Optimised crystal morphologies for active pharmaceutical ingredients and related studies

The majority of active pharmaceutical ingredients (APIs) are crystalline solids in their pure forms. Crystalline solids have definable morphologies, i.e. shape and size. Crystal morphology is determined by both the internal structure of the crystals and external factors during growth from solution. The morphology of a crystal batch can affect key processes during manufacturing. Companies generally accept whatever morphology the manufacturing process provides and deal with any subsequent problems by costly trouble‒shooting. Rational design of optimised morphologies for crystalline pharmaceutical solids would be a very significant technical and commercial advance. Chapter one introduces the concept of crystal nucleation and growth. The phenomenon of polymorphism alongside the causes and impact is discussed. A summary of the scope of instrumentation used in the investigation of crystal polymorphism and morphology, including crystal size distribution (CSD), is also included. Chapter two examines the research carried out during an exploration of the optimum crystallisation parameters of phenacetin. Following a morphological study, the impact this induces on particle density and flow properties is examined. The impact of impurities on the crystallisation properties of phenacetin is investigated. Significantly, the location of impurities within individual crystals is also studied. The third chapter describes an industrial collaboration looking at the resolution and polymorphic study of trometamol and lysine salts of ketoprofen and 2‒phenylpropionic acid (2‒PPA). Chapter four incorporates a solid state study on three separate compounds: 2‒chloro‒4‒nitroaniline, 4‒hydroxy‒N‒phenylbenzenesulfonamide and N‒acetyl‒D‒glucosamine‒6‒O‒sulfate. 2‒Chloro‒4‒nitroaniline and 4‒hydroxy‒N‒phenylbenzenesulfonamide both produced interesting, extreme morphologies which warranted further investigation as part of a collaborative study. Following a summarisation of results in chapter five, chapter six contains the full experimental details, incorporating spectral and other analytical data for all compounds synthesised during the course of the research.

Study of the relation between the shape of lacosamide crystals and the composition of crystallization medium

Crystallization is the critical process used by pharmaceutical industries to achieve the desired size, size distribution, shape and polymorphism of a product material. Control of these properties presents a major challenge since they influence considerably downstream processing factors. Experimental work aimed at finding ways to control the crystal shape of Lacosamide, an active pharmaceutical ingredient developed by UCB Pharma, during crystallization was carried out. It was found that the crystal lattice displayed a very strong unidirectional double hydrogen bonding, which was at the origin of the needle shape of the Lacosamide crystals. Two main strategies were followed to hinder the hydrogen bonding and compete with the addition of a Lacosamide molecule along the crystal length axis: changing the crystallization medium or weakening the hydrogen bonding. Various solvents were tested to check whether the solvent used to crystallize Lacosamide had an influence on the final crystal shape. Solvent molecules seemed to slow down the growth in the length axis by hindering the unidirectional hydrogen bonding of Lacosamide crystals, but not enough to promote the crystal growth in the width axis. Additives were also tested. Certain additives have shown to compete in a more efficient way than solvent molecules with the hydrogen bonding of Lacosamide. The additive effect has also shown to be compatible with the solvent effect. In parallel, hydrogen atoms in Lacosamide were changed into deuterium atoms in order to weaken the hydrogen bonds strength. Weakening the hydrogen bonds of Lacosamide allowed to let the crystal grow in the width axis. Deuteration was found to be combinable with solvent effect while being in competition with the additive effect. The Lacosamide molecule was eventually deemed an absolute needle by the terms of Lovette and Doherty. The results of this dissertation are aimed at contributing to this classification.

Effect of solder volume on joint shape with variable chip-to-board contact pad ratio

The objective of this paper is to investigate the effect of the pad size ratio between the chip and board end of a solder joint on the shape of that solder joint in combination with the solder volume available. The shape of the solder joint is correlated to its reliability and thus of importance. For low density chip bond pad applications Flip Chip (FC) manufacturing costs can be kept down by using larger size board pads suitable for solder application. By using “Surface Evolver” software package the solder joint shapes associated with different size/shape solder preforms and chip/board pad ratios are predicted. In this case a so called Flip-Chip Over Hole (FCOH) assembly format has been used. Assembly trials involved the deposition of lead-free 99.3Sn0.7Cu solder on the board side, followed by reflow, an underfill process and back die encapsulation. During the assembly work pad off-sets occurred that have been taken into account for the Surface Evolver solder joint shape prediction and accurately matched the real assembly. Overall, good correlation was found between the simulated solder joint shape and the actual fabricated solder joint shapes. Solder preforms were found to exhibit better control over the solder volume. Reflow simulation of commercially available solder preform volumes suggests that for a fixed stand-off height and chip-board pad ratio, the solder volume value and the surface tension determines the shape of the joint.

Engineering metallic nanoparticles for enhancing and probing catalytic reactions

Recent developments in tailoring the structural and chemical properties of colloidal metal nanoparticles (NPs) have led to significant enhancements in catalyst performance. Controllable colloidal synthesis has also allowed tailor-made NPs to serve as mechanistic probes for catalytic processes. The innovative use of colloidal NPs to gain fundamental insights into catalytic function will be highlighted across a variety of catalytic and electrocatalytic applications. The engineering of future heterogenous catalysts is also moving beyond size, shape and composition considerations. Advancements in understanding structure-property relationships have enabled incorporation of complex features such as tuning surface strain to influence the behavior of catalytic NPs. Exploiting plasmonic properties and altering colloidal surface chemistry through functionalization are also emerging as important areas for rational design of catalytic NPs. This news article will highlight the key developments and challenges to the future design of catalytic NPs.