Acute Kidney Injury (AKI) is poorly diagnosed, ineffectively managed and has been recognised as a condition of global concern (Lancet. 2013. Jul 13;382). As such, the most effective approach to reducing the healthcare burden of this condition is to prevent it from happening at all. Crystalline Drug-induced Acute Kidney Injury (Crystal-DAKI) is one of the most common causes of AKI, resulting from the precipitation of crystals in the kidney which can cause direct damage to this organ. Crystal-DAKI often occurs after a treatment intervention, when clinicians are trying to balance unknown patient pharmacokinetics – to prevent drug toxicity – whilst ensuring therapeutic concentrations are reached. Drug behaviour in solvents such as urine is relatively uncharacterised in the literature, and this lack of knowledge contributes to public health crises such as the 2008 baby powder disaster where >300,000 babies fell ill.
RESEARCH GROUP
To uncover pharmaceutical problems, our team collaborates with a wide range of disciplines, including pharmacists, pharmaceutical scientists, chemists and engineers at internationally renowned pharmacy departments and at multinational pharmaceutical companies. This has led to work in a diverse range of projects built around the central theme of investigating the important pharmaceutical characteristics of solubility and mechanical behaviour which target four key scientific challenges (identified below) which are addressed in two research themes.
- A. Mechanistic understanding of cocrystal solubility behaviour for better PBPK prediction: Current approaches to cocrystal solubility prediction have not accounted for solution activity which would be expected to change drastically after meals. Further, there is little work exploring the effect of dose number on cocrystal behaviour. Better fundamental understanding of cocrystal behaviour in these contexts can enable better predictive capacity and may enable formulation design for new therapeutic contexts (e.g., achlorhydria).
- B. Enabling industrial cocrystal upscale without the need for ternary phase diagrams: Despite much commercial and scientific interest in cocrystals, methods of cocrystal synthesis are often empirically determined. Although researchers can precisely identify the optimum reaction conditions to obtain pure cocrystals via ternary phase diagrams, they are cumbersome, and therefore, synthesis is often carried out by mechanochemical methods (when possible). For cocrystals to be utilised to their full potential in the pharmaceutical industry they must fit into existing processes, which are predominantly solvent based. Notwithstanding the advantages of solution based methods to control particle size and morphology.
- C. High-load, multidrug powders that can be directly compacted into tablets: The development of high-drug load, multidrug tablets is an emerging challenge in the pharmaceutical industry, particularly in the context of multidrug formulations. This is seen most critically in the antiretroviral space (which commonly employs multidrug formulations of several antiretrovirals). We have recently illustrated that cocrystallisation can enable direct compaction to produce robust USP quality tablets with high-drug loading.
- D. Drug solubility determinations relevant to new contexts: Despite its apparent simplicity, there is much misunderstanding around the concept of solubility. This has been discussed in a recent consensus statement2 which highlighted that aqueous drug solubility is often reported as a single unit and often without solution pH, ionic strength and – if you're particularly unlucky – temperature data. The solid phase remaining after these measurements is also seldom reported. As such, there is currently a lack of data exploring the solubility of drugs in biorelevant solvents such as urine.
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