Role of regional absorption and gastrointestinal motility on variability in oral absorption of a model drug.

Variability in oral absorption in pre-clinical species makes human dose projection challenging. In this study, we investigated the mechanistic basis of variability in oral absorption of a model hydrophobic compound with pH-dependent solubility, BMS-955829, after oral dosing in rats, dogs, and cynomolgus monkeys. The contribution of regional absorption to pharmacokinetic variability was assessed in ported monkeys by direct intraduodenal and intraileal administration.

Development of a Control Strategy for Benzene Impurity in HPMCAS-Stabilized Spray-Dried Dispersion Drug Products Using a Science-Based and Risk-Based Approach.

Purpose: To develop a strategy to control benzene, an ICH Q3C Class 1 impurity that may be present in spray solvents at ppm concentration, in amorphous polymer-stabilized spray-dried dispersion (SDD) products.

Methods: Risk assessments included determining the probability for benzene concentration in primary spray solvents, the physical properties of volatiles, and the potential enrichment of benzene from solution to solid. Mechanistic understanding of benzene removal was gained through a benzene-spiked fate and tolerance (F&T) study simulating worst-case spray-drying conditions and application of diffusion models for secondary drying.

Acid-Catalyzed Breakdown of Alkoxide and Thiolate Ion Adducts of Benzylidene Meldrum's Acid, Methoxybenzylidene Meldrum's Acid and Thiomethoxybenzylidene Meldrum's Acid.

A kinetic study of the acid-catalyzed loss of alkoxide and thiolate ions from alkoxide and thiolate ion adducts, respectively, of benzylidene Meldrum's acid (1-H), methoxybenzylidene Meldrum's acid (1-OMe), and thiomethoxybenzylidene Meldrum's acid (1-SMe) is reported. The reactions appear to be subject to general acid catalysis, although the catalytic effect of buffers is weak and the bulk of the reported data refers to H(+)-catalysis. alpha-Carbon protonation and, in some cases, protonation of one of the carbonyl oxygens to form an enol compete with alkoxide or thiolate ion expulsion.

Kinetics of the Reactions of Benzylidene Meldrum's Acid with Thiolate and Alkoxide Ions in Aqueous Dimethyl Sulfoxide.

A kinetic study of the reaction of benzylidene Meldrum's acid, PhCH=C(COO)(2)C(CH(3))(2) (5-H), with a series of thiolate and alkoxide ions in 50% DMSO-50% water (v/v) at 20 degrees C is reported. The reactions with RX(-) (X = S or O) lead to adducts of the type PhCH(XR)C(COO)(2)C(CH(3))(2)(-) ((5-H,XR)(-)()), which can be viewed as a model for the intermediate of a nucleophilic vinylic substitution on substrates such as PhC(LG)=C(COO)(2)C(CH(3))(2) (LG = leaving group). Our measurements allowed a determination of rate and equilibrium constants for these processes with RS(-) = n-BuS(-), HOCH(2)CH(2)S(-), MeO(2)CCH(2)CH(2)S(-), and MeO(2)CCH(2)S(-) and RO(-) = OH(-), MeO(-) (only rate constant of breakdown of adduct), HC&tbd1;CCH(2)O(-), and CF(3)CH(2)O(-).

Unraveling structure-reactivity relationships in SNV reactions: kinetics of the reactions of methoxybenzylidenemalononitrile, 2-(methylthiobenzylidene)-1,3-indandione, 2-(benzylthiobenzylidene)-1,3-indandione, and methyl beta-methylthio-alpha-nitrocinnamate with OH- and thiolate ions in aqueous DMSO.

The kinetics of the title reactions were determined in 50% DMSO-50% water (v/v) at 20 degrees C; n-BuS-, HOCH2CH2S-, and MeO2CCH2S- were used as thiolate ions. The reactions with the thiolate ions gave rise to two separate kinetic processes. The first refers to rapid, reversible attachment of RS- to the substrate leading to a tetrahedral intermediate (k1RS), k(-1)RS, the second to the conversion of the intermediate to products (k2RS).