Definition and validation of the Design Space for co-milled nasal powder containing nanosized lamotrigine

Abstract

Objective: Design of Experiment (DoE), that is a tool of Quality by Design (QbD) paradigm, with which experiments can be planned more effectively and provide more information, while after Design Space (DS) can be set up, which assure the quality of the desired product. The aim of this study was to find the optimal drug-excipient ratio and the optimal process parameters (milling time, milling speed) of our previously used dry co-milling method and validate the DS. Materials and methods: Lamotrigine (LAM), an antiepileptic drug was used as a model API. Poly-vinyl alcohol (PVA) was chosen according to our previous study as a hydrophylic matrix polymer. Milling time, speed, and the API:additive ratio was varied to find out their effect on the product. The optimization was performed on particle size of LAM, its standard deviation and the in vitro dissolution of the samples. Response surface modeling completed the statistical analysis that assessed the effects of independent variables on the responses. Results: Due to the DS estimation, a more economical sample preparation method was set up. Finally, the sample that was prepared according to the optimized parameters (1.5 h, 400 rpm, 0.8 PVA:LAM ratio) showed around 100 nm drug particles and 97% drug release in five minutes. Conclusion: From the DS generated by the software, an optimal formulation was obtained and the results validated the experimental design. The QbD approach was a useful and effective tool of understanding the parameters that affect the quality of the desired product.