Pharmaceutical composition in which production of impurities is suppressed
Inventors
OCHII, Yuya • NISHIDA, Chika • KIMURA, Go • Oda, Shinichi • MAJIMA, Shohei • Oshima, Takahiro
Assignees
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Publication Number
US-12570627-B2
Publication Date
2026-03-10
Expiration Date
Abstract
By wet-pulverizing a compound represented by Formula (I), a pharmaceutically acceptable salt thereof, or a solvate thereof (hereinafter referred to as a compound represented by Formula (I) or the like), it is possible to provide a crystal of the compound represented by Formula (I) or the like and a pharmaceutical composition containing the same having excellent stability. In addition, by wet-kneading and/or wet-granulating the compound represented by Formula (I) or the like, it is possible to provide a pharmaceutical composition containing the compound represented by Formula (I) or the like having excellent stability.
Core Innovation
The document describes a method for producing a pharmaceutical composition containing a compound represented by Formula (I), including a pharmaceutically acceptable salt thereof or a solvate thereof, by wet-pulverizing the compound and/or by wet-kneading and/or wet-granulating the compound. The wet-processing is positioned as a way to generate the pharmaceutical composition while suppressing formation of a related substance, a compound represented by Formula (III), during stability testing.
The disclosed crystal production method is characterized by wet-pulverizing the compound represented by Formula (I), the pharmaceutically acceptable salt thereof, or the solvate thereof to obtain a crystal form. The resulting crystals are defined by particle size distribution, including the 90% particle size distribution of 100 µm or less, and by solid-state characterization, including anhydrous and dihydrate crystals of Formula (I) as well as X-ray powder diffraction peak positions at specified 2θ values.
The document also describes pharmaceutical compositions as tablets or uncoated granules that contain a hydroxycarboxylic acid ester, a polyhydric alcohol ester, and/or a polyether in a core tablet or an uncoated granule. It further specifies combinations of excipients and impurity-related constraints in connection with stability behavior, while maintaining tablet physical properties such as dissolution and tablet hardness profiles as described in the provided content.
Claims Coverage
The partial content includes five independent claims. The claim set centers on wet-pulverizing and wet-kneading/wet-granulating for pharmaceutical composition production, tablet or granule compositions with specified excipients, wet-pulverizing to produce a crystal, and chromatographic analysis methods for determining the content or content ratio of Formula (III).
Wet-pulverizing and wet-kneading/wet-granulating to produce a pharmaceutical composition
A method for producing a pharmaceutical composition containing a compound represented by Formula (I), or a pharmaceutically acceptable salt thereof, or a solvate thereof, comprising wet-pulverizing the compound and/or wet-kneading and/or wet-granulating the compound.
Tablet or granule containing specified ester/polyether excipients in a core
A pharmaceutical composition comprising a compound represented by Formula (I), or a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein the pharmaceutical composition is a tablet or a granule and contains a hydroxycarboxylic acid ester, a polyhydric alcohol ester, and/or a polyether in a core tablet or an uncoated granule.
Wet-pulverizing to produce a crystal of Formula (I)
A method for producing a crystal of a compound represented by Formula (I), or a pharmaceutically acceptable salt thereof, or a solvate thereof, characterized by wet-pulverizing the compound represented by Formula (I), the pharmaceutically acceptable salt thereof, or the solvate thereof.
Chromatographic analysis using a Formula (I) crystal or composition sample to determine Formula (III) content ratio
A method for analyzing a related substance in a sample, comprising using a crystal of a compound represented by Formula (I), or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a pharmaceutical composition containing it, as the sample and performing chromatographic analysis, and obtaining a content or a content ratio of a compound represented by Formula (III) in the chromatographic analysis.
Using Formula (III) as a standard sample to analyze Formula (III) content ratio in a Formula (I) crystal
A method for analyzing a content or a content ratio of a compound represented by Formula (III) in a crystal of a compound represented by Formula (I), or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a pharmaceutical composition containing it, wherein the compound represented by Formula (III) is used as a standard sample.
Overall, claim coverage is anchored in wet-pulverizing to produce crystals and pharmaceutical compositions, optionally with wet-kneading and wet-granulating, and in tablet or granule formulations containing hydroxycarboxylic acid ester, polyhydric alcohol ester, and/or polyether. It also covers chromatographic analysis that determines the content or content ratio of Formula (III), together with crystal characteristics including particle size distribution and X-ray powder diffraction peak positions.
Stated Advantages
Suppresses increase of the compound represented by Formula (III) during stability tests under the stated temperature and relative humidity conditions.
Controls the crystal particle size distribution, including 90% particle size distribution of 100 µm or less, when producing crystals by wet-pulverization.
Maintains dissolution and tablet hardness profiles while improving stability and impurity behavior for Formula (III).
Documented Applications
Producing a pharmaceutical composition containing a compound represented by Formula (I) in forms such as tablets or granules.
Producing a crystal of a compound represented by Formula (I), including anhydrous and dihydrate crystal forms as described in the provided content.
Analyzing a related substance in a sample by using a crystal of Formula (I), or a pharmaceutical composition containing Formula (I), followed by chromatographic analysis and obtaining a content or content ratio of Formula (III).
Analyzing the content or content ratio of Formula (III) in a crystal of Formula (I) using Formula (III) as a standard sample.
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