Title: Utilizing complex coacervation to promote the controlled crystallization of hydrophobic drugs
Abstract:
Controlling polymorphic transitions in pharmaceutical drugs as they are prone to molecular self-assembly is a large challenge in the pharmaceutical industry. With over 50% of small molecule therapeutics spontaneously packing themselves into differing molecular structures, it destabilizes the intended therapeutic properties of a drug compromising its overall function and patient safety. This study investigates the use of complex coacervation, a liquid-liquid phase separation technique utilizing oppositely charged polyelectrolytes (polyDADMAC and polyacrylic acid), as a platform for crystallization to preserve the polymorph of hydrophobic drugs (Mefenamic Acid (MFA)). PDADMA-PA coacervate was added to the MFA/DMF system to enable controlled crystallization from MFA aggregation as the viscoelastic phase transition of the coacervate, from liquid-like to gel-like, occurs. When water diffuses out of the coacervate, MFA supersaturates into crystals on the coacervate interface within 20 minutes. PDADMA-PA was prepared in various MFA/DMF ratios (4mM-207mM) to enhance crystal tunability as increasing MFA concentration thermodynamically produces progressively larger crystal lattices. XRD confirmed that crystals were preserved in polymorph II, despite it being thermodynamically disfavored (but more bioavailable) compared to polymorph I. Thermogravimetric analysis characterizes dehydration kinetics of the system as the mass change of water occurs within t=20 hours driving rapid nucleation. Coacervation as a result is more efficient than traditional pharmaceutical approaches like extensive medication stability testing under temperature and other environmental conditions taking years. Confocal z-stack 3D visualization revealed MFA/DMF penetration into partitioned pores containing MFA crystals. Additionally, image intensity segmentation characterized crystal distribution by identifying greater crystal equivalent diameter but less crystal amounts in higher concentrations of MFA (166mM) defining assembly kinetics. Complex coacervation was demonstrated as a highly cost efficient and time efficient platform to direct crystallization of hydrophobic drugs utilizing forced MFA molecular interactions surrounding the coacervate system. Results suggest exploring these pores to crystallize drugs of different densities to observe drug partitioning and degree of nucleation or applying coacervation to crystallize hydrophilic drugs.
