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The drug release rate of a rapidly dissolving immediate-release tablet formulation with a highly soluble drug is proposed to be controlled by the disintegration rate of the tablet. Disintegration and dissolution test methods used to evaluate the tablets were shown to discriminate manufacturing process differences and compositionally variant tablets. In addition, a correlation was established between disintegration and dissolution. In accordance with ICH Q6A, this work demonstrates that disintegration in lieu of dissolution is suitable as the drug product quality control method for evaluating this drug product.

The aim of accelerated predictive stability (APS) studies is to predict long-term stability behavior on the basis of short-term stability assessments that comprise multiple different accelerated conditions. The effects of temperature and humidity on the rate of degradation are modeled using a humidity-modified Arrhenius equation. APS methods require that an expression for the rate of degradation (k) be obtained for each stability condition; this chapter outlines various methods used to calculate “k” if the degradation profile is not linear. Finally, various methods for data processing and assessing the goodness of fit of the model are discussed.

In order to predict the shelf life of packaged products, it is necessary to know the humidity levels inside the packaging. This chapter provides a comprehensive description of the methods used to simulate the humidity inside packaging, and provides the library data on packaging permeability and the moisture sorption properties of excipients necessary to carry out the simulation. Case studies are presented to demonstrate the accuracy and reliability of the approach, and some of the numerous benefits and applications of performing these simulations are discussed.

A proposed generalized relationship for the impact of excipients on the solid-state chemical stability of drug products is presented and shown to be consistent across multiple degradation products with two example drugs. In this model, when the number of drug particles is comparable to the number of excipient particles, the impact of the excipient on the degradant formation rate is independent of drug concentration. In contrast, when the number of drug particles is in excess of the number of excipient particles, a power-law relation (linear correlation between the logarithm of the degradant formation rate and the logarithm of the reciprocal of the drug concentration) is proposed based on a "quasi-liquid" model where drug particles fill in interstices between excipients. As predicted by this model, the experimental power-law lines have slopes of about 2/3 independent of temperature (0.61 ± 0.13 for n = 30 counting multiple degradation products and a range of temperatures and relative humidities for two drug products).

The chemical reaction rate for solid-state product formation in a pharmaceutical case study was monitored by equilibration with either a 75%, 21.5%, 75% relative humidity (RH) cycle ("high-low-high", HLH) or a 21.5%, 75%, 21.5% RH cycle ("low-high-low", LHL). For the HLH cycle, it was found that the degradant formation rate was reversible; that is, the rate at the final 75% RH step was equivalent to the rate at the initial 75% RH step. For samples equilibrated with the LHL cycle, a significantly higher rate of product formation was seen when the low RH condition was re-established than for the initial sample that had never been exposed to high RH. The observed hysteresis in degradant formation rate as a function of RH is not explained by hysteresis in the bulk moisture sorption isotherm, which is minimal in the case studied. It is suggested that high RH exposure impacts the solid-solid interface by either changing the amount of solid-solution present, by altering the mechanical properties of the material such that there is a greater mobility even when moisture is removed, or by altering the interfacial material to have a greater amount of moisture present even when dried.

The use of synthetic cuffs to simplify and hasten microvascular anastomoses is offered as an alternative to conventional methods. In this study, a soft, non-irritating, silicone rubber cuff was used to construct end-to-end and end-to-side cuff-sutured anastomoses in rats. This technique was as rapid as other non-sutured anastomoses, required no assistant, and provoked no foreign-body reactions.