Kinetic Optimization of the Batch Crystallization of an Active Pharmaceutical Ingredient in the Presence of a Low-Solubility, Precipitating Impurity

Mitchell Paolello, Ilyes Bichari, Davinia Brouckaert, Mirvatte Francis, Dawn Yang, Gerard Capellades

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

The presence of impurities above regulatory thresholds has been responsible for recent recalls of pharmaceutical drugs. Crystallization is one of the most used separation processes to control impurities in the final drug. A particular issue emerges when impurities are poorly soluble in the crystallization solvent and simultaneously precipitate with the product. This publication reports the development of a population balance model to investigate if the impurity crystallization kinetics can be selectively inhibited in a seeded batch crystallization system containing acetaminophen (ACM), a commonly used small-molecule active pharmaceutical ingredient (API), and curcumin (CUR), a simulated low-solubility/co-precipitating impurity. Raman spectroscopy was used in combination with a partial least squares (PLS) model for in situ monitoring of the crystallization process. The Raman data were integrated to calibrate a population balance model in gPROMS FormulatedProducts, to predict the evolution of the product’s purity throughout the process. Process optimization demonstrated that a high purity close to equilibrium is feasible within the first 2 h of crystallization, with ACM seed purity being the primary factor controlling this phenomenon. The optimal approach for kinetically rejecting impurities requires a low nucleation rate for the impurity, high product seed purities, and an adjustable crystallization time so the process can be stopped before equilibrium without allowing the impurity to nucleate. Overall, an improvement in product purity before equilibrium is attainable if there is enough difference in growth kinetics between the product and impurity, and if one can generate relatively pure seed crystals.

Original languageEnglish (US)
Article number1569
JournalCrystals
Volume13
Issue number11
DOIs
StatePublished - Nov 2023
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • General Chemical Engineering
  • General Materials Science
  • Condensed Matter Physics
  • Inorganic Chemistry

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