(M1330-01-05) Creation and Utilization of Polymer “Alloys” to Increase Drug Loading and Dissolution Performance of Ivacaftor Amorphous Solid Dispersion

Purpose: The formulation of poorly-water soluble drugs with polymer carrier into an Amorphous Solid Dispersion (ASDs) to increase solubility has become a well-reported technique to increase the oral bioavailability of formulations. Despite substantial work, there are still limitations in maximum drug loading that can be achieved in these ASDs that are both physically stable and capable of producing sufficient supersaturation. The formulation’s polymeric component aids these goals, and each of the carrier polymers used in amorphous formulations has different advantages and disadvantages due to, for example, differences in viscosity, hydrogen bonding ability, and hydrophobicity. In addition, most ASDs contain only one polymer, although some work has examined multi-polymer systems, and little research has examined the effect on pre-processing different polymers together.

This work describes the processing of a physically mixed “blend” of two polymers (HPMCAS LMP and PVPK30) into a glassy melt called a polymer “alloy” via Kinetisol processing that is then used as the polymeric carrier in ASD formulations. Kinetisol is an ASD manufacturing technique that uses high-energy mixing to heat and combine components to form an ASD in seconds. Kinetisol does not use external heating. Each of the individual polymers, as well as the blend and alloy, were examined for their ability to form ASDs of the model poorly-water soluble drug ivacaftor (melting temperature = 291°C). It was hypothesized that ASDs formulated with PVP/HPMCAS polymer alloys (i.e., pre-processed PVP/HPMCAS blend) would exhibit synergistic increases in drug loading and dissolution release rate over ASDs comprising only one polymer or the polymer blend.

Methods: Polymer “blend” was prepared by physically mixing 49.5-49.5-1 (w/w) HPMCAS L-Grade:PVPK30:sodium lauryl sulfate. This polymer blend was converted into the preformed “alloy” by Kinetisol by processing at 6250-7000 RPM until ejection at 120°C. To create the ASD formulations, either (unprocessed) polymer blend or milled (processed) polymer alloy, or one of the two polymers HPMCAS L or PVPK30, was mixed with ivacaftor and then processed by Kinetisol at the same conditions as above. Drug loadings between 20-60% w/w were evaluated. The ejected material was tested for amorphicity by X-ray powder diffraction (XRD) and differential scanning calorimetry (DSC). A non-sink dissolution test was conducted in pH 6.5 Fasted Simulated Intestinal Fluid (FaSSIF) to determine the solubility of ivacaftor in the formulations. HPLC and H¹ NMR were used to determine the purity and potency of tested formulations. Fourier-transformed Infra-red (FTIR) spectroscopy evaluated the interactions between the polymers and ivacaftor.

Results: Formulations comprising 10%, 20% and 40% w/w ivacaftor were processed into ASDs with either polymer alone (i.e., binary mixtures), polymer blend, or polymer alloy. In contrast, at 50% drug loading, only the formulation comprising polymer alloy was successfully converted into an ASD, while the other formulations either contained recrystallized ivacaftor or did not form an ASD. At the 20% drug loading, the rank order of dissolution performance of ASD powder was polymer alloy > polymer blend ~ PVPK30 > HPMCAS at 6 hours. FTIR results suggested that PVPK30 incorporated into the polymer alloy was less able to hydrogen bond with ivacaftor than the polymer blend or PVPK30 only ASD. Previous work has shown that hydrogen bonding can, counter-intuitively, reduce the dissolution rate of ASDs above certain drug loadings¹. HPLC analysis showed a maximum of 0.05% impurity of ivacaftor, and H¹ showed no changes in the polymer alloy, suggesting that Kinetisol processing does not degrade the processed drug and polymers.

Conclusion: The formulation of Kinetisol ASDs with the polymer alloy allowed for an increase in the maximum achievable drug loading of ivacaftor from 40% to 50% w/w as compared to ASDs comprising polymer blend, or one with the individual polymers, HPMCAS LMP or PVPK30. In addition, at a 20% drug loading, the ASD-containing polymer alloy outperformed the other formulations at all time points through 6 hours due to a decrease in hydrogen bonding between the PVPK30 component and the ivacaftor. None of the processed components showed evidence of degradation.

References: 1 Saboo S, Kestur US, Flaherty DP, Taylor LS. Congruent release of drug and polymer from amorphous solid dispersions: Insights into the role of drug-polymer hydrogen bonding, surface crystallization, and glass transition. Molecular Pharmaceutics. 2020 Mar 5;17(4):1261-75.

Acknowledgements:This work was supported by DisperSol Technologies LLC, Georgetown, Texas. Robert O. Williams III acknowledges financial support for Stephen A. Thompson from Dispersol Technologies LLC.