Crystallization Control Using Fabricated Polymeric Materials
Due to the demand of greater innovation in pharmaceutical manufacturing, process intensification technology (PIT) has received considerable research investment in the past decade. PIT can provide extensive reduction in the number of processes required to manufacture desired product via the combination of multiple processes into a single step. The utilization of crystallization based technology by simultaneous processing of the active pharmaceutical ingredients (APIs) with polymeric excipients in a single unit operation to create a formulation can significantly improve efficiency. However, the adaptation of heterogeneous crystallization into a viable technology for manufacturing drug formulations with desired properties is effectively hindered by the lack of understanding in the impact of polymeric material in crystallization control. The purpose of this study is to develop two PITs for drug formulations and to achieve a more fundamental understanding of the effect of polymeric materials on the crystallization of APIs. Direct crystallization into micro-porous polymeric particles and drop printing on polymeric thin films were established. Acetaminophen (AAP) and sulfathiazole (STZ) were used as model drugs. Sodium alginate (ALG) and sodium carboxymethyl cellulose (CMC) were utilized as polymeric excipients. The influence of the intermolecular interactions between drug and polymeric materials on the drug loading by direct crystallization inside micro-porous polymeric particles was studied. Additionally, the effect of surface chemistry/polarity on the nucleation of a given polymorph and polymorphism by drop printing was investigated. Additives were employed to alter the surface chemistry/polarity of the polymeric films for controlling the nucleation mechanism of AAP. The relationship between the additive and AAP was also investigated. Furthermore, the impact of surface polarity and crystallization routes on the STZ crystallization behavior was determined. It was found that polymer chemistry and available surface area have a significant impact on drug loading capacity and bulk crystallization. Direct crystallization methods with favorable interaction between drugs and polymeric excipients enable higher drug loadings compared to other drug encapsulation technologies. The incorporation of polar additives into the system demonstrated exclusive control with a single nucleation mechanism. Moreover, functional group hydrophobicity/hydrophilicity and density of functional groups, which are the two key factors determining the surface polarity, were both critical to controlling the selectivity of a specific nucleation mechanism. Finally, the crystallization route was found to be critically important for polymorph selection. This study highlights the significant impact of polymeric excipients on the heterogeneous crystallization control and the potential of direct crystallization inside excipients and drop printing as PITs for pharmaceutical manufacturing.
Pinal, Purdue University.
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