A novel QSAR model of Salmonella mutagenicity and its application in the safety assessment of drug impurities.

As indicated in ICH M7 draft guidance, in silico predictive tools including statistically-based QSARs and expert analysis may be used as a computational assessment for bacterial mutagenicity for the qualification of impurities in pharmaceuticals. To address this need, we developed and validated a QSAR model to predict Salmonella t. mutagenicity (Ames assay outcome) of pharmaceutical impurities using Prous Institute's Symmetry(SM), a new in silico solution for drug discovery and toxicity screening, and the Mold2 molecular descriptor package (FDA/NCTR). Data was sourced from public benchmark databases with known Ames assay mutagenicity outcomes for 7300 chemicals (57% mutagens). Of these data, 90% was used to train the model and the remaining 10% was set aside as a holdout set for validation. The model's applicability to drug impurities was tested using a FDA/CDER database of 951 structures, of which 94% were found within the model's applicability domain. The predictive performance of the model is acceptable for supporting regulatory decision-making with 84±1% sensitivity, 81±1% specificity, 83±1% concordance and 79±1% negative predictivity based on internal cross-validation, while the holdout dataset yielded 83% sensitivity, 77% specificity, 80% concordance and 78% negative predictivity. Given the importance of having confidence in negative predictions, an additional external validation of the model was also carried out, using marketed drugs known to be Ames-negative, and obtained 98% coverage and 81% specificity. Additionally, Ames mutagenicity data from FDA/CFSAN was used to create another data set of 1535 chemicals for external validation of the model, yielding 98% coverage, 73% sensitivity, 86% specificity, 81% concordance and 84% negative predictivity.

High-speed particle detection in a micro-Coulter counter with two-dimensional adjustable aperture.

This article presents the fabrication and characterisation of a high-speed detection micro-Coulter counter with two-dimensional (2D) adjustable aperture and differential impedance detection. The developed device has been fabricated from biocompatible and transparent materials (polymer and glass) and uses the principle of hydrodynamic focusing in two dimensions. The use of a conductive solution for the sample flux and non-conductive solutions for the focalising fluxes provides an adjustable sample flow where particles are aligned and the resistive response concentrated, consequently enhancing the sensitivity and versatility of the device. High-speed counting of 20 microm polystyrene particles and 5 microm yeast cells with a rate of up to 1,000 particles/s has been demonstrated. Two-dimensional focusing conditions have been used in devices with physical cross-sectional areas of 180 microm x 65 microm and 100 microm x 43 microm, respectively, in which particles resulted undetectable in the absence of focusing. The 2D-focusing conditions have provided, in addition, increased detection sensitivity by a factor of 1.6 as compared to 1D-focusing conditions.

Kinetics of droplet condensation through a double free-energy barrier.

Results are presented for the kinetics of nucleation of liquid droplets from a one-component vapor phase on a planar lyophobic substrate patterned with a large number of easily wettable (lyophilic) circular domains. If the wettability of these lyophilic domains is characterized by a contact angle smaller than pi2, for intermediate values of the supersaturation, the condensation of a droplet on a lyophilic domain occurs through a free-energy barrier with two maxima, that is, through a double barrier. A simple model is proposed for the kinetics of droplet condensation through a double barrier that combines Kramers's [Physica (Utrecht) 7, 284 (1940)] transition rate theory with known results of nucleation theory. In the framework of this model, the solution is derived for the steady-state limit of the nucleation process. The number of lyophilic domains available for droplet condensation reduces with time as domains are occupied by droplets. The problem of droplet condensation through a double barrier is solved taking into account the effect of the time-dependent depletion in the number of available lyophilic domains.