Reaction kinetics determination and uncertainty analysis for the synthesis of the cancer drug lomustine.
Reaction kinetics determination and uncertainty analysis for the synthesis of the cancer drug lomustine.
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DOI：
10.1016/j.ces.2023.118591
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发表时间：
2023-03
影响因子：
4.7
通讯作者：
Daniel Casas-Orozco;D. Laky;Jaron Mackey;G. Reklaitis;Zoltan K. Nagy
中科院分区：
文献类型：
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作者：
Daniel Casas-Orozco;D. Laky;Jaron Mackey;G. Reklaitis;Zoltan K. Nagy
需要快速可靠的模型开发框架来支持制药加工现代化的当前趋势，促进使用数字平台来辅助工艺设计和操作。在这项工作中，我们使用一个参数估计框架内置到PharmaPy库，以确定速率参数和不确定性区域的不同的机制和半经验的动力学表达式的药物洛莫司汀的合成。参数估计过程中的可识别性分析的补充，从而简化反应机理。工艺设计中的参数和它们的不确定性的比较通过设计空间分析被证明，在模型预测和它们相应的设计空间的程度上显示出重要的差异。该工作的结果可用于分析包括分离和隔离步骤的洛莫司汀生产工艺，其中参数不确定性预计将沿生产线传播沿着影响工艺可行性操作，以及产品关键质量属性的实现。
Fast and reliable model development frameworks are required to support current trends in modernization of pharmaceutical processing, promoting the use of digital platforms to assist process design and operation. In this work, we use a parameter estimation framework built into the PharmaPy library to determine rate parameters and uncertainty regions of different mechanistic and semi-empirical kinetic expressions for the synthesis of the drug lomustine. The parameter estimation procedure was complemented by identifiability analysis, resulting in simplified reaction mechanisms. Comparison of parameters and their uncertainty in process design was demonstrated through design space analysis, showing important differences in model prediction and the extent of their corresponding design spaces. The results of this work can serve to analyze lomustine manufacturing processes that include separation and isolation steps, where parametric uncertainty is expected to propagate along the manufacturing line and impact process feasible operation, and attainment of critical quality attributes of the product.