(W1030-12-80) Polymeric Excipient Selection and Their Role in Physically Stabilising Lumefantrine Amorphous Formulations

Purpose: Lumefantrine serves as a first-line antimalarial compound recommended by WHO. However, the poor aqueous solubility and permeability predispose lumefantrine to sub-optimal clinical performance. Amorphization is a feasible approach to improve the apparent solubility of poorly soluble drugs, with the commonly perceived risk of physical instability over a pharmaceutically relevant time frame, leading to phase separation, insufficient supersaturation, and reduced dissolution. Polymeric excipients can help stabilise amorphous compounds due to their long chain structures and may provide additional effects on solubilisation. The choice of polymer is therefore critical in the design of successful amorphous formulations. This work screened three different polymeric carriers as excipients for the formulation of a lumefantrine amorphous solid dispersion (ASD). Of particular interest was the physical stability of the ASD and the possible mechanism by which the polymeric excipients maintain the drug amorphous state.

Methods: The miscibility of lumefantrine and polymeric excipients was estimated by calculating Hansen solubility parameters (HSP, δ) in accordance with the Hoftyzer/Van Krevelen method[1]. The theoretical glass transition temperatures (Tgs) of binary Drug-Polymer (D-P) systems were predicted using the Gordon-Taylor equation[2]. The neat polymer cylinders of diameter 20 mm and 5 mm were prepared by Vacuum Compression Molding for contact angle measurements using an optical Tensiometer and true density determination for theoretical Tg calculation respectively. The Tg values of D-P physical blends in varying drug weight fractions across 20% to 60% w/w were measured experimentally using Differential Scanning Calorimetry (DSC). The D-P amorphous matrices were prepared by solvent evaporation film-casting method at 50% drug loading and stored under accelerated conditions (40°C, 75% relative humidity (RH)) for 10 days. The thermal behaviour and physical form of samples were characterised by Fourier-transform infrared spectroscopy (FT-IR), Thermogravimetry (TGA), DSC and Powder X-Ray Diffraction (PXRD) immediately after preparation and throughout the storage period. The degradation temperature (Td) was determined by the first derivative of the TGA curves.

Results: Poly-vinyl polymers, PVP K30, PVPVA64, and Soluplus®, with total D-P HSP difference (Δδt) of 0.21, 0.47, 0.89 were examined in this study. The critical value of Δδt indicating very good miscibility has been previously reported to be less than 2 MP1/2 [3]. The Tds and melting enthalpy of lumefantrine loaded amorphous matrices are shown in Table 1. The degradation of PVP K30-based matrix occurred at lower temperature, suggesting its less stable nature compared with the other two polymer-based matrices upon heating. Complete amorphisation was confirmed by the absence of drug endothermic melting in fresh samples. Drug melting enthalpy evolved significantly in PVP K30 and PVPVA64 matrices in contrast to Soluplus® matrix during storage. This is indicative that Soluplus® had a better capability of suppressing recrystallisation of lumefantrine. These trends were also observed in PXRD patterns of fresh and stored samples as shown in Figure 1. To explore the underlying mechanism that Soluplus® stabilises amorphous lumefantrine, the FT-IR spectra of the drug-loaded samples and the respective pure components were compared and analysed. Unfortunately, there was no obvious evidence demonstrating intermolecular interactions, such as hydrogen bonding, between these polymers and lumefantrine. Interestingly, when combinations of drug and polymer were examined using ideal and measure Tg values, a positive Tg deviation appeared in the Soluplus® and lumefantrine mixture, whereas Tg deviations were not significant in the drug blends using PVP K30 or PVPVA64 (Figure 2). Non-ideal mixing would cause stronger drug-polymer (heteronuclear) interactions related to a net expansion, or stronger individual drug-drug or polymer-polymer (homonuclear) interactions associated with net contraction in solid dispersions, the latter of which is prone to phase separation[4]. Deviations from predictions in Tgs of D-P blends are attributed to the relative extent of heteronuclear to homonuclear interactions where positive deviations are usually linked to the case of stronger heteromolecular interactions to achieve favourable exothermic mixing with higher configurational entropy, resulting in a more physically stable D-P binary system. Moreover, Soluplus® showed lower hygroscopicity suggested by a smaller contact angle of 62.6° (± 0.25°) in contrast to PVP K30 with a contact angle of 44.6° (± 0.37°) and PVPVA64 with a contact angle of 40.5° (± 1.06°). In a high RH condition, the thermodynamic factors (enthalpy and entropy of mixing) are highly dependent upon the interactions of drug-polymer-water. While thermodynamic factors are impacted by the amount of water sorbed, which depends on the hygroscopicity of drug and polymer as well as the strength of D-P interactions [5]. In other words, an amorphous system with less hygroscopic polymer materials and stronger intermolecular interactions is less susceptible to moisture-induced D-P de-mixing and subsequent phase separation.

Conclusion: Soluplus^® was the most appropriate polymeric excipient used in lumefantrine amorphous formulations among the assessed polymer candidates from the aspect of product stability. The performance of this polymer and the reduced tendency to recrystallise can be attributed to better miscibility with lumefantrine during melting and the less hygroscopic nature of the polymer.

References: [1] D. W. van Krevelen† and K. te Nijenhuis, Properties of Polymers: Their Correlation with Chemical Structure; their Numerical Estimation and Prediction from Additive Group Contributions. Elsevier, 2009.
[2] H. D. Williams et al., “Strategies to Address Low Drug Solubility in Discovery and Development,” Pharmacol Rev, vol. 65, no. 1, pp. 315–499, Jan. 2013.
[3] D. J. Greenhalgh, A. C. Williams, P. Timmins, and P. York, “Solubility parameters as predictors of miscibility in solid dispersions,” J Pharm Sci, vol. 88, no. 11, pp. 1182–1190, Nov. 1999.
[4] S. Baghel, H. Cathcart, and N. J. O’Reilly, “Polymeric Amorphous Solid Dispersions: A Review of Amorphization, Crystallization, Stabilization, Solid-State Characterization, and Aqueous Solubilization of Biopharmaceutical Classification System Class II Drugs,” JPharmSci, vol. 105, no. 9, pp. 2527–2544, Sep. 2016.
[5] A. C. F. Rumondor and L. S. Taylor, “Effect of Polymer Hygroscopicity on the Phase Behavior of Amorphous Solid Dispersions in the Presence of Moisture,” Mol. Pharmaceutics, vol. 7, no. 2, pp. 477–490, Apr. 2010.

Acknowledgements: The researcher [Dijia Liu] is funded by a full scholarship from China Scholarship Council (CSC).

Table 1. The decomposition temperatures of D-P amorphous samples with a drug loading of 50% w/w and melting enthalpy of recrystallised lumefantrine in polymer matrices during storage.

Figure 1. PXRD patterns of lumefantrine, neat polymer candidates and fresh D-P amorphous samples and the samples stored at 40℃/75% RH condition across 10 days.

Figure 2. Theoretical Tg curves (solid lines) calculated by Gordon-Taylor Eqs. as a function of drug loads and respective experimentally determined Tg curves (dashed lines) with SD bars of D-P physical mixtures at drug loads ranging from 20% to 60%.