Korean Chemical Engineering Research

The Korean Institute of Chemical Engineers (한국화학공학회)
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Study of NIR in-line Monitoring of Physicochemical Changes during the Crystallization Process of Aspirin

Aspirin 결정화 과정 중 특성변화의 NIR 인라인 모니터링 연구

  • Lee, Hea-Eun (Dept. of Pharmaceutical Engineering, Inje University) ;
  • Wang, In-Chun (Dept. of Pharmaceutical Engineering, Inje University) ;
  • Lee, Min-Jeong (Dept. of Smart Foods and Drugs, Inje University) ;
  • Seo, Da-Young (Dept. of Smart Foods and Drugs, Inje University) ;
  • Shin, Sangmun (Dept. of Systems Management & Engineering, Inje University) ;
  • Choi, Yongsun (Dept. of Systems Management & Engineering, Inje University) ;
  • Choi, Guang-Jin (Dept. of Pharmaceutical Engineering, Inje University)
  • 이혜은 (인제대학교 제약공학과) ;
  • 왕인천 (인제대학교 제약공학과) ;
  • 이민정 (인제대학교 식의약생명공학과) ;
  • 서다영 (인제대학교 식의약생명공학과) ;
  • 신상문 (인제대학교 시스템경영공학과) ;
  • 최용선 (인제대학교 시스템경영공학과) ;
  • 최광진 (인제대학교 제약공학과)
  • Received : 2010.05.23
  • Accepted : 2010.06.17
  • Published : 2010.12.31
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Abstract

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 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.

제약산업에서 최종의약품의 품질과 성능은 결정분말의 크기, 모양 및 다형체 등에 의해서 크게 달라지므로, 원료의약품(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.

Keywords

References

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