Pharmaceutical Forced Degradation (Stress Testing) Endpoints: A Scientific Rationale and Industry Perspective.

Forced degradation (i.e., stress testing) of small molecule drug substances and products is a critical part of the drug development process, providing insight into the intrinsic stability of a drug that is foundational to the development and validation of stability-indicating analytical methods.

Inhibition of N-Nitrosamine Formation in Drug Products: A Model Study.

Nitrosamines, in the absence of toxicological data, are regarded as potential mutagens and need to be controlled at nanogram levels in drug products. Recent high profile product withdrawals have increased regulatory scrutiny of nitrosamine formation assessments for marketed products and for new drug applications. Formation of nitrosamine in drug product is possible when nitrite and vulnerable amines are present.

Assessing the Relevance of Solution Phase Stress Testing of Solid Dosage Form Drug Products: A Cross-Industry Benchmarking Study.

Stress testing (also known as forced degradation) of pharmaceutical products has long been recognized as a critical part of the drug development process, providing foundational information related to intrinsic stability characteristics and to the development of stability-indicating analytical methods. A benchmarking study was undertaken by nine pharmaceutical companies and the Brazilian Health Regulatory Agency (Agência Nacional de Vigilância Sanitária, or ANVISA) with a goal of understanding the utility of various stress testing conditions for producing pharmaceutically-relevant chemical degradation of drugs. Special consideration was given to determining whether solution phase stress testing of solid drug products produced degradation products that were both unique when compared to other stress conditions and relevant to the formal drug product stability data.

Enrichment of Relevant Oxidative Degradation Products in Pharmaceuticals With Targeted Chemoselective Oxidation.

The ability to produce and isolate relatively pure amounts of relevant degradation products is key to several aspects of drug product development: (a) aid in the unambiguous structural identification of such degradation products, fulfilling regulatory requirements to develop safe formulations (International Conference on Harmonization Q3B and M7); (b) pursue as appropriate safety evaluations with such material, such as chronic toxicology or Ames testing; (c) for a specified degradation product in a late-stage regulatory filing, use pure and well-characterized material as the analytical standard. Producing such materials is often a resource- and time-intensive activity, either relying on the isolation of slowly formed degradation products from stressed drug product or by re-purposing the drug substance synthetic route. This problem is exacerbated if the material of interest is an oxidative degradation product, because typical oxidative stressing (HO and radical initiators) tends to produce a myriad of irrelevant species beyond a certain stress threshold, greatly complicating attempts for isolating the relevant degradation product.

In-Use Photostability Practice and Regulatory Evaluation for Pharmaceutical Products in an Age of Light-Emitting Diode Light Sources.

This article describes how the increased use of energy-efficient solid-state light sources (e.g., light-emitting diode [LED]-based illumination) in hospitals, pharmacies, and at home can help alleviate concerns of photodegradation for pharmaceuticals.

Iron(III)-Mediated Oxidative Degradation on the Benzylic Carbon of Drug Molecules in the Absence of Initiating Peroxides.

Metal ions play an important role in oxidative drug degradation. One of the most ubiquitous metal ion impurities in excipients and buffers is Fe(III). In the field of oxidative drug degradation chemistry, the role of Fe(III) has been primarily discussed in terms of its effect in reaction with trace hydroperoxide impurities.

Surface-enhanced Raman scattering substrate based on a self-assembled monolayer for use in gene diagnostics.

The development of surface-enhanced Raman scattering (SERS)-active substrates for cancer gene detection is described. The detection method uses Raman active dye-labeled DNA gene probes, self-assembled monolayers, and nanostructured metallic substrates as SERS-active platforms. The mercaptohexane-labeled single-stranded DNA (SH-(CH(2))(6)-ssDNA)/6-mercapto-1-hexanol system formed on a silver surface is characterized by atomic force microscopy.

High-acidity determination in salt-containing acids by optical sensors. The scope of a dual-transducer approach and the Hammett acidity function.

A dual-transducer approach based on sol-gel optical sensors was recently reported to measure acid and salt concentrations, C(acid) and C(salt), in concentrated aqueous LiCl-HCl, CaCl2-HCl, and AlCl3-HCl solutions (C(acid) at 5-6 M; C(salt) < or = 2 M). The scope of this new approach has been studied in salt-containing HCl solutions with C(acid) at 2-9 M, and factors that influence sensor responses and accuracy have been investigated. A linear relationship between (deltaA/deltaC(salt))C(acid) and (dA/dC(acid))C(salt)=0, which is the basis of this dual-transducer approach, was found to lead to an empirical linear relationship between (deltaH0)C(acid) and (deltaC(salt))C(acid) (H0: Hammett acidity function of the indicator encapsulated in the sensor).

Microarray sampling-platform fabrication using bubble-jet technology for a biochip system.

The fabrication of microarrays containing PCR-amplified genomic DNA extracts from mice tumors on a Zetaprobe membrane using a modified thermal ink-jet printer is described. A simple and cost-effective procedure for the fabrication of microarrays containing biological samples using a modified bubble-jet printing system is presented. Because of their mass-produced design, ink-jet printers are a much cheaper alternative to conventional spotting techniques.

Optical sensors and the salt effect: a dual-transducer approach to acidity determination in a salt-containing concentrated strong acid.

A dual-transducer approach has been developed to decompose the optical signals of acid sensors in salt-containing concentrated acid solutions and to give acid and salt concentrations in concentrated LiCl-HCl, CaCl2-HCl, and AICl3-HCl solutions, respectively. The optical acid sensors in this approach are films of porous sol-gel SiO2 or SiO2-Nafion composite doped with low-pKa indicators. A novel linear relationship (dA/dCsalt)cCacid = beta x (dA0/dCacid)Csalt = 0 (A = absorbance of the sensor in a salt-containing HCl solution; A0 = absorbance of the sensor in a salt-free acid solution) was found, and the current approach is based on a set of nonlinear equations derived from this relationship.

Crown ether-doped sol-gel materials for strontium(II) separation.

Hybrid organic/inorganic sol-gel materials containing an encapsulated crown ether ligand were found to selectively remove 91.4 +/- 1.3% of Sr2+ from a solution containing excess of competing ions such as Ca2+.

Optical sensors for the determination of concentrated hydroxide.

An optical sensor system has been developed for the determination of concentrated strong bases ([OH-] = 1-10 M). The base sensors consist of SiO2/ZrO2-organic polymer composites and doped high-pKa indicators. Films were obtained by spin-casting these composite materials on glass substrates and were used as sensor elements for the spectrometric determination of hydroxide.

Doped Thin-Film Sensors via a Sol-Gel Process for High-Acidity Determination.

An optical sensor has been developed for high-acidity ([H(+)] = 1-11 M) measurements. The sensor is made of thin films of silica sol-gels doped with an acid indicator. Acid- and base-catalyzed methods to make the sol-gel films have been studied, and the properties of the sol-gel sensors prepared by these methods are discussed.