(T1530-09-61) Hansen Solubility Parameter-Based Modeling to Improve Solubility Profiling of Challenging APIs and Accelerate Formulation Development

Purpose: To investigate a standard model for API solubility studies utilizing a limited number of solvents occupying a representative portion of the Hansen space allowing for in-silico screen of potential solvent systems reducing the duration and expense of bench trials. Contained herein is the methodology and results for the Hansen solubility analysis using a total of nine solvents to build a solubility model. Three different APIs were selected to screen the feasibility of the proposed model and the solvents were selected to cover a broad base of Hansen coordinates. By measuring the solubilities of the APIs in the model solvents, empirical Hansen parameters of the target APIs were obtained along with Hansen distances for each solvent/API pair. By developing a model that correlates Hansen distance with measured solubility, it is possible to estimate the solubility of API in a wide range of solvent system allowing virtual screening of dozens to hundreds of solvent systems, thus reducing bench trials to the handful of acceptable solvents that have the potential to meet the solubility target.

Methods: Materials: APIs- Compound A (BSC II), Compound B (BSC II/IV), Compound C (BSC IV). Hansen solvents- Acetone (Sigma-Aldrich), benzyl alcohol (EMD), benzyl benzoate (EMD), ethanol (Decon Labs), dimethyl sulfoxide (BTC), diethylene glycol monoethylether (Gattefosse), glyceryl monooleate (Gattefosse), super refined sesame oil (Croda), polysorbate 80 (Croda). Mobile phase components- Water (Milli-Q), acetonitrile (Fisher), THF (Sigma Aldrich), TFA (TCI). Instrumentation and consumables- Vortex shaker (Fisher), HPLC (Agilent 1200) equipped with VWD and phenyl hexyl column (Ascentis), orbital shaker (Solaris), 0.45µm PTFE syringe filters (PALL), 15mL centrifuge tubes (VWR). Data analysis- HSPiP 6^th edition (Hansen), Empower 3 chromatography software (Waters), Minitab Statistical Software (Minitab, LLC).Sample prep: Samples were prepared by adding API in portions to centrifuge tubes containing 10 mL of one of the nine solvents with vortex mixing between each addition to aid dissolution. Once saturated, the tubes were set to shake overnight at 50 rpm after which they were centrifuged at 3000G for 15 min. Aliquots of the supernatant in each tube were filtered through 0.45 µm PTFE and appropriately diluted with ACN based on the total amount of API added to the tubes. Analysis:  Solubility data was obtained via reversed phase HPLC utilizing a 55° C phenyl hexyl column, 4.6 mm x 150 mm, 2.7 µm particles and gradient elution with 0.05% v/v TFA in 50:50 H2O:ACN for mobile phase A and 0.05% v/v TFA in 85:15 ACN:THF for mobile phase B. UV wavelength detection was set at 240 nm and injections were made in 5 µL volumes. Values of total amount of API dissolved in mg/mL were entered into the HSPiP software and Hansen distances for the APIs were calculated based on said values.

Results: The results (Table 1) for all three APIs demonstrated a strong linear correlation between Hansen distance and solubility in the selected solvents. The smaller the distance, the more chemically “similar” the API and solvent, thus the greater the solubility. Similar solubilities and Hansen distances are observed between Compounds A and B which point to chemical similarity regarding dispersion forces, dipole moments, and H-bonding capacity. Initial estimated values of δD, δP, and δH were produced by the HSPiP software’s Y-MB functionality using the SMILES of each compound and were respectively as follows: Cpd A- 21.5, 10.1, and 15.8, Cpd B- 19.5, 9.5, 5.4, Cpd C- 18.8, 6.8, 8.5. The model empirical values for the Hansen solubility parameters δD, δP, and δH were found to be: Cpd A- 18.2, 16.9, 8.2m, Cpd B- 18.2, 17.1, 8.2, Cpd C- 17.9, 18.3, 11.4, respectively. Little appreciable difference exists between the δD values when comparing the estimated values to those measured, however, significant differences between the estimated and measured values for δP, and δH are observed, most likely due to different thermodynamic molecular interactions not accounted for in the estimated values e.g. possible nuances in the existence of solvation spheres between API and solvent molecules. Despite the differences between estimated and measured solubilities (Table 2) and higher variability among values less than 10 mg/mL, a good correlation for the three APIs are illustrated in Figure 1. The coefficients of determination (r²) were found to be 0.987, 0.987, and 0.974 for compounds A, B, and C, respectively. The equations of the regression lines (estimated vs measured) are all close to the ideal equation y=x demonstrating the HSP are driving the correlation thus supporting the model being used to predict solubility across multiple compounds.

Conclusion: The Hansen model utilizing nine different solvents showed good correlation between solubility and Hansen distance demonstrating its potential for virtual screening of APIs in various solvent systems. Next steps would be to test the model against the three APIs in binary and tertiary mixes of the nine solvents. The model would also benefit from expanding the number of APIs used to test the nine solvent system.

References: (1) Petříková, E.; Patera, J.; Gorlová, O. Influence of Active Pharmaceutical Ingredient Structures on Hansen Solubility Parameters. Eur. J. Pharm. Sci. 2021, 167 (106016), 106016. https://doi.org/10.1016/j.ejps.2021.106016.
(2) Louwerse, M. J.; Maldonado, A.; Rousseau, S.; Moreau-Masselon, C.; Roux, B.; Rothenberg, G. Revisiting Hansen Solubility Parameters by Including Thermodynamics. Chemphyschem 2017, 18 (21), 2999–3006. https://doi.org/10.1002/cphc.201700408.
(3) Mathieu, D. Pencil and Paper Estimation of Hansen Solubility Parameters. ACS Omega 2018, 3 (12), 17049–17056. https://doi.org/10.1021/acsomega.8b02601.

Table 1: Measured Solubility and Hansen Distance Summary

Table 2: Predicted Solubility and % Agreement Summary

Figure 1: Predicted and measured solubility correlation