Neither too little nor too much: finding the ideal proportion of excipients using confocal Raman and chemometrics

The applications of Raman imaging in pharmaceutical field are ever-increasing due its ability to obtain spatial and spectral information simultaneously, once it allows determine the chemical distribution of compounds. In this sense, it is used to study homogeneity, of paramount importance during the development of pharmaceutical formulations due to its relation to stability, safety and efficacy. Commonly, just surface is analyzed, but confocal Raman spectroscopy can also characterize the inner part of samples, allowing to determine phase separation in the early stages.

In this sense, confocal 3D Raman microscopy was crucial to obtain the optimal proportion of Apifil®, Capryol® 90 and Transcutol® to promote controlled release of the local anesthetic butamben (BTB). 3D chemical maps were obtained by classical least squares (CLS) using pure compound spectra as S matrix, showing that chemical distribution throughout the material was different. Knowing that the composition of samples affects the homogeneity parameter, standard deviation and distributional homogeneity index (DHI) were used in mixture experimental design (DoE). From this analysis, it was revealed that a correct amount of Capryol® 90 enhances both miscibility and solubility. Furthermore, suitable miscibility was observed in two ratio proportions of excipients with a desirability of 0.783 and 0.742. These results unequivocally demonstrated that confocal Raman microscopy combined to DoE can bring pharmaceutical development to a higher level.

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2.1. Materials

Butamben (butyl 4-aminobenzoate, hereafter BTB) was purchased from Fluka Analytical (≥ 98.0%, w/w). Apifil® GC, the first wax derivative created by Gattefossé, based on beeswax and functionalized with polyethylene glycol-8, Capryol® 90, (propylene glycol monocaprylate) is a nonionic water-insoluble surfactant that can be used as cosurfactant, and Transcutol® GC, (diethylene glycol monoethyl ether), a solvent and solubilizer used for enhancing solubility and bioavailability in oral and alternative routes were donated by Gattefossé (France). All samples were analyzed as received. These excipients were selected based on the screening studies carried out previously by the authors [6].

Hery Mitsutake, Gustavo H. Rodrigues da Silva, Márcia C. Breitkreitz, Eneida de Paula, Heloisa N. Bordallo, Neither too little nor too much: finding the ideal proportion of excipients using confocal Raman and chemometrics, European Journal of Pharmaceutics and Biopharmaceutics, 2022, ISSN 0939-6411
https://doi.org/10.1016/j.ejpb.2022.11.008.