Date of Award
2021
Document Type
Dissertation
Degree Name
Doctor of Philosophy in Pharmaceutical Sciences
Department
Pharmaceutical Sciences
First Advisor
Rahul Haware
Committee Chair and Members
Rahul Haware, Chair
William Stagner
Rutesh Dave
David Taft
Keywords
Amorphous, Micelles, Nanoparticles, Nanotechnology, Solubility enhancement, Spray drying
Abstract
Combined product development strategy of antisolvent precipitation and spray drying was adopted to create a hybridized redispersible spray dried ritonavir (RTV, BCS Class IV) nanoamorphous micellar dispersion (RTV-rSD-NAMD) to enhance the solubility and masked the bitterness of RTV. Initially, a proof of concept study was designed using DM3 research strategy to develop RTV-NAMD. It was employed in conjunction with the quality-by-design spaces, and quality target product profile to link the critical material attributes and critical process parameters to the quality target product profile’s critical product attributes QbD elements. RTV-NAMD was successfully optimized with Soluplus® as the stabilizer using the response surface methodology Box-Behnken design (BBD) and multivariate analysis using multiple linear regression and partial least squares. The impact of drug concentration, Soluplus® concentration, and solvent:antisolvent ratio, their interactions and square effects on the critical product attributes were assessed. Multiple linear regression and partial least squares computational predictability was evaluated using three verification batches. The prediction error for critical product attributes of three verification batches was < 5%. RTV-NAMD. The hybridized strategy leveraged three different mechanisms to increase RTV's solubility and four mechanisms to increase its dissolution rate. X-ray diffraction confirmed the amorphous nature of the RTV-NAMD. RTV-NAMD exhibited a ‘spring-hover’ dissolution profile at pH 4.5. At pH 6.8, a classic ‘spring-parachute’ dissolution behavior was observed. Later to the successful development of proof of concept study design, RTV-rSD-NAMD were systematically developed. The objective in the current study was to screen and optimize the critical formulation and process variables for converting liquid RTV-NAMDs into stable and redispersible spray dried (rSD) powder form of NAMD (RTV-rSD-NAMD). Initially, a fractional factorial screening design (FFD, resolution IV, 7 variables, 18 runs, 2 center points, 1/8 fraction) was employed. Later, another set of Box-Behnken optimization design (BBD, resolution V, 3 variables, 15 runs, 3 center points) was utilized to study the effect of screened significant formulation parameters and process parameter on particle size (PS), polydispersibility index (PDI), zeta potential (ZP), redispersibility index, percent yield (PY), average d50 particle size, and outlet temperature (OT). Kolliphor® 407, sucrose, and Eudragit® EPO were screened as wetting, matrix former, and taste-masking agent respectively. The data from BBD were modeled with MLR equation to decode the statistically significant impact of design variables, their two-way interactions, and quadratic effects. The optimized formulation predicted by the developed model was further verified experimentally. The optimized RTV-rSD-NAMD were characterized by Xray powder diffraction (XRPD) technique and evaluated for short term (8 weeks) storage stability at 25 °C/60% RH and 40 °C/75% RH. PXRD diffractogram confirmed the amorphicity for RTVrSD-NAMD and maintained its amorphicity displaying redispersibility index (1.00; PS: 292.9 nm and PDI: 0.289) over a period of 8 weeks at 25 °C/60% RH. The prediction error (%) for PS, PDI, ZP, and PY using DoE based MLR models was found to be less than 10% which conforms the maximum computational predictability and compliments to the verification of the optimized RTVrSD-NAMD. Clearly, a systematic hybridized-design approach of screening and optimization of variables provides a better solution to develop a stable RTV-rSD-NAMD with maintaining the critical attributes of amorphicity and nanoredispersibility.
Recommended Citation
Rathod, Vishal Ravindra, "The impact of perfectionism on well-being: Shame in perfectionism’s influence on emotion regulation" (2021). Selected Full-Text Dissertations 2020-. 34.
https://digitalcommons.liu.edu/brooklyn_fulltext_dis/34