Theoretical Modeling and Mechanism of Drug Release from Long-Acting Parenteral Implants by Microstructural Image Characterization

Abstract

This work develops a mechanistic understanding and a simplified model to understand changes in drug release profiles of an active pharmaceutical ingredient in a long-acting parenteral polymer formulation from changes in its microstructure determined using X-ray computed tomography (XRCT) imaging. The system studied is an implant composed of a solid dispersion of crystalline drug microdomains embedded in a polymer matrix and fabricated by hot melt extrusion. We conduct material characterization of these devises using microCT and introduce, for the first time, imaging of such pharmaceutical devices by means of nanoCT, showing finer structures that cannot be captured by ordinary CT methods. We propose a simplified theoretical mechanistic model that estimates the drug release by extracting relevant microscopic features that modulate the release rate from microCT images to construct an idealized geometry. Using this analysis, we found that although the primary mechanism of resistance was originating from submicrometer features, which are below the resolution of the microCT, the main features that determine changes in diffusivity as a result of different process conditions were microscale pore volume and pore connectivity distributions. The parameters were extracted from the microCT images and in conjunction with the theory were able to explain changes in experimental drug release under different process conditions. These results demonstrate that the modeling strategy can explain the dominant release mechanism and estimate drug release of formulations, even when the equations are simplified due to many assumptions and a lack of subscale information. The proposed approach, due to its simplicity and reliance on the widely employed microCT technique, holds promise for guiding formulation development by providing a rapid initial assessment of batch consistency and process parameter selection before embarking upon lengthy and costly clinical trials.

Islatravir Case Study for Enhanced Screening of Thermodynamically Stable Crystalline Anhydrate Phases in Pharmaceutical Process Development by Hot Melt Extrusion

“…Islatravir is a highly potent nucleoside reverse transcriptase translocation inhibitor (NRTTI). Islatravir has generated great excitement in the HIV treatment community due to its high potency, long half-life, and unique mechanism of action. , Islatravir is a crystalline API material that is shown to convert from a single monohydrate phase into one of four anhydrate phases. Notably, the discovery of the thermodynamically stable anhydrate occurred by an unusual mechanism.…”

Flexibility in Drug Product Development: A Perspective

“…Further, there is a high interest in using AI to predict product performance and long-term stability as well as improve the translation from small-scale to commercial-scale manufacture, while narrowing down the experimental space using theoretical modeling. With these technologies, great progress has been made in recent years to predict, e.g., product performance from underlying core physical attributes . In conjunction with AI technologies, once the underlying relationship between physiochemical attributes and performance has been established, such tools hold the potential to alter DP design at a fundamental level.…”

“…With these technologies, great progress has been made in recent years to predict, e.g., product performance from underlying core physical attributes. 40 In conjunction with AI Figure 6. Complete 3D microrepresentation of a long-acting polymeric implant via X-ray imaging, highlighting the formation of microchannels of drug release in green.…”

Islatravir Dimer: Crystal Form Dependence of a Radiation-Induced Degradation Product

“…A set of 2D NMR experiments (COSY, 1 H− 13 C HSQC, 1 H− 13 C HMBC, and ROESY) was used for structure elucidation. Chemical shifts were referenced to the solvent peak of DMF-d 7 (2.75 ppm for 1 H, 29.76 ppm for 13 voltage was 65 V. Nitrogen gas was used for drying (325 °C, 13 L/min) and nebulization (35 psig). Single Crystal X-ray Diffraction.…”