Step-By-Step Standardization of the Bottom-Up Semi-Automated Nanocrystallization of Pharmaceuticals: A Quality By Design and Design of Experiments Joint Approach

Nanosized drug crystals have been reported with enhanced apparent solubility, bioavailability, and therapeutic efficacy compared to microcrystal materials, which are not suitable for parenteral administration. However, nanocrystal design and development by bottom-up approaches are challenging, especially considering the non-standardized process parameters in the injection step. This work aims to present a systematic step-by-step approach through Quality-by-Design (QbD) and Design of Experiments (DoE) for synthesizing drug nanocrystals by a semi-automated nanoprecipitation method. Curcumin is used as a drug model due to its well-known poor water solubility (0.6 mu g mL-1, 25 degrees C). Formal and informal risk assessment tools allow identifying the critical factors. A fractional factorial 24-1 screening design evaluates their impact on the average size and polydispersity of nanocrystals. The optimization of significant factors is done by a Central Composite Design. This response surface methodology supports the rational design of the nanocrystals, identifying and exploring the design space. The proposed joint approach leads to a reproducible, robust, and stable nanocrystalline preparation of 316 nm with a PdI of 0.217 in compliance with the quality profile. An orthogonal approach for particle size and polydispersity characterization allows discarding the formation of aggregates. Overall, the synergy between advanced data analysis and semi-automated standardized nanocrystallization of drugs is highlighted. This article presents a breakthrough in bottom-up nanocrystallization, improving the reproducibility, robustness, and potential scalability of the solvent-antisolvent methodology for pharmaceutical nanocrystals. This approach provides a risk-, statistical-, mathematical-, and quality-based protocol to fulfill the defined quality profile of nanopharmaceutical preparations. Overall, the development of a more systematic strategy for decision-making in the early development of nanocrystalline formulations is highlighted. image