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Conflict of Interest: In relation to this article, we declare that there is no conflict of interest.

Publication history: Received May 23, 2010
Accepted June 17, 2010

This is an Open-Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/bync/3.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Aspirin 결정화 과정 중 특성변화의 NIR 인라인 모니터링 연구

Study of NIR in-line Monitoring of Physicochemical Changes during the Crystallization Process of Aspirin

이혜은¹ 왕인천¹ 이민정² 서다영² 신상문³ 최용선³ 최광진^{1 2†}

Hea-Eun Lee¹ In-Chun Wang¹ Min-Jeong Lee² Da-Young Seo² Sangmun Shin³ Yongsun Choi³ Guang-Jin Choi^{1 2†}

¹인제대학교 제약공학과, 621-749 경남 김해시 어방동 607번지 ²인제대학교 식의약생명공학과, 621-749 경남 김해시 어방동 607번지 ³인제대학교 시스템경영공학과, 621-749 경남 김해시 어방동 607번지

¹Dept. of Pharmaceutical Engineering, Inje University, 607 Obang-dong, Gimhae-si, Gyeongnam 621-749, Korea ²Dept. of Smart Foods and Drugs, Inje University, 607 Obang-dong, Gimhae-si, Gyeongnam 621-749, Korea ³Dept. of Systems Management & Engineering, Inje University, 607 Obang-dong, Gimhae-si, Gyeongnam 621-749, Korea

pegchoi@inje.ac.kr

Korean Chemical Engineering Research, December 2010, 48(6), 757-762(6), NONE Epub 11 January 2011

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Abstract

제약산업에서 최종의약품의 품질과 성능은 결정분말의 크기, 모양 및 다형체 등에 의해서 크게 달라지므로, 원료의 약품(API)의 결정화 공정은 매우 중요한 제약공정이다. 본 연구에서는 NIR 분광기와 광섬유 탐침을 이용하여, API 결정화 공정을 인라인 모니터링하여, 결정화 진행과정에서 핵성성, 결정성장, 다형체 등의 주요 특성을 실시간으로 감시하고 예측할 수 있는지를 탐구하였다. NIR 스펙트럼 분석에는 주요인분석법(PCA)을 적용하였고, 잘 알려진 aspirin를 대상 API로 하여 에탄올과 아세톤의 용매 혼합비율에 따른 결정특성 변화를 관찰하였다. 여러 특성분석 결과, 생성되는 aspirin 결정체의 다형은 용매 혼합비에는 무관하게 상온에서 가장 안정상인 form-I이었지만, 핵생성 개시점, 결정입도 및 결정의 형상은 용매의 혼합비에 따라 크게 달라진다는 것을 확인하였다. 이러한 결과는 NIR 스펙트럼의 PCA 해석결과와 매우 긴밀한 상관성을 보여주었다. 결론적으로, NIR 인라인 모니터링을 통해서, 약물의 결정화 과정에서 관심사가 되는 주요 결정특성을 실시간으로 관찰하고 예측할 수 있음이 실증되었다.

Since the quality and performance of medicinal products are heavily dependent upon the size, shape and polymorphism of active pharmaceutical ingredients(APIs), their crystallization has been regarded as one of the most important pharmaceutical processes. In this study, NIR-based inline measurements were employed to monitor key attributes of API particles real-time during the crystallization process. Principal component analysis(PCA) method was selected to correlate inline NIR spectra while the well-known aspirin was studied as a model drug. According to our_x000D_ characterization results, the ratio of ethanol to acetone did not cause any change in polymorphism, but resulted in a significant difference in the nucleation time, crystal growth and crystal shape. These phenomenological changes were well correlated with the PCA’s implications. It turned out that the NIR-based inline monitoring technology can be employed well in observing and predicting key quality attributes such as crystal size during pharmaceutical crystallization processes.

Keywords

Aspirin Crystallization In-line Monitoring Near-Infrared PCA PAT

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