Solid forms of (R)-oxybutynin D-malate

Abstract

(R)-oxybutynin D-malate, including crystalline and amorphous forms, is prepared and characterized. The use of (R)-oxybutynin D-malate for treating obstructive sleep apnea (OSA) is also disclosed. A solid form of (R)-oxybutynin L-tartrate is also disclosed.

Description

[Technical field]

[0001] REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Application No. 63 / 248,684, filed September 27, 2021, and PCT Application PCT / US2021 / 030571, filed May 4, 2021, the entire contents of each of which are incorporated herein by reference.

[0002] Technical Field The present invention discloses a solid form of (R)-oxybutynin D-malate, as well as its pharmaceutical composition, its preparation method and its use. A solid form of (R)-oxybutynin L-tartrate is also disclosed. [Background technology]

[0003] background Oxybutynin and its derivatives are typically taken by mouth or applied to the skin and can be used as a bronchodilator or a remedy for overactive bladder. Oxybutynin also 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. Racemic oxybutynin is sold in the form of a hydrochloride salt. The chemical name for oxybutynin is 4-(diethylamino)but-2-yn-1-yl 2-cyclohexyl-2-hydroxy-2-phenylacetate, the chemical structure of which is provided below as I: [ka]

[0004] The R enantiomer of oxybutynin has utility as an active pharmaceutical ingredient for the treatment of conditions associated with pharyngeal airway collapse, such as obstructive sleep apnea. See WO 2019 / 152475 A1. Thus, there is a need for pharma- ceutically useful forms of oxybutynin, such as (R)-oxybutynin. [Brief description of the drawings]

[0005] BRIEF DESCRIPTION OF THE DRAWINGS The following drawings are provided as examples and are not intended to limit the scope of the claimed invention. [Figure 1] FIG. 1 is an XRPD pattern for (R)-oxybutynin D-malate Form A. [Diagram 2] FIG. 2 is an FT-Raman spectrum for (R)-oxybutynin D-malate Form A. [Diagram 3] FIG. 3 shows the DSC and TGA traces for (R)-oxybutynin D-malate Form A. [Figure 4] FIG. 4 shows the structure of (R)-oxybutynin D-malate Form A as analyzed by SCXRD. [Diagram 5] 5A and 5B show the hydrogen bonding scheme and packing of the crystal for (R)-oxybutynin D-malate Form A as analyzed by SCXRD. [Figure 6] FIG. 6 is an XRPD pattern for (R)-oxybutynin L-tartrate. [Figure 7] FIG. 7 is an FT-Raman spectrum for (R)-oxybutynin L-tartrate. [Figure 8] FIG. 8 shows the DSC and TGA traces for (R)-oxybutynin L-tartrate. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0006] Detailed Description I. (R)-Oxybutynin D-Malate The present invention relates in part to novel solid forms of (R)-oxybutynin, including novel salts and novel crystalline forms. In general, the efficacy of a solid compound as a drug can be affected by the properties of the solid it contains. As described in the Examples section below, crystalline forms of (R)-oxybutynin D-malate have been prepared and characterized. The (R) enantiomer of oxybutynin D-malate is provided below as II: [ka]

[0007] An amorphous form of (R)-oxybutynin D-malate was also prepared.

[0008] The definitions provided herein are intended to clarify, but not limit, the terms defined. If terms used herein are not specifically defined, such terms should not be considered indefinite. Rather, terms are used in their accepted meanings.

[0009] As used herein, (R)-oxybutynin D-malate refers to the D-malate salt form, where the molar ratio of (R)-oxybutynin to D-malic acid 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 D-malic acid assayed can be due, without limitation, to measurement variability and the presence of excess of any reagent due to processing and / or isolation.

[0010] As used herein, "crystalline" refers to a solid having a highly ordered chemical structure. In particular, a crystalline free base or salt form may be produced as one or more single crystalline forms.

[0011] The term "substantially crystalline" refers to a form that may be at least a certain weight percent crystalline. The certain 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.

[0012] As used herein, "amorphous" refers to a solid material that contains non-crystalline material. In some embodiments, an amorphous sample of a material can be prepared by lyophilization of a mixture of the material and a solvent, where the mixture can be homogeneous (e.g., a solution) or heterogeneous (e.g., a slurry).

[0013] The term "substantially free" refers to forms and compositions that may be at least a certain weight percentage free of impurities and / or crystalline compounds. The certain weight percentage 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.

[0014] In many embodiments disclosed herein, (R)-oxybutynin D-malate is disclosed as having a crystalline structure.

[0015] 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.

[0016] In some embodiments, the crystalline structures in this disclosure have one or more characteristic endothermic peaks in differential scanning calorimetry, as disclosed herein.

[0017] In one embodiment, a method for preparing a crystalline form of (R)-oxybutynin D-malate is provided. In a further embodiment, the conversion of (R)-oxybutynin D-malate to a crystalline form having a predetermined stability under expected storage conditions and the storage thereof are described.

[0018] Certain embodiments disclosed herein provide crystalline (R)-oxybutynin D-malate.

[0019] Certain embodiments disclosed herein provide Form A of crystalline (R)-oxybutynin D-malate.

[0020] In some embodiments, the crystalline (R)-oxybutynin D-malate (e.g., Form A) has an X-ray powder diffraction (XRPD) pattern comprising at least three peaks selected from the group consisting of peaks at 11.0, 14.3, 17.5, 19.8, and 22.0 °2θ±0.2 °2θ.

[0021] In some embodiments, the crystalline (R)-oxybutynin D-malate (e.g., Form A) has an XRPD pattern including peaks at 11.0, 17.5, and 22.0 degrees 2θ±0.2 degrees 2θ.

[0022] In some embodiments, the crystalline (R)-oxybutynin D-malate (e.g., Form A) has an XRPD pattern including peaks at 11.0, 14.3, 17.5, 19.8, and 22.0 °2θ±0.2 °2θ.

[0023] In some embodiments, the crystalline (R)-oxybutynin D-malate (e.g., Form A) has an XRPD pattern comprising at least 5, 6, 7, 8, or 9 peaks selected from the group consisting of peaks at 11.0, 14.3, 17.5, 18.8, 19.8, 21.4, 22.0, 23.3, 24.1, and 33.2 °2θ±0.2 °2θ.

[0024] In some embodiments, the crystalline (R)-oxybutynin D-malate (e.g., Form A) has an XRPD pattern including peaks at 11.0, 14.3, 17.5, 18.8, 19.8, 21.4, 22.0, 23.3, 24.1, and 33.2 °2θ±0.2 °2θ.

[0025] In some embodiments, the crystalline (R)-oxybutynin D-malate (e.g., Form A) has an XRPD pattern substantially as shown in FIG.

[0026] Certain embodiments disclosed herein provide crystalline (R)-oxybutynin D-malate (e.g., Form A) having an FT-Raman spectrum substantially as shown in FIG.

[0027] Certain embodiments disclosed herein provide crystalline (R)-oxybutynin D-malate (e.g., Form A) having a differential scanning calorimetry (DSC) thermogram exhibiting a melting onset at about 108.1°C and / or an endothermic peak at about 109.4°C.

[0028] Certain embodiments disclosed herein provide crystalline (R)-oxybutynin D-malate (e.g., Form A) having a differential scanning calorimetry (DSC) thermogram substantially as shown in FIG.

[0029] Certain embodiments disclosed herein are directed to a method for producing a gypsum-based ... composite having the following unit cell parameters: [Table 1] The present invention provides a crystalline (R)-oxybutynin D-malate salt (e.g., Form A) having the formula:

[0030] Certain embodiments disclosed herein provide compositions comprising (R)-oxybutynin, wherein at least 5% w / w, at least 10% w / w, at least 25% w / w, at least 50% w / w, at least 75% w / w, at least 80% w / w, at least 90% w / w, at least 95% w / w, at least 98% w / w, at least 99% w / w, or at least 99.9% w / w of the total amount of (R)-oxybutynin is (R)-oxybutynin D-malate Form A.

[0031] Certain embodiments disclosed herein provide pharmaceutical compositions comprising (R)-oxybutynin D-malate Form A in any of its specific embodiments and one or more pharma- ceutically acceptable excipients.

[0032] Certain embodiments disclosed herein provide an amorphous (R)-oxybutynin D-malate salt.

[0033] Certain embodiments disclosed herein provide one or more crystalline and / or amorphous forms of (R)-oxybutynin D-malate dispersed in a matrix.

[0034] Certain embodiments are disclosed that include a dosage form of (R)-oxybutynin D-malate that comprises 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 D-malate in one or more crystalline and / or amorphous forms, optionally wherein the one or more crystalline and / or amorphous forms are dispersed in a solid or liquid matrix.

[0035] (R)-Oxybutynin L-tartrate Also disclosed herein are solid forms of (R)-oxybutynin L-tartrate. In some embodiments, the (R)-oxybutynin L-tartrate is a crystalline solid.

[0036] In some embodiments, the crystalline (R)-oxybutynin L-tartrate salt has an XRPD pattern substantially as shown in FIG.

[0037] In some embodiments, the crystalline (R)-oxybutynin L-tartrate salt has an FT-Raman spectrum substantially as shown in FIG.

[0038] In some embodiments, the crystalline (R)-oxybutynin L-tartrate salt has a differential scanning calorimetry (DSC) thermogram that exhibits an endotherm (eg, a large endotherm) at about 92°C.

[0039] In some embodiments, the crystalline (R)-oxybutynin L-tartrate salt has a DSC thermogram substantially as shown in FIG.

[0040] II. Pharmaceutical Compositions of (R)-Oxybutynin D-Malate Provided herein is a pharmaceutical composition that comprises one or more forms of (R)-oxybutynin D-malate and physiologically acceptable carrier (also referred to as pharmaceutically acceptable carrier or solution or diluent).Such carrier and solution include the pharmaceutically acceptable salt and solvate of the compound used in the method of the present invention, as well as mixtures that comprise two or more of such compounds, the pharmaceutically acceptable salt of the compound and the pharmaceutically acceptable solvate of the compound.Such compositions are prepared according to acceptable pharmaceutical procedures, such as those described in Remington's Pharmaceutical Sciences, 17th edition, ed. Alfonso R. Gennaro, Mack Publishing Company, Eaton, Pa. (1985), which is incorporated herein by reference.

[0041] The term "pharmaceutically acceptable carrier" refers to a carrier that does not cause an allergic reaction or other untoward effects 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 that are appropriately selected with respect to 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 include 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.

[0042] One or more crystalline and / or amorphous forms of (R)-oxybutynin D-malate and pharmaceutical compositions thereof disclosed herein can be prepared into unit dosage form, which means a physically discrete unit suitable as a unitary dose for a subject undergoing treatment, each unit containing a predetermined amount of active material calculated to produce a desired therapeutic effect, optionally in association with a suitable pharmaceutical carrier. The unit dosage form can be for a single daily dose or one of multiple daily doses (e.g., about 1-4 or more times per day). When multiple daily doses are used, the unit dosage form can be the same or different for each dose. In some embodiments, the compound can be formulated for controlled release.

[0043] One or more crystalline and / or amorphous forms of (R)-oxybutynin D-malate disclosed herein and its pharmaceutical composition can be formulated according to any available conventional method. In the formulation, commonly used additives such as diluents, binders, disintegrants, lubricants, colorants, flavorings, and stabilizers, emulsifiers, absorption promoters, surfactants, pH adjusters, preservatives, antioxidants, etc. can be used. For the purpose of oral therapeutic administration, active compound(s) can be combined 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 flowable carrier. Pharmaceutically compatible binders and / or adjuvant materials can be included as part of the composition. Dosage forms such as tablets, powders, granules, granules, coated tablets, capsules, syrups, lozenges and the like may contain any of the following ingredients: binders such as microcrystalline cellulose, gum tragacanth or gelatin; excipients such as starch or lactose, disintegrants such as alginic acid, Primogel, crospovidone or corn starch; lubricants such as magnesium stearate or Sterotes; glidants such as colloidal silicon dioxide; sweeteners such as sucrose or saccharin; or flavorings such as peppermint, methyl salicylate or orange flavoring, or compounds having similar properties.

[0044] Systemic administration can also be by transdermal means, for example, using a patch gel or lotion applied to the skin. For transdermal administration, a penetrant suitable for penetrating the epithelial 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 generally known in the art. Gel and / or lotion can be provided in individual sachets or via a metered dose pump that is applied daily; see, for example, Cohn et al., Ther Adv Urol. 2016 Apr; 8(2): 83-90.

[0045] In some embodiments, the therapeutic compound is prepared with a carrier that protects the therapeutic compound against rapid elimination from the body, for example, a controlled release formulation, such as implants and microencapsulated delivery systems.Biodegradable and biocompatible polymers such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters and polylactic acid can be used.Such formulations can be prepared using standard techniques or can be commercially obtained, for example, from Alza Corporation and Nova Pharmaceuticals, Inc.As pharmaceutically acceptable carriers, liposome suspensions can also be used.These can be prepared according to the method known to those skilled in the art, for example, as described in U.S. Pat. No. 4,522,811.

[0046] The pharmaceutical compositions can be included in a container, pack, or dispenser together with instructions for administration or use in the methods described herein.

[0047] Some embodiments disclosed herein provide a pharmaceutical dosage form comprising about 0.1 mg, about 0.5 mg, about 0.75 mg, about 1 mg, about 1.5 mg, about 2 mg, about 2.5 mg, about 3 mg, about 4 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 D-malate Form A. In some 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 pharmaceutical dosage form is (R)-oxybutynin D-malate Form A.

[0048] Certain embodiments disclosed herein provide a pharmaceutical dosage form comprising, as a tablet, about 0.1 mg, about 0.5 mg, about 0.75 mg, about 1 mg, about 1.5 mg, about 2 mg, about 2.5 mg, about 3 mg, about 4 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 D-malate Form A. 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 D-malate Form A.

[0049] Certain embodiments disclosed herein provide pharmaceutical compositions comprising about 0.1 mg, about 0.5 mg, about 0.75 mg, about 1 mg, about 1.5 mg, about 2 mg, about 2.5 mg, about 3 mg, about 4 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 D-malate Form A and one or more pharma- ceutically acceptable excipients. 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 pharmaceutical composition is (R)-oxybutynin D-malate Form A.

[0050] Certain embodiments disclosed herein include pharmaceutical compositions thereof that are substantially free of (R)-oxybutynin D-malate Form A or other crystalline or amorphous forms. For example, in some embodiments, (R)-oxybutynin D-malate Form A or pharmaceutical compositions thereof comprises 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% by weight of Form A relative to other crystalline or amorphous forms of (R)-oxybutynin D-malate.

[0051] III. Use of (R)-Oxybutynin D-Malate In some embodiments, provided herein is a method for treating a subject with a condition related to pharyngeal airway collapse, comprising administering to a subject in need of treatment an effective amount of (i) norepinephrine reuptake inhibitor (NRI) and (ii) (R)-oxybutynin D-malate.Also provided herein is the use of (i) norepinephrine reuptake inhibitor (NRI) and (ii) (R)-oxybutynin D-malate in the manufacture of a medicament for treating a condition related to pharyngeal airway collapse.Also provided herein is the use of (i) norepinephrine reuptake inhibitor (NRI) and (ii) (R)-oxybutynin D-malate or a pharmaceutical composition thereof for use in treating a condition related to pharyngeal airway collapse.

[0052] In some embodiments, the (R)-oxybutynin D-malate is crystalline. In some embodiments, the (R)-oxybutynin D-malate is crystalline form A. In some embodiments, the method comprises administering a pharmaceutical composition comprising an NRI and (R)-oxybutynin D-malate (e.g., form A). In some embodiments, the condition is sleep apnea, e.g., obstructive sleep apnea. In some embodiments, the condition is snoring, e.g., simple snoring. In some embodiments, the NRI is atomoxetine or a pharma- ceutically acceptable salt thereof. In some embodiments, the NRI is reboxetine or a pharma- ceutically acceptable salt thereof.

[0053] In some embodiments, provided herein is a method for treating a subject having a condition associated with pharyngeal airway collapse, the method comprising administering to a subject in need of treatment an effective amount of (i) atomoxetine or a pharma- ceutically acceptable salt thereof; and (ii) (R)-oxybutynin D-malate. In some embodiments, the method comprises administering to the subject a therapeutically effective amount of crystalline (R)-oxybutynin D-malate (e.g., Form A) or a pharmaceutical composition thereof.

[0054] In some embodiments, provided herein is a method of treating a subject having a condition associated with pharyngeal airway collapse, further comprising administering a hypnotic agent to a subject in need of treatment for said condition.

[0055] In some embodiments, provided herein are methods of treating a subject having a condition associated with pharyngeal airway collapse, further comprising administering a carbonic anhydrase inhibitor to a subject in need of treatment for said condition.

[0056] Exemplary norepinephrine reuptake inhibitors (NRIs) include the selective NRIs amidabutyric acid (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, Vestra), talopram (Lu 3-010), talsupram (Lu 5-005), tandamine (AY-23,946), viloxazine (Vivalan); nonselective NRIs include amitriptyline, amoxapine, bupropion, cyclazindol, desipramine, desvenlafaxine, dexmethilphenidate, diethylpropion, doxepin, duloxetine, imipramine, levomilnacipran, manifaxine (GW-320,659), maprotiline, methylphenidate, milnacipran, nefazodone, nortriptyline, phendimetrazine, phenmetrazine, protriptyline, radafaxine (GW-353,162), tapentadol (Nucynta), teniloxazine (Lucelan, Metatone) and venlafaxine and pharmaceutically acceptable salts thereof.

[0057] In some embodiments, the norepinephrine reuptake inhibitor is atomoxetine or a pharma- ceutically acceptable salt thereof. In other embodiments, the norepinephrine reuptake inhibitor is reboxetine or a pharma- ceutically acceptable salt thereof. In yet other embodiments, the norepinephrine reuptake inhibitor is a combination of atomoxetine and reboxetine or a pharma- ceutically acceptable salt thereof.

[0058] Oxybutynin is an antimuscarinic agent and a muscarinic receptor antagonist, and refers to a racemic mixture of (R) and (S) enantiomers. (R)-oxybutynin refers to the (R) enantiomer. In the compositions described herein, (R)-oxybutynin is in enantiomeric excess of (R)-oxybutynin relative to its enantiomeric pair (i.e., (S)-oxybutynin). The enantiomeric excess of (R)-oxybutynin in these compositions can be ≧80%, ≧90%, ≧95%, ≧98%, ≧99%, ≧99.5%, ≧99.8% or ≧99.9%.

[0059] The carbonic anhydrase inhibitor may be selected from the group consisting of acetazolamide, dichlorophenamide, dorzolamide, brinzolamide, methazolamide, zonisamide, ethoxzolamide, 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.

[0060] In some embodiments, hypnotics such as zolpidem, zopiclone, eszopiclone, trazodone, zaleplon, benzodiazepines, gabapentin, tiagabine and xyrem or pharma- ceutically acceptable salts thereof may be incorporated into the composition.

[0061] In some embodiments, the patient is a human subject.

[0062] In some embodiments, the method includes administering a dose of about 20 mg to about 150 mg of atomoxetine or a pharma- ceutically acceptable salt thereof, about 20 mg to about 100 mg of atomoxetine or a pharma- ceutically acceptable salt thereof, about 50 mg to about 100 mg of atomoxetine or a pharma- ceutically acceptable salt thereof, or about 75 mg to about 100 mg of atomoxetine or a pharma- ceutically acceptable salt thereof. In some embodiments, the method includes administering a dose of about 0.1 mg to about 25 mg of (R)-oxybutynin D-malate, about 1 mg to about 20 mg of (R)-oxybutynin D-malate, about 1 mg to about 10 mg of (R)-oxybutynin D-malate, about 1 mg to about 5 mg of (R)-oxybutynin D-malate, or about 2.5 mg to about 7.5 mg of (R)-oxybutynin D-malate. In other embodiments, the method includes administering from about 20 mg to about 150 mg of atomoxetine or a pharma- ceutically acceptable salt thereof in combination with about 0.1 mg to about 25 mg of (R)-oxybutynin D-malate, from about 20 mg to about 150 mg of atomoxetine or a pharma- ceutically acceptable salt thereof in combination with about 1 mg to about 20 mg of (R)-oxybutynin D-malate, from about 1 mg to about 10 mg of (R)-oxybutynin D-malate, The method includes administering a dose of 20 mg to about 150 mg of atomoxetine or a pharma- ceutically acceptable salt thereof, about 20 mg to about 150 mg of atomoxetine or a pharma- ceutically acceptable salt thereof in combination with about 1 mg to about 5 mg of (R)-oxybutynin D-malate, or about 20 mg to about 150 mg of atomoxetine or a pharma- ceutically acceptable salt thereof in combination with about 2.5 mg to about 7.5 mg of (R)-oxybutynin D-malate.

[0063] An effective amount may be administered in one or more administrations, applications or doses. The composition may be administered one or more times per day to one or more times per week; for example, once every other day. In some embodiments, the composition is administered daily, for example, before going to bed. Those skilled in the art will appreciate that certain factors, including but not limited to, the severity of the disease or disorder, previous treatments, general health and / or age of the subject, and other diseases present, may affect the dosage and timing required to effectively treat a subject. Furthermore, treatment of a subject with a therapeutically effective amount of a therapeutic compound described herein may include a single treatment or a series of treatments.

[0064] IV. Preparation and Characterization of Crystalline (R)-Oxybutynin D-Malate Form A Provided herein is a method for preparing (R)-oxybutynin D-malate Form A. In some embodiments, crystalline (R)-oxybutynin D-malate Form A can be prepared by combining (R)-oxybutynin free base and D-malic acid (e.g., about 1.0 eq) in a solvent having ethyl acetate and methyl tert-butyl ether (MTBE) (e.g., ethyl acetate:MTBE volume ratio of 1:4). Crystals can then be isolated from the resulting mixture.

[0065] In some embodiments, crystalline (R)-oxybutynin D-malate Form A can be prepared by adding D-malic acid to racemic oxybutynin in the presence of a solvent. In some embodiments, the solvent is 2-propanol. In some embodiments, seed crystals of (R)-oxybutynin D-malate Form A are utilized.

[0066] Figure 1 provides the XRPD pattern for (R)-oxybutynin D-malate Form A, with corresponding peaks provided in Table 1 below, which shows that (R)-oxybutynin D-malate Form A material is composed primarily or exclusively of a single crystalline phase. (R)-oxybutynin D-malate Form A is the mono-D-malate salt of (R)-oxybutynin. Form A is a non-solvated crystal. It was produced as a white crystalline powder with a sharp endotherm at about 108°C and negligible weight loss up to 150°C as measured by TGA. EXAMPLES

[0067] Working Example Apparatus and method A. X-ray Powder Diffraction (XRPD) XRPD diffractograms were obtained using Ni-filtered Cu Ka (45 kV / 40 mA) irradiation and a step size of 0.03° 2θ and an X'celerator TM Acquired on a PANalytical X'Pert Pro diffractometer using a RTMS (Real Time Multi-Strip) detector. Incident beam configuration: variable divergence slit (10 mm exposure length), 0.04 rad Soller slit, fixed anti-scatter slit (0.50°) and 10 mm beam mask. Diffracted beam configuration: variable anti-scatter slit (10 mm observed length) and 0.04 rad Soller slit. Samples were mounted flat on a zero background Si wafer.

[0068] B. FT-Raman Spectroscopy Raman spectra were collected using a Nicolet NXR9650 (Thermo Scientific) equipped with a 1064 nm Nd:YVO4 excitation laser, InGaAs and liquid N2-cooled Ge detectors and a MicroStage. All spectra were collected at 4 cm using the Happ-Genzel apodization function and two-level zero-filling. -1 was obtained at resolution.

[0069] C. Differential Scanning Calorimetry (DSC) DSC was performed using a TA Instruments Q200 or Q2000 differential scanning calorimeter equipped with an autosampler and a refrigerated cooling system under N2 purge at 40 mL / min or 50 mL / min for the Q2000 and Q200, respectively. DSC thermograms of samples were acquired at 10 °C / min in crimped Al pans. The temperatures of exothermic and endothermic transitions recorded by the DSC analysis are reported as onset values.

[0070] D. Thermogravimetric analysis (TGA) TGA thermograms were obtained using a TA Instruments Q500 Thermogravimetric Analyzer under a N purge of 40 mL / min for the balance and 60 mL / min for the samples in Al pans. TGA thermograms of the samples were obtained at 10° C. / min.

[0071] E. Gravimetric Vapor Sorption (GVS) GVS experiments were performed on a surface measurement system DVS-Advantage. The experiments were performed at 25°C. The instrument was operated in step mode, where the relative humidity was increased in 10% RH increments from 0% RH to 90% RH with an extra step at 75% RH, and then decreased from 90% RH to 0% RH with an extra step at 75% RH. The mass balance criterion was set at 0.005% change in mass over time (dm / dt). A minimum step time of 15 minutes and a maximum step time of 240 minutes were specified.

[0072] Example 1: Preparation of crystalline (R)-oxybutynin D-malate and seed crystals (R)-oxybutynin free base was prepared from (R)-oxybutynin HCl salt as follows: (R)-oxybutynin HCl salt (506 mg, 1.28 mol) was dissolved in 3.0 mL of water (6 vol) at RT. One equivalent of aqueous 1 M NaOH was added (1.28 mL) to give a gum. The aqueous layer was decanted from the gum and any free base was extracted with hexane. The gum was dissolved in hexane and washed with water. The combined hexane layers were concentrated in vacuo to give 452 mg of (R)-oxybutynin free base as an oil (98% yield).

[0073] Approximately 20 mg of (R)-oxybutynin free base was combined with 1.0 eq of D-malic acid. Ethyl acetate / MTBE in a ratio (volume) of 1:4 was added. Crystals were produced and isolated. Thus, crystalline (R)-oxybutynin D-malate was produced, and the crystals were used as seeds for further experiments.

[0074] Example 2: Preparation and Characterization of (R)-Oxybutynin D-Malate Form A (R)-Oxybutynin D-Malate was prepared and its solid form was analyzed and characterized. A large amount of (R)-Oxybutynin free base as supplied was used as the starting material. (R)-Oxybutynin free base (9.52 g) was dissolved in 2-propanol (76 mL) at 50° C. One equivalent of D-Malic acid (3.69 g) was added and the mixture was stirred at 50° C. for 5 min until dissolution was observed. The solution was cooled to 40° C. and seeded with (R)-Oxybutynin D-Malate crystals. After 10 min, the heat was turned off and the mixture was cooled to RT with stirring for 20 h. The solid was isolated by vacuum filtration and air-dried for 30 min. The yield of (R)-Oxybutynin D-Malate was 83% (10.9 g, 22.1 mmol) as a white powder. Form A is the non-solvated crystalline form.

[0075] The solid state properties of the prepared batches were determined by the following analytical techniques: X-ray powder diffraction (XRPD), FT-Raman spectroscopy, differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA).

[0076] The XRPD pattern of (R)-oxybutynin D-malate is shown in Figure 1 and was a crystalline material designated Form A. The relative XRPD peak intensities are shown below in Table 1. [Table 2]

[0077] The FT-Raman spectrum is shown in FIG.

[0078] DSC and TGA analyses are shown in Figure 3. DSC analysis showed a sharp endotherm at 108 °C (ΔH = 106 J / g). TGA analysis showed negligible weight loss (<0.1% wt loss) up to 150 °C, with further weight loss above 150 °C due to possible decomposition. GVS analysis showed 0.1% moisture uptake between 0-90% RH, indicating that Form A is a non-hygroscopic solid. No change in crystal morphology was observed following GVS testing. Proton NMR confirmed the monosalt (actual ratio of counterion:API ratio of 1.0:1).

[0079] Large crystals of form A suitable for single crystal X-ray diffraction (SCXRD) were observed from a visual solubility experiment in ethyl acetate and were subjected to SCXRD analysis. The SCXRD data showed that the atomic connectivity was consistent with the proposed molecular structure and that the absolute configuration of both oxybutyninin and malic acid was R. The calculated powder pattern matched the XRPD pattern in Figure 1. A Bruker D8 Venture Photon II CPAD diffractometer equipped with a CuKαINCOATEC ImuS microfocus source (λ = 1.54178 Å) was used for SCXRD. The temperature was 100 K. The structure analyzed by SCXRD is shown in Figure 4. The molecule exhibited a monoclinic P21 structure that is non-centrosymmetric (chiral). The absolute configuration of both the chiral C7 and C34 atoms was R. The packing of the crystals, including (A) the hydrogen bonding scheme and (B) the packing as seen along the ~

[0010] or b direction, is shown in Figure 5. The unit cell parameters were determined at room temperature using the Difference Vectors method based on 64 reflections collected from a 0.5° diffraction frame. The parameters were refined during data integration and are based on 62 reflections recorded between 8 and 1.02 Å resolution. The unit cell parameters are provided below. [Table 3]

[0080] Example 3: Solubility Evaluation of Form A The solubility of Form A was assessed visually in 12 different solvents at RT and 40°C. The solubility data are shown in Table 2. Solubility was estimated visually by administering small aliquots of solvent to a fixed amount of solid (approximately 10 mg) until the dissolution point or maximum volume (1.8 mL) was reached. Samples containing solids that did not dissolve at RT were heated to 40°C for 1 h and dissolution was assessed visually. [Table 4]

[0081] Example 4: Crystal Morphology Screen The crystal form screen consisted of approximately 144 crystallization experiments, including 48 solvents, three crystallization modes (slurry maturation, cooling, evaporation) and a temperature range of 5-40 °C. Form A was utilized as the input form. Products were obtained from thermocycling (TC), cooling (RC) and evaporation (EV) experiments.

[0082] The crystallization modes were as follows: TC: stirred API suspension while cycling temperature between 40 and 5 °C for 2 d; RC: clarified API solution was cooled from 40 °C to 4 °C and then held at 4 °C for 6 d; EV: slow evaporation of solvent from API solution at RT for up to 4 days, followed by concentration in vacuum for 4 h for any remaining solution.

[0083] The crystal form screen yielded only one crystalline form, Form A. Form A crystalline solids were produced in many solvents, particularly under thermocycling and cooling conditions. For example, Form A crystalline solids were produced in acetonitrile, 2-butanone, ethyl acetate, and ethanol, particularly under thermocycling and cooling conditions. Amorphous (R)-oxybutynin D-malate was produced in certain solvents under evaporative conditions. For example, amorphous (R)-oxybutynin D-malate was produced in water, methanol, and dichloromethane, particularly under evaporative conditions.

[0084] Example 5: Preparation from racemic oxybutynin HCl 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 oxybutynin free base were added and the mixture was held at 30° C. Aqueous sodium hydroxide (1.0 eq of a 1M solution, 254 mL) was added dropwise over 4 hours to prevent gum formation. During the base addition, a free-flowing white slurry was observed that thickened over time. The reactor temperature was set to 20° C. and the mixture was stirred overnight for 19 hours. The solid was isolated by filtration and then dried under vacuum at 40° C. with nitrogen bleed for 20 hours. The overall yield of racemic oxybutynin (free base) was 95% (86.1 g), adjusted to 93% yield after subtracting the seeds. The solid was a white powder and was determined to be crystalline racemic oxybutynin free base.

[0085] 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), then solid D-malic acid (24.2 g) was 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 at 0.1° C. / min to 20° C. and held at 20° C. for about 60 hours. Aliquots were taken to estimate the yield (about 30%) and chiral purity (about 93% R, 86% ee) of R-oxybutynin D-malate. To increase the yield, the mixture was slowly cooled at 0.1° C. / min to 5° C. and held at 5° C. for 16 hours. A second aliquot showed slightly increased yield with comparable chiral purity (approximately 90% R, 80% ee). The mixture was filtered. The combined solids were washed with additional MTBE and air-dried for 1.5 hours. The yield was 41% (49.1 g).

[0086] R-oxybutynin D-malate (44 g) was combined with MIBK (methyl isobutyl ketone) (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 by TGA up to 50° C.). 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. The crystalline product was analyzed by XRPD and identified as Form A.

[0087] It was therefore determined that racemic oxybutynin could be converted to a crystalline (R)-oxybutynin salt by the use of the chiral acid, D-malic acid. Eleven other chiral acids were tested for the preparation of (R)-oxybutynin salts from racemic oxybutynin: L-tartaric acid, D-tartaric acid, L-(+)-lactic acid, D-glucuronic acid, D-gluconic acid, L-malic acid, (1R,3S)-(+)-camphoric acid, (S)-(+)-mandelic acid, (1R)-(-)-10-camphorsulfonic acid, L-pyroglutamic acid and D-(-)-quinic acid. None of the other eleven chiral acids were successful in chiral resolution for the preparation of (R)-oxybutynin salts from racemic oxybutynin.

[0088] Example 6: Preparation and characterization of (R)-oxybutynin L-tartrate Approximately 20 mg of (R)-oxybutynin free base was combined with 1.0 eq of L-tartaric acid. THF / MTBE solvent was added and isooctane was added as an anti-solvent. Three crystallization techniques were used (slurry maturation, cooling, evaporation) and a temperature range of 5-40°C was attempted to produce the crystalline form. After evaporation, the experiment yielded a gum / unreacted chiral acid. The gum / unreacted chiral acid was seeded with (R)-oxybutynin D-malate. This resulted in the production of crystalline (R)-oxybutynin L-tartrate.

[0089] (R)-Oxybutynin L-tartrate was crystalline by XRPD and had a mixture of birefringent plates and irregularly shaped particles by polarized light microscopy. Figure 6 is the XRPD pattern for (R)-Oxybutynin L-tartrate. Figure 7 is the FT-Raman spectrum for (R)-Oxybutynin L-tartrate. DSC analysis showed a large endotherm at 92°C (ΔH=54 J / g). TGA analysis showed a small weight loss of 1.4% from 50 to 100°C, likely trapped solvent. Figure 8 shows the DSC and TGA traces for (R)-Oxybutynin L-tartrate. Proton NMR confirmed the monosalt (actual ratio of counterion:API ratio of 1.0:1) with traces of MTBE.

[0090] Example 7: Chiral salt screen results using seed crystals Seed crystals of (R)-oxybutynin D-malate or (R)-oxybutynin L-tartrate were introduced to (R)-oxybutynin with various chiral acids in various solvents listed in Table 3. The results are shown in Table 3. A = amorphous. S = isolated solids consistent with the acid. C = birefringent (crystalline) salt hits. [Table 5]

[0091] Further aspects of the present invention: Aspect E1. A crystalline D-malate salt of (R)-oxybutynin. Embodiment E2. The crystalline D-malate salt of embodiment E1, which is a Form A crystalline salt. Embodiment E3. The crystalline D-malate salt of embodiment E2, characterized by an X-ray powder diffraction (XRPD) pattern comprising at least three peaks selected from the group consisting of peaks at 11.0, 14.3, 17.5, 19.8 and 22.0 °2θ±0.2 °2θ. Embodiment E4. The crystalline D-malate salt of embodiment E3, characterized by an XRPD pattern comprising peaks at 11.0, 17.5, and 22.0 degrees 2θ±0.2 degrees 2θ. Embodiment E5. The crystalline D-malate salt of embodiment E4, characterized by an XRPD pattern comprising peaks at 11.0, 14.3, 17.5, 19.8 and 22.0 degrees 2θ±0.2 degrees 2θ. Embodiment E6. The crystalline D-malate salt of embodiment E2, characterized by an XRPD pattern comprising at least five peaks selected from the group consisting of peaks at 11.0, 14.3, 17.5, 18.8, 19.8, 21.4, 22.0, 23.3, 24.1 and 33.2 °2θ±0.2 °2θ. Embodiment E7. The crystalline D-malate salt of embodiment E6, characterized by an XRPD pattern comprising peaks at 11.0, 14.3, 17.5, 18.8, 19.8, 21.4, 22.0, 23.3, 24.1 and 33.2 °2θ±0.2 °2θ. Embodiment E8. The crystalline D-malate salt of embodiment E2 having an XRPD pattern substantially as shown in FIG. Embodiment E9. The crystalline D-malate salt of any of embodiments E1-E8, having a differential scanning calorimetry (DSC) thermogram comprising an onset of melting at about 108.1°C and an endothermic peak at about 109.4°C. Embodiment E10. The crystalline D-malate salt of embodiment E9 having a differential scanning calorimetry (DSC) thermogram substantially as shown in FIG. Embodiment E11. A pharmaceutical composition comprising the crystalline D-malate salt of any of embodiments E1-E10 and one or more pharma- ceutically acceptable excipients. Embodiment E12. A method of treating a condition associated with pharyngeal airway collapse comprising administering to a subject in need of treatment thereof a crystalline D-malate salt of any of embodiments E1-E10 or a pharmaceutical composition of embodiment E11. Embodiment E13. The method of embodiment E13, wherein the condition associated with pharyngeal airway collapse is sleep apnea or snoring. Embodiment E14. The method of embodiment E13, wherein the condition associated with pharyngeal airway collapse is obstructive sleep apnea (OSA). Aspect E15. An amorphous D-malate salt of (R)-oxybutynin. Embodiment E16. A method of making crystalline (R)-oxybutynin D-malate of form A, comprising adding D-malic acid to racemic oxybutynin in the presence of a solvent to make (R)-oxybutynin D-malate of form A. The method of embodiment E16, wherein the solvent is 2-propanol. Embodiment E18. A method of making crystalline (R)-oxybutynin D-malate Form A comprising adding D-malic acid to (R)-oxybutynin free base in the presence of ethyl acetate and MTBE. Embodiment E19. The method of claim E18, wherein the ethyl acetate and MTBE are in a volume ratio of about 1:4 ethyl acetate:MTBE. Aspect E20. A crystalline L-tartrate salt of (R)-oxybutynin.

[0092] Although specific embodiments of the present invention are shown 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 are 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 with the scope of the appended claims.

Claims

1. Crystalline D-malate salt of (R)-oxybutynin.

2. 2. The crystalline D-malate salt of claim 1, which is a Form A crystalline salt.

3. 3. The crystalline D-malate salt of claim 2, characterized by an X-ray powder diffraction (XRPD) pattern comprising at least three peaks selected from the group consisting of peaks at 11.0, 14.3, 17.5, 19.8 and 22.0°2θ±0.2°2θ.

4. 4. The crystalline D-malate salt of claim 3, characterized by an XRPD pattern comprising peaks at 11.0, 17.5 and 22.0°2θ±0.2°2θ.

5. 5. The crystalline D-malate salt of claim 4, characterized by an XRPD pattern comprising peaks at 11.0, 14.3, 17.5, 19.8 and 22.0°2θ±0.2°2θ.

6. 3. The crystalline D-malate salt of claim 2, characterized by an XRPD pattern comprising at least five peaks selected from the group consisting of peaks at 11.0, 14.3, 17.5, 18.8, 19.8, 21.4, 22.0, 23.3, 24.1 and 33.2 °2θ±0.2 °2θ.

7. 7. The crystalline D-malate salt of claim 6, characterized by an XRPD pattern comprising peaks at 11.0, 14.3, 17.5, 18.8, 19.8, 21.4, 22.0, 23.3, 24.1 and 33.2 °2θ±0.2 °2θ.

8. 3. The crystalline D-malate salt of claim 2, having an XRPD pattern substantially as shown in FIG.

9. 9. The crystalline D-malate salt of any one of claims 1 to 8, having a differential scanning calorimetry (DSC) thermogram with a melting onset at about 108.1°C and an endothermic peak at about 109.4°C.

10. 10. The crystalline D-malate salt of claim 9, having a differential scanning calorimetry (DSC) thermogram substantially as shown in Figure 3.

11. A pharmaceutical composition comprising the crystalline D-malate salt of any one of claims 1 to 10 and one or more pharma- ceutically acceptable excipients.

12. A method for treating a condition associated with pharyngeal airway collapse, comprising the step of administering to a subject in need of such treatment a crystalline D-malate salt according to any one of claims 1 to 10 or a pharmaceutical composition according to claim 11.

13. 13. The method of claim 12, wherein the condition associated with pharyngeal airway collapse is sleep apnea or snoring.

14. 14. The method of claim 13, wherein the condition associated with pharyngeal airway collapse is obstructive sleep apnea (OSA).

15. Amorphous D-malate salt of (R)-oxybutynin.

16. A method of making crystalline (R)-oxybutynin D-malate of form A, comprising the step of adding D-malic acid to racemic oxybutynin in the presence of a solvent to make (R)-oxybutynin D-malate of form A.

17. 17. The method of claim 16, wherein the solvent is 2-propanol.

18. A method of making crystalline (R)-oxybutynin D-malate Form A comprising adding D-malic acid to (R)-oxybutynin free base in the presence of ethyl acetate and MTBE.

19. 20. The process of claim 18, wherein the ethyl acetate and MTBE are in a volume ratio of about 1:4 ethyl acetate:MTBE.

20. Crystalline L-tartrate salt of (R)-oxybutynin.

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