Selection of In Vivo Predictive Dissolution Media Using Drug Substance and Physiological Properties.

The rate and extent of drug dissolution in the gastrointestinal (GI) tract are highly dependent upon drug physicochemical properties and GI fluid properties. Biorelevant dissolution media (BDM), which aim to facilitate in vitro prediction of in vivo dissolution performance, have evolved with our understanding of GI physiology. However, BDM with a variety of properties and compositions are available, making the choice of dissolution medium challenging. In this tutorial, we describe a simple and quantitative methodology for selecting practical, yet physiologically relevant BDM representative of fasted humans for evaluating dissolution of immediate release formulations. Specifically, this methodology describes selection of pH, buffer species, and concentration and evaluates the importance of including bile salts and phospholipids in the BDM based upon drug substance log D, pKa, and intrinsic solubility. The methodology is based upon a mechanistic understanding of how three main factors affect dissolution, including (1) drug ionization at gastrointestinal pH, (2) alteration of surface pH by charged drug species, and (3) drug solubilization in mixed lipidic aggregates comprising bile salts and phospholipids. Assessment of this methodology through testing and comparison with literature reports showed that the recommendations correctly identified when a biorelevant buffer capacity or the addition of bile salts and phospholipids to the medium would appreciably change the drug dissolution profile. This methodology can enable informed decisions about when a time, complexity, and/or cost-saving buffer is expected to lead to physiologically meaningful in vitro dissolution testing, versus when a more complex buffer would be required.

An investigation into the ability of alendronate ion pairs to increase oral absorption.

The purpose of this study is to increase oral absorption of the highly charged drug alendronate using an ion pair strategy. Ion pairing is a formulation approach in drug delivery that is performed to improve the lipophilicity of ionized drugs. Cationic counter ions, such as arginine, phenazopyridine, hyoscine and pyridostigmine, were selected to enhance the lipophilicity and permeability of alendronate. Data obtained from quasi-equilibrium analysis were used to calculate the binding constant and intrinsic partition coefficient of ion pairs in an octanol/water system. The results of the partitioning study in an octanol/water system were confirmed using in vitro transport models with PAMPA and Caco-2 monolayer assays. Two counter ions, phenazopyridine and arginine, substantially increased the partition coefficient of alendronate by up to 1.15 and 0.73 units, respectively, in the octanol/water system. Binding constants of 117M-1 for alendronate-arginine and 90M-1 for alendronate-phenazopyridine ion pairs were obtained using quasi equilibrium analysis. Arginine and phenazopyridine enhanced the apparent permeability of alendronate by 14- and 26-fold in the PAMPA model and 6.5- and 4.4-fold across caco-2 cell monolayers, respectively. Based on this study, the lipophilicity and permeability of alendronate across lipophilic membranes was increased by suitable counter ions and could be used to establish a new formulation to increase the oral absorption of alendronate.

Development and Validation of an HPLC Method for Determination of Amifostine and/or Its Metabolite (WR-1065) In Human Plasma Using OPA Derivatization and UV Detection.

A rapid, sensitive and reproducible HPLC method was developed and validated for the analysis of amifostine (AMF) and/or its metabolite, WR-1065 in human plasma. The method involves the alkylation of free sulfydryl group with iodoacetic acid followed by derivatization of the drug and its metabolite with o-phthaldialdehyde (OPA) and UVdetection at 340 nm. The derivatized AMF and WR-1065 were eluted in less than 11 min, and in the case of the metabolite with no interferences from the endogenous plasma peaks. Cystein was used as the internal standard. Analysis was carried out on a Eurosphere Performance (RP-18e, 100 × 4.6 mm) analytical column. The mobile phase was a mixture of methanol and phosphate buffer 0.03 M pH = 2.7 at a ratio of 40: 60v/v, respectively, with a flow rate of 1.5 mLmin(-1). Limit of detection was 0.5 µgmL(-1). The method involved a simple extraction procedure for AMF and/or its metabolite and analytical recovery was 90 ± 0.9%.The calibration curve was linear over the concentration range of 1-200 µgmL(-1). The coefficients of variation for intra-day and inter-day assays were less than 10%.