Exploring Excipient Functionality - Pharmaceutical Technology

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PharmTech Europe

Exploring Excipient Functionality
This technical forum is part of a special issue on Solid Dosage and Excipients.

Pharmaceutical Technology
Volume 35, pp. s6-s11

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.

Table I: Predictions from MemFis calculations and experimental results from film castings.
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.

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).


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