Experimental and computational approaches for control and prediction of solid-state of pharmaceuticals

This thesis illustrates techniques for discovery of solid-state forms and probing the relationship between molecular structure and crystallisability. Also, the value of combined experimental and computational approaches to provide better understanding of the key factors underpinning the structural diversity in two groups each comprising of two structurally related pharmaceutical compounds is demonstrated. An effective methodology of high throughput crystallisation and analysis for polymorph, solvate and salt screening using quartz 96/48 multi well plate with an automated system for collecting high quality Raman spectra was developed and validated. Using this efficient technique, 10 novel salts of amoxapine, 3 novel physical forms of clozapine and 16 novel solid forms of olanzapine were obtained by utilising a total of only ~640 mgs of API and ~65 ml of solvents. A statistical model with ~70% prediction accuracy has been built for predicting the crystallisability of small organic molecules. This model is first of its type and provides an opportunity to identify problematic systems at early stages and would allow early targeting for improvements. Structurally related molecules within each group were found to have markedly different experimental solid-state diversity after comprehensive physical form screening using multiple crystallisation techniques selected to maximise the crystallisation search space. Crystal structure prediction studies have been proved to be an important tool in rationalisation of the observed solid-state diversity. PIXEL calculations revealed that the largest contribution to crystal stabilisation comes from dispersion energy and enabled the identification of dominant intermolecular interactions in the crystal structures. Structural packing analysis using XPac and Mercury has enabled the structural relationship amongst all the crystal structures to be investigated. In case of olanzapine solvates XPac analysis provides a rationale of desolvation products by highlighting the close relationships between the forms and desolvated 'end product'. Statistical modelling analysis revealed that the physicochemical properties of the solvents were directing the crystal packing in olanzapine solvates.

Name dc:type.qualificationname

phd

Level dc:type.qualificationlevel

doctoral-pg

Grantor dc:publisher.institution

University of Strathclyde

Year dc:date.issued

2013

Author dc:creator

• Bhardwaj, Rajni Miglani

Advisor dc:contributor.advisor

• Florence, Alastair

DOI

10.48730/wm6e-bm47

Identifier

T13630

OAI identifier oai:identifier

oai:strathclyde:79407x19s