厚生労働科学研究費補助金

医薬品・医療機器等レギュラトリーサイエンス

総合研究事業

医薬品品質システムにおける医薬品製造・品質管理手

法の系統化及び国際調和に関する研究

（H23-医薬―一般―010）

平成24年度総括・分担研究報告書

研究代表者 香取 典子

平成25年(2013) 5月

目 次

I 総括研究報告書

医薬品の国際調和された品質管理監督システムの我が国への

導入に際しての最適化に関する研究 1

香取 典子

II 分担研究報告書

１ 包括的医薬品品質管理監督システムに関する研究 11

檜山 行雄、香取 典子

添付資料 1. 安定性モニタリング検討課題 17

添付資料 2. 安定性モニタリング GMP 施行通知案 29

添付資料 3. 安定性モニタリングにおける保存条件

に関する考察 31

添付資料 4. PDA Q10 コンフェランスプログラム 35

添付資料 5. 日本薬局方および関連事項に関する

非公式意見聞き取り論点 41

添付資料 6. ジェネリック医薬品開発企業への

聞き取り調査要項 42

２ 品質システムにおける新評価技術に関する研究 45 坂本 知昭

添付資料 1. 海外旅行記録書 53

添付資料 2.、3. 国際学会発表要旨、資料 55

添付資料 4.〜9. 国内学会発表要旨、資料 61

３ 品質システムの実践・導入に関する研究 77 小出 達夫

添付資料 国内学会発表要旨 87

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20

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Pharmaceutical Quality System (ICH Q10) Conference A Practical Approach to Effective Lifecycle Implementation of Systems and Processes for

Pharmaceutical Manufacturing Keio Plaza Hotel (Oogi Ballroom)

Located on 4F South Tower November 5 – 6, 2012 | Tokyo, Japan

As of October 25, 2012

Monday, November 5, 2012

7:00 a.m. – 5:00 p.m. Oogi Foyer Registration Open 7:00 a.m. – 8:30 a.m. Oogi Foyer Continental Breakfast 8:30 a.m. – 8:40 a.m. Welcome and Opening Remarks from Co-Chair of the Planning Committee Richard Friedman, Associate Director, OMPQ, CDER, FDA and Co-Chair, Program Planning Committee

10:10 a.m. – 10:30 a.m. Oogi Foyer Refreshment Break

8:40 a.m. – 10:10 a.m. P1: Pharmaceutical Quality System Moderator: Junko Sasaki, QA Principal, Dainippon Sumitomo and Co-Chair, Program Planning Committee Session Description: Why is a strong Quality System so fundamental to achieving and maintaining operational excellence? What can we learn from other industries? What are the cost benefits of more effective and efficient manufacturing? In the opening session, senior leaders will discuss how the industry and consumers benefit when science-based risk management is used throughout the lifecycle to assure a robust state of control. The session will address the tangible quality-business synergy reaped by "learning organizations" who proactively seek out sources of variability through daily vigilance and take advantage of contemporary technological solutions to improve product quality. 8:40 a.m. – 9:10 a.m. Outline of ICH Q10 Kouichirou Koike, Deputy Director, Compliance and Narcotics Division, Pharmaceutical and Food Safety Bureau Ministry of Health, Labour and Welfare

9:10 a.m. – 9:40 a.m. Industry Keynote Anders Vinther, PhD, Vice President, Quality Biologics Operating Unit, Global Quality, Roche

9:40 a.m. – 10:10 a.m. The Cost of Non-Compliance and Other Industries G.K. Raju, PhD, CEO, Light Pharma, Inc.

10:30 a.m. – 12:00 p.m. P2: Pharmaceutical Quality System - Continued Moderator: Anders Vinther, PhD, Vice President, Quality Biologics Operating Unit, Global Quality, Roche Session Description: Why is a strong Quality System so fundamental to achieving and maintaining operational excellence? What can we learn from other industries? What are the cost benefits of more effective and efficient manufacturing? In the opening session, senior leaders will discuss how the industry and consumers benefit when science-based risk management is used throughout the lifecycle to assure a robust state of control. The session will address the tangible quality-business synergy reaped by "learning organizations" who proactively seek out sources of variability through daily vigilance and take advantage of contemporary technological solutions to improve product quality. 10:30 a.m. – 11:00 a.m. U.S. Regulatory Perspectives Richard Friedman, Associate Director, OMPQ, CDER, FDA

11:00 a.m. – 11:30 a.m. Pharmaceuticals Quality Management System (PQS) from the Perspective of Japanese Regulations Takao Kiyohara, PhD, Advisory Expert, Pharmaceuticals and Medical Devices Agency (PMDA)

11:30 a.m. – 12:00 p.m. Q&A – Panel Discussion P1 & P2

添付資料４　PDAQ10コンフェレンスプログラム

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Monday, November 5, 2012 – Page 2 (continued) 12:00 p.m. – 1:00 p.m. TBD Lunch

2:30 p.m. – 3:00 p.m. Oogi Foyer Refreshment Break

1:00 p.m. – 2:30 p.m. P3: Management Responsibility Moderator: Neil Wilkinson, Senior Partner, NSF-DBA Session Description: ICH Q10 deliberately brings to the forefront the critical area of management responsibility within a Pharmaceutical Quality System (PQS). Deming recognized this 50 years ago, and it subsequently became a key part of the ISO 9000 series of Quality Management standards. ICH Q10 aims to reinforce the importance of management in establishing and maintaining a companywide quality culture and an effective PQS that assures a state of control and drives improvement. In this session we will hear how these concepts are used in practice within companies, and throughout their supply chains for outsourced activities and purchased materials. We will also hear current expectations as to how management should oversee the PQS. 1:00 p.m. – 1:30 p.m. What QS Means and How Management Should Oversee the System Steven Mendivil, Executive Director International Quality External Affairs, Amgen, Inc. 1:30 p.m. – 2:00 p.m. Case Study: Role of Management to Drive Industry Improvement Anders Vinther, PhD, Vice President, Quality Biologics Operating Unit, Global Quality, Roche 2:00 p.m. – 2:30 p.m. Case Study: Use of Management Review to Drive Quality and Business Improvement Xiao Zhijian, Regional Quality Director, Astra Zeneca

3:00 p.m. – 4:30 p.m. P4: Management Responsibility- Continued Moderator: Neil Wilkinson, Senior Partner, NSF-DBA Session Description: ICH Q10 deliberately brings to the forefront the critical area of management responsibility within a Pharmaceutical Quality System (PQS). Deming recognized this 50 years ago, and it subsequently became a key part of the ISO 9000 series of Quality Management standards. ICH Q10 aims to reinforce the importance of senior management in establishing and maintaining a companywide quality culture and an effective PQS that assures a state of control and drives improvement. In this session we will hear how these concepts are used in practice within companies, and throughout their supply chains for outsourced activities and purchased materials. We will also hear the regulators current expectations as to how management should oversee the PQS. 3:00 p.m. – 4:00 p.m. Case Study: Management of Outsourced Activities and Purchased Materials: Addressing the Interfaces and Management of Supply Chain (APIs and Excipients) Janeen Skutnik-Wilkinson, Partner, NSF-DBA 4:00 p.m. – 4:30 p.m. Q&A /P3 & P4 Panel Discussion

4:30 p.m. – 5:30 p.m. P5: Lifecycle Goals Moderator: Richard Johnson, President, PDA Session Description: While the PQS is applicable from development through to product discontinuation, certain elements of the PQS become more and less relevant over the lifecycle. The principles of Quality by Design can be embraced during development stage to help assure a product can be successfully commercialized using effective manufacturing and testing approaches. This session will look at how the elements and the tools of the PQS can be applied to development of drug substance and drug product, and enhance the potential for smooth technology transfer into commercial launch. Moreover, this session will look at lessons learned through commercialization and post market surveillance to effect continuous improvement of the product. 4:30 p.m. – 4:50 p.m. Technology Transfer Neil Wilkinson, Senior Partner, NSF-DBA

4:50 p.m. – 5:20 p.m. Commercial Manufacturing - Integration of PQS into GQP Tetsuhito Takarada, Advisory Deputy Director/QA, Mochida Pharmaceutical Co., Ltd 5:20 p.m. – 5:30 p.m. Q&A/Discussion

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Monday, November 5, 2012 (continued) - Tuesday, November 6, 2012 – Page 3 5:30 p.m. – 6:30 p.m. Starlight/Subaru/Comet Networking Reception

Tuesday, November 6, 2012 7:00 a.m. – 5:00 p.m. Oogi Foyer Registration Open

7:00 a.m. – 8:00 a.m. Oogi Foyer Continental Breakfast

9:30 a.m. – 10:00 a.m. Oogi Foyer Refreshment Break in Exhibit Area

8:00 a.m. – 9:30 a.m. P6: Quality System Enablers: Knowledge Management and Quality Risk Management Moderator: Barbara Mary Allen, PhD., Senior Director Global Quality Systems, Eli Lilly & Company Session Description: The lifecycle of a product can extend over many decades and so it is important that product and process knowledge is acquired, analyzed, stored and disseminated in a systematic manner. Having knowledge enables confident quality risk management to assure quality. Use of structured, formal risk management methodology facilitates consistent science-based decision-making related to products and process controls. Speakers at this session will share how these key topics relate to their quality management system and achievement of quality objectives. 8:00 a.m. – 8:30 a.m. Case Study: Knowledge Management: An Iterative Process Marty Lipa, Director, Knowledge Management Leader, Global Science, Merck & Co., Inc.

8:30 a.m. – 9:00 a.m. Regulatory Perspective on QRM and Knowledge Management Yukio Hiyama, PhD., Visiting Scientist, National Institute of Health Sciences, and Co-Chair, Program Planning Committee 9:00 a.m. – 9:30 a.m. Q&A/Discussion

10:00 a.m. – 11:00 a.m. P7: Establishing and Maintaining a State of Control Moderator: Yukio Hiyama, PhD., Visiting Scientist, National Institute of Health Sciences, and Co-Chair, Program Planning Committee Session Description: As defined by Q 10 a state of control is a condition in which the set of controls consistently provides assurance of continued process performance and product quality. This session will discuss the effective monitoring and control systems that can achieve assurance of continued suitability and capability of processes. Featured in this session will be how effective monitoring can support these goals and how they enable lifecycle approaches to validation, i.e., continued process verification. This session applies to both conventionally manufactured products and those that feature advanced manufacturing and control technologies that enable innovations in process validation. 10:00 a.m. – 10:30 a.m. State of Control Over the Lifecycle and Process Validation (New and Legacy Products) Richard Friedman, Associate Director, OMPQ, CDER, FDA

10:30 a.m. – 11:00 a.m. Case Study: Conventional and Modernized Process using Knowledge from Development and Lifecycle Monitoring to Support Continued Product Verification Barbara Mary Allen, PhD, Senior Director, Global Quality Systems, Eli Lilly & Company

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37

Tuesday, November 6, 2012 – Page 4 (continued)

12:00 p.m. – 1:00 p.m. Hana Room (Main Tower) Lunch

3:00 p.m. – 3:15 p.m. Oogi Foyer Refreshment Break

11:00 a.m. – 12:00 p.m. P8: Pharmaceutical Quality System Elements: Process Performance and Product Quality Monitoring System Moderator: Richard Friedman, Associate Director, OMPQ, CDER, FDA Session Description: This session will focus on the ability of a company to drive continual improvement of the lifecycle of a product through a robust PPPQM system element. Using sound approaches in development form the basis for a quality product, however implementation of this PQS element captures the rich data and knowledge that is obtained throughout the lifecycle phases of tech transfer, commercial manufacturing, through product discontinuation. Topics will include traditional indicators such as batch data, deviations, complaints, CAPAs, and leading indicators such as the product steward model, evaluating quality across a global network and use of statistical tools. The opportunity exists to provide process capability measurements to have a true state of control in pharmaceutical manufacturing and support modern day approaches to lifecycle validation. 11:00 a.m. – 11:25 a.m. Product Quality Management Zena Kaufman, Senior Vice President, Global Quality, Hospira, Inc.

11:25 a.m. – 11:45 a.m. Case Study: Use of Statistical Process Control Approaches to Detect Process Drift; Using Process Capability Measurement Takuya Suenaga, Program and Coordination Group, Quality Assurance Department, Chugai Pharmaceutical Co., Ltd. A member of Roche Group 11:45 a.m. – 12:00 p.m. Q&A /P7 & P8 Panel Discussion

1:00 p.m. – 2:30 p.m. P9: Pharmaceutical Quality System Elements: Continual Improvement of the Process (CAPA) Moderator: David Chesney, Vice President, Strategic Compliance Services, PAREXEL Consulting Session Description: An effective CAPA system has been an expectation for many years for companies operating to ISO 9000 Quality Management standards, including Medical Devices operating to ISO 13485. The Pharmaceutical Industry has over last decade put significant effort and resources, in a reactive mode, to managing and investigating deviations, resulting in corrective actions. However, there has been less focus on proactively undertaking preventative actions within the CAPA system. ICH Q10 requires an effective CAPA system that identifies areas that need special attention as product and process understanding expands, and implements and monitors effectiveness of related improvements. It is essential that the CAPA system does not work in isolation and that there are strong linkages with other aspects of the PQS, including Management Review. In this session speakers will present real examples of how a CAPA system can be linked within the PQS to contribute to continual improvement and a reduction in repeat issues. 1:00 p.m. – 1:30 p.m. CAPA Steven Mendivil, Executive Director International Quality External Affairs, Amgen, Inc.

1:30 p.m. – 2:00 p.m. Process Improvement John Geissler, Head of Group Compliance and Audit, Novartis

2:00 p.m. – 2:30 p.m. Management Support for Continual Improvement Susumu Endo, Global Quality Assurance Department, Takeda Pharmaceutical Co., Ltd 2:30 p.m. – 3:00 p.m. Q&A/Discussion

添付資料４　PDAQ10コンフェレンスプログラム

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Tuesday, November 6, 2012 – Page 5

5:35 p.m. – 5:45 p.m. Closing Remarks from Co-Chair of the Planning Committee Richard Friedman, Associate Director, OMPQ, CDER, FDA

3:15 p.m. – 3:45 p.m. P10: Change Management Moderator: Barbara Mary Allen, Senior Director Global Quality Systems, Eli Lilly & Company Session Description: The management of change is critical in our business, whether it concerns changes to our facilities, products, processes, equipment, computerized systems, etc. Our change management system has on the one hand to be robust enough to deal with both major change and small incremental change, but also simple and efficient enough on the other hand for people to easily understand and apply correctly. While change management systems are generally well understood and defined, lack of timely and thorough change management can lead to lingering or new quality and compliance issues. This session will reinforce the importance of carefully managing all changes, even if a change appears to be small. 3:15 p.m. – 3:45 p.m. Change Management: Enabling Quality Improvement Janeen Skutnik-Wilkinson, Partner, NSF-DBA

3:45 p.m. – 5:35 p.m. P11: Continual Improvement of the Pharmaceutical Quality System Moderator: Richard Friedman, Associate Director, OMPQ, CDER, FDA Session Description: Throughout the conference participants will have been shown how the key elements that make up a successful pharmaceutical quality system can be implemented in a practical way including continual improvement of products and processes. Once the pharmaceutical quality system is established it will need to be maintained and developed. The final session focuses on continual improvement of the pharmaceutical quality system itself. The session will show how the system contributes to its own improvement, and will include discussion of the internal and external factors that must be taken into account to keep the system fit for purpose. 3:45 p.m. – 4:15 p.m. GMP Compliance Inspection by ICH Q10 & PMDA Masatoshi Morisue, RPh., MSc., Director of GMP Inspection, Office of GMP/QMS Inspection, Pharmaceuticals and Medical Devices Agency (PMDA) 4:15 p.m. – 4:45 p.m. Case Study: How do You Know if Your PQS is a Healthy One? Zena Kaufman, Senior Vice President, Global Quality, Hospira, Inc.

4:45 p.m. – 5:15 p.m. Complacency is not an Option Barbara Mary Allen, Senior Director Global Quality Systems, Eli Lilly & Company

5:15 p.m. – 5:35 p.m. Panel Discussion

添付資料４　PDAQ10コンフェレンスプログラム

39

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,�w�DŽʼnƘ+ǣý�=�60ªęȯǹnjȰ+-_tH-2(@)ǣý�=*�*;�120ªęȯǂnjȰ+-ó¡+Ŵë� 4 �120ªę+��&70.95 THz�Ǿ+ÊÁ,©Ƌ-ǣý�=*�# ȯÙȻȰ{(�&ªðDžŋitX?Šƣ�<ȉ

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DžŋǷ�:ȡŋǷ0,ǻƮ+��&�ÊÁ,º�

Ċ�č�<((7+ÊÁĔĎ�ŸĂ�<�(�ȇ

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:�ŸÛƍäw'-�uūÏƇ�:ƂūƇ0,¦

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|Ɔę1200ªDŽȇ� ȨƻƇ�:Ě:= ÊÁ-ȡŋǷ¶0,ȇƯ?ƪ�&�<7,(Ĵý�

4 �1.64 THz�Ǿ,ÊÁ-M`W�&�;��,�(-uūÏƇ,DžŋitX,IJµ+ƒř�<

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ǚ�&�<�(�ǐ�:= y|Ɔ¢+Ç�Ź

ĎŘ�' <�(�:�ƠƲƍäw+��<ğȂ

*Ǔū,ȅǚ(ũǼ�&�ÍØ,ȞØŪ,5+9

;+Ē�Ǻ��=<ȡĉ+Ǎ8�*ǓūȂĎ�Dž

ŋitX,IJµ+ėȤ?¿3�&�<7,(Ĵý

�&�<ŕƋDz,ǤŇ-�ę,ŠǦǭȩ(�

� C-4ȳƠƲ|ƆƇ+þ�<±Ź,ėȤ � Ùȼ+ȨƻƇ?120ª,ƠƲƍäw+ļǎ�<�('Ě |ƆƇ�:Ě:= UlcnTOeH

Wn¿/|ƆƇ?70�+±Ź� ț,|ƆƇ�:Ě UlcnTOeHWn,DŽʼnç¶?ƪ�|

Ɔ®,OeHWnȯȮnjȰ'ǣý�= 1.64 THz,ÊÁ-ƠƲ|Ɔę+Ŵë��ȡŋǷ' <�(

�ƪÒ�=<OeHWn^Qtq?ƪ� ��

70�,|ƆȖïę5ª'1.60 THz�Ǿ+ŇƧ*_tH��4 0.95 THz�Ǿ+ā�*ÊÁ�©Ƌ� �=:,2$,ÊÁĔĎ-|Ɔ120ªę4'DŽʼnƘ+åê� �,Džŝ-70�,ƅ+9;5ª�¥+ǽȂ+ƂūƇDžŋ+ǻƮ���,ǻƮ�120ªę+-23ƂūƇ0ǻƮ�ó}� �(?ƪÒ

�<7,' # Ùȸ,9�+uūÏƇ�:,

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C-5ȳDžƯ,ȡ¢ñw+��<UE`Bmq,ĺ

47

�

�DžŋĖǻƮ � UE`BmqƂūƇ+ū?ŷ±�&Ě:= ±

ūŶÆƇ,UlcnTOeHWn?ÙȽ+ƪ�

ū?ŷ±®-ƂūƇ(Ç�OeHWn^Qtq?

ƪ� ��±ūŶÆę-uūÏƇ(Çţ,OeH

Wn^Qtq?ƪ��ūÏ� �(�ƧǬ�=

�,ŶÆƇ?70�'|Ɔ�<(1.64 THz,_tH�ǎ?ƪ� ÊÁ-1.60 THz+M`W��4 0.95 THz+ÊÁ�©Ƌ� ȯÙȾȰ�,Džŝ-�ȨƻƇ,|Ɔʼn(Çţ+15ª�¥+ƂūƇ+¦ǻƮ� �(?ƪ�&�;�DžƯ,ñÜ�ǓūȂĎ

+ėȤ?x�*��� <�-�,ėȤ-ā��

7,(ǐ�:= � uń�±ūŶÆƇ,ƠƲ|Ɔ'-1.64 THz,_tH�ǎ-M`W�<�(*��ȨƻƇ,ãÆ(

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,DŽʼnç¶?Ùȶȶ+ƪ� ȨƻƇ�:Ě ū

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48

�

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ž��ƥƱĦŝ?Ċč�ǃ��<�(�'� FȳƥƱƖǝ ȶȳǯŀƖǝ (1) �T. Sakamoto, A. Portieri, D.D. Arnone, P.F.

Taday, T. Kawanishi, Y. Hiyama, Coating and density distribution analysis of commercial ciprofloxacin hydrochloride monohydrate tablets by terahertz pulsed spectroscopy and imaging, J

Pharm Innov, 7, 87-93 (2012). (2) �T. Sakamoto, Y. Fujimaki, Y. Takada, K. Aida,

T. Terahara, T. Kawanishi, Y. Hiyama, Non-destructive analysis of tulobuterol crystal reservoir-type transdermal tapes using near infrared spectroscopy and imaging, J Pharm and Biomed

Anal, 74, 14-21 (2013) ȷȳò�Ɩǝ (1) Þŕ ƣňȱ�œÑőȱœŗüðȱǡƁƀuȱŧăǚȜȱȬ¤ðȱíƑŊô�UlcnTª

�ůƐ� ŻđĩȓƐȨƻƇǠȃąƯ+��

<UE`Bmq,IJµª�òƘǤŜ�ŅŕªŜ

¶ò�ƴ61Č��ȒŬȯ2012.9Ȱ (2) T. Sakamoto, T. Sasaki, J. Nishizawa, Y. Hiyama, N.

Katori, H. Okuda, Vibrational spectroscopic analysis of theophylline in a pharmaceutical granulation process using near-, mid- and far-infrared/terahertz spectroscopy, 37th

International Conference on Infrared Millimeter and Terahertz Waves, Wollongong, NSW, Australia (2012.9)

(3) T. Sasaki, K. Itatani, T. Sakamoto, J. Nishizawa, Nondestructive sample preparation of pharmaceutical samples for wide frequency range THz spectroscopy, 37th International Conference on Infrared Millimeter and Terahertz Waves (2012.9)

(4) T. Sakamoto, T. Sasaki, H. Kimura, T. Tanabe, J. Nishizawa, Y. Hiyama, N. Katori, H. Okuda, Understanding of pseudo-polymorphism conversion mechanism of theophylline under a wet granulation process using terahertz spectroscopy, International Symposium on Frontiers in Terahertz Technology, Nara (2012.11)

(5) Þŕƣňȱ�œÑőȱœŗüðȱƑȌ¸ƎȱǡƁƀuȱŧăǚȜȱȬ¤ðȱíƑŊô, UlcnTª�ů?Ɛ� Ɣ�DžŋĖǻƮbp

PO,ǤŜ, Ņŕǘò�ƴ 133 Č��ťŲȯ2013.3Ȱ

(6) T. Sakamoto, T. Sasaki, H. Kimura, T. Tanabe, Y. Fujimaki, J. Nishizawa, Y. Hiyama, N. Katori, H. Okuda, Vibrational spectroscopic analysis of pseudo-polymorphism conversion of theophylline during a tableting process, Pittsburgh Conference on Analytical Chemistry and Applied Spectroscopy, Philadelphia, PA, USA (2013.3)

GȳƣƘdzƏŤ,©ȪsƗȔƉŮ � � ƈ+*�

49

50

添付資料 図表

図１ テオフィリン無水物と一水和物の標準物質から得たテラヘルツスペクトル

0

0.1

0.2

0.3

0.4

0.5

0.6 0.8 1 1.2 1.4 1.6 1.8 2 2.2 2.4 2.6

Abs

orba

nce

Frequency (THz)

Theophylline anhydride

Theophylline monohydrate

1.60 THz

1.64 THz

図２ 造粒工程前後におけるテオフィリン及び結合剤混合物のテラヘルツスペクトル

Share granulation

Wet granulesWater

TP anhydride form

HPC

0

0.2

0.4

0.6

0.6 1 1.4 1.8 2.2 2.6

Abso

rban

ce

Frequency (THz)

1.64 THz

0

0.1

0.2

0.3

0.4

0.5

0.6 1 1.4 1.8 2.2 2.6

Abso

rban

ce

Frequency (THz)

0.95 THz

1.60 THz

図３ 70 ºCの乾燥温度における顆粒物から得たテラヘルツスペクトルの経時変化

Drying process

70 ºC

0

0.2

0.4

0.6

0.6 1 1.4 1.8 2.2 2.6

Abso

rban

ce

Frequency (THz)

1.64 THz

0

0.2

0.4

0.6

0.6 1 1.4 1.8 2.2 2.6

Abso

rban

ce

Frequency (THz)

0 min15 min

1.64 THz

1.60 THz

Wet granulesMonohydrate form

Granules (within 15 min)Converted to anhydride form

図４ 50 ºCの乾燥温度における顆粒物から得たテラヘルツスペクトルの経時変化

Drying process

50 ºC

0

0.2

0.4

0.6

0.6 1 1.4 1.8 2.2 2.6

Abso

rban

ce

Frequency (THz)

1.64 THz

0

0.1

0.2

0.3

0.4

0.6 1 1.4 1.8 2.2 2.6

Abso

rban

ce

Frequency (THz)

0 min30 min60 min120 min

1.64 THz1.60 THz

Wet granulesMonohydrate form

Granules (after 60 min)Converted to anhydride form

図５ 室温での乾燥条件（乾燥空気流入）におけるテラヘルツスペクトルの経時変化

Drying process

Wet granules (before dryness)

22.5 ºC (r.t.)

0

0.2

0.4

0.6

0.6 1 1.4 1.8 2.2 2.6

Abso

rban

ce

Frequency (THz)

1.64 THz

0

0.1

0.2

0.3

0.4

0.6 1 1.4 1.8 2.2 2.6

Abso

rban

ce

Frequency (THz)

0 min120 min1200 min

1.64 THz1.58THz

Monohydrate formGranules (after 1200 min)

During a conversion to amorphous form

図６ 真空乾燥条件におけるテラヘルツスペクトルの経時変化

Drying process

Wet granules

In vacuum, r.t.

0

0.2

0.4

0.6

0.6 1 1.4 1.8 2.2 2.6

Abso

rban

ce

Frequency (THz)

1.64 THz

Monohydrate formGranules (after 60 min)

Converted to amorphous form

0

0.1

0.2

0.3

0.4

0.5

0.6 1 1.4 1.8 2.2 2.6

Abso

rban

ce

Frequency (THz)

0 min15min60 min120 min

1.64 THz

51

図７ 真空乾燥物を70℃環境に放置した際のテラヘルツスペクトルの経時変化

0.2

0.6 0.8 1 1.2 1.4 1.6 1.8 2 2.2

0 min 2h in vacuum 5 min 15 min30 min 60 min 120 min

Frequency (THz)

1.64 THz (TPMH)

After 2hour in vacuum(Amorphous form)

1.60 THz (TPAH)

0.95 THz (TPAH)

図８ テオフィリン無水物及び加水混合のテラヘルツスペクトル

Mixing

Monohydrate formWaterAnhydride form

0

0.1

0.2

0.3

0.4

0.5

0.6 1 1.4 1.8 2.2 2.6

Abso

rban

ce

Frequency (THz)

0.95 THz

1.60 THz

0

0.1

0.2

0.3

0.4

0.5

0.6 1 1.4 1.8 2.2 2.6

Abso

rban

ce

Frequency (THz)

1.64 THz

図９ 70℃環境にテオフィリン一水和物を放置した時のテラヘルツスペクトルの変化

Monohydrate form

70 ºCDrying process

0

0.1

0.2

0.3

0.4

0.5

0.6 1 1.4 1.8 2.2 2.6

Abso

rban

ce

Frequency (THz)

1.64 THz

Anhydride form

0

0.1

0.2

0.3

0.4

0.5

0.6 1 1.4 1.8 2.2 2.6

Abso

rban

ce

Frequency (THz)

0 min15 min

1.64 THz

1.60 THz

図１０ 真空環境にテオフィリン一水和物を放置した時のテラヘルツスペクトルの経時変化

Monohydrate form

In vacuum, r.t.Drying process

0

0.1

0.2

0.3

0.4

0.5

0.6 1 1.4 1.8 2.2 2.6

Abso

rban

ce

Frequency (THz)

1.64 THz

Amorphous form

0

0.1

0.2

0.3

0.6 1 1.4 1.8 2.2 2.6

Abso

rban

ce

Frequency (THz)

0 min

60 min

240 min

1200 min

1.64 THz

Granules(TPMH+HPC)

In vacuum, r.t.

Drying process

Monohydrate form was converted to amorphous form after 120 min.

NIR absorption (O-H combination) disappeared after 120 min.

Dehydration was also completed after 120 min.

0

0.1

0.2

0.3

0.4

0.5

0.6 1 1.4 1.8 2.2 2.6

Abso

rban

ce

Frequency (THz)

0 min15min60 min120 min

1.64 THz

0.004

0.009

0.014

0.019

0.024

0.029

47004900510053005500

0 min 5 min15 min 30 min60 min 120 min180 min TPTPMH

Wavenumbers (cm-1)

図１１ 真空乾燥における顆粒中のテオフィリンのテラヘルツスペクトルと水和水の経時変化

TPMH

0

0.1

0.2

0.3

0.6 1 1.4 1.8 2.2 2.6

Abso

rban

ce

Frequency (THz)

0 min

60 min

240 min

1200 min

1.64 THz

In vacuum, r.t.

Drying process

Monohydrate form was converted to amorphous form after 1200 min.

NIR absorption (O-H combination) disappeared after 120 min.

Dehydration was also completed after 120 min.0

0.005

0.01

0.015

0.02

0.025

0.03

47004900510053005500

0 min 5 min 15 min

30 min 60 min 120 min

TP TPMH

Wavenumbers (cm-1)

図１２ 真空乾燥におけるテオフィリン一水和物のテラヘルツスペクトルと水和水の経時変化

52

添付資料１ 海外旅行記録書

外国旅行記録とその成果について

所属先 国立医薬品食品衛生研究所 薬品部

研究者 坂本 知昭 １．渡航目的 ピッツバーグ分析化学及び応用分光学に関する国際会議年会で厚生労働科学研

究費補助金政策創薬総合研究事業における研究成果を発表するとともに、学会

参加者と当該研究分野に関する議論を行い、今後の研究の方向付けを行った。 ２．旅行日程 日程 出発地 到着地 訪問先

3/16 成田 シカゴ 3/16 シカゴ ﾌｨﾗﾃﾞﾙﾌｨｱ 3/16 ～ 3/21

ペンシルバニア国際会議場

3/22 ﾌｨﾗﾃﾞﾙﾌｨｱ シカゴ 3/22 シカゴ 機中泊 3/23 機中泊 ﾛﾝﾄﾞﾝ ３．訪問先 ペンシルバニア国際会議場（学会会場、ペンシルバニア州フィラデルフィア） ４．成果 厚生労働科学研究費補助金研究（H23-医薬-一般-010）で実施している研究テー

マに関して、現在までの研究成果をPittsburgh Conference on Analytical Chemistry and Applied Spectroscopyで発表して参加者と討論を行うとともに、

本研究に関連が深い他の参加者の発表を聴講し今後の研究の方向付けのための

議論を行った。また共同研究者と国際会議での検討結果を踏まえた今後の研究

の進め方に関する打合せを行った。

53

54

添付資料２ 国際学会発表要旨 ピッツバーグ分析化学及び応用分光学に関する国際会議発表要旨

Vibrational spectroscopic analysis of pseudo-polymorphism conversion of theophylline during a tableting process Tomoaki Sakamoto1, Tetsuo Sasaki2, Hiroko Kimura2, Tadao Tanabe3, Yasuto Fujimaki4, Jun-ichi Nishizawa2, Yukio Hiyama1, Noriko Katori1, Haruhiro Okuda1 1 Division of Drugs, National Institute of Health Sciences, Tokyo 158-8501, Japan 2 Research Institute of Electronics, Shizuoka University, Shizuoka 432-8561, Japan 3 Institute of Multidisciplinary Research for Advanced Materials, Tohoku University, Miyagi 980-8577, Japan 4 Tokyo Metropolitan Industrial Technology Research Institute, Tokyo 135-0064, Japan A pseudo-polymorphism conversion of theophylline (TP) during a pharmaceutical tableting process was investigated. In the THz spectrum obtained from theophylline granules before drying, one of two major absorptions of theophylline anhydride at 0.95 THz disappeared. The waveform which has single absorption at 1.6 THz in the frequency range below 2 THz showed the same waveform pattern as theophylline monohydrate. In case of the drying process in vacuum circumstance, the intensity of the absorption at 1.6 THz observed in both forms decreased gradually with the passage of time, and disappeared at 120 min after the drying process was started. The absorption at 0.95 THz had not appeared through the drying process under ambient atmosphere at room temperature. However, in case the temperature was set at 70 ºC, the absorption was already observed at 15 min after the drying process was started. This phenomenon indicates that temperature is the important factor to convert its pseudo-polymorphism from a monohydrate form to an anhydride form. In case of vacuum circumstance, the absorption at 1.6 THz disappeared gradually with the passage of time. We guess this observation would be based on conversion from monohydrate form to amorphous form during a dehydration process. These results suggest that a binder would affect pseudo-polymorphism conversion and a dehydration of theophylline during a wet granulation process for a tableting. We will present and discuss about these phenomena using not only THz spectroscopy but also near-, mid-infrared and Raman spectroscopy.

55

56

添付資料３ 国際学会発表資料

ピッツバーグ分析化学及び応用分光学に関する国際会議ポスター発表資料

1

Vibrational spectroscopic analysis of pseudo-polymorphism conversion of theophylline during a

tableting process

Tomoaki Sakamoto1, Tetsuo Sasaki2, Hiroko Kimura2, Tadao Tanabe3, Yasuto Fujimaki4, Jun-ichi Nishizawa5, Yukio Hiyama1, Noriko Katori1, and Haruhiro Okuda1

1Division of Drugs, National Institute of Health Sciences, Tokyo 158-8501, Japan2Research Institute of Electronics, Shizuoka University, Shizuoka 432-8561, Japan 3Institute of Multidisciplinary Research for Advanced Materials, Tohoku University, Miyagi 980-8577, Japan4 Tokyo Metropolitan Industrial Technology Research Institute, Tokyo 135-0064, Japan5Sophia University, Tokyo 102-8554, Japan

The Pittsburgh Conference on Analytical Chemistry and Applied Spectroscopy, 17-21 March 2013, Pennsylvania Convention Center, Philadelphia, PA USA 1

2

Introduction

Theophylline tablets contains an anhydride form oftheophylline (TP) as an active pharmaceutical ingredient(API). It is known that theophylline anhydride (TPAH) willconvert to monohydrate under a high humidity environment.In this study, a pseudo-polymorphism conversion whichaffects physico-chemical property such as a dissolutionproperty during a tableting process was focused on.Moreover, time-dependent changes of characteristicabsorptions of TP during a wet granulation process andTPMH during drying processes were investigated using anear-infrared, mid-infrared and far-infrared/terahertz electro-magnetic wave.

2

3

GaP Terahertz generation system

Q-swNd:YAG

laser

ATN

ATN

GaPBeam combiner

THzwave

2 CHCr:Forsterite

laser

Cr:Forsterite

cryostat

laser

Trans.DTGS

IR cutfilter

Sample or PE

off-axisparaboloidalreflectors

dry N2purged

Ref.DTGS

beamsplitter

double beam method

different frequency generation

・Excited light: Nd:YAG laser・Incident light: Cr:Forsterite laser・Detector: DTGS detector・Measurement area:0.6 -5 THz (20 cm-1 – 165 cm-1)・Measurement step:15 GHz (0.5 cm-1)

3

4

Analytical condition

4

Near-infrared measurementInstrument: MPA FT-NIR Spectrometer (Bruker Optics)Measurement Range: 12500 cm-1 – 4000 cm-1

Resolution: 2 cm-1

Scan Number: 32Measurement Mode: Diffuse reflectance

Mid-infrared measurementInstrument: FT-IR 6300 Spectrometer (JASCO)Measurement Range: 4000 cm-1 – 400 cm-1

Resolution : 2 cm-1

Scan Number: 64Measurement Mode: ATR (Single)

5

Experimental design(Granulation and drying processes)

Theophylline anhydride (TPAH)(Active pharmaceutical Ingridient (API))

TPAH + HPC(10 : 3)

Binder:Hydroxypropyl celluloce

(HPC)

TPAH

+ H2OShare granulation process

+ H2OShare granulation process

Mixture (Powder)Granules

Under ambient atmosphereat 70 ºC (or 50 ºC)

In vacuumAt 22.5 ºC

Drying process

Drying process Samplingat 0 min (before drying), 15 min, 30 min, 60 min, 120 min, 240 min and (1200 min)

5

Dried granulesDrying process

6

Terahertz spectra of theophylline anhydride (TPAH, a blue line) and theophylline monohydrate (TPMH, a red line)

0

0.1

0.2

0.3

0.4

0.5

0.6 0.8 1 1.2 1.4 1.6 1.8 2 2.2 2.4 2.6

Abs

orba

nce

Frequency (THz)

Theophylline anhydride

Theophylline monohydrate

1.60 THz

1.64 THz

7

57

7

Pseudo-polymorphism conversion of theophylline during a share granulation process

Share granulation

TP granules (before dryness)Water

TP anhydride form

HPC

0

0.2

0.4

0.6

0.6 1 1.4 1.8 2.2 2.6

Abso

rban

ce

Frequency (THz)

1.64 THz

0

0.1

0.2

0.3

0.4

0.5

0.6 1 1.4 1.8 2.2 2.6

Abso

rban

ce

Frequency (THz)

0.95 THz

1.60 THz

8

8

Pseudo-polymorphism conversion of theophylline during a drying process at 70 ºC under an ambient atmosphere

Drying process

70 ºC

0

0.2

0.4

0.6

0.6 1 1.4 1.8 2.2 2.6

Abso

rban

ce

Frequency (THz)

1.64 THz

0

0.2

0.4

0.6

0.6 1 1.4 1.8 2.2 2.6

Abso

rban

ce

Frequency (THz)

0 min15 min

1.64 THz

1.60 THz

TP granules (before dryness)Monohydrate form

TP granules (within 15 min)Converted to anhydride form

9

9

Pseudo-polymorphism conversion of theophylline during a drying process at 22.5 ºC in vacuum

Drying process

TP granules (before dryness)

In vacuum, r.t.

0

0.2

0.4

0.6

0.6 1 1.4 1.8 2.2 2.6

Abso

rban

ce

Frequency (THz)

1.64 THz

Monohydrate formTP granules (after 60 min)

Converted to amorphous form

0

0.1

0.2

0.3

0.4

0.5

0.6 1 1.4 1.8 2.2 2.6

Abso

rban

ce

Frequency (THz)

0 min15min60 min120 min

1.64 THz

10

10

Pseudo-polymorphism conversion of theophylline(without HPC) during a mixing

Mixing

TP monohydrate formWaterTP anhydride form

0

0.1

0.2

0.3

0.4

0.5

0.6 1 1.4 1.8 2.2 2.6

Abso

rban

ce

Frequency (THz)

0.95 THz

1.60 THz

0

0.1

0.2

0.3

0.4

0.5

0.6 1 1.4 1.8 2.2 2.6

Abso

rban

ce

Frequency (THz)

1.64 THz

11

11

Pseudo-polymorphism conversion of theophylline (without HPC) during a drying process at 70 ºC in vacuum

Monohydrate form 70 ºCDrying process

0

0.1

0.2

0.3

0.4

0.5

0.6 1 1.4 1.8 2.2 2.6

Abso

rban

ce

Frequency (THz)

1.64 THz

Anhydride form

0

0.1

0.2

0.3

0.4

0.5

0.6 1 1.4 1.8 2.2 2.6

Abso

rban

ce

Frequency (THz)

0 min15 min

1.64 THz

1.60 THz

12

12

Pseudo-polymorphism conversion of theophylline (without HPC) during a drying process at 22.5 ºC in vacuum

Monohydrate form In vacuum, r.t.Drying process

0

0.1

0.2

0.3

0.4

0.5

0.6 1 1.4 1.8 2.2 2.6

Abso

rban

ce

Frequency (THz)

1.64 THz

Amorphous form

0

0.1

0.2

0.3

0.6 1 1.4 1.8 2.2 2.6

Abso

rban

ce

Frequency (THz)

0 min

60 min

240 min

1200 min

1.64 THz

13

58

13

C-H combination vibrations (C-H stretching plus C-H bending) of Theophylline monohydrate

4432 cm-1: v2(CH) + δ4(CH)4418 cm-1: v1(CH) + δ4(CH)4351 cm-1: v1(CH) + δ3(CH)4334 cm-1: v1(CH)  +  δ5(CH)4308 cm-1: v1(CH) + δ2(CH)4270 cm-1: v1(CH) + δ1(CH)

14

. H2O

14

-0.05

0

0.05

0.1

0.15

10001050110011501200125013001350

TP TPMH Wave numbers (cm-1)

δ1(CH): 1163 cm-1

1188 cm-1

δ2(CH): 1200 cm-1

δ3(CH): 1244 cm-1

δ4(CH): 1314 cm-1

δ5(CH): 1230 cm-1

15

Mid-IR spectra of C-H aromatic in-plane bending region for theophylline anhydride and monohydrate

15

-0.025

-0.015

-0.005

0.005

0.015

0.025

0.035

0.045

240026002800300032003400

TP TPMH Wave numbers (cm-1)

v1(CH): 3103 cm-1

v2(CH): 3122 cm-1

Mid-IR spectra of C-H stretching region fortheophylline anhydride and monohydrate

16

16

Time-dependent change of THz waveforms of granules during a drying process at 70 ºC after 2hours dryness in vacuum

17

0.2

0.6 0.8 1 1.2 1.4 1.6 1.8 2 2.2

0 min 2h in vacuum 5 min 15 min30 min 60 min 120 min

Frequency (THz)

1.64 THz (TPMH)

After 2hour dryness in vacuum(Amorphous form)

1.60 THz (TPAH)

0.95 THz (TPAH)

17

Conclusion-1

1. Terahertz spectra show that pseudo-polymorphism conversion of TPAH to TPMH occurred during a wet share granulation process.

2. A monohydrate was quickly re-converted to its original form at 70 ºC under atmospheric pressure condition.

3. The THz spectrum of granules obtained in vacuum suggests that TPMH converted to amorphous form.

4. According to near- and mid-IR spectroscopic information, a time-dependent changes of the absorption derived from an aromatic in-plane bending (C-H) during drying processes were observed. These observations suggest that an C-H in aromatic ring will be affected by dehydration.

18

18

Conclusion-2

19

5. The range of peak shift on C-H combination of granules (with HPC) was wider than that of the mixture (without HPC), though the tendencies of time-dependent changes of crystal water obtained from both samples were almost similar. This observation suggests that the HPC will affect an anharmonic oscillation of an aromatic in-plane bending of C-H during dehydration.

6. The waveform which shows an amorphous form after 2 hours dryness in vacuum was changed to the waveform which shows an anhydride form by heating at 70 ºC. This observation suggests that a molecular structure in amorphous form was converted to anhydride form by thermal energy.

59

19

Acknowledgement

This study was supported in part by a research grant from the Ministry of Health, Labour and Welfare of Japan and a research grant for Research on Health Sciences Focusing on Drug Innovation from Japan Health Science Foundation.

20

60

添付資料４ 国内学会発表要旨１ フロンティアテラヘルツ波技術に関する国際会議2012発表要旨 Understanding of pseudo-polymorphism conversion mechanism of theophylline under a wet granulation process using terahertz spectroscopy

Tomoaki Sakamoto1, Tetsuo Sasaki2, Hiroko Kimura2, Tadao Tanabe3, Jun-ichi Nishizawa2, Yukio Hiyama1, Noriko Katori1, Haruhiro Okuda1 1 Division of Drugs, National Institute of Health Sciences, Tokyo, Japan 2 Research Institute of Electronics, Shizuoka University, Shizuoka, Japan 3 Institute of Multidisciplinary Research for Advanced Materials, Tohoku University, Miyagi, Japan

A pseudo-polymorphism conversion of theophylline (TP) under a wet granulation and dryness processes in vacuum circumstance or under an ambient atmosphere was investigated. An attachment (jig) was made to obtain suitable spectrum of the granules, and the granules with the particle size which was below 100 µm were used for measurements. The terahertz (THz) spectrum of the granules made from TP anhydride and the binder was changed to the different waveform compared with that of the original or a converted form (monohydrate) during the dryness process in vacuum circumstance. However, the THz spectrum obtained from mixture of TP anhydride and water without the binder was changed to that of monohydrate form and was re-changed to the waveform of the original form with the passage of time. The THz spectra obtained from the granules were re-changed to the original waveform after conversion to monohydrate form at 70 ºC under an ambient atmosphere, but the time-dependent change of the spectra of the TP granules dried at room temperature showed no re-conversion from monohydrate form to the original form. We will present and discuss about the mechanism of pseudo-polymorphism of TP based on a vibrational spectroscopic study.

61

62

添付資料５ 国内学会発表資料１ フロンティアテラヘルツ波技術に関する国際会議2012ポスター発表資料

Understanding of pseudo-polymorphism conversion mechanism of theophylline under a wet granulation process using terahertz spectroscopyTomoaki Sakamoto1, Tetsuo Sasaki2, Hiroko Kimura2, Tadao Tanabe3, Jun-ichi Nishizawa4, Yukio Hiyama1, Noriko Katori1, and Haruhiro Okuda1

1Division of Drugs, National Institute of Health Sciences, Tokyo 158-8501, Japan2Research Institute of Electronics, Shizuoka University, Shizuoka 432-8561, Japan 3Institute of Multidisciplinary Research for Advanced Materials, Tohoku University, Miyagi 980-8577, Japan4Sophia University, Tokyo 102-8554, Japan

IntroductionTheophylline tablets contains an anhydride form oftheophylline (TP) as an active pharmaceuticalingredient (API). It is known that theophyllineanhydride (TPAH) will convert to monohydrate undera high humidity environment. In this study, apseudo-polymorphism conversion which affectsphysico-chemical property such as a dissolutionproperty during a wet granulation process wasfocused on. Moreover, time-dependent changes ofcharacteristic absorptions of TP during dryingprocesses under several dryness conditions wereinvestigated using terahertz spectroscopy.

GaP Terahertz generation system

Q-swNd:YAG

laser

ATN

ATN

GaPBeam combiner

THzwave

2 CHCr:Forsterite

laser

Cr:Forsterite

cryostat

laser

Trans.DTGS

IR cutfilter

Sample or PE

off-axisparaboloidalreflectors

dry N2purged

Ref.DTGS

beamsplitter

double beam method

different frequency generation

・Excited light: Nd:YAG laser・Incident light: Cr:Forsterite laser・Detector: DTGS detector・Measurement area:0.6-6THz・Measurement step:15GHz

Experimental design(Granulation and dryness processes)

Theophylline anhydride (TPAH)(Active pharmaceutical Ingridient (API))

TPAH + HPC(10 : 3)

Binder:Hydroxypropyl celluloce

(HPC)

TPAH

+ H2OShare granulation process

+ H2OShare granulation process

Mixture (Powder)Granules

Under ambient atmosphereAt 22.5 ºC, 50 ºC, and 70 ºC

In vacuumAt 22.5 ºC

Dryness processDryness process

Samplingat 0 min (before drying), 15 min, 30 min, 60 min, 120 min, 240 min and (1200 min)

Terahertz spectra of theophylline anhydride (TPAH, a blue line) and theophylline monohydrate (TPMH, a red line)

0

0.1

0.2

0.3

0.4

0.5

0.6 0.8 1 1.2 1.4 1.6 1.8 2 2.2 2.4 2.6

Abs

orba

nce

Frequency (THz)

Theophylline anhydride

Theophylline monohydrate

1.60 THz

1.64 THz

Pseudo-polymorphism conversion of theophyllineduring a share granulation process

Share granulation

TP granules (before dryness)WaterTP anhydride form

HPC

0

0.2

0.4

0.6

0.6 1 1.4 1.8 2.2 2.6

Abso

rban

ce

Frequency (THz)

1.64 THz

0

0.1

0.2

0.3

0.4

0.5

0.6 1 1.4 1.8 2.2 2.6

Abs

orba

nce

Frequency (THz)

0.95 THz

1.60 THz

Pseudo-polymorphism conversion of theophylline during a dryness process at 70 ºC under an ambient atmosphere

Dryness process

70 ºC

0

0.2

0.4

0.6

0.6 1 1.4 1.8 2.2 2.6

Abso

rban

ce

Frequency (THz)

1.64 THz

0

0.2

0.4

0.6

0.6 1 1.4 1.8 2.2 2.6

Abs

orba

nce

Frequency (THz)

0 min15 min

1.64 THz1.60 THz

TP granules (before dryness)Monohydrate form

TP granules (within 15 min)Converted to anhydride form

Pseudo-polymorphism conversion of theophylline during a dryness process at 50 ºC under an ambient atmosphere

Dryness process

50 ºC

0

0.2

0.4

0.6

0.6 1 1.4 1.8 2.2 2.6

Abs

orba

nce

Frequency (THz)

1.64 THz

0

0.1

0.2

0.3

0.4

0.6 1 1.4 1.8 2.2 2.6

Absorbance

Frequency (THz)

0 min30 min60 min

1.64 THz1.60 THz

TP granules (before dryness)Monohydrate form

TP granules (after 60 min)Converted to anhydride form

Pseudo-polymorphism conversion of theophylline during a dryness process at 22.5 ºC under an ambient atmosphere

Dryness process

TP granules (before dryness)22.5 ºC (r.t.)

0

0.2

0.4

0.6

0.6 1 1.4 1.8 2.2 2.6

Abs

orba

nce

Frequency (THz)

1.64 THz

0

0.1

0.2

0.3

0.4

0.6 1 1.4 1.8 2.2 2.6

Abs

orba

nce

Frequency (THz)

0 min120 min1200 min

1.64 THz1.58THz

Monohydrate formTP granules (after 1200 min)

During a conversion to amorphous form

Pseudo-polymorphism conversion of theophylline during a dryness process at 22.5 ºC in vacuum

Dryness process

TP granules (before dryness)

In vacuum, r.t.

0

0.2

0.4

0.6

0.6 1 1.4 1.8 2.2 2.6

Abs

orba

nce

Frequency (THz)

1.64 THz

Monohydrate formTP granules (after 60 min)

Converted to amorphous form

0

0.1

0.2

0.3

0.4

0.5

0.6 1 1.4 1.8 2.2 2.6

Abs

orba

nce

Frequency (THz)

0 min15min60 min120 min

1.64 THz

Pseudo-polymorphism conversion of theophylline(without HPC) during a mixing

Mixing

TP monohydrate formWater

TP anhydride form

0

0.1

0.2

0.3

0.4

0.5

0.6 1 1.4 1.8 2.2 2.6

Abs

orba

nce

Frequency (THz)

0.95 THz

1.60 THz

0

0.1

0.2

0.3

0.4

0.5

0.6 1 1.4 1.8 2.2 2.6

Abs

orba

nce

Frequency (THz)

1.64 THz

Pseudo-polymorphism conversion of theophylline (without HPC) during a dryness process at 70 ºC in vacuum

Monohydrate form 70 ºCDryness process

0

0.1

0.2

0.3

0.4

0.5

0.6 1 1.4 1.8 2.2 2.6

Abs

orba

nce

Frequency (THz)

1.64 THz

Anhydride form

0

0.1

0.2

0.3

0.4

0.5

0.6 1 1.4 1.8 2.2 2.6

Abs

orba

nce

Frequency (THz)

0 min15 min

1.64 THz

1.60 THz

Pseudo-polymorphism conversion of theophylline (without HPC) during a dryness process at 22.5 ºC in vacuum

Monohydrate form

In vacuum, r.t.Dryness process

0

0.1

0.2

0.3

0.4

0.5

0.6 1 1.4 1.8 2.2 2.6

Abs

orba

nce

Frequency (THz)

1.64 THz

Amorphous form

0

0.1

0.2

0.3

0.6 1 1.4 1.8 2.2 2.6

Abs

orba

nce

Frequency (THz)

0 min60 min240 min1200 min

1.64 THz

Granules(TPMH+HPC)

In vacuum, r.t.

Dryness process

Monohydrate form was converted to amorphous form after 60 min.

NIR absorption (O-H combination) was still observed after 120 min.

Water still remained after monohydrate was converted to amorphous.

0

0.1

0.2

0.3

0.4

0.5

0.6 1 1.4 1.8 2.2 2.6

Abs

orba

nce

Frequency (THz)

0 min15min60 min120 min

1.64 THz

5000504050805120

-0.0

0008

-0.0

0004

0.00

000

Abso

rban

ce U

nits

Wavenumbers (cm-1)

HPC

TPAH

15 min

TPMH

120 min60 min

0 min

TPMH

0

0.1

0.2

0.3

0.6 1 1.4 1.8 2.2 2.6

Abso

rban

ce

Frequency (THz)

0 min60 min240 min1200 min

1.64 THz

Wavenumbers (cm-1)5000504050805120

-0.0

0006

-0.0

0002

0.00

002

Abso

rban

ce U

nits

TPAHTPMH

240 min60 min

0 min

In vacuum, r.t.

Dryness process

Monohydrate form was converted to amorphous form after 240 min.

NIR absorption (O-H combination) disappeared after 240 min.

Dehydration was also completed after 240 min.

Conclusion1. Pseudo-polymorphism conversion of TPAH to TPMH

occurred during a wet share granulation process.2. A monohydrate was quickly re-converted to its original form

at 70 ºC under both atmospheric pressure conditions.3. The lowering of the dryness temperature from 70 ºC to 50

ºC under an ambient atmosphere prolonged the re-conversion time to the original form. However, the lowestdryness temperature (22.5 ºC ) under an ambientatmosphere or in vacuum made TPMH converted toamorphous form.

4. Dryness temperature is important factor about re-conversionfrom monohydrate to anhydride.

5. Although the amorphization of TPMH with HPC quicklyprogressed with a incomplete dehydration, that of TPMHwithout HPC progressed slowly with a complete dehydration.This means that a binder such as HPC prevents smoothprogression of a dehydration and polymorphism conversionfrom TPMH to an amorphous form in vacuum.

International Symposium on Frontiers in Terahertz Technology, 27-29 Nov. 2012, Todaiji Culture Center, Nara, Japan

63

64

添付資料６ 国内学会発表要旨２ 日本分析化学会第61年会発表要旨 テラヘルツ分光法用いた湿式打錠用顆粒物製造工程におけるテオフィリ

ンの振動分光学的解析 Vibrational spectroscopic analysis of theophylline during a wet-granulation process

using terahertz spectroscopy

国立医薬品食品衛生研 1 上智大半研 2

○坂本 知昭 1、佐々木哲朗 2、木村寛子 2、西澤潤一 2、檜山行雄 1、香取典子 1、奥田晴宏 1

【目的】テオフィリンは無水物が主薬成分として用いられるが、一水和物に転移すること

で溶解性が低下し、溶出遅延などの製剤上の問題が発生することが知られている。そこで著

者らはテオフィリン錠の製錠工程における重要工程の一つである造粒工程に着目し、乾燥工

程でのテオフィリン顆粒物をテラヘルツ分光法により経時的に測定し、異なる乾燥条件にお

ける疑似結晶多形転移現象について振動分光学的解析を行った。 【方法】テオフィリン無水物と結合剤 (HPC)の混合物に水を加えて撹拌造粒を行い、顆粒

物を得た。これについて、減圧（室温）下又は常圧乾燥空気気流下（70℃又は室温）で乾燥

し、経時的に測定を行った。顆粒物は整粒し（100 µm 以下）、治具に封入して測定した。

室温動作の焦電型検出器を装備した GaP-テラヘルツ波信号発生装置を用いて 1 THz～4 THzの範囲でスペクトルを測定した。

【結果及び考察】HPC を加えて製した顆粒では、無水物に観察される 0.95 THz と 1.5 THz付近の吸収について、調製直後は 0.95 THz 付近の吸収が消失し、一水和物と同様に 1.5 THzの吸収のみが観察された。減圧乾燥の場合では、両化合物で観察される 1.5 THz 付近の吸収

は経時的に減少し、240 分で消失した。常圧環境下では、室温で 0.95 THz 付近の吸収は消

失したままであったが、70℃では 15 分で

当該吸収が観察され、無水物に転移した

と考えられた。本結果から、常圧環境下

では、乾燥温度が湿式造粒工程で得られ

るテオフィリンの疑似結晶形転移に影響

を与えることが明らかとなった。また、

減圧乾燥では 1.5 THz 付近の吸収が経時

的に消失し、一水和物が脱水過程で非晶

質状態になったものと推察している。こ

の点について、HPC なしに造粒工程を経

て得た粉末では無水物への転移が示唆さ

れ、HPC が水の脱水過程に関与している

と考えられた。

THz spectra of Leucine

65

66

添付資料７ 国内学会発表資料２ 日本分析化学会第61年会発表資料

テラヘルツ分光法用いた湿式打錠用顆粒物製造工程における

テオフィリンの振動分光学的解析

○坂本知昭1，佐々木哲朗 2，木村寛子 2，西澤潤一3，檜山行雄 1，香取典子1，奥田晴宏1

1国立医薬品食品衛生研究所，2静岡大学，3上智大学

Terahertz (far-infrared) region

Wavenumber 3 cm-1 400 cm-130 cm-1

Visible-UV Light

Radio Waves

PhononVibration

Local Vibration

4000 cm-1

Inter-molecularVibration

Intra-molecularVibration

Combination, Overtone of fundamental vibration

X-H

Near-IR regionMid-IR regionFar-IR／terahertz region

12500 cm-1

Frequency 0.1 THz 10 THz1 THz 100 THz 300 THz

GaP Terahertz generation system

Q-swNd:YAG

laser

ATN

ATN

GaPBeam combiner

THzwave

2 CHCr:Forsterite

laser

Cr:Forsterite

cryostat

laser

Trans.DTGS

IR cutfilter

Sample or PE

off-axisparaboloidalreflectors

dry N2purged

Ref.DTGS

beamsplitter

double beam method

different frequency generation

・Excited light: Nd:YAG laser・Incident light: Cr:Forsterite laser・Detector: DTGS detector・Measurement area:0.6-6THz・Measurement step:15GHz

Experimental design(Granulation process)

Theophylline anhydride (TPAH)(Active pharmaceutical Ingridient (API))

TPAH + HPC(10 : 3)

Binder:Hydroxypropyl celluloce

(HPC)

TPAH

+ H2OShare granulation

+ H2OShare granulation

Mixture (Powder)Granules

Drying condition for granules or powderUnder ambient pressure

at 70 ºC, 50 ºC or 22.5 ºC (room temperature)In vacuum

at 22.5 ºC

at 0 min (before drying), 15 min, 30 min, 60 min, 120 min, 240 min and (1200 min)

Sampling

Non-destructive measurement of granules

Attachment (Jig)

ex. 100 m

plastic plate

sample powder

measurement area

spacer

THzwave

steel frame

Fig. 1 Terahertz spectra obtained from theophylline anhydride (TPAH, blue line) and theophylline monohydrate (TPMH, red line) reference substances

0

0.1

0.2

0.3

0.4

0.5

0.6 0.8 1 1.2 1.4 1.6 1.8 2 2.2 2.4 2.6

Abs

orba

nce

Frequency (THz)

Theophylline anhydride

Theophylline monohydrate

Fig. 2 Typical terahertz spectrum obtained from granules before a drying process.TPAH converted to its pseudo-polymorph form (TPMH) during a wet share granulation process.

0

0.2

0.4

0.6

0.6 0.8 1 1.2 1.4 1.6 1.8 2 2.2 2.4 2.6

Abs

orba

nce

Frequency (THz)

1.64 THz

Fig. 3 Terahertz spectra obtained from granules during a drying process under an ambient atmosphere at 70 ºC.TPMH was re-converted to its original form within 15 min.

0

0.2

0.4

0.6

0.6 0.8 1 1.2 1.4 1.6 1.8 2 2.2 2.4 2.6

Abs

orba

nce

Frequency (THz)

0 min

15 min

30 min

60 min

1.64 THz

1.60 THz

Fig. 4 Terahertz spectra obtained from granules during a drying process under an ambient atmosphere at 50 ºC (A) or at room temperature (B).TPMH was converted to an amorphous form under a room temperature.

0

0.1

0.2

0.3

0.4

0.6 0.8 1 1.2 1.4 1.6 1.8 2 2.2 2.4 2.6

Abs

orba

nce

Frequency (THz)

0 min

15 min

30 min

60 min

120 min

0

0.1

0.2

0.3

0.4

0.6 0.8 1 1.2 1.4 1.6 1.8 2 2.2 2.4 2.6

Abs

orba

nce

Frequency (THz)

0 min

15 min

120 min

1200 min

1.64 THz

1.58THz

(A)

(B)

0

0.1

0.2

0.3

0.4

0.5

0.6 0.8 1 1.2 1.4 1.6 1.8 2 2.2 2.4

Abs

orba

nce

Frequency (THz)

0 min

15 min

30 min

60 min

1.64 THz

1.60 THz

0

0.1

0.2

0.3

0.6 1 1.4 1.8 2.2 2.6

Abs

orba

nce

Frequency (THz)

0 min

15 min

60 min

240 min

1200 min

0

0.1

0.2

0.3

0.4

0.5

0.6 1 1.4 1.8 2.2 2.6

Abs

orba

nce

Frequency (THz)

0 min

15min

30 min

60 min

120 min

(A)

(B)

Fig. 7 Terahertz spectra obtained from a mixture during drying processes. (A: under an ambient atmosphere at 70 ºC, B: in vacuum at r.t.)A polymorphism conversion process of TPMH to an amorphous form slowly progressed in vacuum.

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

3 3.5 4 4.5 5

Abso

rban

ce

Frequency (THz)

0 min

15 min

60 min

240 min

1200 min

0

0.2

0.4

0.6

0.8

1

1.2

1.4

3 3.5 4 4.5 5

Abso

rban

ce

Frequency (THz)

0 min

15 min

30 min

60 min

(A)

(B)4.5 THz (0 min)

4.5 THz (0 min)3.9 THz

4.0 THz

まとめ

開発した治具を用いることにより、テラヘルツ分光法による顆粒状試料の非破壊測定を行うことができた。

湿式撹拌造粒工程において、テオフィリン無水物は一水和物に転移した。

常圧下70℃の乾燥条件において、テオフィリン一水和物は15分以内に無水物に再転移した。

テオフィリン一水和物は常圧室温乾燥または真空乾燥で非晶質に転移した。

HPCなどの結合剤の存在により、水和水の脱水過程及び一水和物から非晶質への結晶形転移の円滑な進行が阻害される可能性が示唆された。

Fig. 8 Time-dependent changes of OH combination derived from water obtained from the granules and mixture during drying processes in vacuum at room temperature. (A: granules, B: mixture)A dehydration process of TPMH without HPC was completed within 240 min.

50005020504050605080510051205140-0.0

0010

-0.0

0008

-0.0

0006

-0.0

0004

-0.0

0002

0.00

000

0.00

002

Abso

rban

ce U

nits

Wavenumbers (cm-1) Wavenumbers (cm-1)50005020504050605080510051205140

-0.0

0006

-0.0

0004

-0.0

0002

0.00

000

0.00

002

Abso

rban

ce U

nits

(A) (B)

HPC

TPAH

15 min

TPMH

120 min240 min

60 min30 min

0 min

TPAH

15 min

TPMH

120 min240 min

60 min

30 min

0 min

参考

緒言

テオフィリンは無水物が主薬成分として用いられるが、

一水和物に転移することで溶解性が低下し、溶出遅

延などの製剤上の問題が発生することが知られてい

る。そこで著者らはテオフィリン錠の製錠工程におけ

る重要工程の一つである造粒工程に着目し、撹拌造

粒工程及び乾燥工程でのテオフィリン顆粒物をテラ

ヘルツ分光法により経時的に測定し、異なる乾燥条

件における疑似結晶多形転移現象について振動分

光学的解析を行った。

Fig. 5 Terahertz spectra obtained from a mixture of TPAH and water (without HPC) during a drying process under an ambient atmosphere at 70 ºC.A pseudo-polymorph form was re-converted to its original form within 15 min at 70 ºC irrespective of the existence of HPC..

Fig. 6 Terahertz spectra obtained from a mixture during a drying process in vacuum(A: with HPC, B: without HPC).A polymorphism conversion process of TPMH to an amorphous form was affected by HPC.

日本分析化学会第61年会，2012年9月19日～21日，金沢大学角間キャンパス

67

68

添付資料８ 国内学会発表要旨３ 日本薬学会第133年会発表要旨

テラヘルツ分光法を用いた疑似結晶形転移プロセスの解析

坂本知昭 1、佐々木哲朗 2、木村寛子 2、田邉匡生 3、西澤潤一 4、檜山行雄 1、香取典子 1、

奥田晴宏 1 1国立医薬品食品衛生研、2静岡大、3東北大、4上智大

【目的】医薬品製造工程において起こり得る主薬成分の水和または脱水等の疑似結晶形

転移は、溶出性など物性の変化を引き起こす可能性があり、製剤開発及び製造工程におい

て重要な管理項目の 1 つである。そこで、演者らはテオフィリン水和物を用いて脱水（乾

燥）条件と疑似結晶形転移について着目し、テラヘルツ分光法を用いて転移現象の解析を行

った。

【方法】テオフィリン水和物と HPC の混合顆粒物及びテオフィリン水和物を減圧（室温）

下又は常圧乾燥空気気流下（70℃、50℃又は室温）で乾燥し、経時的に測定を行った。顆粒

物は整粒し（100 µm 以下）、冶具に封入して測定した。室温動作の焦電型検出器を装備し

た GaP-テラヘルツ波信号発生装置を用いて 0.6 THz～5 THz の範囲でスペクトルを測定し

た。

【結果及び考察】常圧下 70℃の乾燥条件では、混合顆粒物及び水和物ともに乾燥開始後

15 分で 0.95 THz 付近に吸収が観察され、無水物に転移したことがわかった。乾燥温度が

50℃の場合では、混合顆粒物において無水物に特徴的な吸収の増大が 60 分以降はほぼ一定

となり、無水物となったが、温度の低下により無水物となるまでの時間が長くなることが

観察された。しかしながら、室温（22.5 ℃）の乾燥温度では、1.6THz 付近に観察される特

徴的な吸収が経時的にブロード化しながら消失し、非晶質となったことが示唆された。さ

らに一水和物を室温で減圧乾燥した場合では、混合顆粒物の場合と比較して早めに非晶質

化が進行することが明らかとなった。 【謝辞】本研究は厚生労働科学研究費補助金医薬品・医療機器等レギュラトリーサイエ

ンス総合研究推進事業の一部として行ったものである。

69

70

添付資料９ 国内学会発表資料３ 日本薬学会第133年会ポスター発表資料

1

テラヘルツ分光法を用いた疑似結晶形転移プロセスの解析

○坂本知昭1, 佐々木哲朗2, 木村寛子2, 田邉匡生3,西澤潤一4, 檜山行雄1, 香取典子1, 奥田晴宏1

1 国立医薬品食品衛生研究所, 2 静岡大学, 3 東北大学, 4 上智大学

1

2

緒言

テオフィリンは高湿度環境下で無水物が一水和物に擬

似結晶形転移することが知られている。水和等の擬似

結晶形転移は溶解性などの物性に影響を与えることが

あり、医薬品の品質上重要な管理項目のひとつである。

本年会ではテオフィリンを用いた製錠工程における擬

似結晶形転移をテラヘルツ分光法を用いて解析を行っ

たので報告する。

2

3

GaP Terahertz generation system

Q-swNd:YAG

laser

ATN

ATN

GaPBeam combiner

THzwave

2 CHCr:Forsterite

laser

Cr:Forsterite

cryostat

laser

Trans.DTGS

IR cutfilter

Sample or PE

off-axisparaboloidalreflectors

dry N2purged

Ref.DTGS

beamsplitter

double beam method

different frequency generation

・Excited light: Nd:YAG laser・Incident light: Cr:Forsterite laser・Detector: DTGS detector・Measurement area:0.6-6THz・Measurement step:15GHz

3

4 Experimental design

(Granulation and drying processes)

4

Theophylline anhydride (TPAH)(Active pharmaceutical Ingridient (API))

TPAH + HPC(10 : 3)

Binder:Hydroxypropyl celluloce

(HPC)

TPAH

+ H2OShare granulation process

+ H2OShare granulation process

Mixture (Powder)Granules

Under ambient atmosphereat 70 ºC, 50 ºC and 22.5 ºC

In vacuumAt 22.5 ºC

Drying process

Drying process Samplingat 0 min (before drying), 15 min, 30 min, 60 min, 120 min, 240 min and (1200 min)

Dried granulesDrying process

5

Terahertz spectra of the reference substances of theophylline anhydride (TPAH, a red line) and theophylline monohydrate (TPMH, a black line)

0

0.1

0.2

0.3

0.4

0.5

0.6 0.8 1 1.2 1.4 1.6 1.8 2 2.2 2.4 2.6

Abs

orba

nce

Frequency (THz)

Theophylline anhydride

Theophylline monohydrate

1.60 THz

1.64 THz

5

6

Pseudo-polymorphism conversion of theophyllineduring a share granulation process

Share granulation

Wet granulesWater

TP anhydride form

HPC

0

0.2

0.4

0.6

0.6 1 1.4 1.8 2.2 2.6

Abso

rban

ce

Frequency (THz)

1.64 THz

0

0.1

0.2

0.3

0.4

0.5

0.6 1 1.4 1.8 2.2 2.6

Abso

rban

ce

Frequency (THz)

0.95 THz

1.60 THz

6

71

7

Time-dependent change of THz spectra of granules during a drying process at 70 ºC

Drying process

70 ºC

0

0.2

0.4

0.6

0.6 1 1.4 1.8 2.2 2.6

Abso

rban

ce

Frequency (THz)

1.64 THz

0

0.2

0.4

0.6

0.6 1 1.4 1.8 2.2 2.6

Abso

rban

ce

Frequency (THz)

0 min15 min

1.64 THz

1.60 THz

Wet granulesMonohydrate form

Granules (within 15 min)Converted to anhydride form

7

8

Time-dependent change of THz spectra of granules during a drying process at 50 ºC

Drying process

50 ºC

0

0.2

0.4

0.6

0.6 1 1.4 1.8 2.2 2.6

Abso

rban

ce

Frequency (THz)

1.64 THz

0

0.1

0.2

0.3

0.4

0.6 1 1.4 1.8 2.2 2.6

Abso

rban

ce

Frequency (THz)

0 min30 min60 min120 min

1.64 THz1.60 THz

Wet granulesMonohydrate form

Granules (after 60 min)Converted to anhydride form

8

9

Time-dependent change of THz spectra of granules during a drying process at 22.5 ºC

Drying process

Wet granules (before dryness)

22.5 ºC (r.t.)

0

0.2

0.4

0.6

0.6 1 1.4 1.8 2.2 2.6

Abso

rban

ce

Frequency (THz)

1.64 THz

0

0.1

0.2

0.3

0.4

0.6 1 1.4 1.8 2.2 2.6

Abso

rban

ce

Frequency (THz)

0 min120 min1200 min

1.64 THz1.58THz

Monohydrate formGranules (after 1200 min)

During a conversion to amorphous form

9

10

Time-dependent change of THz spectra of granules during a drying process in vacuum

Drying process

Wet granules

In vacuum, r.t.

0

0.2

0.4

0.6

0.6 1 1.4 1.8 2.2 2.6

Abso

rban

ce

Frequency (THz)

1.64 THz

Monohydrate formGranules (after 60 min)

Converted to amorphous form

0

0.1

0.2

0.3

0.4

0.5

0.6 1 1.4 1.8 2.2 2.6

Abso

rban

ce

Frequency (THz)

0 min15min60 min120 min

1.64 THz

10

11

Time-dependent change of THz waveforms of granules during a drying process at 70 ºC after 2hours in vacuum

11

0.2

0.6 0.8 1 1.2 1.4 1.6 1.8 2 2.2

0 min 2h in vacuum 5 min 15 min30 min 60 min 120 min

Frequency (THz)

1.64 THz (TPMH)

After 2hour in vacuum(Amorphous form)

1.60 THz (TPAH)

0.95 THz (TPAH)

12

Polymorphism conversion of theophylline during a wet granulation and drying processes

12

TPAHWet granulation

TPMH

TPAH TPAH TPAmorphous form

TPAmorphous form

TPAH

70 ºC(within 15 min)

50 ºC(after 60 min)

22.5 ºC(over 1200 min)

22.5 ºC(in vacuum)(after 120 min)

70 ºC(after 5 min)

Drying process

Binder: HPC

72

13

Time-dependent change of THz spectra of theophylline (without HPC) during a mixing

Mixing

Monohydrate formWaterAnhydride form

0

0.1

0.2

0.3

0.4

0.5

0.6 1 1.4 1.8 2.2 2.6

Abso

rban

ce

Frequency (THz)

0.95 THz

1.60 THz

0

0.1

0.2

0.3

0.4

0.5

0.6 1 1.4 1.8 2.2 2.6

Abso

rban

ce

Frequency (THz)

1.64 THz

13

14

Time-dependent change of THz spectra of theophylline (without HPC) during a drying process at 70 ºC

Monohydrate form

70 ºCDrying process

0

0.1

0.2

0.3

0.4

0.5

0.6 1 1.4 1.8 2.2 2.6

Abso

rban

ce

Frequency (THz)

1.64 THz

Anhydride form

0

0.1

0.2

0.3

0.4

0.5

0.6 1 1.4 1.8 2.2 2.6

Abso

rban

ce

Frequency (THz)

0 min15 min

1.64 THz

1.60 THz

14

15

Time-dependent change of THz spectra of theophylline (without HPC) during a drying process at 22.5 ºC in vacuum

Monohydrate form

In vacuum, r.t.Drying process

0

0.1

0.2

0.3

0.4

0.5

0.6 1 1.4 1.8 2.2 2.6

Abso

rban

ce

Frequency (THz)

1.64 THz

Amorphous form

0

0.1

0.2

0.3

0.6 1 1.4 1.8 2.2 2.6

Abso

rban

ce

Frequency (THz)

0 min

60 min

240 min

1200 min

1.64 THz

15

16

Polymorphism conversion of theophylline monohydrate during a drying process

16

TPAHMixing

TPMH

TPAHTP

Amorphous form

70 ºC(within 5 min)

22.5 ºC(in vacuum)(after 1200 min)

Drying process

Water

New absorption+

17

Granules(TPMH+HPC)

In vacuum, r.t.

Drying process

Monohydrate form was converted to amorphous form after 120 min.

NIR absorption (O-H combination) disappeared after 120 min.

Dehydration was also completed after 120 min.

0

0.1

0.2

0.3

0.4

0.5

0.6 1 1.4 1.8 2.2 2.6

Abso

rban

ce

Frequency (THz)

0 min15min60 min120 min

1.64 THz

17

0.004

0.009

0.014

0.019

0.024

0.029

47004900510053005500

0 min 5 min15 min 30 min60 min 120 min180 min TPTPMH

Wavenumbers (cm-1)

18

TPMH

0

0.1

0.2

0.3

0.6 1 1.4 1.8 2.2 2.6

Abso

rban

ce

Frequency (THz)

0 min

60 min

240 min

1200 min

1.64 THz

In vacuum, r.t.

Drying process

Monohydrate form was converted to amorphous form after 1200 min.

NIR absorption (O-H combination) disappeared after 120 min.

Dehydration was also completed after 120 min.

18

0

0.005

0.01

0.015

0.02

0.025

0.03

47004900510053005500

0 min 5 min 15 min

30 min 60 min 120 min

TP TPMH

Wavenumbers (cm-1)

73

19

Dehydration of theophylline monohydrate with HPC in vacuum

19

Granules (with HPC)

TPAmorphous form1200 min

Dehydration

New absorption+

TPMH

Dehydration

120 min

120 min

TPAmorphous form

120 min

20

まとめ

1. 造粒工程において、テオフィリン無水物は一水和物に転移した。2. 70 ºC及び50 ºC の加熱乾燥では、15分以内及び60分以内に無水物と同じに波形に変化し、無水物に再転移した。また温度が高いほど早く再転移した。

3. 室温での乾燥及び真空乾燥では、テラヘルツ波形は経時的にブロード化し、一水和物が非晶質化したことが推察された。

4. 一水和物（結合剤なし）の加熱乾燥では結合剤の存在下と同様に15分以内に無水物に再転移したが、真空乾燥では非晶質化を示すテラヘルツ波形の経時的変化の他、2 THz付近に新たな吸収が発現した。この吸収について、結晶モードと異なる、例えば分子間水素結合等が新たに形成された可能性が示唆された。

5. HPCを含む顆粒物では、一水和物と比較して脱水終了までの時間は同じであったが、非晶質化の時間は約1/10であり、HPCが一水和物の非晶質化に影響を与えることがわかった。

20

21

謝辞

21

本研究は厚生労働科学研究費補助金医薬品・医療機器

等レギュラトリーサイエンス総合研究推進事業及び政策

創薬総合研究事業の一部として行ったものである。

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of ingredient on measurement Tatsuo Koide,1 Noriko Katori,1 Toshiro Fukami,2 Yoshihisa Yamamoto3 and Haruhiro Okuda1

1National Institute of Health Sciences, 2Nihon University and 3Teikyo Heisei University, E-mail: koide@nihs.go.jp

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Non-destructive analysis of tulobuterol crystal reservoir-type transdermal tapes using near infrared spectroscopy and imaging

J Pharm Biomed Anal

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Tomoaki Sakamoto, Alessia Portieri, Donald D. Arnone, Philip F. Taday, Toru Kawanishi, Yukio Hiyama

Coating and density distribution analysis of commercial ciprofloxacin hydrochloride monohydrate tablets by terahertz pulsed spectroscopy and imaging

J Pharm Innov 7 87-93 2012

Yoshihisa. Yamamoto, Toshiro Fukami, Tatsuo Koide, Toyofumi Suzuki, Yukio Hiyama, Kazuo Tomono

Pharmaceutical evaluation of steroidal ointments by ATR-IR chemical imaging: Distribution of active and inactive pharmaceutical ingredients

Int. J. Pharmaceutics

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