Development of quantification methods for crystalline polymorphs in pharmaceutical dosage form using low-frequency Raman spectroscopy

• Project/Area Number: 16K18867
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Physical pharmacy
• Research Institution: Meiji Pharmaceutical University
• Principal Investigator: Inoue Motoki 明治薬科大学, 薬学部, 助教 (90722950)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2018: ¥650,000 (Direct Cost: ¥500,000、Indirect Cost: ¥150,000); Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: Raman分光法 / 結晶多形 / 固形製剤 / 低波数ラマン分光法 / 透過測定 / 定量 / 製剤分析 / 物性評価 / 薬学

Outline of Final Research Achievements

The purpose of this study was to quantify polymorphs of active pharmaceutical ingredients in pharmaceutical tablets using low-frequency Raman spectroscopy. Low-frequency Raman spectroscopy can discriminate crystal polymorphs. It is well known that the quantification ability of transmission mode is high than that of backscattering mode. We therefore developed transmission low-frequency Raman spectroscopy and obtained novel transmission low-frequency Raman spectra. Carbamazepine form I and III were selected as model polymorphs, and prepared mixture of polymorphs as model tablets. The root-mean-square error of cross-validation (RMSECV) of the transmission mode was 3.9 compared to 4.9 for the backscattering mode. These findings indicate that transmission mode is superior to quantify crystallinity of an API in the pharmaceutical tablet.

Academic Significance and Societal Importance of the Research Achievements

本研究では錠剤中原薬の結晶多形の定量を目的とし透過型低波数ラマン分光法を開発した。本手法は、低波数領域のラマンスペクトルを使用するため、これまで結晶形の把握に汎用されてきた通常領域ラマンスペクトルよりも識別が容易であること、後方散乱測定を透過測定とすることで、定量性を向上させることに成功した。本手法を活用した製品も発売されることからも社会的な意義は大きかったものと考えられる。

Research Products

• [Int'l Joint Research] Ondax INC(米国)
• [Int'l Joint Research] ONDAX(米国)
• [Journal Article] Transmission Low-Frequency Raman Spectroscopy for Quantification of Crystalline Polymorphs in Pharmaceutical Tablets (2019)
  • Author(s): Inoue Motoki、Hisada Hiroshi、Koide Tatsuo、Fukami Toshiro、Roy Anjan、Carriere James、Heyler Randy
  • Journal Title: Analytical Chemistry Volume: 91 Issue: 3 Pages: 1997-2003
  • DOI: 10.1021/acs.analchem.8b04365
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Real-Time Formation Monitoring of Cocrystals with Different Stoichiometries Using Probe-Type Low-Frequency Raman Spectroscopy (2017)
  • Author(s): Motoki Inoue,Hiroshi Hisada,Tatsuo Koide,James Carriere,Randy Heyler, Toshiro Fukami
  • Journal Title: Ind. Eng. Chem. Res. Volume: 56 Issue: 44 Pages: 12693-13697
  • DOI: 10.1021/acs.iecr.7b03141
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] In Situ Monitoring of Crystalline Transformation of Carbamazepine Using Probe-Type Low-Frequency Raman Spectroscopy (2017)
  • Author(s): Inoue M, Hisada H, Koide T, Carriere J, Heyler R, Fukami T
  • Journal Title: Organic Process Research Development Volume: 21 Issue: 2 Pages: 262-265
  • DOI: 10.1021/acs.oprd.6b00329
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Presentation] Quantification of Polymorphs in Pharmaceutical Tablets using Transmission Low-Frequency Raman Spectroscopy (2019)
  • Author(s): Inoue Motoki、Hisada Hiroshi、Koide Tatsuo、Fukami Toshiro、Roy Anjan、Carriere James、Heyler Randy
  • Organizer: 3rd European Conference on Pharmaceutics
  • Int'l Joint Research
• [Presentation] 透過および反射低波数ラマン分光法を用いた錠剤中共結晶の定量性比較 (2019)
  • Author(s): 長田拓美、竹内勇輝、井上元基、久田浩史、小出達夫、深水啓朗
  • Organizer: 日本薬学会第138年会
• [Presentation] 透過低波数ラマン分光法による結晶多形の定量 (2018)
  • Author(s): 井上元基、大西 優、久田浩史、小出達夫、深水啓朗
  • Organizer: 日本薬剤学会第33年会
• [Presentation] 透過型低波数ラマン分光法を用いた医薬品錠剤中共結晶の定量 (2018)
  • Author(s): 長田拓美、竹内勇輝、井上元基、久田浩史、大西優、小出達夫、深水啓朗
  • Organizer: 第62回日本薬学会関東支部大会
• [Presentation] 結晶品質の分析で活用するRaman分光測定の先端技：Raman測定で知る結晶品質と最先端分析技術 (2018)
  • Author(s): 井上元基
  • Organizer: 第12回晶析操作の基礎と実践
  • Invited
• [Presentation] 低波数ラマン分光法を用いたシクロデキストリン包接複合体の分析 (2017)
  • Author(s): 井上元基、落合陸夫、久田浩史、小出達夫、深水啓朗
  • Organizer: 日本薬学会第137年会
  • Place of Presentation: 仙台
  • Year and Date: 2017-03-25
• [Presentation] プローブ型低波数ラマン分光器によるコクリスタル形成のモニタリング (2017)
  • Author(s): 井上元基、久田浩史、小出達夫、深水啓朗
  • Organizer: 日本薬剤学会第32年会
• [Presentation] “In situ Crystallization monitoring using probe type low frequency Raman spectroscopy (2017)
  • Author(s): M. Inoue, H. Hisada, T. Koide, J. Carriere, R. Heyler, T. Fukami
  • Organizer: 6th FIP Pharmaceutical Sciences World Congress 2017
  • Int'l Joint Research
• [Presentation] Evaluation of Carbamazepine Polymorphs in Solid Dosage Forms Using Low-Frequency Raman Spectroscopy (2017)
  • Author(s): M. Inoue, H. Hisada, T. Koide, J. Carriere, R. Heyler, T. Fukami
  • Organizer: 2017 AAPS Annual Meeting
  • Int'l Joint Research
• [Presentation] Real-time monitoring of crystalline compounds using in situ low frequency Raman probe (2016)
  • Author(s): Inoue M, Hisada H, Koide T, Fukami T
  • Organizer: SCIX2016
  • Place of Presentation: Minneapolis, Minnesota, USA
  • Year and Date: 2016-09-18
  • Int'l Joint Research / Invited
• [Book] 医薬品原薬の結晶化と物性評価:その最先端技術と評価の実際 (2019)
  • Author(s): 監修： 川上亘作
  • Total Pages: 261
  • Publisher: （株）シーエムシー出版
  • ISBN: 9784781314020
• [Remarks] https://u-lab.my-pharm.ac.jp/molpharm/
• [Remarks] 明治薬科大学分子製剤学研究室
  • URL: https://www.my-pharm.ac.jp/molpharm/index.html