Remington: The Science and Practice of Pharmacy, earlier; Santus and Baker, J. Controlled Release, 1995, 35, 1 -21; Verma et. al., Drug Development and Industrial Pharmacy, 2000, 26, 695-708; Verma et. al., J. Controlled Release, 2002, 79, 7-27).

In certain embodiments, the pharmaceutical compositions provided herein are formulated in a controlled-release AMT dosage form that contains an asymmetric osmotic membrane that covers a core containing the active ingredient(s) and other pharmaceutically acceptable excipients. See US Pat. No. 5,612,059 and International Patent Publication WO 2002/17918. Controlled-release AMT dosage forms can be prepared according to conventional methods and technologies known to those skilled in the art, including direct compression, dry granulation, wet granulation, and dip coating.

In a certain embodiment, the pharmaceutical compositions provided herein are formulated in a controlled release ESC dosage form that contains an osmotic membrane that covers a core containing the active ingredient(s), hydroxyethyl cellulose and other pharmaceutically acceptable excipients.

Multiparticle devices for controlled release.

The pharmaceutical compositions provided herein in a modified release dosage form can be prepared using a multiparticle controlled release device that contains a plurality of particles, granules or beads with a diameter ranging from about 10 μm to about 3 mm to about 50 μm to about 2.5 mm or from about 100 µm to 1 mm. Such a plurality of particles can be produced by methods known to those skilled in the art, including wet and dry granulation, extrusion/spheronization, roll compression, melt congealing, and spray coating of seed cores. See, for example, Multiparticulate Oral Drug Delivery, Marcel Dekker, 1994; and Pharmaceutical Pelletization Technology, Marcel Dekker, 1989.

Other excipients described herein can be mixed with pharmaceutical compositions to assist in processing and formation of multiple particles. Received

- 36 043769 the particles themselves can form a multiparticle device, or they can be coated with various film-forming materials, such as enteric polymers, water-swellable polymers and water-soluble polymers. The plurality of particles can be further processed to form a capsule or tablet.

Directed delivery.

Pharmaceutical compositions provided herein may also be formulated to target a specific tissue, receptor, or other site of the body of the subject being treated, including delivery systems based on liposomes, red blood cell release, and antibodies. Examples include, without limitation, US Pat. No. 6,316,652; 6274552; 6271359; 6253872; 6139865; 6131570; 6120751; 6071495; 6060082; 6048736; 6039975; 6004534; 5985307; 5972366; 5900252; 5840674; 5759542 and 5709874.

Mode of application.

In one embodiment, provided herein is a method of treating, preventing, or ameliorating one or more symptoms associated with human vesicular monoamine transporter isoform 2 (VMAT2) inhibition, comprising administering to a subject a therapeutically effective amount of di(4-methylbenzenesulfonate) (S)-( 2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-yl2-amino-3 -methylbutanoate (formula I) in amorphous form or crystalline form I, II, III, IV, V or VI, or an isotopic variant thereof, or a solvate thereof.

In another embodiment, provided herein is a method of treating, preventing, or ameliorating one or more symptoms of hyperkinetic disorders comprising administering to a subject a therapeutically effective amount of di(4-methylbenzenesulfonate) (S)-(2R,3R,11bR)-3-isobutyl- 9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1Hpyrido[2,1-a]isoquinolin-2-yl-2-amino-3-methylbutanoate (formula I) in amorphous or crystalline form form I, II, III, IV, V or VI, or an isotopic variant thereof, or a solvate thereof.

In one embodiment, provided herein is a method of treating, preventing, or ameliorating one or more symptoms associated with inhibition of human vesicular monoamine transporter isoform 2 (VMAT2) comprising administering to a subject a therapeutically effective amount of (S)-(2R,3R,11bR) dihydrochloride )-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-yl2-amino-3-methylbutanoate (formula II ) in amorphous form or crystalline form I or II, or an isotopic variant thereof, or a solvate thereof.

In another embodiment, provided herein is a method of treating, preventing, or reducing one or more symptoms of hyperkinetic disorders comprising administering to a subject a therapeutically effective amount of (S)-(2R,3R,11bR)-3-isobutyl-9,10-dimethoxy dihydrochloride -2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2yl-2-amino-3-methylbutanoate (formula II) in amorphous form or crystalline form I or II, or an isotopic variant thereof, or a solvate thereof.

In one embodiment, conditions that can be treated with the compounds described herein include, but are not limited to, hyperkinetic disorders such as Huntington's disease, tardive dyskinesia, Tourette's syndrome, dystonia, hemiballismus, chorea, senile chorea, or tics. In some embodiments, conditions that can be treated with the compounds described herein include, but are not limited to, tardive dyskinesia in subjects with schizophrenia, schizoaffective disorder, or mood disorder. In one embodiment, conditions that can be treated with the compounds described herein include, but are not limited to, neurological disorders or diseases such as bipolar disorder, major depressive disorder, anxiety disorder, attention deficit hyperactivity disorder, dementia, depression, insomnia, psychosis, post-traumatic stress disorder, substance abuse, levodopa-induced dyskinesia in Parkinson's disease, movement disorders or oppositional defiant disorder.

Movement disorders include, but are not limited to, the following: ataxia, corticobasal degeneration, dyskinesia (paroxysmal), dystonia (general, segmental, focal), including blepharospasm, spasmodic torticollis (cervical dystonia), graphospasm (upper limb dystonia), laryngeal muscle dystonia (spastic dysphonia) and oromandibular dystonia, essential tremor, hereditary paraplegia, Huntington's disease, multiple system atrophy (Shy-Drager syndrome), myoclonus, Parkinson's disease, progressive supranuclear palsy, restless legs syndrome, Rett syndrome, spasticity due to stroke, cerebral palsy, multiple sclerosis, spinal cord or brain injury, Sydenham's chorea, tardive dyskinesia/dystonia, tics, Tourette's syndrome and Wilson's disease.

Depending on the disease being treated and the condition of the subject, the compositions provided herein can be administered by oral, parenteral (e.g.,

- 37 043769 intramuscular, intraperitoneal, intravenous, ICV, intracisternal injection or infusion, subcutaneous injection or implant), inhalation, nasal, vaginal, rectal, sublingual or local (for example, transdermal or local) routes of administration and these can be formulated, separately or together , into a suitable dosage unit with pharmaceutically acceptable carriers, adjuvants and carrier media suitable for each route of administration. In addition, provision is made for the introduction of the particles provided herein in a depot formulation, which releases the active ingredient over a predetermined period of time.

When treating, preventing, or reducing the intensity of one or more symptoms of hyperkinetic disorder or other conditions, disorders, or diseases associated with VMAT2 inhibition, the appropriate dosage level is generally approximately 0.001 to 100 mg per kg of patient body weight per day (mg/kg per day), from about 0.01 to about 80 mg/kg per day, from about 0.1 to about 50 mg/kg per day, from about 0.5 to about 25 mg/kg per day, or about 1 to approximately 20 mg/kg per day, which can be administered in single or multiple doses. Within this range, dosages may be 0.005-0.05, 0.05-0.5, or 0.5-5.0, 1-15, 1-20, or 1-50 mg/kg per day. In certain embodiments, the dosage level is from about 0.001 to 100 mg/kg per day. In certain embodiments, the dosage level is from about 0.01 mg/kg to about 40 mg/kg per day. In certain embodiments, the dosage level is from about 0.1 mg/kg to about 80 mg/kg per day. In certain embodiments, the dosage level is from about 0.1 mg/kg to about 50 mg/kg per day. In certain embodiments, the dosage level is from about 0.1 mg/kg to about 40 mg/kg per day. In certain embodiments, the dosage level is from about 0.5 mg/kg to about 80 mg/kg per day. In certain embodiments, the dosage level is from about 0.5 mg/kg to about 40 mg/kg per day. In certain embodiments, the dosage level is from about 0.5 mg/kg to about 25 mg/kg per day. In certain embodiments, the dosage level is from about 1 mg/kg to about 80 mg/kg per day. In certain embodiments, the dosage level is from about 1 mg/kg to about 40 mg/kg per day. In certain embodiments, the dosage level is from about 1 mg/kg to about 25 mg/kg per day.

For oral administration, the pharmaceutical compositions can be prepared in the form of tablets containing 1.0-1000 mg of active ingredient, in particular about 1 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg , approximately 40 mg, approximately 45 mg, approximately 50 mg, approximately 75 mg, approximately 80 mg, approximately 100 mg, approximately 150 mg, approximately 200 mg, approximately 250 mg, approximately 300 mg, approximately 400 mg, approximately 500 mg, approximately 600 mg, approximately 750 mg, approximately 800 mg, approximately 900 mg and approximately 1000 mg of the active ingredient for symptomatic dosage adjustment for the patient being treated. In certain embodiments, the pharmaceutical compositions can be prepared in the form of tablets containing approximately 100 mg of active ingredient. In certain embodiments, the pharmaceutical compositions can be prepared in the form of tablets containing approximately 80 mg of active ingredient. In certain embodiments, the pharmaceutical compositions can be prepared in the form of tablets containing approximately 50 mg of active ingredient. In certain embodiments, the pharmaceutical compositions can be prepared in the form of tablets containing approximately 40 mg of active ingredient. In certain embodiments, the pharmaceutical compositions can be prepared in the form of tablets containing approximately 25 mg of active ingredient. The compositions can be administered in a schedule of 1-4 times per day, including once, twice, three times and four times per day.

However, it should be understood that the specific dose level and dosing frequency for any particular patient may vary and will depend on a variety of factors, including the potency of the particular compound used, the metabolic stability and duration of action of the compound, age, body weight, general health, sex, diet, route and time of administration, rate of excretion, combination of drugs, severity of the specific condition and host being treated.

In addition, provided herein are methods of modulating VMAT2 activity by contacting the transporter with compounds in one or more solid forms as provided herein. In one embodiment, the transporter is expressed by the cell.

The compounds provided herein may also be combined or used in combination with other agents useful in the treatment, prevention or amelioration of one or more symptoms of the diseases or conditions for which they are provided.

- 38 043769 The compounds herein are applicable including Huntington's disease, tardive dyskinesia, Tourette's syndrome or the tics mentioned above. In one embodiment, the compounds provided herein may also be combined or used in combination with other agents useful in the treatment, prevention, or amelioration of one or more symptoms of diseases or conditions associated with schizophrenia, schizoaffective disorder, bipolar disorder, major depressive disorder, and other conditions that are usually treated with antipsychotic medications.

Such other agents, or drugs, can be administered by such route and in the amount as they are typically used, concurrently or sequentially with the compounds provided herein. If the particles provided herein are used concomitantly with one or more other drugs, a pharmaceutical composition containing such other drugs in addition to the compounds provided herein may be used, but is not necessary. Accordingly, pharmaceutical compositions provided herein include those that also contain one or more other active ingredients or therapeutic agents in addition to the compounds provided herein.

The weight ratio of the compounds provided herein to the second active ingredient may vary and will depend on the effective dose of each ingredient. Typically, an effective dose of each ingredient will be used. Thus, for example, if the compounds provided herein are used in combination with a second drug or a pharmaceutical composition containing such another drug, the weight ratio of particles to second drug may range from about 1000:1 to about 1:1000 or from about 200:1 to about 1:200. Combinations of particles and other active ingredients provided herein will generally also be within the above range, but in each case an effective dose of each active ingredient should be used.

Examples

The characteristics of the crystalline compounds according to Formula I and/or Formula II in the following examples were determined using the following: X-ray powder diffractometry (XRPD), differential scanning calorimetry (DSC), thermogravimetry (TGA), gravimetric vapor sorption (GVS), scanning electron microscopy (SEM ) and ion chromatography (IC).

X-ray powder diffraction patterns were collected on a Bruker AXS C2 GADDS diffractometer using Cu Ka radiation (40 kV, 40 mA), a θ-2θ goniometer and V4 divergence and reception slits, a Ge monochromator, and a Lynxeye detector. Samples were analyzed at room temperature as flat samples using powdered material. The samples were carefully packed into a cavity in a polished zero-background silicon wafer (510). The samples were rotated in their plane during analysis. Data were collected from 2 to 42° 2-theta at 0.05° 2-theta per stage and 0.5 seconds per stage.

Differential scanning calorimetry was performed using a Mettler DSC 823E instrument equipped with a 34-position autosampler. Typically, 0.5-3 mg of each sample in an aluminum pinhole pan was heated at a rate of 10°C/min from 25°C up to 250°C. A nitrogen purge was maintained over the sample at a rate of 50 mL/min.

Thermogravimetric analysis was performed on a Mettler TGA/SDTA 851e instrument equipped with a 34-position autosampler. The instrument was temperature calibrated using certified indium. Typically, 5-30 mg of each sample was loaded onto a pre-weighed aluminum crucible and heated at a rate of 10°C/min from ambient temperature to 350°C. A nitrogen purge was maintained over the sample at a rate of 50 mL/min.

Gravimetric sorption isotremes were obtained using a Hiden IGASorp moisture absorption analyzer controlled by CFRSorp software. The sample temperature was maintained at 25°C using a Huber recirculating water bath. Humidity was controlled by mixing flows of dry and wet nitrogen, with a total flow rate of 250 ml/min. Relative humidity (RH) was measured using a calibrated Vaisala RH probe (dynamic range 0-95%RH) placed near the sample. The change in sample mass as a function of %RH was continuously monitored using a microbalance (accuracy ±0.001 mg). Typically, 10-20 mg of sample was placed in a tared stainless steel mesh basket at room temperature. The sample was loaded and unloaded at 40% RH and 25°C (normal room conditions). The moisture sorption isotherm was constructed as indicated below (2 scans, giving 1 full cycle). A standard isotherm was obtained at 25°C at 10% RH intervals over the range 0-90% RH.

Scanning electron microscopy (SEM) photographs were obtained by depositing a thin layer of gold on the desired material (sputter coating) and examining it using an FEI-Philips XL30 scanning electron microscope. The electron accelerating voltage used for analysis was 2.0 kV. All images were acquired using a computer-controlled CCD photographic head.

Ion chromatography (IC) was performed on a Metrohm 861 Advanced Compact IC using IC Net v2.3 software. Accurately weighed samples were prepared as stock solutions in the appropriate dissolution solution and diluted appropriately before testing. Quantification was carried out by comparison with standard solutions of known concentration of the ion to be analyzed.

The water content of each sample was determined by Karl Fischer titration measured on a Mettler Toledo DL39 coulometer using Hydranal Coulomat AG reagent and argon purge. Weighed solid samples were introduced into the vessel on a platinum TGA cup, which was attached to a septum to prevent water ingress. Approximately 10 mg of sample was used per titration and determinations were performed in duplicate.

Thermodynamic solubility in water was determined by suspending a sufficient amount of the compound in water to obtain a maximum final concentration that was >10 mg/ml of the original free form of the compound. The suspension was equilibrated at 25°C for 24 hours and then the pH was measured. The suspension was then filtered through a Class C glass fiber filter. The filtrate was then diluted by an appropriate amount, for example 101 times. Quantitative measurement was performed by HPLC against a standard solution of approximately 0.25 mg/ml in DMSO. Various volumes of standard, diluted, and undiluted sample solutions were injected. Solubility was calculated using peak regions determined by integrating the peak found with the same retention time as the main peak when the standard was injected.

Example 1. Determination of the solubility of di(4-methylbenzenesulfonate) (S)-(2R,3R,11bR)-3-isobutyl9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2 ,1-a]isoquinolin-2-yl-2-amino-3-methylbutanoate.

Solubility studies of di(4-methylbenzenesulfonate) (S)-(2R,3R,11bR)-3-isobutyl-9,10dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1- a]isoquinolin-2-yl-2-amino-3-methylbutanoate (formula I) in the solvents listed in table. 1 was carried out on Form I, both at 5°C and at 10°C above the reflux temperature of each solvent. Form I was suspended for at least 2 hours before filtration. Solubility was calculated using gravimetric analysis after evaporation of the collected mother liquors.

Example 2. Preparation of di(4-methylbenzenesulfonate) (S)-(2R,3R,11bR)-3-isobutyl-9,10-dimethoxy2,3,4,6,7,11b-hexahydro-1H-pyrido[2, 1-a]isoquinolin-2-yl-2-amino-3-methylbutanoate, form I.

537 mg free base (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2Hpyrido[2,1-a]isoquinolin-2-yl ester (S)-2-Amino-3-methylbutyric acid was weighed into a glass vial and dissolved in 5 ml MIBK. Then 2.56 ml (2.0 eq.) of a 1 M solution of p-toluenesulfonic acid in ethanol was added to obtain a clear solution. This solution was seeded with approximately 2 mg of the bis-tosylate salt isolated from the screen, inducing immediate crystallization. The resulting suspension was incubated for 16 hours with temperature cycling between ambient temperature and 50°C at 4 hour intervals. After this period of time, the solid present was isolated by filtration and dried under vacuum for 3 hours to obtain 675 mg (69%) of a fine white solid.

The X-ray powder diffraction pattern of Form I is illustrated in FIG. 1. Form I exhibits characteristic 2-theta XRP diffraction peaks at approximately 6.3, 17.9 and 19.7°, indicating that the compound is crystalline. As shown in FIG. 4, the particles are characterized by a geometrically regular shape and lamellar morphology.

The differential scanning calorimetric thermogram of Form I is illustrated in FIG. 2. Form I exhibits an endothermic event with an onset temperature of approximately 240°C and a peak temperature of 243°C.

The thermogravimetric analysis thermogram of Form I is shown in FIG. 2. Form I is very stable and shows less than about 0.4% weight loss when heated from about 25°C to about 140°C.

A plot of the form I gravimetric vapor sorption system is shown in FIG. 3. Form I exhibits a weight increase of less than about 1% when subjected to an increase in relative humidity from about 0% to about 95% relative humidity.

Example 3. Recrystallization studies of di(4-methylbenzenesulfonate) (S)-(2R,3R,11bR)-3isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[ 2,1-a]isoquinolin-2-yl-2-amino-3 methylbutanoate, form I.

To 24.10 g of Form I was added 24 ml of acetonitrile/3% water (v/v). The suspension was heated to 76°C, a clear solution was observed, which was then cooled at a rate of 0.2°C/min to 5°C without seeding. The solid was filtered and dried in a vacuum oven for 2.5 days at 50°C to yield 72% Form I with characteristic XRPD according to FIG. 1.

- 40 043769

In another experiment, 8 ml of 1-propanol (5.3 vol.) was added to 1.50 g of Form I. The suspension was heated at 88°C, a clear solution was observed, which was then cooled at a rate of 0.5°C/min to

5°C without seeding. The solid was filtered and dried in a vacuum oven for 2.5 days at 50°C to yield 88% Form I with characteristic XRPD according to FIG. 1.

Typically, Form I can be successfully recrystallized using 10 volumes of acetonitrile/3% water (v/v) or 1-propanol. The amount of water is critical when using a mixture of acetonitrile: 3% water to obtain good solubility of the material, but 4% water may result in Form IV.

Example 4. Solubility of di(4-methylbenzenesulfonate) (S)-(2R,3R,11bR)-3-isobutyl-9,10dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2, 1-a]isoquinolin-2-yl-2-amino-3-methylbutanoate, form I, in aqueous solutions and organic solvents.

100 mg di(4-methylbenzenesulfonate) (S)-(2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11bhexahydro-1H-pyrido[2,1- a]isoquinolin-2-yl-2-amino-3-methylbutanoate, Form I, was weighed into a glass vial and 1 ml of the appropriate aqueous media was added. The bottles were shaken. After 1 h, the sample (~0.5 ml) was removed using a syringe and filtered through a syringe filter (0.2 μm) into a second vial. 200 μL of each solution was then transferred to an HPLC vial and made up to 1 ml by adding 800 μL of diluent. These samples were analyzed directly by HPLC and the response was outside the linearity range. Therefore, a second dilution was performed by taking 0.1 ml of each sample and making up to 2 ml with diluent. Samples were reanalyzed by HPLC. Then, after shaking the suspensions for a total of 18 h, a second sample was taken as described above. All samples were then diluted and analyzed by HPLC as described above. The temperature (22°C) was noted and the absence of gelatinization was observed.

Form I shows fairly uniform and fairly high solubility over the entire range of pH values studied (1.2-6.8). It is slightly higher at pH 1.2 and 6.8.

The above procedure was repeated, but using 8 different organic solvents instead of aqueous media (analysis only after 18 hours). The solvents used were acetonitrile, diethyl ether, ethanol, ethyl acetate, isopropanol, methanol, heptane and THF. All solvents were suspended at a concentration of 100 mg/ml, except methanol, which was dissolved at 100 mg in 0.3 ml. Therefore, an additional 70 mg of Form I was added to the methanol vial to result in a suspension. Samples from these experiments were collected once after 18 hours of suspension. The results are presented in table. 3.

Example 5 Particle size measurement of di(4-methylbenzenesulfonate) (S)-(2R,3R,11bR)-3-isobutyl9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[ 2,1-a]isoquinolin-2-yl-2-amino-3-methylbutanoate, form I.

The average particle size and particle size distribution of Form I were measured using a Malvern Mastersizer MicroPlus Analyzer (Malvern Instruments, UK) using isooctane as the dispersant for the above experiment. The apparatus was allowed to warm up for approximately 1 hour and approximately 100 ml of dispersant was added to the sample dispersion cell. Background values were measured first using a dispersant. A fresh sample was prepared by adding ~100 mg of Form I to 2 mL of dispersant and sonicating for ~5 min. The sample was added dropwise into the sample dispersion cell while stirring the dispersant until a suitable degree of darkness (ie, 16-25%) was achieved and the particle size distribution could be measured. A minimum of three measurements were performed for each sample.

Particle size distribution (PSD) results for di(4-methylbenzenesulfonate) (S)-(2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro -1H-pyrido[2,1-a]isoquinolin-2-yl2-amino-3-methylbutanoate, form I, can be found in table. 4. Selected values from repeated measurements are shown.

Example 6 Stability studies of di(4-methylbenzenesulfonate) (S)-(2R,3R,11bR)-3-isobutyl9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2 ,1-a]isoquinolin-2-yl-2-amino-3-methylbutanoate, form I.

Two series of di(4-methylbenzenesulfonate) (S)-(2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11bhexahydro-1H-pyrido[2,1- a]isoquinolin-2-yl-2-amino-3-methylbutanoate, Form I, was subjected to stability testing for 60 months under long-term and intermediate storage conditions and for 6 months under accelerated storage conditions. The storage conditions include a long-term storage condition of 25±2°C/60±5% RH, an intermediate storage condition of 30±2°C/65±5% RH, and an accelerated storage condition of 40±5% RH. 2°C/75±5% RH. The stability results are presented in table. 5.

Stability data up to 3 months are presented in table. 5 for two batches of Form I. The results of stability studies under accelerated and long-term storage conditions for these batches demonstrate the chemical and physical stability of Form I when stored for up to months under long-term storage conditions of 25°C/60% RH, and 3 months under accelerated storage conditions, which is 40°C/75% RH.

Table 1

Solubility of formula I in form I at 5 and 10°C below the reflux temperature for each solvent

Solvent Boiling point Solubility at high temperature (mg/ml) Solubility at 5°C (mg/ml) Ethyl acetate 77 2 1 Isopropyl acetate 89 4 4 IPA 89 22 5 THF 66 6 4 MIBK 117 5 6 MEK 80 4 3 Acetone 56 Cannot filter 5 Acetonitrile 81 48 17 MeOH 65 >250 >250 EtOH 78 212 24 1-propanol 98 160 8

table 2

Water solubility of Form I

Solubility (mg/ml) pH of the aquatic environment 1 hour 18h 1.2 31.61 33.17 3 28.45 27.97 4 28.06 27.75 5 18.58 27.87 6.8 33.98 35.35

Table 3

Solubility of Form I in organic solvents

Solvent Solubility (mg/ml) -18h Water 28.2 Methanol 480.8 Ethanol 35.5 Isopropanol 1.15 Ethyl acetate 0.04 Acetonitrile 1.36 THF 0.05 Diethyl ether 0.01 Heptane 0.003

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Table 4

Form I particle size distribution

Form Treatment Particle size parameter (µm) D10 D20 D50 D80 D90 Form I Suspended in isooctane and sonicated for 5 min. 10.29 17.84 34.72 56.22 69.39

Table 5

Stability data for three batches of Form I

Series Storage condition Available stability data 1 25°C/60% RH 3 months 40°С/75% RH 3 months 2 25°C/60% RH 3 months 40°С/75% RH 3 months 3 25°C/60% RH 24 months 40°С/75% RH 6 months

Table 6

Form I recrystallization studies

Recrystallization XRPD NMR (nuclear magnetic resonance) Purity according to HPLC Exit — Crystal formI No residual solvent -2.0 eq. acids 100% — Acetonitrile/3% water Crystal formI No residual solvent -2.0 eq. acids 100% 72% 1-propanol Crystal formI No residual solvent -1.9 eq. acids 97.4% 88%

Example 7. Preparation of di(4-methylbenzenesulfonate) (S)-(2R,3R,11bR)-3-isobutyl-9,10-dimethoxy2,3,4,6,7,11b-hexahydro-1H-pyrido[2, 1-a]isoquinolin-2-yl-2-amino-3-methylbutanoate, form II.

186 mg amorphous di(4-methylbenzenesulfonate) (S)-(2R,3R,11bR)-3-isobutyl-9,10-dimethoxy2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1 -a]isoquinolin-2-yl-2-amino-3-methylbutanoate (Formula I) was suspended in 3 volumes of water overnight (4 hour heat/cool cycle from RT to 50°C). White crystalline material was obtained and dried in a vacuum oven at 40°C for 4 hours.

The X-ray powder diffraction pattern of Form II is illustrated in FIG. 5. Form II is characterized by characteristic diffraction peaks of XRP, expressed in 2-theta, at approximately 5.7, 15.3 and 22.5°, indicating that the compound is in a crystalline form (Form II), which is different from the form I.

The differential scanning calorimetric thermogram of Form II is illustrated in FIG. 6. Form II exhibits an endothermic event with an onset temperature of approximately 143°C and a peak temperature of 155°C.

Example 8. Preparation of di(4-methylbenzenesulfonate) (S)-(2R,3R,11bR)-3-isobutyl-9,10-dimethoxy2,3,4,6,7,11b-hexahydro-1H-pyrido[2, 1-a]isoquinolin-2-yl-2-amino-3-methylbutanoate, form III.

Maturation of 100 mg of amorphous di(4-methylbenzenesulfonate) (S)-(2R,3R,11bR)-3-isobutyl-9,10dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2, 1-a]isoquinolin-2-yl-2-amino-3-methylbutanoate (formula I) in 95:5 1,4-dioxane/water for 72 hours with temperature cycling between ambient temperature and 50°C every 4 hours resulted in a solid. The solid was isolated by filtration and dried under vacuum for 3 hours.

The X-ray powder diffraction pattern of Form III is illustrated in FIG. 8. Form III exhibits characteristic 2-theta XRP diffraction peaks at approximately 6.3, 18.3, 18.9, 19.8 and 20.4°, indicating that the compound is in crystalline form ( form III), which is different from form I or II.

The differential scanning calorimetric thermogram of Form III is illustrated in FIG. 9. Form III exhibits endothermic event temperatures of approximately 93°C, approximately 158°C, and approximately 230°C.

Example 9. Preparation of di(4-methylbenzenesulfonate) (S)-(2R,3R,11bR)-3-isobutyl-9,10-dimethoxy2,3,4,6,7D1b-hexahydro-III-pyrido[2D-a] isoquinolin-2-yl-2-amino-3-methylbutanoate, form IV.

Di(4-methylbenzenesulfonate) (S)-(2R,3RD1bR)-3-isobutyl-9D0-dimethoxy-2,3,4,6,7D1b-hexahydro1H-pyrido[2,1-a]isoquinolin-2-yl- 2-amino-3-methylbutanoate (Formula I) (500 mg) was dissolved in 1.0 ml acetonitrile/10% water at 71°C. The clear solution was then cooled at a rate of 10°C/h to 5°C. The solid was filtered and dried at 30°C under vacuum for 1.5 hours.

The X-ray powder diffraction pattern of Form IV is illustrated in FIG. 10. Form IV is characterized by characteristic diffraction peaks of XRP, expressed in 2-theta, at approximately 6.2, 10.4, 17.9, 19.2, 19.9 and 20.2°, indicating that the compound is located in a crystalline form (Form IV) that is different from Form I, II or III.

The differential scanning calorimetric thermogram of Form IV is illustrated in FIG. 11. Form IV exhibits endothermic event temperatures of approximately 128°C, approximately 159°C, and approximately 237°C.

Example 10. Preparation of di(4-methylbenzenesulfonate) (S)-(2R,3R,11bR)-3-isobutyl-9,10-dimethoxy2,3,4,6,7D1b-hexahydro-III-pyrido[2D-a] isoquinolin-2-yl-2-amino-3-methylbutanoate, form V.

1.41 g of amorphous di(4-methylbenzenesulfonate) (S)-(2R,3R,11bR)-3-isobutyl-9,10-dimethoxy2,3,4,6,7D1b-hexahydro-III-pyrido[2D-a ]isoquinolin-2-yl-2-amino-3-methylbutanoate (Formula I) was suspended in 5 ml of water for 4 hours. The white crystalline material was filtered and dried. The stock solutions were saved.

Needle crystals precipitated from the mother liquors after 48 hours. The particles were dried in a vacuum oven at RT (room temperature) for 2 hours.

The X-ray powder diffraction pattern of Form V is illustrated in FIG. 13. Form V is characterized by characteristic diffraction peaks of XRP, expressed in 2-theta, at approximately 6.7, 7.9, 10.7, 12.8, 17.1 and 23.7°, indicating that the compound is located in a crystalline form (Form V), which is different from any Form I, II, III or IV.

A Form V differential scanning calorimetric thermogram is illustrated in FIG. 14. Form V exhibits endothermic event temperatures of approximately 113°C and approximately 181°C.

Example 11. Preparation of di(4-methylbenzenesulfonate) (S)-(2R,3R,11bR)-3-isobutyl-9,10-dimethoxy2,3,4,6,7D1b-hexahydro-III-pyrido[2D-a] isoquinolin-2-yl-2-amino-3-methylbutanoate, form VI.

1.41 g of amorphous di(4-methylbenzenesulfonate) (S)-(2R,3R,11bR)-3-isobutyl-9,10-dimethoxy2,3,4,6,7D1b-hexahydro-III-pyrido[2D-a ]isoquinolin-2-yl-2-amino-3-methylbutanoate (Formula I) was suspended in 5 ml of water for 4 hours. The white crystalline material was filtered and dried in a vacuum oven at 40°C overnight.

The X-ray powder diffraction pattern of Form VI is illustrated in FIG. 16. Form VI is characterized by characteristic diffraction peaks of XRP, expressed in 2-theta, at approximately 6.8, 8.0, 16.3 and 17.5°, indicating that the compound is in crystalline form (Form VI), which is different from any form I, II, III, IV or V.

The differential scanning calorimetric thermogram of Form VI is illustrated in FIG. 17. Form VI exhibits endothermic event temperatures of approximately 175°C and approximately 238°C.

Example 12. Phase equilibration between Form I, II and IV according to Formula I.

Form I (80 mg), Form II (50 mg) and Form IV (20 mg) were mixed together.

Approximately 10 mg of the mixture was then suspended in 200 μl of presaturated solvent at the required temperatures for 13 days. The solids were then quickly filtered and analyzed by XRPD.

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Form IV was found to be a thermodynamic product at 5°C for acetonitrile/water >2%. At 25°C only form I was observed. The results are summarized in table. 7.

Example 13. Phase equilibrium between form I and IV according to formula I.

Suspensions of Forms I and IV from equilibrium studies were exposed to a temperature of 25 °C. Form IV did not convert after stirring overnight. The samples were then heated to 30°C for 2 days, the conversion to Form I was then complete. The results are presented in table. 8.

Table 6a

Studies on the balance between form I, II and IV

Solvent 5°С 25°C 50°С Acetonitrile Form I Form I Form I Acetonitrile/2% water Form I - weakly crystalline Form I Form I Acetonitrile/5% water Form IV Form I Form I Acetonitrile/10% water Form IV Form I Form I

Table 7

Studies of the equilibrium between form I and IV according to formula I

Observation after heating at 30°C (overnight) results XRPD Observation after heating at 30°C (2 days) XRPD results White sediment Form IV+ traces of form I White sediment Form I White sediment Form IV White sediment Form I White sediment Form IV White sediment Form I White sediment Form IV White sediment Form I White sediment Form IV White sediment Form I

Table 8

Powder X-ray diffraction of Form I according to Formula I

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23.1 6 23.5 5 24.6 4 27.0 6 27.6 6 28.6 5 28.9 6 30.2 4 40.3 4

Table 10

Powder X-ray diffraction of Form III according to Formula I

Corner 2-theta° Intensity, % 6.3 100 7.1 4 11.7 4 12.2 8 13.2 5 14.1 8 14.3 AND 14.8 4 15.3 14 15.6 3 16.3 9 16.6 5 16.9 9 17.4 9 18.3 29 18.9 21 19.8 35 20.4 25 21.2 10 21.3 9 22.3 4 22.8 7 23.5 6 24.1 13 24.3 7 24.5 5 24.8 5 29.7 6 29.9 7

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Table 11

Powder X-ray diffraction of Form IV according to Formula I

Powder X-ray diffraction of Form V according to Formula I

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13.1 17 13.5 15 14.1 6 14.3 5 14.7 4 15.4 4 15.8 29 16.0 26 17.1 thirty 17.8 5 18.4 16 19.4 AND 19.9 AND 20.2 13 20.4 10 20.6 And 20.9 And 21.5 27 21.8 9 22.7 9 23.7 31 24.0 13 24.2 14 24.5 5 24.8 7 25.1 7 25.8 6 26.3 6 26.5 7 26.9 5 27.5 AND 28.3 8 29.5 8 29.8 13 30.7 5 31.6 7 33.0 5 37.1 6 39.6 9 41.2 5

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Table 13

Powder X-ray

Example 14. Preparation of (S)-(2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11bhexahydro-1H-pyrido[2,1-a]isoquinoline dihydrochloride -2-yl-2-amino-3-methylbutanoate (formula II), form I.

To a suspension of salt (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1a]isoquinolin-2-ol (32 .3 g, 58.54 mmol) in dichloromethane (300 ml) was added 0.5 M aq. NaOH solution (150 ml). The organic layer was separated and washed with water (50 ml) and then dried over Na ₂ SO ₄ . The organic layer was filtered and DMAP (1.79 g, 0.25 eq, 14.63 mmol) and Boc-L-Val-OH (15.26 g, 1.2 eq, 70.25 mmol) were added to the resulting mixture ). The reaction mixture was cooled to -10°C, EDC (16.83 g, 1.5 eq., 87.81 mmol) was added and the resulting mixture was stirred for 3 hours. 0.2 eq. Boc-L-Val-OH (2.54 g) and 0.25 eq. EDC (2.8 g). After 1.5 hours of stirring, water (50 ml) was added, the organic layer was separated and washed with aq. 5% citric acid solution (2x100 ml). The combined organic extracts were washed with water (100 ml) and then dried over Na ₂ SO ₄ . The organic layer was filtered and dried.

The crude product was taken up in dichloromethane and cooled to 5°C. A 4 M solution of HCl in dioxane (64.37 mL, 4.4 eq., 257.50 mmol) was added to the mixture. An additional 20 ml of 4 M HCl in dioxane was added. After 5 hours, the reaction mixture was cooled to 10°C and 8% aq. was added. NaHCO ₃ solution (700 ml). The organic layer was separated and the aqueous layer was extracted with dichloromethane (100 ml). The combined organic extracts were washed with water and then dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to leave a residue. Acetonitrile was added to the residue and the resulting mixture was treated with 2.1 eq. 3.5 n. HCl in IPA solution at 5°C. The reaction mixture was heated to room

- 50 043769 natural temperature. EtOAc was added and the mixture was heated to 50°C and seeded with 165 mg of (S)-(2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b- hexahydro-1H-pyrido[2,1a]isoquinolin-2-yl-2-amino-3-methylbutanoate. After 30 minutes of stirring at 50° C., more EtOAc was added and the mixture was refluxed for 1 hour. Heating was completed and the mixture was allowed to cool to room temperature. Solids were removed by filtration and washed with EtOAc to give 15.4 g of (S)-(2R,3R,11bR)-3-isobutyl-9,10-dimethoxy2,3,4,6,7,11b-hexahydro -1H-pyrido[2,1-a]isoquinolin-2-yl-2-amino-3-methylbutanoate.

The X-ray powder diffraction pattern of Form I is illustrated in FIG. 20. Form I exhibits characteristic 2-theta XRP diffraction peaks at approximately 7.2, 9.2 and 18.0°, indicating that the compound is in crystalline form (Form I). Thermal analysis reveals a mass increase of approximately 14% as relative humidity increases from approximately 0% to approximately 90% relative humidity. Storage at 25°C/92% RH and 40°C/75% RH for seven days caused a change in shape. Water solubility was estimated to be >90 mg/mL free form equivalent at pH 4.1.

Example 15. Preparation of (S)-(2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11bhexahydro-1H-pyrido[2,1-a]isoquinoline dihydrochloride -2-yl-2-amino-3-methylbutanoate (formula II), form II.

Form II was prepared by seeding with 200 mg of (S)-(2R,3R,11bR)-3-isobutyl-9,10dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1- α]isoquinolin-2-yl-2-amino-3-methylbutanoate (Formula II), in Form I, in a thin layer in a plate and exposing the sample to the environment: 25°C/75% RH for 72 hours.

The X-ray powder diffraction pattern of Form II is illustrated in FIG. 24. Form II is characterized by characteristic XRP diffraction peaks expressed in 2-theta at approximately 4.8, 13.3 and 24.9°, indicating that the compound is in a crystalline form (Form II) that is different from that of , characteristic of Form I. Thermal analysis showed 10.4% mass loss, while Karl Fischer analysis showed a water content of 13.9% m/m. Water solubility was estimated to be >67 mg/mL free form equivalent at pH 4.1.

VT-XRPD study showed no conversion to form I upon heating; the material becoming amorphous at temperatures above approximately 160°C without subsequent crystallization upon cooling. GVS analysis showed that the material lost approximately 12% of its mass when RH was reduced to 0%. It is unclear whether the change in shape is accompanied by this loss of water, since water is easily recovered when the sample is returned to the ambient RH.

Table 14

Powder X-ray

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24.0 13 24.2 7 25.3 7 25.7 8 25.9 19 27.7 6 29.0 7 29.6 8 30.3 7 31.0 8 33.2 8 36.6 9

Table 15

Form II powder X-ray diffraction according to formula II

Angle 2-theta° Intensity, % 4.3 52 4.8 100 7.2 18 7.6 20 8.4 44 8.7 45 9.5 36 10.6 20 10.9 24 11.5 19 12.4 15 12.8 16 13.3 69 14.1 53 14.6 40 15.3 21 16.3 13 16.6 18 17.1 18 18.4 47 19.0 13

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Example 16. Preparation of amorphous di(4-methylbenzenesulfonate) (S)-(2R,3R,11bR)-3-isobutyl-9,10dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2 ,1-a]isoquinolin-2-yl-2-amino-3-methylbutanoate (formula I) and (S)-(2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3 dihydrochloride, 4,6,7,11b-hexahydro-1Hpyrido[2,1-a]isoquinolin-2-yl-2-amino-3-methylbutanoate (formula II).

Approximately 15 mg each of di(4-methylbenzenesulfonate) (S)-(2R,3R,11R)-3-isobutyl-9,10dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2 ,1-a]isoquinolin-2-yl-2-amino-3-methylbutanoate (formula I) and (S)-(2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3 dihydrochloride, 4,6,7,11b-hexahydro-1Hpyrido[2,1-a]isoquinolin-2-yl-2-amino-3-methylbutanoate (formula II) was added to 2 ml of a 2:1 tert-BuOH:water mixture. The resulting clear solutions were quickly frozen in a dry ice/acetone bath and lyophilized to fluffy white solids. XRPD analysis showed that the lyophilized material was amorphous in each case, and 1H NMR analysis confirmed that the appropriate counterions were still present.

Example 17. Maturation series of amorphous di(4-methylbenzenesulfonate) (S)-(2R,3R,11bR)-3-isobutyl9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[ 2,1-a]isoquinolin-2-yl-2-amino-3-methylbutanoate (formula I) and (S)-(2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3 dihydrochloride ,4,6,7,11b-hexahydro-1Hpyrido[2,1-a]isoquinolin-2-yl-2-amino-3-methylbutanoate (formula II).

Approximately 50 mg of amorphous di(4-methylbenzenesulfonate) (S)-(2R,3R,11bR)-3-isobutyl-9,10dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2, 1-a]isoquinolin-2-yl-2-amino-3-methylbutanoate (formula I) and (S)-(2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4 dihydrochloride ,6,7,11b-hexahydro-1Hpyrido[2,1-a]isoquinolin-2-yl-2-amino-3-methylbutanoate (Formula II) was weighed into each of the 48 vials. Sufficient amounts of the specified solvent were added to form a mobile thick suspension and the vials were incubated for 72 hours with temperature cycling between ambient temperature and 50°C every 4 hours. Any solids present at the indicated time point were isolated by filtration and analyzed using XRPD. Experiments without solids were left uncapped and allowed to nucleate the crystal; none of them contained any crystalline material, and all formed sticky resins. The results are shown in table. 16.

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Table 16

Maturation series on amorphous salts according to formula I and formula II

Details Bis-tosylate Bis hydrochloride Solvent Volume (µl) The solid released after XRPD Volume (µl) The solid released after XRPD Heptane 500 maturation Form I 500 maturation amorphous Dioxane 250 maturation Possible mixture 500 maturation Form I Toluene 500 maturation New X-ray (2) 500 maturation partially crystal form II Kumen 500 maturation New X-ray (2) 500 maturation partially crystal form II TVME 500 maturation Form I 500 maturation amorphous Tetralin 500 resin after evaporation But 500 resin after evaporation But DIPE 500 maturation Form I 500 maturation amorphous Anisole 250 maturation New X-ray (2) 500 resin after evaporation But Isobutyl acetate 250 maturation New X-ray (2) 500 maturation amorphous Ethyl acetate 500 maturation Form I 500 maturation Form I Isopropyl acetate 500 maturation Form I 500 maturation amorphous

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Methyl acetate 500 maturation Possible mixture 500 maturation Form I IPA 250 maturation Form I 500 resin after evaporation But Ethyl formate 250 maturation Form I 500 maturation new radiograph (3) THF 250 maturation Form I 500 maturation Form I DCE 250 maturation Weak crystalline 500 resin after evaporation But MIBK 500 maturation Form I 500 maturation amorphous MEK 250 maturation Form I 500 maturation Form I Acetone 250 maturation Form I 500 maturation Form I Methanol 250 resin after evaporation But 500 resin after evaporation But Ethanol 250 resin after evaporation But 500 resin after evaporation But Acetonitrile 250 maturation Form I 500 resin after evaporation But Nitromethane 250 maturation Form I 500 resin after evaporation But Water 250 maturation New X-ray (2) 500 resin after evaporation But

Example 18 Screening for counterions of (S)-2-amino-3-methylbutyric acid (2R,3R,11bR)-3isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido [2,1-a]isoquinolin-2-yl ester.

Approximately 50 mg free base (S)-2-amino-3-methylbutyric acid (2R,3R,11bR)3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H- Pyrido[2,1-a]isoquinolin-2-yl ether was weighed into each of 54 HPLC vials, 500 μl of the appropriate solvent was then added to each vial and the vials were shaken at room temperature for 1 h, obtaining clear solutions in all cases. 2.0 eq. the appropriate acid was then added to each experiment. The vials were then placed in an incubator for 16 hours, cycling the temperature between ambient temperature and 50°C every 4 hours. Any visible solids were filtered and analyzed by XRPD. Any vials containing resins were incubated for an additional 60 hours, after which any solids were isolated by filtration and characterized by XRPD.

Example 19 Antisolvent-mediated screening of (S)-2-amino-3methylbutyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2Hpyrido counterions [2,1-a]isoquinolin-2-yl ester.

Approximately 50 mg free base (S)-2-amino-3-methylbutyric acid (2R,3R,11bR)3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H- Pyrido[2,1-a]isoquinolin-2-yl ester was weighed into each of the 27 reaction tubes. To 18 of these tubes, 500 μl of acetonitrile was added, to the other nine, 500 μl of a mixture of 99:1 acetonitrile/water was added. Then 2.1 eq. was added. the corresponding acid in the most accessible concentrated form. Sufficient ethyl acetate was added to each tube to induce turbidity and the tubes were heated to 50°C for 1 hour before being cooled to RT with continuous stirring. Anyone present

- 55 043769 solids were filtered and analyzed by XRPD. In addition to the reproducing crystalline salt forms of tosylic (p-toluenesulfonic) acid and oxalic acid isolated in Example 18, new crystalline hydrobromide and methanesulfonate salts, as well as a benzenesulfonate salt, were identified with diffraction patterns different from those previously observed. DSC analysis of this new besylate form showed an early endothermic event followed by apparent recrystallization and subsequent melting. The results are shown in table. 17.

Table 17

Results of Antisolvent-Mediated Counterion Screening

Experiment details MeCN (without adding water) - A MeCN (1% added water) A Acid added as observations XRPD observations XRPD hydrobromic acid 48% aq. solution oil (crystal during storage) crystalline oil hydrochloric acid 4 M dioxane solution fine-grained solid liquefying oil sulfuric acid 97.50% oil oil 1,2 ethandisulfonovaya acid hard substance resin oil parato lu o lsu l fonovaya acid solid (monohydrate) fine-grained solid crystalline fine-grained solid crystalline methanesulfonic acid hard substance oil (crystal during storage) crystalline fine-grained solid crystalline benzo lsu l fo novaya acid hard substance fine-grained solid crystalline fine-grained solid crystalline

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oxalic acid hard substance fine-grained solid partially crystalline fine-grained solid partially crystalline maleic acid hard substance oil oil phosphoric acid 85% aq. solution fine-grained solid liquefying the experiment was not carried out L-tartaric acid hard substance resin the experiment was not carried out fumaric acid hard substance unfiltered gel the experiment was not carried out lemon acid hard substance fine-grained solid liquefying the experiment was not carried out L-malic acid hard substance resin the experiment was not carried out hippuric acid hard substance fine-grained solid injected acid the experiment was not carried out D-gluconic acid 45% mass, in water oil the experiment was not carried out L-lactic acid hard substance oil the experiment was not carried out succinic acid hard substance oil the experiment was not carried out

Example 20 Polymorphic evaluation of salts from antisolvent-mediated counterion screening of (S)-2-amino-3-methylbutyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7 ,11bhexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester.

Approximately 10 mg of the corresponding salt form was suspended in 100 μl of the indicated solvent. The suspensions were then incubated for 72 hours with temperature cycling between ambient temperature and 50°C every 4 hours. After cooling to RT, any solids present were filtered off and analyzed by XRPD. The results are shown in table. 18.

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Polymorphism assessment results

Table 18

Details A-tosylate B - oxalate C - mesylate D - besylate E - hydrobromide Solvent X-ray diffraction pattern X-ray diffraction pattern X-ray diffraction pattern X-ray diffraction pattern X-ray diffraction pattern MeOH But But But But But MeCN possible new diffraction pattern (1) amorphous possible new diffraction pattern (1) Mostly amorphous form one IPA form one form one form one possible new diffraction pattern (1) form one MEK possible new diffraction pattern (2) possible new diffraction pattern (1) form one possible new diffraction pattern (2) possible new diffraction pattern (1) MIBK form one possible new diffraction pattern (2) form one form one new diffraction pattern (2) DCM form one possible new diffraction pattern (3) form one form one new diffraction pattern (2) THF form one mostly amorphous form one possible new diffraction pattern (1) form one IPAc form one form one form one form one form one DIPE form one form one form one form one form one TBME form one form one Mostly amorphous form one form one

While X-ray diffraction patterns with additional peaks were observed for all salts (labeled as possible new diffraction patterns in the table above), a new form was confidently identified for the hydrobromide salt isolated from MIBK and DCM. In other cases, the material was essentially the same shape as that introduced into the experiments, with a few additional peaks present.

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Claims (24)

Table 19 Generalized representation of the salts formed Synthesis Details Definition of characteristics Solubility in water Stability against humidity Salt form Exit Purity Eq. counterion XRPD initial melting point (°C) mg/ml St. forms pH 40°C/75% RH 25°C/92% RH Absorption according to GVS tosylate 69% 99.1% 2.1 according to NMR crystalline 239 15.00 5.24 without changes without changes 1.0% oxalate 74% 98.2% 2.1 according to IC crystalline 200 >50 2.43 without changes without changes 0.8% mesylate 85% 98.4% 2.1 according to NMR crystalline 177 >70 3.97 without changes liquefying 3.4% besilate 86% 99.1% 2.0 according to NMR crystalline 239 25.1 4.74 without changes without changes 3.7% hydrobromide 61% 98.7% 2.0 according to IC crystalline 158, 248 85.3 3.38 shape change shape change > 3.9% hydrochloride But 99.0% 2.1 according to IC crystalline 244 >90 4.09 shape change shape change 15.2% (shape change) All salts formed show bis-stoichiometry and purity comparable to the starting material. The above examples are provided to provide those skilled in the art with complete disclosure and description of how to make and apply the embodiments and are not intended to limit the scope of the present disclosure. It is intended that modifications to the above described methods of carrying out the present disclosure that will be apparent to those skilled in the art are within the scope of the following claims. All publications, patents and patent applications cited in the specified specification are incorporated herein by reference as if each such publication, patent or patent application were specifically and individually incorporated herein by reference. . CLAIM 1. Crystalline form of the compound according to formula I (I) containing X-ray powder diffraction peaks at approximately 6.3, 17.9 and 19.7° 2-theta±0.2 theta. - 59 043769 2. Crystalline form of the compound according to formula I containing X-ray powder diffraction peaks at approximately 5.7, 15.3 and 22.5° 2-theta±0.2 theta. 3. Crystalline form of the compound according to formula I containing X-ray powder diffraction peaks at approximately 6.3, 18.3, 18.9, 19.8 and 20.4° 2-theta±0.2 theta. 4. Crystalline form of the compound according to formula I containing X-ray powder diffraction peaks at approximately 6.2, 10.4, 17.9, 19.2, 19.9 and 20.2° 2-theta±0.2 theta. 5. Crystalline form of the compound according to formula I containing X-ray powder diffraction peaks at approximately 6.7, 7.9, 10.7, 12.8, 17.1 and 23.7° 2-theta±0.2 theta. - 60 043769 6. Crystalline form of the compound according to formula I (I), containing X-ray powder diffraction peaks at approximately 6.8, 8.0, 16.3 and 17.5° 2-theta±0.2 theta. 7. Amorphous form (I) 8. A pharmaceutical composition for the treatment, prevention or amelioration of one or more symptoms of a hyperkinetic disorder, comprising a crystalline form according to any one of claims 1 to 6, and a pharmaceutically acceptable carrier. 9. The pharmaceutical composition according to claim 8, wherein the composition is formulated for oral administration. 10. The pharmaceutical composition according to claim 8, wherein the composition is formulated in a dosage form in single doses. 11. A method of treating, preventing or reducing the intensity of one or more symptoms of a hyperkinetic disorder, comprising administering a crystalline form according to any one of claims 1 to 6. 12. The method of claim 11, wherein the hyperkinetic disorder is Huntington's disease, tardive dyskinesia, Tourette's syndrome, dystonia, hemiballismus, chorea, senile chorea or tics. 13. The method of claim 12, wherein the hyperkinetic disorder is Huntington's disease. 14. The method of claim 12, wherein the hyperkinetic disorder is tardive dyskinesia. 15. The method of claim 12, wherein the hyperkinetic disorder is Tourette's syndrome. 16. The method of claim 12, wherein the hyperkinetic disorder is tics. 17. A method of inhibiting vesicular monoamine transporter isoform 2 in a subject, comprising administering to the subject a crystalline form according to any one of claims 1 to 6. 18. Use of a crystalline form according to any one of claims 1 to 6 for the treatment, prevention or amelioration of one or more symptoms of a hyperkinetic disorder. 19. The use of claim 18, wherein the hyperkinetic disorder is Huntington's disease, tardive dyskinesia, Tourette's syndrome, dystonia, hemiballismus, chorea, senile chorea or tics. 20. Use according to claim 19, wherein the hyperkinetic disorder is Huntington's disease. 21. Use according to claim 19, wherein the hyperkinetic disorder is tardive dyskinesia. 22. Use according to claim 19, wherein the hyperkinetic disorder is Tourette's syndrome. 23. Use according to claim 19, wherein the hyperkinetic disorder is tics. 24. Use of a crystalline form according to any one of claims 1 to 6 for inhibiting vesicular monoamine transporter isoform 2 in a subject. -