Biowaiver Applications in Support of a Polymorph During Late-Stage Clinical Development of Verubecestat-Current Challenges and Future Opportunities for Global Regulatory Alignment.

Dissolution experiments to support an active pharmaceutical ingredient (API) form change in Verubecestat immediate release tablets were performed following current regulatory guidance published by health authorities in Canada, Australia, Japan, the EU, and the USA. Verubecestat API meets the requirements of a Biopharmaceutics Classification System class 1 compound and tablets are very  rapidly dissolving in aqueous dissolution media. While the in vitro data were reviewed favorably by these agencies, the divergence in regulatory requirements led to unnecessary work and highlights several issues companies operating globally face to justify product changes that have very little impact on quality. The data presented in this manuscript provide a compelling case for adjustments to the current draft ICH M9 guidance which provides recommendations for biowaiver applications. Specifically, this manuscript contains recommendations with respect to API attributes, selection of dissolution media and apparatus, and methods to assess dissolution similarity if needed, which should be considered for inclusion in a science- and risk-based global guidance document to benefit patients, regulators, and the pharmaceutical industry.

Daptomycin: a comparison of two intravenous formulations.

Daptomycin is a cyclic lipopeptide antibacterial agent with potent bactericidal activity against a broad range of Gram-positive organisms. In 2003, daptomycin for injection received approval from the US Food and Drug Administration (FDA) for the treatment of patients with complicated skin and skin structure infections (cSSSIs); in 2006, it was approved for the treatment of patients with Staphylococcus aureus bacteremia, including those with right-sided infective endocarditis caused by methicillin-susceptible and methicillin-resistant isolates. In 2016, the FDA approved a new formulation of daptomycin for injection (daptomycin RF) for the same indications. The efficacy and safety of daptomycin for injection have been established in pivotal clinical trials, and the findings of nonclinical studies indicate that both formulations of daptomycin for injection are equivalent. Herein we refer to the new daptomycin formulation as daptomycin RF to distinguish it from the original formulation. Daptomycin RF provides clinicians and clinical pharmacists with a product that offers improved stability and more rapid, in-vial reconstitution with either sterile or bacteriostatic water for injection, while maintaining the same antibacterial coverage. Here we discuss the rationale for and the potential value of daptomycin RF, and briefly review the similarities and differences between the original formulation of daptomycin and daptomycin RF.

Probing the effect of drug loading and humidity on the mechanical properties of solid dispersions with nanoindentation: antiplasticization of a polymer by a drug molecule.

Amorphous solid dispersions of clotrimazole in the polymer Kollidon VA64 were prepared as films in concentrations from 0% to 100% in 10% by weight increments. Nanoindentation was performed on each film at 18% and 49% relative humidity to assess the effect of drug loading and humidity on the mechanical properties of the solid dispersions. Although the addition of clotrimazole to the polymer reduces the glass transition temperature of the system as measured by differential scanning calorimetry, the hardness, reduced elastic modulus, and storage modulus were found to increase to values greater than those of either pure component up to drug loadings of approximately 60% by weight. Further addition of clotrimazole to the system resulted in decreased hardness and moduli with increased drug load. Dynamic vapor sorption of the dispersions shows that the hygroscopicity of the system is reduced as clotrimazole is added to the polymer.

Separation and detection of peroxynitrite using microchip electrophoresis with amperometric detection.

Peroxynitrite (ONOO(-)) is a highly reactive species implicated in the pathology of several cardiovascular and neurodegenerative diseases. It is generated in vivo by the diffusion-limited reaction of nitric oxide (NO(*)) and superoxide anion ((*)O(2)(-)) and is known to be produced during periods of inflammation. Detection of ONOO(-) is made difficult by its short half-life under physiological conditions (approximately 1 s). Here we report a method for the separation and detection of ONOO(-) from other electroactive species utilizing a microchip electrophoresis device incorporating an amperometric detection scheme. Microchip electrophoresis permits shorter separation times (approximately 25 s for ONOO(-)) and higher temporal resolution than conventional capillary electrophoresis (several minutes). This faster analysis allows ONOO(-) to be detected before substantial degradation occurs, and the increased temporal resolution permits more accurate tracking of dynamic changes in chemical systems.

Dual contactless conductivity and amperometric detection on hybrid PDMS/glass electrophoresis microchips.

A new approach for the integration of dual contactless conductivity and amperometric detection with an electrophoresis microchip system is presented. The PDMS layer with the embedded channels was reversibly sealed to a thin glass substrate (400 microm), on top of which a palladium electrode had been previously fabricated enabling end-channel amperometric detection. The thin glass substrate served also as a physical wall between the separation channel and the sensing copper electrodes for contactless conductivity detection. The latter were not integrated in the microfluidic device, but fabricated on an independent plastic substrate allowing a simpler and more cost-effective fabrication of the chip. PDMS/glass chips with merely contactless conductivity detection were first characterized in terms of sensitivity, efficiency and reproducibility. The separation efficiency of this system was found to be similar or slightly superior to other systems reported in the literature. The simultaneous determination of ionic and electroactive species was illustrated by the separation of peroxynitrite degradation products, i.e. NO(3)(-) (non-electroactive) and NO(2)(-) (electroactive), using hybrid PDMS/glass chips with dual contactless conductivity and amperometric detection. While both ions were detected by contactless conductivity detection with good efficiency, NO(2)(-) was also simultaneously detected amperometrically with a significant enhancement in sensitivity compared to contactless conductivity detection.

Separation and detection of peroxynitrite and its metabolites by capillary electrophoresis with UV detection.

A method for the separation and direct detection of peroxynitrite (ONOO(-)) and two of its degradation products, nitrite (NO(2)(-)) and nitrate (NO(3)(-)), using capillary electrophoresis with ultraviolet detection is described. The separation parameters were optimized and included electrokinetic injection, a run buffer consisting of 25 mM K(2)HPO(4) 7.5 mM DTAB, pH 12, and a field strength of -323 V/cm. A diode array UV detector was employed in these studies as it allowed the determination of all three species simultaneously. Nitrate and nitrite provided the maximum response at 214 nm while peroxynitrite generated the best response at 302 nm. All three species could be detected at 214 nm, while simultaneous detection at 214 and 302 nm positively identified each peak.

Recent developments in electrochemical detection for microchip capillary electrophoresis.

Significant progress in the development of miniaturized microfluidic systems has occurred since their inception over a decade ago. This is primarily due to the numerous advantages of microchip analysis, including the ability to analyze minute samples, speed of analysis, reduced cost and waste, and portability. This review focuses on recent developments in integrating electrochemical (EC) detection with microchip capillary electrophoresis (CE). These detection modes include amperometry, conductimetry, and potentiometry. EC detection is ideal for use with microchip CE systems because it can be easily miniaturized with no diminution in analytical performance. Advances in microchip format, electrode material and design, decoupling of the detector from the separation field, and integration of sample preparation, separation, and detection on-chip are discussed. Microchip CEEC applications for enzyme/immunoassays, clinical and environmental assays, as well as the detection of neurotransmitters are also described.