2021 Fiscal Year Final Research Report
Controls of polymorph and morphology in the crystallization of pharmaceutical nanoparticles by flow process and computational chemistry
| Project/Area Number |
19K05135
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Review Section |
Basic Section 27010:Transport phenomena and unit operations-related
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| Research Institution | National Institute of Advanced Industrial Science and Technology |
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Principal Investigator |
Takebayashi Yoshihiro 国立研究開発法人産業技術総合研究所, 材料・化学領域, 主任研究員 (70357416)
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| Co-Investigator(Kenkyū-buntansha) |
三浦 俊明 国立研究開発法人産業技術総合研究所, 材料・化学領域, 主任研究員 (20358071)
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| Project Period (FY) |
2019-04-01 – 2022-03-31
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| Keywords | 医薬品 / 結晶多形 / 溶解度 / 溶媒 / 晶析 / 計算化学 / フロープロセス / 微粒子 |
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| Outline of Final Research Achievements |
To develop the experimental and computational basis for the development of continuous-flow anti-solvent crystallization of pharmaceutical solids with controlled polymorphs, we studied the solubility and thermal stability of the polymorphs and the microflow apparatus for the crystallization. The solubility of the polymorphs of famitidine and sulfathiazole was measured in various solvents and the solubility ratio between the polymorphs was analyzed on the basis of thermodynamic equations. To computationally study the solvent dependence of the solubility, the solvation free energy change was calculated by molecular dynamics simulation with thermodynamic integration method. The calculated solubility in protic solvents was in qualitative agreement with the experimental result. Using the solubility data, continuous-flow crystallization of famotidine was performed to clarify how the solvent affects the polymorph of the precipitate.
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| Free Research Field |
化学工学
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| Academic Significance and Societal Importance of the Research Achievements |
医薬品の結晶多形の違いは薬効に大きく影響するため、特定の多形をもつ結晶を再現性良く連続的に生産できる手法の開発は製薬プロセスを進化させるために求められている技術である。また、多形間の溶解度や熱安定性の違い、および、それらに対して溶媒の種類が与える影響を熱力学的・計算化学的に明らかにすることは、それらを支配するメカニズムを解明するとともに、より精度よく予測するための手法を開発するうえで学術的にも重要な意義をもつ。
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