Crystal engineering approaches to solid-state pharmaceutical systems

Control of a solid drug's physical form is an important stage of drug development, in order to best optimise the physicochemical properties of the drug. It is also important for intellectual property and regulatory considerations. Commonly, optimisation of a solid drug form moves beyond controlling the solid-state and actively manipulating it, via salt formation, co-crystal synthesis or inclusion complexation, for example. Presented in this work are three distinct approaches to the control and development of solid-state form of organic molecules and pharmaceuticals. The first of these approaches reports a novel, relatively simple technique for polymorph screening of compounds that are thermally stable, wherein homopolymer surface interactions direct the polymorph of a drug recrystallising from the supercooled melt. The study carried out demonstrates the ability to selectively crystallise the α polymorph of indomethacin using specific polymer substrates. The second theme details a crystal engineering strategy for a drug molecule to obtain a novel solid form. It is shown how knowledge of intermolecular hydrogen bonded supramolecular synthons can be exploited to rationally select potential co-crystal formers based on the likely growth unit formed. The structure of the co-crystal, solved using single-crystal X-ray diffraction, is reported and verifies the design strategy. The potential to enhance a drug's properties is demonstrated by an increased melting point compared to the native drug form, such that the liquid drug becomes a stable solid at room temperature. There is also an improved intrinsic dissolution rate as a direct result of the application of the methodology. In the last chapter, a systematic structural investigation of cyclodextrin inclusion complexes with an isomeric series of guest molecules has generated a large number of single-crystal structures and X-ray powder diffraction patterns. These provide structural understanding of these systems and highlight isostructural trends that can be used to make some general structural predictions. A heavy emphasis is placed on the method used to synthesise the crystalline inclusion complex and the structural role of cosolvents. A complementary solution-state investigation was also performed to detail the solution-state chemistry of these systems and enable the relationship between solution-state and solid-state complexation to be investigated.

Name dc:type.qualificationname

phd

Level dc:type.qualificationlevel

doctoral-pg

Grantor dc:publisher.institution

University of Strathclyde

Year dc:date.issued

2012

Author dc:creator

• McKellar, Scott Campbell

DOI

10.48730/ed4w-dr31

Identifier

T13165

OAI identifier oai:identifier

oai:strathclyde:n583xv01b