(T1230-01-04) Application of Experimentally Derived Hansen Solubility Parameters to Optimize Amorphous Solid Dispersion Formulation

Purpose: A pressing issue in the pharmaceutical industry is the prevalence of poorly soluble active pharmaceutical ingredients (APIs), with over 85% of new drug candidates exhibiting low solubility. This limitation directly impacts the bioavailability of drugs, hindering their therapeutic efficacy. Among the numerous strategies proposed to mitigate this challenge, amorphous solid dispersions (ASDs) stand out as a promising technique. ASDs involve dispersing the crystalline lattice of an API within an amorphous polymeric matrix, increasing solubility by reducing intermolecular forces between drug molecules. Despite their advantages, ASDs face critical challenges, such as limited drug loading capacity and a propensity for recrystallization, which compromise patient compliance and drug stability in storage. Addressing these limitations requires innovative approaches to optimize API-polymer compatibility. This research proposes the use of experimentally derived Hansen Solubility Parameters (HSP) as a predictive tool to enhance ASD formulation, thereby conserving time and resources in the drug delivery design.^{1, 2}
The use of solubility parameters in pharmaceutics is well-documented, current HSP calculations often rely on group contribution methods, which are limited by inaccuracies due to molecular weight and group additivity assumptions as well as absence of novel functional groups in databases. By experimentally deriving HSP values, this project aims to provide a more reliable and accurate database for researchers, significantly improving formulation efficiency.³

Methods: This project utilizes a solubility study to determine the HSP values of ten ASD polymers commonly utilized in literature and industry. The method is adapted from Patel et al.,⁴ wherein the mass differences between swollen and dried polymers immersed in solvents are scored on a scale from 1 (good solvent) to 6 (poor solvent). These scores are input into HSPip software, which uses the genetic algorithm to compute solubility parameters (dD, dP, dH, and dTotal), interaction radii, and fit values. RED values for model drug-polymer combinations are then calculated, with lower RED values signifying better compatibility. Four polymers—Eudragit EPO, Eudragit RLPO, Kollidon VA 64, and HPMCAS—were selected for detailed study, with model API – resveratrol, based on initial solubility screening. Thermal analyses using thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) provided degradation, melting, and glass transition temperatures, in addition to crystallinity profiles of the polymers and API; all of which further dictated processing conditions. Samples containing varying concentrations (10%, 20%, 30%, and 40%) of the API resveratrol were prepared and mixed using a tubular mixer. These mixtures were analyzed using polarized optical microscopy (POM) to assess miscibility during stepwise heating. Subsequently, they were extruded at polymer-specific temperatures, cryo-ground, and characterized via powder X-ray diffraction (XRD), FTIR spectroscopy, and USP dissolution to confirm ASD formation, detect API-polymer interactions and assess drug dissolution profile respectively.

Results: The solubility study revealed RED values for resveratrol with HPMCAS (0.83), Eudragit EPO (0.77), Eudragit RLPO (0.57), and Kollidon VA 64 (0.51). Thermal analyses confirmed resveratrol’s melting point at 277°C and degradation threshold at 286°C, establishing a narrow processing window, although well above processing temperatures of 150–170°C. POM experiments demonstrated increasing API solubility with decreasing RED values: Kollidon VA 64 (30%), Eudragit RLPO (20%), and Eudragit EPO (10%). This is corroborated by the maximum loading of amorphous drug that is soluble in each extruded matrix observed via powder XRD. FTIR analysis indicates increased hydrogen bonding interactions between drug and polymers that possess lower RED values, as seen by the drastic carbonyl peak shift to lower wavenumbers in Kollidon VA 64 and Eudragit RLPO, as opposed to milder shifts in Eudragit EPO and HPMCAS.^5-7 These interactions elucidate the lower percentage drug release of Kollidon VA 64 and Eudragit RLPO. The dissolution profile of the milled extrudates reveal smaller RED values between drug and polymer led to decreased drug release, while larger RED values led to higher percent of drug release over a two-hour time period. This results indicates presence of intermolecular interactions between highly miscible molecules can inhibit drug release.

Conclusion: Results so far indicates the validity of experimentally derived HSP in optimizing ASD manufacturing through the reduction of trial and error while enabling precise drug-polymer pairing. Additional experiments for this project include NMR spectroscopy to further validate intermolecular interactions between the drug and polymers, and experimentation with other poorly soluble APIs is underway, following the same experimental sequence established with resveratrol.

References: (1) Kalepu, S.; Nekkanti, V. Insoluble drug delivery strategies: review of recent advances and business prospects. Acta Pharmaceutica Sinica B 2015, 5 (5), 442-453.
(2) Kokott, M.; Breitkreutz, J.; Wiedey, R. The interplay of poorly soluble drugs in dissolution from amorphous solid dispersions. International Journal of Pharmaceutics: X 2024, 7.
(3) Mathieu, D. Pencil and Paper Estimation of Hansen Solubility Parameters. ACS Omega 2018, 3 (12), 17049-17056.
(4) Patel, K. G.; Maynard, R. K.; Ferguson, L. S.; Broich, M. L.; Bledsoe, J. C.; Wood, C. C.; Crane, G. H.; Bramhall, J. A.; Rust, J. M.; Williams-Rhaesa, A.; Locklin, J. J. Experimentally Determined Hansen Solubility Parameters of Biobased and Biodegradable Polyesters. ACS Sustainable Chemistry & Engineering 2024, 12 (6), 2386-2393.
(5) França, M. T.; Mendes, C.; Silva, A. H.; Valentini, G.; Cisilotto, J.; Parize, A. L.; Creczynski-Pasa, T. B.; Stulzer, H. K. Blended polymeric films containing the drugs simvastatin and resveratrol: The supersaturation approach for melanoma treatment. Colloid and Interface Science Communications 2022, 46.
(6) Li, B.; Wegiel, L. A.; Taylor, L. S.; Edgar, K. J. Stability and solution concentration enhancement of resveratrol by solid dispersion in cellulose derivative matrices. Cellulose 2013, 20 (3), 1249-1260.
(7) Yu, C.; Zhang, C.; Guan, X.; Yuan, D. The solid dispersion of resveratrol with enhanced dissolution and good system physical stability. Journal of Drug Delivery Science and Technology 2023, 84.


Polarized Optical Microscopy (POM) images of resveratrol powder mixtures in polymers.


Drug release profile of resveratrol from matrix extrudates


FTIR of pristine resveratrol, polymers, and 10% & 20% resveratrol in polymer extrudates