The thermodynamically most stable polymorph under ambient conditions is almost without exception the most desirable crystalline form for development by a pharmaceutical company. It is, therefore, beneficial to discover and to characterize this polymorph at the earliest possible stage of development. A screen for discovering the stable polymorph of a pharmaceutical compound early in the drug discovery-development process is developed and described. In this screen, a small amount of compound is suspended in a diverse group of solvents for two weeks in an effort to crystallize the most stable polymorph. The solubility of the compound in each solvent utilized in the stable polymorph screen is also simultaneously determined using a simple gravimetric method. Ritonavir and an early development candidate (Pfizer compound A) are used as model compounds to demonstrate the utility of the screen for finding the stable polymorph early in the drug discovery-development process.

Thick-film printed lead zirconate titanate (PZT) structures can be combined with micromachined silicon structures and offer relatively large actuation forces compared to alternative techniques. This paper describes the initial investigation into the compatibility issues of micromachining silicon wafers with PZT layers printed on the surface. It assesses the effect of many standard photolithography and micromachining upon the printed PZT layer. In particular the adhesion of the printed layer to the substrate and its internal structure have been studied after exposure to each process. Standard photolithography using positive resists has been found to destroy the adhesion of the platinum electrode and an alternative masking technique using a thick-film printed dielectric polymer has been developed. Aluminium top electrodes have been fabricated using this masking technique combined with ion beam milling. Finally many standard micromachining etching processes have been carried out on a range of silicon substrates incorporating platinum electrode/thick-film PZT structures. Wet silicon and silicon dioxide etches were found to be unsuitable since they also attacked the adhesion of the bottom electrode. Plasma etching processes appear to be well suited for the combination of materials since there is a wide range of etches available that do not affect the PZT. These can therefore be used for the micromachining of the silicon substrate after thick-film processing greatly expanding the range of applications suited to this combination of technologies.

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APD334 was discovered as part of our internal effort to identify potent, centrally available, functional antagonists of the S1P 1 receptor for use as next generation therapeutics for treating multiple sclerosis (MS) and other autoimmune diseases. APD334 is a potent functional antagonist of S1P 1 and has a favorable PK/PD profile, producing robust lymphocyte lowering at relatively low plasma concentrations in several preclinical species. This new agent was efficacious in a mouse experimental autoimmune encephalomyelitis (EAE) model of MS and a rat collagen induced arthritis (CIA) model and was found to have appreciable central exposure.

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