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Nucleation and Growth Kinetics for Combined Cooling and Antisolvent Crystallization in a Mixed-Suspension, Mixed-Product Removal System: Estimating Solvent Dependency
Crystal Growth & Design ( IF 3.2 ) Pub Date : 2018-01-31 00:00:00 , DOI: 10.1021/acs.cgd.7b01528 Jennifer M. Schall 1 , Jasdeep S. Mandur 1 , Richard D. Braatz 1 , Allan S. Myerson 1
Crystal Growth & Design ( IF 3.2 ) Pub Date : 2018-01-31 00:00:00 , DOI: 10.1021/acs.cgd.7b01528 Jennifer M. Schall 1 , Jasdeep S. Mandur 1 , Richard D. Braatz 1 , Allan S. Myerson 1
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Combined cooling and antisolvent crystallization is a critical unit operation in pharmaceutical manufacturing, especially for heat-sensitive or poorly soluble active pharmaceutical ingredients. The model-based design of these systems relies on the accuracy of the underlying growth and nucleation kinetic parameters. Unlike temperature where these kinetic parameters are well-known to follow an Arrhenius relation, their dependency on solvent composition still remains unclear, especially in continuous mixed-suspension, mixed-product removal (MSMPR) systems. In this paper, we use population balance modeling coupled with nonlinear regression to estimate growth and nucleation parameters as a function of both temperature and solvent composition. As solvent composition increases from 44 vol % to 66 vol % solvent, both growth and nucleation rates were observed to decrease monotonically with their values reduced by almost one-third. It was also shown that, if the solvent dependency is ignored, the yield can be overpredicted or underpredicted by as much as 15%.
中文翻译：
混合悬浮，混合产物去除系统中联合冷却和反溶剂结晶的成核和生长动力学：估计溶剂依赖性
冷却和抗溶剂结晶相结合是制药生产中的关键单元操作，特别是对于热敏性或难溶性活性药物成分而言。这些系统的基于模型的设计依赖于基础生长和成核动力学参数的准确性。与众所周知的这些动力学参数遵循阿伦尼乌斯（Arrhenius）关系的温度不同，它们对溶剂组成的依赖性仍然不清楚，尤其是在连续混合悬浮，混合产物去除（MSMPR）系统中。在本文中，我们使用总体平衡模型与非线性回归相结合，以估计生长和成核参数随温度和溶剂组成的变化。随着溶剂成分从44％（体积）增加到66％（体积），观察到生长速率和成核速率均单调降低，其值降低了近三分之一。还表明，如果忽略溶剂依赖性，则产率可能被高估或低估了多达15％。
更新日期：2018-01-31
中文翻译：
混合悬浮，混合产物去除系统中联合冷却和反溶剂结晶的成核和生长动力学：估计溶剂依赖性
冷却和抗溶剂结晶相结合是制药生产中的关键单元操作，特别是对于热敏性或难溶性活性药物成分而言。这些系统的基于模型的设计依赖于基础生长和成核动力学参数的准确性。与众所周知的这些动力学参数遵循阿伦尼乌斯（Arrhenius）关系的温度不同，它们对溶剂组成的依赖性仍然不清楚，尤其是在连续混合悬浮，混合产物去除（MSMPR）系统中。在本文中，我们使用总体平衡模型与非线性回归相结合，以估计生长和成核参数随温度和溶剂组成的变化。随着溶剂成分从44％（体积）增加到66％（体积），观察到生长速率和成核速率均单调降低，其值降低了近三分之一。还表明，如果忽略溶剂依赖性，则产率可能被高估或低估了多达15％。
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