NMR and Thermal Studies for the Characterization of Mass Transport and Phase Separation in Paracetamol/Copovidone Hot-Melt Extrusion Formulations

Abstract

The formulation of drug/polymer amorphous solid dispersions (ASDs) is one of the most successful strategies for improving the oral bioavailability of poorly soluble active pharmaceutical ingredients (APIs). Hot-melt extrusion (HME) is one method for preparing ASDs that is growing in importance in the pharmaceutical industry, but there are still substantial gaps in our understanding regarding the dynamics of drug dissolution and dispersion in viscous polymers and the physical stability of the final formulations. Furthermore, computational models have been built to predict optimal processing conditions, but they are limited by the lack of experimental data for key mass transport parameters, such as the diffusion coefficient. The work presented here reports direct measurements of API diffusion in pharmaceutical polymer melts, using high-temperature pulsed-field gradient NMR. The diffusion coefficient of a model drug/polymer system (paracetamol/copovidone) was determined for different drug loadings and at temperatures relevant to the HME process. The mechanisms of the diffusion process are also explored with the Stokes–Einstein and Arrhenius models. The results show that diffusivity is linked exponentially to temperature. Furthermore, this study includes rheological characterization, differential scanning calorimetry (DSC), and 1H ssNMR T 1 and T 1ρ measurements to give additional insights into the physical state, phase separation, and API/polymer interactions in paracetamol/copovidone ASD formulations.

Drug–Polymer Interactions in Acetaminophen/Hydroxypropylmethylcellulose Acetyl Succinate Amorphous Solid Dispersions Revealed by Multidimensional Multinuclear Solid-State NMR Spectroscopy

“…Here, we report the stability of amorphous acetaminophen in HPMC-AS ASDs at different drug loadings by identifying the presence of drug–polymer intramolecular interactions with multinuclear multidimensional NMR experiments. Acetaminophen ( Figures 1 and SI-1 ) is one of the most widely used API and its chemical–physical data, including melting point and solubility profiles, as well as crystalline data, 53 , 54 NMR spectra, 55 are largely known. The HPMC-AS polymer was chosen as excipient due to its excellent capacity to stabilize amorphous dispersion.…”

“…Here, we report the stability of amorphous acetaminophen in HPMC-AS ASDs at different drug loadings by identifying the presence of drug–polymer intramolecular interactions with multinuclear multidimensional NMR experiments. Acetaminophen (Figures and SI-1) is one of the most widely used API and its chemical–physical data, including melting point and solubility profiles, as well as crystalline data, , NMR spectra, are largely known. The HPMC-AS polymer was chosen as excipient due to its excellent capacity to stabilize amorphous dispersion. , Morevoer, the lack of overlap between acetaminophen and polymer signals in the 13 C NMR spectra allows monitoring of the changes in chemical shift and line width of the signals of both components to establish API–polymer interactions and crystalline/amorphous behavior.…”

Electrospinning: A promising technique for drug delivery systems

“…Because the proton distribution represents uniformity of the entire mixture, time relaxation time of protons can sensitively characterize the miscibility between a drug and polymer matrix, The 1 H relaxation properties can evaluate it, semi-quantitatively at sub-100 domain size [96][97][98]. Also, the diffusion in polymer melts also can be characterized by means of high-temperature pulsed-field gradient NMR [99].…”

Drug-Eluting Biodegradable Implants for the Sustained Release of Bisphosphonates

“…In general, the extrudates were seemingly homogenous, as indicated by the low standard deviations in ALN-loading observed between implants of the same formulation. The comparatively higher variability in ALN-loading for the 9:1-PLGA-13% implants indicates more uneven drug distribution throughout the extrudate, which may have occurred as the ALN approached its solubility limit within the polymer, leading to the formation of phase-separated domains of ALN throughout the length of the extrudate that could subsequently reduce drug uniformity between these implants [53].…”

“…While some small variation in ALN-loading may be expected due to the nature of the heterogenous dispersion, there is significant variation in ALN-loading between implants of the PLA-3% implant formulation, despite the low standard deviation obtained in earlier total drug extractions. This discrepancy may be attributed to inefficient incorporation or phase separation of the ALN within the polymer matrix, resulting in implants of high ALN-loading variability [53]. Additionally, incomplete extraction of ALN during the total drug extraction stage could also result in lower calculated estimates of ALN-loading, which may further contribute to this high apparent percentage.…”