Rolf Hilfiker

Polymorphism - integrated approach from high-throughput screening to crystallization optimization

Crystal structure (polymorphism) as well as crystal shape (morphology) and size have a huge practical and commercial impact on active substances all the way from research to manufacture of the final product. For an optimal development process, it is important to have an integrated approach to these issues ranging from a systematic polymorphism screening to a controlled scale-up of the crystallization process. The polymorphism program has to be tailored according to the development stage. Particularly suitable for an early development stage is a high-throughput polymorphism screening, which is the basis for a more thorough investigation if the product proceeds further in development. Such a comprehensive polymorphism investigation involves further crystallization experiments and extensive physicochemical characterization of the various forms. In this article the high-throughput polymorphism screening method that we have developed is described. Using carbamazepine as an example, the power of this high-throughput polymorphism screening system is demonstrated. Not only were all published forms found, but also new forms were identified. In the second part of the article, important considerations for crystallization optimization are discussed, again using the example of carbamazepine.

Chapter 12:Application of Phase Diagrams in Co-crystal Search and Preparation

Typical selection criteria for co-crystal formers include toxicological considerations, physico-chemical properties such as water solubility, and the functional groups that are available for interaction with the substance to be co-crystallized (e.g., a drug substance). Some degree of predictability for the formation of a crystalline multi-component compound is often claimed for certain combinations of functional groups. The expression crystal engineering has been coined for this strategy and combined with the concept of synthons from organic chemistry. Computer modeling may further improve the predictive potential based on interaction energies and steric aspects.Thermodynamic considerations offer a complementary approach for targeted co-crystal search and development. They can provide selection criteria for suitable co-crystal formers and can also help to predict the most promising preparation conditions. This includes the potential to reduce experimental effort in co-crystal search and crystallization optimization significantly. Phase diagrams are the method of choice for visualizing the thermodynamic relationships and simplifying their application. Phase diagrams are thus a powerful and intuitive tool for planning co-crystal screenings and crystallization optimizations.

Multianalytical approach to characterise adsorption of industrial grade surfactants or polymers on different crystalline agrochemicals

Abstract Surfactant adsorption on different agrochemicals is analysed with different techniques. Obtaining adsorption isotherm data is substantially made more difficult by industrial grade adsorbing molecules and active substances. Two classes of techniques are discussed, direct probing of surfactant concentration and measurement of properties linked to the adsorption of surfactant to particles.