Modeling, Screening and PAT: The Development of a Pharmaceutical Crystallization

Modeling, Screening and PAT: The Development of a Pharmaceutical Crystallization.

Crystallization is a critical unit operation in pharmaceutical processing because it determines the crystal form, particle size distribution and purity of the drug substance. Maintaining a consistent process upon scale-up requires an understanding of growth and nucleation kinetics, relevant mixing time-scales, and local shear forces in varying geometries.  The development of a robust crystallization process for an HCl salt of Compound 1 had been particularly difficult due to polymorphism issues, purity and particle size/shape concerns and poor bulk density in existing processes. Form control was particularly difficult due to several undesirable hydrates and solvates.  A previous process produced a mixture of crystal forms, solids with bulk density was less than 0.1 g/cm³, and required two processing steps.  The requirements for optimal drug product formulation were crystals smaller than 20 microns, aspect ratios between 1:5 and 1:3 and maximum obtainable bulk density.

A new single-step process was developed, which made use of synergistic solubility in a binary system, and desupersaturated in a ternary solvent system which consistently controlled crystal form.  Single solvent screens failed to yield an acceptable solvent, but an optimal mixture of toluene/methanol was indentified in binary screens.  Extensive process modeling using commercially available software and de novo algorithms enabled processing parameters for mixing, acid addition rate, and filtration rate to be accurately estimated, leading to a well-controlled growth-dominated crystallization.  Process performance was further optimized by on-line particle size tracking and HPLC monitoring.  Using this comprehensive approach, a robust crystallization was developed for a challenging salt form of Compound 1, producing over 90% yield, consistently meeting particle size specifications, doubling bulk density to 0.17 g/cm³, and improving purity from ~96 to >99%.