Thesis

Impacts of structurally related impurities on crystal growth and purity in acetaminophen : a study of single crystal stagnant solution and bulk suspension crystallisation

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Awarding institution
  • University of Strathclyde
Date of award
  • 2024
Thesis identifier
  • T17020
Person Identifier (Local)
  • 201481789
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Qualification Name
Department, School or Faculty
Abstract
  • Crystallisation is a widely used technique in the purification, separation, and preformulation processes, yielding crystals with diverse shapes and sizes. The morphology of a crystal, including its faces and habits, determines its overall appearance. External factors like supersaturation, temperature, and solvent choice greatly influence the crystal habit. While it is possible to stabilise these factors, the removal of impurities presents a significant challenge, whether they originate from chemical sources or other origins. Although various methods, such as filtration, washing, and recrystallisation are employed to remove impurities, they have limitations. Impurities exhibit varied effects in crystallisation systems, whether intentionally introduced or generated during the process. It is crucial not only to identify the source but also to understand the impact on drug solubility and crystal growth. Batch-to-batch variations can hinder downstream processes, making optimisation challenging. Changes in crystal habit can affect the compressibility and consolidation behaviour of drugs, resulting in the loss of valuable Active Pharmaceutical Ingredients (APIs). Impurities can also alter the flowability of fluids and the cake's permeability, leading to increased particle breakage. In this study, the influence of metacetamol and acetanilide additives on the solubility of paracetamol in ethanol and isoamyl alcohol is investigated. Typically, drug substances exhibit higher solubility in alcohols compared to water, and evaluating solubility provides insights into dissolution rates in different solvents. Impurities were observed to have a modest effect on solubility at loadings of 1-4%. Metacetamol significantly reduced solubility in ethanol at low temperatures, while acetanilide decreased solubility at higher temperatures (25°C to 55°C). In isoamyl alcohol, the effects of impurities on solubility varied, with metacetamol generally increasing solubility at each temperature and acetanilide decreasing solubility from 25°C to 55°C Furthermore, the growth rates of single crystals in a stagnant ethanol solution was evaluated the influence of impurities (metacetamol and acetanilide) on habit modification and growth rates specific to crystal faces was also investigated. The growth of multiple crystal habits in a single system on several occasions was observed. As impurity concentrations increased, the growth rate of inhibited crystal faces decreased along with alterations in crystal habits. Additionally, the effect of an ultrasonic toothbrush was found to induced nucleation and growth of single crystals in all cases, leading to the formation of previously unseen habits. Finally, the addition of ultrasound in a bulk suspension crystallisation system was explored to assess its impact on nucleation, temperature, crystal size distribution, habit, filtration rate, and product purity. Ultrasound increased the rate of nucleation, overall yield, and product purity, resulting in smaller particle sizes, reduced agglomeration, and a narrower particle size distribution. Metacetamol proved to be the most challenging impurity in terms of incorporation and its overall influence on nucleation, growth, and crystal habits. These findings highlight the potential of sonocrystallisation to modify crystal habits and enhance the growth, purity, and yield of drug substances. Future studies examining the impact of ultrasound on purity will contribute to better control and optimisation of crystallisation parameters, thereby preventing the formation of undesired crystal habits and impurity concentrations.
Advisor / supervisor
  • Price, Chris J.
Resource Type
DOI

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