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JP-2026076262-A - Salt, crystalline form, and method for producing the same

JP2026076262AJP 2026076262 AJP2026076262 AJP 2026076262AJP-2026076262-A

Abstract

[Problem] To provide a pharmaceutical formulation of (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. [Selection Diagram] None

Inventors

  • アンドレア・バウアー
  • ナンドクマール・ニブリッティ・ボグル
  • シャオシア・チェン
  • シャーラ・ジャムザド
  • ロバート・ジョセフ・プリトコ
  • コスタス・サランテアス
  • ハロルド・スコット・ウィルキンソン
  • ハイタオ・ジャン
  • マイケル・ジョセフ・シゼンスキー

Assignees

  • スミトモ・ファーマ・アメリカ・インコーポレイテッド

Dates

Publication Date
20260511
Application Date
20260123
Priority Date
20180216

Claims (20)

  1. A formulation comprising a salt of (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine 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-methylmethanamine 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 The formulation according to claim 1, selected from (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethaneamine L-malic acid.
  3. 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 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 containing 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, 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.
  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. A formulation according to any one of claims 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°C.
  9. A formulation according to any one of claims 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 Figure 3A.
  10. A 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. A formulation according to any one of claims 3 to 10, wherein 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 containing 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 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°C.
  17. The formulation according to any one of claims 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.
  18. The formulation according to any one of claims 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.
  19. A formulation according to claim 3 and any one of claims 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°.
  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.

Description

This application, which cross-references related applications , claims priority to U.S. Provisional Application No. 62/710,416 filed February 16, 2018, the entirety of which disclosure is incorporated into this application 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. (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: The use of (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine in the treatment, prevention, or management of emotional disorders and various other central nervous system disorders is also disclosed in Patent 245. Active pharmaceutical ingredients (APIs) are most commonly 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., accurate dosage, compactness, portability, tastelessness, and ease of administration). In tablet preparation, the active pharmaceutical ingredient (API) almost always needs to be solid. The manufacture of solid APIs requires obtaining products with reproducible properties, such as chemical purity and composition. In the case of polymorphic crystalline solid APIs, it is crucial to generate the desired polymorphism to ensure the bioavailability and stability of the API. In addition to polymorphism considerations, tablet manufacturing 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. Figures 1A and 1B show SEM images of the crystalline (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine hydrochloride; polymorphic form A (Figures 1A and 1B).Figures 1C and 1D show SEM images of the 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 shows the XRPD pattern of form A (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine hydrochloride measured in permeation mode.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 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 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 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 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 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 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 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 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 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 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 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 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 shows various PSD (particle size distribution) data fo