Pang, Yuying; (2021) Studying and controlling polymorphic transitions and co-crystallization in pharmaceutical materials. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Regardless of the pathway by which a drug is taken, it must be soluble in an aqueous environment – this is required for the drug to be absorbed by the body. However, up to 70% of new drug candidates have poor aqueous solubility and do not dissolve easily. Accessing and stabilising more soluble solid forms of a drug can alleviate these problems, but systemic approaches to doing this remain highly elusive. In this work a novel method to analyse phase transitions is utilised by combining high energy synchrotron X-ray powder diffraction with differential scanning calorimetry (XRD-DSC). This allows for a detailed real-time characterisation of a drug formulation, with both structural and calorimetric data collected simultaneously on the same sample. Initial work (Chapter 2) was carried out to study polymorphic transition in three active pharmaceutical ingredients (APIs): flufenamic acid (FFA), mefenamic acid (MA) and salmeterol xinafoate (SX). The XRD-DSC study on an FFA glass found a new FFA form (form X). Attempts were made to solve this using computationally predicted FFA structures, but the refinement was not satisfactory. Variable temperature (VT-XRD) shows form X is very unstable and will convert to form IV with a change of temperature. Studies on FFA form III indicate form I and form III are enantiotropes, and that the transition from form III to I occurred via a solid-solid pathway rather than a melt-recrystallisation. For MA, XRD-DSC experiments show an enantiotropic transition between forms I and II/III, and form III then converts to form II when heating continues. However, the diffraction patterns contain reflections which cannot be matched with any of the known forms of MA, suggesting the existence of an as-yet unknown polymorph. Studies on SX also illustrates an endothermic event coinciding with a polymorphic transition, but whether this peak relates to an enantiotropic transition from form I to II or the melting of form I followed by recrystallization of form II cannot be confirmed because the crystal structure of form II is unknown, and could not be solved in this work. Building on this, further studies aimed to provide additionally understanding of ability of additives to stabilise unstable forms of APIs. The work described in Chapter 3 and 4 explores the use of XRD-DSC to study phase transitions in the stabilisation of the amorphous form and metastable polymorphs of flufenamic acid through the addition of polymers and trehalose respectively. The studies show hydroxypropyl methylcellulose (HPMC) 6 and 100000 cp and ethyl cellulose (EC) 4 cp can stabilise FFA form IV by inhibiting the transition to form I during heating. Polymers stabilise FFA in both amorphous and metastable forms by both Intermolecular interaction and viscosity. Increasing the polymer content of the ASD also inhibits polymorphic transitions, with drug: polymer ratios of 1:5 w/w resulting in FFA remaining amorphous during heating. Studies on FFA-trehalose mixtures reveal that different trehalose ratios have the ability to selectively stabilise FFA polymorphs. During storage, blends with FFA: trehalose ratio at 5:1 w/w recrystallised into form I FFA, while higher trehalose content led to FFA form IV being generated after storage. When heated in the DSC, all FFA-trehalose mixtures ultimately recrystallised into form I. Upon a second cooling cycle, mixtures with FFA: trehalose ratio 5:1 w/w recrystallised into form IV, while FFA with higher trehalose content converted to form I. Next, the studies in Chapter 5 outline the use of additives to separately target nucleation and particle growth and generate flufenamic acid nanoparticles. Five additives and combinations of them were explored, and their effect on the particle size of the isolated flufenamic acid crystals investigated. The influence of additives on polymorphic form is studied by DSC and XRD. FFA form III was produced in all experiments, and despite the additives all reducing the particle size none of them led to a nanosize product. Therefore, it appears that antisolvent precipitation is not a suitable method to prepare FFA nanocrystals. Finally, Chapter 6 is concerned with the formation of cocrystals between flufenamic acid and three pharmaceutically relevant coformers: nicotinamide (NCT), L-proline (LP) and meloxicam (MXM). The stability and solubility of the four cocrystals were studied. FFA-NCT cocrystal were reported by Fibian et al. before while FFA-LP and FFA-MXM cocrystal have not been reported to date. XRD-DSC was employed to understand of the behaviour of the cocrystals during heating. Three cocrystals were successfully prepared in this study. All remain stable when stored at room temperature for 6 months and have a higher solubility than that of pure FFA.

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