(23e) Impact of a Reversible Solid State Form Change On Particle Morphology and Bulk Powder Properties of a Pharmaceutical Compound

For efficient formulation
processing of a pharmaceutical drug product, it is desirable to have an active
pharmaceutical ingredient (API) that handles well in terms of flow and bulk
density, especially for products with high drug loadings.  To improve bulk API powder property behavior,
particle engineering techniques can be employed during the crystallization step
to alter the morphology of the API crystals from needles, which normally have
poor flowing powders, to bricks or rods. 
Although particle engineering can have a significant impact on particle
morphology, the susceptibility of the API to crystalline form change from
environmental factors such as relative humidity must also be carefully studied
and controlled. 

A case study is presented for
Compound A whose thermodynamically desired crystalline form has an undesired
morphology but can be modified to bricks or rods through a particle engineering
approach.  Compound A is known to
crystallize as iso-structural solvates (Form I) in
all solvent systems that have been studied. 
Upon isolation and drying, Form I desolvates
to Form II which can reversibly convert to Form III in the solid state at a
critical relative humidity.   In this
presentation, the crystal structures of Forms I, II and III will be discussed
and used to explain how the form changes impact the integrity and morphology of
the API crystal as well as the bulk powder properties.  The importance of this work is to gain a
fundamental understanding of how the API crystal morphology improvement made
during crystallization can be retained in the post crystallization steps of
drying, storage and handling.  The
thorough understanding of the crystal structures can provide valuable insights
for handling bulk powders to maintain desired API powder properties for drug
product processing.