Kinetic Barriers to Disproportionation of Salts of Weakly Basic Drugs.

Disproportionation is a major issue in formulations containing salts of weakly basic drugs. Despite considerable interest in risk assessment approaches for disproportionation, the prediction of salt-to-base conversion remains challenging. Recent studies have highlighted several confounding factors other than pHmax that appear to play an important role in salt disproportionation and have suggested that kinetic barriers need to be considered in addition to the thermodynamic driving force when assessing the risk of a salt to undergo conversion to parent free base. Herein, we describe the concurrent application of in situ Raman spectroscopy and pH monitoring to investigate the disproportionation kinetics of three model salts, pioglitazone hydrochloride, sorafenib tosylate, and atazanavir sulfate, in aqueous slurries. We found that even for favorable thermodynamic conditions (i.e., pH ≫ pHmax), disproportionation kinetics of the salts were very different despite each system having a similar pHmax. The importance of free base nucleation kinetics was highlighted by the observation that the disproportionation conversion time in the slurries showed the same trend as the free base nucleation induction time. Pioglitazone hydrochloride, with a free base induction time of <1 min, rapidly converted to the free base in slurry experiments. In contrast, atazanavir sulfate, where the free base induction time was much longer, took several hours to undergo disproportionation in the slurry for pH ≫ pHmax. Additionally, we altered an established thermodynamically based modeling framework to account for kinetic effects (representing the nucleation kinetic barrier) to estimate the solid-state stability of salt formulations. In conclusion, a solution-based thermodynamic model is mechanistically appropriate to predict salt disproportionation in a solid-state formulation, when kinetic barriers are also taken into consideration.

Investigation of a Weak Temperature-Rate Relationship in the Carbamoylation of a Barbituric Acid Pharmaceutical Intermediate.

The rate of reaction between N, N'-dicyclohexylbarbituric acid 1 and ethyl 2-isocyanatoacetate 2 is invariant with temperature. Positive orders in each reactant and dissociation of triethylammonium salts of 1 and product 3 at elevated temperature indicate that reaction occurs via a catalytic mechanism where changes to the positions of equilibria negate changes in the rate of the turnover-limiting step. A model for the consumption of 1 in a flow reactor accurately predicted the outcome of a laboratory-scale multivariate study.

Kinetic Model Development for Accelerated Stability Studies.

Accelerated stability coupled with modeling to predict the stability of compounds, blends, and products at long-term storage conditions provides significant benefits in science-based decision-making throughout drug substance and drug product development. The study can often be completed, including data analysis in the space of three working weeks, and the information gathered and learning made in this time period can rival years of traditional analysis. The speed of the studies allows an earlier assessment of risk to quality enabling appropriate risk mitigation strategies to be implemented in a timely manner. The scientific foundation is based upon Arrhenius kinetic equations that can be linear or nonlinear in time, and can be based upon water vapor pressure or liquid water activity (relative humidity). A variety of kinetic models are evaluated, and the best model is chosen based upon both Bayesian information criteria and an automated assessment of kinetic model parameters fitting within acceptable ranges. Confidence intervals are estimated based upon a bootstrapping approach. Moisture vapor transmission rate models are applied on top of the resulting kinetic models in order to simulate different packaging types and the use of desiccant. The kinetic models are integrated with the prediction of packaging humidity over time to create a long-term prediction of impurities and other phenomena. The resulting models have been shown to be useful for not only the prediction of drug product impurities in long-term storage but other physical phenomena as well such as hydrate development and solvate loss.

Computer vision for non-contact monitoring of catalyst degradation and product formation kinetics.

We report a computer vision strategy for the extraction and colorimetric analysis of catalyst degradation and product-formation kinetics from video footage. The degradation of palladium(ii) pre-catalyst systems to form 'Pd black' is investigated as a widely relevant case study for catalysis and materials chemistries. Beyond the study of catalysts in isolation, investigation of Pd-catalyzed Miyaura borylation reactions revealed informative correlations between colour parameters (most notably ΔE, a colour-agnostic measure of contrast change) and the concentration of product measured by off-line analysis (NMR and LC-MS). The breakdown of such correlations helped inform conditions under which reaction vessels were compromised by air ingress. These findings present opportunities to expand the toolbox of non-invasive analytical techniques, operationally cheaper and simpler to implement than common spectroscopic methods. The approach introduces the capability of analyzing the macroscopic 'bulk' for the study of reaction kinetics in complex mixtures, in complement to the more common study of microscopic and molecular specifics.

The even-handed approach: strategies for the deployment of racemic chiral catalysts.

Asymmetric catalysis is predominantly associated with the use of enantiomerically pure chiral ligands and catalysts. Although racemic chiral catalysts have been employed quite extensively in polymerization, their utility in mainstream organic synthesis and catalyst development has arguably been rather overlooked. This Minireview collates various themes for the strategic application of racemic ligands and catalysts, ranging from the estimation of selectivity and determination of enantiomeric excess, through to control of regio- and stereochemical outcomes, and mechanistic studies. What emerges is a clear picture that, in isolation or in concert with enantiopure catalysts, the "even-handed" approach has much to offer.

Identification and characterisation of a salt form of Danirixin with reduced pharmacokinetic variability in patient populations.

The natural variability of gastric pH or gastric acid reducing medications can result in lower and more variable clinical pharmacokinetics for basic compounds in patient populations. Progressing alternative salt forms with improved solubility and dissolution properties can minimise this concern. This manuscript outlines a nonclinical approach comprising multiple biopharmaceutical, in vitro and physiologically based pharmacokinetic model (PBPK) modelling studies to enable selection of an alternative salt form for danirixin (DNX, GSK1325756), a pharmaceutical agent being developed for chronic obstructive pulmonary disease (COPD). The hydrobromide salt of DNX was identified as having superior biopharmaceutical properties compared to the free base (FB) form in clinical development and the impact of switching to the hydrobromide salt (HBr) was predicted by integrating the nonclinical data in a PBPK model (using GastroPlus™) to enable simulation of clinical drug exposure with FB and HBr salts in the absence and presence of a gastric acid reducing comedication (omeprazole, a proton pump inhibitor (PPI)). Subsequent investigation of DNX pharmacokinetics in a Phase 1 clinical study comparing FB with HBr salt forms confirmed that DNX HBr had reduced the variability of drug exposure and that exposure was not affected by PPI co-administration with DNX HBr. This case study therefore adds to the surprisingly few examples of a more soluble salt of a weak base translating to an improvement in human pharmacokinetics and illustrates a clear clinical benefit of salt selection during drug development.

Testing Racemic Chiral Catalysts for Kinetic Resolution Potential.

An even-handed approach: by use of an enantiomerically enriched substrate and study of the changes in enantiomer ratio of substrate under pseudo zero-order conditions, racemic catalysts may be employed to determine whether the enantiomerically pure catalyst would be effective for kinetic resolution of the racemic substrate (see scheme; E=CO2 Me).

Mechanistic implications of pseudo zero order kinetics in kinetic resolutions.

This work provides simulations as well as experimental results from kinetic resolutions to demonstrate that a constant product enantioselectivity versus conversion profile in kinetic resolution is not a general consequence of pseudo zero order kinetics in [substrate] but occurs only under specific mechanistic constraints. For such a profile to be observed, the reaction must follow a mechanism exhibiting saturation kinetics for only one enantiomeric [substrate] on the only one of the two parallel pathways. For a single catalyst species, this will be limited to situations of near-perfect selectivity. Combining kinetic profiles with the enantioselectivity/conversion relationship in kinetic resolution can help to distinguish between proposed mechanisms and provide information about relative binding constants, the reactivity of intermediate species, and turnover by more than one active catalyst species.

A catalytic asymmetric bioorganic route to enantioenriched tetrahydro- and dihydropyranones.

A conceptually novel approach to hetero Diels-Alder adducts of carbonyl compounds is described using as the key steps an antibody-mediated kinetic resolution of hydroxyenones followed by a ring-closure process. Various beta-hydroxyenones proved to be very good substrates for antibodies 84G3- and 93F3-catalyzed retro-aldol reactions, allowing the preparation of highly enantiomerically enriched (up to 99% ee) precursors of pyranones. An attractive feature of this methodology is the possibility to convert these acyclic-enantioenriched beta-hydroxyenones into tetrahydropyranones by a conventional Michael-type addition procedure or into the corresponding dihydropyranones using an alternative palladium-catalyzed oxidative ring closure. For the palladium-mediated cyclization, a biphasic system has been implemented that allows the direct preparation of enantiopure dihydropyranones from the corresponding racemic aldol precursors using a sequential antibody-resolution/palladium-cyclization strategy, without isolation of the intermediate enantioenriched hydroxyenones. This bioorganic route is best applied to the preparation of hetero Diels-Alder adducts otherwise derived from less nucleophilic dienes and unactivated dienophiles.