Mechanistic Computational Modeling of Implantable, Bioresorbable Drug Release Systems.

Implantable, bioresorbable drug delivery systems offer an alternative to current drug administration techniques; allowing for patient-tailored drug dosage, while also increasing patient compliance. Mechanistic mathematical modeling allows for the acceleration of the design of the release systems, and for prediction of physical anomalies that are not intuitive and may otherwise elude discovery. This study investigates short-term drug release as a function of water-mediated polymer phase inversion into a solid depot within hours to days, as well as long-term hydrolysis-mediated degradation and erosion of the implant over the next few weeks. Finite difference methods are used to model spatial and temporal changes in polymer phase inversion, solidification, and hydrolysis. Modeling reveals the impact of non-uniform drug distribution, production and transport of H+ ions, and localized polymer degradation on the diffusion of water, drug, and hydrolyzed polymer byproducts. Compared to experimental data, the computational model accurately predicts the drug release during the solidification of implants over days and drug release profiles over weeks from microspheres and implants. This work offers new insight into the impact of various parameters on drug release profiles, and is a new tool to accelerate the design process for release systems to meet a patient specific clinical need.

Crystal structures of two coordination isomers of copper(II) 4-sulfo-benzoic acid hexa-hydrate and two mixed silver/potassium 4-sulfo-benzoic acid salts.

A reaction of copper(II) carbonate and potassium 4-sulfo-benzoic acid in water acidified with hydro-chloric acid yielded two crystalline products. Tetra-aqua-bis-(4-carb-oxy-benzene-sulfonato)-copper(II) dihydrate, [Cu(O3SC6H4CO2H)2(H2O)4]·2H2O, (I), crystallizes in the triclinic space group P with the Cu2+ ions located on centers of inversion. Each copper ion is coordinated to four water mol-ecules in a square plane with two sulfonate O atoms in the apical positions of a Jahn-Teller-distorted octa-hedron. The carboxyl-ate group is protonated and not involved in coordination to the metal ions. The complexes pack so as to create a layered structure with alternating inorganic and organic domains. The packing is reinforced by several O-H⋯O hydrogen bonds involving coordinated and non-coordinated water mol-ecules, the carb-oxy-lic acid group and the sulfonate group. Hexa-aqua-copper(II) 4-carb-oxy-benzene-sulfonate, [Cu(H2O)6](O3SC6H4CO2H)2, (II), also crystallizes in the triclinic space group P with Jahn-Teller-distorted octa-hedral copper(II) aqua complexes on the centers of inversion. As in (I), the carboxyl-ate group on the anion is protonated and the structure consists of alternating layers of inorganic cations and organic anions linked by O-H⋯O hydrogen bonds. A reaction of silver nitrate and potassium 4-sulfo-benzoic acid in water also resulted in two distinct products that have been structurally characterized. An anhydrous silver potassium 4-carb-oxy-benzene-sulfonate salt, [Ag0.69K0.31](O3SC6H4CO2H), (III), crystallizes in the monoclinic space group C2/c. There are two independent metal sites, one fully occupied by silver ions and the other showing a 62% K+/38% Ag+ (fixed) ratio, refined in two slightly different positions. The coordination environments of the metal ions are composed primarily of sulfonate O atoms, with some participation by the non-protonated carboxyl-ate O atoms in the disordered site. As in the copper compounds, the cations and anions cleanly segregate into alternating layers. A hydrated mixed silver potassium 4-carb-oxy-benzene-sulfonate salt dihydrate, [Ag0.20K0.80](O3SC6H4CO2H)·2H2O, (IV), crystallizes in the monoclinic space group P21/c with the Ag+ and K+ ions sharing one unique metal site coordinated by two water mol-ecules and six sulfonate O atoms. The packing in (IV) follows the dominant motif of alternating inorganic and organic layers. The protonated carboxyl-ate groups do not inter-act with the cations directly, but do participate in hydrogen bonds with the coordinated water mol-ecules. (IV) is isostructural with pure potassium 4-sulfo-benzoic acid dihydrate.