MemFis uses the classical Flory-Huggins equation to identify volume fractions of drug–polymer binary mixtures that would minimize
the Gibbs free energy of mixing (i.e., saturation solubility limit).
Where n1 = number of moles of polymer; θ1 = volume fraction of polymer; n2 = number of moles of drug; θ2 = volume fraction of drug; χ12 = Chi parameter, energy to disperse molecules of polymer and drug; R = gas constant; and T = absolute temperature.
MemFis can help in reducing the number of experiments by identifying the pairs of polymer and drug that are potentially miscible
and have intrinsically better stability via hydrogen bonding or ionic interactions.
Melt Extrusion Modeling is a process database that contains more than 1300 experiments collected over a decade of pharmaceutical
melt extrusion at Evonik. Once lead formulations are selected from the screening studies, the formulation scientists face
the challenge of selecting processing conditions for successful melt-extrusion experiments. Process-setting variables are
included, but not limited to extruder screw-element design, heating-zone temperatures, energy-input rate, screw speeds, feed
rates, and processing-aide selections. The MemFis process database is expanding and is fully searchable and can provide help
with initial melt-extrusion process settings.
Case study. Naproxen, a BCS II drug substance, was selected for miscibility estimation using MemFis. Film casting from ethanol solutions
and cross-polarized optical microscopy was used to measure the experimental drug-substance solubility in the polymers. Estimated
predictions from MemFis calculations and experimentally determined results from film casting are presented in Table I.
Table I: Predictions from MemFis calculations and experimental results from film castings.
These results show that MemFis predictions were reasonably consistent with experimental measurements. The slight underestimation
of solubility in Eudragit E PO is likely due to the ionic interactions between the drug and the polymer, which are not considered
in the calculation model. The overestimations for a few of the polymers are most likely due to the fact that such polymers
could engage in intramolecular hydrogen bonding rather than intermolecular bonding with the drug and that not all hydrogen-bonding
sites on the polymer backbone are available to interact with the drug.
MemFis predictions help in reducing the number of experiments by identifying polymer–drug formulations with higher potential
for miscibility and stability through hydrogen bonding formation. The calculations, therefore, can be used to screen many
compounds for miscibility and solid-solution formation minimizing API use and development time.
Solid dispersion (predictive approaches) section references
1. C.Y. Wu and L.Z. Benet et al., Bull. Technique Gattefosse
99, 9–16 (2006).
2. F. Qian et al., Int. J. Pharm. 395 (1–2), 232–235 (2010).
3. Lauer et al., Pharm. Res.
28 (3), 572–584 (2011).
4 A. Shanbhag et al. Int. J. Pharm
351 (1–2), 209–218 (2008).