Statistical modeling, optimization and characterization of spray-dried solid self-microemulsifying drug delivery system using design of experiments

Abstract

The present study systematically and simultaneously investigates the influence of process variables of spray-drying on the properties of solid self-microemulsifying drug delivery system (SmeddS) using design of experiment (DOE) and optimizes them in order to produce solid-SMEDDS satisfying pre-defined powder quality attributes. Flurbiprofen-loaded liquid-SMEDDS was dispersed in dextran and spray-dried. After preliminary screening, the independent factors selected according to three-factor, three-level Box-Behnken design were inlet temperature (X 1 ), feed rate (X 2 ) and carrier concentration (X 3 ). The responses used to compute the effects of independent factors were moisture content (Y 1 ), yield (Y 2 ), drug content (Y 3 ) and droplet size (Y 4 ) of the micro-emulsion. SMEDDS powder characteristics such as morphology, thermal behavior, crystallinity and flowability were also considered. Models were developed and model fitting analysis showed an adequate fit for all responses, indicating good predictability. Significant effects of processing parameters on powder characteristics were observed. The spray-drying process parameters were optimized as inlet temperature (134°C), feed rate (5%) and carrier concentration (0.6%) to produce solid-SMEDDS with acceptable moisture content (0.72±0.02%), yield (58.5±2.9%), drug content (70.1±2.7 mg/g) and droplet size (166.8±13.8 nm). Validation of the optimization process in five batches showed experimental value very close to the predicted one, ensuring the reproducibility of the developed models. Furthermore, optimized parameters resulted a highly crystalline flurbiprofen changed to an amorphous form. In conclusion, this study demonstrated the applicability of the DOE approach for optimizing the process parameters to manufacture solid-SMEDDS with desired quality attributes.Key words design of experiment; Box-Behnken design; optimization; self-microemulsifying drug delivery system; spray-drying Self-microemulsifying drug delivery system (SMEDDS) has been emphasized in recent years for its ability to improve the solubility and bioavailability of poorly water-soluble drugs. Conventionally, SMEDDS are prepared as liquid formulations that are either delivered in soft or hard gelatin capsules 1) However, a liquid form of SMEDDS has several potential drawbacks in manufacturing scale-up such as less stability due to the precipitation of active ingredients, especially at lower temperatures, interactions of formulation components with the capsule shells, and leakage from the capsules.2,3) In order to overcome these limitations, the liquid-based dispersion must be converted into a dry product. In addition, a solid form of SMEDDS formulation combines the advantages of enhanced solubility and bioavailability with a higher stability compared to its corresponding liquid formulation. 4) Solidification can be achieved by dispersion of liquid SMEDDS into a suitable inert solid carrier in an aqueous medium, followed by elimination of the water via several techniques such as spray-drying. Th...

Exploiting gelatin nanocarriers in the pulmonary delivery of methotrexate for lung cancer therapy

“…Finally, adequate precision is a measure of the experimental signal to noise ratio. The adequate precision scored 24.848, a value higher than the critical value of 4, indicating high signal to noise ratio and sufficiency of the model to navigate the experimental space (Zhang and Youan, 2010;Marasini et al, 2013;Abdel-Hafez et al, 2014). Consequently, the model could be utilized for GNPs size optimization and prediction.…”

“…Additionally, in order to investigate the effect of formulation variables on responses (dependent variables), BBD exclude simultaneous implementation of variables at their maximum or minimum levels, thereby the design points are selected as middle value for one factor and maximum or minimum for the other factors. By avoiding corners in the design space, BBD provides safety in its experiments setting (Marasini et al, 2013). Accordingly, DoE could contribute to enhanced quality attributes of the final product and cost and time reduction of the formulation process (Zhang and Youan, 2010;Marasini et al, 2013;Abdel-Hafez et al, 2014).…”

“…By avoiding corners in the design space, BBD provides safety in its experiments setting (Marasini et al, 2013). Accordingly, DoE could contribute to enhanced quality attributes of the final product and cost and time reduction of the formulation process (Zhang and Youan, 2010;Marasini et al, 2013;Abdel-Hafez et al, 2014).…”

Development of Solid Self-Emulsifying Formulation for Improving the Oral Bioavailability of Erlotinib

“…The air pressure was 4 kg/cm 2 , and aspiration was set at 80%, which indicated that the pressure of the aspirator filter vessel was −30 mbar. The direction of air flow was the same as that of the sprayed product (27,28,31,33,35). The physical mixtures of erlotinib and carriers were prepared by mixing erlotinib and each carrier with the same weight ratio in the solid SEDDS formulations.…”

“…However, although these systems have some advantages over emulsions, compared to solid dosage forms, there are still some practical drawbacks associated with the conventional (liquid) SEDDS, including storage instability and interaction with hard or soft capsules. Solidification of liquid SEDDS has been used increasingly in an effort to overcome the abovementioned limitations and combine the advantages of conventional lipid-based drug delivery systems (i.e., increased solubility and bioavailability) with those of solid dosage forms (e.g., high stability and reproducibility, ease of process control, and relatively low production cost) (26)(27)(28)(29)(30)(31)(32)(33)(34).…”