(410d) API Form Selection and Scale-up for a Complex Solid Form System: A Case Study of a Development Compound

A Gilead development compound exhibits complex solid state behavior with eight crystalline forms (I – VIII) discovered to date. A number of studies to understand this solid state system have been performed, including a Stable Form Screen, Hydrate Screen, XRPD, Single Crystal X-Ray Crystallography (SCXC), TGA, and DSC.   These studies have revealed that the polymorphic outcomes are principally determined by solvent, temperature, and water activity. Organic solvents consistently yield Form II. Two very different crystalline forms, Form III (anhydrous) and Form V (tetrahydrate) interconvert under the influence of water activity and temperature. Above ambient temperature (> 25 ºC), Form III is favored. Form V and Form VIII (monohydrate and monomethanolate) are very similar in their crystal structure and vary in the number and kind of solvate molecules.

Among all the crystalline forms discovered, Form III provides the best physical characteristics with greater physical stability to withstand changes in moisture, mechanical stress, pharmaceutical processing and temperature changes, in addition to a suitable level of in vivo exposure. This has led to the need for a robust process to deliver Form III on scale. Conditions to crystallize Form III from a homogeneous solution with consistent form control remain elusive. Alternatively, the inherent ability of Form II to crystallize from a homogenous solution in a well controlled manner from a variety of organic solvents makes its isolation as an intermediate crystalline form a useful option. To achieve appropriate scale up for this compound, a two-stage isolation process has been developed.  First, Form II is crystallized, isolated, and dried. Then a heterogeneous aqueous mixture is used to convert Form II to Form III. This two-stage isolation process has been successfully demonstrated at ~100 Kg scale.