(187m) Process Intensification in Solid Dosage Formulation By Hot Melt Extrusion

The pharmaceutical community has realized the need to shift from batch to continuous manufacturing to minimize cost and increase efficiency. Traditional batch methods for solid dosage formulation (up to date, the most convenient and industrially relevant drug delivery for peroral administration) often involve multiple costly and time consuming powder handling steps such as milling, wet or dry granulation, drying, sieving, and tableting. Common efforts to transition from batch to continuous manufacturing often focus on mere integration of traditional batch processes into a continuous production line. However, continuous drug product manufacturing allows to decrease and/or combine process and handling steps by innovative integration of excipients and active pharmaceutical ingredients (APIs) via process intensification. Hot melt extrusion (HME) represents such a process intensification technology for continuous solid dosage formulation, especially when coupled with injection molding or 3D printing to produce well-defined shapes and sizes of drug products in a single step. When contrasted with traditional solid dosage formulation processes, HME offers various advantages including; (1) reduced processing steps, (2) reduced processing time, (3) reduced space, energy and carbon foot-print, (4) solvent-free, and (5) increased manufacturing capacity and efficiency due to continuous operation. However, to date, polymorphic stability of an API is thought to be a prerequisite to employ HME. Polymorphism, a phenomenon that enables molecules to exhibit multiple crystalline phases, is one of the most scrutinized critical quality attributes of solid drug products. Polymorphism is estimated to occur in 80% of APIs, affecting properties of the solid state and, therefore, the quality and efficacy of the final drug product. The unsubstantiated notion that undesired polymorphic phase transformations might occur during the HME process limits the application of this process intensification technique to a narrow set of APIs that are both thermally stable and monomorphic (∼20%). The present study showes that despite the process intensification by HME polymorphic control can be achieved, similar to traditional continuous solid dosage formulation efforts, simply by understanding and controlling critical process parameters that accompany a HME process (e.g. temperature, pressure, drug-polymer composition, polymer properties, and residence time). Drug products were analyzed by powder-x-ray diffraction and Raman spectroscopy and compared to conventional products.