Diastereoselective Synthesis of P-Stereogenic Secondary Phosphine Oxides (SPOs) Bearing a Chiral Substituent by Ring Opening of (+)-Limonene Oxide with Primary Phosphido Nucleophiles.

Kinetic separation of the commercially available cis/trans-(+)-limonene oxide mixture by ring opening with primary phosphido nucleophiles LiPHR (R = ferrocenyl, Ph, Cy, t-Bu, Mes* (Mes* = 2,4,6-(t-Bu)3C6H2)), followed by treatment with aqueous NH4Cl and H2O2, gave unreacted cis-(+)-limonene oxide and diastereoenriched mixtures of the secondary phosphine oxides (SPOs) PHR(trans-(+)-Lim-OH)(O), which could be separated by chromatography and/or recrystallization. This one-pot synthesis uses a cheap chiral material and commercially available primary phosphines to control the configuration of the new P-stereogenic SPOs, which are potentially useful as ligands for metal complexes in asymmetric catalysis.

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.