Insights into Factors Affecting Ethylene-Vinyl Acetate Copolymer Crystallinity in Islatravir Implant.

Islatravir, a highly potent nucleoside reverse transcriptase translocation inhibitor (NRTTI) for the treatment of HIV, has great potential to be formulated as ethylene-vinyl acetate (EVA) copolymer-based implants via hot melt extrusion. The crystallinity of EVA determines its physical and rheological properties and may impact the drug-eluting implant performance. Herein, we describe the systematic analysis of factors affecting the EVA crystallinity in islatravir implants. Differential scanning calorimetry (DSC) on EVA and solid-state NMR revealed drug loading promoted EVA crystallization, whereas BaSO4 loading had negligible impact on EVA crystallinity. The sterilization through γ-irradiation appeared to significantly impact the EVA crystallinity and surface characteristics of the implants. Furthermore, DSC analysis of thin implant slices prepared with an ultramicrotome indicated that the surface layer of the implant was more crystalline than the core. These findings provide critical insights into factors affecting the crystallinity, mechanical properties, and physicochemical properties of the EVA polymer matrix of extruded islatravir implants.

Poly(vinylpyridine-co-vinylpyridine N-oxide) Excipients Mediate Rapid Dissolution and Sustained Supersaturation of Posaconazole Amorphous Solid Dispersions.

The chemical structure of excipients molecularly mixed in an amorphous solid dispersion (ASD) has a significant impact on properties of the ASD including dissolution behavior, physical stability, and bioavailability. Polymers used in ASDs require a balance between hydrophobic and hydrophilic functionalities to ensure rapid dissolution of the amorphous dispersion as well as sustained supersaturation of the drug in solution. This work demonstrates the use of postpolymerization functionalization of poly(vinylpyridine) excipients to elucidate the impact of polymer properties on the dissolution behavior of amorphous dispersions containing posaconazole. It was found that N-oxidation of pyridine functionalities increased the solubility of poly(vinylpyridine) derivatives in neutral aqueous conditions and allowed for nanoparticle formation which supplied posaconazole into solution at concentrations exceeding those achieved by more conventional excipients such as hydroxypropyl methylcellulose acetate succinate (HPMCAS) or Eudragit E PO. By leveraging these functional modifications of the parent poly(vinylpyridine) excipient to increase polymer hydrophilicity and minimize the effect of polymer on pH, a new polymeric excipient was optimized for rapid dissolution and supersaturation maintenance for a model compound.

Correlative Image-Based Release Prediction and 3D Microstructure Characterization for a Long Acting Parenteral Implant.

Imaging-based characterization of polymeric drug-eluting implants can be challenging due to the microstructural complexity and scale of dispersed drug domains and polymer matrix. The typical evaluation via real-time (and accelerated in vitro experiments not only can be very labor intensive since implants are designed to last for 3 months or longer, but also fails to elucidate the impact of the internal microstructure on the implant release rate. A novel characterization technique, combining multi-scale high resolution three-dimensional imaging, was developed for a mechanistic understanding of the impact of formulation and manufacturing process on the implant microstructure. Artificial intelligence-based image segmentation and imaging analytics convert "visualized" structural properties into numerical models, which can be used to calculate key parameters governing drug transport in the polymer matrix, such as effective permeability. Simulations of drug transport in structures constructed on the basis of image analytics can be used to predict the release rates for the drug-eluting implant without running lengthy experiments. Multi-scale imaging approach and image-based characterization generate a large amount of quantitative structural information that are difficult to obtain experimentally. The direct-imaging based analytics and simulation is a powerful tool and has potential to advance fundamental understanding of drug release mechanism and the development of robust drug-eluting implants.

Producing Amorphous Solid Dispersions via Co-Precipitation and Spray Drying: Impact to Physicochemical and Biopharmaceutical Properties.

Many small-molecule active pharmaceutical ingredients (APIs) exhibit low aqueous solubility and benefit from generation of amorphous dispersions of the API and polymer to improve their dissolution properties. Spray drying and hot-melt extrusion are 2 common methods to produce these dispersions; however, for some systems, these approaches may not be optimal, and it would be beneficial to have an alternative route. Herein, amorphous solid dispersions of compound A, a low-solubility weak acid, and copovidone were made by conventional spray drying and co-precipitation. The physicochemical properties of the 2 materials were assessed via X-ray diffraction, differential scanning calorimetry, thermal gravimetric analysis, and scanning electron microscopy. The amorphous dispersions were then formulated and tableted, and the performance was assessed in vivo and in vitro. In human dissolution studies, the co-precipitation tablets had slightly slower dissolution than the spray-dried dispersion, but both reached full release of compound A. In canine in vitro dissolution studies, the tablets showed comparable dissolution profiles. Finally, canine pharmacokinetic studies showed that the materials had comparable values for the area under the curve, bioavailability, and Cmax. Based on the summarized data, we conclude that for some APIs, co-precipitation is a viable alternative to spray drying to make solid amorphous dispersions while maintaining desirable physicochemical and biopharmaceutical characteristics.