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Influence of impurities on the solubility, nucleation, crystallization and compressibility of paracetamol
Date
2019
Abstract
The striking ability of impurities to signiï¬ cantly inï¬ uence crystallization processes is a topic of paramount interest in the pharmaceutical industry. Despite being present in small quantities, impurities tend to considerably change a crystallization process as well as the ï¬ nal crystalline product. In the present work, the eï¬ ect of two markedly diï¬ erent impurities 4-nitrophenol and 4â ²-chloroacetanilide on the solubility, nucleation, and crystallization of paracetamol is described. In the ï¬ rst part of this work, the fundamentals are outlined and show that, although each impurity led to a small increase in solubility of paracetamol, their eï¬ ect as a nucleation inhibitor was much more pronounced. Induction time experiments were used in conjunction with the classical nucleation theory to show that the impurities did not aï¬ ect the solidâ liquid interfacial energy but instead signiï¬ cantly reduced the kinetic factor, overall resulting in reduced nucleation rates. Intriguingly, both impurities inï¬ uenced the solubility and nucleation of paracetamol in a similar fashion despite their signiï¬ cant diï¬ erences in terms of molecular structure, solubility, and ability to incorporate into the crystal structure of paracetamol. In the second part of this work, the incorporation of 4â ²-chloroacetanilide into the solid phase of paracetamol was investigated. The presence of 4â ²-chloroacetanilide in the solid phase of paracetamol signiï¬ cantly increased the compressibility of paracetamol, resulting in improved processability properties of paracetamol. The compressibility eï¬ ciency of paracetamol could be controlled using the amount of incorporated 4â ²-chloroacetanilide. Therefore, an experimental design space was developed and utilized to select the most important process parameters for impurity incorporation. Intriguingly, the number of carbon atoms in the aliphatic chain of the alcohol solvent strongly correlated to the impurity incorporation eï¬ ciency. As a result, it was feasible to accurately control the compressibility and the amount of 4â ²-chloroacetanilide in the solid phase of paracetamol by simply choosing the required alcohol as the solvent for crystallization. Thus, the present work comprehensively shows how diï¬ erent impurities impact the key crystallization mechanisms and properties of a pharmaceutical product. Rational process control over the incorporation of impurities and additives allows for advanced manufacturing of products with tailored speciï¬ cations.
Supervisor
Description
peer-reviewed
Publisher
American Chemical Society
Citation
Crystal Growth and Design;19 (7), pp. 4193-4201
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Funding code
Funding Information
Science Foundation Ireland (SFI)
Sustainable Development Goals
External Link
Type
Article
Rights
https://creativecommons.org/licenses/by-nc-sa/1.0/