Influence of impurities on the crystallisation of pharmaceutical materials

Rights statement
Awarding institution
  • University of Strathclyde
Date of award
  • 2017
Thesis identifier
  • T14535
Person Identifier (Local)
  • 201279128
Qualification Level
Qualification Name
Department, School or Faculty
  • The major part of this thesis describes work done to investigate the organic and inorganic impurity content in metformin hydrochloride samples and their effect on induction time and nucleation kinetics. Crystallisation from solution plays a significant role in the pharmaceutical, chemical and food industry, because it is widely used as a separation and purification technique. Nucleation is the first step of crystallisation, where the extremely small species called nuclei are formed in solution. This step determines the quality of a new crystalline material, however, at present the understanding of this process is relatively poor. One of the factors affecting the nucleation pathway and kinetics is the impurity content.;Impurity control in the pharmaceutical industry should be planned at the drug design stage and carried throughout the entire drug production process. Acceptable levels for impurities in drugs are defined in official regulations released by the International Conference of Harmonisation (ICH), the United States Food and Drug Administration (FDA) and the Canadian Drug and Health Agency (CDHA). A liquid chromatography/mass spectrometry (LC/MS) method for the determination and quantification of metformin hydrochloride and five out of six known impurities was developed and validated during this project. This method was then used to determine the levels of these impurities in samples taken during the temperature stability test of metformin hydrochloride.;The results revealed that the chosen model compound was relatively stable under the chosen conditions and the levels of impurities were within the acceptable levels. A separate ion chromatography method was developed for the determination of dimethylamine. Initial experiments showed that the raw material of metformin hydrochloride contained several inorganic impurities, however, due to time limitations only ammonium sulfate was chosen as the source of sulfate ions to test their effect on nucleation rate of metformin hydrochloride. It was found that when up to 0.5 %w/w of ammonium sulfate was added to the solution it caused a decrease in nucleation rate and an increase in the average induction time.;On the other hand, addition of 1.0 %w/w of ammonium sulfate had no influence on either nucleation rate or average induction time. The unexpected loss of the impurity effect was investigated further using many analytical techniques such as Scanning Electron Microscope (SEM), Time of Flight - Secondary Ion Mass Spectrometry (ToF-SIMS), Differential Scanning Calorimetry (DSC), Dynamic Light Scattering (DLS) and Ion Chromatography (IC). The results obtained did not provide a definitive answer with regard to why the highest concentration of impurity had no effect on nucleation kinetics. It was thought the effects on induction times were due interactions between sulfate and the nucleation clusters formed during crystallisation of metformin hydrochloride, however further investigation is required.;In a separate part of this project was an investigation into whether or not a batch CoFlux reactor could be used to produce a pure polymorphic form of L-glutamic acid and whether or not enthalpy measurements were an advantage of this reactor for monitoring the crystallisation. Particles obtained from crystallisation experiments in this reactor were analysed using in-situ Raman spectrometry (for several experiments) and off-line X-Ray diffraction (XRPD), laser diffraction (LD) and microscope imaging. The results obtained in the CoFlux reactor were reproducible and a narrower particle size distribution was achieved with the improved temperature control. Enthalpy measurements were not an advantage when monitoring the crystallisation of L-glutamic acid.
Resource Type
Date Created
  • 2017
Former identifier
  • 9912546092302996