Factors affecting the stability and performance of amorphous solid dispersions of poorly soluble active pharmaceutical ingredients
Citation:
BROWNE, EMER, Factors affecting the stability and performance of amorphous solid dispersions of poorly soluble active pharmaceutical ingredients, Trinity College Dublin.School of Pharmacy & Pharma. Sciences, 2020Abstract:
This thesis focuses on factors affecting the stability and performance of amorphous solid dispersions (ASDs) of poorly soluble active pharmaceutical ingredients (APIs). The poor aqueous solubility of pipeline drugs has limited their development as oral solid dosage forms. Formulating these APIs as ASDs is one strategy to overcome this. The major limitation to ASD development is the physical instability of the amorphous state. The work carried out in this thesis has highlighted the influence that chiral recognition, polymer choice and manufacturing method have on the stability and performance of amorphous solid dispersions of three poorly soluble APIs; ibuprofen, ketoprofen and nifedipine. The effect of chiral recognition on the facilitation of amorphisation for opposing enantiomers of ibuprofen and the cellulose polymer HPMC was explored. When cryo-milled, the S-ibuprofen-HPMC sample contained only 52 ± 4 % of total ibuprofen content in the crystalline form while the equivalent R-ibuprofen-HPMC sample contained 76 ± 9 % of total ibuprofen content in the crystalline form . The influence of ASD manufacturing route was found to affect chiral recognition, with spray dried material exhibiting reduced chiral recognition, in terms of a difference in crystalline ibuprofen content, relative to the equivalent cryo-milled material. The effect that polymer physicochemical properties have on ASD performance was comprehensively evaluated with the aim of aiding polymer selection at an early stage of development. The relative humidity induced glass transition value (RHTg) was found to be useful in describing the effect that co-polymer substitution ratio has on moisture sorption and associated plasticisation. Polyvinylpyrrolidone vinyl acetate (PVPVA) containing systems with a VP:VA ratio less than 7:3 did not achieve supersaturation within 2 hours at pH 1.2. The relationship between the route of ASD generation and performance was also evaluated for two processes; electrospraying and spray drying. It was determined that solution conductivity had no impact on the morphology of the particles produced via spray drying, while it did impact the morphology of particles produced via electrospraying. While the dissolution profile of the ketoprofen-PVP material was similar for both electrosprayed and spray dried material, the smaller particle size of the electrosprayed material resulted in higher surface moisture sorption rates compared to the equivalent spray dried material. Factors affecting the chemical stability, specifically the photostability of spray dried ASDs of nifedipine were also investigated. It was discovered that the solvent composition of the solution which was spray dried was critical to the photostability of the amorphous solid dispersion. This is believed to be due to the effect that these factors have on the surface enrichment of nifedipine. Lastly, the potential of ASDs of nifedipine in the treatment of autonomic dysreflexia (AD) was explored. Soluplus and HPMC were determined to be unsuitable polymers for this purpose due to negligible/delayed nifedipine release profiles, while PVP-based systems exhibited nifedipine release profiles which were similar to the nifedipine release profile from a ruptured Adalat® capsule, which is the current standard of care.
Sponsor
Grant Number
SSPC
Science Foundation Ireland (SFI)
Author's Homepage:
https://tcdlocalportal.tcd.ie/pls/EnterApex/f?p=800:71:0::::P71_USERNAME:BROWNEE3Description:
APPROVED
Author: BROWNE, EMER
Advisor:
Healy, Anne MariePublisher:
Trinity College Dublin. School of Pharmacy & Pharma. Sciences. Discipline of PharmacyType of material:
ThesisCollections
Availability:
Full text availableKeywords:
amorphous solid dispersion, ibuprofen, ketoprofen, nifedipineMetadata
Show full item recordLicences: