Polymorphic forms of (R)-oxybutynin hydrochloride

Abstract

Polymorphic forms of (R)-oxybutynin HCl, including three crystalline forms, have been prepared and characterized. The use of various polymorphic forms of (R)-oxybutynin HCl for the treatment of obstructive sleep apnea (OSA) is also disclosed.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Application No. 63 / 020,301, filed May 5, 2020, and U.S. Provisional Application No. 63 / 136,691, filed January 13, 2021, the entire contents of each of which are incorporated herein by reference.

[0002] The present invention provides various polymorphic forms of (R)-oxybutynin, as well as pharmaceutical compositions thereof, methods for their preparation, and uses thereof. [Background technology]

[0003] Oxybutynin and its derivatives are typically taken orally or applied to the skin and can be used as bronchodilators or to relieve overactive bladder. In addition, oxybutynin exerts a direct antispasmodic effect on various forms of smooth muscle, primarily by inhibiting the action of acetylcholine on smooth muscle as an anticholinergic agent. Oxybutynin is commercially available in the form of hydrochloride. The chemical name of oxybutynin is 4-(diethylamino)but-2-yn-1-yl 2-cyclohexyl-2-hydroxy-2-phenylacetate, and its chemical structure is provided below as I: [ka]

[0004] The following figures are provided as examples and are not intended to limit the scope of the claimed invention. [Brief explanation of the drawings]

[0005] [Figure 1] 1 is an overlay of XRPD patterns obtained from crystalline Forms A, B, and C polymorphs of (R)-oxybutynin HCl. [Figure 2]1 is an XRPD pattern of (R)-oxybutynin HCl Form A polymorph at ambient relative humidity (e.g., 40-65% relative humidity). [Figure 3] 1 is an XRPD pattern of (R)-oxybutynin HCl Form B polymorph at ambient relative humidity (e.g., 40-65% relative humidity). [Figure 4] 1 is an XRPD pattern of (R)-oxybutynin HCl Form C polymorph at ambient relative humidity (e.g., 40-65% relative humidity). [Figure 5] Thermal analysis of (R)-oxybutynin HCl Form A polymorph by TGA (top) and DSC (bottom). [Figure 6] Thermal analysis of (R)-oxybutynin HCl Form B polymorph by TGA (top) and DSC (bottom). [Figure 7] 1 is a thermal analysis of (R)-oxybutynin HCl Form C polymorph by DSC. [Figure 8] 1 is a plot of yield and potency versus HCl equivalents in the synthesis of (R)-oxybutynin HCl. [Figure 9] 1 is an overlay with additional peaks observed in (R)-oxybutynin HCl Form B polymorph after two weeks of room temperature slurry in MIBK and heptane. [Figure 10] 1H NMR spectrum of (R)-oxybutynin hydrochloride. [Figure 11] FT-IR spectrum of (R)-oxybutynin hydrochloride Form C polymorph. [Figure 12] FIG. 1 is an LCMS trace of (R)-oxybutynin hydrochloride Form C polymorph. [Figure 13] 1 is an achiral HPLC chromatogram of (R)-oxybutynin hydrochloride Form C polymorph. [Figure 14] Ion chromatography of (R)-oxybutynin hydrochloride Form C polymorph. DETAILED DESCRIPTION OF THE INVENTION

[0006] I. Polymorphic Forms of (R)-Oxybutynin HCl Three crystalline forms of (R)-oxybutynin HCl were prepared and characterized as described in the Examples section below. The (R) enantiomer of oxybutynin hydrochloride is provided below as II: [ka]

[0007] The definitions provided herein are intended to clarify, but not limit, the terms defined. If a term used herein is not specifically defined, such term should not be considered indefinite. Rather, the term is used within its accepted meaning.

[0008] As used herein, (R)-oxybutynin HCl refers to the hydrochloride salt form in which the molar ratio of (R)-oxybutynin to HCl is about 1, e.g., 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 assayed can be due to, but are not limited to, measurement variability and small amounts of HCl loss due to storage and / or handling.

[0009] In some embodiments, (R)-oxybutynin free base can be converted into a salt by conventional methods. As used herein, the term "salt" is not intended to be limited, as long as the salt formed with (R)-oxybutynin is pharmacologically acceptable. In some embodiments, the salt can include a hydrogen halide salt (e.g., HCl, HBr, etc.), a citrate or other organic carboxylic acid salt (e.g., acetate, maleate, tartrate, fumarate, etc.), an inorganic acid salt (e.g., sulfate, nitrate, perchlorate, phosphate, etc.), an organic sulfonate (e.g., methanesulfonate, ethanesulfonate, benzenesulfonate, etc.), an amino acid salt (e.g., aspartate, glutamate, etc.), an alkali metal salt (e.g., sodium, potassium, etc.), and / or an alkaline earth metal salt (e.g., magnesium, calcium, etc.). In some embodiments, the pharmacologically acceptable salt of (R)-oxybutynin is (R)-oxybutynin HCl. In another embodiment, the pharmacologically acceptable salt of (R)-oxybutynin is (R)-oxybutynin citrate.

[0010] As used herein, "crystalline" refers to a solid having a highly ordered chemical structure. Specifically, a crystalline free base or salt form may be produced as one or more single crystalline forms. For purposes of this application, the terms "crystalline form," "single crystalline form," and "polymorph" are synonymous, and the terms distinguish between crystals with different properties (e.g., different XRPD patterns and / or different DSC scan results). The term "polymorph" typically includes pseudopolymorphs, which are different solvates of a substance and therefore have different properties from one another. Thus, each distinct polymorph and pseudopolymorph of a free base or salt form is considered herein to be a distinct single crystalline form. In some embodiments, the solid form is a solid crystalline form.

[0011] 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 at room temperature is between about 0% and about 100%, between about 25% and about 75%, between about 0% and about 50%, between about 50% and about 100%, or between about 40% and about 65%.

[0012] The term "substantially crystalline" refers to a form in which at least a specified weight percentage may be crystalline. The specified weight percentage may be 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 a free base or salt form that is at least 70% crystalline. In other embodiments, substantially crystalline refers to a free base or salt form that is at least 90% crystalline.

[0013] As used herein, "amorphous" refers to a solid material that contains non-crystalline material. In certain embodiments, an amorphous sample of a material can be prepared by freeze-drying a mixture of the material with a solvent, where the mixture can be homogeneous (e.g., a solution) or heterogeneous (e.g., a slurry).

[0014] The term "substantially free" refers to forms and compositions that are free of impurities and / or crystalline compounds at least a specified percentage by weight. A specified percentage by weight may be 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 refers to a free base or salt form that is at least 70% pure. In other embodiments, substantially free refers to a free base or salt form that is at least 90% pure. In other embodiments, substantially free of crystalline compounds refers to a composition having less than about 30%, less than about 20%, less than about 15%, less than about 10%, less than about 5%, or less than about 1% crystalline compounds.

[0015] The term "hydrate" refers to a solvate in which the solvent molecule is HO and exists in a defined stoichiometric or non-stoichiometric amount. Stoichiometric solvates can include, for example, hemihydrate, monohydrate, dihydrate, or trihydrate forms, among others. Non-stoichiometric solvates can include, for example, channel hydrates, including cases in which the water content can change depending on the humidity of the environment. In some embodiments, the (R)-oxybutynin salt can exist as a hemihydrate, monohydrate, dihydrate, or trihydrate form.

[0016] The term "solvate or solvated" refers to a physical association of a compound of the present invention (including crystalline forms thereof) with one or more solvent molecules. This physical association includes hydrogen bonding. In certain instances, the solvate is capable of isolation, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. "Solvate or solvated" encompasses both solution-phase and isolatable solvates. Representative solvates include, for example, hydrates, ethanolates, or methanolates.

[0017] The term "stable" in the context of the polymorphic forms disclosed herein refers to the stability of the polymorphic form to, for example, heat and / or humidity.

[0018] As used herein, the crystalline forms of (R)-oxybutynin HCl are referred to as Forms A, B, and C, respectively. Form A is an isopropanol solvate polymorph prepared by reacting (R)-oxybutynin dissolved in isopropanol with hydrochloric acid at 20-25°C. Form B is a desolvated polymorph prepared at ambient temperature by fast evaporation of Form A dissolved in toluene or upon vacuum drying of Form A. Form C polymorph was prepared by reacting (R)-oxybutynin dissolved in methyl t-butyl ether (MTBE) with hydrochloric acid at approximately 35°C. Forms A, B, and C exhibited distinct X-ray powder diffraction (XRPD) patterns, as provided in Figure 1.

[0019] In many embodiments disclosed herein, (R)-oxybutynin HCl is disclosed as having a crystalline structure.

[0020] In certain embodiments, the crystalline structures in this disclosure can be identified by having one or more characteristic peaks in an XRPD spectrum, as disclosed herein.

[0021] In some embodiments, the crystalline structure in the present disclosure has one or more characteristic endothermic peaks in differential scanning calorimetry, as disclosed herein.

[0022] In certain embodiments, methods for preparing and / or interconverting one or more crystalline forms of (R)-oxybutynin HCl are provided. Further embodiments describe the conversion and storage of crystalline forms of (R)-oxybutynin HCl that have the desired stability under expected storage conditions.

[0023] Certain embodiments disclosed herein provide a solid form of (R)-oxybutynin HCl, e.g., Form C, having an X-ray powder diffraction pattern including a peak at 6.9 degrees 2θ±0.2 degrees 2θ at about ambient relative humidity.

[0024] Certain embodiments disclosed herein provide a solid form of (R)-oxybutynin HCl, e.g., Form C, having an X-ray powder diffraction pattern comprising peaks, in terms of 2θ, at 6.9 degrees 2θ±0.2 degrees 2θ and / or 18.3 degrees 2θ±0.2 degrees 2θ at about ambient relative humidity.

[0025] Certain embodiments disclosed herein provide a solid form of (R)-oxybutynin HCl, e.g., Form C, having an X-ray powder diffraction pattern comprising at least two peaks (e.g., two or three peaks) in terms of 2θ 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 at about ambient relative humidity.

[0026] Certain embodiments disclosed herein provide a solid form of (R)-oxybutynin HCl, e.g., Form C, having an X-ray powder diffraction pattern comprising at least three peaks (e.g., three, four, or five peaks) in terms of 2θ 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 at about ambient relative humidity.

[0027] Certain embodiments disclosed herein provide a solid form of (R)-oxybutynin HCl, e.g., Form C, having an X-ray powder diffraction pattern comprising at least four peaks (e.g., four, five, six, or seven peaks) in terms of 2θ 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 at about ambient relative humidity.

[0028] Certain embodiments disclosed herein provide a solid form of (R)-oxybutynin HCl, e.g., Form C, having an X-ray powder diffraction pattern comprising at least five peaks, in terms of 2θ, 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, 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 at about ambient relative humidity.

[0029] Certain embodiments disclosed herein provide a solid form of (R)-oxybutynin HCl, e.g., Form C, having an X-ray powder diffraction pattern comprising at least seven peaks, in terms of 2θ, 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, 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 at about ambient relative humidity.

[0030] Certain embodiments disclosed herein provide a solid form of (R)-oxybutynin HCl, e.g., Form C, having an X-ray powder diffraction pattern comprising at least eight peaks, in terms of 2θ, 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, 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 at about ambient relative humidity.

[0031] Certain embodiments disclosed herein provide a solid form of (R)-oxybutynin HCl, e.g., Form C, having an X-ray powder diffraction pattern comprising at least nine peaks, in terms of 2θ, 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, 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 at about ambient relative humidity.

[0032] Certain embodiments disclosed herein provide a solid form of (R)-oxybutynin HCl, e.g., Form C, having an X-ray powder diffraction pattern comprising peaks in terms of 2θ at about ambient relative humidity: 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.

[0033] Certain embodiments disclosed herein exhibit, in terms of 2θ, values ​​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, 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 at about ambient relative humidity. A solid form of (R)-oxybutynin HCl, e.g., Form C, is provided having an X-ray powder diffraction pattern comprising at least one peak, at least two peaks, at least three peaks, at least four peaks, at least five peaks, at least six peaks, at least seven peaks, at least eight peaks, at least nine peaks, at least ten peaks, or at least eleven peaks selected from the group consisting of degrees 2θ±0.2 degrees 2θ.

[0034] 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.

[0035] Certain embodiments disclosed herein provide a solid form of (R)-oxybutynin HCl, e.g., Form C, having a differential scanning calorimetry (DSC) thermogram showing a melting onset at 109.6° C. and an endothermic peak at 119.1° C. Form C exhibited a higher melting temperature compared to both Form A and Form B.

[0036] Certain embodiments disclosed herein provide a solid form of (R)-oxybutynin HCl, e.g., Form C, having a differential scanning calorimetry (DSC) thermogram substantially as shown in FIG.

[0037] Certain embodiments disclosed herein provide a solid form of (R)-oxybutynin (e.g., Form C) disclosed herein, wherein the solid form comprises at least 1% w / w of the total sample of (R)-oxybutynin HCl. Certain embodiments disclosed herein provide a composition comprising (R)-oxybutynin, wherein at least 5% w / w of the total amount of (R)-oxybutynin is a solid form of (R)-oxybutynin (e.g., Form C) disclosed herein. Certain embodiments disclosed herein provide a composition comprising (R)-oxybutynin, wherein at least 10% w / w of the total amount of (R)-oxybutynin is a solid form of (R)-oxybutynin (e.g., Form C) disclosed herein. Certain embodiments disclosed herein provide compositions comprising (R)-oxybutynin, wherein at least 25% w / w of the total amount of (R)-oxybutynin is a solid form of (R)-oxybutynin disclosed herein (e.g., Form C). Certain embodiments disclosed herein provide compositions comprising (R)-oxybutynin, wherein at least 50% w / w of the total amount of (R)-oxybutynin is a solid form of (R)-oxybutynin disclosed herein (e.g., Form C). Certain embodiments disclosed herein provide compositions comprising (R)-oxybutynin, wherein at least 90% w / w of the total amount of (R)-oxybutynin is a solid form of (R)-oxybutynin disclosed herein (e.g., Form C). Certain embodiments disclosed herein provide compositions comprising (R)-oxybutynin, wherein at least 95% w / w of the total amount of (R)-oxybutynin is a solid form of (R)-oxybutynin disclosed herein (e.g., Form C). Certain embodiments disclosed herein provide compositions comprising (R)-oxybutynin, wherein at least 98% w / w of the total amount of (R)-oxybutynin is a solid form of (R)-oxybutynin disclosed herein (e.g., Form C). Certain embodiments disclosed herein provide compositions comprising (R)-oxybutynin, wherein at least 99% w / w of the total amount of (R)-oxybutynin is a solid form of (R)-oxybutynin disclosed herein (e.g., Form C).

[0038] Certain embodiments disclosed herein provide pharmaceutical compositions comprising Form C in any of its specific embodiments and one or more pharmaceutically acceptable excipients.

[0039] Certain embodiments disclosed herein provide a solid form of (R)-oxybutynin HCl, e.g., Form B, having an X-ray powder diffraction pattern including a peak at 7.5 degrees 2θ±0.2 degrees 2θ at about ambient relative humidity.

[0040] Certain embodiments disclosed herein provide a solid form of (R)-oxybutynin HCl, e.g., Form B, having an X-ray powder diffraction pattern comprising peaks, in terms of 2θ, at 7.5 degrees 2θ±0.2 degrees 2θ and / or 17.2 degrees 2θ±0.2 degrees 2θ at about ambient relative humidity.

[0041] Certain embodiments disclosed herein provide a solid form of (R)-oxybutynin HCl, e.g., Form B, having an X-ray powder diffraction pattern comprising at least two peaks (e.g., two or three peaks) in terms of 2θ 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 at about ambient relative humidity.

[0042] Certain embodiments disclosed herein provide a solid form of (R)-oxybutynin HCl, e.g., Form B, having an X-ray powder diffraction pattern comprising at least three peaks (e.g., three, four, or five peaks) in terms of 2θ selected from the group consisting of 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 ± 0.2 degrees 2θ at about ambient relative humidity.

[0043] Certain embodiments disclosed herein exhibit, in terms of 2θ, the following at about ambient relative humidity: 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 degrees 2θ ± 0.2 degrees 2θ, 6.6 degrees 2θ ± 0.2 degrees 2θ, Provided is a solid form of (R)-oxybutynin HCl, e.g., Form B, having an X-ray powder diffraction pattern comprising at least one peak, at least two peaks, at least three peaks, at least four peaks, at least five peaks, at least six peaks, at least seven peaks, at least eight peaks, at least nine peaks, at least ten peaks, or at least eleven peaks selected from the group consisting of 2θ ± 0.2 degrees 2θ, 8.2 degrees 2θ ± 0.2 degrees 2θ, and 20.4 degrees 2θ ± 0.2 degrees 2θ.

[0044] Certain embodiments disclosed herein provide a solid form of (R)-oxybutynin HCl, e.g., Form B, having an X-ray powder diffraction pattern at about ambient relative humidity substantially as shown in FIG. 3.

[0045] Certain embodiments disclosed herein provide a solid form of (R)-oxybutynin HCl, e.g., Form B, having a differential scanning calorimetry (DSC) thermogram that exhibits an onset of melting at about 40°C and an endothermic peak at 64.8°C.

[0046] Certain embodiments disclosed herein provide a solid form of (R)-oxybutynin HCl, e.g., Form B, having a differential scanning calorimetry (DSC) thermogram substantially as shown in FIG.

[0047] Certain embodiments disclosed herein provide pharmaceutical compositions comprising a solid form of (R)-oxybutynin HCl (e.g., Form B) disclosed herein and one or more pharmaceutically acceptable excipients.

[0048] In some embodiments, the solid form (R)-oxybutynin HCl is a crystalline mixture containing less than 1% Form B. In certain embodiments, the solid form (R)-oxybutynin HCl is a crystalline mixture containing more than 0.1% but less than 2% Form B. In some embodiments, the solid form (R)-oxybutynin HCl contains at least 10% Form B. In some embodiments, the solid form (R)-oxybutynin HCl contains at least 25% Form B. In some embodiments, the solid form (R)-oxybutynin HCl contains at least 50% Form B. In some embodiments, the solid form (R)-oxybutynin HCl contains at least 75% Form B. In some embodiments, the solid form (R)-oxybutynin HCl contains at least 95% Form B. In some embodiments, the solid form (R)-oxybutynin HCl contains at least 97% Form B. In some embodiments, the solid form (R)-oxybutynin HCl contains at least 99% Form B.

[0049] Certain embodiments disclosed herein provide solid and solvated (hereinafter "solid solvated") forms of (R)-oxybutynin HCl, e.g., Form A. In some embodiments, the solid hydrated form of (R)-oxybutynin HCl comprises an isopropanol solvate.

[0050] Certain embodiments disclosed herein provide a solid solvated form of (R)-oxybutynin HCl, e.g., Form A, having an X-ray powder diffraction comprising a peak at 19.2 degrees 2θ±0.2 degrees 2θ at about ambient relative humidity.

[0051] Certain embodiments disclosed herein provide a solid solvated form of (R)-oxybutynin HCl, e.g., Form A, having an X-ray powder diffraction pattern comprising peaks, in terms of 2θ, at 19.2 degrees 2θ±0.2 degrees 2θ and / or 6.1 degrees 2θ±0.2 degrees 2θ at about ambient relative humidity.

[0052] Certain embodiments disclosed herein provide a solid solvated form of (R)-oxybutynin HCl, e.g., Form A, having an X-ray powder diffraction pattern comprising at least two peaks (e.g., two or three peaks) in terms of 2θ 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 at about ambient relative humidity.

[0053] Certain embodiments disclosed herein provide a solid solvated form of (R)-oxybutynin HCl, e.g., Form A, having an X-ray powder diffraction pattern comprising at least three peaks (e.g., three, four, or five peaks) in terms of 2θ selected from the group consisting of 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 ± 0.2 degrees 2θ at about ambient relative humidity.

[0054] Certain embodiments disclosed herein provide a solid solvated form of (R)-oxybutynin HCl, e.g., Form A, having an X-ray powder diffraction pattern comprising at least four peaks (e.g., four or five peaks) in terms of 2θ selected from the group consisting of 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 ± 0.2 degrees 2θ at about ambient relative humidity.

[0055] Certain embodiments disclosed herein exhibit, in terms of 2θ, at about ambient relative humidity, 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 Provided is a solid solvated form of (R)-oxybutynin HCl, e.g., Form A, having an X-ray powder diffraction pattern comprising at least one peak, at least two peaks, at least three peaks, at least four peaks, at least five peaks, at least six peaks, at least seven peaks, at least eight peaks, at least nine peaks, at least ten peaks, or at least eleven peaks selected from the group consisting of 20.8 degrees two-theta ± 0.2 degrees two-theta.

[0056] Certain embodiments disclosed herein provide a solid form of (R)-oxybutynin HCl, e.g., Form A, having an X-ray powder diffraction pattern substantially as shown in Figure 2 at about ambient relative humidity.

[0057] Certain embodiments disclosed herein provide a solid form of (R)-oxybutynin HCl, e.g., Form A, having a differential scanning calorimetry (DSC) thermogram showing a broad endothermic transition with an initial endothermic peak at 70.2° C. and additional endothermic peaks at 87.9° C. and 119.4° C. The sample exhibits a 28% weight loss between 29° C. and 158° C.

[0058] Certain embodiments disclosed herein provide a solid form of (R)-oxybutynin HCl, e.g., Form A, having a differential scanning calorimetry (DSC) thermogram substantially as shown in FIG.

[0059] Certain embodiments disclosed herein provide solid forms of (R)-oxybutynin HCl that are amorphous.

[0060] Certain embodiments disclosed herein provide one or more crystalline and / or amorphous forms of (R)-oxybutynin HCl dispersed in a matrix.

[0061] Certain embodiments disclose dosage forms of (R)-oxybutynin HCl 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 of (R)-oxybutynin HCl in one or more crystalline forms (e.g., Forms A, B, and C) and / or amorphous forms, wherein the one or more crystalline forms and / or amorphous forms are dispersed in a solid or liquid matrix.

[0062] II. Pharmaceutical Compositions and / or Formulas of Polymorphic Forms of (R)-Oxybutynin HCl Provided herein are pharmaceutical compositions comprising one or more polymorphic forms of (R)-oxybutynin HCl and a physiologically acceptable carrier (also referred to as a pharmaceutically acceptable carrier, solution, or diluent). Such carriers and solutions include pharmaceutically acceptable salts and solvates of the compounds used in the methods of the present invention, as well as mixtures containing two or more of such compounds, pharmaceutically acceptable salts, and pharmaceutically acceptable solvates of the compounds. Such compositions are prepared according to accepted pharmaceutical procedures, such as those described in Remington's Pharmaceutical Sciences, 17th edition, ed. Alfonso R. Gennaro, Mack Publishing Company, Eaton, Pa. (1985) (incorporated herein by reference).

[0063] The term "pharmaceutically acceptable carrier" refers to a carrier that does not cause an allergic reaction or other untoward effect in a subject to which it is administered and is compatible with other ingredients in the formulation. Pharmaceutically acceptable carriers include, for example, pharmaceutical diluents, excipients, or carriers appropriately selected for the intended form of administration and consistent with conventional pharmaceutical practice. For example, solid carriers / diluents include, but are not limited to, gums, starches (e.g., corn starch, pregelatinized starch), sugars (e.g., lactose, mannitol, sucrose, dextrose), cellulose materials (e.g., microcrystalline cellulose), acrylates (e.g., polymethylacrylate), calcium carbonate, magnesium oxide, talc, or mixtures thereof. Pharmaceutically acceptable carriers may further contain minor amounts of auxiliary substances, such as wetting or emulsifying agents, preservatives, or buffers, which enhance the shelf life or effectiveness of the therapeutic agent.

[0064] One or more polymorphic and / or amorphous forms of (R)-oxybutynin HCl and pharmaceutical compositions thereof disclosed herein can be formulated into unit dosage forms, which refer to physically discrete units suitable as a single dosage form for a subject to be treated, each unit containing a predetermined amount of active substance calculated to produce a desired therapeutic effect, and optionally, can be combined with a suitable pharmaceutical carrier. The unit dosage form can be a single daily dose or multiple daily doses (e.g., about 1 to 4 or more times per day). When multiple daily dosages are used, the unit dosage form can be the same or different for each dose. In certain embodiments, the compound can be formulated for controlled release.

[0065] One or more polymorphic forms and / or amorphous forms of (R)-oxybutynin HCl disclosed herein and pharmaceutical compositions thereof can be formulated according to any available conventional method. Commonly used additives such as diluents, binders, disintegrants, lubricants, colorants, flavoring agents, and, if necessary, stabilizers, emulsifiers, absorption enhancers, surfactants, pH adjusters, disinfectants, and antioxidants can be used in the formulation. For oral therapeutic administration, the active compound(s) can be incorporated with excipients and used in the form of pills, tablets, lozenges, or capsules, such as gelatin capsules. Oral compositions can also be prepared using a fluid carrier. Pharmaceutically compatible binders and / or adjuvant materials can be included as part of the composition. Dosage forms, including tablets, powders, granules, granules, coated tablets, capsules, syrups, lozenges, and the like, can contain any of the following ingredients or compounds of similar nature: a binder such as microcrystalline cellulose, gum tragacanth, or gelatin; an excipient such as starch or lactose; a disintegrating agent such as alginic acid, Primogel, crospovidone, or corn starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.

[0066] Systemic administration of one or both of the compounds described herein (i.e., one or both of the norepinephrine reuptake inhibitor and the substantially enantiomerically pure (R)-oxybutynin) can also be achieved by transdermal means, for example, using a patch, gel, or lotion applied to the skin. For transdermal administration, a penetrant suitable for permeating the epidermal barrier can be used in the formulation. Such penetrants are generally known in the art. For example, for transdermal administration, the active compound can be formulated into an ointment, salve, gel, or cream, as is generally known in the art. Gels and / or lotions can be provided in individual sachets or via a daily-applied metered-dose pump. See, for example, Cohn et al., Ther Adv Urol. 2016 Apr;8(2):83-90.

[0067] In some embodiments, therapeutic compounds are prepared with carriers that protect the therapeutic compound from 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 are commercially available, for example, from Alza Corporation and Nova Pharmaceuticals, Inc. Liposomal suspensions can also be used as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art, for example, as described in U.S. Pat. No. 4,522,811.

[0068] The pharmaceutical compositions can be included in a container, pack, or dispenser together with instructions for administration or use in the methods described herein.

[0069] Some embodiments disclosed herein provide a pharmaceutical dosage form comprising (R)-oxybutynin 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.

[0070] Certain embodiments disclosed herein provide a drug dosage form as a tablet 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)-oxybutynin HCl 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)-oxybutynin in the tablet is (R)-oxybutynin HCl crystalline Form C.

[0071] 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)-oxybutynin HCl disclosed herein (e.g., including Form B and / or Form C), and one or more pharmaceutically acceptable excipients.

[0072] In certain embodiments, the pharmaceutical dosage form comprises Form C disclosed herein.

[0073] Certain embodiments disclosed herein include (R)-oxybutynin HCl Form C or pharmaceutical compositions thereof that are substantially free of other crystalline or amorphous forms. For example, in some embodiments, (R)-oxybutynin HCl Form C or pharmaceutical compositions thereof contain 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% Form C by weight compared to other crystalline or amorphous forms of (R)-oxybutynin HCl.

[0074] III. Uses of Polymorphic Forms of (R)-Oxybutynin HCl In some embodiments, provided herein are methods for treating a subject having a condition associated with pharyngeal airway collapse, the methods comprising administering to a subject in need thereof effective amounts of (i) a norepinephrine reuptake inhibitor (NRI) (e.g., atomoxetine or a pharmaceutically acceptable salt thereof) and (ii) substantially enantiomerically pure (R)-oxybutynin HCl. The methods comprise administering to the subject a therapeutically effective amount of one or more polymorphic forms of (R)-oxybutynin HCl disclosed herein, or pharmaceutical compositions thereof. In some embodiments, the substantially enantiomerically pure (R)-oxybutynin HCl is Form C.

[0075] In other embodiments, provided herein are methods for treating a subject having a condition associated with pharyngeal airway collapse, comprising administering to a subject in need thereof (i) 4-hydroxyatomoxetine or a pharmaceutically acceptable salt thereof, and (ii) substantially enantiomerically pure (R)-oxybutynin HCl. The method comprises administering to the subject a therapeutically effective amount of one or more polymorphic forms of (R)-oxybutynin HCl disclosed herein, or a pharmaceutical composition thereof. In some embodiments, the substantially enantiomerically pure (R)-oxybutynin HCl is Form C.

[0076] In other embodiments, provided herein are methods for treating a subject having a condition associated with pharyngeal airway collapse, comprising administering to a subject in need thereof (i) 4-hydroxyatomoxetine or a pharmaceutically acceptable salt thereof, (ii) substantially enantiomerically pure (R)-oxybutynin HCl, and (iii) a hypnotic agent. The method comprises administering to the subject a therapeutically effective amount of one or more polymorphic forms of (R)-oxybutynin HCl disclosed herein, or pharmaceutical compositions thereof. In some embodiments, the substantially enantiomerically pure (R)-oxybutynin HCl is Form C.

[0077] In yet another embodiment, provided herein are methods for treating a subject having a condition associated with pharyngeal airway collapse, comprising administering to a subject in need thereof a pharmaceutical composition comprising effective amounts of a norepinephrine reuptake inhibitor (e.g., atomoxetine or a pharmaceutically acceptable salt thereof), substantially enantiomerically pure (R)-oxybutynin HCl, and a carbonic anhydrase inhibitor as active ingredients. The norepinephrine reuptake inhibitor, (R)-oxybutynin HCl, and carbonic anhydrase inhibitor may be administered in a single composition or in separate compositions. The method comprises administering to the subject a therapeutically effective amount of one or more polymorphic forms of (R)-oxybutynin HCl disclosed herein together with the norepinephrine reuptake inhibitor and the carbonic anhydrase inhibitor. In some embodiments, (R)-oxybutynin HCl is administered as Form C.

[0078] Exemplary norepinephrine reuptake inhibitors (NRIs) include selective NRIs amidaline (UK-3540-1), atomoxetine (Strattera), CP-39,332, daredalin (UK-3557-15), edivoxetine (LY-2216684), esreboxetine, lortalamine (LM-1404), nisoxetine (LY-94,939), reboxetine (Edronax, Bestra), talopram (Lu3-010), talspram (Lu5-005), tandamine (AY-23,946), viloxazine (Vivaran); non-selective NRIs include amitriptyline, amopropane, thiazolinone ... These include fluoxaphine, bupropion, cyclazindol, desipramine, desvenlafaxine, dexylphenidate, diethylpropion, doxepin, duloxetine, imipramine, levomilnacipran, manifaxine (GW-320,659), maprotiline, methylphenidate, milnacipran, nefazodone, nortriptyline, phendimetrazine, phenmetrazine, protriptyline, radafaxine (GW-353,162), tapentadol (Nucinta), teniloxazine (Luseran, Metatone), and venlafaxine, and pharmaceutically acceptable salts thereof.

[0079] 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 yet other embodiments, the norepinephrine reuptake inhibitor is a combination of atomoxetine and reboxetine or a pharmaceutically acceptable salt thereof.

[0080] Oxybutynin is an antimuscarinic agent and a muscarinic receptor antagonist. In some embodiments, oxybutynin is a racemic mixture of (R)-oxybutynin and (S)-oxybutynin. In some embodiments, the salt forms or compositions include mixtures of oxybutynin enantiomers described herein, where there is an enantiomeric excess of (R)-oxybutynin over its enantiomeric pair (i.e., (S)-oxybutynin). The enantiomeric excess of (R)-oxybutynin in these mixtures can be 10% or more, 20% or more, 25% or more, 30% or more, 40% or more, 50% or more, 60% or more, 70% or more, 75% or more, 80% or more, or 90% or more.

[0081] In some embodiments, the muscarinic receptor antagonist is substantially enantiomerically pure (R)-oxybutynin. In some embodiments, substantially enantiomerically pure (R)-oxybutynin, referred to herein as "(R)-oxybutynin" and / or salts thereof, is better tolerated over long-term use in subjects than racemic oxybutynin forms. Compositions comprising substantially enantiomerically pure (R)-oxybutynin having various polymorphs described herein can have an enantiomeric excess of substantially enantiomerically pure (R)-oxybutynin of 80% or more, 90% or more, 95% or more, 98% or more, 99% or more, 99.5% or more, 99.8% or more, or 99.9% or more.

[0082] The carbonic anhydrase inhibitor may be selected from the group consisting of acetazolamide, dichlorophenamide, dorzolamide, brinzolamide, methazolamide, zonisamide, etoxozolamide, topiramate, sulthiame, 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.

[0083] In some embodiments, hypnotics can be incorporated into the composition, such as zolpidem, zopiclone, ezopiclone, trazodone, zaleplon, benzodiazepines, gabapentin, tiagabine, and xylem, or a pharmaceutically acceptable salt thereof. In some embodiments, patients with OSA have a low awakening threshold, which can be exacerbated by atomoxetine and / or 4-hydroxyatomextine. In embodiments where a patient has a low awakening threshold caused or exacerbated by the use of atomoxetine and / or 4-hydroxyatomextine, a hypnotic can be used as an adjunct active compound to increase the awakening threshold of patients with OSA, pharyngeal airway collapse, or a combination thereof. In some embodiments, the patient's awakening threshold can be measured by polysomnography (PSG). In some embodiments, the patient is a human subject.

[0084] In some embodiments, the method comprises administering a dose of about 20 mg to about 150 mg of atomoxetine or a pharmaceutically acceptable salt thereof (or its dose equivalent of another NRI), about 20 mg to about 100 mg of atomoxetine or a pharmaceutically acceptable salt thereof, about 50 mg to about 100 mg of atomoxetine or a pharmaceutically acceptable salt thereof, or about 75 mg to about 100 mg of atomoxetine or a pharmaceutically acceptable salt thereof. In some embodiments, the method comprises administering about 0.1 mg to about 25 mg of (R)-oxybutynin HCl, about 1 mg to about 20 mg of (R)-oxybutynin HCl, about 1 mg to about 10 mg of (R)-oxybutynin HCl, or about 2.5 mg to about 7.5 mg of (R)-oxybutynin HCl. In other embodiments, the method comprises administering about 20 mg to about 150 mg of atomoxetine or a pharmaceutically acceptable salt thereof (or a dose equivalent of another NRI) in combination with about 0.1 mg to about 25 mg of (R)-oxybutynin HCl, about 20 mg to about 150 mg of atomoxetine or a pharmaceutically acceptable salt thereof in combination with about 1 mg to about 20 mg of (R)-oxybutynin HCl, about 20 mg to about 150 mg of atomoxetine or a pharmaceutically acceptable salt thereof in combination with about 1 mg to about 10 mg of (R)-oxybutynin HCl, or about 20 mg to about 150 mg of atomoxetine or a pharmaceutically acceptable salt thereof in combination with about 2.5 mg to about 7.5 mg of (R)-oxybutynin HCl. In some embodiments, (R)-oxybutynin HCl may be formulated and applied as an active coating on an NRI or atomoxetine. In other embodiments, (R)-oxybutynin HCl may be formulated as a blend with an NRI or atomoxetine.

[0085] In some embodiments, the method comprises administering a 20-100 mg dose of atomoxetine and / or 4-hydroxyatomoxetine or a pharmaceutically acceptable salt thereof, a 2-15 mg dose of oxybutynin (i.e., a muscarinic receptor antagonist), and a 0.5-15 mg dose of zolpidem (or a dose equivalent of another hypnotic agent). In some embodiments, the methods involve administering 75 mg atomoxetine and / or 4-hydroxyatomoxetine / 6 mg (R)-oxybutynin / 10 mg zolpidem; 75 mg atomoxetine and / or 4-hydroxyatomoxetine / 5 mg oxybutynin / 10 mg zolpidem; 75 mg atomoxetine and / or 4-hydroxyatomoxetine / 4.5 mg oxybutynin / 5 mg zolpidem; 50 mg atomoxetine and / or 4-hydroxyatomoxetine / 4 mg oxybutynin / 3.5 mg zolpidem; or 25 mg atomoxetine and / or 4-hydroxyatomoxetine / 3 mg oxybutynin / 1.75 mg zolpidem, e.g., 15 to 60, 15 to 25, 20 to 30, or 20 to 45 minutes before sleep time. In some embodiments, the hypnotic agent is present in an amount of about 0.5 to about 15 mg, about 0.5 to about 10 mg, about 0.5 to about 5 mg, about 0.5 to about 3.5 mg, or about 0.5 to about 1.75 mg.

[0086] In some embodiments, the method comprises administering a dose of about 20 mg to about 150 mg of atomoxetine or a pharmaceutically acceptable salt thereof (or its dose equivalent of another NRI), about 20 mg to about 100 mg of atomoxetine or a pharmaceutically acceptable salt thereof, about 50 mg to about 100 mg of atomoxetine or a pharmaceutically acceptable salt thereof, or about 75 mg to about 100 mg of atomoxetine or a pharmaceutically acceptable salt thereof. In some embodiments, the method comprises administering about 0.1 mg to about 25 mg of (R)-oxybutynin HCl, about 1 mg to about 20 mg of (R)-oxybutynin HCl, about 1 mg to about 10 mg of (R)-oxybutynin HCl, or about 2.5 mg to about 7.5 mg of (R)-oxybutynin HCl. In some embodiments, the method comprises administering about 50 mg to about 1000 mg of acetazolamide (or a dose equivalent of another CAI), about 100 mg to about 800 mg of acetazolamide, about 250 mg to about 750 mg of acetazolamide, about 500 mg to about 750 mg of acetazolamide, or about 450 mg to about 650 mg of acetazolamide. In some embodiments, the method comprises administering about 20 mg to about 150 mg of an NRI, about 1 mg to about 25 mg of an MRA, including (R)-oxybutynin, and about 250 mg to about 750 mg of a carbonic anhydrase inhibitor. In another embodiment, the method comprises administering about 50 mg to about 100 mg of an NRI, about 1 mg to about 15 mg of an MRA comprising (R)-oxybutynin, and about 250 mg to about 750 mg of a carbonic anhydrase inhibitor.In yet other embodiments, the method comprises administering 80 mg atomoxetine / 5 mg (R)-oxybutynin / 500 mg acetazolamide; 80 mg atomoxetine / 5 mg oxybutynin / 500 mg acetazolamide; 100 mg atomoxetine / 5 mg (R)-oxybutynin / 500 mg acetazolamide; 100 mg atomoxetine / 5 mg (R)-oxybutynin / 750 mg acetazolamide; or 80 mg atomoxetine / 5 mg (R)-oxybutynin / 750 mg acetazolamide, either in combined or separate doses, e.g., 15 to 60, e.g., 15 to 25, 20 to 30, or 20 to 45 minutes before sleep time.

[0087] An effective amount may be administered in one or more administrations, applications, or dosages. The compositions can be administered from one or more times daily to one or more times weekly, including once every two days. In some embodiments, the compositions are administered daily. One of ordinary skill in the art will appreciate that certain factors may influence the dosage and timing required to effectively treat a subject, including, but not limited to, the severity of the disease or disorder, previous treatments, the subject's overall health and / or age, and other diseases present. Furthermore, treatment of a subject with a therapeutically effective amount of a therapeutic compound described herein can include a single treatment or a series of treatments.

[0088] The dosage, toxicity, and therapeutic efficacy of therapeutic compounds (i.e., NRIs, MRAs, hypnotics, and CAIs in a single composition or separate compositions) can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, for example, to determine the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population). The dose ratio of toxic to therapeutic effects is the therapeutic index, which can be expressed as the ratio LD50 / ED50.

[0089] Data obtained from cell culture assays and animal studies can be used to formulate a range of dosages for use in humans. The dosage of such compounds preferably lies within a range of circulating concentrations that include the ED50 with little or no toxicity. Dosages may vary within this range depending on the dosage used and the route of administration utilized. For any compound used in the methods of the invention, a therapeutically effective dose can be initially estimated from cell culture assays. A dose can be formulated in animal models to achieve a circulating plasma concentration range that includes the IC50 (i.e., the concentration of the test compound that achieves a half-maximal inhibition of symptoms), as determined in cell culture. Such information can be used to more accurately determine useful doses in humans. Plasma levels can be measured, for example, by high-performance liquid chromatography.

[0090] IV. Preparation and Characterization of Polymorphic Forms of (R)-Oxybutynin HCl Provided herein are methods for preparing crystalline polymorphic Forms A, B, and C of (R)-oxybutynin HCl. R-oxybutynin HCl Form A is the mono-HCl salt of R-oxybutynin and is solvated / hydrated and can be converted to R-oxybutynin HCl Form B upon drying under vacuum at room temperature and upon storage at ambient conditions. R-oxybutynin HCl Form C is obtained as a single crystalline phase that competes with the formation of Form B under certain solvents and preparation conditions, such as slurries of R-oxybutynin HCl in heptane or MIBK at room temperature for various periods of time.

[0091] Form A In some embodiments, crystalline R-oxybutynin HCl Form A can be prepared by directly adding excess 1.25 M HCl in IPA to R-oxybutynin. The resulting golden solution can be stirred at room temperature to produce a thick white paste. A wet solid can be isolated and analyzed from the thick white paste. Figure 2 provides the XRPD pattern, and the corresponding peaks are listed in Table 1, indicating that the R-oxybutynin HCl Form A material is composed primarily or exclusively of a single crystalline phase. The indexed volume (1312.8 Å)3 / cell) indicates that the sample is likely to be solvated / hydrated based on molecular weight considerations.

[0092] To a solution of (R)-oxybutynin free base (10 g, 28 mmole, 1.00 equiv.) in isopropanol (100 mL, 10 vol.) was added HCl in isopropanol (21.3 mL, 26.6 mmole, 0.95 equiv.) over 5 min at 25 °C. The resulting solution was aged for 1 h before the batch was cooled to 0 °C and aged for 30 min (3 × 2 vol.). The resulting thick white slurry was filtered under nitrogen and washed with isopropanol (3 × 20 mL). The hygroscopic solid (see Figure 2) was dried in a vacuum oven at 20-25 °C for 24 h to give 9.8 g of (R)-oxybutynin hydrochloride (78% yield, 11.5 wt. % isopropanol, 0.5 wt. % diethylamine retained).

[0093] 1 The H NMR spectrum is consistent with the structure of R-oxybutynin and contains 0.3 moles of IPA based on the presence of peaks at 4.1 ppm and 3.7 ppm. Water is also observed based on the 3.3 ppm peak. The solubilized R-oxybutynin HCl Form A material 1 Additional minor peaks were observed in the 1 H NMR spectrum.

[0094] R-oxybutynin HCl Form A material was analyzed by ion chromatography (IC) to determine chloride content. IC analysis confirmed the presence of chloride ions in an API:Cl molar ratio of approximately 1:1, suggesting a monochloride salt of R-oxybutynin.

[0095] Thermal analysis of the R-oxybutynin HCl Form A material is shown in Figure 5. A broad endotherm with peak maxima at 70.2 °C, 87.9 °C, and 119.4 °C is observed in the DSC data, which is associated with a continuous weight loss in the TGA thermogram. The sample exhibits a 28% weight loss between 29 °C and 158 °C.

[0096] R-oxybutynin HCl Form A polymorph was prepared on an approximately 2 g scale. A subsample of the scaled-up R-oxybutynin HCl Form A was dried under vacuum at room temperature for 24 hours to yield a unique crystalline material designated R-oxybutynin HCl Form B. R-oxybutynin HCl Form B is discussed further below.

[0097] Form B In some embodiments, R-oxybutynin HCl Form B can be prepared by drying R-oxybutynin HCl Form A under vacuum after storage at room temperature for 24 hours or at ambient conditions. The XRPD pattern of R-oxybutynin HCl Form B is provided in Figure 3 and shows that the Form B material is composed primarily or exclusively of a single crystalline phase. The indexed volume (4705.2 Å) 3 / cell) indicates that the sample is likely anhydrous based on molecular weight considerations. Characterization data and preparation methods suggest that R-oxybutynin HCl Form B is an anhydrous / non-solvated mono-HCl salt of R-oxybutynin.

[0098] 1 H NMR analysis shows that the material is consistent with the API structure. Water is present in the spectrum at 3.3 ppm; however, this may be due to potential water in the deuterated solvent.

[0099] A single broad endotherm (peak maximum) at 64.8° C. is observed in the DSC thermogram (FIG. 6) due to melting based on hot stage microscopy. Upon heating to melting, no significant weight loss is observed.

[0100] IC analysis confirmed the presence of chloride ions at an API:Cl molar ratio of approximately 1:1, suggesting the monochloride salt of R-oxybutynin.

[0101] DVS analysis of R-oxybutynin HCl Form B indicated that the material was hygroscopic; the sample showed a 26.6% weight gain from 5% to 95% RH. The majority of the weight gain was from 75% to 95% RH (23% weight gain). All of the weight gain decreased upon desorption from 95% to 5% RH. XRPD analysis of the post-DVS sample indicated that Form B remained, suggesting that no change in physical form had occurred. A sample of R-oxybutynin HCl Form B was exposed to 75% and 85% RH in an open container for 24 hours. 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 no longer free-flowing, but XRPD analysis of the sample indicated that the white solid consisted of Form B. When stressed at 93% RH, the sample deliquesced.

[0102] Form C In some embodiments, R-oxybutynin HCl Form C can be prepared as a single crystalline phase in competition with the formation of Form B using slurries of R-oxybutynin HCl in heptane or MIBK at room temperature for various periods of time. The XRPD pattern of R-oxybutynin HCl Form C is provided in Figure 4 and shows that the Form C material is composed primarily or exclusively of a single crystalline phase. The indexed volume indicates that the sample is likely anhydrous based on molecular weight considerations. The characterization data and preparation method suggest that R-oxybutynin HCl Form C is an anhydrous / non-solvated mono-HCl salt of R-oxybutynin.

[0103] A three-necked round-bottom flask equipped with an overhead stirrer, nitrogen inlet, and temperature probe was charged with (R)-oxybutynin free base (15.47 g, 210 mol, 1 equiv.) followed by MTBE (943 mL, 15.5 vol.). To the resulting solution was charged HCl in EtOAc (298 mL, 298 mmol, 1 M HCl in ETOAc, 1.3 equiv.) over 45 min. After approximately one-quarter of the HCl volume had been added, a thick slurry was observed to form. The thick slurry was warmed to 40 °C and aged for 1 h. The batch was then cooled to 0 °C (aged for 30 min), filtered under nitrogen, and washed with 2 × 2 volumes (2 × 164 mL) of cold MTBE. The solid was dried under vacuum at 20–25 °C for 24 h to yield crystalline (R)-oxybutynin hydrochloride Form C (83 g, 94% yield, 99% potency).

[0104] R-Oxybutynin HCl 1 The 1 H NMR spectrum is shown in FIG. 10, and the FT-IR spectrum is shown in FIG. 1 Analysis of both the H NMR and FT-IR spectra indicates that the (R)-oxybutynin hydrochloride Form C material is consistent with the structure of the API.

[0105] A broad endotherm (peak maximum) at 119.4°C is observed in the DSC thermogram (Figure 7). The LCMS trace of (R)-oxybutynin Form C is shown in Figure 12 and illustrates a predominantly single peak with a mass of 358.49, which corresponds to the [M+1] mass of R-oxybutynin. Referring to Figure 13, the achiral HPLC chromatogram of (R)-oxybutynin Form C demonstrates the purity of the Form C sample. Finally, IC analysis, provided in the ion chromatogram of Figure 14, confirms the presence of chloride ions at an approximately 1:1 API:Cl molar ratio, suggesting a monochloride salt of R-oxybutynin in the Form C material.

[0106] The target R-oxybutynin stereoisomer can be prepared by chromatographic separation of a racemic mixture of oxybutynin 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 the hydrochloride salt is shown below. [ka]

[0107] The first step in the scheme is carried out to remove residual diethylamine (DEA) that is contaminated in the free base product from the purification step. The second step involves carbon treatment of the R-oxybutynin free base and partial reverse addition of the MTBE free base solution to the HCl solution to form the hydrochloride salt. The reverse order of addition prevents the product from precipitating on the reactor walls as a glass or shell. An exemplary process for producing Form C oxybutynin hydrochloride is shown in further detail as follows:

[0108] R-oxybutynin (611 g) was dissolved in methyl tert-butyl ether (MTBE) (6 L) with stirring. Purified water (3 L) was added and the batch was stirred for 15 minutes. The layers were allowed to separate and the lower aqueous phase was removed. The MTBE layer was washed two more times with purified water (2 x 3 L), and the product content of the combined lower aqueous phases was confirmed and discarded. The organic phase was filtered into a pre-weighed, clean, dry rotary evaporator bulb and then attached to the rotary evaporator. The bath temperature was set to 33 °C and the contents of the bulb were concentrated until distillation stopped. MTBE (6 L) was added to the rotary evaporator bulb and the contents were concentrated until distillation stopped. A final charge of MTBE (6 L) was added to the rotary evaporator bulb and the contents were concentrated until distillation stopped. A sample from the rotary evaporator bulb was analyzed for residual water by Karl Fischer titration (typical result: approximately 0.2%).

[0109] The contents of the rotary evaporator valve 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 and then filtered through a Celite pad. MTBE (1 L) was used to rinse all material from the reactor to the filter cake. The filtrate was collected in a clean glass carboy labeled Charcoal-Treated Batch. A solution of MTBE (3.0 L) and 1 M HCl / EtOAc (2.32 L) was inline filtered into a clean vessel. The batch temperature was set to 20 ± 5°C. The charcoal-treated batch (1.2 L) was charged over 20 minutes while maintaining the batch temperature at 20 ± 5°C. R-oxybutynin HCl seeds (3.2 g) were charged and stirred for 5 minutes. The remainder of the charcoal-treated batch (4.8 L) was charged over 33 minutes while maintaining the batch temperature at 20 ± 5°C. MTBE (640 mL) wash from the charcoal-treated batch vessel was added to the crystallizer. 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 2 more hours and then adjusted to 0±5°C over 2 hours. After stirring the batch at 0±5°C for at least 10 hours, the solids were isolated by filtration. Two washes of pre-chilled MTBE (1.8 L x 2) were in-line filtered and charged to the reactor to remove any solids from the reactor and then passed through the filter cake. The wet filter cake was transferred to a drying tray and placed in a vacuum oven at 25±5°C until residual solvent met specifications. 582 g of dried product was packaged and sampled. This process produced Form C HCl salt of R-oxybutynin in high yields, including a batch yield of 86.5%.

[0110] An alternative process can be used to remove the DEA impurity without using aqueous extraction of the MTBE layer. When R-oxybutynin free base is dissolved in MTBE, the DEA separates out along with the impurities as an insoluble precipitate. Therefore, the MTBE solution can be carbon treated, and subsequent carbon filtration also removes the DEA and impurities. The azeotrope step with water can then be omitted, since there is no water to remove before HCl salt formation. The filtered MTBE solution of the free base can then be added directly to the MTBE solution and 1 M HCl / EtOAc solution.

[0111] Another process for producing R-oxybutynin HCl Form C is described in Example 27. In general, in some embodiments, the present invention provides a process for producing crystalline R-oxybutynin HCl Form C, the process comprising isolating (R)-oxybutynin from racemic oxybutynin via chiral resolution with D-malic acid (or other optically active acid) and adding HCl to the isolated (R)-oxybutynin to produce crystalline (R)-oxybutynin HCl Form C. In some embodiments, isolating (R)-oxybutynin from racemic oxybutynin comprises adding D-malic acid (or other optically active acid) to racemic oxybutynin free base. In some embodiments, D-malic acid (or other optically active acid) is added to racemic oxybutynin 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 comprises adding MTBE to the isolated (R)-oxybutynin after the addition of HCl. Other optically active acids (e.g., tartaric acid) can be used in place of D-malic acid for chiral resolution of oxybutynin.

[0112] (R)-Oxybutynin Citrate Material In some embodiments, the R-oxybutynin citrate material can be prepared by precipitating R-oxybutynin citrate from a solution resulting from adding diethyl ether to a p-dioxane solution containing a 2:1, 1:1, or 1:2 molar ratio of (R)-oxybutynin and citric acid at room temperature with stirring. In some embodiments, a gel phase is observed prior to producing a solid R-oxybutynin citrate material. The solid R-oxybutynin citrate typically precipitates within 1 hour after stirring at room temperature and is allowed to stir for 7 to 10 days.

[0113] Experiments were conducted on two samples of R-oxybutynin citrate material produced 1 H NMR analysis confirmed the 2:1 and 1:1 molar ratios of API to acid. 1 The H NMR spectrum confirms the presence of both R-oxybutynin and citric acid, but indicates the presence of an excess of citric acid (e.g., API:citric acid molar ratios of 1:2.6 and 1:1.3). [Example]

[0114] Equipment and Methodology AX-ray powder diffraction (XRPD) Two X-ray diffractometer instruments were used to collect X-ray diffraction patterns as described below.

[0115] a. PANalytical X'Pert Pro MPD or PANalytical Empyrean Diffractometer - Transmission XRPD patterns were collected on a PANalytical X'Pert Pro MPD or PANalytical Empyrean diffractometer using an incident beam of Cu radiation generated using a long, fine-focus source. An elliptically graded multilayer mirror was used to focus the Cu Kα X-rays through the specimen onto the detector. Prior to analysis, a silicon specimen (NIST SRM640e) was analyzed to verify that the observed position of the Si111 peak matched the NIST-certified position.

[0116] Sample specimens were sandwiched between 3 μm thick films and analyzed in transmission geometry. A beam stop, a short anti-scatter extension, and an anti-scatter knife edge were used to minimize background generated by air. Soller slits were used on the incident and diffracted beams to minimize broadening and asymmetry from axial divergence. Diffraction patterns were collected using a scanning position-sensitive detector (X'Celerator) positioned 240 mm from the specimen and Data Collector software v. 2.2b or 5.5. Data acquisition parameters were as follows: X-ray tube: Cu (1.54059 Å), voltage: 45 kV, amperage: 40 mA, scan range: 1–40° 2θ, step size: 0.017° 2θ, scan speed: 3.3° / min, slits: DS: fixed slit 1 / 2°, SS: null, rotation time: 1.0 s. All images, regardless of the instrument used, are labeled as X'Pert PRO MPD.

[0117] b. PANalytical X'PERT Pro MPD Diffractometer - Reflection XRPD patterns were collected on a PANalytical X'Pert Pro MPD diffractometer using an incident beam of Cu Kα radiation generated using a long, fine-focus source and a nickel filter. The diffractometer was configured using a symmetric Bragg-Brentano geometry. Prior to analysis, a silicon specimen (NIST SRM640e) was analyzed to verify that the observed position of the Si111 peak matched the NIST-certified position. Sample preparations were prepared as thin circular layers centered on a silicon zero-background substrate. Anti-scatter slits (SS) were used to minimize background generated by air. Soller slits were used on the incident and diffracted beams to minimize off-axis divergence. Diffraction patterns were collected using a scanning position-sensitive detector (X'Celerator) positioned 240 mm from the sample and Data Collector software v.5.5. Data acquisition parameters were as follows: X-ray tube: Cu (1.54059 Å), voltage: 45 kV, amperage: 40 mA, scan range: 3.51-40°2θ, step size: 0.017°2θ, scan speed: 1.2° / min, slits: DS: fixed slit 1 / 8°, SS: fixed slit 1 / 4°.

[0118] B. Nuclear Magnetic Resonance (NMR): 1 H NMR and 13 C NMR Solution 1H NMR spectra were acquired on an Agilent DD2-400 spectrometer or an Avance 600 MHz NMR spectrometer. Samples were prepared by dissolving in DMSO-d6 containing TMS.

[0119] C. Thermogravimetric Analysis / Differential Scanning Calorimetry (TGA / DSC) TGA / DSC analysis was performed using a Mettler-Toledo TGA / DSC3+ analyzer. Temperature calibration was performed using indium, tin, and zinc. Samples were placed in aluminum pans and covered with lids. The pans were sealed, the lids pierced, and then inserted into the TG furnace. A weighed aluminum pan configured as the sample pan was placed on the reference platform. The furnace was heated under nitrogen. Data collection parameters for the thermograms are displayed in the images in the Figures section of this report.

[0120] D. Thermogravimetric analysis - infrared spectroscopy Thermogravimetric infrared (TG-IR) analysis was performed on a TA Instruments Q5000 IR TG analyzer interfaced to a Magna-IR560® Fourier transform infrared (FT-IR) spectrophotometer (Thermo Nicolet) equipped with an Ever-Glo mid / far-infrared source, a potassium bromide (KBr) beam splitter, and a cadmium mercury 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, which was then inserted into the TG furnace. The TG instrument was started first, followed immediately by the FT-IR instrument. The TG instrument was operated under helium flow at 90 and 10 cc / min for purging and balancing, respectively. The furnace was heated under helium at a rate of 10 °C / min to a final temperature of 350 °C. 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. Volatiles were identified from a search of a high-resolution Nicolet vapor-phase spectral library.

[0121] E. Ion Chromatography (IC) Ion chromatography analysis was performed using a Dionex ICS-5000+ series ion chromatograph. The ICS-5000+ consists of two chromatography systems sharing an autosampler. The system used for anion detection was equipped with a gradient pump, eluent generator module, conductivity detector, and suppressor (AERS 4 mm). A Dionex UTAC-ULP1 5 x 23 mm concentrator column was installed in place of the sample loop. A Dionex IonPac™ AG19 4 x 50 mm guard column and a Dionex IonPac™ AS19 4 x 250 mm analytical column were installed. Water (18.2 MΩ, distributed from an ELGA Purelab Flex2) was used to fill the eluent reservoir and for standard preparation and autosampler flush. DMSO was used for sample preparation and associated blank injections. [Table 1] [Table 2]

[0122] Examples 1-11. Isolation of solid (R)-oxybutynin as crystalline forms A, B, and C Examples 1-11 focused on optimizing the amount of solvent and co-solvent addition to understand the effect of hydrochloric acid (HCl) equivalents and the effect of temperature on (R)-oxybutynin salt formation. A preliminary screen of reaction conditions is summarized in Table 1.

[0123] The hydrochloride salt of R-oxybutynin was first prepared using 3.3 equivalents of HCl in isopropanol. As seen in Examples 1-4 in Table 1 below, using three times the amount of HCl resulted in an oily form of the salt, regardless of the solvent amount or combination. Combining ethyl acetate / MTBE with a substoichiometric charge of HCl similarly yielded an oil (see Example 5). The combination of isopropanol and MTBE shown in Example 5 yielded needle-like hydrochloride salt. These solids retained 13% by weight of isopropanol (1:1 molar ratio of API to isopropanol) after extensive drying under high vacuum, but did not correspond to any known form of R-oxybutynin hydrochloride, nor did the solid crystallize from isopropanol with 0.95 equivalents of HCl after 48 hours (see Examples 6 and 7).

[0124] Further analysis showed that 5 g (see Example 8) and 10 g (see Example 9) scale-up of the reaction conditions mentioned in Example 5, when stirred for a shorter time (1 hour) at 20° C., resulted in the crystallization of a solid of Form A. Form A is a hygroscopic isopropanol solvate of R-oxybutynin hydrochloride, retaining 11-13% by weight of solvent.

[0125] The salt formation reaction when carried out in MTBE (see Example 10) at temperatures above 10° C. (35° C.) resulted in powdery solids with very low water retention (1.6 wt %). These solids were non-hygroscopic and corresponded to new powder XRPD patterns. 1 The H NMR spectrum matched the achiral reference standard of R-oxybutynin purchased from Sigma-Aldrich. The new powder diffraction pattern observed was designated Form C. Salt formation when carried out in cyclopentyl methyl ether (CPME) also resulted in a solid of Form C (see Example 11). [Table 3-1] [Table 3-2]

[0126] Examples 12-17. Isolation of solid (R)-oxybutynin as crystalline forms A, B, and C Form A was considered a reasonable starting material for producing the more stable Form B. Table 2 summarizes efforts toward the synthesis of Form B from Form A. Recrystallization of an oil of R-oxybutynin hydrochloride from acetone and heptane (see Example 5, Table 1) yielded a non-hygroscopic solid of Form C. The solid was isolated in 71% yield with 0.62% residual water (see Example 12, Table 2).

[0127] Form A solid ("Form A Solid") was also used to recrystallize at elevated temperatures using MTBE in tetrahydrofuran and ethyl acetate as antisolvents (see Examples 13 and 14), which demonstrates the stability of Form C.

[0128] Reslurrying Form A in MTBE at 50°C for 24 hours also resulted in Form C crystals (see Example 15). The same form was also produced after seeded recrystallization of Form A in toluene at 70°C with Form B seeds (see Example 16). Higher temperature vacuum drying (50°C, 24 hours) also did not convert Form A to Form B (see Example 17), but instead isolated Form C. Thus, Form C was found to be a very stable form. Diffraction patterns of Form C were observed after separate extended slurries of both Form A and Form B in both MIBK and heptane, indicating that Form C is a thermodynamically favored and more stable polymorph of R-oxybutynin hydrochloride. [Table 4-1] [Table 4-2]

[0129] Examples 18-20. Further Preparations R-oxybutynin free base was treated with HCl in IPA to give the expected solid Form A. There was no significant difference in the powder diffraction pattern of Form A with or without diethylamine. Form C was isolated from a salt-forming reaction carried out in MTBE (see Examples 18-19 in Table 3).

[0130] Recrystallization of purified Form A was carried out in toluene at 70° C. seeded with Form B. The isolated product corresponded to Form C by XRPD (see Example 20). [Table 5]

[0131] Examples 21-26. Process Development Examples 1-20 confirmed that Form B was not easy or reproducible to prepare and difficult to scale up. Therefore, additional examples were performed to prepare Form C of (R)-oxybutynin hydrochloride. MTBE was the best option to demonstrate the formation of unsolvated Form C. Table 4 provides a summary of the process development. As shown in Examples 21 and 22 in Table 4, reaction of (R)-oxybutynin free base with a substoichiometric equivalent of HCl in ethyl acetate yielded only 60-65% of the salt with 99% potency.

[0132] The yield of this process improved with increasing HCl charge. As seen previously, 1.1 equivalents of HCl gave 82% of the product, while a charge of 1.5 equivalents of HCl improved recovery to 96% with a 3% decrease in efficacy. The optimal conditions involved a charge of 1.3 equivalents of HCl, resulting in 98% efficacy and a 90% isolated yield (Examples 23-25 ​​in Table 4).

[0133] These results demonstrated a successful process with an input of 83 g of R-oxybutynin using 1.3 equivalents of 1.0 M HCl in ethyl acetate (see Example 26). The XRPD pattern confirmed Form C solid (83 g, 94% yield, 99% potency). Therefore, the production of Form C could be advantageously scaled up.

[0134] Form C isolated from all runs summarized in Table 4 retained 0.5-0.6 wt% water, except for Example 21, where 0.8 equivalents of HCl were used (resulting in 1.5 wt% water retention).

[0135] The results from Table 4 below are summarized graphically in Figure 8. [Table 6-1] [Table 6-2]

[0136] Characterization of (R)-oxybutynin Forms A, B, and C Samples of each of the three crystalline polymorphs of R-oxybutynin HCl were analyzed using XRPD analysis. The XRPD patterns of R-oxybutynin HCl Forms A, B, and C did not match any of the known polymorphic forms of oxybutynin or (S)-oxybutynin. Referring to Figure 1, an overlay of the XRPD patterns of R-oxybutynin HCl Forms A, B, and C is shown. The individual XRPD patterns of Forms A and B are shown in Figures 2 and 3, respectively. Lists of the XRPD peaks for Forms A and B shown in Figures 2 and 3 are set forth below in Tables 5 and 6. Table 7 provides a list of XRPD peaks corresponding to the R-oxybutynin HCl polymorph Form C illustrated in Figure 4. [Table 7-1] [Table 7-2] [Table 8-1] [Table 8-2] [Table 9-1] [Table 9-2]

[0137] 9, slurrying a mixture of Form A and Form B (R)-oxybutynin polymorphs in methyl isobutyl ketone (MIBK) or heptane for two weeks at room temperature resulted in peak transitions detectable using XRPD, with the additional peak observed in the presence of Form B for the post-slurry sample being attributed to Form C. Still referring to FIG. 9, the XRPD pattern, from top to bottom, was as follows: File 957398: R-Oxybutynin HCl Form B Reference Pattern (Top) File 972085: Obtained after slurrying a mixture of Form A and Form B in heptane at room temperature for 2 weeks File 972087: Obtained after slurrying a mixture of Form A and Form B in MIBK at room temperature for 2 weeks File 979945: R-Oxybutynin HCl Lot EAB-A-66-2 (bottom)

[0138] Example 27. Conversion of racemic oxybutynin chloride to R-oxybutynin chloride D-Malic acid was identified as a potential chiral resolution salt for investigation. The objective of this study was to convert 100 grams of racemic oxybutynin chloride to R-oxybutynin chloride using chiral resolution D-malic acid. The conversion was carried out in four steps, each of which produced an isolable crystalline solid. The four steps are shown in the scheme below. [ka]

[0139] Step 1: Preparation of racemic oxybutynin free base Racemic oxybutynin HCl salt was provided. Racemic oxybutynin HCl salt (100 g) was suspended in water (600 mL). The mixture was heated to 30°C until dissolution was observed. Seed crystals of crystalline free base were added, and the mixture was maintained at 30°C. Aqueous sodium hydroxide solution (1.0 equivalent of a 1 M solution, 254 mL) was added dropwise over 4 hours to prevent gum formation. During the base addition, a free-flowing white slurry was observed, which thickened over time. After the base addition was complete, a noticeable gradual gradient of solids was observed on the sides of the reactor. The reactor temperature was set to 20°C, and the mixture was stirred for 19 hours. Hard solids, which mostly adhered to the sides of the reactor, were removed by scraping with a spatula. The solids were isolated by filtration and then dried under vacuum with a nitrogen bleed at 40°C for 20 hours. The overall yield of racemic oxybutynin (free base) was 95% (86.1 g), with an adjusted yield of 93% after subtracting the seeds. The solid was a white powder and was determined to be crystalline racemic oxybutynin free base.

[0140] Step 2: Chiral resolution with D-malic acid Racemic oxybutynin free base (86.1 g) was combined with 2-propanol (400 mL). The mixture was heated to 50°C to obtain a solution. Seed crystals of R-oxybutynin D-malate were added (0.55 g), followed by solid D-malic acid (24.2 g) rinsed with 30 mL of 2-propanol to produce R-oxybutynin D-malate. 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 approximately 60 hours. Aliquots were taken to estimate the yield (approximately 30%) and chiral purity (approximately 93% R, 86% ee) of R-oxybutynin D-malate. To increase the yield, the mixture was slowly cooled to 5°C at 0.1°C / min and held at 5°C for 16 hours. A second aliquot showed a slightly increased yield with comparable chiral purity (approximately 90% R, 80% ee). The mixture was filtered. A slight gradient on the sides was observed, and the sides of the reactor were rinsed with MTBE. The combined solids were washed with additional MTBE and air-dried for 1.5 hours. The yield was 41% (49.1 g).

[0141] Step 3: Recrystallization R-oxybutynin 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 approximately 12 hours. An aliquot of the recrystallized product showed 97% R, 3% S (94% ee), and the filtrate showed 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 moist (14% loss of MIBK up to 50° C. by TGA). The product was dried overnight in a vacuum oven at 40° C. with a nitrogen bleed. The yield of the recrystallized product was 93% (40.8 g). Use of MTBE in place of MIBK is also contemplated.

[0142] Steps 4 and 5: Conversion of D-malate to R-oxybutynin chloride The D-malate salt of R-oxybutynin (40.8 g) was mixed with 1 M HCl in ethyl acetate (83 mL). Additional ethyl acetate (39 mL) was added, and the slurry was heated to 40°C to obtain a solution. The reactor was cooled to 20°C, and then MTBE (1220 mL) was added. The reactor was further cooled to 5°C, followed by the addition of seed crystals or R-oxybutynin chloride (2.01 g) and the dropwise addition of MTBE (122 mL). No gumming was observed. The moderately thick 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 had coprecipitated with the desired HCl salt, resulting in a physical mixture of the two salts. The yield was 21.1 g of a solid mixture that was 98.4% R, 1.6% S (97% ee) by chiral analysis. The filtrate was concentrated under vacuum to dryness, yielding 26.1 g of a yellow oil with a chirality of 93.6% R, 6.4% S (87% ee) by chiral analysis. The R-oxybutynin salt mixture was mixed with 100 mL of 1:4 ethyl acetate / MTBE, 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 an aliquot showed only R-oxybutynin chloride by PXRD analysis. To increase the yield, additional MTBE (40 mL) was slowly added. A second aliquot showed only R-oxybutynin chloride by PXRD analysis. Specifically, R-oxybutynin chloride Form C was produced. The solid was filtered and washed with approximately 10 mL of 1:4 ethyl acetate / MTBE, then vacuum dried at 40 °C for 2 hours with a nitrogen bleed. The yield was 40% (13.2 g) of R-oxybutynin chloride over the two steps. The process for converting racemic oxybutynin chloride to R-oxybutynin chloride gave an overall yield of 13% with 99% ee of isolatable crystalline solid at each step.

[0143] Further embodiments of the present invention: Embodiment E1. A crystalline form of (R)-oxybutynin HCl.

[0144] Embodiment E2. Regarding 2θ, a solid form of (R)-oxybutynin HCl, e.g., Form C, having an X-ray powder diffraction pattern comprising a peak at 6.9 degrees 2θ±0.2 degrees 2θ at about ambient relative humidity.

[0145] Regarding embodiment E3.2θ, a solid form of (R)-oxybutynin HCl, e.g., Form C, having an X-ray powder diffraction pattern comprising peaks at 6.9 degrees 2θ±0.2 degrees 2θ and / or 18.3 degrees 2θ±0.2 degrees 2θ at about ambient relative humidity.

[0146] Regarding embodiment E4.2θ, a solid form of (R)-oxybutynin HCl, e.g., Form C, having an X-ray powder diffraction pattern comprising at least two peaks 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 at about ambient relative humidity.

[0147] Regarding embodiment E5.2θ, a solid form of (R)-oxybutynin HCl, e.g., Form C, having an X-ray powder diffraction pattern comprising at least three peaks 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 at about ambient relative humidity.

[0148] Regarding embodiment E6.2θ, a solid form of (R)-oxybutynin HCl, e.g., Form C, having an X-ray powder diffraction pattern comprising at least four peaks 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 at about ambient relative humidity.

[0149] 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 at about ambient relative humidity.

[0150] 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 at about ambient relative humidity.

[0151] 9. With respect to embodiment E9.2θ, a solid form of (R)-oxybutynin HCl, e.g., Form C, having an X-ray powder diffraction pattern comprising at least eight peaks 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, 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 at about ambient relative humidity.

[0152] Regarding embodiment E10.2θ, a solid form of (R)-oxybutynin HCl, e.g., Form C, having an X-ray powder diffraction pattern comprising at least nine peaks 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, 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 at about ambient relative humidity.

[0153] Regarding embodiment E11.2θ, a solid form of (R)-oxybutynin HCl, e.g., Form C, having an X-ray powder diffraction pattern comprising peaks 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, 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 at about ambient relative humidity.

[0154] Embodiment E12. A solid form of (R)-oxybutynin HCl having an X-ray powder diffraction pattern substantially as shown in Figure 4 at ambient relative humidity.

[0155] Embodiment E13. A solid form of (R)-oxybutynin HCl having a differential scanning calorimetry (DSC) thermogram comprising an onset of melting at 109.6°C and an endothermic peak at 119.1°C.

[0156] Embodiment E14. The solid form of any of embodiments E1-E13 having a differential scanning calorimetry (DSC) thermogram substantially as shown in the bottom panel of FIG.

[0157] Embodiment E15. A composition comprising (R)-oxybutynin, wherein at least 5% w / w of the total amount of (R)-oxybutynin is a solid form of any one of the preceding embodiments.

[0158] Embodiment E16. A composition comprising (R)-oxybutynin, wherein at least 25% w / w of the total amount of (R)-oxybutynin is the solid form of any one of the preceding embodiments.

[0159] Embodiment E17. A composition comprising (R)-oxybutynin, wherein at least 50% w / w of the total amount of (R)-oxybutynin is the solid form of any one of the preceding embodiments.

[0160] Embodiment E18. A composition comprising (R)-oxybutynin, wherein at least 90% w / w of the total amount of (R)-oxybutynin is the solid form of any one of the preceding embodiments.

[0161] Embodiment E19. A composition comprising (R)-oxybutynin, wherein at least 95% w / w of the total amount of (R)-oxybutynin is the solid form of any one of the preceding embodiments.

[0162] Embodiment E20. A composition comprising (R)-oxybutynin, wherein at least 98% w / w of the total amount of (R)-oxybutynin is the solid form of any one of the preceding embodiments.

[0163] Embodiment E21. A pharmaceutical composition comprising the solid form of any one of embodiments E1-E20 and a pharmaceutically acceptable excipient.

[0164] Embodiment E22. A process for preparing a solid form of any one of Embodiments E1-E21 comprising: forming a slurry of (R)-oxybutynin free base and HCl in a solvent to form a slurry; and precipitating one or more crystals of (R)-oxybutynin hydrochloride from the slurry.

[0165] 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 t-butyl ether (MTBE), 1,4-dioxane, toluene, 1,2-dimethoxyethane, tetrahydrofuran, dichloromethane, acetonitrile, nitromethane, and mixtures thereof.

[0166] Embodiment E24. The process of any one of Embodiments E22 and E23, wherein the solvent is selected from the group consisting of ethyl acetate, heptane, methyl t-butyl ether (MTBE), and mixtures thereof.

[0167] Embodiment E25. A method of treating pharyngeal airway collapse comprising administering to a subject in need thereof a solid form of any one of embodiments E1-E21.

[0168] Embodiment E26. The method of embodiment E25, wherein said pharyngeal airway collapse is obstructive sleep apnea (OSA), sleep apnea, or simple snoring.

[0169] Embodiment E27. A method of treating pharyngeal airway collapse comprising administering to a subject in need thereof (R)-oxybutynin HCl in a solid form as described in any one of Embodiments E1-E21 in any combination with one or more of a norepinephrine reuptake inhibitor (NRI), a hypnotic agent, a carbonic anhydrase inhibitor, and a muscarinic receptor antagonist.

[0170] Regarding embodiment E28.2θ, a solid form of (R)-oxybutynin HCl, e.g., Form B, having an X-ray powder diffraction pattern comprising a peak at 7.5 degrees 2θ±0.2 degrees 2θ at about ambient relative humidity.

[0171] With respect to embodiment E29.2θ, a solid form of (R)-oxybutynin HCl, e.g., Form B, having an X-ray powder diffraction pattern including peaks at 7.5 degrees 2θ±0.2 degrees 2θ and / or 17.2 degrees 2θ±0.2 degrees 2θ at about ambient relative humidity.

[0172] Regarding embodiment E30.2θ, a solid form of (R)-oxybutynin HCl, e.g., Form B, having an X-ray powder diffraction pattern comprising at least two peaks 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 at about ambient relative humidity.

[0173] Regarding embodiment E31.2θ, a solid form of (R)-oxybutynin HCl, e.g., Form B, having an X-ray powder diffraction pattern comprising at least three peaks selected from the group consisting of 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 ± 0.2 degrees 2θ at about ambient relative humidity.

[0174] For embodiment E32.2θ, at about ambient relative humidity, 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 θ, 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, e.g., Form B.

[0175] Embodiment E33. A solid form of (R)-oxybutynin HCl having an X-ray powder diffraction pattern substantially as shown in FIG. 3 at about ambient relative humidity.

[0176] Embodiment E34. A pharmaceutical composition comprising a solid form according to any one of embodiments E1-E21 and / or E28-E33, and one or more pharmaceutically acceptable excipients.

[0177] Embodiment E35. A method of treating pharyngeal airway collapse comprising administering to a subject in need thereof a solid form of any one of embodiments E1-E21 and / or E28-E33.

[0178] Embodiment E36 The method of embodiment E35, wherein said pharyngeal airway collapse is obstructive sleep apnea (OSA), sleep apnea, or simple snoring.

[0179] Embodiment E37. A method of treating pharyngeal airway collapse comprising administering to a subject in need thereof (R)-oxybutynin HCl in a solid form as described in any of embodiments E1-E21 and / or E28-E33, in any combination with one or more of a norepinephrine reuptake inhibitor (NRI), a hypnotic agent, a carbonic anhydrase inhibitor, and a muscarinic receptor antagonist.

[0180] Embodiment E38. A solid form of (R)-oxybutynin HCl which is a solvate.

[0181] Embodiment E39. A solid form of (R)-oxybutynin HCl as described in embodiment E38 which is an isopropanol solvate.

[0182] Regarding embodiment E40.2θ, a solid form of (R)-oxybutynin HCl, e.g., Form A, having an X-ray powder diffraction pattern comprising a peak at 19.2 degrees 2θ±0.2 degrees 2θ at about ambient relative humidity.

[0183] Regarding embodiment E41.2θ, a solid form of (R)-oxybutynin HCl, e.g., Form A, having an X-ray powder diffraction pattern comprising peaks at 19.2 degrees 2θ±0.2 degrees 2θ and / or 6.1 degrees 2θ±0.2 degrees 2θ at about ambient relative humidity.

[0184] Regarding embodiment E42.2θ, a solid form of (R)-oxybutynin HCl, e.g., Form A, having an X-ray powder diffraction pattern comprising at least two peaks 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 at about ambient relative humidity.

[0185] With respect to embodiment E43.2θ, a solid form of (R)-oxybutynin HCl, e.g., Form A, having an X-ray powder diffraction pattern comprising at least three peaks selected from the group consisting of 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 ± 0.2 degrees 2θ at about ambient relative humidity.

[0186] With respect to embodiment E44.2θ, a solid form of (R)-oxybutynin HCl, e.g., Form A, having an X-ray powder diffraction pattern comprising at least four peaks selected from the group consisting of 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 ± 0.2 degrees 2θ at about ambient relative humidity.

[0187] 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, e.g., Form A, having an X-ray powder diffraction pattern comprising peaks at about ambient relative humidity: 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 20.8 degrees 2θ ± 0.2 degrees 2θ.

[0188] Embodiment E46. A solid form of (R)-oxybutynin HCl having an X-ray powder diffraction pattern substantially as shown in Figure 2 at ambient relative humidity.

[0189] Embodiment E47. A pharmaceutical composition comprising a solid form according to any one of embodiments E1-E21, E28-E33, and / or E38-E46, and one or more pharmaceutically acceptable excipients.

[0190] Embodiment E48. A method of treating pharyngeal airway collapse comprising administering to a subject in need thereof a solid form of any of embodiments E1-E21, E28-E33, and / or E38-E46.

[0191] Embodiment E49. The method of embodiment E48, wherein said pharyngeal airway collapse is obstructive sleep apnea (OSA), sleep apnea, or simple snoring.

[0192] Embodiment E50. A method of treating pharyngeal airway collapse comprising administering to a subject in need thereof an (R)-oxybutynin HCl solid form according to any one of embodiments E1-E21, E28-E33, and / or E38-E46, in any combination with one or more of a norepinephrine reuptake inhibitor (NRI), a hypnotic agent, a carbonic anhydrase inhibitor, and a muscarinic receptor agonist.

[0193] Embodiment E51. A solid form of (R)-oxybutynin HCl that is amorphous.

[0194] Embodiment E52. (R)-oxybutynin HCl forms as an amorphous material in a dispersion matrix.

[0195] Although specific embodiments of the present invention are exemplified and described in detail herein, the present invention is not limited thereto. The above 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 obvious to those skilled in the art, and all modifications that do not depart from the spirit of the present invention are intended to be included within the scope of the appended claims. The present invention includes the following aspects. Item 1 A solid crystalline form of (R)-oxybutynin HCl designated as Form C. Section 2 Item 1. The solid crystalline form of item 1, having an X-ray powder diffraction pattern comprising at least three peaks in terms of 2θ 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 at about ambient relative humidity. Section 3 Item 1. The solid crystalline form of item 1, having an X-ray powder diffraction pattern comprising at least four peaks in terms of 2θ 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 at about ambient relative humidity. Section 4 2. The solid crystalline form of claim 1, having an X-ray powder diffraction pattern comprising at least five peaks in terms of 2θ 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 degrees 2θ, 13.9 degrees 2θ ± 0.2 degrees 2θ, and 8.7 degrees 2θ ± 0.2 degrees 2θ at about ambient relative humidity. Section 5 2. The solid crystalline form of claim 1, having an X-ray powder diffraction pattern comprising at least seven peaks in terms of 2θ 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 degrees 2θ, 13.9 degrees 2θ ± 0.2 degrees 2θ, and 8.7 degrees 2θ ± 0.2 degrees 2θ at about ambient relative humidity. Section 6 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 at about ambient relative humidity. Section 7 Item 1. The solid crystalline form of item 1, having an X-ray powder diffraction pattern substantially as shown in FIG. 4 at about ambient relative humidity. Section 8 8. The solid crystalline form of any one of items 1 to 7, having a differential scanning calorimeter (DSC) thermogram comprising an onset of melting at 109.6°C and an endothermic peak at 119.1°C. Section 9 Item 9. The solid crystalline form of item 8, having a differential scanning calorimeter (DSC) thermogram substantially as shown in FIG. 7. Section 10 Solid crystalline forms of (R)-oxybutynin HCl having a combination of Form B and Form C polymorphs as shown in FIG. Section 11 A pharmaceutical composition comprising the solid crystalline form according to any one of items 1 to 9 and one or more pharmaceutically acceptable excipients. Section 12 10. A process for preparing the solid crystalline form of any one of items 1 to 9, comprising precipitating the solid crystalline form from a solution comprising (R)-oxybutynin HCl and a solvent, or slurrying (R)-oxybutynin HCl in a solvent, wherein the solvent comprises an organic solvent, excluding methanol, and wherein the water content is 5% v / v or less. Section 13 Item 13. The process of item 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 t-butyl ether (MTBE), 1,4-dioxane, toluene, 1,2-dimethoxyethane, tetrahydrofuran, dichloromethane, acetonitrile, nitromethane, and mixtures thereof. Section 14 Item 14. The process of item 13, wherein the organic solvent is MTBE. Section 15 10. A method for treating a condition associated with pharyngeal airway collapse, comprising administering to a subject in need thereof the solid crystalline form of any one of items 1 to 9. Section 16 Item 16. The method of item 15, wherein the condition associated with pharyngeal airway collapse is sleep apnea or snoring. Section 17 Item 16. The method of item 15, wherein the condition associated with pharyngeal airway collapse is obstructive sleep apnea (OSA). Section 18 A solid crystalline form of (R)-oxybutynin HCl. Section 19 19. The solid crystalline form according to paragraph 18, which is Form A. Section 20 20. The solid crystalline form of paragraph 19, having an X-ray powder diffraction pattern substantially as shown in Figure 2 at about ambient relative humidity. Section 21 19. The solid crystalline form according to paragraph 18, which is form B. Section 22 22. The solid crystalline form of paragraph 21, having an X-ray powder diffraction pattern substantially as shown in Figure 3 at about ambient relative humidity. Section 23 23. A pharmaceutical composition comprising the solid crystalline form of (R)-oxybutynin HCl according to any one of items 18 to 22, and optionally one or more pharmaceutically acceptable excipients. Section 24 A solid crystalline form of (R)-oxybutynin citrate. Section 25 Item 25. A pharmaceutical composition comprising the solid crystalline form of (R)-oxybutynin citrate according to item 24, and optionally one or more pharmaceutically acceptable excipients. Section 26 1. A process for producing crystalline R-oxybutynin HCl Form C, comprising: isolating (R)-oxybutynin from racemic oxybutynin via chiral resolution with D-malic acid; adding HCl to the isolated (R)-oxybutynin to produce Form C crystalline (R)-oxybutynin HCl. Section 27 27. The process of claim 26, wherein isolating (R)-oxybutynin from racemic oxybutynin comprises adding D-malic acid to racemic oxybutynin free base. Section 28 28. The process of paragraph 27, wherein D-malic acid is added to racemic oxybutynin free base in the presence of 2-propanol. Section 29 27. The process of claim 26, wherein the HCl is added in the presence of ethyl acetate. Section 30 27. The process of claim 26, further comprising adding MTBE to the isolated (R)-oxybutynin after the addition of HCl.

Claims

1. Crystals of Form C of (R)-oxybutynin HCl having an X-ray powder diffraction pattern containing three peaks in terms of 2θ at ambient relative humidity: 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.

2. 2. The crystal of claim 1, having an X-ray powder diffraction pattern comprising four peaks in terms of 2θ at ambient relative humidity: 6.9 degrees 2θ±0.2 degrees 2θ, 18.3 degrees 2θ±0.2 degrees 2θ, 11.7 degrees 2θ±0.2 degrees 2θ, and 16.8 degrees 2θ±0.2 degrees 2θ.

3. 2. The crystal of claim 1, having an X-ray powder diffraction pattern comprising five peaks in terms of 2θ at ambient relative humidity: 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.

4. 2. The crystal of claim 1, having an X-ray powder diffraction pattern comprising six peaks in terms of 2θ at ambient relative humidity: 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, and 7.6 degrees 2θ ± 0.2 degrees 2θ.

5. 2. The crystal of claim 1, having an X-ray powder diffraction pattern comprising seven peaks in terms of 2θ at ambient relative humidity: 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.

6. 2. The crystal of claim 1, having an X-ray powder diffraction pattern comprising peaks in terms of 2θ at ambient relative humidity: 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 degrees 2θ, 13.9 degrees 2θ ± 0.2 degrees 2θ, and 8.7 degrees 2θ ± 0.2 degrees 2θ.

7. At ambient relative humidity, 2. The crystal of claim 1, having an X-ray powder diffraction pattern shown in

8. The crystal according to any one of claims 1 to 7, having a differential scanning calorimeter (DSC) thermogram comprising a melting onset at 109.6°C and an endothermic peak at 119.1°C.

9. The following:

9. The crystal of claim 8, having a differential scanning calorimeter (DSC) thermogram shown in

10. A pharmaceutical composition comprising the crystal according to any one of claims 1 to 9 and one or more pharmaceutically acceptable excipients.

11. 10. A process for preparing the crystals of any one of claims 1 to 9, comprising precipitating the crystals from a solution comprising (R)-oxybutynin HCl and a solvent, or slurrying (R)-oxybutynin HCl in an organic solvent, wherein the organic solvent is selected from the group consisting of acetone, n-heptane, propyl acetate, ethyl acetate, isopropyl acetate, methyl isobutyl ketone (MIBK), methyl ethyl ketone (MEK), 1-propanol, ethanol, methyl t-butyl ether (MTBE), 1,4-dioxane, toluene, 1,2-dimethoxyethane, tetrahydrofuran, dichloromethane, acetonitrile, nitromethane, cyclopentyl methyl ether, and mixtures thereof.

12. 12. The process of claim 11, wherein the organic solvent is selected from the group consisting of n-heptane, ethyl acetate, methyl isobutyl ketone (MIBK), methyl t-butyl ether (MTBE), tetrahydrofuran, toluene, acetone, cyclopentyl methyl ether (CPME), and mixtures thereof.

13. 13. The process of claim 12, wherein the organic solvent is MTBE.

14. 10. A crystal according to any one of claims 1 to 9 for use in treating a condition associated with pharyngeal airway collapse in a subject in need of such treatment.

15. 15. The crystal of claim 14, wherein the condition associated with pharyngeal airway collapse is sleep apnea or snoring.

16. 15. The crystal of claim 14, wherein the condition associated with pharyngeal airway collapse is obstructive sleep apnea (OSA).

17. A process for producing the crystal according to any one of claims 1 to 9, comprising: isolating (R)-oxybutynin from racemic oxybutynin via chiral resolution with D-malic acid; adding HCl to the isolated (R)-oxybutynin to produce crystals of (R)-oxybutynin HCl Form C; The process includes:

18. 18. The process of claim 17, wherein isolating (R)-oxybutynin from racemic oxybutynin comprises adding D-malic acid to racemic oxybutynin free base.

19. 20. The process of claim 18, wherein D-malic acid is added to racemic oxybutynin free base in the presence of 2-propanol.

20. 18. The process of claim 17, wherein the HCl is added in the presence of ethyl acetate.

21. 18. The process of claim 17, further comprising adding MTBE to the isolated (R)-oxybutynin after the addition of HCl.

22. 12. The process of claim 11, wherein the organic solvent is selected from the group consisting of ethyl acetate, n-heptane, methyl t-butyl ether (MTBE), and mixtures thereof.

23. 23. The process of claim 22, wherein the organic solvent is n-heptane.

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