2026-09-18T18:56:42Zhttps://dora.dmu.ac.uk/server/oai/requestoai:dora.dmu.ac.uk:2086/211272023-09-20T19:31:17Zcom_2086_2388col_2086_2389
Mechanistic Understanding of Co-crystal solubility and dissolution by using a combination of Experimental and Molecular Modelling Techniques
Kirubakaran, Preyanthiny
The purpose of this study is to improve the solubility, dissolution rate and permeability of poorly water-soluble drugs by understanding the mechanism of dissolution at molecular level of Flufenamic acid and Carbamazepine co-crystals in the presence of polymers. This study has been separated into four sections: (1) Formation of pharmaceutical co-crystals: Three pharmaceutical co-crystals of poorly water soluble active pharmaceutical ingredient (API) of Flufenamic acid (FFA) and Carbamazepine (CBZ) were synthesized, including 1:1 Flufenamic acid-theophylline co-crystal (FFATP CO), 1:1 Flufenamic acid-nicotinamide co-crystal (FFA-NIC CO) and 1:1 Carbamazepine-nicotinamide co-crystal (CBZ-NIC CO). The results of Fourier Transform Infrared spectroscopy (FTIR), Differential scanning calorimetry (DSC) and X-ray Powder Diffraction (XRPD) confirmed the formation of co-crystals. (2) The effect of polymers on the surface dissolution of co-crystals: The influence of three polymers (polyethylene glycol (PEG), polyvinylpyrrolidone (PVP), and a copolymer of N-vinly-2- pyrrolidone (60%) and vinyl acetate (40%) (PVP-VA)) on the surfaces of FFA-TP CO, FFA-NIC CO and CBZ-NIC CO was studied using Atomic force Microscopy (AFM), Scanning electron microscopy (SEM) and Raman spectroscopy. It was found that the co-crystals have different dissolution mechanisms, and that addition of polymers can alter the dissolution properties of co-crystals by interacting with the crystal faces. (3) The molecular interactions between the drugs, co-formers and polymers were investigated using Nuclear Magnetic Resonance (NMR) and Diffusion Ordered Spectroscopy (DOSY). It was found that the type of a polymer, its concentration, and the interaction of the polymer with a co-former in solution will significantly affect the FFA and CBZ co-crystals (4). Molecular modelling of free drug molecules with coformers and polymers in the presence of water molecules: Results indicate bulk precipitation could be occurring for FFA molecules in solution and that PVP-VA was an effective precipitation inhibitor for all three co-crystals studied in solution. Overall, PVP was an effective polymer for surface precipitation inhibitor and PVP-VA was the most effective inhibitor for precipitation in solution.
De Montfort University
2021-01
Thesis or dissertation
Doctoral
PhD
en
https://dora.dmu.ac.uk/handle/2086/21127
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https://dora.dmu.ac.uk/bitstreams/26967df4-a459-44bf-9c34-4a12d32fadde/download
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Faculty of Health and Life Sciences