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Probing effects of organic solvents on paracetamol crystallization using in silico and orthogonal in situ methods

  • Polymorphism is the property exhibited by many inorganic and organic molecules to crystallize in more than one crystal structure. There is a strong need for understanding the influencing factors on polymorphism, as it is responsible for differences in many physicochemical properties such as stability and solubility. Nearly 80 % of marketed drugs exhibit polymorphism. In this work, we took the model system of paracetamol to investigate the influence of solvent choice on its polymorphism. Different methods were developed and employed to understand the influence of small organic solvents on the crystallization of paracetamol. Non-equilibrium molecular dynamics simulations with periodic simulated annealing were used as a tool to probe the nature of precursors of the metastable intermediates occurring in the crystallization process. Using this method, it was found that the structures of the building blocks of crystals of paracetamol is governed by solvent-solute interactions. In situ Raman spectroscopy was used with a custom-made acoustic levitator to follow crystallization. This set-up is a reliable method for investigating solvent influence, attenuating heterogeneous nucleation and stabilizing other environmental factors. It was established that as a solvent, ethanol is much stronger than methanol in its effect of driving paracetamol solutions to their crystal form. The time-resolved Raman spectroscopy crystallization data was processed using a newly developed objective function based non-negative matrix factorization method (NMF). An orthogonal time-lapse photography was used in conjunction with NMF to get unique and accurate factors that pertain to the spectra and concentrations of different moieties of paracetamol crystallization existing as latent components in the untreated data.

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Metadaten
Author:Surahit Chewle
Document Type:Doctoral Thesis
MSC-Classification:92-XX BIOLOGY AND OTHER NATURAL SCIENCES
CCS-Classification:J. Computer Applications
PACS-Classification:80.00.00 INTERDISCIPLINARY PHYSICS AND RELATED AREAS OF SCIENCE AND TECHNOLOGY
Granting Institution:Humboldt-Universität zu Berlin
Advisor:Marcus Weber, Franziska Emmerling
Date of final exam:2023/08/22
Year of first publication:2023
URL:https://edoc.hu-berlin.de/handle/18452/27957
Licence (German):License LogoCreative Commons - CC BY - Namensnennung 4.0 International
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