BIN-MOHD-NAJIB, MOHD,NADZRI (2019) STUDY OF PHARMACEUTICAL CRYSTAL HYDRATES AND THEIR PREDICTION BASED ON PRE-NUCLEATION AGGREGATION. Doctoral thesis, Durham University.
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Author-imposed embargo until 04 October 2024.
It is well documented that hydrate formation is a constant problem in the pharmaceutical industry as its formation can reduce the drug’s aqueous solubility and may impact the overall stability and safety. Furthermore, the current technology used in the prediction and screening process demands time, money, effort, as well as some elements of serendipity, leaving hydrate formation largely unpredictable and a challenge. This study probes hydrate formation passively and actively. Passive investigation demands the crystalline hydrate form to be present prior to analysis, while the active probe does not. The use of common solid-state characterisation techniques in the passive analysis shows the complexity in the solid-state landscape of crystalline hydrate forms. Two different systems in the form of charged and neutral pharmaceutical compounds, namely sodium diatrizoate and tranilast (Chapter 3 and 4) best highlight the passive approach. The focus of the research then shifts to the development of an active hydrate prediction technology (Chapter 5) exploiting the principles of host-guest chemistry, titration techniques and binding constants to show the affinity of solute molecules to water in the pre-nucleation state for compounds forming stable hydrates. The novel active approach is further scrutinised in Chapter 6 with the analysis of metastable and non-hydrate forming compounds, followed by a blind study to predict the hydrate-forming ability of several other compounds. In the final chapter, the potential usage of the developed prediction method is expanded to stable solvated crystal forms and protein binding affinity prediction. The usefulness of the developed method will grow with more compounds and systems analysed. In addition, analysis of more hydrate-forming compounds with different hydrate-forming ability will further clarify, update and expand the current database.
|Item Type:||Thesis (Doctoral)|
|Award:||Doctor of Philosophy|
|Keywords:||hydrate; prediction; binding constant; pre-nucleation state|
|Faculty and Department:||Faculty of Social Sciences and Health > Medicine and Health, School of|
|Copyright:||Copyright of this thesis is held by the author|
|Deposited On:||19 Sep 2019 08:03|