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Title: The influence of crystallization on the mechanical and interfacial properties of active pharmaceutical ingredients
Author: Kubavat, Harshal A.
ISNI:       0000 0004 2714 0636
Awarding Body: University of Bath
Current Institution: University of Bath
Date of Award: 2011
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Crystallisation of organic molecules is a fundamental process routinely used for purification and isolation of active pharmaceutical ingredients (APIs). In the formulation of traditional dry powder inhaler (DPI) products, harvested primary crystalline APIs are secondarily processed and subsequently blended with excipients to form an ordered mixture. In DPI formulations containing drug particles and coarse carrier material, the delicate balance of cohesive and adhesive forces between the drug(s) and carrier enable delivery of respirable APIs to the targeted regions of the lungs. The destructive and relative uncontrolled nature of secondary-processing techniques such as milling, leads to the generation of respirable formulations of varying performance, resulting in varying clinical efficacy. The relationship between the primary crystallisation of APIs and the physical, chemical, mechanical properties of the primary crystals and the relationship to the secondary processing of these materials remain poorly understood. This body of work aimed to address the paucity of data within this area, within the context of DPI formulations. A nanoindentation approach using atomic force microscopy (AFM) developed to determine the elastic modulus of crystalline pharmaceutical samples provided the Young's modulus of a range of pharmaceutical materials. Differences were observed indicating lactose monohydrate to have the highest stiffness (high Young's modulus) and formoterol fumerate dihydrate having the lowest of the materials tested (0.93 GPa). Utilising AFM cohesive-adhesive force measurements against a reference Highly Ordered Pyrolytic Graphite (HOPG) substrate, fluticasone propionate was seen to have the greatest cohesive tendency of 1.13 times greater to itself over HOPG. In contrast, budesonide had the most adhesive tendency towards HOPG, with a cohesive-adhesive balance (CAB) value of 0.65, indicating that the differences in DPI performance of these materials may be as a result of differences in their interfacial properties which could be a influenced by prior processing history. Crystallisation of fluticasone propionate (FP) was conducted using four different solvent/anti-solvent combinations to investigate the influence of different endsolvents on the Young's modulus of the resultant crystals, their micronisation behaviour and in vitro performance in carrier based DPI formulations. The Young's modulus of FP crystals produced varied significantly and these differences were reflected in the number of passes required in the microniser to reduce the particle size of the primary crystals to less than 5 µm. Furthermore, the resultant micronised materials were determined to have different cohesive-adhesive balance values, supporting differences in their respective DPI formulation performance attributes, both in binary formulation and in combination with a second drug, salmeterol xinafoate. The impact of changes in crystal habit on the mechanical properties of budesonide crystals was investigated alongside the resultant effect on interactive forces of the micronised material and the performance in a DPI formulation. The Young's modulus determined by AFM nanoindentation on the {002} face of each habit confirmed a Young's modulus four times greater for one of the habits and supported the particle size data of the resultant micronised materials from each primary crystal samples. Cohesive-adhesive balance measurements of the micronised budesonide samples with respect to lactose monohydrate supported in vitro aerosolisation performance studies, whereby the fine particle dose and fine particle fraction of the emitted dose of the sample with lower adhesive tendency towards the lactose carrier particle was greater. The relative mechanical and processing differences between anhydrous and monohydrate forms of ipratropium bromide (IB) was evaluated using supercritical fluid technology and temperature drop crystallisation techniques, respectively. The aerosolisation efficiency of these materials from DPI formulations determined the effect of crystal form on the functionality of the two samples. Repeated force-distance measurements revealed no significant differences between the anhydrous and monohydrate form of IB and revealed both forms to have an average elastic modulus of approximately 4 GPa. No differences were seen in the secondary processing of these materials relating the milling behaviour, interfacial properties or aerosolisation performance in vitro, demonstrating the suitability of supercritical fluid technology in producing an anhydrous form of ipratropium bromide for inclusion in a carrier based DPI formulation.
Supervisor: Price, Robert Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: nanoindentation micronisation ; Young's modulus dry powder inhaler ; crystallization