Experimental and Computational Studies of Physicochemical Properties Influence NSAID-Cyclodextrin Complexation

Abstract

Abstract. The objective of this research was to investigate physicochemical properties of an active pharmaceutical ingredient (API) that influence cyclodextrin complexation through experimental and computational studies. Native β-cyclodextrin (B-CD) and two hydroxypropyl derivatives were first evaluated by conventional phase solubility experiments for their ability to complex four poorly watersoluble nonsteroidal anti-inflammatory drugs (NSAIDs). Differential scanning calorimetry was used to confirm complexation. Secondly, molecular modeling was used to estimate Log P and aqueous solubility (S o ) of the NSAIDs. Molecular dynamics simulations (MDS) were used to investigate the thermodynamics and geometry of drug-CD cavity docking. NSAID solubility increased linearly with increasing CD concentration for the two CD derivatives (displaying an A L profile), whereas increases in drug solubility were low and plateaued in the B-CD solutions (type B profile). The calculated Log P and S o of the NSAIDs were in good concordance with experimental values reported in the literature. Side chain substitutions on the B-CD moiety did not significantly influence complexation. Explicitly, complexation and the associated solubility increase were mainly dependent on the chemical structure of the NSAID. MDS indicated that each NSAID-CD complex had a distinct geometry. Moreover, complexing energy had a large, stabilizing, and fairly constant hydrophobic component for a given CD across the NSAIDs, while electrostatic and solvation interaction complex energies were quite variable but smaller in magnitude.

Optimizing ophthalmic delivery of a poorly water soluble drug from an aqueous in situ gelling system

“…These experiments revealed that the solubility of FBP increased linearly with increased amount of HβCD (fig 2). The solubility of FBP was 48.53 mM at maximum concentration of HβCD (137 mM or 20%) which was in good agreement with the reported solubility of FBP in phosphate buffer system (pH 7.4) by Felton et al, (2014) [6]. According to Higuchi & Connors [14], the graph was type A which indicated the formation of a soluble complex.…”

“…A number of other strategies have been employed to increase the solubility of poorly soluble drugs, such as, use of solubilizing systems such as liposomes and microemulsions to increase the solubility in the aqueous tear fluid, formulating as nanogels to enhance the residence time on the surface of the eye [4] and use of drug-cyclodextrin inclusion complexation to enhance the aqueous solubility, stability and bioavailability of ocular drugs [6,7]. Cyclodextrin (CD) complexation in particular, has been successfully employed in recent years and not only have shown to improve solubility but also can increase the rate of dissolution [5].…”

Non-ionic thiolated cyclodextrins — the next generation

“…Caco-2 cells were purchased from the European Collection of Authenticated Cell Cultures (Wiltshire, UK). Cells (passage number [25][26][27][28][29][30][31][32][33] were seeded at a density of 2.5 × 10 4 cells/well in a 24-well plate in a final volume of 500 µL of MEM with Earle's balanced salts supplemented with 10% FBS, 1% penicillin-streptomycin, and 2.0 mM L-glutamine at 37 °C in a 5% CO 2 environment. The medium was refreshed every other day.…”

“…Complexation mechanisms of drug-like chemical compounds with different CDs to establish a host-guest complex in solution result in the improvement of pharmacokinetic parameters and physicochemical properties of the guest component, such as higher stability, increased aqueous solubility, decreased plasma protein binding, and cellular toxicity. 32 In order to obtain data about the dissolution kinetic of unmodified and thiolated β-CD/miconazole inclusion complexes, dissolution studies were performed. Results showed a significantly different dissolution profile for all tested complexes being based on β-CD-SH 1200 exhibiting much higher dissolution velocity than the others.…”

Ionization States, Cellular Toxicity and Molecular Modeling Studies of Midazolam Complexed with Trimethyl-β-Cyclodextrin

“…Complexation mechanisms of drug-like chemical compounds with different cyclodextrins (CD) to establish a host-guest complex in solution, result in the improvement of pharmacokinetic parameters and physicochemical properties of the guest component, such as higher stability, increased aqueous solubility, decreased plasma protein binding, and cellular toxicity [1,2,3,4]. Molecular modelling and NMR studies have generated proposals on the mode of inclusion of the drug molecule by β-cyclodextrins [5,6] or their derivatives [7,8], including heptakis-(2,3,6-tri- O -methyl)-β-cyclodextrin or trimethyl-β-cyclodextrin, denoted as TRIMEB [9].…”