(M1530-09-60) Algorithm-Based Excipient Selection for Solid Dispersion Development

Purpose: Nearly 90% of drug candidates suffer from poor aqueous solubility, limiting oral bioavailability. Amorphous solid dispersions (ASDs) enhance solubility by dispersing APIs in polymers that ensure stability and promote supersaturation. This study used a Formulation by Design (FbD) approach with ZoomLab® to predict optimal API–polymer combinations, streamlining development and reducing experimental efforts.

Methods: The Flory-Huggins (FH) model was employed to evaluate the thermodynamic miscibility between Rivaroxaban (RXB) and polymers by incorporating enthalpic and entropic contributions. Binary physical mixtures of RXB and polymer (95:5 to 80:20) were analyzed using DSC at 1°C/min. The resulting melting point depression data were fitted to the FH model to extract the interaction parameter (χ). A lower or negative χ value indicates better miscibility, reflecting stronger drug-polymer interactions. These results were compared to ZoomLab predictions for validation. For Hot Melt Extrusion (HME), formulations comprising RXB (10–30% w/w), Soluplus®, and Kollidon® VA 64 (up to 90% w/w each) were blended via acoustic mixing (LabRAM I) and processed using a twin-screw granulator (Pharma 11) with a defined kneading configuration and heating profile (50–200°C). The extrudates were milled and further characterized. In vitro drug release was evaluated for granules (20 mg RXB equivalent) in 500 mL DI water using USP-II at 75 RPM with in situ fiber optic probes. XRD analysis (Rigaku Smartlab) assessed crystallinity over 2θ range 7–50°. The optimized formulation was subjected to 1-month stability at 40°C/75% RH, with XRD and dissolution testing confirming retained amorphicity, while binary systems showed recrystallization under the same conditions.>

Results: ZoomLab^® calculated the Hansen Solubility Parameters of RXB and their difference to a known database of polymers, excipients and solvents to the rank these in order of highest predicted crystalline solubility in the pure Polymers. On the suggested polymers, aqueous solubility was carried out. The ranking results in descending solubilization order were: Soluplus^® > povidone K-30 (Kollidon^® 30) > copovidone (Kollidon^® VA 64) > polyethylene glycol (Kollisolv^® PEG 1450) > poloxamer (Kolliphor^® P 407) > poloxamer (Kolliphor^® P 188). The pharmaceutical industry often favors Hot Melt Extrusion (HME) over spray drying to produce solid dispersion systems, primarily because HME being a solvent-free technology. Based on recommendations from ZoomLab^® and solubility studies, two polymers were identified as candidates for preparing solid dispersions of RXB using HME: Soluplus^® and copovidone. These studies are critical as they indicate the solid-dispersion system stability. ZoomLab^® predictions indicated superior miscibility between Rivaroxaban (RXB) and Kollidon^® VA 64, as evidenced by a lower interaction parameter compared to RXB–Soluplus systems. These in silico findings were well-aligned with experimental results (Figure 1 (a)). For the solid dispersion prepared, all RXB-polymer combinations containing 10% w/w of RXB resulted in amorphous in nature, regardless of the polymer ratio. However, at 15% w/w drug loading, formulations containing a higher proportion of Kollidon^® VA 64 maintained their amorphous nature, while those with increased Soluplus^® content exhibited partial crystallinity (Figure 1(b)). At drug loads exceeding 15% w/w, a progressive decrease in crystallinity was observed with increasing Kollidon^® VA 64 content, reinforcing its critical role in promoting both miscibility and solubilization of RXB. This behavior highlights the importance of selecting the appropriate polymer to stabilize the drug in its amorphous form (Figure 1(b)). An optimized ternary formulation comprising 10% w/w RXB, 45% w/w Kollidon VA 64, and 45% w/w Soluplus was identified based on its favorable dissolution performance and miscibility profile. Importantly, this formulation retained its amorphous structure and functional characteristics after one month of storage under accelerated conditions (40 °C/75% RH), indicating good physical stability. In contrast, after onemonth under accelerated condition, a binary solid dispersion (ASD) of RXB with Soluplus^® which were initially amorphous in nature (Figure 3 (a)), exhibited the onset of crystallinity, whereas the binary RXB–Kollidon VA 64 system remained fully amorphous nature (Figure 3 (b)), These results further confirm the superior miscibility and stabilizing potential of Kollidon^® VA 64 for Rivaroxaban in amorphous formulations.

Conclusion: This study employed a Formulation by Design (FbD) approach, integrating predictive modeling via ZoomLab® with experimental validation to develop optimized amorphous solid dispersions (ASDs) of Rivaroxaban (RXB), a poorly soluble BCS Class II drug. Experimental results confirmed that higher Kollidon^® VA 64 content enhanced amorphicity and physical stability, particularly at elevated drug loads. An optimized ternary formulation (10% w/w RXB, 45% Kollidon^® VA 64, 45% Soluplus^®) combined the properties of higher miscibility of RXB in Kollidon^® VA 64 and higher solubility using Soluplus^® The optimized formulation maintained its amorphicity and  dissolution performance after one month at 40 °C/75% RH. In contrast, binary RXB–Soluplus^® systems showed recrystallization under the same conditions, whereas RXB–Kollidon^® VA 64 remained stable. These findings underscore the importance of polymer selection in ASD design and demonstrate the utility of digital tools in accelerating formulation development.

Figure 1. (a) ZoomLab ® predicted Flory-Huggins interaction parameter vs. its experimental values. (b) % Crystallinity of solid dispersion formulation with varied percentage of RXB, Soluplus®, and Kollidon® VA 64

Figure 2. (a) In-vitro release of the optimized formulation in de-ionized water, 500 mL, 75 RPM, USP-II at 37 C. (b) XRD patterns of the optimized formulation compared to Pure RXB

Figure 3 (a) Initial and 1 M ACC (40 C/ 75%RH) XRD pattern of 10% w/w and 90% w/w Soluplus Solid dispersion. (b) Initial and 1 M ACC (40 C/ 75%RH) XRD pattern of 10% w/w and 90% w/w Kolldion VA 64 Solid dispersion.