Article

Download article 		Title: Evaluation of miscibility and polymorphism of synthetic and natural lipids for nanostructured lipid carrier (NLC) formulations by Raman mapping and multivariate curve resolution (MCR)
Author: Mitsutake, Hery; Ribeiro, Lígia N.M.; Rodrigues Da Silva, Gustavo H.; Castro, Simone R.; De Paula, Eneida; Poppi, Ronei J.; Breitkreitz, Márcia C.
Year: 2019
Is part of: EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES, v. 135, p. 51 - 59
DOI: https://doi.org/10.1016/j.ejps.2019.05.002

Citation: Mitsutake, Hery; Ribeiro, Lígia N.M.; Rodrigues Da Silva, Gustavo H.; Castro, Simone R.; De Paula, Eneida; Poppi, Ronei J.; Breitkreitz, Márcia C.; Evaluation of miscibility and polymorphism of synthetic and natural lipids for nanostructured lipid carrier (NLC) formulations by Raman mapping and multivariate curve resolution (MCR). EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES, v.135, p. 51-59, 2019

Abstract: Nanostructured lipid carriers (NLC) belong to youngest lipid-based nanocarrier class and they have gained increasing attention over the last ten years. NLCs are composed of a mixture of solid and liquid lipids, which solubilizes the active pharmaceutical ingredient, stabilized by a surfactant. The miscibility of the lipid excipients and structural changes (polymorphism) play an important role in the stability of the formulation and are not easily predicted in the early pharmaceutical development. Even when the excipients are macroscopically miscible, microscopic heterogeneities can result in phase separation during storage, which is only detected after several months of stability studies. In this sense, this work aimed to evaluate the miscibility and the presence of polymorphism in lipid mixtures containing synthetic (cetyl palmitate, Capryol 90 (R), Dhaykol 6040 LW (R), Precirol ATO5 (R) and myristyl myristate) and natural (beeswax, cocoa and shea butters, copaiba, sweet almond, sesame and coconut oils) excipients using Raman mapping and multivariate curve resolution - alternating least squares (MCR-ALS) method. The results were correlated to the macroscopic stability of the formulations. Chemical maps constructed for each excipient allowed the direct comparison among formulations, using standard deviation of the histograms and the Distributional Homogeneity Index (DHI). Lipid mixtures of cetyl palmiae/Capryol (R); cetyl palmliae/Dhaykol (R); myristyl myrisae/Dhaykol (R) and myristyl myristate/coconut oil presented a single histogram distribution and were stable. The sample with Precirol (R)/Capryol (R) was not stable, although the histogram distribution was narrower than the samples with cetyl palmitate, indicating that miscibility was not the factor responsible for the instability. Structural changes before and after melting were identified for cocoa butter and shea butter, but not in the beeswax. Beeswax + copaiba oil sample was very homogenous, without polymorphism and stable over 6 months. Shea butter was also homogeneous and, in spite of the polymorphism, was stable. Formulations with cocoa butter presented a wider histogram distribution and were unstable. This paper showed that, besides the miscibility evaluation, Raman imaging could also identify the polymorphism of the lipids, two major issues in lipid-based formulation development that could help guide the developer understand the stability of the NLC formulations.

Keywords: lipid nanoparticles; raman spectroscopy;
Subjects: CIENCIAS_BIOLOGICAS; Biofísica de Processos e Sistemas;

Funding: The authors thank INCT-Bioanalitica (FAPESP/INCT 14/50867-3; CNPq/INCT 465389/2014-7), CNPq (H.M. scholarship) and CAPES (Finance Code 001) for financial support; Gattefosse (France) for the donation of Capryol 90 (R) and Precirol ATO5 (R) and Pierre-Yves Sacre (University of Liege, Belgium) for the MATLAB code and helpful discussions about DHI. 		Financed by: