Date of Award

8-31-2019

Document Type

Dissertation

Degree Name

Doctor of Philosophy in Chemical Engineering - (Ph.D.)

Department

Chemical and Materials Engineering

First Advisor

Ecevit Atalay Bilgili

Second Advisor

Rajesh N. Dave

Third Advisor

Robert Benedict Barat

Fourth Advisor

Murat Guvendiren

Fifth Advisor

Ilgaz Akseli

Abstract

Drug nanocomposites and amorphous solid dispersions (ASDs) are two major formulation platforms used for the bioavailability enhancement of BCS Class II drugs. The major drawback of nanocomposites is their inability to attain high drug supersaturation during in vitro (<50% relative supersaturation) and in vivo dissolution. On the other hand, formulating an amorphous solid dispersion (ASD) with high drug loading (>20%) that releases drug rapidly, while generating and maintaining high supersaturation over at least three hours is challenging. The goal of this thesis is to develop a fundamental understanding of the impact of anionic surfactants–polymers on in vitro drug release from nanocomposites and ASDs, while addressing the above challenges. To achieve this goal, the following objectives are set: (1) compare griseofulvin (GF, drug) release from spray-dried nanocomposites and ASDs with identical formulation that has low GF:polymer (HPC/Soluplus) mass ratio (1:1 to 1:5) and an anionic surfactant (SDS), (2) examine the presence/absence of SDS on drug release from nanocomposites, (3) develop rapidly supersaturating ternary ASDs of GF with HPC/Sol and SDS as a minor component, (4) investigate GF release from ternary ASDs of GF with a hydrophilic, wettability-enhancing polymer (HPC/PVP-VA64) as a minor component and an amphiphilic polymer as drug precipitation inhibitor (Soluplus), and (5) apply the fundamental knowledge generated for GF to another BCS Class II drug, itraconazole (ITZ).

Spray-drying of aqueous GF nanosuspensions with 1:5 GF:Sol–0.125% SDS has led to formation of a novel class of nanocomposites, HyNASDs, which have notable amorphous GF content (~5–20%). Their dissolution has generated 300% supersaturation within 20 min that is largely maintained after 3 h (250%). Such remarkable drug supersaturation is made possible by strong intermolecular interactions/miscibility between GF–Soluplus at 1:5 ratio and ensuing fast kinetic solubilization of GF nanoparticles upon contact of HyNASDs with water. While HyNASDs do not generate as high saturation as ASDs (480%), they can be rendered competitive to ASDs upon further optimization. The supersaturation generation by HyNASDs is affected by presence of SDS either in the formulation or in the dissolution medium, drug–polymer interactions/miscibility as well as the size of the drug (nano)crystals in the polymeric matrix. Incorporating even 1.23% SDS in Sol-based ASDs has led to dramatic increase in supersaturation (max. 570%), but it has no notable improvement for HPC-based ASDs. SDS provides Sol-based ASDs with enhanced wettability and augments Sol in solubilizing GF, without interfering with Sol’s ability to inhibit GF recrystallization. Combination of Sol with HPC/VA64 has led to a trade-off between rapid drug release and high supersaturation. A strong synergistic effect exists for the ASD with 11:1 Sol:VA64. The inclusion of a hydrophilic polymer as a minor component in an amphiphilic, precipitation-inhibiting polymer of a ternary ASD exhibited optimal drug release. General findings from GF regarding HyNASD formation and impact of SDS are applicable to ITZ as well. Overall, this thesis has generated fundamental knowledge about the impact of SDS and binary polymers on improved in vitro release of BCS Class II drugs.

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