Salt, crystalline form, and method for producing the same

Abstract

The present invention provides a pharmaceutical formulation for (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine that has high storage stability and is easily bioavailable. [Solution] Salts of (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethaneamine and various crystalline forms thereof, as well as compositions thereof, pharmaceuticals, pharmaceutically acceptable formulations, and methods for producing the same. Furthermore, compounds containing a specific particle size distribution of crystalline (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethaneamine HCl and methods for creating and adjusting such particle size distributions are provided.

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims priority to U.S. Provisional Application No. 62 / 710,416 filed on 16 February 2018, the entire disclosure of which is incorporated herein by reference. Technical field This specification provides (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine salt and its polymorphs, formulations containing them, methods for producing the same, and methods for using them for the treatment of various diseases and disorders. This specification provides pharmaceutical compositions containing (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine hydrochloride and its polymorphs, methods for producing the composition, and methods for using them for the treatment of various diseases and disorders. [Background technology]

[0002] (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethaneamine is described in U.S. Patent No. 8,710,245 ('245 Patent). It has the following chemical structure: [ka]

[0003] The use of (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine in the treatment, prevention, or management of mood disorders and various other central nervous system disorders is also disclosed in the '245 patent.

[0004] Active pharmaceutical ingredients (APIs) are most often administered orally in solid dosage forms such as tablets and capsules. Tablets remain a popular dosage form due to the advantages they offer to both manufacturers (e.g., simplicity and cost-effectiveness of manufacture, stability and convenience of packaging) and consumers (e.g., accuracy of dosage, compactness, portability, tastelessness, and ease of administration). In tablet preparation, the active pharmaceutical ingredient (API) almost always needs to be solid. In the manufacture of solid APIs, it is necessary to obtain a product with reproducible properties, such as chemical purity and composition. In the case of polymorphic crystalline solid APIs, it is important to generate the desired polymorphism to ensure the bioavailability and stability of the API. In addition to polymorphism considerations, tablet manufacture is often sensitive to crystal size and morphology. While the goal of many crystallization operations is to produce crystals of sufficient size that can be easily isolated with standard filtration equipment, smaller particle sizes are often desired to increase dissolution rates, improve bioavailability, and facilitate tablet formation. [Overview of the project] [Problems that the invention aims to solve]

[0005] A reliable and reproducible process is highly desirable for preparing a pharmaceutical dosage form of (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine that is highly stable for storage and readily bioavailable. [Means for solving the problem]

[0006] Outline This disclosure provides salts of (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine, formulations or compositions containing these salts, compounds, salts, methods for producing formulations or compositions thereof, and polymorphs of salts. In various embodiments, the present invention relates to substantially pure crystalline forms of (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine hydrochloride, methods for producing the same, compositions containing the same, pharmaceuticals and formulations, and methods for treating various diseases and disorders using the same.

[0007] In various embodiments, (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine hydrochloride ((S)-TPMA HCl) is provided. In various embodiments, the crystalline form A of crystalline form A of (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine hydrochloride is provided. In various embodiments, the crystalline (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine hydrochloride of form A is characterized by a powder X-ray diffraction pattern with respect to 2 theta, including peaks at 9.6±0.2°, 14.9±0.2°, 20.5±0.2°, and 25.1±0.2°, and in various embodiments, further including peaks at 20.2±0.2° and 20.8±0.2°, and including two or more prominent peaks at 17.9±0.2°, 24.8±0.2°, and 27.1±0.2°.

[0008] In various embodiments, the present invention provides a substantially enantiomerically pure crystalline form of (S)-TPMA HCl of form A. For example, in various embodiments, the present invention provides crystalline forms of TPMA HCl including greater than about 90% (S)-TPMA HCl and less than 10% (R)-TPMA HCl, greater than about 95% (S)-TPMA HCl and less than 5% (R)-TPMA HCl, greater than about 97% (S)-TPMA HCl and less than 3% (R)-TPMA HCl, greater than about 99% (S)-TPMA HCl and less than 1% (R)-TPMA HCl, greater than about 99.5% (S)-TPMA HCl and less than 0.5% (R)-TPMA HCl, greater than about 99.7% (S)-TPMA HCl and less than 0.3% (R)-TPMA HCl, greater than about 99.9% (S)-TPMA HCl and less than 0.1% (R)-TPMA HCl.

[0009] In various embodiments, the present invention provides a substantially chemically pure crystalline form of (S)-TPMA HCl of form A. For example, in various embodiments, the present invention provides (S)-TPMA HCl of form A having a chemical purity greater than about 80%, greater than about 90%, greater than about 95%, greater than about 97%, greater than about 99%, greater than about 99.5%, greater than about 99.7%, or greater than about 99.9%. In various embodiments, the present invention provides (S)-TPMA HCl of crystalline form A having a residual solvent of less than 8000 ppm, less than 6000 ppm, less than 4000 ppm, less than 2000 ppm, less than 1000 ppm, less than 800 ppm, or less than 500 ppm. Parts per million (ppm) is based on the weight of the solvent as the weight ratio of compound + solvent, as is commonly understood. (USP 40, § <467> reference)

[0010] In various embodiments, a method for producing (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine hydrochloride as crystalline form A is provided.

[0011] In various embodiments, the method is as follows: (a) Dissolve the (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethaneamine free base in a solvent system containing an alkyl alcohol with four or fewer carbon atoms; (b) Adding excess HCl to an alkyl alcohol with four or fewer carbon atoms; and (c) Isolating crystalline (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine hydrochloride; in various embodiments, the alkyl alcohol is one or more n-propanols, isopropanols, and n-butanols, and in various embodiments, the alkyl alcohol is preferably isopropanol.

[0012] In various embodiments of the method for producing (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine hydrochloride as Form A, the method is as follows: (a) Combining racemic-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethaneamine with a stoichiometric excess of (R)-mandelic acid in a solvent; (b) Isolate (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine R-mandelate; (c)(R)-mandelate to release (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethaneamine; (d) Dissolve (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethaneamine in a solvent system containing an alkyl alcohol with four or fewer carbon atoms; (e) Adding HCl to an alkyl alcohol with four or fewer carbon atoms; (f) Isolating the crystalline (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine hydrochloride; in various embodiments, the alkyl alcohol is one or more n-propanols, isopropanols, and n-butanols, and in various embodiments, the alkyl alcohol is preferably isopropanol.

[0013] In various embodiments, a solid oral dosage form is provided comprising a tablet core and an optional coating. The tablet core comprises: about 30 mg to about 120 mg of crystalline (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine hydrochloride of Form A; and one or more fillers such as (a) mannitol and microcrystalline cellulose; (b) a disintegrant; and (c) a lubricant. In various embodiments, the optional tablet coating comprises (a) a polymer coating system and (b) one or more abrasives such as carnauba wax.

[0014] In various embodiments, the present disclosure relates to methods for treating neurological diseases or neuropathy with compositions, formulations and / or pharmaceuticals comprising (S)-TPMA, salts, and polymorphs thereof. In various embodiments, the present invention relates to methods for treating neurological diseases or neuropathy with compositions, formulations and / or pharmaceuticals comprising crystalline (S)-TPMA HCl. In various preferred embodiments, crystalline (S)-TPMA HCl comprises (S)-TPMA HCl of crystalline form A. Neuro diseases and disorders include, but are not limited to, the following: schizophrenia spectrum disorders, negative symptoms of schizophrenia, prodromal schizophrenia, delusional disorder, psychosis, attenuated psychosis syndrome, Parkinson's disease psychosis, psychotic disorder, delirium, Tourette syndrome, post-traumatic stress disorder, behavioral disorder, affective disorder, depression, bipolar depression, major depressive disorder, mood swings, bipolar disorder, mania, seasonal affective disorder, obsessive-compulsive disorder, narcolepsy, REM sleep behavior disorder, drug abuse or addiction, Lesch-Nyhan disease, Wilson's disease, autism, Alzheimer's disease with excitatory and / or psychotic symptoms, and Huntington's disease.

[0015] These and other objects, features, and advantages of the present invention will become apparent from the following detailed description of various aspects and embodiments of the present invention, in conjunction with the accompanying tables and drawings.

[0016] In the accompanying drawings, like reference numerals indicate like elements and features in the various figures. For clarity, not all elements are labeled in every figure. Further, the drawings are not necessarily complete when viewed without reference to the text, and emphasis is placed on explaining the principles of the invention.

[0017] The following abbreviations are used in this specification. The abbreviation DSC means differential scanning calorimetry; the abbreviation XRD means X-ray diffraction; the abbreviation XRPD means X-ray powder diffraction; the abbreviation NMR means nuclear magnetic resonance; the abbreviation DVS means dynamic vapor sorption; the abbreviation FBRM means focused beam reflectance measurement; the abbreviation HPLC means high performance liquid chromatography; and the abbreviation GC means gas chromatography; the abbreviation PSD means particle size distribution; the abbreviations D4,3 and D(4,3) mean the volume average diameter of the volume percent PSD; the abbreviation D50 means the median of a distribution where half of the population is above this value and half is below; the abbreviation D10 means the point on the distribution where 10% of the population is below this value; the abbreviation D90 means the point on the distribution where 90% of the population is below this value; the abbreviation PVM means particle vision and measurement; the abbreviation TPMA means (4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine. Other abbreviations not explicitly described in this specification have their ordinary meanings in the art.

Brief Description of the Drawings

[0018] [Figure 1A-B] Figures 1A and 1B show SEM images of crystalline (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine hydrochloride; polymorphic form A (Figures 1A and 1B). [Figure 1C-D] Figures 1C and 1D show SEM images of crystalline (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine hydrochloride; polymorphic form B (Figures 1C and 1D). [Figure 2A] Figure 2A shows the XRPD pattern measured in transmission mode of (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine hydrochloride of form A. [Figure 2B]Figure 2B shows the XRPD pattern of form A (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine hydrochloride measured in reflection mode. [Figure 2C] Figure 2C shows the XRPD pattern of (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine hydrochloride of form B. [Figure 3A] Figure 3A is the DSC thermogram of polymorphic form A (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine hydrochloride. [Figure 3B] Figure 3B is the DSC thermogram of polymorphic form B (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine hydrochloride. [Figure 3C] Figure 3C is a DSC thermogram of polymorphic form B (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine hydrochloride. [Figure 4A] Figure 4A shows the Raman spectrum of polymorphic form A (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine hydrochloride. [Figure 4B] Figure 4B shows the Raman spectrum of polymorphic form B (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine hydrochloride. [Figure 4C] Figure 4C shows the Raman spectra of (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethaneamine hydrochloride for both polymorphic form A (lower waveform) and polymorphic form B (upper waveform). [Figure 4D] Figure 4D shows the terahertz (THz) Raman spectrum of the form A peak of polymorph form A (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine hydrochloride at 1089 cm⁻¹ (wavenumber). [Figure 4E]Figure 4E shows the terahertz (THz) Raman spectrum of the form B peak of polymorph form B (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine hydrochloride at 1162 cm⁻¹ (wavenumber). [Figure 5] Figure 5 shows the DVS water adsorption isotherm of (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine hydrochloride of polymorph form A. [Figure 6A] Figure 6A shows the various HCl dosage profile data for polymorphic form A against (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine hydrochloride in Example 2. [Figure 6B] Figure 6B shows the various HCl dosage profile data for Example 2 against (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine hydrochloride of polymorphic form A. [Figure 7A] Figure 7A shows various PSD (particle size distribution) data for Example 2 for (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine hydrochloride of polymorphic form A. [Figure 7B] Figure 7B shows various PSD (particle size distribution) data for Example 2 for (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine hydrochloride of polymorphic form A. [Figure 8A] Figure 8A shows various PSD (particle size distribution) data for Polymorphic Form A of (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine hydrochloride in Example 2. [Figure 8B] Figure 8B shows various PSD (particle size distribution) data for Example 2 for (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine hydrochloride of polymorphic form A. [Figure 8C]Figure 8C shows various PSD (particle size distribution) data for Example 2 for (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine hydrochloride of polymorphic form A. [Figure 9A-C] Figure 9A shows various PSD (particle size distribution) data for Polymorphic Form A of (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine hydrochloride in Example 2. Figures 9B and 9C show SEM images of crystalline (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine hydrochloride of Polymorphic Form A. [Figure 10] Figure 10 shows the 1H NMR spectrum of the crystalline polymorph form A, (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethaneamine hydrochloride. [Figure 11] Figure 11 shows the XRPD pattern of (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethaneamine R-mandelate. [Figure 12] Figure 12 is a DSC thermogram of (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine R-mandelate. [Figure 13] Figure 13 shows the DVS isotherm of (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine R-mandelate. [Figure 14] Figure 14 shows the XRPD pattern of (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethaneamine L-tartrate. [Figure 15] Figure 15 is a DSC thermogram of (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine L-tartrate. [Figure 16]Figure 16 shows the DVS isotherm of (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine L-tartrate. [Figure 17] Figure 17 shows the XRPD pattern of (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethaneamine D-tartrate form DA. [Figure 18] Figure 18 shows the XRPD pattern of the (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine D-tartrate form DB. [Figure 19] Figure 19 shows the XRPD pattern of (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethaneamine D-tartrate form DC. [Figure 20] Figure 20 is the DSC thermogram of (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine D-tartrate form DA. [Figure 21] Figure 21 is a DSC thermogram of (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine D-tartrate form DB. [Figure 22] Figure 22 is the DSC thermogram of (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine D-tartrate form DC. [Figure 23] Figure 23 shows the DVS isotherm of (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine D-tartrate DA. [Figure 24] Figure 24 shows the DVS isotherm of (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine mesylate. [Figure 25]Figure 25 shows the XRPD pattern of (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine D-besylate form BA. [Figure 26] Figure 26 is the DSC thermogram of (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine D-besylate form BA. [Figure 27] Figure 27 shows the DVS isotherm of (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethaneamine D-besylate form BA. [Figure 28] Figure 28 shows the XRPD of (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine D-besylate form BA, which is the result of index creation. [Figure 29] Figure 29 is a schematic diagram showing controlled subsurface addition of acid flow in the high-mixing zone region near the impeller tip. [Figure 30] Figure 30 shows the dosing profile of HCl IPA solution (mL) over time (minutes). [Figure 31] Figure 31 is a graph of the drug delivery profile and the particle distribution of volume (%) relative to particle size (µm). [Figure 32] Figure 32 shows the XRPD pattern of (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethaneamine free base. [Modes for carrying out the invention]

[0019] Detailed description All published documents cited herein are incorporated herein by reference in their entirety.

[0020] In this specification, any reference to “one embodiment,” “one aspect,” or “aspect” means that any particular feature, structure, or characteristic described in relation to an embodiment or aspect is included in at least one embodiment or aspect of the teaching. Where used herein, the singular forms “a,” “an,” and “the” are intended to include the plural form unless the context explicitly indicates otherwise. Where used herein, the singular forms “a,” “an,” and “the” are intended to include the plural form unless otherwise specified.

[0021] Unless otherwise specified, the word "includes" (or its variations, such as "include" or "including") is intended to be unrestricted. For example, "A includes 1, 2, and 3" means that A includes 1, 2, and 3, but is not limited to them.

[0022] As used herein, the term “subject” to which the administration is intended includes, but is not limited to, humans (i.e., males or females of any age group, e.g., pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young adults, middle-aged adults, or elderly), and / or other primates (e.g., crab-eating macaques, rhesus macaques, etc.); mammals, including commercially important mammals such as cattle, pigs, horses, sheep, goats, cats, and / or dogs; and birds, including commercially important birds such as chickens, ducks, geese, quail, and / or turkeys. In some embodiments, the term “subject” means a patient, such as a human patient.

[0023] As used herein, the terms “treatment,” “treat,” and “treating” mean a disease or disorder, or one or more of its symptoms, and include, but are not limited to, therapeutic benefits. In various embodiments, treatment may be performed after the onset of one or more symptoms. In other embodiments, treatment may be performed even when there are no symptoms. For example, treatment may be administered to a subject before the onset of symptoms (for example, in light of the symptom history and / or in light of genetic or other susceptibility factors). After the symptoms have subsided, treatment may be continued, for example, to prevent or delay relapse.

[0024] Therapeutic benefits include the elimination and / or improvement of the underlying disease being treated; and also the elimination and / or improvement of one or more symptoms associated with the underlying disease, to which the subject shows improvement, but the subject may still be suffering from the underlying disease. In some embodiments, “treatment” or “treating” includes one or more of the following: (a) suppression of the disability (e.g., reduction of one or more symptoms caused by the disability and / or reduction of the degree of the disability); (b) delaying or preventing the onset of one or more symptoms associated with the disability (e.g., stabilizing the disability and / or slowing the worsening or progression of the disability); and / or (c) mitigating the disability (e.g., causing regression of clinical symptoms, improving the disability, slowing the progression of the disability and / or improving the quality of life).

[0025] As used herein, the terms “therapeutic effective dose” or “effective dose” mean the amount effective to induce a desired biological or medical response, such as the amount of a compound that, when administered to a subject to treat a disorder, is sufficient to produce such a therapeutic effect on the disorder. The effective dose varies depending on the compound, the disorder and its severity, as well as the age, weight, etc., of the subject being treated. The effective dose may be a single dose or multiple doses (for example, a single or multiple doses may be required to achieve a desired therapeutic endpoint). The effective dose may be considered effective if, when combined with one or more other agents, a desired or beneficial outcome can or will be achieved. The appropriate dose of any concurrently administered compound may be reduced in some cases due to the concomitant, additive, or synergistic effects of compounds.

[0026] As used herein, “delaying” the onset of a disorder means postponing, preventing, delaying, stabilizing, and / or postponing the onset of the disorder. The delay may be of varying lengths depending on the disease history and / or the individual being treated.

[0027] As used herein, “prevention” or “preventing” refers to a therapy that prevents the onset of a disorder so that the clinical symptoms of the disorder do not occur. Therefore, “prevention” relates to the administration of a therapy, such as administering a compound disclosed herein to a subject before any signs of the disease are detected in the subject (for example, administration of a compound disclosed herein to a subject when there are no detectable disorder symptoms). The subject may be an individual at risk or already suffering from the disorder.

[0028] As used herein, an individual at risk is an individual at risk of developing a disorder that should be treated. This may be indicated, for example, by one or more risk factors, which are measurable parameters known in the art that correlate with the development of a disease.

[0029] The compositions of the present invention may be administered orally, parenterally, by inhalation, topically, rectally, nasally, buccally, sublingually, transvaginally, or via an implanted reservoir. As used herein, the term “parenteral” encompasses subcutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intra-sternal, subarachnoid, intrahepatic, intrafocal, and intracranial injection or infusion techniques. Preferably, the compositions are administered orally, intraperitoneally, or intravenously. The sterile injectable forms of the compositions of the present invention may be aqueous or oily suspensions. These suspensions may be formulated according to techniques known in the art using appropriate dispersants or wetting agents and suspending agents. Sterile injectable preparations may also be sterile injectable solutions or suspensions in non-toxic parenterally acceptable diluents or solvents, such as a solution in 1,3-butanediol. Acceptable vehicles and solvents that can be used include, but are not limited to, water, Ringer's solution, and isotonic sodium chloride solution. Furthermore, sterile, fixative oils have conventionally been used as solvents or suspension media. The pharmaceutically acceptable compositions of the present invention can be administered orally in any orally acceptable dosage form, such as capsules, tablets, aqueous suspensions, or solutions.

[0030] Polymorphism is the ability of an element or compound to crystallize into a distinct crystalline phase. While the term polymorphism means multiple forms, it is still used in the art and herein to refer to the crystalline structure of a compound as a polymorph, even if only one crystalline phase is currently known. Thus, polymorphs are distinct solids that share the same molecular formula as other polymorphs and amorphous (non-crystalline) phases, but because the properties of a solid depend on its structure, polymorphs often exhibit physical properties that differ from each other and from the amorphous phase, such as different solubility profiles, different melting points, different dissolution profiles, different thermal stabilities, different photostability, different hygroscopicity, different shelf life, different suspension properties, and different physiological absorption rates. The encapsulation of a solvent in a crystalline solid yields a solvate, and in the case of water as the solvent, the hydrate often yields a distinguishable crystalline form with one or more physical properties that are distinctly different from the non-solvated and non-hydrated (e.g., anhydrous) crystalline forms.

[0031] As used herein, the term “polymorph” refers to a different crystalline structure achieved by a particular chemical substance. As used herein, the term “solvate” refers to a crystalline form in which a stoichiometric or non-stoichiometric amount of solvent, or a mixture of solvents, is incorporated into the crystalline structure. Similarly, the term “hydrate” refers to a crystalline form in which a stoichiometric or non-stoichiometric amount of water is incorporated into the crystalline structure.

[0032] As used herein, the term "span" is evaluated as follows when referring to PSD: for the D value of a volume-based PSD distribution, span = [(D90-D10) / D50].

[0033] As used herein, the term “significant peak” in relation to XRPD refers to a peak with a relative intensity greater than approximately 15%. As used herein, the term “non-significant peak” in relation to XRPD refers to a peak with a relative intensity of less than 2%.

[0034] As used herein, the term “polymorphic purity” refers to the weight percent of a particular polymorph. For example, if (S)-TPMA HCl of crystalline form A is characterized as having a polymorphic purity greater than 95%, it means that more than 95 wt% of the substance is (S)-TPMA HCl of crystalline form A, and less than 5 wt% is any other polymorph (e.g., form B) or amorphous (S)-TPMA HCl.

[0035] As used herein, the terms “chiral purity” and “enantiomer purity” are used interchangeably and refer to the weight percent of a particular enantiomer. For example, if a (S)-TPMA-containing substance (such as a compound or crystal) is characterized as having a chiral purity greater than 95%, it means that more than 95% by weight of TPMA in the substance is the (S)-TPMA enantiomer, and less than 5% by weight is any other enantiomer of TPMA.

[0036] As used herein, the term “chemical purity” refers to the weight percent of a particular chemical substance, including a specific enantiomer or polymorph. For example, if (S)-TPMA HCl of crystalline form A is characterized as having a chemical purity greater than 95%, it means that more than 95% by weight of the substance is (S)-TPMA HCl of crystalline form A, and less than 5% by weight is any other compound other than the enantiomer and polymorph.

[0037] "Pharmacologically acceptable" or "physiologically acceptable" means compounds, salts, compositions, dosage forms, and other substances that are useful for preparing pharmaceutical compositions suitable for veterinary or human pharmaceutical use.

[0038] As used herein, the term “pharmaceutically acceptable salt” refers to a salt that, within the bounds of sound medical judgment, is suitable for use in contact with human and lower animal tissues without excessive toxicity, irritation, allergic reactions, etc., and that is commensurate with a reasonable benefit / risk ratio. Pharmacochemically acceptable salts are well known in the art. For example, S.M. Berge et al. describe details of pharmaceutically acceptable salts in J. Pharmaceutical Sciences, 1977, 66, 1-19. Pharmacochemically acceptable salts of the compounds of the present invention include those derived from appropriate inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts of amino groups formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or by using other methods used in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipine, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphor sulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfonate, ethanesulfonate, formate, fumarate, glucoheptone, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, and 2-hydroxyethanol. Examples include nasulfonates, lactobionates, lactates, laurates, lauryl sulfates, malates, maleates, malons, methanesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, oleates, oxalates, palmitates, pamoates, pectins, persulfates, 3-phenylpropionates, phosphates, pivalates, propions, stearates, succinates, sulfates, tartrates, thiocyanates, p-toluenesulfonic acids, undecanoic acids, and valersates. Pharmaceutically acceptable counterions are preferred for preparing pharmaceutical formulations, while other anions are highly acceptable as synthetic intermediates.Therefore, if such a salt is a chemical intermediate, X may be a pharmaceutically undesirable anion such as iodide, oxalate, or trifluoromethanesulfonate.

[0039] As used herein, the term “pharmaceutically acceptable excipient” includes, but is not limited to, any binder, filler, adjuvant, carrier, excipient, flow enhancer, sweetener, diluent, preservative, dye / colorant, flavor enhancer, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent, emulsifier, anticaking agent, fragrance, desiccant, plasticizer, disintegrant, lubricant, polymer matrix system, and abrasive, which are approved by the U.S. Food and Drug Administration as acceptable for use in human or animal.

[0040] It should be understood that in various embodiments, the pharmaceutical compositions of the present invention may include, but are not limited to, one or more pharmaceutically acceptable excipients, such as binders, fillers, buffers, stabilizers, surfactants, wetting agents, lubricants, diluents, disintegrants, thickeners or reducing agents, emulsifiers, suspending agents, preservatives, antioxidants, opacifiers, flow enhancers, processing aids, colorants, sweeteners, taste-masking agents, fragrances, flavorings, abrasives, polymer matrix systems, plasticizers and other known additives, in order to provide a qualified presentation or aid for a drug in the manufacture of a drug or pharmaceutical comprising the composition of the present invention. Examples of carriers and excipients well known to those skilled in the art are described in detail, for example, Ansel, Howard C., et al., Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems. Philadelphia: Lippincott, Williams & Wilkins, 2004; Gennaro, Alfonso R., et al. Remington: The Science and Practice of Pharmacy. Philadelphia: Lippincott, Williams & Wilkins, 2000; and Rowe, Raymond C. Handbook of Pharmaceutical Excipients. Chicago, Pharmaceutical Press, 2005.

[0041] In various embodiments, non-limiting examples of excipients include corn starch, potato starch, or other starches, gelatin, acacia, sodium alginate, alginic acid, other alginates, natural and synthetic rubbers such as powdered tragacanth, guar gum, cellulose and its derivatives (e.g., ethylcellulose, cellulose acetate, calcium carboxymethylcellulose, sodium carboxymethylcellulose), polyvinylpyrrolidone, methylcellulose, pregelatinized starch, hydroxypropyl methylcellulose, (e.g., No. 2208, 2906, 2910), hydroxypropylcellulose, titanium dioxide, talc, calcium carbonate (e.g., granules or powder), microcrystalline cellulose, powdered cellulose, dextrose, kaolin, silicic acid, sorbitol, starch, pregelatinized starch, agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, potassium polaritrate, sodium starch glycolate, potato or tapioca starch, other starches, pregelatinized starch, other starches, clay, other algins Other celluloses, gums, calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oils (e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), zinc stearate, ethyl oleate, ethyl laurate, agar, siloid silica gel (AEROSIL200 (fumed silica, manufactured by Evonik)), synthetic silica agglomeration aerosols (sold by Evonik Degussa), CAB-O-SIL (a pyrogenic silicon dioxide product sold by Cabot Co. in Boston, MA), colorants, and mixtures thereof are not limited to these.

[0042] In various embodiments, the composition is formulated with one or more pharmaceutically acceptable excipients according to known practice. In various embodiments, the composition described herein is referred to as a formulation or pharmacopoeia. Thus, in various embodiments, the composition is formulated as, for example, a liquid, powder, elixir, solution for injection, or suspension. Formulations for oral use are preferred and may be provided, for example, as tablets, caplets, or capsules, where the pharmacologically active ingredient is mixed with an inert solid diluent. In various embodiments, the composition described herein is formulated as a tablet. In various embodiments, the oral dosage form is a solid oral dosage form. In various embodiments, the solid oral dosage form includes tablets, and the solid oral dosage form includes capsules. Tablets may also contain granulators and disintegrants and may be coated or uncoated. Formulations for topical use may be provided as, for example, topical solutions, lotions, creams, ointments, gels, foams, patches, powders, solids, sponges, tapes, vapors, pastes, or tinctures.

[0043] Accordingly, various embodiments and models provided herein offer methods for preparing specific salts of particular enantiomers in crystalline polymorphs that themselves serve as pharmaceutical dosage forms. Furthermore, various embodiments and models provide salt polymorph formulations for unique dosage forms that exhibit pharmaceutically advantageous properties.

[0044] This specification has the following structure: [ka] (S)-TPMA The present invention provides the compound (S)-(-)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethaneamine, which has the compound (S)-(-)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethaneamine.

[0045] (S)-(-)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethaneamine is named or identified using other commonly recognized nomenclature systems. For example, compounds are named or identified by a common name, a systematic name, or a non-systematic name. Commonly recognized nomenclature systems in the field of chemistry include, but are not limited to, the Chemical Abstract Service (CAS) and the International Pure Union of Pure and Applied Chemistry (IUPAC). The IUPAC name provided by ChemDraw Professional 15.0 is used here for compound 1.

[0046] (S)-(-)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine is referred to herein as (S)-TPMA for brevity. In some embodiments, (S)-TPMA may be prepared as a pharmaceutically acceptable salt. As an example of a non-limiting pharmaceutically acceptable salt, Hydrochloride, maleate, tartrate, citrate, phosphate, sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caproate, heptane, propionate, oxalate, malonate, succinate, suberic acid, sebacinate, fumarate, maleate, butin-1,4-diate, hexyl Examples include 1,6-diates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, sulfonates, methylsulfonates, propylsulfonates, besilates, tosilates, xylenesulfonates, naphthalene-1-sulfonates, naphthalene-2-sulfonates, phenylacetates, phenylpropionates, phenylbutyrates, lactates, γ-hydroxybutyrates, glycolates, and mandelates. A list of other suitable pharmaceutically acceptable salts can be found in Remington: The Science and Practice of Pharmacy, 21st Edition, Lippincott Williams and Wilkins, Philadelphia, Pa., 2006.

[0047] In some embodiments, this specification refers to (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine hydrochloride, (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine besylate, (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine R-mandelate, (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine L-tartrate, (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine The present invention provides D-tartrate, (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethaneamine mesylate, and (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethaneamine L-maleate.

[0048] The present inventors have introduced (S)-(-)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethaneamine hydrochloride anhydride (hereinafter referred to as (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethaneamine hydrochloride, and for brevity, also referred to as (S)-TPMA HCl): [ka] (S)-TPMA HCl However, we found that crystalline solids possess the desired solubility under physiological conditions, are chemically stable, and are physically suitable for formulation.

[0049] The inventors also found that (S)-TPMA HCl exists in two polymorphs, polymorph form A and polymorph form B. Furthermore, form A was found to be thermodynamically stable and not substantially converted to the other polymorphs or amorphous forms. The formation of form B was found to be kinetically preferable to form A. However, form B was found to be less thermodynamically stable than form A; when form B is held as a slurry and slightly heated, form B is converted to form A.

[0050] The crystalline forms of (S)-TPMA and (S)-TPMA HCl, and the crystalline forms of other salts, hydrates, and solvates (including the crystalline forms of the present invention), can be characterized and distinguished using several conventional analytical techniques, including, but not limited to, X-ray powder diffraction (XRPD) patterns, nuclear magnetic resonance (NMR) spectra, Raman spectra, infrared (IR) absorption spectra, dynamic vapor adsorption (DVS), differential scanning calorimetry (DSC), and melting point. Chemical purity can be characterized using many conventional analytical techniques, including, but not limited to, high-performance liquid chromatography (HPLC) and gas chromatography (GC). Chiral purity (also known as enantiomer purity) can be characterized using many conventional analytical techniques, including, but not limited to, high-performance liquid chromatography (HPLC).

[0051] In various embodiments, the crystalline form of (S)-TPMA HCl is characterized by X-ray powder diffraction (XRPD). XRPD is a technique for characterizing powder samples of a substance by measuring the diffraction of X-rays by the substance. The result of an XRPD experiment is a diffraction pattern. Each crystalline solid produces a characteristic diffraction pattern containing sharp peaks as a function of the scattering angle 2θ (2-theta). Both the position of the diffraction pattern (corresponding to the lattice spacing) and the relative intensity of the peaks indicate a particular phase and substance. This provides a "fingerprint" for comparison with other substances. In contrast to crystalline patterns containing a series of sharp peaks, amorphous materials (liquids, glasses, etc.) produce a broad background signal in their diffraction patterns.

[0052] It should be understood that the appearance, intensity, and position of lines in the diffraction pattern may vary slightly depending on the equipment used, humidity, temperature, orientation of the powder crystals, and other parameters related to the acquisition of the XRPD pattern. An XRPD pattern that is "substantially identical" to that of the drawings provided herein (e.g., Figure 2A) is an XRPD pattern that a person skilled in the art would consider to represent a compound having the same crystalline morphology as the compound providing the XRPD pattern in that drawing. That is, the XRPD pattern may be the same as or slightly different from the pattern in the drawing. Such an XRPD pattern may not necessarily show each line of the diffraction pattern presented herein and / or may show a shift in the position of said lines due to differences in appearance, intensity, or conditions related to data acquisition. A person skilled in the art can determine whether a sample of a crystalline compound has the same or different morphology as the morphology disclosed herein by comparing its XRPD patterns.

[0053] For example, a person skilled in the art can use HPLC to determine the enantiomer identity of a (4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine hydrochloride (TPMA HCl) sample, and if the sample is identified as (S)-TPMA HCl, a person skilled in the art can superimpose the XRPD pattern of the sample onto Figure 2A and / or Figure 2B and, using their expertise and knowledge in the art, easily determine whether the XRPD pattern of the sample substantially matches the XRPD pattern of (S)-TPMA HCl of crystalline form A shown in Figure 2A or (S)-TPMA HCl of form B shown in Figure 2B. For example, if HPLC identifies the sample as (S)-TPMA HCl and the sample XRPD pattern substantially matches Figure 2A, the sample can be easily and accurately identified as (S)-TPMA HCl of form A.

[0054] In various embodiments, the crystalline form of (S)-TPMA HCl is characterized by Raman spectroscopy and THz Raman spectroscopy. The peak positions and relative intensities can indicate the vibrations and other low-frequency modes of the compound, providing a "fingerprint" for comparison with other compounds. THz Raman spectroscopy provides further "fingerprint" information by extending the range to the terahertz frequency region for both Stokes and anti-Stokes signals, and generally provides greater structural information than Raman spectroscopy, such as distinctions between polymorphs.

[0055] In various embodiments, the crystalline form of (S)-TPMA HCl is characterized by its melting point. The melting point is determined by conventional methods such as capillary tubes and may extend beyond the range in which complete melting occurs, or, in the case of a single numerical value, may indicate a melting point within ±1°C of that temperature.

[0056] In various embodiments, the crystalline form of (S)-TPMA HCl is characterized by differential scanning calorimetry (DSC). DSC is a thermal analysis technique that measures the difference in the amount of heat required to raise the temperature of a sample and a reference as a function of temperature. During the experiment, both the sample and the reference are maintained at substantially the same temperature. The result of a DSC experiment is a heat flow versus temperature curve called a DSC thermogram.

[0057] In various embodiments, the hygroscopicity of the crystalline form of (S)-TPMAHCl is characterized by dynamic vapor adsorption (DVS). DVS is a gravimetric technique that measures the amount of solvent adsorbed onto a sample by changing the concentration of vapor (such as relative humidity) surrounding the sample and measuring the change in mass. In this application, DVS is used to generate an sorption isotherm of water, which represents the equilibrium amount of sorbed vapor as a function of the steady-state relative vapor pressure at a constant temperature.

[0058] As used herein, the term "substantially non-hygroscopic" refers to a compound in which the maximum mass change of the moisture adsorption isotherm, measured by dynamic vapor sorption (DVS) scanned over relative humidity from 0 to 90% at 25°C, is less than 1%.

[0059] In various aspects and embodiments, the present invention relates to Form A and Form B, which are novel crystalline forms of (S)-TPMAHCl. Form A is a polymorph distinct from Form B, and it has been found that not only are its structure and XRPD pattern clearly different, but its THz Raman spectrum is also different.

[0060] Figures 1A and 1B show SEM images of (S)-TPMA HCl form A crystals, and Figures 1C and 1D show SEM images of (S)-TPMA HCl form B crystals. Form A was observed to form plate-like crystals and was determined to be monoclinic by XRPD, while form B was observed to form hollow acicular crystals and was determined to be orthorhombic by XRPD. As isolated from conventional synthesis or salt conversion, (S)-TPMA hydrochloride usually appears as a mixture of forms A and B.

[0061] Form B was determined to be less thermodynamically stable than Form A and can be converted to Form A through a solid-state transformation. The solid-state transformation from the acicular crystal of polymorph Form B to the block crystal of polymorph Form A could be monitored by X-ray diffraction, and unexpectedly, it was found that the visible morphology retained its acicular shape even when the crystal lattice changed to that of Form A.

[0062] The XRPD patterns in Figure 2A were obtained in transmission mode using a Stoe Stadi P (G.52.SYS.S072) with a Mythen1K detector, using Cu Kα emission with a step scan at 40 kV and 40 mA tube power; a curved Ge monochromator detector; a 0.02°20 step size, a 12-second step time, and a scan range of 1.5–50.5°20. The detector mode was set as follows: step scan at 1°20 detector steps; and the sample preparation was a 10–20 mg sample placed between two acetate foils and clamped in a Stoe transmission sample holder. The sample was rotated during measurement.

[0063] The XRPD patterns in Figures 2B and 2C were obtained by reflection measurements using a Bruker 08 Advance, Cu Kα emission (λ=1.54180 Å), 40 kV / 40 mA tube power; LynxEye detector, step size 0.02°, 37 sec / step, and 2.5°-50° scanning range. The sample was prepared on a silicon single crystal sample holder with a depth of 1.0 mm and covered with Kapton foil. The sample was rotated during the measurement.

[0064] Table 1 summarizes the details of the crystal data and crystallographic data acquisition parameters. Table 2A lists the XRPD peaks in Figure 2A, Table 2B lists the XRPD peaks in Figure 2B, and Table 2C lists the XRPD peaks in Figure 2C.

[0065] Table 1 (S)-TPMA hydrochloride Form A and Form B Single crystal data and data acquisition parameters [Table 1]

[0066] In some embodiments, this specification provides crystalline (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine hydrochloride characterized by monoclinic space group P21. In some embodiments, the crystalline (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine hydrochloride has unit cell dimensions of a = about 9.2 Å, b = about 11.2 Å, c = about 10.2 Å, α = about 90°, β = about 92°, and γ = about 90°.

[0067] In some embodiments, this specification provides crystalline (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine hydrochloride characterized by orthorhombic space group P212121. In some embodiments, the crystalline (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine hydrochloride has unit cell dimensions of a = about 5.1 Å, b = about 10.2 Å, c = about 20.5 Å, α = about 90°, β = about 90°, and γ = about 90°.

[0068] Table 2A (S)-TPMA hydrochloride Form A XRPD (Figure 2A) Peak List [Table 2] [Table 3]

[0069] Table 2B (S)-TPMA hydrochloride Form A XRPD (Figure 2B) Peak List [Table 4] [Table 5]

[0070] Table 2C (S)-TPMA hydrochloride Form B XRPD (Figure 2C) Peak List [Table 6]

[0071] Raman and THz Raman spectra Using the Kaiser-Raman RXN-Hybrid-785 system, at a laser wavelength of 785 nm, the Raman spectrum has a spectral range of +100 cm⁻¹. -1 ~+1875 cm -1 For THz Raman spectra, the spectral range is -200 cm⁻¹. -1 ~+200 cm -1 Raman and THz Raman spectral analysis was performed; spectral resolution was 4 cm. -1 The Raman spectra in Figures 4A, 4B, and 4C were collected using a regular immerse Raman probe, and the THz Raman spectra in Figures 4D and 4E were collected using a THz-Raman® probe.

[0072] For Figures 4A and 4C, the (S)-TPMA HCl Form A crystal was used as a powder, and the spectra were acquired in a darkroom. For Figures 4B and 4C, the (S)-TPMA HCl Form B crystal was newly generated by dissolving the Form A crystal in isopropanol, then removing the solvent by rotational evaporation, and then the Form B crystal was used as a powder, and the spectra were acquired in a darkroom. A list of the various peaks in the spectrum of Figure 4A is shown in Table 3A, and a list of the various peaks in the spectrum of Figure 4B is shown in Table 3B.

[0073] For Figure 4D, (S)-TPMA HCl form A crystals were suspended in isopropanol at room temperature, and the spectrum was obtained from the suspension using a THz-Raman® probe. For Figure 4E, (S)-TPMA HCl form B crystals were generated by reverse damping addition of the free base (S)-TPMA to an HCl solution, and the spectrum was obtained from the suspension using a rapid THz-Raman® probe.

[0074] Both Raman spectra and THz Raman spectra were acquired using (a) cosmic ray filtering and (b) baseline correction and smoothing to obtain interpretable data as needed; and for THz Raman spectra, background subtraction of IPA-filled wells collected under the same conditions was also acquired under the same conditions.

[0075] Table 3A (S)-TPMA hydrochloride Form A Raman spectrum (Figure 4A) Peak list [Table 7]

[0076] Table 3B (S)-TPMA hydrochloride Form B Raman spectrum (Figure 4B) Peak list [Table 8]

[0077] Regarding Figures 4D and 4E, the THz Raman spectra of the two polymorphs are clearly different. For example, in various embodiments, 1162 cm⁻¹ -1 THZ Raman spectrum of the Raman peak of form B and 1089 cm⁻¹ -1 These polymorphs can be distinguished using the THZ Raman spectrum of the Raman peak of form A.

[0078] Forms A and B of crystalline (S)-TPMA HCl exhibit different properties and distinct "fingerprints." Table 4 summarizes the various measurements presented herein for these polymorphs.

[0079] Table 4 [Table 9]

[0080] In various embodiments, the present invention provides a crystalline form of (S)-TPMA HCl characterized by an XRPD pattern having peaks at 9.6±0.2°, 14.9±0.2°, 20.5±0.2°, and 25.1±0.2°, with 2-theta as the unit, and a DSC thermogram having a peak at 214±2°C.

[0081] In various embodiments, the present invention provides a crystalline form of (S)-TPMA HCl characterized by an XRPD pattern including peaks at 9.6±0.2°, 14.9±0.2°, 20.5±0.2°, and 25.1±0.2° in units of 2-theta, as well as a differential scanning calorimetry thermogram substantially consistent with Figure 3A.

[0082] In various embodiments, the present invention provides a crystalline form of (S)-TPMA HCl characterized by an XRPD pattern including peaks at 9.6±0.2°, 14.9±0.2°, 20.5±0.2°, and 25.1±0.2° in 2-theta units, as well as a Raman spectrum substantially consistent with Figure 4A and / or a THz Raman spectrum substantially consistent with Figure 4D.

[0083] In various embodiments, the present invention provides a crystalline form of (S)-TPMA HCl characterized by an XRPD pattern having peaks at 8.6±0.2°, 17.2±0.2°, and 25.9±0.2° in units of 2-theta, and a DSC thermogram having a peak at 215±2°C.

[0084] In various embodiments, the present invention provides a crystalline form of (S)-TPMA HCl characterized by an XRPD pattern including peaks at 8.6±0.2°, 17.2±0.2°, and 25.9±0.2° in units of 2-theta, as well as a differential scanning calorimetry thermogram substantially consistent with Figure 3B or Figure 3C.

[0085] In various embodiments, the present invention provides a crystalline form of (S)-TPMA HCl characterized by an XRPD pattern including peaks at 8.6±0.2°, 17.2±0.2°, and 25.9±0.2° in 2-theta units, as well as a Raman spectrum substantially consistent with Figure 4B and / or a THz Raman spectrum substantially consistent with Figure 4E.

[0086] In various embodiments, the present invention provides (S)-TPMAHCl of crystalline form A, which is substantially nonhygroscopic. In various embodiments, the present invention provides (S)-TPMAHCl of crystalline form A having a maximum mass change of less than 1%, less than 0.5%, less than 0.3%, less than 0.2%, or less than 0.1% in a moisture adsorption isotherm measured by dynamic vapor sorption (DVS) scanned over relative humidity from 0 to 90% at 25°C.

[0087] Figure 5 and Table 5 show the DVS moisture adsorption isotherms of (S)-TPMA HCl in crystalline form A. Moisture adsorption isotherms were generated using a VTI SGA-100 dynamic vapor adsorption analyzer. Samples were dried at 25°C prior to analysis to meet the equilibrium criterion of a change of 0.0000 wt% over 5 minutes or up to 180 minutes. The isothermal equilibrium criterion was less than a change of 0.01 wt% over 5 minutes or 180 minutes at each relative humidity (RH) step. The temperature was fixed at 25°C, and the relative humidity steps (5%~95%~5%) were in 5% increments. Initial sample sizes ranged from 41 to 47 mg.

[0088] Figure 5 shows the DVS moisture adsorption of two different lots of (S)-TPMA HCl in crystalline form A, and Table 5 shows the data plotted in Figure 5. As can be seen from these, crystalline (S)-TPMA HCl form A is substantially non-hygroscopic, showing a maximum mass change of only 0.2% at 95% relative humidity (RH) and less than 0.1% at 90% RH and below.

[0089] Table 5 Figure 5 shows the (S)-TPMA HCl foam A DVS moisture absorption isotherm. [Table 10]

[0090] In various embodiments, the present invention provides a crystalline form of (S)-TPMA HCl characterized by an XRPD pattern including peaks at 9.6±0.2°, 14.9±0.2°, 20.5±0.2°, and 25.1±0.2°, with 2-theta units; further characterized by peaks at 0.2±0.2° and 20.8±0.2°; and further characterized by two or more prominent peaks in an XRPD pattern selected from 17.9±0.2°, 24.8±0.2°, and 27.1±0.2°, with 2-theta units. In various embodiments, the present invention provides a crystalline form of (S)-TPMA HCl characterized by an XRPD pattern substantially consistent with Figure 2B.

[0091] In various embodiments, the present invention provides a crystalline form of (S)-TPMA HCl characterized by the following properties: an XRPD pattern including peaks at 9.6±0.2°, 14.9±0.2°, 20.5±0.2°, and 25.1±0.2° with 2-theta units; a melting point of 214±2°C; chiral purity greater than about 99%; chemical purity greater than about 99%; residual solvent content less than 8000 ppm; and being substantially non-hygroscopic.

[0092] In various embodiments, the present invention provides an XRPD pattern with the following characteristics: peaks at 9.6±0.2°, 14.9±0.2°, 20.5±0.2°, and 25.1±0.2° in units of 2-theta, and One or more of the following characteristics: (a) Powder X-ray diffraction pattern with 2-theta units, further including peaks at 0.2±0.2° and 20.8±0.2°; (b) Powder X-ray diffraction pattern further including two or more prominent peaks among 17.9±0.2°, 24.8±0.2°, and 27.1±0.2°, with 2-theta as the unit; (c) Melting point of 214±2℃; (d) Differential scanning calorimetry thermogram showing a peak at 214±2℃; (e) A differential scanning calorimetry thermogram substantially consistent with Figure 3A; (f) A Raman spectrum substantially consistent with Figure 4A, a THz Raman spectrum substantially consistent with Figure 4D, or both; (g) Approximately: (i) 90%, (ii) 95%, (iii) 97%, (iv) 99%, (v) 99.5%, (vi) 99.7%, or (vii) 99.9% greater chiral purity; (h) Approximately: (i) 80%, (ii) 90%, (iii) 95%, (iv) 97%, (v) 99%, (vi) 99.5%, (vii) 99.7%, or (viii) 99.9% greater chemical purity; (i) Approximately: Residual solvent present in amounts of (i) 8000 ppm, (ii) 6000 ppm, (iii) 4000 ppm, (iv) 2000 ppm, (v) 1000 ppm, (vi) 800 ppm, or less than 500 ppm; (j) Maximum mass change of moisture adsorption isotherms measured by dynamic vapor sorption (DVS) scanned over relative humidity from 0 to 90% at 25°C with relative humidity levels of less than 2%, (ii) 1%, (iii) 0.5%, (iv) 0.4%, (v) 0.3%, (vi) 0.2%, or (vii) 0.1%; (k)(i)1%, (ii)0.5%, (iii)0.4%, (iv)0.3%, (v)0.2%, or (vi)less than 0.1%; and preferably, the maximum mass change of the moisture adsorption isotherm measured by dynamic vapor sorption (DVS) scanned over relative humidity from 0 to 90% at 25°C with a relative humidity of less than 0.2%; This provides the crystalline form of (S)-TPMA HCl characterized by the following.

[0093] In various embodiments, the crystalline form of (S)-TPMA HCl is provided, characterized by an XRPD pattern including peaks at 8.6±0.2°, 17.2±0.2°, and 25.9±0.2°, with 2-theta units; and in various embodiments, further characterized by peaks at 23.2±0.2° and 31.5±0.2°, with 2-theta units. In various embodiments, the present invention provides a crystalline form of (S)-TPMA HCl characterized by an XRPD pattern substantially consistent with Figure 2C.

[0094] In various embodiments, the present invention provides a crystalline form of (S)-TPMA HCl of form B characterized by the following properties: an XRPD pattern including peaks at 8.6±0.2°, 17.2±0.2°, and 25.9±0.2° with 2-theta as units, and a melting point of 215±2°C.

[0095] In various embodiments, the following characteristics are observed: an XRPD pattern including peaks at 8.6±0.2°, 17.2±0.2°, and 25.9±0.2° in units of 2-theta, and One or more of the following characteristics: (a) Powder X-ray diffraction pattern with 2-theta units, further including peaks at 23.2±0.2° and 31.5±0.2°; (b) Melting point of 215±2℃; (c) Differential scanning calorimetry thermogram showing a peak at 215±2℃; (d) A differential scanning calorimetry thermogram substantially consistent with Figure 3B or 3C; (e) A Raman spectrum substantially consistent with Figure 4B, a THz Raman spectrum substantially consistent with Figure 4E, or both; (f) Approximately: (i) 90%, (ii) 95%, (iii) 97%, (iv) 99%, (v) 99.5%, (vi) 99.7%, or (vii) 99.9% greater chiral purity; (g) Approximately: (i) 80%, (ii) 90%, (iii) 95%, (iv) 97%, (v) 99%, (vi) 99.5%, (vii) 99.7%, or (viii) greater than 99.9% chemical purity; (h) Approximately: (i) 8000 ppm, (ii) 6000 ppm, (iii) 4000 ppm, (iv) 2000 ppm, (v) 1000 ppm, (vi) 800 ppm, or less than 500 ppm of residual solvent; and This provides the crystalline form of (S)-TPMA HCl characterized by the following.

[0096] In some embodiments, this specification is as follows: (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine besylate, (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine R-mandelate, (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine L-tartrate, (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine D-tartrate, (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine mesylate, and (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine L-maleate, The present invention provides compounds selected from the following.

[0097] (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine besylate This specification provides (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine besylate, also known as (S)-TPMA besylate. In some embodiments, (S)-TPMA besylate is crystalline.

[0098] In some embodiments, the crystalline form of (S)-TPMA besylate is characterized by a powder X-ray diffraction pattern including peaks at 6.1±0.2°, 12.3±0.2°, and 16.7±0.2°, with 2-theta units. In some embodiments, the crystalline (S)-TPMA besylate is characterized by a powder X-ray diffraction pattern including a peak at 6.1±0.2°, with 2-theta units. In some embodiments, the crystalline (S)-TPMA besylate is characterized by a powder X-ray diffraction pattern including a peak at 12.3±0.2°, with 2-theta units. In some embodiments, the crystalline (S)-TPMA besylate is characterized by a powder X-ray diffraction pattern including a peak at 16.7±0.2°, with 2-theta units. In some embodiments, the crystalline (S)-TPMA besilate is further characterized by a powder X-ray diffraction pattern that further includes peaks at 19.0±0.2° and 24.7±0.2°, with 2-theta units. In some embodiments, the crystalline (S)-TPMA besilate is further characterized by a powder X-ray diffraction pattern that further includes two or more peaks at 21.9±0.2°, 22.4±0.2° and 22.8±0.2°, with 2-theta units.

[0099] In some embodiments, the crystalline (S)-TPMA besylate is characterized by an XRPD pattern substantially consistent with that shown in Figure 25.

[0100] In some embodiments, the crystalline (S)-TPMA besylate has a differential scanning calorimetry thermogram with a peak at 142±2°C. In some embodiments, the crystalline (S)-TPMA besylate has a differential scanning calorimetry thermogram substantially consistent with that of Figure 26.

[0101] In some embodiments, the crystalline morphology of (S)-TPMA besylate is characterized by a powder X-ray diffraction pattern with peaks at 6.1±0.2°, 12.3±0.2°, and 16.7±0.2°, with 2-theta units, and a powder X-ray diffraction pattern substantially consistent with Figure 25. In some embodiments, the crystalline morphology of (S)-TPMA besylate is characterized by a powder X-ray diffraction pattern with peaks at 6.1±0.2°, 12.3±0.2°, and 16.7±0.2°, with 2-theta units, and has a differential scanning calorimetry thermogram with a peak at 142±2°C. In some embodiments, the crystalline morphology of (S)-TPMA besylate is characterized by a powder X-ray diffraction pattern that includes peaks at 6.1±0.2°, 12.3±0.2°, and 16.7±0.2° with 2-theta units, and has a powder X-ray diffraction pattern that substantially matches that of Figure 26.

[0102] In some embodiments, the crystalline (S)-TPMA besylate is characterized by a monoclinic space group P21. In some embodiments, the crystalline (S)-TPMA besylate has unit cell dimensions of a = approximately 7.7 Å, b = approximately 7.5 Å, c = approximately 14.8 Å, α = approximately 90°, β = approximately 103°, and γ = approximately 90°.

[0103] In some embodiments, the substance comprises an (S)-TPMA besilate whose chiral purity is greater than approximately 90%. In some embodiments, the substance comprises an (S)-TPMA besilate whose chiral purity is greater than approximately 95%. In some embodiments, the substance comprises an (S)-TPMA besilate whose chiral purity is greater than approximately 97.5%. In some embodiments, the substance comprises an (S)-TPMA besilate whose chiral purity is greater than approximately 99%.

[0104] In some embodiments, the substance comprises (S)-TPMA besilate, which has a chemical purity of about 90% or more. In some embodiments, the substance comprises (S)-TPMA besilate, which has a chemical purity of about 95% or more. In some embodiments, the substance comprises (S)-TPMA besilate, which has a chemical purity of about 97.5% or more. In some embodiments, the substance comprises (S)-TPMA besilate, which has a chemical purity of about 99% or more.

[0105] (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine R-mandelate This specification provides (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine R-mandelate, also known as (S)-TPMA R-mandelate. In some embodiments, (S)-TPMA R-mandelate is crystalline.

[0106] In some embodiments, the crystalline form of (S)-TPMA R-mandelate is characterized by a powder X-ray diffraction pattern that includes peaks at 9.4±0.2°, 14.3±0.2°, and 16.3±0.2°, with 2-theta units. In some embodiments, the crystalline (S)-TPMA R-mandelate is characterized by a powder X-ray diffraction pattern that includes a peak at 9.4±0.2°, with 2-theta units. In some embodiments, the crystalline (S)-TPMA R-mandelate is characterized by a powder X-ray diffraction pattern that includes a peak at 14.3±0.2°, with 2-theta units. In some embodiments, the crystalline (S)-TPMA R-mandelate is characterized by a powder X-ray diffraction pattern that includes a peak at 16.3±0.2°, with 2-theta units. In some embodiments, the crystalline (S)-TPMA R-mandelate is further characterized by a powder X-ray diffraction pattern that further includes peaks at 4.7±0.2° and 19.6±0.2°, with 2-theta units. In some embodiments, the crystalline (S)-TPMA R-mandelate is further characterized by a powder X-ray diffraction pattern that further includes two or more peaks at 21.8±0.2°, 23.7±0.2° and 25.0±0.2°, with 2-theta units.

[0107] In some embodiments, the crystalline (S)-TPMA R-mandelate is characterized by a powder X-ray diffraction pattern that substantially matches that of Figure 11.

[0108] In some embodiments, crystalline(S)-TPMA R-mandelate has a differential scanning calorimetry thermogram with a peak at 129±2°C. In some embodiments, crystalline(S)-TPMA R-mandelate has a differential scanning calorimetry thermogram substantially consistent with that of Figure 12.

[0109] In some embodiments, the crystalline morphology of (S)-TPMA R-mandelate is characterized by a powder X-ray diffraction pattern with peaks at 9.4±0.2°, 14.3±0.2°, and 16.3±0.2°, with 2-theta units, and a powder X-ray diffraction pattern substantially consistent with Figure 11. In some embodiments, the crystalline morphology of (S)-TPMA R-mandelate is characterized by a powder X-ray diffraction pattern with peaks at 9.4±0.2°, 14.3±0.2°, and 16.3±0.2°, with 2-theta units, and has a differential scanning calorimetry thermogram with a peak at 129±2°C. In some embodiments, the crystalline morphology of (S)-TPMA R-mandelate is characterized by a powder X-ray diffraction pattern that includes peaks at 9.4±0.2°, 14.3±0.2°, and 16.3±0.2° with 2-theta units, and has a powder X-ray diffraction pattern that substantially matches that of Figure 12.

[0110] In some embodiments, the substance comprises (S)-TPMA R-mandelate, which has a chiral purity of about 90% or more. In some embodiments, the substance comprises (S)-TPMA R-mandelate, which has a chiral purity of about 95% or more. In some embodiments, the substance comprises (S)-TPMA R-mandelate, which has a chiral purity of about 97.5% or more. In some embodiments, the substance comprises (S)-TPMA R-mandelate, which has a chiral purity of about 99% or more.

[0111] In some embodiments, the substance comprises (S)-TPMA R-mandelate, which has a chemical purity of about 90% or more. In some embodiments, the substance comprises (S)-TPMA R-mandelate, which has a chemical purity of about 95% or more. In some embodiments, the substance comprises (S)-TPMA R-mandelate, which has a chemical purity of about 97.5% or more. In some embodiments, the substance comprises (S)-TPMA R-mandelate, which has a chemical purity of about 99% or more.

[0112] (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine L-tartrate This specification provides (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethaneamine L-tartrate, also known as (S)-TPMA L-tartrate. In some embodiments, (S)-TPMA L-tartrate is crystalline.

[0113] In some embodiments, the crystalline form of (S)-TPMA L-tartrate is characterized by a powder X-ray diffraction pattern that includes peaks at 6.3±0.2°, 12.7±0.2°, and 19.1±0.2°, with 2-theta units. In some embodiments, the crystalline (S)-TPMA L-tartrate is characterized by a powder X-ray diffraction pattern that includes a peak at 6.3±0.2°, with 2-theta units. In some embodiments, the crystalline (S)-TPMA L-tartrate is characterized by a powder X-ray diffraction pattern that includes a peak at 12.7±0.2°, with 2-theta units. In some embodiments, the crystalline (S)-TPMA L-tartrate is characterized by a powder X-ray diffraction pattern that includes a peak at 19.1±0.2°, with 2-theta units. In some embodiments, the crystalline (S)-TPMA L-tartrate is further characterized by a powder X-ray diffraction pattern that further includes peaks at 12.9±0.2°, 16.0±0.2°, 17.1±0.2°, and 17.4±0.2°, with 2-theta units. In some embodiments, the crystalline (S)-TPMA L-tartrate is further characterized by a powder X-ray diffraction pattern that further includes two or more peaks at 18.1±0.2°, 22.9±0.2°, 25.8±0.2°, and 26.3±0.2°, with 2-theta units.

[0114] In some embodiments, crystalline (S)-TPMA L-tartrate is characterized by a powder X-ray diffraction pattern substantially consistent with Figure 14. In some embodiments, crystalline (S)-TPMA L-tartrate has a differential scanning calorimetry thermogram with a peak at 152±2°C.

[0115] In some embodiments, the crystalline (S)-TPMA L-tartrate has a differential scanning calorimetry thermogram substantially consistent with that of Figure 15.

[0116] In some embodiments, the crystalline morphology of (S)-TPMA L-tartrate is characterized by a powder X-ray diffraction pattern with peaks at 6.3±0.2°, 12.7±0.2°, and 19.1±0.2°, with 2-theta units, and a powder X-ray diffraction pattern substantially consistent with Figure 14. In some embodiments, the crystalline morphology of (S)-TPMA L-tartrate is characterized by a powder X-ray diffraction pattern with peaks at 6.3±0.2°, 12.7±0.2°, and 19.1±0.2°, with 2-theta units, and has a differential scanning calorimetry thermogram with a peak at 152±2°C. In some embodiments, the crystalline morphology of (S)-TPMA L-tartrate is characterized by a powder X-ray diffraction pattern with peaks at 6.3±0.2°, 12.7±0.2°, and 19.1±0.2°, with 2-theta units, and has a differential scanning calorimetry thermogram substantially consistent with Figure 15.

[0117] In some embodiments, the substance comprises (S)-TPMA L-tartrate, which has a chiral purity of about 90% or more. In some embodiments, the substance comprises (S)-TPMA L-tartrate, which has a chiral purity of about 95% or more. In some embodiments, the substance comprises (S)-TPMA L-tartrate, which has a chiral purity of about 97.5% or more. In some embodiments, the substance comprises (S)-TPMA L-tartrate, which has a chiral purity of about 99% or more.

[0118] In some embodiments, the substance comprises (S)-TPMA L-tartrate, which has a chemical purity of about 90% or more. In some embodiments, the substance comprises (S)-TPMA L-tartrate, which has a chemical purity of about 95% or more. In some embodiments, the substance comprises (S)-TPMA L-tartrate, which has a chemical purity of about 97.5% or more. In some embodiments, the substance comprises (S)-TPMA L-tartrate, which has a chemical purity of about 99% or more.

[0119] (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine D-tartrate This specification provides (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethaneamine D-tartrate, also known as (S)-TPMA D-tartrate. In some embodiments, (S)-TPMA D-tartrate is crystalline. In some embodiments, the crystalline form of (S)-TPMA D-tartrate is referred to as form DA, form DB, or form DC.

[0120] In some embodiments, the crystalline form DA of (S)-TPMA D-tartrate is characterized by a powder X-ray diffraction pattern including peaks at 7.0±0.2°, 15.0±0.2°, and 17.6±0.2°, with 2-theta units. In some embodiments, the crystalline form DA of (S)-TPMA D-tartrate is characterized by a powder X-ray diffraction pattern including a peak at 7.0±0.2°, with 2-theta units. In some embodiments, the crystalline form DA of (S)-TPMA D-tartrate is characterized by a powder X-ray diffraction pattern including a peak at 15.0±0.2°, with 2-theta units. In some embodiments, the crystalline form DA of (S)-TPMA D-tartrate is characterized by a powder X-ray diffraction pattern including a peak at 17.6±0.2°, with 2-theta units. In some embodiments, the crystalline form DA of (S)-TPMA D-tartrate is further characterized by a powder X-ray diffraction pattern that further includes peaks at 12.9±0.2°, 19.5±0.2°, and 20.8±0.2°, with 2-theta units. In some embodiments, the crystalline form DA of (S)-TPMA D-tartrate is further characterized by a powder X-ray diffraction pattern that further includes two or more peaks at 21.8±0.2°, 22.0±0.2°, 26.0±0.2°, and 27.8±0.2°, with 2-theta units.

[0121] In some embodiments, the crystalline form DA of (S)-TPMA D-tartrate is characterized by a powder X-ray diffraction pattern substantially consistent with that shown in Figure 17.

[0122] In some embodiments, the crystalline form DA of (S)-TPMA D-tartrate has a differential scanning calorimetry thermogram with a peak at 169±2°C. In some embodiments, the crystalline form DA of (S)-TPMA D-tartrate has a differential scanning calorimetry thermogram substantially consistent with that of Figure 20.

[0123] In some embodiments, the crystalline form DA of (S)-TPMA D-tartrate is characterized by a powder X-ray diffraction pattern including peaks at 7.0±0.2°, 15.0±0.2°, and 17.6±0.2° in units of 2-theta, and a powder X-ray diffraction pattern substantially consistent with Figure 17. In some embodiments, the crystalline form DA of (S)-TPMA D-tartrate is characterized by a powder X-ray diffraction pattern including peaks at 7.0±0.2°, 15.0±0.2°, and 17.6±0.2° in units of 2-theta, and has a differential scanning calorimetry thermogram including a peak at 169±2°C. In some embodiments, the crystalline form DA of (S)-TPMA D-tartrate is characterized by a powder X-ray diffraction pattern with peaks at 7.0±0.2°, 15.0±0.2°, and 17.6±0.2°, with 2-theta as the unit, and has a differential scanning calorimetry thermogram substantially consistent with Figure 20.

[0124] In some embodiments, the crystalline form DB of (S)-TPMA D-tartrate is characterized by a powder X-ray diffraction pattern including peaks at 11.6±0.2°, 17.5±0.2°, and 20.7±0.2°, with 2-theta units. In some embodiments, the crystalline form DB of (S)-TPMA D-tartrate is characterized by a powder X-ray diffraction pattern including a peak at 11.6±0.2°, with 2-theta units. In some embodiments, the crystalline form DB of (S)-TPMA D-tartrate is characterized by a powder X-ray diffraction pattern including a peak at 17.5±0.2°, with 2-theta units. In some embodiments, the crystalline form DB of (S)-TPMA D-tartrate is characterized by a powder X-ray diffraction pattern including a peak at 20.7±0.2°, with 2-theta units. In some embodiments, the crystalline form DB of (S)-TPMA D-tartrate is further characterized by a powder X-ray diffraction pattern that further includes peaks at 23.4±0.2°, 29.2±0.2°, and 35.8±0.2°, with 2-theta units. In some embodiments, the crystalline form DB of (S)-TPMA D-tartrate is further characterized by a powder X-ray diffraction pattern that further includes two or more peaks at 26.9±0.2°, 33.4±0.2°, 35.3±0.2°, and 36.7±0.2°, with 2-theta units.

[0125] In some embodiments, the crystalline form DB of (S)-TPMA D-tartrate is characterized by a powder X-ray diffraction pattern substantially consistent with that shown in Figure 18.

[0126] In some embodiments, the crystalline form DB of (S)-TPMA D-tartrate has a differential scanning calorimetry thermogram with a peak at 111±2°C. In some embodiments, the crystalline form DB of (S)-TPMA D-tartrate has a differential scanning calorimetry thermogram substantially consistent with that of Figure 21.

[0127] In some embodiments, the crystalline form DB of (S)-TPMA D-tartrate is characterized by a powder X-ray diffraction pattern including peaks at 11.6±0.2°, 17.5±0.2°, and 20.7±0.2° in units of 2-theta, and a powder X-ray diffraction pattern substantially consistent with Figure 18. In some embodiments, the crystalline form DB of (S)-TPMA D-tartrate is characterized by a powder X-ray diffraction pattern including peaks at 11.6±0.2°, 17.5±0.2°, and 20.7±0.2° in units of 2-theta, and has a differential scanning calorimetry thermogram including a peak at 111±2°C. In some embodiments, the crystalline form DB of (S)-TPMA D-tartrate is characterized by a powder X-ray diffraction pattern with peaks at 11.6±0.2°, 17.5±0.2°, and 20.7±0.2°, with 2-theta units, and has a differential scanning calorimetry thermogram substantially consistent with Figure 21.

[0128] In some embodiments, the crystalline form DC of (S)-TPMA D-tartrate is characterized by a powder X-ray diffraction pattern including peaks at 10.8±0.2°, 15.8±0.2°, and 17.5±0.2°, with 2-theta units. In some embodiments, the crystalline form DC of (S)-TPMA D-tartrate is characterized by a powder X-ray diffraction pattern including a peak at 10.8±0.2°, with 2-theta units. In some embodiments, the crystalline form DC of (S)-TPMA D-tartrate is characterized by a powder X-ray diffraction pattern including a peak at 15.8±0.2°, with 2-theta units. In some embodiments, the crystalline form DC of (S)-TPMA D-tartrate is characterized by a powder X-ray diffraction pattern including a peak at 17.5±0.2°, with 2-theta units. In some embodiments, the crystalline form DC of (S)-TPMA D-tartrate is further characterized by a powder X-ray diffraction pattern that further includes peaks at 20.7±0.2° and 23.6±0.2°, with 2-theta units. In some embodiments, the crystalline form DC of (S)-TPMA D-tartrate is further characterized by a powder X-ray diffraction pattern that further includes two or more peaks at 19.4±0.2°, 21.7±0.2° and 26.8±0.2°, with 2-theta units.

[0129] In some embodiments, the crystalline form DC of (S)-TPMA D-tartrate is characterized by a powder X-ray diffraction pattern substantially consistent with that shown in Figure 19.

[0130] In some embodiments, the crystalline form DC of (S)-TPMA D-tartrate has a differential scanning calorimetry thermogram with a peak at 185±2°C. In some embodiments, the crystalline form DC of (S)-TPMA D-tartrate has a differential scanning calorimetry thermogram substantially consistent with that of Figure 22.

[0131] In some embodiments, the crystalline form DC of (S)-TPMA D-tartrate is characterized by a powder X-ray diffraction pattern including peaks at 10.8±0.2°, 15.8±0.2°, and 17.5±0.2° in units of 2-theta, and a powder X-ray diffraction pattern substantially consistent with Figure 19. In some embodiments, the crystalline form DC of (S)-TPMA D-tartrate is characterized by a powder X-ray diffraction pattern including peaks at 10.8±0.2°, 15.8±0.2°, and 17.5±0.2° in units of 2-theta, and has a differential scanning calorimetry thermogram including a peak at 185±2°C. In some embodiments, the crystalline form DC of (S)-TPMA D-tartrate is characterized by a powder X-ray diffraction pattern with peaks at 10.8±0.2°, 15.8±0.2°, and 17.5±0.2°, with 2-theta units, and has a differential scanning calorimetry thermogram substantially consistent with Figure 22.

[0132] In some embodiments, the substance comprises (S)-TPMA D-tartrate, which has a chiral purity of about 90% or more. In some embodiments, the substance comprises (S)-TPMA D-tartrate, which has a chiral purity of about 95% or more. In some embodiments, the substance comprises (S)-TPMA D-tartrate, which has a chiral purity of about 97.5% or more. In some embodiments, the substance comprises (S)-TPMA D-tartrate, which has a chiral purity of about 99% or more.

[0133] In some embodiments, the substance comprises (S)-TPMA D-tartrate, which has a chemical purity of about 90% or more. In some embodiments, the substance comprises (S)-TPMA D-tartrate, which has a chemical purity of about 95% or more. In some embodiments, the substance comprises (S)-TPMA D-tartrate, which has a chemical purity of about 97.5% or more. In some embodiments, the substance comprises (S)-TPMA D-tartrate, which has a chemical purity of about 99% or more.

[0134] (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine mesylate This specification provides (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine mesylate, also known as (S)-TPMA mesylate. In some embodiments, the crystalline form of (S)-TPMA mesylate is characterized by DVS substantially consistent with that shown in Figure 24.

[0135] In some embodiments, the substance comprises (S)-TPMA mesilate, which has a chiral purity of about 90% or more. In some embodiments, the substance comprises (S)-TPMA mesilate, which has a chiral purity of about 95% or more. In some embodiments, the substance comprises (S)-TPMA mesilate, which has a chiral purity of about 97.5% or more. In some embodiments, the substance comprises (S)-TPMA mesilate, which has a chiral purity of about 99% or more.

[0136] In some embodiments, the substance comprises (S)-TPMA mesilate, which has a chemical purity of about 90% or more. In some embodiments, the substance comprises (S)-TPMA mesilate, which has a chemical purity of about 95% or more. In some embodiments, the substance comprises (S)-TPMA mesilate, which has a chemical purity of about 97.5% or more. In some embodiments, the substance comprises (S)-TPMA mesilate, which has a chemical purity of about 99% or more.

[0137] (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine L-maleate This specification provides (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethaneamine L-maleate, also known as (S)-TPMA L-maleate.

[0138] In some embodiments, the substance comprises (S)-TPMA L-maleate, which has a chiral purity of about 90% or more. In some embodiments, the substance comprises (S)-TPMA L-maleate, which has a chiral purity of about 95% or more. In some embodiments, the substance comprises (S)-TPMA L-maleate, which has a chiral purity of about 97.5% or more. In some embodiments, the substance comprises (S)-TPMA L-maleate, which has a chiral purity of about 99% or more.

[0139] In some embodiments, the substance comprises (S)-TPMA L-maleate, which has a chemical purity of about 90% or more. In some embodiments, the substance comprises (S)-TPMA L-maleate, which has a chemical purity of about 95% or more. In some embodiments, the substance comprises (S)-TPMA L-maleate, which has a chemical purity of about 97.5% or more. In some embodiments, the substance comprises (S)-TPMA L-maleate, which has a chemical purity of about 99% or more.

[0140] (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethaneamine free base This specification provides (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethaneamine free base, also referred to as (S)-TPMA or (S)-TPMA free base. In some embodiments, the (S)-TPMA free base is crystalline.

[0141] In some embodiments, the crystalline form of (S)-TPMA free base is characterized by a powder X-ray diffraction pattern containing peaks at 13.6±0.2°, 16.4±0.2°, 20.0±0.2°, and 20.4±0.2°, with 2-theta units. In some embodiments, the crystalline (S)-TPMA free base is characterized by a powder X-ray diffraction pattern containing a peak at 13.6±0.2°, with 2-theta units. In some embodiments, the crystalline (S)-TPMA free base is characterized by a powder X-ray diffraction pattern containing a peak at 16.4±0.2°, with 2-theta units. In some embodiments, the crystalline (S)-TPMA free base is characterized by a powder X-ray diffraction pattern containing a peak at 20.0±0.2°, with 2-theta units. In some embodiments, the crystalline (S)-TPMA free base is characterized by a powder X-ray diffraction pattern that includes a peak at 20.4±0.2°, with 2-theta units. In some embodiments, the crystalline (S)-TPMA free base is further characterized by a powder X-ray diffraction pattern that includes peaks at 22.4±0.2°, 23.2±0.2°, and 27.3±0.2°, with 2-theta units.

[0142] In some embodiments, the crystalline (S)-TPMA free base is characterized by a powder X-ray diffraction pattern that substantially matches that of Figure 32.

[0143] In some embodiments, the crystalline (S)-TPMA free base is characterized by a powder X-ray diffraction pattern containing peaks at 13.6±0.2°, 16.4±0.2°, 20.0±0.2°, and 20.4±0.2°, with 2-theta units, and a powder X-ray diffraction pattern substantially consistent with Figure 32.

[0144] In various embodiments, the present invention provides a method for producing (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethaneamine hydrochloride as crystalline form A. In various embodiments, the method for producing (S)-TPMA HCl of form A begins with (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethaneamine, and in various other embodiments, it begins with a substantially racemic (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethaneamine.

[0145] In various embodiments, the present invention provides a method for producing (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethaneamine hydrochloride as a crystalline form A having various particle size distributions.

[0146] Examples 1A-1C provide and illustrate various embodiments of the method for producing (S)-TPMA HCl of form A. Example 2 provides and illustrates the method for producing (S)-TPMA HCl of form A with various particle size distributions.

[0147] Racemic (4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethaneamine HCl: [ka] The synthesis of is disclosed in US 8,710,245. In the 245 patent, the racemic mixture is synthesized by column chromatography into (R) and (S) enantiomers: [ka] (R) Enantiomer (S) Enantiomer It is divided into (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethaneamine. The free base of (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethaneamine is a yellow oily substance that deteriorates over time when exposed to air.

[0148] In various embodiments of the manufacturing method of the present invention, the balance of polymorphs A and B is substantially pure polymorph form A by controlled addition of about 5% to about 10% HCl solution in isopropanol to a solution of (S)-TPMA free base in isopropanol at a temperature of 20°C to 60°C, preferably about 40°C. In various embodiments, the controlled addition is preferably carried out as a logarithmic addition in which the HCl solution is initially added slowly and the rate steadily increases. In various embodiments, the HCl addition rate is such that 10% of the HCl solution is added over a first period of about 10 minutes to about 90 minutes, 30% of the HCl solution is added over a second period of about 10 minutes to about 90 minutes, and the remaining HCl solution is added over a third period of about 10 minutes to about 90 minutes.

[0149] In various embodiments, slow addition of the acidic solution in a logarithmic addition profile (e.g., a slower supersaturation rate), higher operating temperature, lower starting free base solution concentration, and higher water content in the crystallization mixture promotes the formation of larger crystals of (S)-TPMA HCl of form A; conversely, lower operating temperature, higher free base solution concentration, and lower water content in the crystallization mixture promote the formation of smaller crystals of (S)-TPMA HCl of form A. It should be understood that the mean, representative, and / or median particle size is generally not the sole determinant of the desired PSD, and the width of the PSD is often important.

[0150] The inventors have also found a method for adjusting the particle size distribution of crystalline (S)-TPMA hydrochloride, particularly crystalline (S)-TPMA hydrochloride of form A, to a desired range, for example, a PSD preferred for providing a tablet compression and / or excellent dissolution rate. In various embodiments, it has been found that the particle size distribution of (S)-TPMA hydrochloride can be adjusted by (i) the rate of HCl addition during the formation of (S)-TPMA HCl (e.g., step 4b of Scheme 4); (ii) the concentration of (S)-TPMA free base in the solution before HCl addition (compound F concentration between steps 4a and 4b of Scheme 4); (iii) the temperature of the solution during HCl addition; (iv) the water content of the crystallization mixture; and (v) the reaction process.

[0151] Figures 7A, 7B, 8A, 8B, 8C, and 9A show various PSD data for Form A (S)-TPMA HCl obtained under various conditions, which will be further examined in Example 2. The PSD data in Figures 7A, 7B, 8A, 8B, and 8C were obtained by laser diffraction particle sizing technique using a Malvern Mastersizer 2000 analyzer, and the PSD data in Figure 9A were obtained by laser diffraction particle sizing technique using a Horiba LA-920 instrument. All data are expressed as volume % as a function of particle size.

[0152] It has been found that the PSD of crystals of (S)-TPMA HCl of form A can be affected in various embodiments by the supersaturation formation rate (e.g., controlled by the dosing profile of the HCl solution in step 4b of scheme 4), the operating temperature, the water content, and the reaction process (e.g., mixing, sonication, etc.). For example, in various embodiments, it has been found that sonication during the addition of HCl to form (e.g., step 4b of scheme 4) can dramatically reduce the final (S)-TPMA HCl crystal size of form A (e.g., D50 = 20-30 μm) by promoting nucleation during the HCl addition process.

[0153] In various embodiments of the reactive crystallization of (S)-TPMA HCl, the supersaturation formation rate can be directly controlled by the rate of addition of the HCl solution; faster dosing (addition of HCl) promotes the formation of smaller crystals, while slower dosing promotes the formation of larger crystals. However, faster dosing results in a broader PCD distribution.

[0154] In various embodiments, the operating temperature can be used to influence the kinetic behavior of nucleation and crystal growth, as well as solubility. Higher temperatures have been found to increase the average crystal size and width of PSDs.

[0155] In various embodiments, the starting (S)-(-)-TPMA free base concentration prior to reactive recrystallization can be used to influence the kinetic behavior of nucleation and crystal growth. It has been found that higher starting (S)-(-)-TPMA free base concentrations lead to a decrease in both median particle size and PSD width.

[0156] In Example 1A and the experiments described above, the solvent is isopropanol, but in various embodiments, however, other alkyl alcohols with four or fewer carbon atoms, such as n-propanol, isopropanol, and n-butanol, may be used depending on temperature / solubility.

[0157] In various embodiments, the (S)-TPMA free base is dissolved in a solvent system containing 90% to 100% isopropanol.

[0158] In various embodiments, the solvent system consists of 90% to 99% isopropanol and the remainder is water. In various embodiments, the solvent system consists of 93% to 97% isopropanol and the remainder is water.

[0159] In various embodiments, the solvent system is >99% isopropanol. In various embodiments, the presence of up to about 5% water results in crystals of (S)-TPMA HCl polymorph A that are cubic rather than hexagonal in morphology. In various embodiments, the method of the present invention provides (S)-TPMA HCl crystals of form A having an increased cubic morphology. In various embodiments of the compositions, pharmaceuticals, and formulations of the present invention, (S)-TPMA HCl crystals of form A having an increased cubic morphology are preferred because they are more fluid than the hexagonal morphology and offer advantages in the formation of certain solid oral dosage forms, for example, in certain tableting operations.

[0160] In Example 1A, the hydrogen chloride in isopropanol was prepared at 6% by weight, but other concentrations could also be used; for example, in various embodiments, about 4% to about 10%. In various embodiments, alkyl alcohols with four or fewer carbon atoms, such as isopropanol, could be added in stoichiometric ratios from 1.0:1 to 1.2:1 based on the amine in (S)-TPMA.

[0161] It has been observed that the concentration of (S)-TPMA free base in alkyl alcohols with four or fewer carbon atoms, such as isopropanol, is controllable over a wide range. In various embodiments, the concentration of the (S)-TPMA free base solution is about 5.0% to 25.0% by weight, and preferably about 10% to about 15%. In various embodiments, the concentration of the (S)-TPMA free base solution is about 10.0%, about 11.0%, about 13.0%, or in some cases, about 15.0% by weight.

[0162] By referring to the teachings herein, those skilled in the art will understand that very dilute solutions of (S)-TPMA free base are likely to yield lower yields due to the limited solubility of (S)-TPMA hydrochloride in alkyl alcohols with four or fewer carbon atoms, such as isopropanol.

[0163] In some embodiments, the particle size distribution of the (S)-TPMAHCl crystals of form A can be controlled by a balance between reactant addition rate, local and global supersaturation, mass transfer, and crystal surface area. For example, it has been found that addition profiles such as Mullin-Nyvlt, higher operating temperatures, lower free base solution concentrations, the presence of water in the solvent system, and slow addition of the acid solution with seeding promote the formation of larger polymorphic form A(S)-TPMAHCl crystals, while sonication during supersaturation promotes the formation of smaller polymorphic form A(S)-TPMAHCl crystals.

[0164] In various embodiments, the present invention provides compounds comprising form A crystals of (S)-TPMAHCl having a particle size distribution (for example, measured by laser diffraction as shown in Example 2) of a median (D50) of about 15 μm to about 30 μm, a D10 greater than about 10 μm, and a D90 less than about 40 μm; and preferably a D50 of about 20 μm to about 30 μm.

[0165] In various embodiments, the present invention provides compounds comprising Form A crystals of (S)-TPMA HCl having a particle size distribution (measured by laser diffraction, for example, as shown in Example 2) with a median (D50) of about 15 μm to about 30 μm (and preferably about 20 μm to about 30 μm), and a span of less than 1.75, less than 1.5, less than 1, or less than 0.8.

[0166] In various embodiments, the present invention provides compounds comprising form A crystals of (S)-TPMAHCl having a particle size distribution (for example, measured by laser diffraction as shown in Example 2) of a median (D50) of about 100 μm to about 135 μm (and preferably D50 of about 100 μm to about 110 μm), D10 greater than about 60 μm and D90 less than about 165 μm; and preferably D10 greater than about 70 μm and D90 less than about 150 μm.

[0167] In various embodiments, the present invention provides compounds comprising form A crystals of (S)-TPMAHCl having a particle size distribution (measured by laser diffraction, for example, as shown in Example 2) with a median (D50) of about 100 μm to about 135 μm (and preferably about 100 μm to about 110 μm), as well as a span of less than 1.75, less than 1.5, less than 1, or less than 0.8.

[0168] In various embodiments, the present invention provides compounds comprising form A crystals of (S)-TPMAHCl having a particle size distribution (for example, measured by laser diffraction as shown in Example 2) of a median (D50) of about 135 μm to about 180 μm (and preferably D50 of about 160 μm to about 170 μm), a D10 greater than about 100 μm and a D90 less than about 250 μm; and preferably a D10 greater than about 110 μm and a D90 less than about 230 μm.

[0169] In various embodiments, the present invention provides compounds comprising form A crystals of (S)-TPMA HCl having a particle size distribution (measured by laser diffraction, for example, as shown in Example 2) with a median (D50) of about 135 μm to about 180 μm (and preferably a D50 of about 160 μm to about 170 μm), and a span of less than 1.75, less than 1.5, less than 1, or less than 0.8.

[0170] In various embodiments, the present invention provides compounds comprising form A crystals of (S)-TPMAHCl having a particle size distribution (as measured by laser diffraction, for example, as shown in Example 2) of a median (D50) of about 185 μm to about 23 μm (and preferably a D50 of about 190 μm to about 220 μm), a D10 greater than about 110 μm and a D90 less than about 350 μm; and preferably a D10 greater than about 120 μm and a D90 less than about 340 μm.

[0171] In some embodiments, D10 is greater than about 50 μm. In some embodiments, D10 is greater than about 75 μm. In some embodiments, D10 is greater than about 80 μm. In some embodiments, D10 is greater than about 90 μm. In some embodiments, D10 is greater than about 100 μm. In some embodiments, D10 is greater than about 110 μm. In some embodiments, D10 is greater than about 120 μm. In some embodiments, D10 is greater than about 130 μm. In some embodiments, D10 is greater than about 150 μm. In some embodiments, D90 is greater than about 200 μm. In some embodiments, D90 is greater than about 250 μm. In some embodiments, D90 is greater than about 300 μm. In some embodiments, D90 is greater than about 350 μm. In some embodiments, D90 is greater than about 400 μm. In some embodiments, the median (D50) is within the range of any of the embodiments provided herein, such as about 50 μm to about 400 μm, about 100 μm to about 300 μm, or about 120 μm to about 300 μm.

[0172] In various embodiments, the present invention provides compounds comprising form A crystals of (S)-TPMAHCl having a particle size distribution (measured by laser diffraction, for example, as shown in Example 2) with a median (D50) of about 180 μm to about 230 μm (and preferably a D50 of about 190 μm to about 220 μm), and a span of less than 1.75, less than 1.5, less than 1, or less than 0.8.

[0173] In various embodiments, the present invention provides a compound comprising form A crystals of (S)-TPMA HCl having a PSD (as measured by laser diffraction, for example, as shown in Example 2) having a median (D50) of about 15 μm to about 30 μm, a D10 greater than about 10 μm, and a D90 less than about 40 μm; and preferably a PSD (as measured by laser diffraction, for example, as shown in Example 2) of about 20 μm to about 30 μm, a D50 greater than about 10 μm, and a D90 less than about 40 μm; wherein the method comprises sonication during a supersaturation step of a free base solution of (S)-TPMA for forming (S)-TPMA HCl.

[0174] In various embodiments, the method of the present invention is In various embodiments, we provide Form A crystals of (S)-TPMA HCl having a PSD (measured by laser diffraction, for example, as shown in Example 2) with a median (D50) of about 100 μm to about 230 μm, about 100 μm to about 135 μm, about 135 μm to about 180 μm, or about 180 μm to about 230 μm, as well as having spans of less than 1.75, less than 1.5, less than 1, or less than 0.8; where the method involves the use of logarithmic-like addition of HCl during the reactive recrystallization of (S)-TPMA to form (S)-TPMA HCl. In various embodiments, the logarithmic-like addition includes the addition of about 10% to about 15% of the HCl solution over a first period, the addition of about 30% to about 40% of the HCl solution over a second period after the first period, and the addition of the remainder (about 45% to about 60%) of the HCl solution over a third period after the second period. In various embodiments, the first, second, and third periods are independently in the range of about 10 minutes to about 90 minutes. In various embodiments, the first, second, and third periods are substantially equal to each other, within ±10% of each other.

[0175] In various embodiments, the present invention provides a method for producing (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethaneamine hydrochloride as crystalline form A. In various embodiments, the method is as follows: (a) Dissolve the (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethaneamine free base in a solvent system containing an alkyl alcohol with four or fewer carbon atoms; (b) Adding excess HCl to an alkyl alcohol with four or fewer carbon atoms; and (c) Isolating the crystalline (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine hydrochloride; in various embodiments, the alkyl alcohol is one or more n-propanols, isopropanols and n-butanols, and in various embodiments, the alkyl alcohol is preferably isopropanol.

[0176] In various embodiments of the method for producing (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine hydrochloride as Form A, the method is as follows: (a) Combining racemic-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethaneamine with a stoichiometric excess of (R)-mandelic acid in a solvent; (b) Isolate (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine R-mandelate; (c)(R)-mandelate to release (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethaneamine; (d) Dissolve (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethaneamine in a solvent system containing an alkyl alcohol with four or fewer carbon atoms; (e) Adding HCl to an alkyl alcohol with four or fewer carbon atoms; (f) Isolating the crystalline (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethaneamine hydrochloride; in various embodiments, the alkyl alcohol is one or more n-propanols, isopropanols, and n-butanols, and in various embodiments, the alkyl alcohol is preferably isopropanol.

[0177] The synthesis of (S)-TPMA hydrochloride is disclosed in US 8,710,245. The synthesis procedure reported in the 245 patent is used to produce small amounts of the compound. This procedure requires chromatographic separation, which is generally not suitable for large-scale production. For example, normal-phase or chiral-phase chromatographic separation is not practical for large-scale production. A resolution procedure was developed to replace chiral chromatographic separation. The resolution procedure is robust, practical, and easy to scale up, and is routinely used in the production of chiral compounds at various scales. For the large-scale production of (S)-TPMA hydrochloride, R-mandelic acid-mediated resolution of the (S)-TPMA free base was developed as an alternative to chiral chromatographic separation of N-Boc-TPMA.

[0178] The procedure in the 245 patent is carried out on a 1g scale. Workup of the reaction includes neutralization of the product (S)-TPMA triflate salt with potassium carbonate, and the resulting free base is treated with methanolic HCl to produce (S)-TPMA HCl salt, which is isolated after the addition of the poor solvent MTBE. The method described herein provided high-purity (S)-TPMA triflate. Typically, (S)-TPMA triflate is obtained with a purity of >99.2% and a yield of 76–80%. The method described herein is shorter in time because it does not require the preparation of a free base and further conversion of it to the (S)-TPMA HCl salt. 2-methyl THF is a suitable solvent for this step. MTBE is used as a poor solvent for the crystallization step. 2-methyl THF is a much more desirable green solvent than 1,4-dioxane, a Class II solvent used in the method of the '245 patent.

[0179] In some embodiments, the present invention relates to a method for producing (4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethaneamine, which is as follows: (a) Reacting 2-(thiophen-3-yl)ethane-1-ol with N-methylaminoacetaldehyde dimethyl acetal and trifluic acid to obtain (4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethaneamine triflate; and (b) Reacting (4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethaneamine triflate with a base to obtain (4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethaneamine; This provides a method that includes this.

[0180] In some embodiments, the present invention provides a method for producing (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethaneamine, which is as follows: (a) Reacting 2-(thiophen-3-yl)ethane-1-ol with N-methylaminoacetaldehyde dimethyl acetal and trifluic acid to obtain (4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethaneamine triflate; (b) Reacting (4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethaneamine triflate with a base to obtain (4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethaneamine; (c) Reacting (4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethaneamine with (R)-mandelic acid to obtain (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethaneamine (R)-mandelate; and (d)(S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethaneamine (R)-mandelate is reacted with a base to obtain (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethaneamine; This provides a method that includes this.

[0181] In some embodiments, the present invention provides a method for producing (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethaneamine, comprising reacting (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethaneamine with an acid. For example, reacting (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethaneamine with HCl produces the corresponding HCl salt.

[0182] In some embodiments, the present invention provides a method for producing (4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethaneamine triflate. In some embodiments, the method comprises reacting 2-(thiophen-3-yl)ethane-1-ol with N-methylaminoacetaldehyde dimethyl acetal and trifluic acid to provide (4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethaneamine triflate. In some embodiments, the reaction may be carried out in the presence of a solvent. The solvent may be an ether such as 2-methyltetrahydrofuran. In some embodiments, the reaction of 2-(thiophen-3-yl)ethane-1-ol with N-methylaminoacetaldehyde dimethyl acetal and trifluic acid is carried out at a temperature of about 50°C to 100°C. In some embodiments, the temperature is about 75°C to 85°C, for example, 80°C. In some embodiments, the method involves reacting 2-(thiophen-3-yl)ethane-1-ol with sulfuric acid, N-methylaminoacetaldehyde dimethyl acetal, and trifluic acid.

[0183] In some embodiments, the present invention provides a method for producing (4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethaneamine. In some embodiments, the method comprises reacting (4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethaneamine triflate with a base to provide (4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethaneamine. In some embodiments, the base is an alkali metal base such as KOH. In some embodiments, the reaction is carried out in the presence of a solvent. The solvent may be an ether such as methyl t-butyl ether.

[0184] In some embodiments, the present invention provides a method for producing (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethaneamine (R)-mandelate. In some embodiments, the method comprises reacting (4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethaneamine with (R)-mandelic acid to provide (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethaneamine (R)-mandelate. In some embodiments, the reaction is carried out in a polar aprotic solvent such as acetonitrile and acetone, or a mixture thereof.

[0185] In some embodiments, the present invention provides a method for producing (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethaneamine. In some embodiments, the method comprises reacting (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethaneamine (R)-mandelate with a base to provide (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethaneamine. In some embodiments, the base is an alkali metal base such as KOH. In some embodiments, the reaction is carried out in a solvent. The solvent may be an ether or water, or a mixture thereof. In some embodiments, the solvent is an ether such as methyl t-butyl ether.

[0186] Example 1A: Preparation of crystalline form A of (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethaneamine HCl

[0187] Scheme 1: Preparation of (4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethaneamine trifluoromethanesulfonate [ka]

[0188] 3-thiophenethanol (compound A) (77 g) was added to a solution of N-methylaminoacetaldehyde dimethyl acetal (69 g) in 2-methyltetrahydrofuran (2Me THF) (595 ml, 508 g). After stirring for 5 minutes, trifluoromethanesulfonic acid (99 g, 58.2 ml) was added. It is important to recognize that trifluoromethanesulfonic acid is an extremely toxic substance. The reaction mixture was heated under reflux for 1 hour (80 ± 2 °C). The reaction mixture was then distilled under atmospheric pressure for 4–8 hours to remove the by-product methanol and reduce the volume of the reaction mixture to the target 460 ml. The reaction was considered complete when the remaining compound 1B was less than 1.0% by HPLC analysis of the sample (HPLC peak area %) of the peaks of the target compounds A, B, and C.

[0189] If the amount of compound B was 1% or more, an appropriate amount of 2-methyl THF was added, and distillation was continued until the target volume was reached. If the target volume was reached before the end of the reaction (approximately 4 hours), 300 ml of 2-methyl THF was added to the reactant, and distillation was continued. After the reaction was complete, the reactant was cooled to approximately 40-50°C and concentrated to a target volume of 325 ml under vacuum distillation. Next, toluene (218 g (325 ml)) was added over approximately 15 minutes, and the resulting reaction slurry was stirred at 50±2°C for 1 hour, and then cooled linearly to 20±2°C over 1 hour and 45 minutes while stirring. The slurry was filtered, and the product cake was washed with 2-methyl THF and toluene (1:1 volume / volume). The wet cake was dried under vacuum at 40±5°C until the weight became constant, producing a racemic TPMA trifluoromethanesulfonate (compound C) as an off-white solid in approximately 79% yield.

[0190] Scheme 2: Preparation of (S)-(-)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine(R)-mandelate [ka]

[0191] In various embodiments, di-p-toluyl-D-tartaric acid (D-DTTA) was used as a resolving agent to produce (S)-TPMA-D-DTTA salts, and the inventors found that the separation was kinetically achieved by using D-DTTA. However, in scheme 2 of this embodiment, it was found that the crystallization of the diastereomer using (R)-mandelic acid was a thermodynamic separation.

[0192] To a suspension of TPMA trifluoromethanesulfonate (compound 1C) (555.3 g) in methyl tert-butyl ether (MTBE, 1668 ml), 1.77 N aqueous KOH (1076 g) was added. After stirring for 10 minutes, the pH was checked, and if it was less than 13, a small amount of 1.77 N KOH was added until the pH was 13 or higher. The aqueous and organic layers were allowed to stand and separated, and each was collected separately. The organic phase layer (upper) of MTBE was retained for further processing. The aqueous phase layer (lower) was extracted twice with MTBE (first 835 ml and second 150 ml), and the organic (MBBE) layer was collected each time. The MTBE layers (organic layers) were combined, washed with 20% NaCl aqueous solution (492.9 g), stirred, and the phases were allowed to stand for 10 minutes. The aqueous layer was removed, and the remaining MTBE organic layer was distilled under atmospheric pressure to reduce the reaction volume to the target level of 1.9 L. After completion, the process stream was cooled to approximately 45°C and concentrated to a target volume of 890 ml under vacuum distillation while maintaining the temperature at 35-45°C. The water content after vacuum evaporation was found to be approximately 0.37 wt%. Next, filtration was performed, and insoluble materials were removed using a washing solution of MTBE (204 ml), and the process stream (filtrate) was transferred to a clean reaction vessel. Acetonitrile (2512 mL) was added, and solvent exchange was carried out by vacuum distillation to a target volume of 800 ml at 35-45°C, the reactor was washed with acetonitrile (150 ml), and added to the process stream. Next, if necessary, acetonitrile was added to the acetonitrile solution of TPMA free base (compound D) to obtain approximately 33 wt% compound D.

[0193] A solution of (R)-mandelic acid (250.3 g) in acetone (1828 ml) was heated to 48 ± 2 °C. The acetone solvent can be replaced with acetonitrile. Then, a solution of TPMA free base in acetonitrile (a solution of compound D (302.1 g) in acetonitrile (917.7 g)) was added at a rate that maintained the reaction temperature below 51 °C. After stirring at 48 ± 2 °C for about 10 minutes, the process stream was cooled to 45 ± 2 °C, and 1.5 g of (S)-TPMA (R)-mandelate crystal species was added. The process stream was held at 45 ± 2 °C for about 30 minutes and then linearly cooled to 21 ± 2 °C over 90 minutes. After holding at 45 ± 2 °C for about 30 minutes, the process stream was linearly cooled to 10 ± 2 °C over 45 minutes. Next, the reaction slurry was stirred at 10±2°C for 60 minutes, filtered, and the product cake was washed with a mixture of acetone / CH3CN (2.3:1 wt / wt). The wet cake was dried under vacuum at 40±2°C until the weight was constant, yielding crude (S)-TPMA·(R)-mandelate (compound E) as a white crystalline solid in approximately 41% yield.

[0194] Scheme 3: Recrystallization of (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethaneamine (R)-mandelate

[0195] Scheme 3 provides a method for recrystallizing (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethaneamine (R)-mandelate ((S)-TPMA (R)-mandelate). It should be understood that various other recrystallization solvents may be used. Scheme 3 in this example provides the use of acetone, and the inventors have found that acetone can provide a combination of sufficiently high yield and effective removal of problematic impurities. In various embodiments, the amount of acetone was selected based on the solubility of (S)-TPMA (R)-mandelate in acetone at reflux temperature, preferably the minimum amount of acetone required to dissolve the crude (S)-TPMA (R)-mandelate at reflux temperature. In various embodiments, the solvent is acetonitrile instead of acetone, where (S)-TPMA (R)-mandelate dissolves at about 52 ± 2°C. In various embodiments, Scheme 3 demonstrates seed-induced crystallization, in which linear cooling is performed from 47±2°C to 21±2°C over 90 minutes, followed by holding at 21±2°C for 30 minutes, followed by linear cooling to 10±2°C over 45 minutes, and then holding at 10±2°C, preferably for a minimum of 1 hour. [ka]

[0196] A slurry of crude (S)-TPMA (R)-mandelate (Compound E) (200.1 g) from Scheme 2 in acetone (4205 ml) was subjected to heating to about 56 °C (the boiling point of acetone) and stirred until a clear solution was obtained. The solution was cooled to 47 ± 2 °C over about 20 minutes, and then a seed crystal of (S)-TPMA (R)-mandelate was added. The process stream was stirred at 47 ± 2 °C for about 30 minutes and cooled linearly to 21 ± 2 °C over 90 minutes. After holding at 21 ± 2 °C for about 30 minutes, the slurry was cooled linearly over 45 minutes, then stirred at 10 ± 2 °C for 1 hour, filtered, and the product cake was washed with acetone (twice with 401 ml each). The wet cake was dried under vacuum at about 40 ± 2 °C until the weight became constant, and (S)-TPMA (R)-mandelate (purified Compound E) was produced as a white crystalline solid and obtained in a yield of about 77%.

[0197] Scheme 4: Formation of Crystal Form A of (S)-(-)-(4,5-Dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine Hydrochloride [Chemical formula]

[0198] Scheme 4 of this example provides reaction crystallization of (S)-(-)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine HCl ((S)-TPMA·HCl) as Crystal Form A. The inventors have found that when (S)-TPMA·HCl crystallizes, it exhibits two different forms (polymorphs), the first block-like crystal (Form A) and the second needle-like crystal (Form B). Based on single crystal x-ray diffraction studies, as described herein, Form A has a monoclinic crystal system, while Form B has an orthorhombic crystal system. The inventors have found that Form A is the stable form under the reaction conditions of this example and have found a method to avoid the formation of Form B. In various embodiments, (S)-TPMA·(R)-mandelate is first converted to the free base and a slurry is formed by the addition of HCl.

[0199] To a suspension of (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine(R)-mandelate (compound E) (100 g) from Scheme 3 in MTBE (305 ml), 172.5 ml of 10% KOH aqueous solution was added. After stirring at 20±2°C for 10 minutes, the aqueous layer and organic layer were separated. The organic MTBE (upper) layer was set aside for further processing. If the pH of the aqueous layer was less than 13, a small amount of 10% KOH solution was added to raise the pH to 13. The aqueous (lower) layer was back-extracted twice with MTBE (first with 208 ml of MTBE, then with 155 ml of MTBE), with the organic layer set aside each time for further processing. The set aside organic layers were combined, and the combined organic layer was subjected to azeotropic distillation to remove water, and then distilled to a target volume of 140 ml under atmospheric pressure. Next, the process stream was filtered to remove insoluble materials (e.g., salts precipitated due to the removal of water), and the filtrate was transferred to a clean reaction vessel. Isopropanol (775 ml) was added (to bring the total volume of the process stream to approximately 1030 ml), and solvent exchange was carried out by vacuum distillation at a temperature below 45°C to obtain a 16-19% solution of (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethaneamine in isopropanol.

[0200] In various embodiments, the amount of isopropanol added was selected to adjust the weight percentage concentration of the free base (compound F) to 16-19%. The reaction mixture was cooled to 20±2°C, subjected to polish filtration, washed with 78 ml of isopropanol, and transferred to a clean reaction vessel. Next, a 6% (w / w) solution of HCl in isopropanol (201.6 g) was added to the reaction vessel over 45 minutes at approximately 20±2°C. In various embodiments, it should be noted that the target amount of HCl is approximately 10% in excess of the molar equivalent of the free base (compound F). The HCl was added as follows: first 10% over 15 minutes, then 30% over 15 minutes, and then the remainder over 15 minutes. A receding curve impeller was used in a 5 L scale reaction vessel at 160 rpm to 270 rpm with a process stream volume of approximately 740 ml, producing particles of reasonable size and particle distribution without observing any apparent aggregation. A slurry was formed and linearly heated to 40 ± 2 °C over 20 minutes, and held at 40 ± 2 °C for approximately 30 minutes. It was then linearly cooled to 20 ± 2 °C over 20 minutes. After stirring at 20 ± 2 °C for approximately 30 minutes, the slurry was filtered, and the product cake was washed with isopropanol (first 86 ml, then 92 ml). The cake was dried under vacuum at 40 ± 2 °C until the weight was constant, yielding (S)-(-)-TPMA hydrochloride (compound G) as a white crystalline solid in approximately 84% yield.

[0201] In step 4b of Scheme 4, slow addition, which results in a low supersaturation rate, favors the formation of the desired bulky (S)-(-)-TPMA·HCl crystals (form A) while reducing the formation of undesirable needle-like crystals (form B). Higher temperatures also favor the formation of bulky crystal form A compared to form B.

[0202] The (S)-(-)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine hydrochloride (compound G) obtained in Example 1A 1The 1H NMR spectrum is shown in Figure 10 and has the following characteristics: 1 1H NMR (300 MHz, DMSO-d6); δ (ppm): 2.53 (s, 3H, -CH3); 2.5 - 2.8 (m, 2H, -CH2-); 3.15 - 3.37 (2dd, 2H, CH2-NH); 3.77 and 4.13 (2ddd, 2H, CH2-O); 5.19 (dd, 1H, O-CH-C=); 6.95 (d, J = 5 Hz, 1H, HC=); 7.49 (dd, J = 5 Hz, 1H, HC=); 9.12 (br, 2H, NH2 + )

[0203] Example 1B: Another preparation of (4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine trifluoromethanesulfonate

[0204] 40 g, 0.31 mol of 2-(thiophen-3-yl)ethanol was placed in a 1 L reaction vessel equipped with a mechanical stirrer, an N2 inlet, and a thermocouple. 38.8 g, 0.28 mol of N-methylaminoacetaldehyde dimethyl acetal and 600 mL of 2-methyltetrahydrofuran were added. The resulting solution was cooled to approximately 5°C. Sulfuric acid (111.3 g, 1.13 mol) was slowly added while maintaining the reaction temperature below 20°C. The reaction mixture was heated to 35°C and stirred for 4 hours. HPLC analysis of the reaction showed approximately 31% formation of the product (4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine (TPMA). The reaction mixture was cooled to room temperature, and the solvent was removed under vacuum. The resulting residue was diluted with methyl tert-butyl ether (MTBE) (300 mL). The mixture was cooled to approximately 10°C, and 25% by weight of NaOH (500 mL) was added while maintaining the reaction temperature below 30°C. The mixture was stirred for 20 minutes, and the layers were separated. The aqueous layer was extracted twice with MTBE (150 mL and 100 mL). The organic layers were then combined and concentrated by removing the solvent by distillation. The concentrated organic layers were then cooled to 0°C, and trifluic acid (20 g, 0.13 mol) was slowly added while maintaining the reaction temperature below 10°C. The resulting slurry was stirred at 0°C for 30 minutes. The slurry was filtered, the wet cake was washed with MTBE (2 x 20 mL), and dried under vacuum to obtain TPMA-trifluoromethanesulfonate (13.0 g, yield 13.75%, purity 97%) as a white solid.

[0205] 1 H NMR (400MHz, DMSO-d6) δ ppm 2.62(s,3H), 2.64-2.76(m,2H), 3.22(dd,J=12.91, 9.78Hz,1H), 3.40(dd,J=12.91, 2.74Hz,1H), 3.79(ddd,J=11.54, 8.80, 4 .30Hz,1H), 4.00-4.20(m,1H), 5.09(dd,J=9.59, 1.76Hz,1H), 6.95(d,J=5.09Hz,1H), 7.50(d,J=5.02Hz,1H), 8.59(brs,2H)

[0206] 13 C NMR (101MHz, DMSO-d6) δ ppm 25.53, 33.02, 52.19, 62.73, 70.23, 124.62, 127.54, 131.01, 134.87

[0207] Example 1C. Another preparation of (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethaneamine (R)-mandelate

[0208] To a slurry of TPMA-trifluoromethanesulfonate (1.0 g, 3.0 mmol) in MTBE (3 mL), 10% KOH (0.217 g, 3.8 mmol in 2 mL of water) was added and the mixture was stirred for 15 minutes. The organic layer was separated, and the aqueous layer was extracted with MTBE (2 x 3 mL). The organic layers were combined and washed with 20 wt% aqueous NaCl (1 x 2 mL). The organic layers were dried over sodium sulfate, filtered, and evaporated to dryness to obtain (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethaneamine free base as a colorless oil (0.473 g, 86.2%). This was dissolved in acetonitrile (2.4 mL) and added to a solution of R-mandelic acid (0.392 g, 2.5 mmol) in acetonitrile (2.4 mL). The resulting solution was heated to 38°C, and 15 mg of (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine (R)-mandelate crystals were added. The mixture was stirred at 38°C for 30 minutes, then cooled to room temperature, and then to 10°C. The slurry was stirred at 10°C for 30 minutes and filtered. The wet cake was washed with cold (10°C) acetonitrile (2 x 1 mL) and dried to obtain crude (S)-TPMA (R)-mandelate as a white solid (0.292 g, yield 33.75%, purity 96%, R:S isomer ratio 9.3:91.7).

[0209] 1H NMR (400MHz, DMSO-d6) δ ppm 2.49(s,3H), 2.57-2.79(m,2H), 3.00-3.17(m,2H), 3.69(ddd,J=11.64, 8.90, 4.50Hz,1H), 4.08(ddd,J=11.35, 5.48, 3.52Hz,1H), 4.66(s,1H), 4.89-5.07(m,1H), 6.91(d,J=4.70Hz,1H), 7.13-7.32(m,3H), 7.36-7.44(m,3H)

[0210] 13 C NMR (101MHz, DMSO-d6) δ ppm 25.63, 33.72, 53.42, 62.70, 71.26, 73.20, 124.23, 126.36, 126.42, 127.29, 127.52, 132.48, 134.24, 142.85, 174.78

[0211] Example 2: Adjustment of the crystal grain size distribution of Form A of (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethaneamineHCl

[0212] A series of experiments were conducted for various forms of reactive recrystallization (e.g., Scheme 4 in Example 1A) to develop a method and provide various particle size distributions of crystals of form A of (S)-(-)-TPMA·HCl. The reaction conditions were substantially the same as those described in Example 1A with respect to Scheme 4, except that they were modified as described in this Example 2.

[0213] The PSD data for this Example 2 were obtained by subjecting a sample dispersed in a solvent to laser diffraction particle size measurement. The data in Figures 7A, 7B, 8A, 8B, and 8C were obtained using a Malvern Mastersizer 2000 analyzer, and the data in Figure 9A was obtained using a Horiba LA-920 laser diffraction particle size analyzer. Particle size and values ​​such as D(4,3), D10, D50, and D90 are all expressed in micrometers (μm), and all distributions are shown as volume % as a function of particle size.

[0214] (S)-TPMA·HCl samples were dispersed in a solution of Span®-85 (sorbitan trioleate) and hexane. In this example, the dispersant solution was a solution of Span®-85 (2 g) in hexane (1 liter), and a 0.2% (w / v) Span®-85 solution in hexane was prepared. All samples were gently sieved through a #30 mesh screen before being added to the dispersant solution.

[0215] The suspension for analysis was prepared by adding a 0.2% SPAN-85 dispersant solution in approximately 5 mL of hexane to a 1.5–3 g sieved (S)-TPMA·HCl sample, and slowly stirring the solution until all solids were wet. Next, 35 mL of a 0.2% SPAN-85 dispersant solution in hexane was added, and the solution was mixed for at least 1 minute before measurement using an impeller set to 500 rpm to prepare the suspension described above. The actual amount of (S)-TPMA·HCl sample was experimentally determined and adjusted so that when the dispersant solution was added to it and 2–3 mL of the resulting suspension was measured using the instrument, the laser attenuation rate was between 10% and 20%.

[0216] Before measurement, the apparatus was set up, the background was measured, and 2-3 mL of the suspended solution was transferred to the sample cell of the measuring apparatus.

[0217] The data in Figures 7A, 7B, 8A, 8B, and 8C were obtained using a Malvern Mastersizer 2000 analyzer, and Table 6 provides further details on the instrument settings of the Malvern Mastersizer 2000 analyzer used in this example. Corresponding and similar settings were also used for the Horiba LA-920 laser diffraction particle size analyzer, which was used to obtain the data in Figure 9A, specifically the PSD data generated with the Horiba LA-920 using 3% lecithin in Isopar G. Table 6 Settings of Malvern Mastersizer 2000 Analyzer [Table 11]

[0218] Adjustment of supersaturation generation rate

[0219] (S)-(-)-TPMA free base-containing solution (e.g., solution of compound F in Scheme 4) was subjected to reactive recrystallization as the crystalline form of (S)-(-)-TPMA·HCl by adding HCl in isopropanol (IPA), forming supersaturated (S)-(-)-TPMA·HCl and crystallization occurred. Figures 6A and 6B show the addition profiles of various 6% HCl / IPA, which are also summarized in Table 7. The PSDs obtained for the addition profiles of Figures 6A and 6B were measured and are shown in Figures 7A and 7B, respectively. Table 8 provides various PSD parameters of the PSD data shown in Figures 7A and 7B.

[0220] It was found that the logarithmic-like addition of the reagent involved in supersaturation (HCl in IPA) favors the formation of crystals of Form A, and a slower addition rate results in a larger median particle size and a narrower span by PSD. Table 7 Addition profile of HCL IPA solution [Table 12] Table 8 Particle size distribution parameters for addition profile [Table 13]

[0221] Adjustment by temperature

[0222] A solution containing (S)-(-)-TPMA free base (e.g., the solution of compound F in Scheme 4) was subjected to reactive recrystallization as the crystalline form of (S)-(-)-TPMA·HCl salt by adding HCl in isopropanol (IPA) at two different temperatures, 25°C and 40°C. Table 9 provides various PSD parameters for the PSD data measured at these two temperatures.

[0223] It was found that while increasing temperature increases the median and mean grain sizes of Form A crystals of (S)-(-)-TPMA·HCl, heating also increases the PSD span. Table 9 Particle size distribution parameters for various temperatures [Table 14]

[0224] Adjustment by free base concentration

[0225] Solutions containing (S)-(-)-TPMA free base (e.g., a solution of compound F in Scheme 4) were subjected to reactive recrystallization as the crystalline form of (S)-(-)-TPMA·HCl salt by adding HCl in isopropanol (IPA) to three starting concentrations, namely 10.8%, 13.0%, and 15.2% (S)-(-)-TPMA free base. Table 10 provides various PSD parameters of the measured PSD data shown in Figures 8A-8C; here, Figure 8A shows the PSD data at a concentration of 15.2% (S)-(-)-TPMA free base, Figure 8B shows the PSD data at a concentration of 13.0% (S)-(-)-TPMA free base, and Figure 8C shows the PSD data at a concentration of 10.8% (S)-(-)-TPMA free base.

[0226] It was found that increasing the starting concentration of (S)-(-)-TPMA free base decreased both the median particle size and PSD span, while decreasing the starting concentration of (S)-(-)-TPMA free base increased both the median particle size and PSD span. Table 10 Particle size distribution parameters for various free base concentrations [Table 15]

[0227] Adjustment based on water content

[0228] Solutions containing (S)-(-)-TPMA free base (e.g., a solution of compound F in Scheme 4) were subjected to reactive recrystallization as a crystalline form of (S)-(-)-TPMA·HCl salt by adding HCl in isopropanol (IPA) to solutions of (S)-(-)-TPMA free base with different water content ranging from 2% to 5.5% (i.e., water content before nucleation). Table 11 provides various PSD parameters of the measured PSD data for the suggested water content.

[0229] It was found that increasing the water content generally results in a larger median particle size, but also a reduction in the PSD span. Table 11 Particle size distribution parameters for various moisture content levels [Table 16]

[0230] Adjustment by reaction process

[0231] Reactive recrystallization was carried out by two different processes: (i) Process 1, which utilizes a Plug Flow Reactor (PFR) step in which ultrasound is applied to the reaction mixture during nucleation (e.g., during step 4b of Scheme 4); and (ii) Process 2, which includes a multi-step process including mixed suspension and mixed product removal (MSMPR).

[0232] The chemistry used for the recrystallization of the reactivity under Process 1 and Process 2, e.g., compounds, concentrations, and stoichiometry, was substantially the same as that of Example 1A (processes 1 and 2 were initiated with solutions of (S)-(-)-TPMA free base (compound F) at various concentrations as in Scheme 4 of Example 1A).

[0233] Reactivity recrystallization under Process 1 was carried out as follows: A solution of (S)-(-)-TPMA free base and a solution of HCl / IPA were supplied as separate feedstreams via a Tee mixer to a tubing crystallizer using a peristaltic pump, with controlled temperature (e.g., to 40°C) and residence time, and step 4b of Scheme 4 was performed. Crystallization occurred as a process stream flowing through the tubing after contact at Tee. An N2 injection system was coupled to both feedstreams to allow periodic introduction of gas. The output solution after the Tee mixer was passed through a tubular coil (1 / 8-inch PFA tubing) of a predetermined length depending on the desired residence time. A coil length of 3.5 m was used for a residence time of approximately 2.5 minutes, and a coil length of 7 m was used for a residence time of approximately 5 minutes. The coil temperature was controlled using a water bath in which the Tee, each of the approximately 10 cm input stream tubes, and the coil were immersed. Sonication was achieved by subjecting the water bath to ultrasonic treatment during the process flow.

[0234] Recrystallization of the reaction under Process 2 was carried out as follows: The multi-stage MSMPR process utilized a three-stage process stream, in which the starting material was continuously pumped into the first reaction vessel (first-stage crystallizer), continuously pumped from the first reaction vessel to the second reaction vessel (second-stage crystallizer), continuously pumped from the second reaction vessel to the third reaction vessel (third-stage crystallizer), and continuously pumped from the third reaction vessel to the product receiving vessel. The operating volume and reaction conditions were kept steady throughout the process, and each reaction vessel was stirred.

[0235] The starting materials, an isopropanol solution of (S)-(-)-TPMA free base and a 13% HCl solution in isopropanol, were pumped into the first stage at a set flow rate, and the residence time and the ratio of (S)-(-)-TPMA free base to HCl at each stage were adjusted. The suspension was transferred from the first stage crystallizer to the second stage crystallizer, and a 37% HCl isopropanol solution was pumped into the second stage crystallizer. The suspension was transferred from the second stage crystallizer to the third stage crystallizer, and the remaining (50%) HCl isopropanol solution was pumped into the third stage crystallizer. Pumping was performed using a peristaltic pump. Various flow conditions and other conditions at each stage are summarized in Table 12. Table 12 MSMPR stage conditions and parameters [Table 17]

[0236] Table 13 provides various PSD parameters for the measured PSD data shown in Figure 9A; Figures 9B and 9C represent SEM images of crystalline form A of (S)-(-)-TPMA·HCl obtained by process 2 and process 1, respectively.

[0237] It was found that sonication during the supersaturation process resulted in PSD with a smaller central particle size and an acceptable PSD span. In addition, it was found that sonication during the supersaturation process favored the primary formation of the bulky crystalline form (form A) of (S)-(-)-TPMA·HCl and promoted the avoidance of the needle-like morphology (form B). Table 13 [Table 18]

[0238] In various embodiments, the crystalline form of the present invention has several advantageous physical properties. For example, the crystalline form of polymorph A of (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine hydrochloride is substantially nonhygroscopic and, in various embodiments, when scanned at 0-90% relative humidity at 25°C as measured by a dynamic vapor sorption (DVS) device, showed a maximum mass change of less than about 0.2%, preferably less than about 0.1%, on the moisture sorption isotherm (see, for example, Figure 5).

[0239] It should be recognized that various embodiments of the present invention provide polymorph A of crystalline (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine hydrochloride with high chiral purity and high chemical purity.

[0240] In various embodiments, the present invention provides a substantially pure crystalline form as an enantiomer of polymorph A of (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine hydrochloride.For example, in various embodiments, the present invention contains more than 90% of (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine hydrochloride and less than 10% of (R)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine hydrochloride, or more than 95% of (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine hydrochloride and (R)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7- It contains less than approximately 5% of (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine hydrochloride, or more than approximately 97% of (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine hydrochloride and less than approximately 3% of (R)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine hydrochloride, or more than approximately 99% of (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine hydrochloride and (R)-(4,5-dihydro-7H-thieno[2,3- Contains less than approximately 1% of (c)pyran-7-yl)-N-methylmethanamine hydrochloride, or more than approximately 99.5% of (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine hydrochloride and less than approximately 0.5% of (R)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine hydrochloride, or more than approximately 99.7% of (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine hydrochloride and (R)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine hydrochloride. The present invention provides a crystalline form of (4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine containing less than approximately 0.3% of dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine hydrochloride, or containing more than approximately 99.9% of (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine hydrochloride and less than approximately 0.01% of (R)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine hydrochloride.

[0241] In various embodiments, the present invention provides a substantially chemically pure crystalline form of polymorph A of (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine hydrochloride. For example, in various embodiments, the present invention provides polymorph A of crystalline (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine hydrochloride having a chemical purity greater than about 80%, greater than about 90%, greater than about 95%, greater than about 97%, greater than about 99%, greater than about 99.5%, greater than about 99.7%, or greater than about 99.9%. In various embodiments, polymorph A of crystalline (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine hydrochloride is provided, having a residual solvent content of less than approximately 8000 ppm, less than approximately 6000 ppm, less than approximately 4000 ppm, less than approximately 2000 ppm, less than approximately 1000 ppm, less than approximately 800 ppm, or less than approximately 500 ppm.

[0242] In various embodiments, the present invention provides formulations and compositions comprising (S)-TPMA·HCl and / or its crystalline form, and one or more pharmaceutically acceptable excipients, carriers, adjuvants, or vehicles.

[0243] In various embodiments, the composition is formulated with one or more pharmaceutically acceptable excipients according to known and established practices. Thus, in various embodiments, the composition is formulated, for example, as a liquid, powder, elixir, injection, or suspension. Oral formulations are preferred, in which the pharmacologically active component is mixed with an inert solid diluent, and may be provided, for example, as tablets, caplets, or capsules. Tablets may also contain granulators and disintegrants, and may be coated or uncoated. Topical formulations may be provided, for example, as topical solutions, lotions, creams, ointments, gels, foams, patches, powders, solids, sponges, tapes, vapors, pastes, or tinctures.

[0244] In various embodiments, this specification provides compositions comprising (S)-TPMA or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients, carriers, adjuvants, or vehicles, wherein the amount of (S)-TPMA is between about 10 mg and about 120 mg based on free base. In some embodiments, the amount of (S)-TPMA is about 30 mg to about 100 mg based on free base. In some embodiments, the amount of (S)-TPMA is about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 75 mg, about 80 mg, about 90 mg, or about 100 mg based on free base. In some embodiments, the amount of (S)-TPMA is about 30 mg based on free base. In some embodiments, the amount of (S)-TPMA is about 50 mg based on free base. In some embodiments, the amount of (S)-TPMA is about 75 mg based on free base. In some embodiments, the amount of (S)-TPMA is approximately 100 mg, based on the free base.

[0245] In various embodiments, the present invention includes compositions comprising (S)-TPMA·HCl and one or more pharmaceutically acceptable excipients, carriers, adjuvants, or vehicles, wherein the amount of (S)-TPMA·HCl is between about 30 mg and about 120 mg, and in various embodiments, preferably between about 30 mg and about 90 mg.

[0246] In various embodiments, this specification provides compositions comprising (S)-TPMA·HCl and one or more pharmaceutically acceptable excipients, carriers, adjuvants, or vehicles, wherein the amount of (S)-TPMA·HCl is about 10 mg to about 120 mg based on free base. In some embodiments, the amount of (S)-TPMA·HCl is about 30 mg to about 100 mg based on free base. In some embodiments, the amount of (S)-TPMA·HCl is about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 75 mg, about 80 mg, about 90 mg, or about 100 mg based on free base. In some embodiments, the amount of (S)-TPMA·HCl is about 30 mg based on free base. In some embodiments, the amount of (S)-TPMA·HCl is about 50 mg based on free base. In some embodiments, the amount of (S)-TPMA·HCl is about 75 mg based on free base. In some embodiments, the amount of (S)-TPMA·HCl is approximately 100 mg, based on the free base.

[0247] In various embodiments, compositions containing (S)-TPMA·HCl are formulated as solid oral dosage forms. It should be recognized that the entire amount of the composition containing (S)-TPMA·HCl does not need to be provided in a single-dose unit form, such as a single tablet or capsule. In various embodiments, it is preferable that the composition be provided in a dosage unit form such that, for example, administering two dosage units provides the desired amount of (S)-TPMA·HCl.

[0248] A pharmaceutical composition containing the active ingredient ((S)-TPMA·HCl and its crystalline form) may be in any form suitable for the intended method of administration. For example, tablets, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups, or elixirs are forms suitable for oral administration. Compositions intended for oral use may contain one or more excipients, such as sweeteners, flavoring agents, colorants, and preservatives, to provide a palatable formulation.

[0249] In various embodiments, the compositions of the present invention are formulated for oral administration to a subject; in various preferred embodiments, the compositions are provided in solid oral dosage forms. In various embodiments, the solid oral dosage forms include tablets.

[0250] In various embodiments, tablets are provided containing an active ingredient mixed with non-toxic, pharmaceutically acceptable excipients suitable for manufacturing tablets. These excipients may include, for example, inert diluents such as microcrystalline cellulose, mannitol, calcium or sodium carbonate, lactose, lactose monohydrate, croscarmellose sodium, povidone, calcium or sodium phosphate; granulating and disintegrating agents such as corn starch or alginic acid; binders such as cellulose, microcrystalline cellulose, starch, gelatin or acacia; disintegrants such as crospovidone, croscarmellose sodium or sodium starch glycolate; and lubricants such as magnesium stearate, stearic acid or talc. The tablets may be uncoated or coated by known techniques.

[0251] In the manufacture of tablets, the inclusion of excipients in the formulation is almost always required to facilitate handling, improve appearance, enhance stability, and assist in the delivery of the drug into the bloodstream after administration. These potentially inert components, as well as the manufacturing methods used, often affect the absorption or bioavailability of the drug. Therefore, care must be taken in selecting and evaluating excipients and manufacturing methods to ensure that the target of drug delivery and the therapeutic effect of the active ingredient are not diminished. The solubility and other physicochemical properties of a drug affect its physiological effects from a solid dosage form. Important physicochemical properties include the size of its particles, whether the particles are amorphous or crystalline, whether the particles are solvated or unsolvated, and their polymorphisms. Even when other clinically effective formulations are obtained, variability between dose units in a given batch, as well as between batches, can lead to pharmacologically unacceptable results.

[0252] In various embodiments, formulations are provided containing (S)-TPMA or a pharmaceutically acceptable salt thereof in an amount between about 2 and about 80% w / w based on free base. In various embodiments, formulations are provided containing (S)-TPMA or a pharmaceutically acceptable salt thereof in an amount between about 5 and about 75% w / w based on free base. In various embodiments, formulations are provided containing (S)-TPMA or a pharmaceutically acceptable salt thereof in an amount between about 40 and about 80% w / w based on free base. In various embodiments, formulations are provided containing (S)-TPMA or a pharmaceutically acceptable salt thereof in an amount between about 50 and about 80% w / w based on free base. In various embodiments, formulations are provided containing (S)-TPMA or a pharmaceutically acceptable salt thereof in an amount between about 60 and about 80% w / w based on free base. In some embodiments, the amount is about 70% w / w.

[0253] In various embodiments, formulations are provided containing (S)-TPMA or a pharmaceutically acceptable salt thereof in an amount of about 40, about 45, about 50, about 55, about 60, about 65, about 70, about 75, or about 80% w / w based on free base. In various embodiments, formulations are provided containing (S)-TPMA or a pharmaceutically acceptable salt thereof in an amount of about 10% w / w based on free base. In various embodiments, formulations are provided containing (S)-TPMA or a pharmaceutically acceptable salt thereof in an amount of about 20% w / w based on free base. In various embodiments, formulations are provided containing (S)-TPMA or a pharmaceutically acceptable salt thereof in an amount of about 40% w / w based on free base. In various embodiments, formulations are provided containing (S)-TPMA or a pharmaceutically acceptable salt thereof in an amount of about 50% w / w based on free base. In various embodiments, formulations are provided that contain (S)-TPMA or a pharmaceutically acceptable salt thereof in an amount of about 60% w / w based on the free base. In various embodiments, formulations are provided that contain (S)-TPMA or a pharmaceutically acceptable salt thereof in an amount of about 70% w / w based on the free base.

[0254] In various embodiments, a tablet formulation is provided containing (S)-TPMA hydrochloride in a range of about 2.4% w / w to about 60% w / w, and in various preferred embodiments, in a range of about 10% w / w to about 40% w / w.

[0255] In various embodiments, formulations are provided in which (S)-TPMA·HCl is contained in a range of about 2 to about 80% w / w based on the free base. In various embodiments, formulations are provided in which (S)-TPMA·HCl is contained in a range of about 5 to about 75% w / w based on the free base. In various embodiments, formulations are provided in which (S)-TPMA·HCl is contained in a range of about 5 to about 50% w / w based on the free base. In various embodiments, formulations are provided in which (S)-TPMA·HCl is contained in a range of about 5 to about 40% w / w based on the free base. In various embodiments, formulations are provided in which (S)-TPMA·HCl is contained in a range of about 10 to about 40% w / w based on the free base. In various embodiments, formulations are provided in which (S)-TPMA·HCl is contained in a range of about 10 to about 40% w / w based on the free base.

[0256] In various embodiments, formulations containing (S)-TPMA·HCl in an amount of about 10% w / w based on the free base are provided. In various embodiments, formulations containing (S)-TPMA·HCl in an amount of about 20% w / w based on the free base are provided. In various embodiments, formulations containing (S)-TPMA·HCl in an amount of about 25% w / w based on the free base are provided. In various embodiments, formulations containing (S)-TPMA·HCl in an amount of about 30% w / w based on the free base are provided. In various embodiments, formulations containing (S)-TPMA·HCl in an amount of about 35% w / w based on the free base are provided.

[0257] In some embodiments, the formulation is a tablet. In some embodiments, the formulation further comprises a filler. In some embodiments, the formulation further comprises a disintegrant. In some embodiments, the formulation further comprises a lubricant. In some embodiments, the formulation further comprises a coating agent.

[0258] ; In various embodiments, the tablets provided herein include: (i) a core comprising (i) (S)-TPMA or a pharmaceutically acceptable salt thereof, based on the free base, in a range between about 10 and about 40% w / w; (ii) a filler; (iii) a disintegrant; (iv) a lubricant; and optionally (v) a flow enhancer. In some embodiments, the tablets include: (i) a matrix as a polymer coating system; and optionally one or more (ii) bleaching and coloring agents, (iii) a glossing agent, and (iv) other coloring agents, for example, to provide various tablet colors to meet market needs.

[0259] In some embodiments, the pharmaceutically acceptable salt of (S)-TPMA is (S)-TPMA·HCl. In some embodiments, (S)-TPMA·HCl is form A or form B. In some embodiments, formulations are provided herein comprising (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine or a pharmaceutically acceptable salt thereof in an amount between about 2 and about 80% w / w based on the free base, wherein the (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine hydrochloride is form A or form B.

[0260] In some embodiments, the filler is microcrystalline cellulose, mannitol, or a combination thereof. In some embodiments, the disintegrant is sodium starch glycolate. In some embodiments, the lubricant is magnesium stearate. In some embodiments, the flow enhancer is colloidal silicon dioxide. In some embodiments, the polymer coating system is (hydroxypropyl)methylcellulose (HPMC) / hydroxypropylcellulose (HPC). In some embodiments, the bleaching agent and coloring agent is titanium dioxide. In some embodiments, the polishing agent is carnauba wax.

[0261] In various embodiments, the tablets of the present invention include: (a)(i)(S)-TPMA hydrochloride in a range of about 2.4% w / w to about 60% w / w, in various embodiments, in a range of about 10% w / w to about 40% w / w; (ii) microcrystalline cellulose and mannitol as fillers; (iii) sodium starch glycolate as a disintegrant; (iv) magnesium stearate as a lubricant; and optionally (v) colloidal silicon dioxide (if necessary) as a flow enhancer; and (b)(i) (hydroxypropyl)methylcellulose (HPMC) / hydroxypropylcellulose (HPC) matrix as a polymer coating system; and optionally one or more (ii) titanium dioxide as a bleaching and coloring agent, (iii) carnauba wax as a glossing agent, and (iv) other coloring agents, for example, to provide various tablet colors to meet market needs. In various preferred embodiments, the concentration of each component is selected based on powder flowability, tabletability, and tablet stability after storage under accelerated and long-term conditions.

[0262] Microcracking was observed in some formulations of tablets. This was addressed by modifying the compression process, for example, by changing the compression position within the die. The extrusion force can be reduced by removing colloidal silicon dioxide (Cabosil) from the formulation and increasing the ratio of microcrystalline cellulose (MCC):mannitol. In some embodiments, the formulation does not contain colloidal silicon dioxide, and the MCC:mannitol ratio is approximately 5:1. A binary mixture (1:1) of API with Opadry 03F110000 (green), Opadry 03F180011 (white), Opadry II 85F18422 (white), copovidone, crospovidone, or sodium stearyl fumarate was found to be stable when stored in sealed glass vials at 40°C / 75%RH for 6 or 9 months. Based on the compatibility data of the binary excipients, these excipients can potentially be used in tablet formulations. A binary mixture (1:1) of API and colloidal silicon dioxide remains unstable even after two weeks at 40°C / 75%RH.

[0263] In some embodiments, the formulation does not contain colloidal silicon dioxide (e.g., (S)-TPMA hydrochloride granules, microcrystalline cellulose, mannitol, sodium starch glycolate, and magnesium stearate). In some embodiments, the formulation does not contain mannitol (e.g., (S)-TPMA hydrochloride granules, microcrystalline cellulose, sodium starch glycolate, colloidal silicon dioxide, and magnesium stearate). In some embodiments, the formulation does not contain mannitol and colloidal silicon dioxide (e.g., (S)-TPMA hydrochloride granules, microcrystalline cellulose, sodium starch glycolate, and magnesium stearate).

[0264] In some embodiments, (S)-TPMA hydrochloride is form A or form B. In some embodiments, (S)-TPMA hydrochloride is form A. In some embodiments, (S)-TPMA hydrochloride is form B.

[0265] In various embodiments, methods for producing solid oral dosage forms containing (S)-TPMA are provided. In various embodiments, methods for forming tablets are provided, for example, by direct compression or by dry granulation.

[0266] Example 3: Formation and manufacture of tablets

[0267] Tablets of (S)-TPMA hydrochloride were manufactured using a drying process. Direct compression was used for 25 mg tablets, while for 50, 75, and 100 mg tablets, a drying granulation followed by compression process was used. In some embodiments, the API was crushed before blending with excipients. The composition of the 25 mg tablet content is summarized in Table 14, and the composition of the 50, 75, and 100 mg tablet content is summarized in Tables 15A, 15B, 15C, and 15D; these include the core tablet and the coating agent applied to the core. While yellow is listed as the hue of the coated tablets in these tables, it should be understood that the hue of the tablets may be changed based on market needs, for example, without changing the polymer coating system. Based on the amount of free base, i.e., for (S)-TPMA hydrochloride containing 25 mg of the active ingredient in the compound, microcrystalline cellulose, mannitol, and sodium starch glycolate were individually sieved through a #30 mesh screen and placed in a low-shear blender. The mixture was blended at up to 500 rpm. In some examples, the mixture was blended at up to 300 rpm. Magnesium stearate was sieved through a #60 mesh screen and placed in the blender, and the mixture was blended at a further 75 rpm. The blend was then compressed into tablets of the target 300 mg tablet size. The tablets were then coated with Opadry 20A120006 Yellow, Opadry 20A18407 White, or Opadry 20A110008 Green (hydroxypropyl methylcellulose / hydroxypropylcellulose), dried, and then coated with carnauba wax.

[0268] If the active ingredient content (based on the amount of free base) is greater than 25 mg, the granular blend contains (S)-TPMA hydrochloride, microcrystalline cellulose, and sodium starch glycolate, which are individually sieved through a #30 mesh screen and placed in a low-shear blender. The mixture is blended at up to 500 rpm. In some cases, the mixture is blended at up to 300 rpm. In some cases, the mixture is blended at up to 250 rpm, magnesium stearate is sieved through a #60 mesh screen and placed in the blender, and the mixture is blended at a further 75 rpm. The granular blend is then dried and granulated into ribbons and milled into granules.

[0269] Depending on the content of the target tablet, the granules were dried and granulated, then blended with an external excipient using different amounts of granules before compression. The final blend contained (S)-TPMA hydrochloride granules, microcrystalline cellulose, mannitol, sodium starch glycolate, colloidal silicon dioxide (for 75 and 100 mg only), and magnesium stearate. In some examples, the final blend did not contain colloidal silicon dioxide (e.g., (S)-TPMA hydrochloride granules, microcrystalline cellulose, mannitol, sodium starch glycolate, and magnesium stearate). In some embodiments, the final blend did not contain mannitol (e.g., (S)-TPMA hydrochloride granules, microcrystalline cellulose, sodium starch glycolate, colloidal silicon dioxide, and magnesium stearate). In some examples, the final blend did not contain mannitol or colloidal silicon dioxide (e.g., (S)-TPMA hydrochloride granules, microcrystalline cellulose, sodium starch glycolate, and magnesium stearate). Based on free base, (S)-TPMA hydrochloride in 25 mg, 50 mg, 75 mg, and 100 mg contents can be prepared from the final blend with or without colloidal silicon dioxide, or with or without mannitol. Microcrystalline cellulose, mannitol, sodium starch glycolate, and colloidal silicon dioxide were individually sieved through a #30 mesh screen or sieved together with microcrystalline cellulose (for colloidal silicon dioxide only) and placed in a low-shear blender with granules of (S)-TPMA hydrochloride for blending. The mixture was blended by rotating 250 times. Extragranular magnesium stearate was sieved through a #60 mesh screen and placed in the blender. The mixture was then blended by rotating 75 times and then compressed into tablets of the target tablet amount of 300 mg. Next, the tablets were coated with Opadry 20A120006 Yellow, Opadry 20A18407 White, or Opadry 20A110008 Green (hydroxypropyl methylcellulose / hydroxypropylcellulose), dried, and then coated with carnauba wax.

[0270] If the active ingredient content (based on the amount of free base) was greater than 25 mg, the granular blend containing (S)-TPMA hydrochloride, microcrystalline cellulose, and sodium starch glycolate were individually sieved through a #30 mesh screen and placed in a low-shear blender. In some cases, (S)-TPMA hydrochloride was pulverized before granulation. The mixture was blended by rotating 300 times. Magnesium stearate was sieved through a #60 mesh screen and placed in the blender, and the mixture was blended by rotating 75 times. The granular blend was then subjected to dry granulation to form ribbons and pulverized into granules. After dry granulation, the granules and the external excipients were blended before compression. The final blend contained (S)-TPMA hydrochloride granules, microcrystalline cellulose, sodium starch glycolate, and magnesium stearate. Mannitol was also included as an external excipient in the 50 mg and 75 mg cases. Microcrystalline cellulose, mannitol, and sodium starch glycolate were sieved through a #30 mesh screen and placed in a low-shear blender with granules of (S)-TPMA hydrochloride for blending. The mixture was blended by rotating 300 times. Extragranular magnesium stearate was sieved through a #60 mesh screen and placed in the blender. The mixture was then blended by rotating 75 times and then compressed into tablets weighing 300 mg. The tablets were then coated with OpaDry 20A120006 yellow, OpaDry 20A18407 white, or OpaDry 20A110008 green (hydroxypropyl methylcellulose / hydroxypropylcellulose), dried, and then coated with carnauba wax.

[0271] Tablets weighing 75 mg, 150 mg, 225 mg, and 300 mg can be produced using a standard blend for all four active ingredient content levels: 25 mg, 50 mg, 75 mg, and 100 mg. For example, a granular blend of (S)-TPMA hydrochloride, microcrystalline cellulose, and sodium starch glycolate, each individually sieved through a #30 mesh screen, was placed in a low-shear blender. The mixture was blended by rotating 300 times. Magnesium stearate was sieved through a #60 mesh screen and placed in the blender, and the mixture was blended by rotating 75 times. The granular blend was then subjected to dry granulation to form ribbons and ground into granules. After dry granulation, the granules and external excipients were blended before compression. The final blend contained (S)-TPMA hydrochloride granules, microcrystalline cellulose, sodium starch glycolate, and magnesium stearate. Microcrystalline cellulose and sodium starch glycolate were sieved through a #30 mesh screen and placed in a low-shear blender with granules of (S)-TPMA hydrochloride for blending. The mixture was blended by rotating 300 times. Extragranular magnesium stearate was sieved through a #60 mesh screen and placed in the blender. The mixture was then blended by rotating 75 times. The blend can be compressed into 75 mg, 150 mg, 225 mg, and 300 mg tablets for active ingredient content of 25 mg, 50 mg, 75 mg, and 100 mg tablets, respectively. In other words, (S)-TPMA hydrochloride with different active ingredient content can be tableted by applying the corresponding amount of the blend and compressing them. It can be manufactured from a single blend containing the same components. See, for example, Tables 15C and 15D. Table 14 A composition as an example of a tablet containing 25 mg of (S)-TPMA hydrochloride as an active ingredient. [Table 19] Table 15A Examples of compositions of (S)-TPMA hydrochloride tablets with active ingredient content of 50, 75, and 100 mg. [Table 20] Note: For the 50 mg active ingredient content, a similar batch was manufactured with colloidal silicon dioxide (carbosyl), as shown in Table 15A. Additionally, batches with 75 and 100 mg active ingredient content were manufactured without carbosyl, as shown in Table 15A. Table 15B Compositions as further examples of tablets of (S)-TPMA hydrochloride with active ingredient content of 50, 75, and 100 mg. [Table 21] Table 15C Standard blend formulations [Table 22] Table 15D Tablet formulation composition for compressing formulations using a standard blend [Table 23]

[0272] The amounts of polymer coatings are actually estimates shown in Table 15D. When lower weight tablets are manufactured, the actual amounts may be modified and applied to the coating. Similarly, the amounts of polishing agents are also estimates. When lower weight tablets are manufactured, the actual amounts may be modified and applied to both the coating and the wax / polish.

[0273] XRPD analysis of Examples 4-8 and 12 was performed using a MiniFlex II (Rigaku) ​​desktop X-ray diffractometer with Cu irradiation. The tube voltage and current were set to 30kV and 15mA, respectively. The scattering slit was fixed at 1.25° and the receiving slit at 0.3mm. The diffracted irradiation was detected by a NaI scintillation detector. Continuous scanning of θ-2θ was performed at 1.0° / min with a step size of 0.02-0.05° from 3 to 45°2θ. Data were collected and analyzed using Jade 8.5.4. Each sample was prepared for analysis by placing it in a low-background, round, 0.1mm indented sample holder.

[0274] DSC analysis of Examples 4-8 was performed using a TA Instrument Q100 differential scanning calorimetry system. Each sample was analyzed in an aluminum pan with a crimped lid. Each sample was heated at a heating rate of 10°C / min from room temperature of 25°C to a final temperature of 200-300°C under a nitrogen purge of 50 mL / min. The sample size ranged from 1.6 to 8.0 mg.

[0275] For the analysis of water content in Examples 4-8 by coulometric titration, an EM Scientific Aquastar C3000 titrator was used to measure the water content. The sample sizes ranged from 18 mg to 134 mg.

[0276] DVS moisture adsorption isotherms for Examples 4-8 were prepared using a VTI SGA-100 Symmetric Vapor Sorping Analyzer. The analysis included pre-analysis at 25°C with an equilibrium criterion of a 0.0000 wt% change over 5 minutes or a maximum of 180 minutes. The equilibrium criterion was a change of less than 0.01 wt% over 5 minutes or 180 minutes in each RH step. The temperature was fixed at 25°C, and the relative humidity steps (25%~95%~25%) were increased by 5%. The analysis was repeated for each sample using continuous analysis (the sample was not removed from the analyzer). Sample sizes ranged from 14 mg to 73 mg. Example 4: (S)-TPMA·R-mandelate

[0277] The crystalline morphology of (S)-TPMA·R-mandelate was analyzed using XRPD, DSC, coulometric titration, and DVS. Figure 11 shows the XRPD results, and Table 4 provides a list of peaks. Table 4. Peak list of XRPD for (S)-TPMA·R-mandelic acid (Figure 12) [Table 24] [Table 25]

[0278] The DSC shown in Figure 12 indicates that the starting temperature was 127°C and that there was an endothermic peak at 129°C. The water content measured by coulometric titration was 0.03% water. The TGA is shown in Figure 13. Example 5: (S)-TPMA·L-tartrate

[0279] The crystalline morphology of (S)-TPMA·L-tartrate was analyzed using XRPD, DSC, coulometric titration, and DVS. Figure 14 shows the XRPD results, and Table 5 provides a list of peaks. Table 5. Peak list of (S)-TPMA·L-tartrate XRPD (Figure 14) [Table 26] [Table 27]

[0280] The DSC shown in Figure 15 indicates that the starting temperature was 149°C and that there was an endothermic peak at 152°C. The water content measured by coulometric titration was 0.07% water. The DVS is shown in Figure 16. Example 6: (S)-TPMA·D-tartrate

[0281] The crystalline morphology of (S)-TPMA·D-tartrate was analyzed using XRPD, DSC, coulometric titration, and DVS. Three crystalline morphologies were observed: morphology DA, morphology DB, and morphology DC. Figure 17 shows the XRPD of morphology DA; Table 6A provides a list of peaks. Figure 18 shows the XRPD of morphology DB; Table 6B provides a list of peaks. Figure 19 shows the XRPD of morphology DC; Table 6C provides a list of peaks. The XRPD patterns of morphologies DA, DB, and DC may not show a unique and pure polymorphism, but may be a mixture of morphologies. Table 6A. XRPD peak list of (S)-TPMA·D-tartrate (Figure 17) [Table 28] [Table 29] Table 6B. XRPD peak list of (S)-TPMA·D-tartrate (Figure 18) [Table 30] [Table 31] Table 6C. XRPD peak list of (S)-TPMA·D-tartrate (Figure 19) [Table 32] [Table 33]

[0282] The DSC for morphology DA shown in Figure 20 shows that the starting temperature is 168°C and there is an endothermic peak at 170°C. The DSC for morphology DB shown in Figure 21 shows that the starting temperature is 107°C and there is an endothermic peak at 111°C. The DSC for morphology DC shown in Figure 22 shows that the starting temperature is 158°C and there is an endothermic peak at 160°C, and also that the starting temperature is 183°C and there is an endothermic peak at 185°C. This indicates.

[0283] The water content measured by coulometric titration was 0.12% for form DA, 0.09% water for form DB, and 0.06% for form DC. Figure 23 shows the DVS for form DA. Example 7: (S)-TPMA·mesylate and (S)-TPMA·L-malic acid

[0284] Mesylates were observed in polymorphism experiments and analyzed using DVS. Figure 24 shows the DVS.

[0285] L-maleate was observed in polymorphism experiments and analyzed using DVS. Figure 25 shows the DVS. Example 8: (S)-TPMA besylate

[0286] The crystalline morphology of (S)-TPMA·besylate was analyzed using XRPD, DSC, coulometric titration, and DVS. Form BA was observed. Figure 25 shows the XRPD results, and Table 8 provides a list of peaks for form BA. Table 8. XRPD peak-out of (S)-TPMA besylate form BA (Figure 25). [Table 34] [Table 35]

[0287] The DSC shown in Figure 26 indicates that the starting temperature was 141°C and that there was an endothermic peak at 142°C. The water content measured by coulometric titration was 0.03% water. The DVS is shown in Figure 27. Example 9: Study of solid-phase stability

[0288] Solid samples of (S)-TPMA·HCl and (S)-TPMA·besylate (approximately 25 mg each) were placed in 4 ml clear borosilicate glass screw-cap vials. The samples were stored at 40°C / 75%RH for 27 days and then analyzed by AR&D.

[0289] The results show no change in the area of ​​the parent peak or the area percentage of impurities for either the HCl salt or the besilate salt. The results are referred to in Table 9. Table 9. Solid state stability results for HCl and besylates. [Table 36] HCl and besilates are stable in a solid state after 27 days at 40°C / 75%RH. Impurity 1 is: [ka] That is the case. Example 10: Study of solubility in aqueous systems

[0290] Buffer preparations mimicking gastric juice (pH 1.2, approximately 0.1N HCl, 0.03M NaCl), intestinal juice (pH 6.7, 0.05M KH2PO4, approximately 0.02N NaOH), and acetate buffer (pH 4.6, 0.02M sodium acetate, 0.03M acetic acid) were prepared according to USP27 [Ref3]. No enzymes were added to the mimicked gastric or intestinal juices. Approximately 200 mg of selected salts were weighed into clear glass HPLC vials. 1 mL of deionized water was added to each vial. In each case, a clear solution was obtained, and the pH of the final solution was measured. The results (Table 11a) were reported to be "greater" than the concentration of the solution.

[0291] Further solubility experiments were conducted on (S)-TPMA·HCl salt. Approximately 250 mg of (S)-TPMA·HCl salt was weighed into clear glass HPLC vials. Approximately 900 μL of each test solvent was added to each vial. In each case, a clear yellow solution was obtained, and the pH of the final solution was measured.

[0292] The results (Table 10a) were reported as "greater" than the concentration of the solution. The solubility results are referred to in Tables 10a and 10b. Table 10a. Apparent solubility of (S)-TPMA salts in deionized water. [Table 37] a = Solubility expressed in units of free base Table 10b. Apparent solubility of (S)-TPMA·HCl in aqueous buffer systems. [Table 38] a = Solubility expressed in units of free base The enzyme was not added to the mimicked gastric or intestinal fluid.

[0293] The selected salt exhibits good solubility at physiological pH and conditions such as SGF (pH 1.2), SIF (pH 6.8), and acetate buffer (pH 4.5) (i.e., > The salts tested (HCl, L-tartrate, besilate, and R-mandelate) were all readily soluble in deionized water. The HCl salt was readily soluble in aqueous buffer with a pH in the range of 1.3 to 7.7. Example 11: Study of polymorphs of (S)-TPMA besylate

[0294] Polymorph studies were conducted using (S)-TPMA·besylate. The starting material used in this study is called form BA, and has the characteristics described below.

[0295] (S)-TPMA is photosensitive, therefore, it was treated to minimize exposure to light throughout the experiment. These abbreviations are used in this study: ACN - Acetonitrile, B / E - Birefringence / Annihilation, CC - Crush Cooling, DCM - Dichloromethane, DSC - Differential Scanning Calorimetry, siRNA - Ethyl Acetate, EtOH - Ethanol, FE - Fast Evaporation, H2O - Water, IPA - Isopropanol, IS - Insufficient Sample, MEK - Methyl Ethyl Ketone, MeOH - Methanol, mg - Milligram, mL - Milliliter, PO - Selective Orientation, Rotovap - Rotary Evaporation, RT - Room Temperature / Ambient Temperature, S / AS - Solvent / Antisolvent, SC - Slow Cooling, SE - Slow Evaporation, Tg - Glass Transition Temperature, THF - Tetrahydrofuran, UM - Vacuum Form, v / v - Volume / Volume, vac - Vacuum, VD - Vapor Diffusion, VT - Variable Temperature, and XRPD - X-ray Powder Diffraction.

[0296] Approximate Solubility Determination: Aliquots of the test solvent were added to the weighed sample of (S)-TPMA·besylate, with sonication treatment at each addition. Dissolution was determined by visual inspection. If the sample dissolved upon addition of the first aliquot, the solubility was reported as "greater than or equal to". If the sample did not dissolve, the solubility was reported as "less than". Actual solubility may be higher than reported due to slower dissolution rates and the addition of excessively large aliquots.

[0297] First evaporation: A solution of (S)-TPMA·besylate was prepared and filtered. The sample was left open under ambient conditions to evaporate.

[0298] Slow evaporation: A solution of (S)-TPMA besylate was prepared and filtered. The vial containing the sample was covered with a pinhole wheel. The covered sample was left under ambient conditions to evaporate.

[0299] Slurry formation: A solution of (S)-TPMA·besilate containing an excess amount of solid was prepared and stirred at a predetermined temperature for a predetermined time.

[0300] Slow cooling: A saturated solution of (S)-TPMA besylate was prepared in a high-temperature oil bath. The sample was filtered through a heated filter into a heated vial, and then returned to the oil bath. Heating was stopped, and the sample was allowed to cool slowly to ambient temperature. If no precipitate was observed at ambient temperature, the sample was placed in a refrigerator. After the refrigerator, the sample was moved to a freezer.

[0301] Crush Cooling: A saturated solution of (S)-TPMA besylate was prepared in a hot oil bath. The sample was filtered through a heated filter into a vial and then immersed in a dry ice / acetone bath. If no precipitate formed, the sample was placed in a freezer.

[0302] Solvent / Poor Solvent Crush Precipitation: A solution of (S)-TPMA·besylate was prepared, filtered, and combined with the poor solvent. If no precipitate was observed, the sample was placed in a freezer. If no precipitate was obtained even in the freezer, the sample was evaporated either partially or to dryness.

[0303] Grinding experiment: A sample of (S)-TPMA besylate was placed in an agate canister containing agate spheres. For solvent drop grinding experiments, a small amount (10 μL) of solvent was added. The sample was covered, placed on Parafilm, and ground at 30 Hz for 20 minutes using a Lechs MM200 mixer mill.

[0304] Vapor diffusion: A solution of (S)-TPMA·besylate was prepared and filtered into a vial. This vial was placed, uncapped, into a larger vial containing a poor solvent. The larger vial was then capped, and the sample was brought to equilibrium.

[0305] Rotary evaporation: A solution of (S)-TPMA·besylate was prepared and filtered. The sample was placed in a rotary evaporator at ambient temperature and evaporated to dryness.

[0306] Freeze-drying: An aqueous solution of (S)-TPMA·besilate was prepared, filtered, and frozen using a dry ice / acetone bath. The sample was placed in an FTS-Systems Flexi-Dry freeze-dryer.

[0307] Heating experiment: A sample of (S)-TPMA besylate was placed in a vial, capped, and placed in an oil bath at a specified temperature.

[0308] Mechanical Technology

[0309] XRPD: Most XRPD patterns were collected using a PANalytical X'Pert PRO MPD diffractometer with an incident beam of Cu radiation generated using an Optic long-fine focus source. Cu Kα X-rays were focused through the sample to the detector using a multilayer mirror with an elliptical gradient. Prior to analysis, a silicon specimen (NIST SRM 640d) was analyzed to confirm its Si 111 peak position. The sample specimen was sandwiched between 3 μm thick films and analyzed by transmission geometry. Background generated by air was minimized using a beam stop, short anti-scattering extension, and anti-scattering knife edge. Spreading due to axial divergence was minimized using solar slits for the incident and diffracted beams. Diffraction patterns were collected using a scanning position-sensitized detector (X'Celerator) placed 240 mm away from the sample and Data Collector software v.2.2b. The data acquisition parameters for each pattern, including the divergent slit (DS) in front of the mirror and the anti-scattering slit (SS) for the incident beam, are displayed above the images in the data section of this report.

[0310] The XRPD pattern of sample 1 was collected using a PANalytical X'Pert PRO MPD diffractometer with 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. Prior to analysis, a silicon specimen (NIST SRM 640d) was analyzed to confirm its Si 111 peak position. The sample specimen was fabricated as a circular thin layer centered on a silicon-zero background substrate. Background generated by air was minimized using a scattering prevention slit (SS). Spreading due to axial divergence was minimized using solar slits for the incident and diffracted beams. The diffraction pattern was collected using a scanning position-sensitized detector (X'Celerator) placed 240 mm away from the sample and Data Collector software v.2.2b. The data acquisition parameters for each pattern, including the divergence slit (DS) and incident beam SS, are shown above the images in the data section of this report.

[0311] VT-XRPD (non-cGMP): VT-XRPD patterns were collected using a PANalytical X'Pert PRO MPD diffractometer with an incident beam of Cu Kα radiation generated using a long-fine focus source and nickel filter. The diffractometer was configured using a symmetric Bragg-Brentano geometry. Prior to analysis, silicon specimens (NIST SRM 640d) were analyzed to confirm the location of the Si 111 peak. Data were collected and analyzed using Data Collector software v.2.2b. Prior to analysis, silicon specimens (NIST SRM 640d) were analyzed to confirm that the observed Si 111 peak location matched the NIST-certified location. Sample specimens were filled into nickel-plated copper wells. Background generated by air was minimized using a scattering prevention slit (SS). Broadening due to axial divergence was minimized using solar slits for the incident and diffracted beams. Diffraction patterns were collected using a scanning position-sensitized detector (X'Celerator) positioned 240 mm away from the sample. The data acquisition parameters for each pattern, including the divergent slit (DS) and incident beam SS, are shown above the images in the data section of this report.

[0312] An in-situ XRPD patterns were collected as a function of temperature using an Anton Paar TTK 450 stage. The sample was heated with a resistance heater located directly below the sample holder, and the temperature was monitored using a platinum-100 resistance sensor placed in the sample holder. The heater was powered on and adjusted using an Anton Paar TCU 100 connected to the data collector.

[0313] Standard DSC: Standard DSC was performed using a TA Instruments Q2000 differential scanning calorimeter. Temperature calibration was performed using NIST traceable indium metal. The sample was placed in an aluminum DSC pan, covered, and the lid was pressed down, and the weight was accurately recorded. (This pan configuration is designated as "TOC" in the thermogram comments in the data section.) The weighed aluminum pan, configured as the sample pan, was placed on the reference side of the cell. The sample was heated from -30°C to 250°C at a rate of 10°C / min (abbreviated as "-30-250-10" in the method field of the thermogram).

[0314] Hypercycling-DSC: Hypercycling-DSC was performed using a Perkin-Elmer diamond input compensated differential scanning calorimeter. Temperature calibration was performed using NIST traceable indium metal. The sample was placed in an aluminum DSC pan and its weight was accurately recorded. The pan was covered with a lid and pressed shut. The weighed and pressed aluminum pan was placed on the reference side of the cell. The sample was equilibrated at 50°C and heated to 145°C at a rate of 100°C / min under a helium purge, and held at that level for 5 minutes. The sample was then cooled to -50°C at approximately 500°C / min. The sample was then heated to 50°C at 100°C / min and cooled again to -50°C at approximately 500°C / min. Finally, the sample was heated to a final temperature of 150°C at 100°C / min. It should be noted that the device is not calibrated to cool at 500°C / min, and these cooling processes are considered to be "uncontrolled" cooling.

[0315] Hot Stage Microscopy: Hot stage microscopy was performed using a Linkam hot stage (FTIR600) fixed to a Leica DM LP microscope equipped with a SPOT Insight® color digital camera. Temperature calibration was performed using the USP melting point reference. A sample was placed on a coverslip, and another coverslip was placed on top of the sample. Once the stage was heated, each sample was visually observed using a 20x0.40 N.A. long working distance objective lens equipped with a cross polarizer and primary red compensator. Images were captured using SPOT software (v.4.5.9).

[0316] Optical microscopy: Optical microscopy observations were performed using a Wolfe stereomicroscope equipped with a polarizer and 2x or 4x objective lenses.

[0317] Indexing (non-cGMP): The XRPD pattern of form BA of (S)-TPMA·besylate was indexed using proprietary SSCI software.

[0318] Indexing and structural refinement are computer-aided studies conducted under the "Procedures for SSCI Non-cGMP Activities."

[0319] result

[0320] The approximate solubility of (S)-TPMA·besylate in different solvents indicates that it has high solubility in methanol and water, as well as in aqueous mixtures. Table 11a. Approximate solubility of (S)-TPMA besylate [Table 39]

[0321] a: Solubility is set to the nearest mg / mL value. Dissolution is measured by visual inspection, and actual solubility may be higher than reported due to slower dissolution rates or the addition of excessively large aliquots. If dissolution is not observed, solubility is reported as "less than". If dissolution is observed with the addition of the first aliquot, solubility is reported as "greater than or equal to". b: After conducting experiments at room temperature, the samples were placed on a hot plate at approximately 68°C. Most of the solids melted at high temperatures. The high-temperature observation is considered non-cGMP because the identification information of the hot plate and thermometer was not documented.

[0322] Over 60 polymorphic crystallization experiments of (S)-TPMA·besylate were performed between screenings. Experimental types included evaporation and cooling at different rates, slurry, grinding with and without solvent, anti-solvent crush precipitation, rotary evaporation, vapor diffusion, freeze-drying, and heating experiments. Isolated solids were analyzed using XRPD. XRPD patterns were compared with each other and with the starting materials.

[0323] Overall, materials consistent with form BA were obtained in most of the experiments performed. Selected samples of form BA showed signs of favorable orientation consistent with the observed plate-like morphology. Material B was fabricated in a single experiment. When exhibiting strict selective orientation, material B showed a pattern similar to the XRPD pattern of form BA, but with more peaks. DSC and repeated XRPD data collected from this material appeared to be consistent with form BA, suggesting that a transformation had occurred. Attempting to replicate material B yielded form BA. X-ray amorphous (S)-TPMA was not generated during the polymorphic experiments.

[0324] Form BA

[0325] Hot stage microscopy data are shown in Table 11b. Based on the combined property data, (S)-TPMA foam BA is a crystalline, stable, anhydrous, non-hygroscopic material with a melting point of 142-143°C. Table 11b. Hot-stage microscopy analysis [Table 40]

[0326] The XRPD pattern of (S)-TPMA form BA, suggesting that the sample is primarily composed of a single-crystal phase, was neatly indexed. See Figure 28. The agreement between the acceptable peak positions, labeled with red bars in the figure, and the observed peaks indicates that the unit cell determination is consistent. The assigned vanishing symbols, unit cell parameters, and the space group corresponding to the derived values ​​are shown in a table below the figure. To confirm the provisional indexing solution, the molecular packing motif within the crystallographic unit cell must be determined. No attempt was made to determine the molecular packing.

[0327] DSC data of (S)-TPMA form BA, based on hot-stage microscopy analysis, revealed a single endothermic transition at 142-143°C, possibly due to melting. Hot-stage microscopy experiments showed no evidence of decomposition in melting, and crystallization was observed upon cooling. Reheating the sample revealed that it melted at the same temperature as the initial melting, which is consistent with the sample crystallizing into the same morphology. VT-XRPD experiments showed that the molten material in morphology FB crystallized into form A upon cooling. Specifically, form BA was observed at room temperature, showing a halo at 145°C (a gradient from room temperature of 35°C / min), and a somewhat disordered form BA at -60 to -90°C.

[0328] Material B

[0329] Material B was obtained in a single pass from an acetone slow-cooling experiment starting at 45°C. The XRPD pattern for this material showed a strong preferential orientation effect and showed almost no peaks. Some peaks appeared to coincide with form BA, but further peaks were observed that may not be associated with form BA. These further observed peaks do not appear to have arisen from either (S)-TPMA free base or benzenesulfonic acid.

[0330] A sample of material B was analyzed using DSC. The resulting thermogram was indistinguishable from that of form BA. Subsequently, the sample was repeatedly subjected to XRPD analysis, revealing a conversion to form BA. Further experiments targeting material B were attempted. A sample was selected and subjected to wet analysis under the assumption that the material might be an unstable solvate. However, the experiment, based on XRPD data, resulted in form BA. Alternatively, material B may represent a mixture mainly of form A and low levels of contaminants.

[0331] Amorphous materials

[0332] Amorphous (S)-TPMA·besylate has a glass transition temperature of approximately 20°C and tends to crystallize into form A.

[0333] In summary, polymorphic studies of (S)-TPMA were conducted to estimate the number and types of solid forms. Overall, one crystalline form, referred to as form BA, was observed in most of the screen experiments. The property data for form A of (S)-TPMA·besylate is a crystalline, stable, anhydrous, hygroscopic material that melts in the range of 142–143°C. One experiment yielded material B, suggesting the existence of another possible form. Attempting to regenerate this material yielded form BA. Finally, amorphous (S)-TPMA·besylate appears unstable, exhibiting a glass transition temperature of approximately 20°C and tending to crystallize into form A. Example 12. Crystalline form of (S)-TPMA free base

[0334] The crystalline morphology of (S)-TPMA free base was analyzed using XRPD, DSC, coulometric titration, and DVS. Figure 32 shows the XRPD results, and Table 12a provides a list of peaks for form BA. Table 12a. XRPD peak list of (S)-TPMA free bases (Figure 32) [Table 41] [Table 42]

[0335] Example 13. Control of PSD and aggregation in the scale-up of reaction crystallization.

[0336] During the process of scaling up to industrial-scale production, the crystal aggregation behavior and particle size distribution (PSD) of form A of (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethaneamineHCl were studied and successfully carried out.

[0337] The results showed that mixing control and fluid dynamics influence coagulation and PSD control. When the inflowing HCl solution mixes with the bulk free base solution, the resomixing time plays a certain role in terms of coagulation and PSD control. Therefore, it is necessary to understand the flow pattern and mixing behavior of the reactor through computational fluid dynamics (CFD) calculations using a simulation system.

[0338] To address flocculation and PSD, specific process parameters were identified, including the type of additive (subsurface or overhead), the discharge configuration of the additive tube in subsurface additives (specific mixing zone or dead zone), the diameter of the additive tube (affecting convective transport time), and the additive profile of the HCl flow (addition rate).

[0339] To develop a method for obtaining crystals of form A of (S)-(-)-TPMA·HCl and to provide various particle size distributions, a series of studies were conducted using various forms of reactive recrystallization (e.g., Scheme 4 of Example 1A). The reaction conditions were substantially the same as those described in Example 1A with respect to Scheme 4, except that they were modified as described in the following studies. Research 1

[0340] The elimination of aggregation in the final crystallization of (S)-(-)-TPMA·HCl was explained by controlling the acid flow by subsurface addition in the high-mixing zone near the tip of the impeller. Figure 29 illustrates the impact of such controlled addition at two different addition points; when the acid flow is added to the center of the free base solution, the resulting morphology is aggregated, while when the acid flow is added subsurface near the tip of the impeller (Figure 29), the resulting morphology is aggregate-free and consists of larger crystalline products. Research 2

[0341] In any crystallization process, the balance between nucleation, crystal growth, and aggregation determines the particle size distribution, and the supersaturation rate is the driving force behind crystallization and can be a clear parameter for maintaining equilibrium between nucleation, crystal growth, etc.

[0342] In recent years, in the reaction crystallization of (S)-TPMA·HCl, the supersaturation formation rate can be directly controlled by the rate of addition of the HCl solution. A series of experiments were performed to show the effect of different HCl addition profiles on the particle size distribution. The results are summarized in Tables 13A and 13B, and Figures 30 and 31 show that earlier addition is preferable for the formation of smaller crystals, while later addition is desirable for the formation of larger crystals. Table 13A. Addition Profile of HCl IPA Solution [Table 43] Table 13B. Particle size distribution parameters for the additive profile [Table 44] Note: 1mm ID dosing tube, operating temperature: 20℃ Research 3

[0343] The PSD control strategy was implemented and effectively demonstrated during the process scale-up to a manufacturing plant (100 kg equipment). By using subsurface dosing and maintaining a constant convection transport time throughout the scale-up, simply changing the acid dosing profile from profile A to profile B resulted in a particle size reduction from an average of approximately 175 μm to approximately 100 μm (D50). [Table 45] Addition Profile A: First 10%: Add over approximately 90 minutes; Next 30%: Add over approximately 45 minutes; Remaining: Add over approximately 45 minutes; Addition Profile B: First 10%: Add over approximately 15 minutes; Next 30%: Add over approximately 15 minutes; Remaining: Add over approximately 18 minutes.

[0344] The Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (hereinafter referred to as "DSM-5"), published by the American Psychiatric Association in 2013 and incorporated herein by attribution, provides a standard diagnostic system on which those skilled in the art rely to diagnose various diseases and disorders.

[0345] As used herein, the term “mood disorder” includes depression, major depressive disorder, major depressive disorder, mild depression, severe depression without psychosis, severe depression with psychosis, melancholy (formerly endogenous depression), atypical depression, dysthymic disorder, manic-depressive illness, bipolar disorder, bipolar depression, bipolar I disorder, bipolar II disorder, bipolar III disorder, cyclothymic disorder, and chronic hypomania.

[0346] Mental disorders are pathological conditions of the brain characterized by identifiable signs that result in abnormalities in cognition, emotion, or mood, or in behavior, with the highest degree of integrative expression. These disorders may vary in the severity of the signs, the duration, and the functional impairment. Mental disorders afflict millions of people worldwide, causing immense suffering and economic burdens through loss of productivity. Mood disorders are defined as a heterogeneous, typically relapsing group of mental disorders, often characterized by pervasive mood disorders, psychomotor dysfunction, and autonomic symptoms, including unipolar (depressive) and bipolar (manic-depressive) disorders. Suicide is the most troubling problem in patients with mood disorders, accounting for 15–25% of untreated deaths; failure to recognize depression, or its inadequate treatment, contributes to 50–70% of all suicides.

[0347] In various embodiments, neurological disorders include depression (e.g., major depressive disorder or dysthymia); bipolar disorder, seasonal affective disorder; cognitive impairment; fibromyalgia; pain (e.g., neuropathic pain); sleep-related disorders (e.g., sleep apnea, insomnia, narcolepsy, cataplexy) (including those sleep disorders caused by mental states); chronic fatigue syndrome; attention deficit disorder (ADD); attention deficit hyperactivity disorder (ADHD); restless legs syndrome; schizophrenia; anxiety (e.g., generalized anxiety disorder, social anxiety disorder, panic disorder); obsessive-compulsive disorder; post-traumatic stress disorder; seasonal affective disorder (SAD); premenstrual anxiety; postmenstrual vasomotor symptoms (e.g., feeling hot, night sweats); neurodegenerative diseases (e.g., Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis); manic disorder; dysthymia; cyclothymic disorder; obesity; and substance abuse or addiction (e.g., cocaine addiction, nicotine addiction). In yet another embodiment, the compounds provided herein are useful for treating, preventing, and / or managing two or more coexisting symptoms / disorders, such as psychosis and depression.

[0348] Neurological disorders also include, but are not limited to, brain dysfunctions such as senile dementia, Alzheimer's disease, dementia, memory loss, amnesia / amnesia syndrome, epilepsy, confusion of consciousness, coma, decreased attention, speech disorders, Lennox syndrome, autism and hyperactivity syndrome.

[0349] In various embodiments, the diseases or disorders treated by the pharmaceuticals and methods of the present invention include one or more mood disorders, bipolar disorder (BPD), bipolar depression, sleep disorders, REM behavior disorder, psychiatric disorders, Alzheimer's disease with agitation and / or psychosis, Parkinson's disease with psychosis, schizophrenia, diminished psychotic syndrome, prodromal schizophrenia, and schizoaffective disorder.

[0350] In various embodiments, neurological or psychiatric disorders or disorders include one or more mood disorders, bipolar disorder (BPD), bipolar depression, sleep disorders, REM behavior disorder, mental disorders, Alzheimer's disease with agitation and / or psychosis, Parkinson's disease with psychosis, schizophrenia, diminished psychotic syndrome, prodromal schizophrenia, and schizoaffective disorder.

[0351] In various embodiments, neurological or psychiatric disorders or disorders include psychoses including "schizophrenic spectrum" disorders such as schizophrenia (paranoid, disorganized, catatonic, or undifferentiated), schizophrenic disorder, schizoaffective disorder, delusional disorder, short-term mental disorder, shared mental disorder, psychoaffective disorder, mental aggression, mental confusion, Parkinsonian psychosis, excitatory psychosis, mental disorders attributable to general health conditions, and substance-induced or drug-induced (e.g., phencyclidine, ketamine and other dissociative narcotics, amphetamine and other psychostimulants and cocaine) mental disorders, psychoses associated with affective disorders, short-term response psychosis, schizoaffective psychosis, schizotypal or schizotypal personality disorder, or disorders associated with psychosis including both positive, negative and cognitive signs of schizophrenia and other psychoses (major depressive disorder, manic-depressive disorder (bipolar disorder)). Anxiety disorders including (such as) Alzheimer's disease and post-traumatic stress disorder; acute stress disorder, agoraphobia, generalized anxiety disorder, obsessive-compulsive disorder, panic attacks, panic disorder, post-traumatic stress disorder, separation anxiety disorder, social phobia, specific phobias, substance-induced anxiety disorder and anxiety attributable to a general health condition; substance-related disorders and addictive behaviors (substance-induced confusion, persistent dementia, persistent amnesia, mental disorders or anxiety disorders; including tolerance, dependence or withdrawal from substances including alcohol, amphetamines, cannabis, cocaine, hallucinogens, inhalants, nicotine, opioids, phencyclidine, sedatives, hypnotics, or anxiolytics); and Alzheimer's disease with agitation and / or psychosis.

[0352] In some embodiments, a method for treating schizophrenia is provided, comprising administering (S)-TPMA or a pharmaceutically acceptable salt thereof to a formulation (e.g., a tablet) as described herein, in an amount of about 25 mg to about 100 mg per day, based on the free base. In some embodiments, the amount is about 25 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 75 mg, about 80 mg, about 90 mg, or about 100 mg per day, based on the free base, of (S)-TPMA or a pharmaceutically acceptable salt thereof.

[0353] In various embodiments, neurological or psychiatric disorders or conditions are selected from, but are not limited to, depressive disorders, including unipolar depression, seasonal affective disorder, postpartum depression, atypical depression, catatonic depression, senile depression, endogenous depression, melancholic depression, perinatal depression, situational depression, chronic depression, bipolar depression, major depressive disorder (MDD), major depressive disorder with mixed features (MDD-MF), treatment-resistant depression (TRD), and mood disorders, and are associated with depressed mood (sadness), difficulty concentrating, insomnia, fatigue, loss of appetite, excessive guilt and suicidal thoughts, premenstrual syndrome (PMS) and premenstrual dysphoric disorder (PDD), mood disorders attributable to general health conditions, and substance-induced mood disorders.

[0354] In various embodiments, the neurological or psychiatric disorder or disorder is selected from, but is not limited to, bipolar disorders, including, bipolar depression, bipolar I disorder, bipolar II disorder, cyclothymic disorder, substance / drug-induced bipolar and related disorder, bipolar and related disorder resulting from another medical condition, other specific bipolar and related disorder, and nonspecific bipolar and related disorder.

[0355] In various embodiments, neurological or psychiatric disorders or conditions include, but are not limited to, eating disorders, including, appetite abnormalities such as obesity, bulimia nervosa, pica, and impulsive eating disorders.

[0356] In various embodiments, neurological or psychiatric disorders or conditions are selected from, but are not limited to, sleep disorders including, insomnia, sleep disorders, jet lag, hypersomnia, cataplexy, sleep apnea, obstructive sleep apnea, REM sleep behavior disorder, restless legs syndrome, periodic limb movement disorder, circadian rhythm sleep disorder, delayed sleep phase disorder, somnambulism, night terrors, nocturnal enuresis, REM sleep behavior disorder, shift work sleep disorder, excessive daytime sleepiness, non-24-hour sleep-wake syndrome, sleep paralysis, and narcolepsy.

[0357] In various embodiments, the neurological or psychiatric disorder or disorder is bipolar disorder. Bipolar disorder (including both bipolar I and bipolar II) is a serious mental disorder that has an epidemic of about 2% of the population and affects both sexes equally. It is characterized by relapsing-remitting symptoms that cycle between elevated mood (i.e., manic episodes) and depressed mood, and it is distinguished from other disorders such as major depressive disorder and schizophrenia. Bipolar I is defined by the occurrence of complete mania, although most individuals experience significant depression. Signs of mania include elevated or agitated mood, high activity, grandiosity, decreased need for sleep, dizzying thoughts, and, in some cases, psychosis. Depressive episodes are characterized by anhedonia, sadness, hopelessness, low self-esteem, decreased concentration, and lethargy. Bipolar II disorder is defined as the occurrence of major depressive episodes and hypomanic (less severe than manic) episodes, but patients spend a significant amount of time in depressive states. Other related symptoms include cyclothymic disorder.

[0358] In bipolar I disorder, mature manic and major depressive episodes alternate. Bipolar I disorder typically begins with depression and is characterized by at least one manic and elevated period during its course. The depressive period can be a prelude to the manic episode or a aftermath, and the depression and manic episodes can be separated by months or even years.

[0359] In bipolar II disorder, depressive episodes alternate with hypomania (relatively mild, with a non-psychotic period usually <1 week). During hypomanic episodes, mood becomes brighter, sleep needs decrease, and psychomotor activity accelerates beyond the patient's normal level. Often, the alternation is triggered by circadian factors (e.g., sleeping during depressive episodes and waking up early in hypomanic mornings). Hypersomnia and overeating are characteristic and may recur seasonally (e.g., in fall or winter); insomnia and loss of appetite occur during depressive episodes. For some, the duration of the hypomanic period is applicable because it is associated with high energy, self-confidence, and above-average social functioning. Most patients who experience a euphoric mood elevation at the end of a depressive episode do not report it unless specifically asked.

[0360] Patients with a major depressive episode and a family history of bipolar disorder (informally referred to as bipolar type III) often exhibit elusive hypomanic tendencies; their temperament is described as elevated (i.e., active, motivated, and results-oriented).

[0361] In cyclothymic disorder, periods of mild hypomania and minor depression occur in irregular courses, each lasting two or three days. Cyclothymic disorder is usually a precursor to bipolar II disorder. However, it can also occur as extreme irritability without being aggravated by major mood disorder. In such cases, short cycles of delayed depression, accompanied by low self-confidence and increased sleep, are replaced by increased euphoria or enthusiasm, and sleep duration is also reduced. In another form, mild depressive features are dominant; the bipolar tendency is mainly indicated by how easily euphoria or irritability is induced by antidepressants. In the clinically rare form of chronic hypomania, periods of euphoria are dominant, and sleep duration is habitually reduced to less than six hours. This type of person is always cheerful, confident, energetic, full of plans, overly involved without thinking ahead, and meddlesome; such a person rushes up to people and speaks to them with an unrelenting force.

[0362] Therefore, in various embodiments, neurological or psychiatric disorders or disorders include one or more bipolar I disorder, bipolar II disorder, cyclothymic disorder, other specific bipolar and related disorders, or unspecified bipolar and related disorders, as well as bipolar I or bipolar II disorder with the designation of anxiety disorder, mixed features, rapid circulatory, melancholic, atypical, mood-congruent psychotic, mood-incongruent psychotic, catatonic, perinatal onset, and / or seasonal pattern. A recent paper by Hu et al. [Prim Care Companion CNS Disord. 2014;16(2):PCC.13r01599] emphasizes that bipolar disorder is commonly encountered in the initial treatment setting but is often misdiagnosed or not diagnosed at all. The DSM-5 attempts to capture the majority of patients with subsyndromic mixed signs, including mixed designations.

[0363] In various embodiments, neurological or psychiatric disorders or conditions are depressive disorders. Depressive disorders include, but are not limited to, unipolar depression, seasonal affective disorder and postpartum depression, atypical depression, catatonic depression, senile depression, endogenous depression, melancholic depression, perinatal depression, situational depression, chronic depression, bipolar depression, major depressive disorder (MDD), major depressive disorder with mixed features (MDD-MF), treatment-resistant depression (TRD), and dysthymia, and are associated with depressed mood (sadness), difficulty concentrating, insomnia, fatigue, loss of appetite, excessive guilt and suicidal thoughts, premenstrual syndrome (PMS) and premenstrual dysphoric disorder (PDD), mood disorders attributable to general health conditions, and substance-induced mood disorders.

[0364] Depression is an emotional disorder, and its etiology cannot be explained by any single cause or theory. Unfortunately, treatment options are limited for depressed patients who show a suboptimal clinical response to antidepressant treatment. Approximately 30% of patients who initiate antidepressant treatment show a suboptimal or delayed clinical response to the first-line antidepressant commonly used to treat depression.

[0365] Typically, if a patient shows a suboptimal or delayed clinical response several weeks after being treated with antidepressants, the clinician's first approach is to increase the dose of the antidepressant. If the patient's response remains unsatisfactory even after increasing the dose, the most common approaches that many clinicians will pursue are: a) switching to a different antidepressant; b) adding a second antidepressant; or c) attempting augmentation therapy by administering medications such as lithium carbonate, thyroid hormones (triiodotyrosine), psychostimulants, modafinil, atypical antipsychotics, buspirone, or pindolol.

[0366] In the full manifestation of the syndrome, clinical depression presents as major depressive disorder, with a course of episodes and varying degrees of recurring manifestations between episodes. The mood is typically depressed, irritable, and / or anxious. The patient may appear severely ill, with furrowed brows, downturned lips, a hunched posture, poor eye contact, and curt (or no) conversation. The pathological mood may be accompanied by preoccupation with guilt, self-deprecating thoughts, difficulty concentrating, indecisiveness, decreased interest in normal activities, social withdrawal, helplessness, despair, and recurrent thoughts of death and suicide. Sleep disturbances are common. In some cases, the pathological mood is so severe that tears run dry; the patient complains of being unable to experience normal emotions, including sadness, joy, and contentment, and that the world has become colorless, lifeless, and dead.

[0367] Melancholy (formerly known as endogenous depression) is characterized by marked mental and behavioral blunting or agitation (e.g., restlessness, clasping hands, pressure to speak), weight loss, irrational guilt, and a loss of the ability to experience satisfaction. Mood and activity vary from day to day, but mornings are the worst. Many melancholic individuals complain of difficulty falling asleep, frequent awakenings, and insomnia in the middle of the night or early morning. Sexual desire is often reduced or absent. Amenorrhea may occur. Loss of appetite and weight loss can lead to electrolyte imbalances and secondary disorders.

[0368] In atypical depression, reverse vegetative features influence clinical symptoms: these include anxiety phobias, evening worsening, early insomnia, hypersomnia that often extends into the day, and bulimia with weight gain. Unlike patients with melancholy, patients with atypical depression show bright moods in response to potentially positive events, but often fall into paralytic depression with even minor adversity. Atypical depression and bipolar II disorder overlap considerably.

[0369] In dysthymic disorder, depressive symptoms typically begin unconsciously in childhood or adolescence and progress intermittently or at a low grade over several years or decades; episodes of major depression may exacerbate it (double depression). In pure dysthymia, signs of depression occur at a subthreshold level and largely overlap with signs of a depressive temperament: habitually melancholic, pessimistic, lacking in humor, or unhappy; passive and apathetic; introverted; skeptical, supercritical, or disgruntled; self-critical, blaming, self-deprecating; and preoccupation with shortcomings, failures, and negative events.

[0370] Thorough evaluation of a large number of people with depression revealed the characteristics of bipolar disorder, and one in five patients with depressive disorder also develops frank hypomania or mania. The switch from unipolar disorder to bipolar disorder almost always occurs within five years of the onset of depressive symptoms. Predictors of the switch include early onset of depression (under 25 years of age), postpartum depression, frequent depressive episodes, rapid mood improvement with physical treatments (e.g., antidepressants, phototherapy, sleep deprivation, electroconvulsive therapy), and a three-generation consecutive history of mood disorders.

[0371] Between episodes, patients with bipolar disorder exhibit depressed moods, sometimes high-energy activity; developmental and social dysfunction is more common in bipolar depression than in unipolar disorder. Compared to unipolar disorder, depressive episodes in bipolar disorder are shorter (3-6 months), the age of onset is younger, the onset of episodes is rapid, and the cycle (time from the onset of one episode to the onset of the next) is shorter. Periodicity is particularly pronounced in rapidly cyclical bipolar disorder (usually defined as four or more episodes per year). In addition, depressive episodes in bipolar disorder are a challenging factor in treating BPD. For example, psychiatrists show that while approximately 25% of patients with bipolar disorder as a whole are refractory during manic episodes, approximately 70% are refractory during depressive episodes.

[0372] Therefore, in various embodiments, neurological or psychiatric disorders or disorders include one or more bipolar depression, major depressive disorder (MDD), persistent depressive disorder (dysthymia), premenstrual dysphoric disorder (PMDD), major depressive disorder with mixed features (MDD-MF), depressive disorder due to another condition, other specific depressive disorder, unspecified depressive disorder, or treatment-resistant depression (TRD), and MDD with the designation of anxiety disorder, with mixed features, with melancholic features, with atypical features, with mood-congruent psychotic features, with mood-congruent psychotic features, with catatonic features, with perinatal onset, and / or seasonal pattern, and seasonal affective disorder.

[0373] It should be understood that TRD is a term used in the field of clinical psychiatry to describe cases of major depressive disorder (MDD) that do not respond adequately to an appropriate course of at least two antidepressants.

[0374] In various embodiments, depressive disorders are associated with acute suicidal tendencies or suicidal ideation. The U.S. Food and Drug Administration employs a “black box” label warning indicating that antidepressants may increase the risk of suicidal thoughts and behaviors in certain children, adolescents, and young adults (up to 24 years of age) with depressive disorders such as MDD. In various embodiments, the compositions and methods of the present invention are not considered to increase the risk of suicidal thoughts and behaviors in children, adolescents, and / or young adults with depressive disorders, e.g., MDD. In various embodiments, the present invention provides agents for treating one or more signs of a depressive disorder (e.g., MDD) in children, adolescents, and / or young adults without increasing the risk of suicidal thoughts and behaviors, and provides methods for treating such symptoms.

[0375] In various embodiments, the neurological or psychiatric disorder or disorder is schizophrenia. Schizophrenia is a disorder of unknown cause, usually first appearing in adulthood and becoming prominent by features such as psychotic symptoms, gradual progression and development, and / or declines in social behavior and professional competence. Characteristic psychotic signs include disturbances of thought content (e.g., multiple, fragmented, incoherent, unbelievable, or simply delusional content, or persecutory thoughts), and disturbances of mind (e.g., loss of associative ability, lack of imagination, incomprehensible incoherence), as well as disturbances of perception (e.g., hallucinations), affective disturbances (e.g., superficial or inappropriate feelings), disturbances of self-perception, intention, impulse, and / or relationships with people, and psychomotor disturbances (e.g., catatonia). Other signs may also be associated with the disorder. Schizophrenia is classified into subgroups: paranoid type, characterized by delusions and hallucinations, lack of thought disorder, disorganized behavior, and flattened emotions; disorganized type, also known as "Heferen's schizophrenia," where thought disorder and flattened emotions coexist; catatonic type, characterized by marked psychomotor disturbances and symptoms that may include catatonic stupor and spleen-like flexibility; and undifferentiated type, where signs of psychosis are present but the criteria for paranoid, disorganized, or catatonic types are not met. The signs of schizophrenia usually manifest themselves in three broad categories: positive, negative, and cognitive signs. Positive signs are those that indicate an "excess" of normal experiences, such as hallucinations and delusions. Negative signs are those in which the patient suffers from a lack of normal experiences, such as anhedonia and lack of social interaction. Cognitive signs are associated with cognitive impairments in schizophrenia, such as persistent lack of attention and lack of decision-making.

[0376] Accordingly, in various embodiments, neurological or psychiatric disorders or disorders include one or more schizotypal (personality) disorders, delusional disorders, short-term mental disorders, schizotypal disorders, schizophrenia, schizoaffective disorders, substance / drug-induced mental disorders, mental disorders resulting from other medical conditions, other specific schizotypal spectrum disorders and other mental disorders, unspecified schizotypal spectrum disorders and other mental disorders.

[0377] Schizoaffective disorder encompasses symptoms that include both schizophrenia and mood disorders, such as major depressive disorder and bipolar disorder.

[0378] In various embodiments, a neurological or psychiatric disorder or condition is an anxiety disorder. Anxiety disorders are characterized by fear, worry, and anxiety, which are usually generalized and unfocused as an overreaction to a situation. Anxiety disorders differ in the type of situation or object that triggers fear, anxiety, or avoidance behavior and associated cognitive thoughts. Anxiety differs from fear in that anxiety is an emotional response to the perception of a future threat, whereas fear is perceived or associated with an actual, imminent threat. They also differ in the content of the thoughts and beliefs associated with them. Examples of anxiety disorders include separation anxiety disorder, selective mutism, specific phobias, social anxiety disorder (sociophobia), panic disorder, designated panic attack disorder, agoraphobia, generalized anxiety disorder, substance / drug-induced anxiety disorder, anxiety disorder attributable to another medical condition, illness anxiety disorder, social (practical) communication disorder, other specific anxiety disorders, and unspecified anxiety disorders; stressor-related disorders, including reactive attachment disorder, disinhibited social interaction disorder, post-traumatic stress disorder (PTSD), acute stress disorder, and adjustment disorders.

[0379] In various embodiments, neurological or psychiatric disorders or disorders are sleep disorders that include, but are not limited to, sleep disorders caused by mental conditions, including, insomnia, sleep disturbances, jet lag, hypersomnia, cataplexy, sleep-related disorders (e.g., sleep apnea, insomnia, narcolepsy, cataplexy), obstructive sleep apnea, REM sleep behavior disorder, restless legs syndrome, periodic limb movement disorder, circadian rhythm sleep disorder, delayed sleep phase disorder, sleepwalking, night terrors, nocturnal enuresis, REM sleep behavior disorder, shift work sleep disorder, excessive daytime sleepiness, non-24-hour sleep-wake disorder, sleep paralysis, and narcolepsy.

[0380] The following embodiments are also provided herein. Embodiment 1. A formulation comprising a salt of (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethaneamine and one or more excipients, wherein the amount of the salt of (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethaneamine is about 2 to about 80% w / w based on the free base. Embodiment 2. A salt of (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethaneamine is: (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine hydrochloride, (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine besylate, (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine R-mandelate, (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine L-tartrate, (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine D-tartrate, (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine mesylate, and (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethaneamine L-malic acid A formulation according to Embodiment 1, selected from the above. Embodiment 3. The formulation according to Embodiment 2, wherein the salt of (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethaneamine is crystalline. Embodiment 4. The formulation according to Embodiment 3, characterized by a powder X-ray diffraction pattern in which crystalline (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine hydrochloride is characterized by peaks at 9.6±0.2°, 14.9±0.2°, 20.5±0.2° and 25.1±0.2°, with 2-theta as the unit. Embodiment 5. The formulation according to Embodiment 4, further characterized by a powder X-ray diffraction pattern in which crystalline (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine hydrochloride further includes peaks at 20.2±0.2° and 20.8±0.2° with 2-theta as the unit. Embodiment 6. The formulation according to Embodiment 4 or Embodiment 5, further characterized by a powder X-ray diffraction pattern further comprising two or more prominent peaks of crystalline (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine hydrochloride, with 2-theta units at 17.9±0.2°, 24.8±0.2°, and 27.1±0.2°. Embodiment 7. A formulation according to any one of Embodiments 4 to 6, wherein crystalline (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine hydrochloride is characterized by a powder X-ray diffraction pattern substantially consistent with that of Figure 2B. Embodiment 8. A formulation according to any one of Embodiments 4 to 7, wherein crystalline (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine hydrochloride has a differential scanning calorimetry thermogram including a peak at 214±2℃. Embodiment 9. A formulation according to any one of Embodiments 4 to 8, wherein crystalline (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine hydrochloride has a differential scanning calorimetry thermogram substantially consistent with that of Figure 3A. Embodiment 10. A formulation according to any one of Embodiments 3 to 9, wherein crystalline (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine hydrochloride is characterized by monoclinic space group P21. Embodiment 11. A formulation according to any one of Embodiments 3 to 10, wherein the crystalline (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine hydrochloride has unit cell dimensions: a=approximately 9.2 Å, b=approximately 11.2 Å, c=approximately 10.2 Å, α=approximately 90°, β=approximately 92°, and γ=approximately 90°. Embodiment 12. A formulation according to any one of Embodiments 3 to 11, wherein crystalline (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine hydrochloride has a chiral purity greater than approximately 90% of (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine hydrochloride. Embodiment 13. A formulation according to any one of Embodiments 3 to 12, wherein crystalline (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine hydrochloride has a chiral purity greater than approximately 99% of (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine hydrochloride. Embodiment 14. The formulation according to Embodiment 3, characterized by a powder X-ray diffraction pattern in which crystalline (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine hydrochloride has peaks at 8.6±0.2°, 17.2±0.2°, and 25.9±0.2°, with 2-theta as the unit. Embodiment 15. The formulation according to Embodiment 14, wherein crystalline (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine hydrochloride is characterized by a powder X-ray diffraction pattern substantially consistent with that of Figure 2C. Embodiment 16. The formulation according to Embodiment 14 or Embodiment 15, wherein crystalline (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine hydrochloride has a differential scanning calorimetry thermogram including a peak at 215±2℃. Embodiment 17. A formulation according to any one of Embodiments 14 to 16, wherein crystalline (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine hydrochloride has a differential scanning calorimetry thermogram substantially consistent with Figure 3B. Embodiment 18. A formulation according to any one of Embodiments 14 to 17, wherein crystalline (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine hydrochloride is characterized by the orthorhombic space group P212121. Embodiment 19. A formulation according to any one of Embodiments 3 and 14 to 17, wherein crystalline (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine hydrochloride has unit cell dimensions: a = approximately 5.1 Å, b = approximately 10.2 Å, c = approximately 20.5 Å, α = approximately 90°, β = approximately 90°, and γ = approximately 90°. Embodiment 20. The formulation according to Embodiment 2, wherein the salt of (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine is (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine besylate. Embodiment 21. The formulation according to Embodiment 2, wherein the salt of (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethaneamine is (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethaneamine R-mandelate. Embodiment 22. The formulation according to Embodiment 2, wherein the salt of (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethaneamine is (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethaneamine L-tartrate. Embodiment 23. The formulation according to Embodiment 2, wherein the salt of (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethaneamine is (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethaneamine D-tartrate. Embodiment 24. The formulation according to Embodiment 2, wherein the salt of (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine is (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine mesylate. Embodiment 25. The formulation according to Embodiment 2, wherein the salt of (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethaneamine is (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethaneamine L-malic acid. Embodiment 26. The formulation according to any one of Embodiments 1 to 25, wherein the formulation is a tablet. Embodiment 27. A formulation according to any one of Embodiments 1 to 26, wherein the amount of salt of (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethaneamine is about 50 to about 80% w / w. Embodiment 28. A formulation according to any one of Embodiments 1 to 26, wherein the amount of salt of (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine is about 60 to about 80% w / w. Embodiment 29. A formulation according to any one of Embodiments 1 to 26, wherein the amount of the salt of (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine is approximately 70% w / w. Embodiment 30. The formulation according to any one of Embodiments 1 to 29, wherein the excipient is one or more fillers. Embodiment 31. The formulation according to Embodiment 30, wherein the amount of filler is approximately 10 to approximately 50% w / w. Embodiment 32. The formulation according to Embodiment 30, wherein the amount of filler is approximately 20 to approximately 40% w / w. Embodiment 33. The formulation according to any one of Embodiments 30 to 33, wherein the filler is microcrystalline cellulose, mannitol, or a mixture thereof. Embodiment 34. The formulation according to any one of Embodiments 1 to 33, wherein the excipient is one or more disintegrants. Embodiment 35. The formulation according to Embodiment 34, wherein the amount of disintegrant is approximately 0.5 to approximately 10% w / w. Embodiment 36. The formulation according to Embodiment 35, wherein the amount of disintegrant is approximately 1 to approximately 5% w / w. Embodiment 37. The formulation according to Embodiment 35, wherein the amount of disintegrant is approximately 2% w / w. Embodiment 38. The formulation according to Embodiment 37, wherein the disintegrant is sodium starch glycolate. Embodiment 39. A formulation according to any one of Embodiments 1 to 38, wherein the excipient comprises one or more lubricants. Embodiment 40. The formulation according to Embodiment 39, wherein the amount of lubricant is approximately 0.1 to approximately 0.5% w / w. Embodiment 41. The formulation according to Embodiment 39, wherein the amount of lubricant is approximately 0.2% w / w. Embodiment 42. The formulation according to Embodiment 41, wherein the lubricant is magnesium stearate. Embodiment 43. The formulation according to any one of Embodiments 1 to 42, further comprising a coating agent. Embodiment 44. A formulation according to any one of Embodiments 1 to 29, comprising a salt of (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine, a filler, a disintegrant, and a lubricant. Embodiment 45. A formulation according to any one of Embodiments 1 to 19, comprising (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine hydrochloride, a filler, a disintegrant, and a lubricant. Embodiment 46. A formulation according to any one of Embodiments 1 to 19 and 45, comprising (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine hydrochloride, microcrystalline cellulose, mannitol, sodium starch glycolate, and magnesium stearate. Embodiment 47. A method for treating a neurological disorder or impairment, comprising administering to a subject a therapeutically effective amount of the formulation described in any one of Embodiments 1 to 46. Embodiment 48. The method according to Embodiment 47, wherein the neurological disorder or disorder is schizophrenia. Embodiment 49. The method according to Embodiment 47, wherein the neurological disorder or disorder is schizophrenia spectrum disorder, schizophrenia negative symptoms, diminished psychotic syndrome, prodromal schizophrenia, delusional disorder, psychosis, diminished psychotic syndrome, mental disorder, mental confusion, Tourette syndrome, post-traumatic stress disorder, behavioral disorder, affective disorder, depression, bipolar disorder, major depressive disorder, mood swings, bipolar disorder, manic disorder, seasonal affective disorder, obsessive-compulsive disorder, narcolepsy, REM behavior disorder, substance abuse or addiction, Lesch-Nyhan disease, Wilson's disease, autism, Alzheimer's disease, agitation and psychosis, or Huntington's disease. Embodiment 50. The method according to Embodiment 49, wherein the schizophrenia spectrum disorder is selected from schizophrenia, diminished psychotic syndrome, prodromal schizophrenia, schizoid personality disorder, and schizophrenic personality disorder. Embodiment 51. The method according to any one of Embodiments 47 to 49, wherein the subject is administered approximately 25 mg to approximately 100 mg of a salt of (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine per day. Embodiment 52. A method for producing (4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethaneamine, (a) Reacting 2-(thiophen-3-yl)ethane-1-ol with N-methylaminoacetaldehyde dimethylacetal and trifluic acid to obtain (4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethaneamine trifluoromethanesulfonate; and (b) React (4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethaneamine trifluoromethanesulfonate with a base to obtain (4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethaneamine; A manufacturing method that includes the following. Embodiment 53. A method for producing (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethaneamine, (a) React 2-(thiophen-3-yl)ethane-1-ol with N-methylaminoacetaldehyde dimethylacetal and trifluic acid to obtain (4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethaneamine trifluoromethanesulfonate; (b) React (4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethaneamine trifluoromethanesulfonate with a base to obtain (4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethaneamine; (c)(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine is reacted with (R)-mandelic acid to obtain (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine (R)-mandelate; (d)(S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethaneamine (R)-mandelate is reacted with a base to obtain (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethaneamine; A manufacturing method that includes the following. In addition to the modifications described herein, various modifications of the invention will be apparent to those skilled in the art from the foregoing. Such modifications are also within the scope of the attached claims. All documents listed herein, including all patents, patent applications, and publications, are incorporated herein by attribution.

Claims

1. A formulation comprising a salt of (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethaneamine and one or more excipients, wherein the amount of the salt of (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethaneamine is about 2 to about 80% w / w based on the free base.

2. (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethaneamine salt: (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine hydrochloride, (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine besylate, (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine R-mandelate, (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine L-tartrate, (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine D-tartrate, (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine mesylate, and (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethaneamine L-malic acid A formulation according to claim 1, selected from the following.

3. The formulation according to claim 2, wherein the salt of (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethaneamine is crystalline.

4. The formulation according to claim 3, wherein crystalline (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine hydrochloride is characterized by a powder X-ray diffraction pattern including peaks at 9.6±0.2°, 14.9±0.2°, 20.5±0.2° and 25.1±0.2°, with 2-theta as the unit.

5. The formulation according to claim 4, wherein the crystalline (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine hydrochloride is further characterized by a powder X-ray diffraction pattern that further includes peaks at 20.2 ± 0.2° and 20.8 ± 0.2°, with 2-theta as the unit.

6. The formulation according to claim 4 or 5, wherein the crystalline (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine hydrochloride is further characterized by a powder X-ray diffraction pattern that includes two or more prominent peaks at 17.9±0.2°, 24.8±0.2°, and 27.1±0.2°, with 2-theta as the unit.

7. The formulation according to any one of claims 4 to 6, wherein crystalline (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine hydrochloride is characterized by a powder X-ray diffraction pattern substantially consistent with that of Figure 2B.

8. The formulation according to any one of claims 4 to 7, wherein the crystalline (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine hydrochloride has a differential scanning calorimetry thermogram including a peak at 214 ± 2°C.

9. The formulation according to any one of claims 4 to 8, wherein the crystalline (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine hydrochloride has a differential scanning calorimetry thermogram that substantially matches Figure 3A.

10. The formulation according to any one of claims 3 to 9, wherein crystalline (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine hydrochloride is characterized by monoclinic space group P21.

11. The formulation according to any one of claims 3 to 10, wherein the crystalline (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine hydrochloride has unit cell dimensions: a = approximately 9.2 Å, b = approximately 11.2 Å, c = approximately 10.2 Å, α = approximately 90°, β = approximately 92°, and γ = approximately 90°.

12. The formulation according to any one of claims 3 to 11, wherein the crystalline (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine hydrochloride has a chiral purity greater than approximately 90% of (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine hydrochloride.

13. The formulation according to any one of claims 3 to 12, wherein the crystalline (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine hydrochloride has a chiral purity greater than approximately 99% of (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine hydrochloride.

14. The formulation according to claim 3, wherein crystalline (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine hydrochloride is characterized by a powder X-ray diffraction pattern including peaks at 8.6±0.2°, 17.2±0.2°, and 25.9±0.2°, with 2-theta as the unit.

15. The formulation according to claim 14, wherein crystalline (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine hydrochloride is characterized by a powder X-ray diffraction pattern substantially consistent with that of Figure 2C.

16. The formulation according to claim 14 or claim 15, wherein the crystalline (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine hydrochloride has a differential scanning calorimetry thermogram including a peak at 215 ± 2°C.

17. The formulation according to any one of claims 14 to 16, wherein the crystalline (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine hydrochloride has a differential scanning calorimetry thermogram substantially consistent with Figure 3B.

18. The formulation according to any one of claims 14 to 17, wherein the crystalline (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine hydrochloride is characterized by the orthorhombic space group P212121.

19. The formulation according to claim 3 and any one of claims 14 to 17, wherein the crystalline (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine hydrochloride has unit cell dimensions: a = approximately 5.1 Å, b = approximately 10.2 Å, c = approximately 20.5 Å, α = approximately 90°, β = approximately 90°, and γ = approximately 90°.

20. The formulation according to claim 2, wherein the salt of (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine is (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine besylate.

21. The formulation according to claim 2, wherein the salt of (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethaneamine is (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethaneamine R-mandelate.

22. The formulation according to claim 2, wherein the salt of (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethaneamine is (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethaneamine L-tartrate.

23. The formulation according to claim 2, wherein the salt of (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethaneamine is (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethaneamine D-tartrate.

24. The formulation according to claim 2, wherein the salt of (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine is (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine mesylate.

25. The formulation according to claim 2, wherein the salt of (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethaneamine is (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethaneamine L-malic acid.

26. The formulation according to any one of claims 1 to 25, wherein the formulation is a tablet.

27. The formulation according to any one of claims 1 to 26, wherein the amount of salt of (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine is about 50 to about 80% w / w.

28. The formulation according to any one of claims 1 to 26, wherein the amount of salt of (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethaneamine is about 60 to about 80% w / w.

29. The formulation according to any one of claims 1 to 26, wherein the amount of the salt of (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethaneamine is approximately 70% w / w.

30. The formulation according to any one of claims 1 to 29, wherein the excipient is one or more fillers.

31. The formulation according to claim 30, wherein the amount of filler is approximately 10 to approximately 50% w / w.

32. The formulation according to claim 30, wherein the amount of filler is approximately 20 to approximately 40% w / w.

33. The formulation according to any one of claims 30 to 33, wherein the filler is microcrystalline cellulose, mannitol, or a mixture thereof.

34. A formulation according to any one of claims 1 to 33, wherein the excipient is one or more disintegrants.

35. The formulation according to claim 34, wherein the amount of disintegrant is approximately 0.5 to approximately 10% w / w.

36. The formulation according to claim 35, wherein the amount of disintegrant is approximately 1 to approximately 5% w / w.

37. The formulation according to claim 35, wherein the amount of disintegrant is approximately 2% w / w.

38. The formulation according to claim 37, wherein the disintegrant is sodium starch glycolate.

39. A formulation according to any one of claims 1 to 38, wherein the excipient comprises one or more lubricants.

40. The formulation according to claim 39, wherein the amount of lubricant is approximately 0.1 to approximately 0.5% w / w.

41. The formulation according to claim 39, wherein the amount of lubricant is approximately 0.2% w / w.

42. The formulation according to claim 41, wherein the lubricant is magnesium stearate.

43. A formulation according to any one of claims 1 to 42, further comprising a coating agent.

44. A formulation according to any one of claims 1 to 29, comprising a salt of (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine, a filler, a disintegrant, and a lubricant.

45. A formulation according to any one of claims 1 to 19, comprising (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine hydrochloride, a filler, a disintegrant, and a lubricant.

46. A formulation according to any one of claims 1 to 19 and 45, comprising (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine hydrochloride, microcrystalline cellulose, mannitol, sodium starch glycolate, and magnesium stearate.

47. A method for treating a neurological disease or disorder, comprising administering to a subject a therapeutically effective amount of the formulation described in any one of claims 1 to 46.

48. The method according to claim 47, wherein the neurological disorder or disorder is schizophrenia.

49. The method according to claim 47, wherein the neurological disorder or disorder is schizophrenia spectrum disorder, schizophrenia negative symptoms, diminished psychotic syndrome, prodromal schizophrenia, delusional disorder, psychosis, diminished psychotic syndrome, mental disorder, mental confusion, Tourette syndrome, post-traumatic stress disorder, behavioral disorder, affective disorder, depression, bipolar disorder, major depressive disorder, mood disorder, bipolar disorder, manic disorder, seasonal affective disorder, obsessive-compulsive disorder, narcolepsy, REM behavioral disorder, drug abuse or addiction, Lesch-Nyhan disease, Wilson's disease, autism, Alzheimer's disease, agitation and psychosis, or Huntington's disease.

50. The method according to claim 49, wherein the schizophrenia spectrum disorder is selected from schizophrenia, diminished psychotic syndrome, prodromal schizophrenia, schizoid personality disorder, and schizotypal personality disorder.

51. The method according to any one of claims 47 to 49, wherein the subject is administered approximately 25 mg to approximately 100 mg of a salt of (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine per day.

52. A method for producing (4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethaneamine, (a) Reacting 2-(thiophen-3-yl)ethane-1-ol with N-methylaminoacetaldehyde dimethylacetal and trifluic acid to obtain (4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethaneamine trifluoromethanesulfonate; and (b) React (4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethaneamine trifluoromethanesulfonate with a base to obtain (4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethaneamine; A manufacturing method that includes the following.

53. A method for producing (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethaneamine, (a) React 2-(thiophen-3-yl)ethane-1-ol with N-methylaminoacetaldehyde dimethylacetal and trifluic acid to obtain (4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethaneamine trifluoromethanesulfonate; (b) React (4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethaneamine trifluoromethanesulfonate with a base to obtain (4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethaneamine; (c) React (4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine with (R)-mandelic acid to obtain (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine (R)-mandelate; (d) (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethaneamine (R)-mandelate is reacted with a base to obtain (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethaneamine; A manufacturing method that includes the following.

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