Formation of optimised particles for formulation and processing

Rights statement
Awarding institution
  • University of Strathclyde
Date of award
  • 2018
Thesis identifier
  • T14936
Person Identifier (Local)
  • 201284927
Qualification Level
Qualification Name
Department, School or Faculty
  • Pharmaceutical crystals frequently exhibit unfavourable bulk solid properties leading to low downstream processing efficiency and additional unit operations to enhance processing characteristics. Novel particle engineering techniques such as spherical crystallization or spherical agglomeration can be used in order to obtain spherical agglomerates with enhanced properties. Spherical agglomerates are produced through cooling crystallization in ethanol-water mixture under specific process conditions involving liquid-liquid phase separation; hence ternary phase diagrams were determined experimentally. The liquid-liquid phase region was found to increase with increasing temperature, whilst absent at 20°C. Ibuprofen agglomerates crystallised in the presence of liquid-liquid phase separation showed an increased flowability and higher yield compared to the standard cooling crystallization process. Spherical agglomerates of lovastatin were prepared by suspension of crystals in water and agglomeration through the action of another solvent called bridging liquid. All the solvents except alkenes led to the formation of spherical agglomerates as long as a sufficient amount is added. The influence of amount of bridging liquid and agitation rate on the properties of lovastatin spherical agglomerates obtained from methyl isobutyl ketone are investigated. With increasing amount of bridging liquid the particle size increased and the shape became irregular. In a separate chapter, a combined cooling antisolvent seeded crystallization process was monitored using process analytical technologies to investigate the agglomeration under different process conditions. A novel in-house image analysis algorithm coded in MATLAB was used to analyse images of agglomerates recorded by ParticleView V19 probe through descriptors. Images showed that seeds were already aggregated before addition to the reactor indicating an insufficient dispersion. Experiments using the same seed loading led to products with slightly variable particle size distribution but different degree of breakage ranging from moderate to significant breakage. Stronger crystals with larger size were produced when a temperature cycle was applied. Overall this work showed that agglomeration processes can lead to product with enhanced properties, and advanced the scientific understanding of the agglomeration mechanisms through implementation of process analytical technologies hence facilitating the scale-up and selection of control strategies.
Advisor / supervisor
  • Florence, Alastair
Resource Type
  • This thesis was previously held under moratorium from 10th September 2018 until 10th September 2023.
Date Created
  • 2018
Former identifier
  • 9912621391002996