Surface tension plays an enormous role in the manufacturing of pharmaceuticals. Some of the effects are well known' for example, interfacial phenomena play a key role in determining the shape, size, and degree of agglomeration of many drug crystals. Other effects are more subtle: hydrophobicity of powder blends, which is affected by the processing history, affect the uniformity and performance of functionalized coatings and the dissolution of drug tablets and capsules.

This talk will have three parts. In the first part, we will provide a broad overview of phamaceutical manufacturing and an inventory of critical points where interfacial phenomena are important.

The second part of this presentation will be devoted to a case study where we explore both experimental techniques to de-agglomerate nanoparticles, and simulations to seek the fundamentals governing the surfactant-particle interactions. Our experimental techniques are focused on high pressure homogenization. Griseofulvin, an anti-fungal agent and representative poorly water soluble drug, is homogenized in an aqueous suspension containing various surfactants, including Tween 80, the Poloxamer series, the Brij series, and various polymeric surfactants including HPMC (hydroxypropylmethylcellulose) and Pullulan. The result is a stabilized suspension of Griseofulvin particles that remain stable for several weeks. In addition to experimental techniques, a fundamental analysis of particle-surfactant interactions is conducted using molecular dynamics simulations. Our focus has been on systematically studying the effects of surfactants on the various surfaces of the Griseofulvin crystal by studying the energy of attachment. In our preliminary simulations, HPMC has been found to be the most effective stabilizer for the Griseofulvin crystal faces.

The last part of the presentation focuses on secondary manufacturing. Using a modified Washburn method, we examine the development of hydrophobicity of pharmaceutical powder blends as a result of processing. Experiments readily demonstrate that typical pharmaceutical powders can become substantially hydrophobic when exposed to shear in small scale processing equipment. Much more substantial changes in surface energy can be detected in specially designed experiments seeking to apply shear and strain uniformly at rates comparables to those experienced in full-scale equipment, helping explain numerous heretofoe unexplained observations concerning variability in drug release rates from pharmaceutical tablets during process scale-up.