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

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.

Optimization of fluid bed formulations of metoprolol granules and tablets using an experimental design.

BACKGROUND: The granulation process of a metoprolol tartrate (very difficult to process active pharmaceutical ingredient) formulation in laboratory scale fluid bed equipment was studied. AIM: To study the influence of two formulation factors and three process parameters on the characteristics of the granules and subsequently of the tablets, in the case of fluid bed granulating of a powder mix containing metoprolol tartrate. METHOD: In order to study the influence of formulation factors (binder solution concentration and the silicon dioxide ratio) and process factors (atomizing pressure, the length of the final drying phase, and the inlet air temperature) on the technological and pharmaceutical properties of granules and tablets, a fractional factorial experimental design resolution V+ with five factors and two levels was used. RESULTS: A high atomizing pressure allows us to obtain fine granules with large poly-dispersion index and granules with high tapped and untapped density, tablets with short disintegration time, short mean dissolution time, and a high percentage metoprolol tartrate release in the first 15 minutes. A lower concentration of binder solution allows us to obtain granules with very good flow properties, tablets which have no tendency to stick on the set punch of tabletting machine and no capping. The final drying time of granules has an influence only on the granule's relative humidity and tapped and untapped density, without any influence on the granules flow properties. CONCLUSIONS: The practical experimental results from the formulation processed in optimal working conditions were close to the predicted ones by Modde 6.0 software.