Mechanistic design of effective pharmaceutical cocrystal formulations


   Faculty of Medical Sciences Graduate School

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  Ms Tatiane Cogo Machado  Applications accepted all year round  Self-Funded PhD Students Only

About the Project

It is estimated that more than 70 percent of the compounds in the pharmaceutical pipeline can be poorly water-soluble. Since solid drug forms must dissolve before absorption can occur, strategies to improve drug solubility and dissolution are a continuous need.

The main research approach of my group is focused on improving solubility and dissolution of poorly water-soluble drugs by cocrystal formation, including their synthesis, characterization and formulation. Although many studies on cocrystal synthesis are found in the literature, cocrystal formulation development has thus far been marked by a lack of understanding of cocrystal solution chemistry that governs drug supersaturation. Cocrystals can generate supersaturated drug solutions, then they are likely to convert to the less soluble drug form that precipitates in the solution, decreasing drug absorption. Stabilizing metastable cocrystals during dissolution and pharmaceutical processes is one of the most challenging aspects of cocrystal development. Then, formulation efforts are crucial for cocrystals to succeed. Some approaches can include the addition of polymers as precipitation inhibitors, surfactants and pH-modifiers in formulations. However, the selection of additives remains a largely empirical and time-consuming process.

Our team has been studying cocrystal solubility behavior in the presence of different formulation additives dissolved in solution. From these studies, thermodynamic parameters can be obtained, such as solubility product (Ksp), solubility advantage (SA) and solubilisation power (SP). In combination with mathematical models, these parameters are used to anticipate cocrystal dissolution behaviour and also to rationally select additives for formulations. In addition to that, we have recently proposed a graphical approach to manage cocrystal dissolution-drug precipitation (DSP) behavior. DSPindex, obtained from this quantitative approach can answer the question of whether and how much coformer should be added to a formulation to sustain drug supersaturation and to decrease drug precipitation kinetics. Study can be found here: DOI: 10.1021/acs.molpharmaceut.2c00122.

In this project, the PhD student will apply these concepts and parameters to select functional and suitable additives to be tested in cocrystal formulations and in cocrystal processing, including granulation, extrusion, spheronization and spray coating. This will enable better initial decisions on cocrystal formulation to manage its dissolution performance and drug exposure. Cocrystals of poorly water-soluble drugs with pharmaceutical relevant application will be used as models.

The successful candidate will have the opportunity to develop skills on multiple disciplines including physical chemistry, pre-formulation, formulation, drug crystallization and solid-state chemistry. Candidates will acquire and develop their laboratory skills in a vast array of techniques for solid state characterization, such as calorimetric, spectroscopic and crystallographic methods, imaging, analytical (HPLC) and pharmaceutical processing – that will strengthen their future career progression. Moreover, the candidate will have the opportunity to work in a vibrant research community at Newcastle University’s School of Pharmacy and to interact with academic collaborators across the globe, in the field of cocrystal and drug delivery.

Materials Science (24) Medicine (26)

Funding Notes

This is a self-funded PhD project; applicants will be expected to pay their own fees or have a suitable source of third-party funding. A bench fee may also apply to this project, in addition to the tuition fees. UK students may be able to apply for a Doctoral Loan from Student Finance for financial support.

Applications accepted all year around.
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