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"Green" does not always mean green: drug and drug delivery vehicle design strategies
Dissertation

"Green" does not always mean green: drug and drug delivery vehicle design strategies

Maher Hadaya
Doctor of Philosophy (Ph.D.), Drexel University
Sep 2026
DOI:
https://doi.org/10.17918/00011577
pdf
Hadaya_Maher_20267.05 MB
PDF Embargoed Access, Embargo ends: 30 Sep 2027

Abstract

Hydrophobic drug-loaded hydrogels are an important class of localized drug-delivery systems because they can retain therapeutic agents at a target site, support sustained release, and have the potential to enable patient-specific formulation of one or more drugs. However, the same properties that make hydrogels useful as therapeutic depots also create environmental engineering challenges: for example, gels that sustain the release of hydrophobes in the body may also sustain the release of hydrophobes in bodies of water (such as release through surfactant/ micellar domains). Additionally, personalized small-batch preparation can increase pharmaceutical waste generation ( increasing both cost and environmental health risks), and crosslinking steps can add chemical and processing burden. This dissertation investigated whether drug candidate design, hydrogel fabrication, crosslinking selection, and disposal-relevant release testing could be integrated into an environmentally responsible design work flow that would simultaneously advance personalized medicine in hydrophobic drug delivery. The work addressed three linked research questions. First, greener-by-design principles were evaluated at both the drug and drug-delivery levels by synthesizing hydrophobic nitrate-ester nitric oxide donor candidates from renewable triterpenoid scaffolds and engineering a scalable one-pot micelle-in-hydrogel platform that co-delivers chitosan and hyaluronic acid, achieves tube-inversion stability, sustains rifampicin release for 72 hours, avoids intermediate drug stocks, avoids petroleum-derived poloxamer thermogels, and does not require chemical crosslinking for gel formation. Second, the uncrosslinked hydrogel was compared with chemically crosslinked, freeze-thaw-reinforced, and plasma-treated variants to determine whether crosslinking meaningfully improved sustained-release behavior under finite-volume non-sink conditions. Third, worst-case stagnant-water release was evaluated using a 4 x 2 x 2 experimental design varying pH, salinity, and crosslinking state to determine how receiving-water chemistry affects rifampicin accumulation from the hydrogel. Hydrophobic nitrate-ester nitric oxide donor candidates were synthesized from ursolic acid and asiatic acid through protecting-group-free two-step routes. The ursolic acid series produced the bromoalkyl ester in 80% isolated yield and the nitrate ester in 79% isolated yield, while the asiatic acid series produced the bromoalkyl ester in 80% isolated yield and the nitrate ester in 83% isolated yield. Nitrate ester formation was supported by ¹H NMR, including appearance of a diagnostic nitrate-adjacent methylene signal near [delta] ~4.47 ppm. Net atom economy was calculated as 66.8% for the ursolic acid series and 68.1% for the asiatic acid series. A one-pot micelle-in-hydrogel platform was then developed using Tween 80, rifampicin, chitosan, hyaluronic acid, and gelatin. The final formulation was produced in approximately two hours, achieved tube-inversion stability without mandatory covalent crosslinking, and incorporated the formulation components directly into the final gel without washing, dialysis, solvent exchange, or intermediate drug-stock preparation. Under finite-volume non-sink PBS conditions, rifampicin concentration increased from approximately 10.1 [mu]g/mL at 1 hour to 53.2 [mu]g/mL at 72 hours. A gradient-corrected Higuchi-like model fit the uncrosslinked release profile strongly, with R² = 0.997 and p = 1.227 x 10⁻⁷, and estimated a fitted plateau concentration of 60.57 [mu]g/mL, indicating that release capacity was not exhausted at 72 hours. Crosslinking studies showed that added reinforcement did not uniformly improve sustained-release behavior. In the glyoxal/freeze-thaw comparison, the glyoxal-crosslinked hydrogel had [C-infinity] = 58.3 [mu]g/mL and k = 0.404, compared with [C-infinity] = 60.6 [mu]g/mL and k = 0.250 for the uncrosslinked hydrogel and [C-infinity] = 67.8 [mu]g/mL and k = 0.227 for the freeze-thaw-treated hydrogel. Glyoxal reached 95.2% of fitted [C-infinity] by 72 hours, compared with 87.9% for the uncrosslinked gel and 84.9% for the freeze-thaw-treated gel, indicating faster approach to plateau rather than improved sustained release. Plasma treatment produced a dose-dependent decrease in percent of fitted plateau reached across shared time points, with pooled time-adjusted regression showing a slope of approximately -3.28 %[C-infinity]/min, R² = 0.950, and p < 0.0001. Stagnant water release testing showed that rifampicin accumulated under all 16 stagnant-water conditions in the pH x salinity x crosslinking-state design. Gradient-corrected model fits were significant across the full design, with R² values ranging from 0.9172 to 0.9994. In fresh water, fitted plateau concentration increased significantly with pH for uncrosslinked hydrogels, with slope = 1.6881 [mu]g/mL per pH unit, R² = 0.9980, and p = 0.0010, and for glyoxal-crosslinked hydrogels, with slope = 3.3271 [mu]g/mL per pH unit, R² = 0.9308, and p = 0.0352. In saline water, [C-infinity] did not significantly correlate with pH. ANOVA of percent of fitted plateau concentration showed that time and salinity were significant main effects, while pH and crosslinking state were not significant as isolated main effects; however, pH x salinity and crosslinking state x pH interactions were significant. In summary, these studies demonstrate how environmental engineering principles applied to pharmaceutical design not only can reduce waste generation and account for disposal risks, while also improving upon the design and process of developing pharmaceutical candidate agents and hydrogels. The dissertation integrates these findings in the final chapter into environmentally engineered design rules for pharmaceutical systems.

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