| EPSRC Reference: |
EP/V047329/1 |
| Title: |
Mechanistic Multiscale Co-crystal Dissolution Modelling |
| Principal Investigator: |
Li, Professor M |
| Other Investigators: |
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| Researcher Co-Investigators: |
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| Project Partners: |
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| Department: |
School of Pharmacy |
| Organisation: |
De Montfort University |
| Scheme: |
Standard Research - NR1 |
| Starts: |
01 February 2021 |
Ends: |
31 January 2023 |
Value (£): |
202,422
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| EPSRC Research Topic Classifications: |
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| EPSRC Industrial Sector Classifications: |
| Pharmaceuticals and Biotechnology |
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| Panel History: |
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Summary on Grant Application Form |
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Dissolution of active pharmaceutical ingredients (APIs) in orally administrated drug products (such as tablets and capsules) is a pre-requisite for absorption within the human body because only dissolved drug molecules are able to diffuse through living tissues. Poorly soluble drugs can lead to a low dissolution rate and poor bioavailability. Therefore, the preparation of less conventional solid forms and more innovative formulation strategies are needed. In this work we aim to address improving the oral bioavailability of poorly soluble drugs using co-crystals, which are defined as bringing an API and one or more other molecular species (called co-formers) in stoichiometric amounts to form a crystal lattice. The advantage of co-crystals is to improve the API solubility, dissolution rate, physical and chemical stability as well as in mechanical properties. Therefore, co-crystallisation of APIs can offer a means of improving the oral bioavailability of poorly soluble drugs without compromising their pharmacological activity. For a single component crystalline compound, the dissolution transient typically terminates when the solubility limit of the drug is reached, with the solution concentration being maintained as long as the system thermodynamics remain unperturbed. In this situation, the rates of dissolution and precipitation are in dynamic equilibrium. However, the understanding of dissolution mechanisms of multi-component co-crystals is very limited. It has been observed that the dissolution of co-crystals can lead to solution-mediated phase transformation (SMPT) where precipitation of the parent drug could take place on the surface of the dissolving co-crystal and/or in the bulk solution due to the "spring" effect where the parent drug solution concentration exceeds that of the crystal. The rates of these two processes, working in opposing directions, define the magnitude and duration of the solubility-enhanced "parachute", that can have direct implications on the drug bioavailability. Therefore, characterizing the recrystallization kinetics is of importance for predicting in vitro and in vivo performance of co-crystals. Additionally, stabilizing (nucleation and growth inhibiting) polymers are normally present within a formulation or in the dissolution medium to delay drug precipitation for maximising the benefits of co-crystals. The kinetics of the solution de-supersaturation event are often much more complex and less well understood. For this reason, through modelling such behaviour we can significantly reduce the experimental burden required to characterize the "spring" and "parachute" effects. Furthermore, through our mechanistic modelling of co-crystal dissolution we will facilitate the development and leverage of clinically relevant dissolution specifications (CRS) and play a key role in the successful prediction of clearance in vivo within physiologically-based pharmacokinetic (PBPK) modelling.
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Key Findings |
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This information can now be found on Gateway to Research (GtR) http://gtr.rcuk.ac.uk
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Potential use in non-academic contexts |
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This information can now be found on Gateway to Research (GtR) http://gtr.rcuk.ac.uk
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Impacts |
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| Description |
This information can now be found on Gateway to Research (GtR) http://gtr.rcuk.ac.uk |
| Summary |
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| Date Materialised |
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Sectors submitted by the Researcher |
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This information can now be found on Gateway to Research (GtR) http://gtr.rcuk.ac.uk
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| Project URL: |
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| Further Information: |
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| Organisation Website: |
http://www.dmu.ac.uk |