The bioavailability of poorly water-soluble active pharmaceutical ingredients (APIs) can be improved via the formulation of an amorphous solid dispersion (ASD), where the API is incorporated into a suitable polymeric carrier. Optimal carriers that exhibit good compatibility (i.e., solubility and miscibility) with given APIs are typically identified through experimental means, which are routinely labor- and cost-inefficient. Therefore, the perturbed-chain statistical associating fluid theory (PC-SAFT) equation of state, a popular thermodynamic model in pharmaceutical applications, is examined in terms of its performance regarding the computational pure prediction of API-polymer compatibility based on activity coefficients (API fusion properties were taken from experiments) without any binary interaction parameters fitted to API-polymer experimental data (that is, kij = 0 in all cases). This kind of prediction does not need any experimental binary information and has been underreported in the literature so far, as the routine modeling strategy used in the majority of the existing PC-SAFT applications to ASDs comprised the use of nonzero kij values. The predictive performance of PC-SAFT was systematically and thoroughly evaluated against reliable experimental data for almost 40 API-polymer combinations. We also examined the effect of different sets of PC-SAFT parameters for APIs on compatibility predictions. Quantitatively, the total average error calculated over all systems was approximately 50% in the weight fraction solubility of APIs in polymers, regardless of the specific API parametrization. The magnitude of the error for individual systems was found to vary significantly from one system to another. Interestingly, the poorest results were obtained for systems with self-associating polymers such as poly(vinyl alcohol). Such polymers can form intramolecular hydrogen bonds, which are not accounted for in the PC-SAFT variant routinely applied to ASDs (i.e., that used in this work). However, the qualitative ranking of polymers with respect to their compatibility with a given API was reasonably predicted in many cases. It was also predicted correctly that some polymers always have better compatibility with the APIs than others. Finally, possible future routes to improve the cost-performance ratio of PC-SAFT in terms of parametrization are discussed.

• Keywords
• PC-SAFT, amorphous solid dispersions, compatibility, drugs, polymers, prediction, solubility,
• MeSH
• Pharmaceutical Preparations MeSH
• Polymers * chemistry   MeSH
• Drug Compounding MeSH
• Solubility MeSH
• Thermodynamics MeSH
• Water * chemistry   MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Pharmaceutical Preparations MeSH
• Polymers * MeSH
• Water * MeSH

In this work, the solid-liquid equilibrium (SLE) of four binary systems combining two active pharmaceutical ingredients (APIs) capable of forming co-amorphous systems (CAMs) was investigated. The binary systems studied were naproxen-indomethacin, naproxen-ibuprofen, naproxen-probucol, and indomethacin-paracetamol. The SLE was experimentally determined by differential scanning calorimetry. The thermograms obtained revealed that all binary mixtures investigated form eutectic systems. Melting of the initial binary crystalline mixtures and subsequent quenching lead to the formation of CAM for all binary systems and most of the compositions studied. The experimentally obtained liquidus and eutectic temperatures were compared to theoretical predictions using the perturbed-chain statistical associating fluid theory (PC-SAFT) equation of state and conductor-like screening model for real solvents (COSMO-RS), as implemented in the Amsterdam Modeling Suite (COSMO-RS-AMS). On the basis of the obtained results, the ability of these models to predict the phase diagrams for the investigated API-API binary systems was evaluated. Furthermore, the glass transition temperature (Tg) of naproxen (NAP), a compound with a high tendency to recrystallize, whose literature values are considerably scattered, was newly determined by measuring and modeling the Tg values of binary mixtures in which amorphous NAP was stabilized. Based on this analysis, erroneous literature values were identified.

• Keywords
• COSMO-RS, PC-SAFT, active pharmaceutical ingredients, co-amorphous systems, glass transition temperature, phase diagrams, physical stability, solid–liquid equilibrium,
• Publication type
• Journal Article MeSH

Prediction of compatibility of the active pharmaceutical ingredient (API) with the polymeric carrier plays an essential role in designing drug delivery systems and estimating their long-term physical stability. A key element in deducing API-polymer compatibility is knowledge of a complete phase diagram, i.e., the solubility of crystalline API in polymer and mutual miscibility of API and polymer. In this work, the phase behavior of ibuprofen (IBU) with different grades of poly(D,L-lactide-co-glycolide) (PLGA) and polylactide (PLA), varying in composition of PLGA and molecular weight of PLGA and PLA, was investigated experimentally using calorimetry and computationally by the perturbed-chain statistical associating fluid theory (PC-SAFT) equation of state (EOS). The phase diagrams constructed based on a PC-SAFT EOS modeling optimized using the solubility data demonstrated low solubility at typical storage temperature (25 °C) and limited miscibility (i.e., presence of the amorphous-amorphous phase separation region) of IBU with all polymers studied. The ability of PC-SAFT EOS to capture the experimentally observed trends in the phase behavior of IBU-PLA/PLGA systems with respect to copolymer composition and molecular weight was thoroughly investigated and evaluated.

• Keywords
• API–polymer compatibility, PC-SAFT, PLA, PLGA, amorphous solid dispersion, biodegradable polymers, phase diagrams,
• Publication type
• Journal Article MeSH