The optimisation of the pharmaceutical properties of carboxylic acid drugs is often conducted by salt formation. Often, the salt with the best solubility is not chosen due to other factors such as stability, solubility, dissolution and bioavailability that are taken into consideration during the preformulation stage. This work uses advanced imaging techniques to give insights into the preformulation properties that can aid in the empirical approach often used in industry for the selection of salts. Gemfibrozil (GEM) was used as a model poorly soluble drug. Four salts of GEM were made using cyclopropylamine (CPROP), cyclobutylamine (CBUT), cyclopentylamine (CPENT) and cyclohexylamine (CHEX) as counterions. DSC, XRD and SEM were used to confirm and characterise salt formation. IDR obtained using UV-imaging up to 10 min for all the salts showed that an increase in the chain length of the counterion caused a decrease in the IDR. Past the 10 min mark, there was an increase in the IDR value for the CPROP salt, which was visualised using UV-imaging. The developed interfacial (surface) area ratio (Sdr) showed significant surface gains for the compacts. Full dosage form (capsule) imaging showed an improvement over the GEM for all the salts with an increase in chain length of the counterion bringing about a decrease in dissolution which correlated with the obtained UV-imaging IDR data.

Graphical abstract

Submission: European Journal of Pharmaceutics and Biopharmaceuticsthe dissolution of indomethacin. This work thus highlights the importance of having both complimentary IDR and whole dosage imaging techniques in giving a better understanding of solid dispersion systems.

As the ingestion of drug products with alcohol could have adverse effects on the release of drugs from dosage forms, it is important to understand the mechanisms underpinning the influence on drug release by evaluating the effect of alcohol-containing media on the behaviour of pharmaceutical excipients. In this work, the effect of hydroalcoholic media containing up to 40% v/v absolute ethanol was evaluated, employing both the regular (CR) and direct compression grades (DC) of hypromellose. X-ray microtomography (XµT) and magnetic resonance imaging (MRI) were used as complementary techniques in determining the influence of the media composition on the ability of the CR and DC polymers to form and evolve the gel layer that controls drug release. Particle and powder properties of the polymer were characterised to determine any relationship to performance in hydroalcoholic media. Triboelectrification results showed the CR grade formulation to charge electropositively whereas the DC grade charged electronegatively. The flow properties also showed the DC grade to have a superior flow as compared to its CR counterpart. Differences in particle morphology between the grades influenced charging and flow behaviour of the powders; however, it did not seem to impact significantly either on the mechanical strength or the drug release properties of the compacted formulation using the model drug propranolol HCl. XµT and MRI imaging were successfully used as complementary techniques in determining the gel layer/hydration layer thickness measurements as the layer developed, as well as following ingress of hydroalcoholic media and its impact on the dry core. The result showed that although differences were present in the gel layer thickness potentially due to differences in particle morphology, this also did not impact significantly on the dissolution process, especially in acidic and hydroalcoholic media.