Spray-drying process optimization for manufacture of drug-cyclodextrin complex powder using design of experiments.

BACKGROUND: Design of experiments (DOE), a component of Quality by Design, is systematic and simultaneous evaluation of variables (process or formulation) to develop a product with predetermined quality attributes. This study presents a case study to understand the effects of process variables in a spray-drying process used in the manufacture of drug-cyclodextrin complex for a drug that is prone to chemical instability at elevated temperature conditions encountered during processing. METHODS: Experiments were designed, and data were collected according to a three-factor, three-level face-centered central composite design. The factors investigated were inlet temperature, spray rate, and batch size. Responses analyzed for computing the interaction effects were drug content, impurities, moisture content, and process yield. The spray-drying process conditions were optimized using DOE to maximize production yields while minimizing moisture content and drug-related impurities. Process validation batches were executed using the optimum process conditions obtained from software Design-Expert((R)) to evaluate both the repeatability and reproducibility of spray-drying technique. RESULTS: Optimization of process variables using DOE resulted in a significant improvement of process yields, above 90% and moisture content below 6% (w/w). The impurities were controlled within acceptable limits. The desirability function used to optimize the response variables and observed responses were in agreement with experimental values. These results demonstrated the reliability of selected model for manufacture of powder complex with predictable quality attributes. CONCLUSION: The study indicates the general applicability of DOE approach to optimize critical process parameters in the manufacture of drug product with desired quality attributes.

Production and in vitro characterization of solid dosage form incorporating drug nanoparticles.

The objective of this study was to develop a tablet formulation of ketoconazole incorporating drug nanoparticles to enhance saturation solubility and dissolution velocity for enhancing bioavailability and reducing variability in systemic exposure. The bioavailability of ketoconazole is dissolution limited following oral administration. To enhance bioavailability and overcome variability in systemic exposure, a nanoparticle formulation of ketoconazole was developed. Ketoconazole nanoparticles were prepared using a media-milling technique. The nanosuspension was layered onto water-soluble carriers using a fluid bed processor. The nanosuspensions were characterized for particle size before and after layering onto water-soluble carriers. The saturation solubility and dissolution characteristics were investigated and compared with commercial ketoconazole formulation to ascertain the impact of particle size on drug dissolution. The drug nanoparticles were evaluated for solid-state transitions before and after milling using differential scanning calorimetry (DSC) and powder X-ray diffraction (PXRD). This study demonstrated that tablet formulation incorporating ketoconazole nanoparticles showed significantly faster rate of drug dissolution in a discriminating dissolution medium as compared with commercially available tablet formulation. There was no affect on solid-state properties of ketoconazole following milling. The manufacturing process used is relatively simple and scalable indicating general applicability to enhance dissolution and bioavailability of many sparingly soluble compounds.