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(-).