Dissolution of weak acids under laminar flow and rotating disk hydrodynamic conditions: application of a comprehensive convection-diffusion-migration-reaction transport model.

A steady-state mass transfer model that incorporates convection, diffusion, ionic migration, and ionization reaction processes was extended to describe the dissolution of weak acids under laminar flow and a rotating disk hydrodynamics. The model accurately predicted the experimental dissolution rates of benzoic acid, 2-naphthoic acid, and naproxen in unbuffered and monoprotic buffers within the physiological pH range for both hydrodynamic systems. Simulations at various flow rates indicated a cube root dependency of dissolution rate on the flow rate for a given bulk pH value for the laminar hydrodynamic system, as proposed earlier by Shah and Nelson (1975. J Pharm Sci 64(9):1518-1520) for neutral compounds. The model has limitations in its ability to accurately predict the dissolution of weak acids under certain conditions that imposed steep concentration gradients, such as high pH values, and for polyprotic buffer systems that caused the numerical solution to be unstable, suggesting that alternative numerical techniques may be required to obtain a stable numerical solution at all conditions. The model presents many advantages, most notably the ability to successfully predict the complex process under physiological conditions without simplifying assumptions, and therefore accurately representing the system in a comprehensive manner.

Design, synthesis, and evaluation of orally active benzimidazoles and benzoxazoles as vascular endothelial growth factor-2 receptor tyrosine kinase inhibitors.

Inhibition of the VEGF signaling pathway has become a valuable approach in the treatment of cancers. Guided by X-ray crystallography and molecular modeling, a series of 2-aminobenzimidazoles and 2-aminobenzoxazoles were identified as potent inhibitors of VEGFR-2 (KDR) in both enzymatic and HUVEC cellular proliferation assays. In this report we describe the synthesis and structure-activity relationship of a series of 2-aminobenzimidazoles and benzoxazoles, culminating in the identification of benzoxazole 22 as a potent and selective VEGFR-2 inhibitor displaying a good pharmacokinetic profile. Compound 22 demonstrated efficacy in both the murine matrigel model for vascular permeability (79% inhibition observed at 100 mg/kg) and the rat corneal angiogenesis model (ED(50) = 16.3 mg/kg).

Preclinical formulations for discovery and toxicology: physicochemical challenges.

Formulations play a key role in assessing the biological properties of a molecule during drug discovery. Maximising exposure is the primary objective in early animal experimentation, so that the pharmacokinetics, pharmacodynamics and toxicological signals can be put into context with the biological response to specific targets. Consistency in the exposure is also a key aspect, and effective formulation and drug delivery strategies are important to achieve this. Diversity in the physiology between various animal species, routes of administration and limitations posed by specific pharmacological models make formulation development that much more challenging. Poor physicochemical properties of compounds in the early stages need to be kept under consideration while screening for formulation vehicles. This review captures the various challenges posed at different stages of drug discovery for formulation of a compound to dose in animals. Approaches to formulations for various routes of administration are discussed. Limitations posed by the goals for various animal studies such as early efficacy studies, pharmacokinetic studies and toxicology studies are identified and some strategies are proposed. Physicochemical characterisations that are needed to select formulation vehicles as well as to identify potential issues are suggested.