Use of Terahertz-Raman Spectroscopy to Determine Solubility of the Crystalline Active Pharmaceutical Ingredient in Polymeric Matrices during Hot Melt Extrusion

Abstract

Polymer-based amorphous solid dispersions (ASDs) comprise one of the most promising formulation strategies devised to improve the oral bioavailability of poorly water-soluble drugs. Exploitation of such systems in marketed products has been limited because of poor understanding of physical stability. The internal disordered structure and increased free energy provide a thermodynamic driving force for phase separation and recrystallization, which can compromise therapeutic efficacy and limit product shelf life. A primary concern in the development of stable ASDs is the solubility of the drug in the polymeric carrier, but there is a scarcity of reliable analytical techniques for its determination. In this work, terahertz (THz) Raman spectroscopy was introduced as a novel empirical approach to determine the saturated solubility of crystalline active pharmaceutical ingredient (API) in polymeric matrices directly during hot melt extrusion. The solubility of a model compound, paracetamol, in two polymer systems, Affinisol 15LV (HPMC) and Plasdone S630 (copovidone), was determined by monitoring the API structural phase transitions from crystalline to amorphous as an excess of crystalline drug dissolved in the polymeric matrix. THz-Raman results enabled construction of solubility phase diagrams and highlighted significant differences in the solubilization capacity of the two polymer systems. The maximum stable API-load was 20 wt % for Affinisol 15LV and 40 wt % for Plasdone S630. Differential scanning calorimetry and XRPD studies corroborated these results. This approach has demonstrated a novel capability to provide real-time API–polymer phase equilibria data in a manufacturing relevant environment and promising potential to predict solid-state solubility and physical stability of ASDs.

Mefenamic acid solid dispersions: Impact of formulation composition on processing parameters, product properties and performance

“…However, these do not predict the maximum solubility, or critical API concentration, in a given system. Such information would be useful, as the maximum solubility can vary for different API-polymer combinations (Bordos et al, 2019;Ekblad, 2018;Gupta et al, 2015;Solanki et al, 2018), resulting in different process-and product behaviour as reported in this study. The structured development program based on screening assays applied in this study, offered advantages over predictive models.…”

“…Amorphous solid dispersions (ASD) exhibit higher internal energy than crystalline solid dispersions (CSD) (Zografi and Newman, 2017), which is seen as significant improvement of their aqueous solubility. However, this can also provide a thermodynamic driving force for phase separation and crystallisation (Bordos et al, 2019). This can give rise to stability studies of the amorphous formulations failing to meet product specification regarding their product performance.…”

Innovations in Thermal Processing: Hot-Melt Extrusion and KinetiSol® Dispersing

“…The study discovered that the ASD of paracetamol has maximum stability when its concentration is 20 wt% in HPMC and 40 wt% in copovidone. The study showed that this novel spectroscopy combination can be used to provide real-time API-polymer phase equilibria and can be used to predict the stability of ASDs during the HME process (145).…”

“…Bordos et al proposed a novel approach of using an in-line terahertz (THz)-Raman Spectroscopy as a PAT to determine the saturation point of an API in a polymeric matrix during the HME process ( 145 ). The study carried out here uses paracetamol as a model API dispersed into two polymer systems, HPMC and copovidone.…”

Hot-Melt Extrusion as an Advantageous Technology to Obtain Effervescent Drug Products

“…For further formulation development, two polymeric matrices were selected with similar glass transition temperature, allowing us to combine both in the proposed mixture design: PVPVA and HPMC. These polymers show glass transition at 109 and 115 • C, respectively [36,37].…”