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. RESULTS: The mass ratio of spray solution to solid presented the highest risk of benzene enrichment. With slow spray-drying kinetics, benzene was reduced about 700-fold. Under standard secondary-drying conditions to remove residual solvents, residual benzene was further removed. Using diffusion models, the maximum benzene concentration was approximated for SDDs dried to the in-process control (IPC) limit of primary solvents. CONCLUSIONS: Two critical control points were established to eliminate any risk of residual benzene reaching patients: (1) upstream control of benzene in solvents (≤10 ppm) and (2) IPC of residual solvents in polymer-stabilized SDDs.

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(-). Our results show that there are major differences between the alkoxide and thiolate ions with respect to their thermodynamic and kinetic affinities to 5-H. They arise mainly from differences in the polarizability and solvation between the sulfur and the oxygen bases. Similarities and differences between the reactions of thiolate ions with 5-H and alpha-nitrostilbenes (4-H) are also discussed.

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. This rendered the kinetic analysis more complex but allowed the determination of pK(a) values and of proton-transfer rate constants at the alpha-carbon. In conjunction with previously reported data on the nucleophilic addition of alkoxide and thiolate ions to the same Meldrum's acid derivatives, rate constants for nucleophilic addition by the respective neutral alcohols and thiols could also be calculated. Various structure-reactivity relationships are discussed that help define transition-state structures. Comparisons with similar reactions of alkoxide ion adducts of beta-alkoxy-alpha-nitrostilbenes provide additional insights.