Date of Award

2020

Document Type

Dissertation

Degree Name

Philosophy (Ph.D)

Department

Pharmaceutical Sciences

First Advisor

Abu T. M. Serajuddin

Second Advisor

Tycho Heimbach

Third Advisor

Caesar Lau-Ca

Abstract

The aim of this study was to develop ritonavir amorphous solid dispersion (ASD) formulation, investigate its aqueous dissolution and dispersion behavior, and predict potential pharmacokinetic parameters by in-silico modeling. The binary/ternary ASDs of ritonavir with PVPVA or HPMCAS-MG in the absence or presence of surfactants were prepared by using the hot-melt extrusion method. The amount of ritonavir was fixed at 20 %w/w, while amount of polymer and surfactant in the formulation was varied. The film-casting technique was used to confirm the miscibility of drug and polymer in the absence and presence of surfactant in different formulations. PXRD and DSC analyze were carried out to determine solid state properties of the neat ritonavir and solid dispersion formulations prior to conducting dissolution and dispersion testing. All in-vitro dissolution and dispersion studies were performed under non-sink condition at pH 2 (0.01N HCl), pH 4.5 (acetate buffer), and pH 6.8 (phosphate buffer), as well as in a biorelevant medium (FeSSIF-V2). Particle size analysis of the dispersed phase after dispersion of the extrudates in aqueous media was carried out in-line using a particle size analyzer. Raman spectroscopy coupling with chemometrics method was used to identify the polymorphic form of the precipitates from the extrudates after exposing to dissolution medium. The software simulation was then carried out to predict the oral absorption based on in-vitro studies. Stability studies of the ASDs were carried out at 25°C/60%RH for 1 year and 40°C/75%RH for 1 month. Ritonavir, 20%w/w, was found to be miscible with various ratios of polymers and surfactants used. Supersaturated solutions were formed and the supersaturation was maintained throughout 2 h of dissolution testing. However, above certain concentration in dissolution media, ritonavir phase separated and formed milky dispersions. Particle size analysis of the dispersed phase revealed that nano/micro particles were generated by all ASD formulations. The biorelevant media provided much higher drug dissolution as compared to that in standard phosphate buffer medium. The slurries from the extrudates containing ritonavir:PVPVA:sorbitan monolaurate at 20:70:10 % w/w revealed that mixtures of amorphous and crystalline of ritonavir were present. The predicted fraction absorbed ranged from 65 to 90%. In the solid state, all ASDs did not show any ritonavir crystallization under both the stability testing conditions. In the present study, various factors influencing formulations, physical stability and drug release of ASDs of ritonavir were studied. It was observed that there was a good correlation between in-vitro dissolution, in-line particle size monitoring and in-silico modeling which can served as a predictive tool in pharmaceutical development of the ASD for ritonavir as well as other poorly water-soluble drugs. The dissolution and dispersion testing using biorelevant media provided more accurate results on the behavior of the drug formulation than only the result from dissolution testing in standard buffers.

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