TW202208325A - Polymorphic forms of (r)-oxybutynin hydrochloride - Google Patents

Abstract

Polymorphic forms of (R)-oxybutynin HCl, including three crystalline forms, are prepared and characterized. Uses of the various polymorphic forms of (R)-oxybutynin HCl for Obstructive Sleep Apnea (OSA) treatment are also disclosed.

Description

Polymorphic form of (R)-Oxybutynin hydrochloride

The present invention provides various polymorphic forms of (R)-oxybutynin, as well as pharmaceutical compositions thereof, methods for their preparation and uses thereof.

I 羥布托尼Oxybutonil and its derivatives are usually taken orally or applied to the skin and are suitable as bronchodilators or as a remedy for overactive bladder. In addition, oxybutonil exerts a direct antispasmodic effect on various forms of smooth muscle primarily by acting as an anticholinergic agent and the like by inhibiting the action of acetylcholine on smooth muscle. Hydroxybutonide is sold as the hydrochloride salt. The chemical name of Hydroxybutoni is 2-cyclohexyl-2-hydroxy-2-phenylacetic acid 4-(diethylamino)but-2-yn-1-yl ester, and its chemical structure is provided below as I :

I Hydroxybutoni

Cross-references to related applications

This application claims priority to US Provisional Application 63/020,301 filed on May 5, 2020 and US Provisional Application 63/136,691 filed on January 13, 2021, the entire contents of each of these provisional applications All are incorporated herein by reference. I. Polymorphic Forms of (R)-Hydroxybuttonib Hydrochloride

II (R)-羥布托尼• HClAs set forth in the Examples section below, three crystalline forms of (R)-hydroxybutanoi hydrochloride were prepared and characterized. The (R) enantiomeric isomer of hydroxybutonil hydrochloride is provided below as II :

II (R)-Hydroxybutoni HCl

The definitions provided herein are intended to clarify, but not to limit, the defined terms. If a term used herein is not specifically defined, the term should not be considered ambiguous. Rather, terms are used within their accepted meanings.

As used herein, (R)-Hydroxybuttonib hydrochloride refers to the hydrochloride salt form in which the molar ratio of (R)-Hydroxybutonib to HCl is about 1, eg, about 0.75 to about 1.25, about 0.9 to about 1.1, about 1.0 to about 1.25 or 0.75 to about 1.0. Small variations in the amount of HCl analyzed can be attributed to, but not limited to, measurement variability and loss of small amounts of HCl during storage and/or handling.

In some embodiments, the (R)-hydroxybutyrin free base can be converted to a salt by conventional methods. As used herein, the term "salt" is not intended to be limiting, so long as the salts formed with (R)-hydroxybutronil are pharmacologically acceptable. In some embodiments, salts may include hydrohalide salts (eg, HCl, HBr, and the like), citrates, or other organic carboxylates (eg, acetate, maleate, tartrate, fumarate, and the like) ), inorganic acid salts (such as sulfates, nitrates, perchlorates, phosphates, and the like), organic sulfonates (such as methanesulfonates, ethanesulfonates, benzenesulfonates, and the like), amine groups acid salts (eg, aspartate, glutamate, and the like), alkali metal salts (eg, sodium, potassium, and the like), and/or alkaline earth metal salts (eg, magnesium, calcium, and the like). In some embodiments, the pharmacologically acceptable salt of (R)-hydroxybutytonide is (R)-hydroxybutrone hydrochloride. In other embodiments, the pharmacologically acceptable salt of (R)-Hydroxybutonib is (R)-Hydroxybutoni citrate.

As used herein, "crystalline" refers to a solid with a highly regular chemical structure. In particular, crystalline free base or salt forms can be produced in one or more single crystalline forms. For the purposes of this application, the terms "crystalline form," "single crystalline form," and "polymorph" are synonymous; these terms distinguish between different properties (eg, different XRPD patterns and/or different DSC scans) of crystals. The term "polymorph" includes mimetic polymorphs, which are generally different solvates of a material and which therefore differ in properties from one another. Accordingly, each unique polymorph and mimetic polymorph in free base or salt form is considered herein to be a unique single crystalline form. In some embodiments, the solid form is a solid crystalline form.

The term "ambient relative humidity" refers to the ratio of the partial pressure of water vapor to the equilibrium pressure of water at a given temperature. In some embodiments, the ambient relative humidity is about 0% to about 100%, about 25% to about 75%, about 0% to about 50%, about 50% to about 100%, or about 40% at room temperature to about 65%.

The term "substantially crystalline" refers to a form that can be at least the specified weight percent crystalline. Specific weight percentages are 10%, 20%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 87%, 88%, 89%, 90%, 91%, 92 %, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% or any percentage between 10% and 100%. In some embodiments, substantially crystalline refers to at least 70% crystalline free base or salt form. In other embodiments, substantially crystalline refers to at least 90% crystalline free base or salt form.

As used herein, "amorphous" refers to a solid material comprising amorphous material. In certain embodiments, an amorphous sample of the material can be prepared by lyophilizing a mixture of the material and a solvent, where the mixture can be homogeneous (eg, a solution) or heterogeneous (eg, a slurry).

The term "substantially free" refers to forms and compositions that may be free of at least the specified weight percent of impurities and/or crystalline compounds. Specific weight percentages are 60%, 70%, 75%, 80%, 85%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97% %, 98%, 99%, 99.5%, 99.9% or any percentage between 60% and 100% free of impurities and/or crystalline compounds. In some embodiments, substantially free means that the free base or salt form is at least 70% pure. In other embodiments, substantially free means that the free base or salt form is at least 90% pure. In other embodiments, substantially free of crystalline compounds means that the composition has less than about 30%, less than about 20%, less than about 15%, less than about 10%, less than about 5%, less than about 1% of crystalline compound.

The term "hydrate" refers to a solvate in which the solvent molecule is _H2O present in a defined stoichiometric or non-stoichiometric amount. Stoichiometric solvates may, for example, include hemihydrate, monohydrate, dihydrate, or trihydrate forms, and the like. Non-stoichiometric solvates can include, for example, channel hydrates, including where water content can vary depending on ambient humidity. In some embodiments, the (R)-hydroxybutrone salt may exist in the form of a hemihydrate, monohydrate, dihydrate, or trihydrate.

The term "solvate or solvation" means a physical association of a compound of the invention, including its crystalline forms, with one or more solvent molecules. This physical association includes hydrogen bonding. In certain instances, the solvate will be capable of isolation, such as when one or more solvent molecules are incorporated into the crystal lattice of the crystalline solid. "Solvate or solvate" encompasses both solution phase and isolatable solvates. Representative solvates include, for example, hydrates, ethanolates or methanolates.

In the context of the polymorphic forms disclosed herein, the term "stable" refers to the stability of the polymorphic form, eg, relative to heat and/or humidity.

As used herein, the crystalline forms of (R)-hydroxybutanoi hydrochloride are referred to as Form A, Form B, and Form C, respectively. Form A is an isopropanol solvate polymorph prepared by reacting (R)-hydroxybutytonide dissolved in isopropanol with hydrochloric acid at 20°C-25°C. Form B is a desolvated polymorph prepared by either rapid evaporation of Form A dissolved in toluene or vacuum drying of Form A at ambient temperature. The Form C polymorph is prepared by reacting (R)-hydroxybutyrin dissolved in methyl tertiary butyl ether (MTBE) with hydrochloric acid at about 35°C. As provided in Figure 1, Form A, Form B, and Form C display different X-ray powder diffraction (XRPD) patterns.

In many of the embodiments disclosed herein, (R)-hydroxybutanoi hydrochloride is disclosed as having a crystalline structure.

In certain embodiments, as disclosed herein, the crystalline structures of the present disclosure can be identified by having one or more characteristic peaks in the XRPD spectrum.

In some embodiments, as disclosed herein, the crystalline structures of the present disclosure have one or more characteristic endothermic peaks in differential scanning calorimetry.

In certain embodiments, methods are provided for the preparation and/or interconversion of one or more crystalline forms of (R)-hydroxybutrone hydrochloride. The other examples illustrate the conversion to and preservation of a crystalline form of (R)-hydroxybutanoi hydrochloride, which crystalline form has the desired stability under the expected storage conditions.

Certain embodiments disclosed herein provide a solid form of (R)-hydroxybutanoi hydrochloride having an X-ray powder diffraction pattern at about ambient relative humidity comprising a peak at 6.9 degrees 2Θ ± 2Θ At 0.2 degrees 2Θ, eg Form C.

Certain embodiments disclosed herein provide a solid form of (R)-hydroxybutanoi hydrochloride having an X-ray powder diffraction pattern at about ambient relative humidity comprising a peak at 6.9 degrees 2Θ ± 2Θ 0.2 degrees 2Θ and/or 18.3 degrees 2Θ ± 0.2 degrees 2Θ, eg Form C.

Certain embodiments disclosed herein provide a solid form of (R)-hydroxybutanoi hydrochloride having an X-ray powder surround comprising at least two peaks (eg, 2 or 3 peaks) at about ambient relative humidity A radiation pattern, the peaks, expressed in 2-theta, are selected from the group consisting of 6.9 degrees 2Θ ± 0.2 degrees 2Θ, 18.3 degrees 2Θ ± 0.2 degrees 2Θ, and 11.7 degrees 2Θ ± 0.2 degrees 2Θ, eg, Form C.

Certain embodiments disclosed herein provide a solid form of (R)-hydroxybutanoi hydrochloride having an X comprising at least three peaks (eg, 3, 4, or 5 peaks) at about ambient relative humidity Ray powder diffraction pattern with peaks expressed in 2-theta selected from 6.9 degrees 2Θ ± 0.2 degrees 2Θ, 18.3 degrees 2Θ ± 0.2 degrees 2Θ, 11.7 degrees 2Θ ± 0.2 degrees 2Θ, 16.8 degrees 2Θ ± 0.2 degrees 2Θ, and 14.2 degrees 2Θ A group of 2θ ± 0.2 degrees 2θ, e.g. Form C.

Certain embodiments disclosed herein provide a solid form of (R)-hydroxybutanoi hydrochloride having at least four peaks (eg, 4, 5, 6, or 7 peaks at about ambient relative humidity) ) of the X-ray powder diffraction pattern, the peaks expressed in 2-theta are selected from 6.9 degrees 2Θ ± 0.2 degrees 2Θ, 18.3 degrees 2Θ ± 0.2 degrees 2Θ, 11.7 degrees 2Θ ± 0.2 degrees 2Θ, 16.8 degrees 2Θ ± 0.2 degrees 2Θ , 14.2 degrees 2Θ ± 0.2 degrees 2Θ, 7.6 degrees 2Θ ± 0.2 degrees 2Θ, and 14.8 degrees 2Θ ± 0.2 degrees 2Θ, such as Form C.

Certain embodiments disclosed herein provide a solid form of (R)-hydroxybutanoi hydrochloride having an X-ray powder diffraction pattern at about ambient relative humidity comprising at least five peaks in 2-theta Indicates selected from 6.9 degrees 2θ ± 0.2 degrees 2θ, 18.3 degrees 2θ ± 0.2 degrees 2θ, 11.7 degrees 2θ ± 0.2 degrees 2θ, 16.8 degrees 2θ ± 0.2 degrees 2θ, 14.2 degrees 2θ ± 0.2 degrees 2θ, 7.6 degrees 2θ ± 0.2 degrees 2θ , 14.8 degrees 2Θ ± 0.2 degrees 2Θ, 24.2 degrees 2Θ ± 0.2 degrees 2Θ, and 13.9 degrees 2Θ ± 0.2 degrees 2Θ, such as Form C.

Certain embodiments disclosed herein provide a solid form of (R)-hydroxybutanoi hydrochloride having an X-ray powder diffraction pattern comprising at least seven peaks at about ambient relative humidity, the peaks being 2-theta Indicates selected from 6.9 degrees 2θ ± 0.2 degrees 2θ, 18.3 degrees 2θ ± 0.2 degrees 2θ, 11.7 degrees 2θ ± 0.2 degrees 2θ, 16.8 degrees 2θ ± 0.2 degrees 2θ, 14.2 degrees 2θ ± 0.2 degrees 2θ, 7.6 degrees 2θ ± 0.2 degrees 2θ , 14.8 degrees 2Θ ± 0.2 degrees 2Θ, 24.2 degrees 2Θ ± 0.2 degrees 2Θ, 13.9 degrees 2Θ ± 0.2 degrees 2Θ, and 8.7 degrees 2Θ ± 0.2 degrees 2Θ, such as Form C.

Certain embodiments disclosed herein provide a solid form of (R)-hydroxybutonitrile hydrochloride having an X-ray powder diffraction pattern comprising at least eight peaks at about ambient relative humidity, the peaks being 2-theta Indicates selected from 6.9 degrees 2θ ± 0.2 degrees 2θ, 18.3 degrees 2θ ± 0.2 degrees 2θ, 11.7 degrees 2θ ± 0.2 degrees 2θ, 16.8 degrees 2θ ± 0.2 degrees 2θ, 14.2 degrees 2θ ± 0.2 degrees 2θ, 7.6 degrees 2θ ± 0.2 degrees 2θ , 14.8 degrees 2Θ ± 0.2 degrees 2Θ, 24.2 degrees 2Θ ± 0.2 degrees 2Θ, 13.9 degrees 2Θ ± 0.2 degrees 2Θ, and 8.7 degrees 2Θ ± 0.2 degrees 2Θ, such as Form C.

Certain embodiments disclosed herein provide a solid form of (R)-hydroxybutanoi hydrochloride having an X-ray powder diffraction pattern comprising at least nine peaks at about ambient relative humidity, the peaks being 2-theta Indicates selected from 6.9 degrees 2θ ± 0.2 degrees 2θ, 18.3 degrees 2θ ± 0.2 degrees 2θ, 11.7 degrees 2θ ± 0.2 degrees 2θ, 16.8 degrees 2θ ± 0.2 degrees 2θ, 14.2 degrees 2θ ± 0.2 degrees 2θ, 7.6 degrees 2θ ± 0.2 degrees 2θ , 14.8 degrees 2Θ ± 0.2 degrees 2Θ, 24.2 degrees 2Θ ± 0.2 degrees 2Θ, 13.9 degrees 2Θ ± 0.2 degrees 2Θ, and 8.7 degrees 2Θ ± 0.2 degrees 2Θ, such as Form C.

Certain embodiments disclosed herein provide a solid form of (R)-hydroxybutanoi hydrochloride having an X-ray powder diffraction pattern at about ambient relative humidity comprising peaks located at various locations in 2-theta : 6.9 degrees 2θ ± 0.2 degrees 2θ, 18.3 degrees 2θ ± 0.2 degrees 2θ, 11.7 degrees 2θ ± 0.2 degrees 2θ, 16.8 degrees 2θ ± 0.2 degrees 2θ, 14.2 degrees 2θ ± 0.2 degrees 2θ, 7.6 degrees 2θ ± 0.2 degrees 2θ, 14.8 degrees 2Θ ± 0.2 degrees 2Θ, 24.2 degrees 2Θ ± 0.2 degrees 2Θ, 13.9 degrees 2Θ ± 0.2 degrees 2Θ, 8.7 degrees 2Θ ± 0.2 degrees 2Θ, 22.2 degrees 2Θ ± 0.2 degrees 2Θ, and 19.5 degrees 2Θ ± 0.2 degrees 2Θ, e.g. Form C .

Certain embodiments disclosed herein provide a solid form of (R)-hydroxybutanoi hydrochloride having at least one peak, at least two peaks, at least three peaks, at least four peaks at about ambient relative humidity , X-ray powder diffraction pattern of at least five peaks, at least six peaks, at least seven peaks, at least eight peaks, at least nine peaks, at least ten peaks, at least eleven peaks, the peak(s) with 2 -θ means selected from 6.9 degrees 2θ ± 0.2 degrees 2θ, 18.3 degrees 2θ ± 0.2 degrees 2θ, 11.7 degrees 2θ ± 0.2 degrees 2θ, 16.8 degrees 2θ ± 0.2 degrees 2θ, 14.2 degrees 2θ ± 0.2 degrees 2θ, 7.6 degrees 2θ ± 0.2 Degrees 2θ, 14.8 Degrees 2θ ± 0.2 Degrees 2θ, 24.2 Degrees 2θ ± 0.2 Degrees 2θ, 13.9 Degrees 2θ ± 0.2 Degrees 2θ, 8.7 Degrees 2θ ± 0.2 Degrees 2θ, 22.2 Degrees 2θ ± 0.2 Degrees 2θ, and 19.5 Degrees 2θ ± 0.2 Degrees 2θ Forms of groups, such as form C.

Certain embodiments disclosed herein provide a solid form (Form C) having an X-ray powder diffraction pattern substantially as shown in FIG. 4 at about ambient relative humidity.

Certain embodiments disclosed herein provide a solid form of (R)-hydroxybutanoi hydrochloride having differential scanning calorimetry (DSC) exhibiting a melting onset at 109.6°C and an endothermic peak at 119.1°C Thermogram, e.g. Form C. Form C exhibits a higher melting temperature than both Form A and Form B.

Certain embodiments disclosed herein provide a solid form of (R)-hydroxybutanoi hydrochloride having a differential scanning calorimetry (DSC) thermogram substantially as shown in FIG. 7, eg, Form C .

Certain embodiments disclosed herein provide a solid form (eg, Form C) of (R)-hydroxybutanoi as disclosed herein, wherein the solid form accounts for at least 1 of the total sample of (R)-hydroxybutanoi hydrochloride % w/w. Certain embodiments disclosed herein provide compositions comprising (R)-Hydroxybuterol, wherein at least 5% w/w of the total amount of (R)-Hydroxybutoni is (R)-Hydroxybutrone as disclosed herein Solid form of Tony (eg Form C). Certain embodiments disclosed herein provide compositions comprising (R)-Hydroxybutonil, wherein at least 10% w/w of the total amount of (R)-Hydroxybutoni is (R)-Hydroxybutrone as disclosed herein Solid form of Tony (eg Form C). Certain embodiments disclosed herein provide compositions comprising (R)-Hydroxybutrone, wherein at least 25% w/w of the total amount of (R)-Hydroxybutoni is (R)-Hydroxybutrone as disclosed herein Solid form of Tony (eg Form C). Certain embodiments disclosed herein provide compositions comprising (R)-Hydroxybutonil, wherein at least 50% w/w of the total amount of (R)-Hydroxybutoni is (R)-Hydroxybutrone as disclosed herein Solid form of Tony (eg Form C). Certain embodiments disclosed herein provide compositions comprising (R)-Hydroxybutonil, wherein at least 90% w/w of the total amount of (R)-Hydroxybutoni is (R)-Hydroxybutrone as disclosed herein Solid form of Tony (eg Form C). Certain embodiments disclosed herein provide compositions comprising (R)-Hydroxybutonil, wherein at least 95% w/w of the total amount of (R)-Hydroxybutoni is (R)-Hydroxybutrone as disclosed herein Solid form of Tony (eg Form C). Certain embodiments disclosed herein provide compositions comprising (R)-Hydroxybutonil, wherein at least 98% w/w of the total amount of (R)-Hydroxybutoni is (R)-Hydroxybutrone as disclosed herein Solid form of Tony (eg Form C). Certain embodiments disclosed herein provide compositions comprising (R)-Hydroxybutonide, wherein at least 99% w/w of the total amount of (R)-Hydroxybutoni is (R)-Hydroxybutrone as disclosed herein Solid form of Tony (eg Form C).

Certain embodiments disclosed herein provide pharmaceutical compositions comprising Form C of any given embodiment and one or more pharmaceutically acceptable excipients.

Certain embodiments disclosed herein provide a solid form of (R)-hydroxybutanoi hydrochloride having an X-ray powder diffraction pattern comprising a peak at 7.5 degrees in 2-theta at about ambient relative humidity 2Θ ± 0.2 degrees 2Θ, eg Form B.

Certain embodiments disclosed herein provide a solid form of (R)-hydroxybutanoi hydrochloride having an X-ray powder diffraction pattern comprising a peak at 7.5 degrees in 2-theta at about ambient relative humidity 2Θ ± 0.2 degrees 2Θ and/or 17.2 degrees 2Θ ± 0.2 degrees 2Θ, eg Form B.

Certain embodiments disclosed herein provide a solid form of (R)-hydroxybutanoi hydrochloride having an X-ray powder surround comprising at least two peaks (eg, 2 or 3 peaks) at about ambient relative humidity radiation pattern, the peaks, expressed in 2-theta, are selected from the group consisting of 7.5 degrees 2Θ ± 0.2 degrees 2Θ, 17.2 degrees 2Θ ± 0.2 degrees 2Θ, and 14.1 degrees 2Θ ± 0.2 degrees 2Θ, eg, Form B.

Certain embodiments disclosed herein provide a solid form of (R)-hydroxybutanoi hydrochloride having an X comprising at least three peaks (eg, 3, 4, or 5 peaks) at about ambient relative humidity Ray powder diffraction pattern, the peaks expressed in 2-theta are selected from 7.5 degrees 2Θ ± 0.2 degrees 2Θ, 17.2 degrees 2Θ ± 0.2 degrees 2Θ, 14.1 degrees 2Θ ± 0.2 degrees 2Θ, 21.1 degrees 2Θ ± 0.2 degrees 2Θ, and 15.5 degrees 2Θ A group of 2θ ± 0.2 degrees 2θ, e.g. Form B.

Certain embodiments disclosed herein provide a solid form of (R)-hydroxybutanoi hydrochloride having at least one peak, at least two peaks, at least three peaks, at least four peaks at about ambient relative humidity , X-ray powder diffraction pattern of at least five peaks, at least six peaks, at least seven peaks, at least eight peaks, at least nine peaks, at least ten peaks, at least eleven peaks, and the peaks are 2-theta Indicates selected from 7.5 degrees 2θ ± 0.2 degrees 2θ, 17.2 degrees 2θ ± 0.2 degrees 2θ, 14.1 degrees 2θ ± 0.2 degrees 2θ, 21.1 degrees 2θ ± 0.2 degrees 2θ, 15.5 degrees 2θ ± 0.2 degrees 2θ, 12.9 degrees 2θ ± 0.2 degrees 2θ , 19.3 degrees 2θ ± 0.2 degrees 2θ, 24.4 degrees 2θ ± 0.2 degrees 2θ, 13.7 degrees 2θ ± 0.2 degrees 2θ, 12.4 degrees 2θ ± 0.2 degrees 2θ, 21.4 degrees 2θ ± 0.2 degrees 2θ, 18.1 degrees 2θ ± 0.2 degrees 2θ, 20.1 A group consisting of degrees 2θ ± 0.2 degrees 2θ, 6.6 degrees 2θ ± 0.2 degrees 2θ, 8.2 degrees 2θ ± 0.2 degrees 2θ, and 20.4 degrees 2θ ± 0.2 degrees 2θ, such as Form B.

Certain embodiments disclosed herein provide a solid form of (R)-hydroxybutanoi hydrochloride having an X-ray powder diffraction pattern substantially as shown in FIG. 3 at about ambient relative humidity, eg, Form B .

Certain embodiments disclosed herein provide a solid form of (R)-hydroxybutanoi hydrochloride with differential scanning calorimetry (DSC) exhibiting a melting onset at about 40°C and an endothermic peak at 64.8°C ) thermogram, eg Form B.

Certain embodiments disclosed herein provide a solid form of (R)-hydroxybutanoi hydrochloride having a differential scanning calorimetry (DSC) thermogram substantially as shown in FIG. 6 , eg, Form B .

Certain embodiments disclosed herein provide pharmaceutical compositions comprising a solid form (eg, Form B) of (R)-hydroxybutanoi hydrochloride disclosed herein and one or more pharmaceutically acceptable excipients .

In some embodiments, the solid form (R)-hydroxybutanoi hydrochloride is a crystalline mixture comprising less than 1% of Form B. In certain embodiments, the solid form (R)-hydroxybutrone hydrochloride is a crystalline mixture comprising more than 0.1% but less than 2% of Form B. In some embodiments, the solid form (R)-hydroxybutrone hydrochloride comprises at least 10% Form B. In some embodiments, the solid form (R)-hydroxybutanoi hydrochloride comprises at least 25% Form B. In some embodiments, the solid form (R)-hydroxybutanoi hydrochloride comprises at least 50% Form B. In some embodiments, the solid form (R)-hydroxybutrone hydrochloride comprises at least 75% Form B. In some embodiments, the solid form (R)-hydroxybutanoi hydrochloride comprises at least 95% Form B. In some embodiments, the solid form (R)-hydroxybutrone hydrochloride comprises at least 97% Form B. In some embodiments, the solid form (R)-hydroxybutanoi hydrochloride comprises at least 99% Form B.

Certain embodiments disclosed herein provide solid and solvated (hereinafter "solid solvated") forms, such as Form A, of (R)-hydroxybutanoi hydrochloride. In some embodiments, the solid hydrated form of (R)-hydroxybutanoi hydrochloride comprises isopropanol solvate.

Certain embodiments disclosed herein provide a solid solvated form of (R)-Hydroxybuttonib hydrochloride having an X-ray powder diffraction pattern at about ambient relative humidity comprising a peak, expressed in 2-theta, at At 19.2 degrees 2Θ ± 0.2 degrees 2Θ, eg Form A.

Certain embodiments disclosed herein provide a solid solvated form of (R)-Hydroxybuttonib hydrochloride having an X-ray powder diffraction pattern at about ambient relative humidity comprising a peak, expressed in 2-theta, at 19.2 degrees 2Θ ± 0.2 degrees 2Θ and/or 6.1 degrees 2Θ ± 0.2 degrees 2Θ, eg, Form A.

Certain embodiments disclosed herein provide a solid solvated form of (R)-hydroxybutanoi hydrochloride having X-rays comprising at least two peaks (eg, 2 or 3 peaks) at about ambient relative humidity Powder diffraction pattern, the peaks expressed in 2-theta are selected from the group consisting of 19.2 degrees 2Θ ± 0.2 degrees 2Θ, 6.1 degrees 2Θ ± 0.2 degrees 2Θ, and 7.7 degrees 2Θ ± 0.2 degrees 2Θ, eg, Form A.

Certain embodiments disclosed herein provide solid solvated forms of (R)-Hydroxybuttonib hydrochloride having at about ambient relative humidity comprising at least three peaks (eg, 3, 4, or 5 peaks) The X-ray powder diffraction pattern of , the peaks expressed in 2-theta are selected from 19.2 degrees 2Θ ± 0.2 degrees 2Θ, 6.1 degrees 2Θ ± 0.2 degrees 2Θ, 7.7 degrees 2Θ ± 0.2 degrees 2Θ, 12.9 degrees 2Θ ± 0.2 degrees 2Θ and A group of 21.6 degrees 2θ ± 0.2 degrees 2θ, e.g. Form A.

Certain embodiments disclosed herein provide a solid solvated form of (R)-hydroxybutanoi hydrochloride having X-rays comprising at least four peaks (eg, 4 or 5 peaks) at about ambient relative humidity Powder diffraction pattern with peaks expressed in 2-theta selected from 19.2 degrees 2Θ ± 0.2 degrees 2Θ, 6.1 degrees 2Θ ± 0.2 degrees 2Θ, 7.7 degrees 2Θ ± 0.2 degrees 2Θ, 12.9 degrees 2Θ ± 0.2 degrees 2Θ, and 21.6 degrees 2Θ A group of ± 0.2 degrees 2θ, e.g. Form A.

Certain embodiments disclosed herein provide solid solvated forms of (R)-Hydroxybuttonib hydrochloride having at least one peak, at least two peaks, at least three peaks, at least four peaks at about ambient relative humidity X-ray powder diffraction pattern of 1 peak, at least 5 peaks, at least 6 peaks, at least 7 peaks, at least 8 peaks, at least 9 peaks, at least 10 peaks, or at least 11 peaks, the peaks are represented by 2 -θ means selected from 19.2 degrees 2θ ± 0.2 degrees 2θ, 6.1 degrees 2θ ± 0.2 degrees 2θ, 7.7 degrees 2θ ± 0.2 degrees 2θ, 12.9 degrees 2θ ± 0.2 degrees 2θ, 21.6 degrees 2θ ± 0.2 degrees 2θ, 18.3 degrees 2θ ± 0.2 Degrees 2θ, 15.5 Degrees 2θ ± 0.2 Degrees 2θ, 22.8 Degrees 2θ ± 0.2 Degrees 2θ, 16.7 Degrees 2θ ± 0.2 Degrees 2θ, 17.6 Degrees 2θ ± 0.2 Degrees 2θ, 19.5 Degrees 2θ ± 0.2 Degrees 2θ, 14.6 Degrees 2θ ± 0.2 Degrees 2θ and a group of 20.8 degrees 2θ ± 0.2 degrees 2θ, such as Form A.

Certain embodiments disclosed herein provide a solid form of (R)-hydroxybutanoi hydrochloride having an X-ray powder diffraction pattern substantially as shown in FIG. 2 at about ambient relative humidity, eg, Form A .

Certain embodiments disclosed herein provide a solid form of (R)-hydroxybutanoi hydrochloride having a differential scanning calorimetry (DSC) thermogram exhibiting a broad endothermic transition with an initial endothermic peak at 70.2°C , there are additional endothermic peaks at 87.9°C and 119.4°C, such as Form A. The sample exhibited a weight loss of 28% between 29°C and 158°C.

Certain embodiments disclosed herein provide a solid form of (R)-hydroxybutanoi hydrochloride having a differential scanning calorimetry (DSC) thermogram substantially as shown in FIG. 5 , eg, Form A .

Certain embodiments disclosed herein provide amorphous solid forms of (R)-hydroxybutrone hydrochloride.

Certain embodiments disclosed herein provide for one or more crystalline and/or amorphous forms of (R)-hydroxybutrone hydrochloride dispersed in a matrix.

Disclosed are certain embodiments of dosage forms comprising (R)-hydroxybutonitrile hydrochloride, the dosage forms comprising about 0.1 to about 25 mg, about 0.1 to about 15 mg, about 0.1 to about 10 mg, about 1 to about 25 mg , about 1 to about 20 mg, about 1 to about 15 mg, about 1 to about 10 mg, about 1 to about 5 mg, about 2 to about 25 mg, about 2 to about 20 mg, about 2 to about 15 mg, About 2 to about 10 mg, about 2 to about 5 mg, about 5 to about 25 mg, about 5 to about 20 mg, about 5 to about 15 mg, or about 5 to about 10 mg in one or more crystalline forms (e.g., Form A , B and C) and/or an amorphous form of (R)-hydroxybutrone hydrochloride, wherein the one or more crystalline and/or amorphous forms are dispersed in a solid or liquid matrix. II. Pharmaceutical Compositions and/ or Formulations of Polymorphic Form of (R)-Hydroxybuttonib Hydrochloride

Provided herein are pharmaceutical compositions comprising one or more polymorphic forms of (R)-Hydroxybuttonib hydrochloride and a physiologically acceptable carrier (also known as a pharmaceutically acceptable carrier or solution or dilution) agent). Such carriers and solutions include pharmaceutically acceptable salts and solvates of the compounds used in the methods of the present invention, as well as pharmaceutically acceptable salts and solvates comprising two or more of these compounds, Mixtures of salts and pharmaceutically acceptable solvates of these compounds. These compositions are prepared according to acceptable pharmaceutical procedures such as those set forth in Remington's Pharmaceutical Sciences, 17th Edition, ed. Alfonso R. Gennaro, Mack Publishing Company, Eaton, Pa. (1985), in Incorporated herein by reference.

The term "pharmaceutically acceptable carrier" refers to a carrier that does not cause allergic reactions or other adverse effects in the individual to which it is administered and that is compatible with the other ingredients in the formulation. Pharmaceutically acceptable carriers include, for example, pharmaceutical diluents, excipients or carriers appropriately selected with regard to the intended form of administration and in accordance with conventional pharmaceutical practice. For example, solid carriers/diluents include, but are not limited to, gums, starches (eg corn starch, pregelatinized starch), sugars (eg lactose, mannitol, sucrose, dextrose), cellulosic materials (eg microcrystalline cellulose), acrylates (eg polymethacrylates), calcium carbonate, magnesium oxide, talc, or mixtures thereof. The pharmaceutically acceptable carrier may further contain minor amounts of auxiliary substances, such as wetting or emulsifying agents, preservatives or buffering agents, which prolong the shelf-life or effectiveness of the therapeutic agent.

One or more polymorphic and/or amorphous forms and pharmaceutical compositions of (R)-hydroxybutonitrile hydrochloride disclosed herein, and pharmaceutical compositions thereof, may be formulated into unit dosage forms, which are meant to be suitable for administration as a unitary dosage. Physically discrete units for use by the individual being treated, wherein each unit contains a predetermined amount of active material calculated to produce the desired therapeutic effect in association with an optional pharmaceutical carrier. The unit dosage form can be a single daily dose or one of multiple daily doses (eg, about 1 to 4 or more times per day). When multiple daily doses are used, the unit dosage form for each dose may be the same or different. In certain embodiments, the compounds can be formulated for controlled release.

One or more polymorphic and/or amorphous forms and pharmaceutical compositions of (R)-hydroxybutrone hydrochloride disclosed herein may be formulated according to any available conventional method. In the formulation, commonly used additives such as diluents, binders, disintegrants, lubricants, colorants, flavoring agents, and if necessary, stabilizers, emulsifiers, absorption enhancers, surfactants, pH adjusters, disinfectants, antioxidants and the like. For the purpose of oral therapeutic administration, the active compound can be mixed with excipients and used in the form of pills, troches, dragees, or capsules (eg, gelatin capsules). Oral compositions can also be prepared using fluid carriers. Pharmaceutically compatible binder and/or adjuvant materials can be included as part of the composition. Dosage forms (including lozenges, powders, granules, granules, coated lozenges, capsules, syrups, dragees, and the like) may contain any of the following ingredients or compounds of similar properties: Binders such as microcrystalline Cellulose, tragacanth or gelatin; excipients such as starch or lactose; disintegrants such as alginic acid, Primogel, crospovidone or corn starch; lubricants such as magnesium stearate or Sterotes; glidants , such as colloidal silica; sweeteners, such as sucrose or saccharin; or flavoring agents, such as peppermint, methyl salicylate, or orange flavoring.

Systemic administration of one or both of the compounds as described herein (ie, one or both of a norepinephrine reuptake inhibitor and a substantially spiegelmerically pure (R)-hydroxybutanibide) may also be It is applied to the skin by transdermal means, eg, using a patch, gel or lotion. For transdermal administration, penetrants suitable for penetrating the epidermal barrier can be used in the formulation. Such penetrants are well known in the art. For example, for transdermal administration, the active compounds can be formulated into ointments, salves, gels or creams as are well known in the art. Gels and/or lotions can be provided in individual sachets, or via a metered dose pump for daily application; see, eg, Cohn et al., Ther Adv Urol. 2016 Apr;8(2):83-90.

In some embodiments, the therapeutic compounds are prepared with carriers that will protect the therapeutic compounds against rapid elimination from the body, such as controlled release formulations, including implants and microencapsulated delivery systems. Biodegradable biocompatible polymers can be used, such as ethylene/vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Such formulations can be prepared using standard techniques or obtained commercially (eg, from Alza Corporation and Nova Pharmaceuticals, Inc). Liposomal suspensions can also be used as pharmaceutically acceptable carriers. These formulations can be prepared according to methods known to those skilled in the art, eg, as described in US Pat. No. 4,522,811.

The pharmaceutical compositions can be included in a container, pack, or dispenser along with instructions for administration or use in the methods set forth herein.

Some embodiments disclosed herein provide pharmaceutical dosage forms comprising (R)-Hydroxybutoni HCl Form C in an amount of about 0.1 mg, about 0.5 mg, about 0.75 mg, about 1 mg, about 2.5 mg , about 5 mg, about 7.5 mg, about 10 mg, about 12.5 mg, about 15 mg, about 17.5 mg, about 20 mg, about 22.5 mg, or about 25 mg.

Certain embodiments disclosed herein provide pharmaceutical dosage forms in lozenges comprising about 0.1 mg, about 0.5 mg, about 0.75 mg, about 1 mg, about 2.5 mg, about 5 mg, about 7.5 mg, about 10 mg, About 12.5 mg, about 15 mg, about 17.5 mg, about 20 mg, about 22.5 mg, or about 25 mg of (R)-hydroxybutanoi hydrochloride crystalline Form C. In certain embodiments, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99.5% of the (R)-hydroxybutrone in the lozenge is the (R)-hydroxybutrone salt Salt crystal form C.

Certain embodiments disclosed herein provide pharmaceutical compositions comprising about 0.1 mg, about 0.5 mg, about 0.75 mg, about 1 mg, about 2.5 mg, about 5 mg, about 7.5 mg, about 10 mg, about 12.5 mg , about 15 mg, about 17.5 mg, about 20 mg, about 22.5 mg, or about 25 mg of a solid form of (R)-hydroxybutanoi hydrochloride disclosed herein (eg, comprising Form B and/or Form C) and a or more pharmaceutically acceptable excipients.

In certain embodiments, the pharmaceutical dosage form comprises Form C as disclosed herein.

Certain embodiments disclosed herein comprise (R)-Hydroxybutoni HCl Form C, or pharmaceutical compositions thereof, substantially free of other crystalline or amorphous forms. For example, in some embodiments, relative to other crystalline or amorphous forms of (R)-Hydroxybutoni HCl, (R)-Hydroxybutoni HCl Form C, or a pharmaceutical composition thereof, comprises by weight 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% Form C. III. Use of the Polymorphic Form of (R)-Hydroxybuttonib Hydrochloride

Provided herein, in some embodiments, are methods of treating an individual having a condition associated with pharyngeal airway collapse, the method comprising administering to the individual in need thereof an effective amount of (i) a norepinephrine reuptake inhibitor (NRI) (eg atomoxetine or a pharmaceutically acceptable salt thereof) and (ii) substantially spiegelmerically pure (R)-hydroxybutonitrile hydrochloride. Such methods comprise administering to a subject a therapeutically effective amount of one or more polymorphic forms of (R)-hydroxybutyrin hydrochloride disclosed herein, or a pharmaceutical composition thereof. In some embodiments, the substantially enantiomerically pure (R)-hydroxybutrone hydrochloride is in Form C.

Provided herein, in other embodiments, is a method of treating an individual suffering from a disorder associated with pharyngeal airway collapse, the method comprising administering to the individual in need thereof an effective amount of (i) 4-hydroxyatomoxetine or a medicament thereof a pharmaceutically acceptable salt; and (ii) a substantially mirror-isomerically pure (R)-hydroxybutonitrile hydrochloride. Such methods comprise administering to a subject a therapeutically effective amount of one or more polymorphic forms of (R)-hydroxybutyrin hydrochloride disclosed herein, or a pharmaceutical composition thereof. In some embodiments, the substantially enantiomerically pure (R)-hydroxybutrone hydrochloride is in Form C.

In other embodiments, provided herein are methods of treating an individual suffering from a condition associated with pharyngeal airway collapse, the methods comprising administering to the individual in need thereof an effective amount of (i) 4-hydroxyatomoxetine or A pharmaceutically acceptable salt thereof; (ii) a substantially mirror-isomerically pure (R)-hydroxybutonitrile hydrochloride; and (iii) a sleeping pill. The method comprises administering to a subject a therapeutically effective amount of one or more polymorphic forms of (R)-hydroxybutrone hydrochloride disclosed herein, or a pharmaceutical composition thereof. In some embodiments, the substantially enantiomerically pure (R)-hydroxybutrone hydrochloride is in Form C.

In other embodiments, provided herein are methods of treating an individual suffering from a condition associated with pharyngeal airway collapse, the methods comprising administering to the individual in need thereof an effective amount of a pharmaceutical composition comprising as an active ingredient norepinephrine reuptake inhibitors (such as atomoxetine or a pharmaceutically acceptable salt thereof), substantially spiegelomerically pure (R)-hydroxybutrone hydrochloride and carbonic anhydrase inhibitors . The norepinephrine reuptake inhibitors, (R)-hydroxybutyrin hydrochloride and carbonic anhydrase inhibitors can be administered in a single composition or in separate compositions. The method comprises administering to a subject a therapeutically effective amount of one or more polymorphic forms of (R)-hydroxybutyrin hydrochloride disclosed herein together with a norepinephrine reuptake inhibitor and a carbonic anhydrase inhibitor. In some embodiments, (R)-Hydroxybuttonib hydrochloride is administered in Form C.

Exemplary norepinephrine reuptake inhibitors (NRIs) include selective NRIs Amedalin (UK-3540-1), atomoxetine (Strattera), CP-39,332, daredalin ( Daledalin) (UK-3557-15), Edivoxetine (LY-2216684), Esreboxetine, Lortalamine (LM-1404), Nisoxetine ( Nisoxetine (LY-94,939), Reboxetine (Edronax, Vestra), Talopram (Lu 3-010), Talsupram (Lu 5-005), Tandamin (Tandamine) (AY-23,946), Viloxazine (Vivalan); non-selective NRIs include Amitriptiline, Amoxapine, Bupropion, Ciclazindol, Desipramine, Desvenlafaxine, Dexmethilphenidate, Diethylpropion, Doxepin, Dulox Duloxetine, Imipramine, Levomilnacipran, Manifaxine (GW-320,659), Maprotiline, Methylphenidate ), Milnacipran, Nefazodone, Nortriptyline, Phendimetrazine, Phenmetrazine, Protryptyline, Radafaxine (GW-353,162), Tapentadol (Nucynta), Teniloxazine (Lucelan, Metatone) and Venlafaxine (Venlafaxine) and their pharmaceutically acceptable of salt.

In some embodiments, the norepinephrine reuptake inhibitor is atomoxetine or a pharmaceutically acceptable salt thereof. In other embodiments, the norepinephrine reuptake inhibitor is reboxetine or a pharmaceutically acceptable salt thereof. In other embodiments, the norepinephrine reuptake inhibitor is a combination of atomoxetine and reboxetine or a pharmaceutically acceptable salt thereof.

Hydroxybutonide is an antimuscarinic drug and a muscarinic receptor antagonist. In some embodiments, the hydroxybutytonide is a racemic mixture of (R)-hydroxybutronil and (S)-hydroxybutanoi. In some embodiments, the salt form or composition comprises a mixture of hydroxybutyrin enantiomers as set forth herein, wherein (R)-hydroxybutanoic is relative to its enantiomer pair (ie, (S)-hydroxybutanoi) Butoni) mirroring excess. The enantiomeric excess of (R)-hydroxybutanoib in such mixtures may be ≥10%, ≥20%, ≥25%, ≥30%, ≥40%, ≥50%, ≥60%, ≥70%, ≥75%, ≥80% or ≥90%.

In some embodiments, the muscarinic receptor antagonist is (R)-hydroxybutanoi which is substantially spiegelmer-pure. In some embodiments, substantially spiegelmer-pure (R)-hydroxybutrone (referred to herein as "(R)-hydroxybutrone") and/or salts thereof are resistant to long-term use in an individual Acceptability is superior to the racemic hydroxybutonitrile form. Compositions comprising substantially enantiomerically pure (R)-hydroxybutyrin as set forth herein and various polymorphs may have > 80%, > 90%, > 95%, > 98%, > 99% , ≥ 99.5%, ≥ 99.8%, or ≥ 99.9% of substantially mirror-pure (R)-hydroxybutanoic in a mirror-enantiomer excess.

Carbonic anhydrase inhibitors can be selected from the group consisting of: acetazolamide, dichlorophenamide, dorzolamide, brinzolamide, methazolamide ), zonisamide, ethoxzolamide, topiramate, sultiame, and any combination thereof or a pharmaceutically acceptable salt thereof. In some embodiments, the carbonic anhydrase inhibitor is acetazolamide or a pharmaceutically acceptable salt thereof.

In some embodiments, hypnotics can be incorporated into the composition, eg, zolpidem, zopiclone, eszopiclone, trazodone, zaleplon , benzodiazepines, gabapentin (gabapentin), tiagabine (tiagabine) and xyrem or a pharmaceutically acceptable salt thereof. In some embodiments, patients with OSA have low arousal thresholds that can be exacerbated by atomoxetine and/or 4-hydroxy atomoxetine. In these embodiments where patients have low arousal thresholds caused or exacerbated by the use of atomoxetine and/or 4-hydroxyatomoxetine, hypnotics may be used as supplemental active compounds to increase patients with Thresholds for arousal in patients with OSA, pharyngeal airway collapse, or a combination thereof. In some embodiments, a patient's arousal threshold may be measured by multi-channel sleep recording (PSG). In some embodiments, the patient is a human individual.

In some embodiments, the methods include administering a dose of about 20 mg to about 150 mg atomoxetine or a pharmaceutically acceptable salt thereof (or a dose equivalent of another NRI therewith), about 20 mg to about 100 mg atomoxetine or a pharmaceutically acceptable salt thereof, about 50 mg to about 100 mg atomoxetine or a pharmaceutically acceptable salt thereof, or about 75 mg to about 100 mg atomoxetine Atomoxetine or a pharmaceutically acceptable salt thereof. In some embodiments, the methods include administering doses of from about 0.1 mg to about 25 mg of (R)-Hydroxybutoni HCl, from about 1 mg to about 20 mg of (R)-Hydroxybutrone HCl , from about 1 mg to about 10 mg of (R)-Hydroxybuttonib hydrochloride, or from about 2.5 mg to about 7.5 mg of (R)-Hydroxybuttonib hydrochloride. In other embodiments, the methods include administering a dose of about 20 mg to about 150 mg atomoxetine or a pharmaceutically acceptable salt thereof (or a dose equivalent of another NRI therewith) and about 0.1 A combination of mg to about 25 mg (R)-hydroxybutrone hydrochloride, about 20 mg to about 150 mg atomoxetine or a pharmaceutically acceptable salt thereof, and about 1 mg to about 20 mg (R) - a combination of hydroxybutonitrile hydrochloride, about 20 mg to about 150 mg atomoxetine or a pharmaceutically acceptable salt thereof, and about 1 mg to about 10 mg (R)-hydroxybutonitrile hydrochloride A combination or a combination of about 20 mg to about 150 mg atomoxetine or a pharmaceutically acceptable salt thereof and about 2.5 mg to about 7.5 mg (R)-hydroxybutrone hydrochloride. In some embodiments, (R)-hydroxybutrone hydrochloride can be formulated and used as an active coating for NRI or atomoxetine. In other embodiments, (R)-Hydroxybutonyl hydrochloride can be formulated as a blend with NRI or atomoxetine.

In some embodiments, the methods comprise administering atomoxetine and/or 4-hydroxy atomoxetine or a pharmaceutically acceptable salt thereof at a dose of 20-100 mg at a dose of 2-15 mg of oxybutonib (that is, a muscarinic receptor antagonist) and a dose of 0.5-15 mg of zolpidem (or the equivalent of another sleeping pill). In some embodiments, the methods include administering 75 mg atomoxetine and/or 4-hydroxyatomoxetine/6 mg (R)-hydroxybutonitrile/10 mg zolpidem; 75 mg Atomoxetine and/or 4-hydroxyatomoxetine/5 mg oxybutonib/10 mg zolpidem; 75 mg atomoxetine and/or 4-hydroxyatomoxetine/4.5 mg hydroxy Buttonib/5 mg zolpidem; 50 mg atomoxetine and/or 4-hydroxyatomoxetine/4 mg hydroxybutonitrile/3.5 mg zolpidem; or 25 mg atomoxetine and/or Or 4-Hydroxyatomoxetine/3 mg Hydroxybutonib/1.75 mg Zolpidem, eg, 15-60 minutes, 15-25 minutes, 20-30 minutes, or 20-45 minutes before sleep time. In some embodiments, the hypnotic is present in an amount of about 0.5 mg to about 15 mg, about 0.5 mg to about 10 mg, about 0.5 mg to about 5 mg, about 0.5 mg to about 3.5 mg, or about 0.5 mg to about 1.75 mg.

In some embodiments, the methods include administering a dose of about 20 mg to about 150 mg atomoxetine or a pharmaceutically acceptable salt thereof (or a dose equivalent of another NRI therewith), about 20 mg to about 100 mg atomoxetine or a pharmaceutically acceptable salt thereof, about 50 mg to about 100 mg atomoxetine or a pharmaceutically acceptable salt thereof, or about 75 mg to about 100 mg atomoxetine Atomoxetine or a pharmaceutically acceptable salt thereof. In some embodiments, the methods include administering doses of from about 0.1 mg to about 25 mg of (R)-Hydroxybutoni HCl, from about 1 mg to about 20 mg of (R)-Hydroxybutrone HCl , from about 1 mg to about 10 mg of (R)-Hydroxybuttonib hydrochloride, or from about 2.5 mg to about 7.5 mg of (R)-Hydroxybuttonib hydrochloride. In some embodiments, the methods include administering doses of about 50 mg to about 1000 mg of acetazolamide (or a dosage equivalent of another CAI therewith), about 100 mg to about 800 mg of acetazolamide, About 250 mg to about 750 mg acetazolamide, about 500 mg to about 750 mg acetazolamide, or about 450 mg to about 650 mg acetazolamide. In some embodiments, the methods include administering doses of about 20 mg to about 150 mg NRI, about 1 mg to about 25 mg MRA comprising (R)-hydroxybutonitrile, and about 250 mg to about 750 mg carbonic acid Anhydrase inhibitors. In other embodiments, the methods comprise administering from about 50 mg to about 100 mg of NRI, from about 1 mg to about 15 mg of an MRA comprising (R)-hydroxybutanoi, and from about 250 mg to about 750 mg of carbonic anhydrase inhibitor agent. In other embodiments, the methods comprise administering in combination or alone the following doses: 80 mg atomoxetine/5 mg (R)-hydroxybutrone/500 mg acetazolamide; 80 mg atomoxetine / 5 mg Hydroxybutonib / 500 mg Acetazolamide; 100 mg Atomoxetine / 5 mg (R)-Hydroxybutoni / 500 mg Acetazolamide; 100 mg Atomoxetine / 5 mg ( R)-Hydroxybutonib/750 mg acetazolamide; or 80 mg atomoxetine/5 mg (R)-Hydroxybutoni/750 mg acetazolamide, e.g. 15-60 minutes before sleep time, For example 15-25 minutes, 20-30 minutes or 20-45 minutes.

An effective amount can be administered in one or more administrations, applications or doses. The compositions may be administered one or more times per day to one or more times per week; including once every other day. In some embodiments, the composition is administered daily. Those skilled in the art will appreciate that certain factors, including but not limited to, the severity of the disease or disorder, previous treatments, the general health of the individual, and/or age and other medical conditions present. Furthermore, treatment of an individual with a therapeutically effective amount of a therapeutic compound described herein can include a single treatment or a series of treatments.

The dosage, toxicity, and therapeutic efficacy of therapeutic compounds (ie, NRIs, MRAs, hypnotics, and CAIs, in a single composition or in separate compositions) can be determined in cell cultures or experimental animals by standard pharmaceutical procedures, For example, for the determination of LD50 (the dose lethal to 50% of the population) and ED50 (the dose therapeutically effective in 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index, and it can be expressed as the ratio LD50/ED50.

Information obtained from cell culture assays and animal studies can be used in the determination of a range of dosage for use in humans. The dosage of these compounds lies preferably within a range of circulating concentrations that include the ED50 with little or no toxicity. The dosage may vary within this range depending upon the dosage form employed and the route of administration utilized. For any compound used in the methods of the invention, the therapeutically effective dose can be estimated initially from cell culture assays. Dosages can be formulated in animal models to achieve a circulating plasma concentration range that includes the IC50 (ie, the concentration of the test compound that achieves half-maximal inhibition of symptoms) as determined in cell culture. This information can be used to more accurately determine useful doses in humans. Levels in plasma can be measured, for example, by high performance liquid chromatography. IV. Preparation and Characterization of Polymorphic Forms of (R)-Hydroxybuttonib Hydrochloride

Provided herein are methods for the preparation of crystalline polymorphic Forms A, B and C of (R)-hydroxybutrone hydrochloride. R-Hydroxybuttonib Hydrochloride Form A is the mono-HCl salt of R-Hydroxybutonitrile, which is solvated/hydrated and can be converted to R-Hydroxybutronil upon vacuum drying at room temperature and upon storage at ambient conditions Hydrochloride salt form B. R-Hydroxybuttonib hydrochloride Form C is obtained as a single crystalline phase which can be obtained in certain solvents and preparation conditions (such as R-Hydroxybuttonib hydrochloride in heptane or MIBK at room temperature for various periods of time) Slurry) competes with the formation of Form B. Form A

In some embodiments, crystalline R-Hydroxybutonib hydrochloride Form A can be prepared by adding an excess of 1.25 M HCl in IPA directly to R-Hydroxybutonib. The resulting golden solution can be stirred at room temperature to yield a thick white paste. A moist solid can be isolated and analyzed from the white thick paste. Figure 2 provides the XRPD pattern, and the corresponding peaks are provided in Table 1 below, indicating that the R-Hydroxybutoni HCl Form A material consists primarily or only of a single crystalline phase. Based on consideration of molecular volume, the index volume (1312.8 Å ³ /unit cell) indicates that the sample is likely to be solvated/hydrated.

To a solution of (R)-hydroxybutanoi free base (10 g, 28 mmol, 1.00 eq) in isopropanol (100 mL, 10 vol.) was added in isopropanol at 25°C over 5 minutes HCl (21.3 mL, 26.6 mmol, 0.95 eq). The resulting solution was aged for 1 hour, after which the batch was cooled to 0°C and aged for 30 minutes (3 x 2 vol.). The resulting thick white slurry was filtered under nitrogen and washed with isopropanol (3 x 20 mL). The hygroscopic solid (see Figure 2) was dried in a vacuum oven at 20°C-25°C for 24 h to obtain 9.8 g of (R)-hydroxybutonitrile hydrochloride (78% yield, 11.5 wt% isopropyl retention) alcohol, 0.5 wt% diethylamine).

The ¹ H NMR spectrum was consistent with the structure of R-hydroxybutanoi and contained 0.3 moles of IPA based on the presence of peaks at 4.1 ppm and 3.7 ppm. Water was also observed based on the peak at 3.3 ppm. Additional trace peaks were observed in the ¹ H NMR spectrum of the dissolved R-hydroxybutrone hydrochloride Form A material.

The R-Hydroxybuttonib hydrochloride Form A material was analyzed by ion chromatography (IC) to determine chloride content. IC analysis confirmed the presence of chloride ions at an API:Cl molar ratio of approximately 1 :1, indicating the monochloride salt of R-hydroxybutoni.

A thermal analysis of the R-hydroxybutonitrile hydrochloride Form A material is provided in FIG. 5 . Broad endotherms with maximum peaks at 70.2°C, 87.9°C, and 119.4°C were observed in the DSC data and correlated with continued weight loss in the TGA thermogram. The sample exhibited a weight loss of 28% between 29°C and 158°C.

R-Hydroxybuttonib hydrochloride Form A polymorph is prepared on a scale of about 2 g. A sub-sample of the scaled-up R-Hydroxybuttonib hydrochloride Form A was vacuum dried at room temperature for 24 hours and yielded a unique crystalline material designated R-Hydroxybuttonib hydrochloride Form B. R-Hydroxybuttonib hydrochloride Form B is discussed further below. Form B

In some embodiments, R-Hydroxybuttonib hydrochloride Form B can be prepared later by vacuum drying R-Hydroxybuttonib hydrochloride Form A at room temperature for 24 hours or at ambient conditions. The XRPD pattern of R-hydroxybutonitrile hydrochloride Form B is provided in Figure 3, indicating that the Form B material consists primarily or only of a single crystalline phase. Based on consideration of molecular volume, the index volume (4705.2 Å ³ /unit cell) indicates that the sample is likely to be anhydrous. Characterization data and methods of preparation indicate that R-Hydroxybutonil hydrochloride Form B is the anhydrous/unsolvated mono-HCl salt of R-Hydroxybutrone.

¹ H NMR analysis indicated that the material was consistent with the structure of API. Water is present in the spectrum at 3.3 ppm, however this may be due to potential water in the deuterated solvent.

A single broad endotherm (maximum peak) at 64.8°C was observed in the DSC thermogram (FIG. 6), which was attributed to melting based on hot stage microscopy. No significant weight loss was observed upon heating to melting.

IC analysis confirmed the presence of chloride ions in an API:Cl molar ratio of approximately 1 :1, indicating the monochloride salt of R-hydroxybutonide.

DVS analysis of R-Hydroxybutoni HCl Form B indicated that the material was hygroscopic, with the sample showing a 26.6% weight gain from 5% RH to 95% RH. Most of the weight gain occurred between 75% RH and 95% RH (23% weight gain). All weight gain disappeared upon desorption from 95% RH to 5% RH. XRPD analysis of the sample after DVS indicated that Form B was still present, indicating that no physical form change had occurred. A sample of R-Hydroxybutoni HCl Form B was exposed to 75% RH and 85% RH for 24 hours in an open container. After 24 hours at 75% RH, the white solid remained free flowing and the XRPD pattern was consistent with Form B. After 24 hours at 85% RH, the white solid was not free flowing, but XRPD analysis of the sample indicated that it consisted of Form B. The samples deliquesced after applying stress at 93% RH. Form C

In some embodiments, R-Hydroxybuttonib hydrochloride Form C can be prepared as a single crystalline phase at room temperature using a slurry of R-Hydroxybuttonib hydrochloride in heptane or MIBK over various periods of time Competes with the formation of Form B. The XRPD pattern of R-hydroxybutonitrile hydrochloride Form C is provided in Figure 4, indicating that the Form C material consists primarily or only of a single crystalline phase. Based on consideration of molecular volume, the index volume indicates that the sample is likely to be anhydrous. Characterization data and methods of preparation indicate that R-Hydroxybuttonib hydrochloride, Form C, is the anhydrous/unsolvated mono-HCl salt of R-Hydroxybutonil.

To a 3-neck round-bottom flask equipped with an overhead stirrer, nitrogen inlet, temperature probe was added (R)-hydroxybutrone free base (15.47 g, 210 moles, 1 eq) followed by MTBE (943 mL, 15.5 vol.). To the resulting solution was added HCl in EtOAc (298 mL, 298 mmol, 1 M HCl in ETOAc, 1.3 eq) over 45 minutes. After adding about a quarter volume of HCl, a thick slurry was observed to form. The thick slurry was warmed to 40°C and aged for 1 hour. The batch was then cooled to 0°C (30 min aging), filtered under nitrogen and washed with 2 x 2 vol. (2 x 164 mL) of cold MTBE. The solid was dried in vacuo at 20°C-25°C for 24 h to obtain crystals of (R)-hydroxybutanoi hydrochloride Form C (83 g, 94% yield, 99% potency).

The ¹ H NMR spectrum of R-hydroxybutanoi hydrochloride is provided in FIG. 10 and the FT-IR spectrum is provided in FIG. 11 . Analysis of both ¹ H NMR and FT-IR spectra indicated that the (R)-hydroxybutrone hydrochloride Form C material was consistent with the structure of the API.

A broad endotherm (maximum peak) at 119.4°C was observed in the DSC thermogram (Figure 7). The LCMS trace of (R)-hydroxybutytonide Form C is provided in FIG. 12 and illustrates that the dominant single peak with mass 358.49 corresponds to the [M+1] mass of R-hydroxybutytonide. Referring to Figure 13, ie, an achiral HPLC chromatogram of (R)-hydroxybutrone Form C, which indicates the purity of the Form C sample. Finally, the IC analysis provided in the ion chromatogram of Figure 14 confirmed the presence of chloride ions in an API:Cl molar ratio of approximately 1 : 1, indicating that the Form C material is the monochloride salt of R-hydroxybutanoi.

The target R-hydroxybutanoic stereoisomer can be prepared by chromatographic separation of the hydroxybutanoic racemic mixture using the chiral selective resin Lux Amylose-1. The isolated free base can then be converted to Form C hydrochloride. The synthetic scheme for the formation of this hydrochloride salt is shown below.

The first step of this scheme was carried out to remove residual diethylamine (DEA) entrained in the free base product from the purification step. The second step involved the carbon treatment of R-hydroxybutanoi free base and the reverse addition of the MTBE free base solution to the HCl solution in portions to form the hydrochloride salt. The reverse addition sequence prevents the product from precipitating on the reactor walls as glass or shell. Exemplary processes for producing Form C hydroxybutanoi hydrochloride are provided in further detail below.

R-Hydroxybutoni (611 g) was dissolved in methyl tertiary butyl ether (MTBE) (6 L) with stirring. Purified water (3 L) was added and the batch was stirred for 15 minutes. The layers were separated and the lower aqueous phase was removed. The MTBE layer was washed two more times with purified water (2 x 3 L) and checked for product content before the combined lower aqueous phase was sent to waste. The organic phase was filtered into a pre-weighed clean and dry rotary evaporation flask, which was then attached to a rotary evaporator. The bath temperature was set to 33°C, and the contents of the bottle were concentrated until distillation ceased. MTBE (6 L) was added to the rotary evaporator and the contents were concentrated until distillation ceased. A final charge of MTBE (6 L) was added to the rotary evaporator and the contents were concentrated until distillation ceased. The residual water in the samples from the rotary evaporator was analyzed by Karl Fischer titration (typical results were about 0.2%).

The contents of the rotary evaporator were dissolved in MTBE (4.6 L) and Darco G60 (activated carbon) (61.3 g) was added. The batch was stirred for at least 1 hour before being filtered through a pad of celite. Use MTBE (1 L) to flush any material from the reactor to the filter cake. The filtrate was collected in a clean glass jar labeled charcoal treated batch. A solution of MTBE (3.0 L) and 1 M HCl/EtOAc (2.32 L) was filtered online into a clean vessel. The batch temperature was set to 20±5°C. The charcoal treatment batch (1.2 L) was added over 20 minutes while maintaining the batch temperature at 20±5°C. R-Hydroxybutoni HCl seed crystals (3.2 g) were added and stirred for 5 minutes. The remainder of the charcoal treated batch (4.8 L) was added over 33 minutes while maintaining the batch temperature at 20±5°C. To the crystallizer was added the MTBE (640 mL) wash of the charcoal treated batch vessel. The batch was stirred at 20±5°C for 35 minutes. The batch temperature was adjusted to 35±5°C over 30 minutes. The batch was stirred at this temperature for more than 2 hours and then adjusted to 0±5°C over 2 hours. The batch was stirred at 0±5°C for at least 10 hours after which the solids were isolated by filtration. Two pre-cooled MTBE washes (1.8 L x 2) were filtered in-line and added to the reactor to remove any solids from the reactor before passing through the filter cake. The wet cake was transferred to a drying pan and placed in a vacuum oven at 25±5°C until residual solvent was within specification. 582 g of dry product were packaged and sampled. This process produced the form C HCl salt of R-hydroxybutanoi in high yields, including a batch yield of 86.5%.

Alternative processes can be used to remove DEA impurities without the use of aqueous extraction of the MTBE layer. When R-Hydroxybuttonib free base was dissolved in MTBE, DEA was isolated as an insoluble precipitate along with impurities. Therefore, the MTBE solution can be carbon treated, and subsequent filtration of the carbon will also remove DEA and impurities. The water-azeotrope step can thus be omitted since there is no water to be removed before the HCl salt is formed. The filtered free base MTBE solution can then be added directly to the MTBE solution and the 1 M HCl/EtOAc solution.

Another procedure to produce R-hydroxybutonitrile hydrochloride Form C is described in Example 27. In general, provided herein, in some embodiments, is a process for producing crystalline R-hydroxybutanoi hydrochloride in Form C, the process comprising utilizing D-malic acid (or other optically active acid) via chiral resolution from outside Isolation of (R)-Hydroxybutrone by Racemic Hydroxybutoni; and HCl was added to the isolated (R)-Hydroxybutoni to produce Form C, crystalline (R)-Hydroxybutrone hydrochloride. In some embodiments, isolating (R)-hydroxybutytonide from racemic oxybutonide comprises adding D-malic acid (or other optically active acid) to racemic oxybutonide free base. In some embodiments, D-malic acid (or other optically active acid) is added to the racemic hydroxybutanoi free base in the presence of 2-propanol. In some embodiments, HCl is added in the presence of ethyl acetate. In some embodiments, the process further includes adding MTBE to the isolated (R)-hydroxybutanoi after adding the HCl. Instead of D-malic acid, other optically active acids (eg, tartaric acid) can be used to chiral resolve oxybutoni. (R)-Hydroxybutoni citrate material

In some embodiments, dioxane may be obtained by adding dioxane to a solution of (R)-hydroxybutytonide and citric acid in a molar ratio of 2:1, 1:1, or 1:2 in p-dioxane at room temperature with stirring. R-Oxybutynin citrate is precipitated from the resulting solution of ether to prepare R-Hydroxybutonitrile citrate material. In some embodiments, a gel phase is observed prior to the production of solid R-hydroxybutanoi citrate material. Solid R-Hydroxybutoni citrate usually precipitates within 1 hour with stirring at room temperature, and it is stirred for a further 7-10 days.

< ¹ >H NMR analysis performed on two samples of R-hydroxybutanoi citrate material generated from the experiments confirmed that the molar ratios of API to acid were 2:1 and 1:1. The ¹ H NMR spectra of the two samples confirmed the presence of both R-hydroxybutanoi and citric acid, but indicated the presence of excess citric acid (eg, 1:2.6 and 1:1.3 API:citric acid molar ratios). Example Apparatus and Methods A. X-ray Powder Diffraction (XRPD)

The X-ray diffraction patterns were collected using two x-ray diffractometers as set forth below. a. PANalytical X'Pert PRO MPD or PANalytical Empyrean diffractometer - transmission

XRPD patterns were collected using a PANalytical X'Pert PRO MPD or a PANalytical Empyrean diffractometer using an incident beam of Cu radiation generated using a long fine focus source. The Cu Kα X-rays were focused through the sample and onto the detector using an elliptically graded multilayer mirror. A silicon sample (NIST SRM 640e) was analyzed prior to analysis to confirm that the observed Si 111 peak location was consistent with the NIST certified location.

Sample coupons were sandwiched between 3-μm thick films and analyzed in transmission geometry. Air-generated background is minimized using beam interceptors, short anti-scatter extensions, and anti-scatter knife edges. Axial divergence induced broadening and asymmetry was minimized using Soller slits for the incident and diffracted beams. Diffraction patterns were collected using a scanning position sensitive detector (X'Celerator) located 240 mm from the sample and Data Collector software version 2.2b or 5.5. The data acquisition parameters are as follows: X-ray tube: Cu (1.54059 Å), voltage: 45 kV, amperage: 40 mA, scanning range: 1-40 °2θ, step size: 0.017 °2θ, scanning speed: 3.3°/min, Slit: DS: Fixed slit 1/2°, SS: Null, rotation time 1.0 s. The instrument is marked as X'Pert PRO MPD in all images, regardless of the instrument used. b. PANalytical X’PERT Pro MPD Diffractometer - Reflection

XRPD patterns were collected using a PANalytical X'Pert PRO MPD diffractometer using an incident beam of Cu Ka radiation generated using a long fine focus source and a nickel filter. The diffractometer is configured using a symmetrical Bragg-Brentano geometry. A silicon sample (NIST SRM 640e) was analyzed prior to analysis to confirm that the observed Si 111 peak location was consistent with the NIST certified location. The sample specimens were prepared as thin circular layers centered on the silicon zero-background substrate. Air-generated background was minimized using an anti-scatter slit (SS). The broadening due to axial divergence is minimized using Soler slits for the incident and diffracted beams. Diffraction patterns were collected using a scanning position sensitive detector (X'Celerator) located 240 mm from the sample and Data Collector software version 5.5. The data acquisition parameters are as follows: X-ray tube: Cu (1.54059 Å), voltage: 45 kV, amperage: 40 mA, scanning range: 3.51-40°2θ, step size: 0.017°2θ, scanning speed: 1.2°/min, Slit: DS: Fixed slit 1/8°, SS: Fixed slit 1/4°. B. Nuclear Magnetic Resonance (NMR): ¹ H NMR and ¹³ C NMR

Solution 1H NMR spectra were acquired using an Agilent DD2-400 spectrometer or an Avance 600 MHz NMR spectrometer. Samples were prepared by dissolving in DMSO-d6 with TMS. C. Thermogravimetric Analysis/Differential Scanning Calorimetry (TGA/DSC)

TGA/DSC analysis was performed using a Mettler-Toledo TGA/DSC3+ analyzer. Temperature correction is performed using indium, tin and zinc. The samples were placed in closed aluminum pans. The pan was hermetically sealed, the lid pierced, and inserted into the TG oven. A weighed aluminum pan, configured as a sample pan, was placed on the reference platform. Heat the furnace under nitrogen. The data acquisition parameters for the thermograms are shown in the images in the graphs section of this report. D. Thermogravimetric Analysis - Infrared Spectroscopy

Thermogravimetric Infrared (TG-IR) analysis was performed on a TA Instruments Q5000 IR Thermogravimetric (TG) analyzer interfaced to an Ever-Glo mid/far IR source, potassium bromide (KBr) beam splitter Magna-IR 560® Fourier transform infrared (FT-IR) spectrophotometer (Thermo Nicolet) with mercury cadmium telluride (MCT-A) detector. FT-IR wavelength verification was performed using polystyrene and TG calibration standards were nickel and Alumel™. The sample was placed in a platinum sample pan, and the pan was inserted into the TG furnace. Start the TG instrument first, followed by the FT-IR instrument. The TG instrument was operated at a helium flow of 90 cc/min. and 10 cc/min. for purging and equilibration, respectively. The furnace was heated to a final temperature of 350°C at a rate of 10°C/min under helium. IR spectra were collected approximately every 32 seconds for approximately 13.5 minutes. Each IR spectrum represents 32 co-additive scans collected at a spectral resolution of 4 cm−1. Volatile species were identified from searches of the high-resolution Nicolet gas-phase spectral library. E. Ion Chromatography (IC)

Ion chromatographic analysis was performed using a Dionex ICS-5000+ series ion chromatograph. The ICS-5000+ consists of two chromatography systems that share an autosampler. The system for anion detection is equipped with gradient pump, eluent generator module, conductivity detector and suppressor (AERS 4 mm). A Dionex UTAC-ULP1 5×23 mm concentrator column was installed in place of the sample loop. Install Dionex IonPac™ AG19 4 x 50 mm guard column and Dionex IonPac™ AS19 4 x 250 mm analytical column. The eluent reservoir was filled with water (18.2 MΩ, dispensed by ELGA Purelab Flex 2) for standard preparation and autosampler flush. DMSO was used for sample preparation and associated blank injections. Run Time: 25.000 min Flow Rate: 1.000 mL/min Injection Volume: 100.0 μL Data Collection Rate: 5.0 Hz Detector Rise Time: 0.50 sec Bath Temperature: 30°C Column Temperature: 30°C Compartment Temperature: 30°C Autosampler Chamber temperature: 30°C Inhibition current: 124 mA Eluent generator column: EGC III KOH Eluent concentration gradient time (min) Concentration (mM) 0.000 3.5 10.000 15.00 20.000 40.00 22.000 40.00 22.500 3.5 25.000 3.50 Examples 1 to 11. Isolation of Solid (R) -Hydroxybutterol in Crystalline Forms A , B and C

Examples 1 to 11 focus on optimizing solvent volume and co-solvent addition to understand the effect of hydrochloric acid (HCl) equivalents and the effect of temperature on (R)-hydroxybutonitrile salt formation. A preliminary screening of reaction conditions is summarized in Table 1.

The hydrochloride salt of R-hydroxybutanoi was first prepared using 3.3 equivalents of HCl in isopropanol. As seen in Examples 1 to 4 of Table 1 below, the use of three equivalents of HCl yielded the oily salt form, regardless of solvent volume or combination. The combination of ethyl acetate/MTBE and substoichiometric HCl charge also produced an oil (see Example 5). The combination of isopropanol and MTBE provided in Example 5 produced hydrochloride needles. After extensive drying under high vacuum, the solids retained 13 wt% isopropanol (API to isopropanol molar ratio of 1 :1), but did not correspond to any of the R-hydroxybutonitrile hydrochloride In known form, the solid crystallized after 48 hours from isopropanol and 0.95 equivalents of HCl also did not correspond (see Examples 6 and 7).

Further analysis confirmed that the 5 g (see Example 8) and 10 g (see Example 9) scale-up of the reaction conditions mentioned in Example 5 resulted in the crystallization of the Form A solid when stirred at 20°C for a short period of time (1 hour). . Form A is a hygroscopic isopropanol solvate of R-hydroxybutonitrile hydrochloride, which retains 11 wt% to 13 wt% solvent.

When the salt formation reaction was carried out in MTBE (see Example 10) at 10 degrees higher temperature (35°C), a powdery solid was produced which retained a very low percentage of water (1.6 wt%). These solids are not hygroscopic and correspond to new powder XRPD patterns. The ¹ H NMR spectrum was matched to an achiral reference standard of R-hydroxybutanoi purchased from Sigma-Aldrich. The new observed powder diffraction pattern was named Form C. Form C solids were also produced when salt formation was carried out in cyclopentyl methyl ether (CPME) (see Example 11). Table 1. Preparation of R-Hydroxybutoni HCl example Reaction conditions Yield % annotation XRPD 1 IPA (10 vol.) 1.25 M HCl in IPA (3.3 eq) 20°C-30°C/24 h/concentrate ND ^a oil ND 2 IPA (10 vol.) MTBE (8 vol.) 1.25 M HCl in IPA (3.3 eq) 20°C-30°C/24 h/concentrate ND oily solid ND 3 IPA (2 vol.) 1.25 M HCl in IPA (3.3 eq) 20°C-30°C/24 h/concentrate ND yellow oil ND 4 1.25 M HCl in IPA (3.3 eq) 20°C-30°C/24 h/concentrate ND thick oil ND 5 EtOAc (4 vol.), MTBE (15 vol.) 1M HCl in EtOAc (0.88 eq) 35°C-45°C/1 h/concentrate 87 Oil (28 wt% EtOAc) ND 6 IPA (4 vol.) MTBE (15 vol.) 1.25 M HCl in IPA (1.1 eq) 20°C-30°C /1 h/filter 88 Solids (13 wt% IPA, 2.4 wt% H ₂ O ^b ) Not Form A or B 7 IPA (10 vol.) 1.25 M HCl in IPA (0.95 eq) 20°C-30°C/3 days/filter 73 Fluffy solid (13 wt% IPA, 5.2 wt% _H2O ) Not Form A or B 8 IPA (10 vol.) 1.25 M HCl in IPA (0.95 eq) 20°C-30°C/1 h/filter 92 Needles (13 wt% IPA, no _H2Ob ⁾ Form A 9 IPA (10 vol) 1.25 M HCl in IPA (0.95 eq) 20°C-30°C/1 h/ 0°C, 0.5 h 78 (Needles, 11.5 wt% IPA and 0.5 wt% DEA) ^c . The product was in the filtrate, (23%, 11 wt% IPA, 9.9 wt% DEA). Form A 10 MTBE (10 vol.) 1.0 M HCl in EtOAc (1.1 eq) 20°C-30°C/1 h/filter 75 Needles (1.6 wt% H ₂ O) Form C 11 CPME (10 vol) 3.0 M HCl in CPME (0.95 eq) 40°C/1 h/filter 77 Solid (by NMR 1.6 wt%, 3.4 wt% DEA) Form C a Not determined b Hygroscopic solid c DEA is diethylamine Examples 12 to 17. Isolation of solids in crystalline forms A , B and C (R) -Hydroxybutoni

Form A is believed to be a reasonable starting material to generate Form B, which is more stable. Table 2 summarizes efforts to synthesize Form B from Form A. Acetone and heptane recrystallisation of the R-hydroxybutonitrile hydrochloride oil (see Example 5, Table 1 ) yielded Form C as a non-hygroscopic solid. The solid was isolated in 71% yield with 0.62% residual water (see Example 12, Table 2).

Recrystallization using a solid of Form A ("Form A solid") in tetrahydrofuran and ethyl acetate at elevated temperature with MTBE as an antisolvent (see Examples 13 and 14) also yielded Form C, which confirms Form C of stability.

Reslurry of Form A in MTBE at 50°C for 24 hours also yielded Form C crystals (see Example 15). The same form was also produced after seeding recrystallization of Form A in toluene using Form B seeds at 70°C (see Example 16). Higher temperature vacuum drying (50°C for 24 h) also did not convert Form A to Form B (see Example 17), but isolated Form C. Therefore, Form C was found to be a highly stable form. Form C diffraction patterns were observed after extended slurries of both Form A and Form B in both MIBK and heptane, respectively, which indicates that Form C is the thermodynamically better and more stable R-hydroxybutanoi The hydrochloride salt polymorph. Table 2. Recrystallization of R-Hydroxybuttonib Hydrochloride Form A example experiment Reaction conditions Yield isolated product XRPD 12 R-Hydroxybuttonib hydrochloride (1 g, Form A solid) Acetone (3 vol.) Heptane (10 vol.) 20℃-25℃ Seed (71%) powder solids The reaction mixture was seeded with the Form A solid and this promoted crystallization. The batch was cooled to 0°C and the filtered solids were dried at 20°C-25°C. Residual water was 0.62 wt%. Form C 13 R-Hydroxybuttonib Hydrochloride Form A (500 mg, Form A solid) EtOAc (14 vol.) MTBE (10 vol.) 50°C, 3 h cooled to 0°C and reslurried (97%) powder solids Cooled and filtered solid, ¹ H NMR indicated 3.5 wt% DEA, 1.7 wt% _H2O Form C 14 R-Hydroxybuttonib Hydrochloride Form A (500 mg, Form A solid) THF (3.4 vol) MTBE (10 vol) 50 ℃, 3 h cooling to 0 ℃ reslurry (69%) powder solids The oil/solid which melted at 20°C-25°C was cooled filtered and dried, which was dried at 20°C-25°C over the weekend to yield a solid. ¹ H NMR indicated 2.5 wt% DEA, 2.5 wt% _H2O and 1.2 wt% IPA. Form C 15 R-Hydroxybuttonib Hydrochloride Form A (1 g, Form A solid) MTBE (10 vol.) 50°C, 24 h cooling to 0°C for reslurrying (100%) Powdered Solids Powdery solid, ¹ H NMR indicated 2.5 wt% diethylamine, 1.7 wt% _H2O Form C 16 R-Hydroxybuttonib Hydrochloride Form A (580 mg, Form A solid) Toluene (9 vol) at 70°C, cooled to 0°C for 2 h, seeded for recrystallization (94%) powder solids Cool filtered and dried at 20°C-25°C. ¹ H NMR indicated 2.6 wt% DEA, 1.5 wt% _H2O . No residual toluene. Form C 17 Dry Form A at 50°C for 2 days N/A N/A High temperature drying form A Form C Examples 18 to 20. Further preparation

Treatment of R-Hydroxybutoni free base with HCl in IPA yielded a Form A solid as expected. There was no significant difference in the powder diffraction pattern of Form A with or without diethylamine. Form C was isolated from salt forming reactions carried out in MTBE (see Examples 18-19 of Table 3).

Recrystallization of purified Form A was performed in toluene at 70°C using seeds of Form B. The isolated product corresponds to Form C by XRPD (see Example 20). Table 3. Further preparation of R-Hydroxybutoni HCl Example input / scale condition Yield % XRPD annotation 18 R-Hydroxybutoni (820 mg) (DEA free, 95.6% potency) 10 vol isopropanol 1.25 M HCl in IPA (0.95 eq) 20°C-25°C, 1 h 0°C, 0.5 h (87) Powdered solid Form A 13 wt% IPA by ¹ H NMR 19 R-Hydroxybutoni (820 mg) (DEA free, 95.6% potency) 15.5 vol MTBE 1.0 M HCl in EtOAc (0.95 eq) 40°C, 1 h (68) Powdered solid Form C H ₂ O 0.8 wt% by ¹ H NMR 20 R-Hydroxybuttonib Hydrochloride Form A (DEA Free) (Solid, 410 mg) Toluene (4.9 mL, 12 vol.) recrystallized at 70°C/1 h (seeded form B) (93) Powdered solid Form C H ₂ O 0.6 wt% by ¹ H NMR Examples 21 to 26. Process Development

Examples 1-20 demonstrate that the preparation of Form B is not straightforward or reproducible and would be difficult to scale up. Therefore, an additional example was carried out to prepare Form C of (R)-hydroxybutanoi hydrochloride. MTBE proved to be the best choice for the formation of unsolvated Form C. Table 4 provides a summary of process development. As indicated in Table 4, Examples 21 and 22, the reaction of (R)-hydroxybutanoic free base with substoichiometric equivalents of HCl in ethyl acetate yielded only 60%-65% of the salt with 99% potency.

The yield of the process improved as the HCl charge was increased. As seen previously, 1.1 equiv of HCl yielded 82% product. On the other hand, the addition of 1.5 equivalents of HCl increased the recovery to 96% and decreased the efficiency by 3%. The optimal conditions involved the addition of 1.3 equivalents of HCl, resulting in 98% potency and 90% isolated yield (Examples 23 to 25 of Table 4).

Based on these results, the procedure was successfully demonstrated using 1.3 equivalents of 1.0 M HCl in ethyl acetate on an input of 83 g R-hydroxybutanoi (see Example 26). The solid conformed to the XRPD pattern of Form C (83 g, 94% yield, 99% potency). Thus, the generation of Form C can be advantageously scaled up.

Form C isolated from all runs summarized in Table 4 retained 0.5 wt% - 0.6 wt% water, except Example 21, in which 0.8 equivalents of HCl was used (1.5 wt% water retained).

The results from Table 4 below are summarized in Figure 8 in graphical form. Table 4. Preparation of R-Hydroxybuttonib Hydrochloride Form C from R-Hydroxybutonitrile Free Base example input / scale condition Yield % ^a Efficacy (wt%) XRPD annotation twenty one R-Hydroxybutoni (1 g) 15.5 vol MTBE 1.0 M HCl in EtOAc (0.8 equiv.) 40°C, 1 h 0°C, 0.5 h (0.74 g, 65%) powdery solid 99 Form C _H2O was 1.5 wt% by ¹ H NMR. twenty two R-Hydroxybutoni (10 g) 15.5 vol MTBE 1.0 M HCl in EtOAc (0.95 equiv.) 40°C, 1 h 0°C, 0.5 h (6.7 g, 60%) powdery solid 99.5 Form C _H2O was 0.6 wt% by ¹ H NMR. The filtrate showed 34% of the free base unreacted. twenty three R-Hydroxybutoni (3.4 g) 15.5 vol MTBE 1.0 M HCl in EtOAc (1.1 equiv.) 40°C, 1 h 0°C, 0.5 h (3.0 g, 82%) powdery solid 100 Form C _H2O was 0.5 wt% by ¹ H NMR. The filtrate showed 7% of the free base unreacted. twenty four R-Hydroxybutoni (3.6 g) 15.5 vol MTBE 1.0 M HCl in EtOAc (1.3 equiv.) 40°C, 1 h 0°C, 0.5 h (3.4 g, 90%) powdery solid 98 Form C _H2O was 0.5 wt% by ¹ H NMR. The filtrate showed 8% of the free base unreacted. 25 R-Hydroxybutoni (3.6 g) 15.5 vol MTBE 1.0 M HCl in EtOAc (1.5 equiv.) 40°C, 1 h 0°C, 0.5 h (3.7 g, 96%) powdery solid 96 Form C _H2O was 0.5 wt% by ¹ H NMR. The filtrate showed 1% of the free base unreacted. 26 R-Hydroxybutoni (67.2 g) 15.5 vol MTBE 1.0 M HCl in EtOAc (1.3 equiv.) 40°C, 1 h 0°C, 0.5 h (83 g, 94%) powdered solid 99 Form C _H2O was 0.4 wt% by ¹ H NMR. A 4% loss of product yield was observed in the filtrate (oil). No unreacted free base was observed in the filtrate. a Corrected yield for both input and output. Characterization of (R) -Hydroxybutoni Forms A , B and C

Samples of each of the three crystalline polymorphs of R-hydroxybutyrin hydrochloride were analyzed using XRPD analysis. Forms A, B and C XRPD patterns of R-Hydroxybutonil hydrochloride do not match any known polymorphic forms of hydroxybutrone or (S)-Hydroxybutoni. Referring to Figure 1, an overlay of the Forms A, B and C XRPD patterns of R-hydroxybutrone hydrochloride is provided. The individual XRPD patterns of Form A and Form B are shown in Figures 2 and 3, respectively. The Form A and Form B XRPD peak lists illustrated in Figures 2 and 3 are provided in Tables 5 and 6 below. Table 7 provides a list of XRPD peaks corresponding to the Form CR-hydroxybutyrin hydrochloride polymorph illustrated in FIG. 4 . Table 5. XRPD Peaks of Form A at Ambient Relative Humidity content Angle (2Ɵ) d space (Å) Strength (%) 6.07 6.07 ± 0.20 14.549 ± 0.479 80 7.7 7.70 ± 0.20 11.472 ± 0.298 52 9.11 9.11 ± 0.20 9.7 ± 0.212 13 10.47 10.47 ± 0.20 8.442 ± 0.161 14 12.14 12.14 ± 0.20 7.285 ± 0.120 16 12.86 12.86 ± 0.20 6.878 ± 0.107 52 13.45 13.45 ± 0.20 6.578 ± 0.097 9 13.73 13.73 ± 0.20 6.444 ± 0.093 8 14.57 14.57 ± 0.20 6.075 ± 0.083 twenty two 15.31 15.31 ± 0.20 5.783 ± 0.075 18 15.46 15.46 ± 0.20 5.727 ± 0.074 28 16.65 16.65 ± 0.20 5.320 ± 0.063 27 17.63 17.63 ± 0.20 5.027 ± 0.057 27 18.3 18.30 ± 0.20 4.844 ± 0.052 36 18.82 18.82 ± 0.20 4.711 ± 0.050 18 19.22 19.22 ± 0.20 4.614 ± 0.048 100 19.49 19.49 ± 0.20 4.551 ± 0.046 27 20.84 20.84 ± 0.20 4.259 ± 0.040 twenty one 21.03 21.03 ± 0.20 4.221 ± 0.040 16 21.56 21.56 ± 0.20 4.118 ± 0.038 45 22.03 22.03 ± 0.20 4.032 ± 0.036 16 22.27 22.27 ± 0.20 3.989 ± 0.035 12 22.8 22.80 ± 0.20 3.897 ± 0.034 28 23.23 23.23 ± 0.20 3.826 ± 0.032 14 23.62 23.62 ± 0.20 3.764 ± 0.031 14 23.8 23.80 ± 0.20 3.736 ± 0.031 13 23.96 23.96 ± 0.20 3.711 ± 0.031 14 24.59 24.59 ± 0.20 3.617 ± 0.029 16 25.14 25.14 ± 0.20 3.540 ± 0.028 15 25.67 25.67 ± 0.20 3.468 ± 0.027 10 25.95 25.95 ± 0.20 3.431 ± 0.026 13 26.57 26.57 ± 0.20 3.352 ± 0.025 13 27.03 27.03 ± 0.20 3.296 ± 0.024 11 27.67 27.67 ± 0.20 3.222 ± 0.023 14 27.86 27.86 ± 0.20 3.199 ± 0.023 14 28.14 28.14 ± 0.20 3.168 ± 0.022 13 28.84 28.84 ± 0.20 3.093 ± 0.021 7 29.1 29.10 ± 0.20 3.066 ± 0.021 9 29.37 29.37 ± 0.20 3.038 ± 0.020 8 29.43 29.43 ± 0.20 3.032 ± 0.020 8 29.73 29.73 ± 0.20 3.003 ± 0.020 10 29.94 29.94 ± 0.20 2.982 ± 0.019 7 30.17 30.17 ± 0.20 2.960 ± 0.019 7 Table 6. XRPD peaks for Form B at ambient relative humidity content Angle (2Ɵ) d space (Å) Strength (%) 4.99 4.99 ± 0.20 17.695 ± 0.709 5 6.55 6.55 ± 0.20 13.484 ± 0.411 30 7.54 7.54 ± 0.20 11.715 ± 0.310 100 8.22 8.22 ± 0.20 10.748 ± 0.261 28 10 10.00 ± 0.20 8.838 ± 0.176 11 10.54 10.54 ± 0.20 8.387 ± 0.159 15 12.41 12.41 ± 0.20 7.127 ± 0.114 35 12.86 12.86 ± 0.20 6.878 ± 0.107 47 13.14 13.14 ± 0.20 6.732 ± 0.102 7 13.68 13.68 ± 0.20 6.468 ± 0.094 37 14.06 14.06 ± 0.20 6.294 ± 0.089 63 14.44 14.44 ± 0.20 6.129 ± 0.084 14 15.14 15.14 ± 0.20 5.847 ± 0.077 20 15.48 15.48 ± 0.20 5.720 ± 0.073 49 15.89 15.89 ± 0.20 5.573 ± 0.070 15 16.48 16.48 ± 0.20 5.375 ± 0.065 20 16.75 16.75 ± 0.20 5.289 ± 0.063 14 17.2 17.20 ± 0.20 5.151 ± 0.059 92 17.7 17.70 ± 0.20 5.007 ± 0.056 19 18.13 18.13 ± 0.20 4.889 ± 0.053 31 18.6 18.60 ± 0.20 4.767 ± 0.051 5 19.25 19.25 ± 0.20 4.607 ± 0.047 46 19.78 19.78 ± 0.20 4.485 ± 0.045 8 20.08 20.08 ± 0.20 4.418 ± 0.044 30 20.37 20.37 ± 0.20 4.356 ± 0.042 25 21.1 21.10 ± 0.20 4.206 ± 0.039 59 21.39 21.39 ± 0.20 4.151 ± 0.038 32 21.68 21.68 ± 0.20 4.096 ± 0.037 16 22.74 22.74 ± 0.20 3.907 ± 0.034 15 23.13 23.13 ± 0.20 3.842 ± 0.033 twenty three 23.38 23.38 ± 0.20 3.802 ± 0.032 twenty two 24.12 24.12 ± 0.20 3.687 ± 0.030 18 24.35 24.35 ± 0.20 3.652 ± 0.030 41 25.06 25.06 ± 0.20 3.55 ± 0.028 twenty two 25.44 25.44 ± 0.20 3.499 ± 0.027 14 25.95 25.95 ± 0.20 3.430 ± 0.026 9 26.37 26.37 ± 0.20 3.377 ± 0.025 16 26.74 26.74 ± 0.20 3.331 ± 0.024 15 26.94 26.94 ± 0.20 3.307 ± 0.024 13 27.53 27.53 ± 0.20 3.237 ± 0.023 17 28.49 28.49 ± 0.20 3.130 ± 0.022 16 Table 7. XRPD peaks for Form C at ambient relative humidity content Angle (2Ɵ) d space (Å) Strength (%) 6.91 6.91 ± 0.20 12.782 ± 0.370 100 7.60 7.60 ± 0.20 11.623 ± 0.305 49 8.67 8.67 ± 0.20 10.191 ± 0.235 38 11.69 11.69 ± 0.20 7.564 ± 0.129 73 13.89 13.89 ± 0.20 6.37 ± 0.091 41 14.24 14.24 ± 0.20 6.215 ± 0.087 66 14.84 14.84 ± 0.20 5.965 ± 0.080 48 15.25 15.25 ± 0.20 5.805 ± 0.076 9 16.81 16.81 ± 0.20 5.270 ± 0.062 68 17.39 17.39 ± 0.20 5.095 ± 0.058 4 17.69 17.69 ± 0.20 5.010 ± 0.056 9 18.31 18.31 ± 0.20 4.841 ± 0.052 82 18.52 18.52 ± 0.20 4.787 ± 0.051 9 19.12 19.12 ± 0.20 4.638 ± 0.048 4 19.47 19.47 ± 0.20 4.556 ± 0.046 32 20.88 20.88 ± 0.20 4.251 ± 0.040 twenty one 21.21 21.21 ± 0.20 4.186 ± 0.039 7 21.45 21.45 ± 0.20 4.139 ± 0.038 13 22.01 22.01 ± 0.20 4.035 ± 0.036 twenty two 22.15 22.15 ± 0.20 4.010 ± 0.036 35 22.98 22.98 ± 0.20 3.867 ± 0.033 9 23.15 23.15 ± 0.20 3.839 ± 0.033 6 23.43 23.43 ± 0.20 3.794 ± 0.032 17 24.19 24.19 ± 0.20 3.676 ± 0.030 48 25.2 25.20 ± 0.20 3.531 ± 0.028 12 25.41 25.41 ± 0.20 3.502 ± 0.027 26 25.93 25.93 ± 0.20 3.433 ± 0.026 11 26.5 26.50 ± 0.20 3.361 ± 0.025 15 26.74 26.74 ± 0.20 3.331 ± 0.024 9 26.96 26.96 ± 0.20 3.305 ± 0.024 26 27.18 27.18 ± 0.20 3.278 ± 0.024 16 27.71 27.71 ± 0.20 3.217 ± 0.023 7 27.96 27.96 ± 0.20 3.189 ± 0.022 9 28.73 28.73 ± 0.20 3.105 ± 0.021 8 29.42 29.42 ± 0.20 3.034 ± 0.020 7 29.95 29.95 ± 0.20 2.981 ± 0.019 9 30.3 30.30 ± 0.20 2.947 ± 0.019 15

Referring to Figure 9, a mixture of Form A and Form B (R)-hydroxybutanoic polymorphs was slurried in methyl isobutyl ketone (MIBK) or heptane for 2 weeks at room temperature to enable the use of XRPD. The detected peaks shifted, with the additional peaks observed in the presence of Form B attributable to Form C for the post-slurry sample. Still referring to Figure 9, from top to bottom, the XRPD pattern is as follows: File 957398: R-Hydroxybutoniate Hydrochloride Form B Reference Pattern (top) File 972085: Obtained after slurrying a mixture of Form A and Form B in heptane for 2 weeks at room temperature File 972087: Obtained after slurrying a mixture of Form A and Form B in MIBK for 2 weeks at room temperature File 979945: R-Hydroxybutoni Hydrochloride Lot EAB-A-66-2 (bottom) Example 27. Conversion of Racemic Hydroxybuttonide Chloride to R-Hydroxybutonitrile Chloride

步驟1：製備外消旋羥布托尼游離鹼D-malic acid was identified as a potential chiral resolving salt for research. The goal of this study was to convert 100 grams of racemic hydroxybutanoic chloride to R-hydroxybutanoic chloride using D-malic acid for chiral resolution. The conversion is carried out in four steps, each producing an isolatable crystalline solid. The four steps are shown in the scheme below.

Step 1: Preparation of Racemic Oxybutonil Free Base

Racemic Hydroxybutonitrile hydrochloride is provided. Racemic hydroxybutonitrile hydrochloride (100 g) was suspended in water (600 mL). The mixture was heated to 30°C until dissolution was observed. Seeds of crystalline free base were added and the mixture was kept at 30°C. Aqueous sodium hydroxide (1.0 eq, 1 M solution, 254 mL) was added dropwise over 4 hours to prevent the formation of a gum. During the base addition, a free flowing white slurry was observed which became thicker with time. After the base addition was complete, a large accumulation of solids was observed on the sides of the reactor. The reactor temperature was set to 20°C and the mixture was stirred overnight for 19 hours. The hard solids mostly adhered to the sides of the reactor and were removed by scraping with a spatula. The solid was isolated by filtration and then dried under vacuum at 40°C for 20 hours using a nitrogen purge. The overall yield of racemic oxybutonib (free base) was 95% (86.1 g), the adjusted yield after subtracting the seed crystals was 93%. The solid was a white powder, which was determined to be crystalline racemic oxybutonib free base. Step 2: Chiral Resolution Using D-Malic Acid

Racemic oxybutoni free base (86.1 g) was combined with 2-propanol (400 mL). The mixture was heated to 50°C, resulting in a solution. D-malate seed crystals (0.55 g) of R-Hydroxybuttonib were added followed by solid D-malic acid (24.2 g), rinsed with 30 mL 2-propanol to yield R-Hydroxybutoni D-malic acid Salt. The very thin slurry was maintained at 50°C for 1 hour, then cooled to 20°C at 0.1°C/min and held at 20°C for about 60 hours. An aliquot was taken to estimate the yield (about 30%) and chiral purity (about 93% R, 86% ee) of R-Hydroxybutoni D-malate. To improve yield, the mixture was cooled slowly to 5°C at 0.1°C/min and held at 5°C for 16 hours. The second aliquot indicated a slightly improved yield and comparable chiral purity (about 90% R, 80% ee). Filter the mixture. A slight buildup was observed and the sides of the reactor were flushed with MTBE. The combined solids were washed with additional MTBE and air dried for 1.5 hours. Yield 41% (49.1 g). Step 3: Recrystallization

R-Hydroxybutoni D-malate (44 g) was combined with MIBK (220 mL). The mixture was heated to 40°C for 2 hours, cooled to 5°C at 0.1°C/min, and held at 5°C for about 12 hours. An aliquot of the recrystallized product indicated 97% R, 3% S (94% ee), and the filtrate indicated a higher amount of the undesired isomer (27% R, 73% S). The product was isolated by vacuum filtration and air dried for 1 hour. The wet cake product was still very wet (14% MIBK loss by TGA to 50°C). The product was dried in a vacuum oven at 40°C overnight under a nitrogen purge. The yield of the recrystallized product was 93% (40.8 g). Consider also using MTBE instead of MIBK. Steps 4 and 5: Conversion of D-malate to R-hydroxybutonitrile chloride

The D-malate salt of R-Hydroxybutoni (40.8 g) was combined with 1 M HCl in ethyl acetate (83 mL). Additional ethyl acetate (39 mL) was added, and the slurry was heated to 40°C, resulting in a solution. The reactor was cooled to 20°C, and then MTBE (1220 mL) was added. The reactor was further cooled to 5°C before seed crystals or R-hydroxybutanoi chloride (2.01 g) were added and MTBE (122 mL) was added dropwise. No cementation was observed. The moderately viscous mixture was stirred at 5°C for 2 days. The solid was isolated by filtration and dried in a vacuum oven at 40°C for 18 hours. PXRD analysis indicated that the D-malate salt co-precipitated with the desired HCl salt, resulting in a physical mixture of the two salts. Yield by chiral analysis was 98.4% R, 1.6% S (97% ee) in 21.1 g solid mixture. The filtrate was concentrated to dryness in vacuo and yielded 26.1 g of a yellow oil, 93.6% R, 6.4% S (87% ee) by chiral analysis. The mixture of R-hydroxybutonitrile salts was combined with 1:4 ethyl acetate/MTBE (100 mL), followed by the addition of 1 M HCl in ethyl acetate (24.5 mL). The mixture was stirred at room temperature for 1.5 hours, and by PXRD analysis, an aliquot indicated only R-hydroxybutanoi chloride. Additional MTBE (40 mL) was added slowly to increase yield. By PXRD analysis, the second aliquot indicated only R-hydroxybutanoi chloride. Specifically, R-Hydroxybutoni chloride Form C is produced. The solids were filtered and washed with about 10 mL of 1 :4 ethyl acetate/MTBE before vacuum drying at 40°C for 2 hours with a nitrogen purge. Yield 40% (13.2 g) of R-Hydroxybutoni chloride over 2 steps. The overall yield of the process for converting racemic hydroxybutanoi chloride to R-hydroxybutanoi chloride was 13%, ee was 99%, and there were separable crystalline solids at each step. Other embodiments of the present invention:

Example E1. A crystalline form of (R)-hydroxybutanoi hydrochloride.

Example E2. A solid form of (R)-hydroxybutanoi hydrochloride having an X-ray powder diffraction pattern comprising peaks at about ambient relative humidity at 6.9 degrees 2Θ ± 0.2 degrees in 2-theta At 2θ, eg Form C.

Example E3. A solid form of (R)-hydroxybutanoi hydrochloride having an X-ray powder diffraction pattern comprising peaks at about ambient relative humidity at 6.9 degrees 2Θ ± 0.2 degrees in 2-theta 2Θ and/or at 18.3 degrees 2Θ ± 0.2 degrees 2Θ, eg Form C.

Example E4. A solid form of (R)-hydroxybutonitrile hydrochloride having an X-ray powder diffraction pattern at about ambient relative humidity comprising at least two peaks, expressed in 2-theta, selected from 6.9 A group consisting of degrees 2θ ± 0.2 degrees 2θ, 18.3 degrees 2θ ± 0.2 degrees 2θ, and 11.7 degrees 2θ ± 0.2 degrees 2θ, such as Form C.

Example E5. A solid form of (R)-hydroxybutonitrile hydrochloride having an X-ray powder diffraction pattern at about ambient relative humidity comprising at least three peaks, expressed in 2-theta, selected from 6.9 A group consisting of degrees 2θ ± 0.2 degrees 2θ, 18.3 degrees 2θ ± 0.2 degrees 2θ, 11.7 degrees 2θ ± 0.2 degrees 2θ, 16.8 degrees 2θ ± 0.2 degrees 2θ, 14.2 degrees 2θ ± 0.2 degrees 2θ, such as Form C.

Embodiment E6. A solid form of (R)-hydroxybutonitrile hydrochloride having an X-ray powder diffraction pattern at about ambient relative humidity comprising at least four peaks, expressed in 2-theta, selected from 6.9 Degrees 2θ ± 0.2 Degrees 2θ, 18.3 Degrees 2θ ± 0.2 Degrees 2θ, 11.7 Degrees 2θ ± 0.2 Degrees 2θ, 16.8 Degrees 2θ ± 0.2 Degrees 2θ, 14.2 Degrees 2θ ± 0.2 Degrees 2θ, 7.6 Degrees 2θ ± 0.2 Degrees 2θ, 14.8 Degrees 2θ A group of ± 0.2 degrees 2θ, e.g. Form C.

Example E7. A solid form of (R)-Hydroxybutonitrile hydrochloride having an X-ray powder diffraction pattern at about ambient relative humidity comprising at least five peaks, expressed in 2-theta, selected from 6.9 Degrees 2θ ± 0.2 Degrees 2θ, 18.3 Degrees 2θ ± 0.2 Degrees 2θ, 11.7 Degrees 2θ ± 0.2 Degrees 2θ, 16.8 Degrees 2θ ± 0.2 Degrees 2θ, 14.2 Degrees 2θ ± 0.2 Degrees 2θ, 7.6 Degrees 2θ ± 0.2 Degrees 2θ, 14.8 Degrees 2θ ± 0.2 degrees 2Θ, 24.2 degrees 2Θ ± 0.2 degrees 2Θ, 13.9 degrees 2Θ ± 0.2 degrees 2Θ, such as Form C.

Example E8. A solid form of (R)-Hydroxybuttonib hydrochloride having an X-ray powder diffraction pattern at about ambient relative humidity comprising at least seven peaks, expressed in 2-theta, selected from 6.9 Degrees 2θ ± 0.2 Degrees 2θ, 18.3 Degrees 2θ ± 0.2 Degrees 2θ, 11.7 Degrees 2θ ± 0.2 Degrees 2θ, 16.8 Degrees 2θ ± 0.2 Degrees 2θ, 14.2 Degrees 2θ ± 0.2 Degrees 2θ, 7.6 Degrees 2θ ± 0.2 Degrees 2θ, 14.8 Degrees 2θ A group consisting of ±0.2 degrees 2Θ, 24.2 degrees 2Θ ± 0.2 degrees 2Θ, 13.9 degrees 2Θ ± 0.2 degrees 2Θ, and 8.7 degrees 2Θ ± 0.2 degrees 2Θ, e.g. Form C.

Embodiment E9. A solid form of (R)-hydroxybutanoi hydrochloride having an X-ray powder diffraction pattern at about ambient relative humidity comprising at least eight peaks, expressed in 2-theta, selected from 6.9 Degrees 2θ ± 0.2 Degrees 2θ, 18.3 Degrees 2θ ± 0.2 Degrees 2θ, 11.7 Degrees 2θ ± 0.2 Degrees 2θ, 16.8 Degrees 2θ ± 0.2 Degrees 2θ, 14.2 Degrees 2θ ± 0.2 Degrees 2θ, 7.6 Degrees 2θ ± 0.2 Degrees 2θ, 14.8 Degrees 2θ A group consisting of ±0.2 degrees 2Θ, 24.2 degrees 2Θ ± 0.2 degrees 2Θ, 13.9 degrees 2Θ ± 0.2 degrees 2Θ, and 8.7 degrees 2Θ ± 0.2 degrees 2Θ, e.g. Form C.

Embodiment E10. A solid form of (R)-hydroxybutanoi hydrochloride having an X-ray powder diffraction pattern at about ambient relative humidity comprising at least nine peaks, expressed in 2-theta, selected from 6.9 Degrees 2θ ± 0.2 Degrees 2θ, 18.3 Degrees 2θ ± 0.2 Degrees 2θ, 11.7 Degrees 2θ ± 0.2 Degrees 2θ, 16.8 Degrees 2θ ± 0.2 Degrees 2θ, 14.2 Degrees 2θ ± 0.2 Degrees 2θ, 7.6 Degrees 2θ ± 0.2 Degrees 2θ, 14.8 Degrees 2θ A group consisting of ±0.2 degrees 2Θ, 24.2 degrees 2Θ ± 0.2 degrees 2Θ, 13.9 degrees 2Θ ± 0.2 degrees 2Θ, and 8.7 degrees 2Θ ± 0.2 degrees 2Θ, e.g. Form C.

Example E11. A solid form of (R)-hydroxybutanoi hydrochloride having an X-ray powder diffraction pattern at about ambient relative humidity comprising peaks located at 2-theta at: 6.9 degrees 2-theta ± 0.2 degrees 2Θ, 18.3 degrees 2Θ ± 0.2 degrees 2Θ, 11.7 degrees 2Θ ± 0.2 degrees 2Θ, 16.8 degrees 2Θ ± 0.2 degrees 2Θ, 14.2 degrees 2Θ ± 0.2 degrees 2Θ, 7.6 degrees 2Θ ± 0.2 degrees 2Θ, 14.8 degrees 2Θ ± 0.2 degrees 2Θ, 24.2 degrees 2Θ ± 0.2 degrees 2Θ, 13.9 degrees 2Θ ± 0.2 degrees 2Θ, and 8.7 degrees 2Θ ± 0.2 degrees 2Θ, eg, Form C.

Example E12. A solid form of (R)-hydroxybutanoi hydrochloride having an X-ray powder diffraction pattern substantially as shown in FIG. 4 at ambient relative humidity.

Example E13. A solid form of (R)-hydroxybutrone hydrochloride having a differential scanning calorimetry (DSC) thermogram comprising melting onset at 109.6°C and an endothermic peak at 119.1°C.

Example E14. The solid form of Examples E1 to E13 having a differential scanning calorimetry (DSC) thermogram substantially as shown in the lower panel of FIG. 7 .

Embodiment E15. A composition comprising (R)-Hydroxybuterol, wherein at least 5% w/w of the total amount of (R)-Hydroxybutoni is in solid form as in any of the previous embodiments.

Embodiment E16. A composition comprising (R)-Hydroxybuterol, wherein at least 25% w/w of the total amount of (R)-Hydroxybutoni is in solid form as in any of the previous embodiments.

Embodiment E17. A composition comprising (R)-Hydroxybuterol, wherein at least 50% w/w of the total amount of (R)-Hydroxybutoni is in solid form as in any of the previous embodiments.

Embodiment E18. A composition comprising (R)-Hydroxybuterol, wherein at least 90% w/w of the total amount of (R)-Hydroxybutoni is in solid form as in any of the previous embodiments.

Embodiment E19. A composition comprising (R)-Hydroxybuterol, wherein at least 95% w/w of the total amount of (R)-Hydroxybutoni is in solid form as in any of the previous embodiments.

Embodiment E20. A composition comprising (R)-Hydroxybutrone, wherein at least 98% w/w of the total amount of (R)-Hydroxybutrone is in solid form as in any of the previous embodiments.

Embodiment E21. A pharmaceutical composition comprising the solid form of any one of Embodiments E1 to E20 and one or more pharmaceutically acceptable excipients.

Embodiment E22. A process for preparing a solid form as in any one of Embodiments E1 to E21 comprising forming a slurry with (R)-hydroxybutanoi free base and HCl in a solvent to be slurried and from the slurry One or more crystals of (R)-hydroxybutonitrile hydrochloride are precipitated.

Embodiment E23. The process of embodiment E22, wherein the solvent is selected from the group consisting of: n-heptane, propyl acetate, ethyl acetate, isopropyl acetate, methyl isobutyl ketone (MIBK), methyl Ethyl ketone (MEK), 1-propanol, ethanol, methyl tert-butyl ether (MTBE), 1,4-dioxane, toluene, 1,2-dimethoxyethane, tetrahydrofuran, dichloride Methane, acetonitrile, nitromethane and mixtures thereof.

Embodiment E24. The process of embodiment E22 or E23, wherein the solvent is selected from the group consisting of ethyl acetate, heptane, methyl tertiary butyl ether (MTBE) and mixtures thereof.

Embodiment E25. A method of treating a collapsed pharyngeal airway comprising administering to an individual in need thereof a solid form of any one of embodiments E1 to E21.

Embodiment E26. The method of embodiment E25, wherein the pharyngeal airway collapse is obstructive sleep apnea (OSA), sleep apnea, or simple snoring.

Embodiment E27. A method of treating a collapsed pharyngeal airway, comprising administering to an individual in need thereof a solid form of (R)-hydroxybutrone hydrochloride according to any one of embodiments E1 to E21 and normethyl Any combination of one or more of an epinephrine reuptake inhibitor (NRI), a sleeping pill, a carbonic anhydrase inhibitor, and a muscarinic receptor agonist.

Example E28. A solid form of (R)-hydroxybutonitrile hydrochloride having an X-ray powder diffraction pattern comprising a peak at about ambient relative humidity at 7.5 degrees 2Θ ± 0.2 degrees in 2-theta At 2θ, eg Form B.

Example E29. A solid form of (R)-hydroxybutonitrile hydrochloride having an X-ray powder diffraction pattern comprising peaks at about ambient relative humidity at 7.5 degrees 2 theta ± 0.2 degrees in 2-theta 2Θ and/or at 17.2 degrees 2Θ ± 0.2 degrees 2Θ, e.g. Form B.

Embodiment E30. A solid form of (R)-hydroxybutanoi hydrochloride having an X-ray powder diffraction pattern at about ambient relative humidity comprising at least two peaks, expressed in 2-theta, selected from 7.5 A group consisting of degrees 2Θ ± 0.2 degrees 2Θ, 17.2 degrees 2Θ ± 0.2 degrees 2Θ, and 14.1 degrees 2Θ ± 0.2 degrees 2Θ, eg Form B.

Embodiment E31. A solid form of (R)-hydroxybutanoi hydrochloride having an X-ray powder diffraction pattern at about ambient relative humidity comprising at least three peaks, expressed in 2-theta, selected from 7.5 A group consisting of degrees 2θ ± 0.2 degrees 2θ, 17.2 degrees 2θ ± 0.2 degrees 2θ, 14.1 degrees 2θ ± 0.2 degrees 2θ, 21.1 degrees 2θ ± 0.2 degrees 2θ, and 15.5 degrees 2θ ± 0.2 degrees 2θ, such as Form B.

Example E32. A solid form of (R)-hydroxybutanoi hydrochloride having an X-ray powder diffraction pattern at about ambient relative humidity comprising peaks at 2-theta at: 7.5 degrees 2theta ± 0.2 degrees 2Θ, 17.2 degrees 2Θ ± 0.2 degrees 2Θ, 14.1 degrees 2Θ ± 0.2 degrees 2Θ, 21.1 degrees 2Θ ± 0.2 degrees 2Θ, 15.5 degrees 2Θ ± 0.2 degrees 2Θ, 12.9 degrees 2Θ ± 0.2 degrees 2Θ, 19.3 degrees 2Θ ± 0.2 Degrees 2θ, 24.4 Degrees 2θ ± 0.2 Degrees 2θ, 13.7 Degrees 2θ ± 0.2 Degrees 2θ, 12.4 Degrees 2θ ± 0.2 Degrees 2θ, 21.4 Degrees 2θ ± 0.2 Degrees 2θ, 18.1 Degrees 2θ ± 0.2 Degrees 2θ, 20.1 Degrees 2θ ± 0.2 Degrees 2θ , 6.6 degrees 2Θ ± 0.2 degrees 2Θ, 8.2 degrees 2Θ ± 0.2 degrees 2Θ, and 20.4 degrees 2Θ ± 0.2 degrees 2Θ, such as Form B.

Example E33. A solid form of (R)-hydroxybutonitrile hydrochloride having an X-ray powder diffraction pattern substantially as shown in FIG. 3 at about ambient relative humidity.

Embodiment E34. A pharmaceutical composition comprising the solid form of any one of Embodiments E1 to E21 and/or E28 to E33 and one or more pharmaceutically acceptable excipients.

Embodiment E35. A method of treating a collapsed pharyngeal airway comprising administering to a subject in need thereof a solid form of any of embodiments E1-E21 and/or E28-E33.

Embodiment E36. The method of Embodiment E35, wherein the pharyngeal airway collapse is obstructive sleep apnea (OSA), sleep apnea, or simple snoring.

Embodiment E37. A method of treating a collapsed pharyngeal airway, comprising administering to an individual in need thereof (R)-hydroxybutanoi hydrochloride as in any one of embodiments E1 to E21 and/or E28 to E33 Any combination of the solid form with one or more of a norepinephrine reuptake inhibitor (NRI), a sleeping pill, a carbonic anhydrase inhibitor, and a muscarinic receptor agonist.

Example E38. A solid form of (R)-hydroxybutonitrile hydrochloride, which is a solvate.

Example E39. The solid form of (R)-hydroxybutanoi hydrochloride of Example E38, which is an isopropanol solvate.

Embodiment E40. A solid form of (R)-Hydroxybutoni hydrochloride having an X-ray powder diffraction pattern comprising a peak at about ambient relative humidity at 19.2 degrees 2 theta ± 0.2 degrees in 2-theta At 2θ, eg Form A.

Example E41. A solid form of (R)-hydroxybutonitrile hydrochloride having an X-ray powder diffraction pattern comprising a peak at about ambient relative humidity at 19.2 degrees 2Θ ± 0.2 degrees in 2-theta 2Θ and/or 6.1 degrees 2Θ ± 0.2 degrees 2Θ, eg, Form A.

Embodiment E42. A solid form of (R)-hydroxybutonitrile hydrochloride having an X-ray powder diffraction pattern at about ambient relative humidity comprising at least two peaks, expressed in 2-theta, selected from 19.2 A group consisting of degrees 2Θ ± 0.2 degrees 2Θ, 6.1 degrees 2Θ ± 0.2 degrees 2Θ, and 7.7 degrees 2Θ ± 0.2 degrees 2Θ, such as Form A.

Example E43. A solid form of (R)-hydroxybutonitrile hydrochloride having an X-ray powder diffraction pattern at about ambient relative humidity comprising at least three peaks, expressed in 2-theta, selected from 19.2 A group consisting of degrees 2θ ± 0.2 degrees 2Θ, 6.1 degrees 2θ ± 0.2 degrees 2Θ, 7.7 degrees 2Θ ± 0.2 degrees 2Θ, 12.9 degrees 2Θ ± 0.2 degrees 2Θ, and 21.6 degrees 2Θ ± 0.2 degrees 2Θ, such as Form A.

Embodiment E44. A solid form of (R)-hydroxybutonitrile hydrochloride having an X-ray powder diffraction pattern at about ambient relative humidity comprising at least four peaks, expressed in 2-theta, selected from 19.2 Degrees 2Θ ± 0.2 Degrees 2Θ, 6.1 Degrees 2Θ ± 0.2 Degrees 2Θ, 7.7 Degrees 2Θ ± 0.2 Degrees 2Θ, 12.9 Degrees 2Θ ± 0.2 Degrees 2Θ, 21.6 Degrees 2Θ ± 0.2 Degrees 2Θ, 18.3 Degrees 2Θ ± 0.2 Degrees 2Θ, and 15.5 Degrees 2Θ A group of ± 0.2 degrees 2θ, e.g. Form A.

Example E45. A solid form of (R)-Hydroxybutonitrile hydrochloride having an X-ray powder diffraction pattern at about ambient relative humidity comprising peaks expressed as 2-theta at: 19.2 degrees 2-theta ± 0.2 degrees 2Θ, 6.1 degrees 2Θ ± 0.2 degrees 2Θ, 7.7 degrees 2Θ ± 0.2 degrees 2Θ, 12.9 degrees 2Θ ± 0.2 degrees 2Θ, 21.6 degrees 2Θ ± 0.2 degrees 2Θ, 18.3 degrees 2Θ ± 0.2 degrees 2Θ, 15.5 degrees 2Θ ± 0.2 Degrees 2θ, 22.8 Degrees 2θ ± 0.2 Degrees 2θ, 16.7 Degrees 2θ ± 0.2 Degrees 2θ, 17.6 Degrees 2θ ± 0.2 Degrees 2θ, 19.5 Degrees 2θ ± 0.2 Degrees 2θ, 14.6 Degrees 2θ ± 0.2 Degrees 2θ, and 20.8 Degrees 2θ ± 0.2 Degrees 2θ , such as Form A.

Example E46. A solid form of (R)-hydroxybutonitrile hydrochloride having an X-ray powder diffraction pattern substantially as shown in FIG. 2 at ambient relative humidity.

Embodiment E47. A pharmaceutical composition comprising the solid form of any one of Embodiments E1 to E21, E28 to E33 and/or E38 to E46 and one or more pharmaceutically acceptable excipients.

Embodiment E48. A method of treating a collapsed pharyngeal airway, comprising administering to a subject in need thereof a solid form of any of embodiments E1-E21, E28-E33, and/or E38-E46.

Embodiment E49. The method of Embodiment E48, wherein the pharyngeal airway collapse is obstructive sleep apnea (OSA), sleep apnea, or simple snoring.

Embodiment E50. A method of treating a collapsed pharyngeal airway, comprising administering to an individual in need thereof (R)-hydroxybutrone of any one of embodiments E1 to E21, E28 to E33, and/or E38 to E46 Any combination of a solid form of Tony hydrochloride with one or more of a norepinephrine reuptake inhibitor (NRI), a sleeping pill, a carbonic anhydrase inhibitor, and a muscarinic receptor agonist.

Example E51. A solid form of (R)-hydroxybutanoi hydrochloride which is amorphous.

Example E52. A form of (R)-Hydroxybuttonib hydrochloride which is an amorphous material in a dispersion matrix.

Although specific embodiments of the present invention are illustrated and described in detail herein, the present invention is not limited thereto. The foregoing detailed description is provided as an example of the present invention and should not be construed as constituting any limitation of the present invention. Modifications will be apparent to those skilled in the art, and all modifications that do not depart from the spirit of the invention are intended to be included within the scope of the appended claims.

The following figures are provided as examples, and are not intended to limit the scope of the claimed invention.

Figure 1 : Overlay of XRPD patterns obtained from the crystalline Forms A, B and C polymorphs of (R)-hydroxybutyrin hydrochloride. Figure 2: XRPD pattern of (R)-Hydroxybutrone hydrochloride Form A polymorph at ambient relative humidity (eg, 40%-65% RH). Figure 3: XRPD pattern of (R)-Hydroxybutonitrile hydrochloride Form B polymorph at ambient relative humidity (eg, 40%-65% RH). Figure 4: XRPD pattern of (R)-hydroxybutrone hydrochloride Form C polymorph at ambient relative humidity (eg 40%-65% RH). Figure 5: Thermal analysis of (R)-Hydroxybuttonib hydrochloride Form A polymorph by TGA (upper panel) and DSC (lower panel). Figure 6: Thermal analysis of (R)-Hydroxybuttonib hydrochloride Form B polymorph by TGA (upper panel) and DSC (lower panel). Figure 7: Thermal analysis by DSC of (R)-Hydroxybuttonib hydrochloride Form C polymorph. Figure 8: Plot of yield and potency versus HCl equivalents in the synthesis of (R)-Hydroxybuttonib hydrochloride. Figure 9: Overlay of additional peaks observed with (R)-Hydroxybutoni HCl Form B polymorph after 2 weeks of room temperature slurrying in MIBK and heptane. Figure 10: ^1H NMR spectrum of (R)-Hydroxybuttonib hydrochloride. Figure 11 : FT-IR spectrum of (R)-Hydroxybutrone hydrochloride Form C polymorph. Figure 12: LCMS trace of (R)-Hydroxybutrone hydrochloride Form C polymorph. Figure 13: Achiral HPLC chromatogram of (R)-Hydroxybutteric acid hydrochloride Form C polymorph. Figure 14: Ion chromatography of (R)-Hydroxybuttonib hydrochloride Form C polymorph.

Claims (30)

A solid crystalline form of (R)-hydroxybutanoi hydrochloride designated Form C. The solid crystalline form of claim 1 having an X-ray powder diffraction pattern at about ambient relative humidity comprising at least three peaks, expressed in 2-theta, selected from the group consisting of 6.9 degrees 2Θ ± 0.2 degrees 2Θ, 18.3 degrees 2Θ ± 0.2 degrees 2Θ, 11.7 degrees 2Θ ± 0.2 degrees 2Θ, 16.8 degrees 2Θ ± 0.2 degrees 2Θ, and 14.2 degrees 2Θ ± 0.2 degrees 2Θ. The solid crystalline form of claim 1 having an X-ray powder diffraction pattern at about ambient relative humidity comprising at least four peaks, expressed in 2-theta, selected from the group consisting of 6.9 degrees 2Θ ± 0.2 degrees 2Θ, 18.3 degrees 2Θ ± 0.2 degrees 2Θ, 11.7 degrees 2Θ ± 0.2 degrees 2Θ, 16.8 degrees 2Θ ± 0.2 degrees 2Θ, 14.2 degrees 2Θ ± 0.2 degrees 2Θ, 7.6 degrees 2Θ ± 0.2 degrees 2Θ, and 14.8 degrees 2Θ ± 0.2 degrees 2Θ. The solid crystalline form of claim 1 having an X-ray powder diffraction pattern at about ambient relative humidity comprising at least five peaks, expressed in 2-theta, selected from the group consisting of 6.9 degrees 2Θ ± 0.2 degrees 2Θ, 18.3 degrees 2Θ ± 0.2 degrees 2Θ, 11.7 degrees 2Θ ± 0.2 degrees 2Θ, 16.8 degrees 2Θ ± 0.2 degrees 2Θ, 14.2 degrees 2Θ ± 0.2 degrees 2Θ, 7.6 degrees 2Θ ± 0.2 degrees 2Θ and 14.8 degrees 2Θ ± 0.2 degrees 2Θ, 24.2 degrees 2Θ ± 0.2 A group consisting of degrees 2Θ, 13.9 degrees 2Θ ± 0.2 degrees 2Θ, and 8.7 degrees 2Θ ± 0.2 degrees 2Θ. The solid crystalline form of claim 1 having an X-ray powder diffraction pattern at about ambient relative humidity comprising at least seven peaks, expressed in 2-theta, selected from the group consisting of 6.9 degrees 2Θ ± 0.2 degrees 2Θ, 18.3 degrees 2Θ ± 0.2 degrees 2Θ, 11.7 degrees 2Θ ± 0.2 degrees 2Θ, 16.8 degrees 2Θ ± 0.2 degrees 2Θ, 14.2 degrees 2Θ ± 0.2 degrees 2Θ, 7.6 degrees 2Θ ± 0.2 degrees 2Θ and 14.8 degrees 2Θ ± 0.2 degrees 2Θ, 24.2 degrees 2Θ ± 0.2 A group consisting of degrees 2Θ, 13.9 degrees 2Θ ± 0.2 degrees 2Θ, and 8.7 degrees 2Θ ± 0.2 degrees 2Θ. The solid crystalline form of claim 1 having, at about ambient relative humidity, an X-ray powder diffraction pattern comprising peaks expressed as 2-theta at: 6.9 degrees 2Θ ± 0.2 degrees 2Θ, 18.3 degrees 2Θ ± 0.2 Degrees 2θ, 11.7 Degrees 2θ ± 0.2 Degrees 2θ, 16.8 Degrees 2θ ± 0.2 Degrees 2θ, 14.2 Degrees 2θ ± 0.2 Degrees 2θ, 7.6 Degrees 2θ ± 0.2 Degrees 2θ, 14.8 Degrees 2θ ± 0.2 Degrees 2θ, 24.2 Degrees 2θ ± 0.2 Degrees 2θ , 13.9 degrees 2Θ ± 0.2 degrees 2Θ and 8.7 degrees 2Θ ± 0.2 degrees 2Θ. The solid crystalline form of claim 1 having an X-ray powder diffraction pattern substantially as shown in FIG. 4 at about ambient relative humidity. The solid crystalline form of any one of claims 1 to 7 having a differential scanning calorimetry (DSC) thermogram comprising an onset of melting at 109.6°C and an endothermic peak at 119.1°C. The solid crystalline form of claim 8 having a differential scanning calorimetry (DSC) thermogram substantially as shown in FIG. 7 . A solid crystalline form of (R)-hydroxybutanoi hydrochloride having a combination of Form B and Form C polymorphs as shown in FIG. 9 . A pharmaceutical composition comprising the solid crystalline form of any one of claims 1 to 9 and one or more pharmaceutically acceptable excipients. A method of preparing a solid crystalline form as claimed in any one of claims 1 to 9, comprising precipitating the solid crystalline form from a solution comprising (R)-hydroxybutanoi hydrochloride and a solvent, or allowing (R) )-Hydroxybuttonib hydrochloride is slurried in a solvent, wherein the solvent comprises an organic solvent other than methanol, and the water content is equal to or lower than 5% v/v. The method of claim 12, wherein the organic solvent is selected from the group consisting of n-heptane, propyl acetate, ethyl acetate, isopropyl acetate, methyl isobutyl ketone (MIBK), methyl ethyl ketone (MEK), 1-propanol, ethanol, methyl tert-butyl ether (MTBE), 1,4-dioxane, toluene, 1,2-dimethoxyethane, tetrahydrofuran, dichloromethane, acetonitrile , nitromethane and mixtures thereof. The method of claim 13, wherein the organic solvent is MTBE. A method of treating a condition associated with pharyngeal airway collapse comprising administering to an individual in need thereof the solid crystalline form of any one of claims 1-9. The method of claim 15, wherein the disorder associated with pharyngeal airway collapse is sleep apnea or snoring. The method of claim 15, wherein the disorder associated with pharyngeal airway collapse is obstructive sleep apnea (OSA). A solid crystalline form of (R)-hydroxybutanoi hydrochloride. The solid crystalline form of claim 18, which is Form A. The solid crystalline form of claim 19 having an X-ray powder diffraction pattern substantially as shown in FIG. 2 at about ambient relative humidity. The solid crystalline form of claim 18, which is Form B. The solid crystalline form of claim 21 having an X-ray powder diffraction pattern substantially as shown in FIG. 3 at about ambient relative humidity. A pharmaceutical composition, comprising the solid crystalline form of (R)-hydroxybutrone hydrochloride as claimed in any one of claims 18 to 22, and optionally one or more pharmaceutically acceptable excipients. A solid crystalline form of (R)-Hydroxybutoni citrate. A pharmaceutical composition comprising the solid crystalline form of (R)-hydroxybutrone citrate as claimed in claim 24 and optionally one or more pharmaceutically acceptable excipients. A method of producing crystalline R-hydroxybutanoi hydrochloride in Form C, the method comprising: (R)-Hydroxybutoni is isolated from racemic hydroxybutoni via chiral resolution using D-malic acid; and HCl was added to the isolated (R)-hydroxybutrone to yield Form C, crystalline (R)-hydroxybutrone hydrochloride. The method of claim 26, wherein isolating (R)-hydroxybutonide from racemic oxybutonide comprises adding D-malic acid to racemic oxybutonide free base. The method of claim 27, wherein D-malic acid is added to racemic oxybutoni free base in the presence of 2-propanol. The method of claim 26, wherein HCl is added in the presence of ethyl acetate. The method of claim 26, further comprising adding MTBE to the isolated (R)-hydroxybutanoi after adding the HCl.

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