Controlling Polymorphism in Pharmaceutical Compounds Using Solution Shearing

In the pharmaceutical industry, significant resources are allocated to control the stability and solubility of a drug product, as the drug needs to be stable during processing and storage, and follow predictable dissolution kinetics in the body. Recently, enhancing solubility of poorly soluble drugs has become an area of study; many new candidate drug molecules are not pursued for further development because their low solubility makes them ineffective in the body.

The crystal morphology and the packing (polymorphism) of the pharmaceutical compound in the solid drug product determines the solubility and the associated bioavailability. For small organic molecules, most drug products are stored and ingested as solid forms. Controlling the crystallization process is necessary to isolating the selected solid form for development. If we are able to enhance the solubility of a drug through changing the crystal structure, then more candidate drugs can be pushed further in development.

We look to control the formation of amorphous and metastable crystalline solid-state phases to improve the solubility of the active pharmaceutical ingredient (API). Non-equilibrium (including metastable polymorphs and amorphous solid phases) formulations are a promising route for increased solubility since the non-equilibrium solid phase is, by definition, less stable than the equilibrium phase. Developing a robust system to screen for polymorphs and isolate metastable forms motivates this work towards solubility control in small organic pharmaceuticals.

Recently, a solution based crystallization technique termed solution shearing has been extensively utilized to control the polymorphism of organic semiconductors and tune device performance. Giri et al. have previously showed that in solution shearing, one-dimensional confinement is responsible for obtaining metastable polymorphs of organic semiconductors. Supported by this previous work showing polymorph control, we apply the solution shearing technique to pharmaceutically relevant systems.

In this work, two model pharmaceutical compounds, glycine and acetaminophen, were crystallized using a flow coating technique termed solution shearing to create thin films with controllable polymorphism. Thin films were characterized using cross-polarized optical microscopy and grazing incidence X-ray diffraction. Films crystallized as different polymorphs (α and β for glycine and form I and form II for acetaminophen) by controlling processing temperature and shearing speed. The amorphous phase of acetaminophen was also stabilized, and the kinetic transformation to the metastable form II was studied. We show that one dimensional confinement plays a significant role to stabilize metastable polymorphs and amorphous phases. We foresee that solution shearing will have vast utility in high throughput screening of candidate drug molecules to determine the polymorphic landscape with minimal material usage.