Crystallisation: Its Relevance During Solid-State Development

Solvias AG

A clear, systematic, and well-tuned approach to crystallisation is essential to minimise problems and turn challenges into opportunities, especially in the areas of production and patent life-cycle management.

The majority of drugs are administered as solids. This means that apart from the molecular structure of the drug substance, solid-state properties significantly influence the performance of the drug product. The solid form of a drug substance can be single-component (e.g., a free base, free acid, or neutral form) or multi-component solid (e.g., a salt, a co-crystal, or a solvated solid).

Many organic compounds can exist in different solid forms. The best solid form for drug product development is selected according to criteria such as physico-chemical behavior (e.g., hygroscopicity, melting point), stability, and pharmacological properties. In addition, organic solids can be amorphous (i.e., disordered), or crystalline (i.e., ordered).

Crystallisation Screening

Crystalline solid forms are preferred for drug substance development, since amorphous solid forms can be highly metastable solids, and transformation to a thermodynamically stable crystalline form is limited only by kinetics. Important physico-chemical parameters, such as solubility or dissolution profile, are determined by the solid-state form and in addition, crystalline solids are generally more stable than noncrystalline forms.

A crystallisation step is a very good way to enhance chemical purity, which can be of paramount importance in obtaining high-purity compounds without the use of costly techniques as chromatography. Solvias has developed a modular approach to crystallisation screening. Our recently introduced Crystallisation Screen utilises solvent mediated approaches as well as solid-phase experiments.

Our multiple-well format crystallisation technology incorporates microscopic visualisation coupled with Raman spectroscopy to deliver rapid information on success of crystallisation without requiring an isolation step for evaluation. Solvent-mediated crystallisation screening is based on the selection of solvents or solvent mixtures with a variety of solvent descriptors from our in-house databank. Different crystallisation techniques are then applied in crystallisation trials of difficult-to-crystallise compounds.

Further studies utilise the solid-state and its physico-chemical characteristics such as glasstransition temperature and vapour pressure.

Crystallisation Optimisation

Once an optimal solid form is identified for further development, an efficient, reliable process for bulk crystallisation is designed with a focus on reproducibility. An optimal process includes such considerations as morphic form, purity, and particle-size distribution.

The basis for developing a crystallisation process involves evaluation of the key parameters that influence a crystallisation outcome. An in-depth physico-chemical understanding of the relationship between various polymorphs provides the path that will lead to the desired crystallisation product. To gain the necessary information, a set of thermodynamic stability curves in the relevant temperature range and in different solvents must be obtained.

Solvias' Integrated Approach to Solid-State Development

Combining our crystallisation experience with our know-how in polymorph, salt, and co- crystal screening and selection allows Solvias to offer our customers a full range of services for faster development of better products Please contact us and discover how Solvias can help you crystallise your ideas.

Solvias Crystallisation Program
Figure 1: Solvias Crystallisation Program

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