(102a) Engineering Diversity through Thermodynamics – the Role of Water Activity in Solid-Liquid Equilibria in a Polymorphic Pharmaceutical System

Active pharmaceutical ingredients (APIs) exhibit polymorphism, hydration and solvation phenomena. These are mainly driven by the conformation flexibility of the organic molecules and the plethora of packing arrangements that they can adopt in a crystalline lattice. The stability of each of the solid forms of the API is a function of the state variables ? T, P as well as the solvent composition in the case where the API forms solvates or hydrates. One solid phase of the API is usually selected for development from the universal set of all crystal forms; this decision is driven by factors such as thermodynamic stability, bioavailability, mechanical properties, morphology and flow behavior.

The isolation of the API invariably involves crystallization from a solvent system at specified conditions of temperature and pressure. The presence of several variables in a crystallization process lends itself to a diversity of crystal forms that are not commonly observed in inorganic or polymeric systems. Naturally, one can imagine the rich thermodynamics that one can link to such processes. This presentation presents a case study of crystallization development for a pharmaceutical compound (Compound I) that exhibits an unusual number of crystal forms ? four anhydrous, two hemihydrates, two monohydrates, four dehydrates, one tetrahydrate and two solvates.

Compound I is a Phosphodiesterase-IV (PDE-IV) inhibitor being developed for the treatment of respiratory disease. Extensive physical property measurements, solubility experiments and thermodynamic calculations resulted in the design of a robust crystallization process that reproducibly produces one anhydrous form, Form A. During this process development several interesting observations were made, most notably

?The thermodynamic water activity is the most critical variable that influences the relative stability of anhydrous forms compared to hydrates.

?The mapping of the SLE phase diagram in terms of water activity, obviates the need for extensive experimental solvent screening.

?Anhydrous forms are more stable up to higher water activities with increasing temperature ? this implies that there could theoretically be a temperature at which the anhydrous form could be more thermodynamically stable than a hydrate in pure water, an observation that has recently been confirmed in several other systems.

?It is possible to isolate an arbitrary crystal form during a crystallization process and the convert it to any other crystal form if the solid-liquid phase equilibira is established.

?The appearance of crystal forms in a solid-state transformation is in many cases controlled by the crystal structure of the starting material and the pathway linking the two forms ? i.e. it is possible that a form can be observed in realistic time scales only when produced from another specific crystal form. This has profound implications in combinatorial polymorph screening routinely carried out in pharmaceutical companies.

Finally, since each crystal form has unique physical attributes this presentation will also introduce the possibility of tuning the crystal form to a specific type of drug delivery ? one form for oral dosage and another for inhalation.