(481a) Optimization of Continuous Crystallization Processes to Maintain Content Uniformity

Content uniformity (CU) is a common critical quality attribute of Solid Oral Dosage Forms (SODF), particularly for low-dose drug products. The CU of SODF is known to be highly dependent upon the particle size distribution of the active ingredient, with control of API particle size being a common approach to ensuring the content uniformity of drug products. In this work, we examine a continuous cascade cooling crystallization process and explore its optimization, while maintaining the content uniformity of the final dosage form. The continuous cooling crystallization of paracetamol and ethanol solutions was employed as an example case. In order to predict the content uniformity of the drug product the following models were employed, whose predictions are dependent upon the particle size distribution (PSD) and the dosage level of the API present in final dosage form:

• Johnson (1972)[1]
• Hilden et al. (2012)[2]
• Rohrs et al. (2006)[3]
• SimCU[4]

A number of optimization objectives were posed, which included increasing throughput of the API and the number of number of crystallizer stages, whilst maintaining a target CU of the final product. A combined objective function was formulated, which incorporates the following process and product parameters:

• Penalty on production levels
• Penalty on CU of final product
• Production cost function

The various trade-offs observed for each optimization objective will also be outlined.