TY - JOUR

T1 - Neither too little nor too much

T2 - Finding the ideal proportion of excipients using confocal Raman and chemometrics

AU - Mitsutake, Hery

AU - da Silva, Gustavo H. Rodrigues

AU - Breitkreitz, Marcia C.

AU - de Paula, Eneida

AU - Bordallo, Heloisa N.

PY - 2022/12

Y1 - 2022/12

N2 - 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 (R), Capryol (R) 90 and Transcutol (R) 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 (R) 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.

AB - 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 (R), Capryol (R) 90 and Transcutol (R) 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 (R) 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.

KW - Butamben

KW - Homogeneity

KW - DHI

KW - Raman mapping

KW - 3D image analysis

KW - DISTRIBUTIONAL HOMOGENEITY

KW - NATURAL LIPIDS

KW - SPECTROSCOPY

KW - FORMULATIONS

KW - NLC

U2 - 10.1016/j.ejpb.2022.11.008

DO - 10.1016/j.ejpb.2022.11.008

M3 - Journal article

C2 - 36400252

VL - 181

SP - 136

EP - 146

JO - European Journal of Pharmaceutics and Biopharmaceutics

JF - European Journal of Pharmaceutics and Biopharmaceutics

SN - 0939-6411

ER -