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.
Highlights
Poor aqueous solubility is a major concern in the pharmaceutical field that can compromise the amount of drug available for absorption, lead to low bioavailability, and detract from the drug’s inherent therapeutic efficacy.[1,2] It is expected that around 90% of the new chemical entities possess poor aqueous solubility and fall into class II or IV of the Biopharmaceutics Classification System (BCS), limiting their further development.[3]
The main premise required to construct an active pharmaceutical ingredient (API)−polymer solubility phase diagram is the determination of the temperature at which a given crystalline API content is soluble in the polymer matrix
Access to this temperature was directly obtained during hot melt extrusion (HME) by monitoring the API structural phase transitions from crystalline to amorphous as it dissolved in the polymeric carrier
Summary
Poor aqueous solubility is a major concern in the pharmaceutical field that can compromise the amount of drug available for absorption, lead to low bioavailability, and detract from the drug’s inherent therapeutic efficacy.[1,2] It is expected that around 90% of the new chemical entities possess poor aqueous solubility and fall into class II or IV of the Biopharmaceutics Classification System (BCS), limiting their further development.[3]. The API is in its highest energy state and as a result, no energy is required to break the crystal lattice and amorphous materials generally have better aqueous solubility than their crystalline counterparts.[9,10] the internal disordered structure and increased free energy provide a thermodynamic driving force for phase separation and recrystallization, which makes the design of stable ASDs highly challenging
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