Purpose: Amorphous solid dispersion formulations (ASDs) are an attractive choice when dealing with low solubility pharmaceutical molecules. However, their success primarily relies on the miscibility between the drug and the polymer carrier, as miscibility enables the adequate dispersion of drug within the polymer, preventing optional phase separation and crystallization through molecular interactions. The majority of recent publications on miscibility investigation revolve around thermodynamic and computational tools, including in silico tools for molecular interaction investigation (molecular modelling), the calculation of the Flory-Huggins chi parameter and the Hansen solubility parameters (HSPs). However, the selection of polymers for ASDs is still being routinely achieved mostly through trial and error practices, creating a gap for reliable experimental protocols for the prediction of drug-polymer miscibility.
With this work we propose a dilute solution rheological method -previously used for investigating the miscibility of polymer blends (Chee, 1990)- for polymer selection in ASDs. The method was evaluated against various frequently applied methodologies including differential scanning calorimetry (DSC), X-ray powder diffraction (XRD), and the in silico estimation of HSPs. Tacrolimus (biopharmaceutics BCS class II) was used as model drug.
Methods: Trial and error methods
Solid dispersions (SD) of 9 polymers with drug loadings ranging from 10-90% were prepared via the rotary evaporator and by casting films. SDs were tested with DSC and XRD for time zero (t_0). Formulations were then stored in normal (25˚C/30% RH) and accelerated (40˚C/75% RH) condition chambers and after one and three months (t_1month,t_3months) they were characterized with DSC. DSC thermograms of the drug-polymer combinations that lack melting curves for both the polymer and the drug and show only one Tg might indicate a miscible system.
Dilute solution rheology
The dilute solution theory is based on the notion that the viscosity of dilute polymer blend solutions can indicate system miscibility. By using a glass Ubbelohde viscometer and by measuring flow time, the relative viscosity (n_rel) of drug-polymer blends can be calculated via equation (1), where t_solution is the flow time of the blend solution and t_solvent is the flow time of the solvent alone. The reduced viscosity (n_red) for each blend was calculated by equation (2), where c is the concentration of total solids in the solution.
n_rel=t_solution/t_solvent (1) n_red=n_rel/C (2)
Following, reduced viscosity Vs concentration linear graphs were constructed, and the intrinsic viscosity (n) and binary interaction parameter (b) values were extrapolated as intercept and slope of the graph respectively (example in Fig.1).
Finally, interaction parameters ΔΒ, μ and α were calculated for the drug-polymer blends via equations (3), (4) and (5), where w is the weight fraction and k=b/n is the Huggins coefficient.
ΔΒ=(b-b ̅)/(2w"1" w"2" ) (3) μ=ΔΒ/〖(n"1" -n"2" )〗^2 (4)
α=k"12"-(k"1" n"12" w"12"+k"2" n"22" w"22"+(2(k"1" k"2" n"1" n"2" w"1" w"2" )"1/2" )/((n"1" w"1" +n"2" w"2" )"2" )) (5)
Interaction parameters can be seen as a measure of miscibility, with positive, or equal to zero, values indicating miscibility.
HSPs have been used as a measure of miscibility in various formulations and they are based on the notion that “like dissolves like”, with molecules with similar HSPs being considered miscible. Consequently, a difference in HSP can be an indication of miscibility (Table 1).
HSPs were calculated by the Hansen Solubility Parameters in Practice software Version 5.0.06, 2008-2017.
Results: The rheology experiments suggested that with higher drug loadings, most combinations would shift towards immiscibility. In theory, higher drug loadings create a re-crystallization friendly environment, as the polymers cannot sufficiently stabilize the amorphous state. However, this was not evident via the traditional methodology.
Moreover, a direct correlation was not obvious between the outcomes predicted with HSP calculations and the trial and error methodology.
On the other hand, the HSP calculations and the rheological method predicted 3 immiscible and 6 miscible systems. From these miscible combinations, 3 scored well in all methodologies used and were chosen for further development into ASDs. In vitro and dissolution characterization of those ASDs will be a comment on the predictive power of our techniques.
Conclusion: This work could indicate that, despite the rheological method potentially showing increased sensitivity, a combination of experimental and computational tools could prove to be more accurate in predicting miscibility and ASD success.
This project has received funding from the European Union’s Horizon 2020 Research and Innovation Program under grant agreement No 674909.
Chee, K.K. "Determination of polymer-polymer miscibility by viscometry." European Polymer Journal 26.4 (1990):423-426.
Greenhalgh, D.J., et al. "Solubility parameters as predictors of miscibility in solid dispersions." Journal of pharmaceutical sciences 88.11 (1999):1182-1190.
Martin Kuentz– University of Applied Sciences and Arts of Northwestern Switzerland, Institute of Pharma Technology
Christos Reppas– Professor of Pharmaceutics, National and Kapodistrian University of Athens, Athens
Lida Kalantzi– Pharmathen S/A
Lida Kalantzi– Pharmathen S/A