Integrated in silico formulation design of self-emulsifying drug delivery systems

The drug formulation design of self-emulsifying drug delivery systems (SEDDS) often requires numerous experiments, which are time- and money-consuming. This research aimed to rationally design the SEDDS formulation by the integrated computational and experimental approaches. 4495 SEDDS formulation datasets were collected to predict the pseudo-ternary phase diagram by the machine learning methods. Random forest (RF) showed the best prediction performance with 91.3% for accuracy, 92.0% for sensitivity and 90.7% for specificity in 5-fold cross-validation. The pseudo-ternary phase diagrams of meloxicam SEDDS were experimentally developed to validate the RF prediction model and achieved an excellent prediction accuracy (89.51%). The central composite design (CCD) was used to screen the best ratio of oil-surfactant-cosurfactant. Finally, molecular dynamic (MD) simulation was used to investigate the molecular interaction between excipients and drugs, which revealed the diffusion behavior in water and the role of cosurfactants. In conclusion, this research combined machine learning, central composite design, molecular modeling and experimental approaches for rational SEDDS formulation design. The integrated computer methodology can decrease traditional drug formulation design works and bring new ideas for future drug formulation design. Continue reading here – open access.

Conclusions
In this research, the pseudo-ternary phase diagram prediction model was successfully constructed by the RF method, which also revealed the important features in SEDDS. The MLX pseudo-ternary phase diagram by experiments validated the prediction model with 89.51% accuracy. The CCD experimental design helped find the optimal MLX-SEDDS and revealed the relationship between excipient content and SEDDS’ s properties. Finally, the MD simulation provided us the molecular interaction between drug and excipient and the role of cosurfactant. The integrated in silico and experimental methodology are well applied in rational formulation design of SEDDS, which also brings new ideas for future drug formulation design.

Materials
MLX with 98% purity was purchased from Tianjin Heowns Biochemical Co., Ltd. (Tianjin, China). Labrafil M 1944 CS and Transcutol HP were obtained from Gattefossé (Saint-Priest Cedex, France). AEO-9, Cremophor RH40, and Cremophor EL were obtained from BASF (Ludwigshafen, Germany). Ethanol and isopropanol were purchased from Tianjin Fuyu Fine Chemical Co., Ltd. (Tianjin, China). Isopropyl myristate (IPM) was purchase from Shanghai CHUXING Chemical Co., Ltd. (Shanghai, China). Isopropyl palmitate (IPP) was purchase from Linyi Lusen Chemicals Co., Ltd. (Linyi, China). Caprylic/Capric Triglyceride (GTCC) was obtained from KLK OLEO (Petaling Jaya, Malaysia). Tween 80 was obtained from Tianjin Kemiou Chemical Reagent Co., Ltd. (Tianjin, China). PEG 400 was obtained from Tianjin Bodi Chemical Co., Ltd. (Tianjin, China).