Bruce C. MacDonald

Correction of fluorescence inner filter effects and the partitioning of pyrene to dissolved organic carbon

Abstract The ability of dissolved organic carbon (DOC) to bind pyrene can be monitored by fluorescence quenching. Inner filter effects, caused by DOC, complicate the interpretation of the partitioning coefficient of DOC to pyrene. Since DOC absorbs and fluoresces at the excitation wavelength of pyrene, by fitting the DOC self-quenching curve to a simple empirical model that quantifies the absorbance in the spectrofluorimeters interrogation zone, one can obtain the necessary information to correct for the inner filter effects. This model can be combined with the Stern-Volmer equation to give a single equation that models the total fluorescence of a quenching experiment, and from which a value for the linear Stern-Volmer quenching constant, corrected for the inner filter effects, may be obtained. The mechanisms of inner filter effects are discussed and then quantified, leading to a mathematical model of a self-quenching curve. This is then reduced to the empirical model of DOC self-quenching.

Package selection for moisture protection for solid, oral drug products

This review describes how best to select the appropriate packaging options for solid, oral drug products based on both chemical and physical stability, with respect to moisture protection. This process combines an accounting for the initial moisture content of dosage form components, moisture transfer into (out of) packaging based on a moisture vapor transfer rate (MVTR), and equilibration between drug products and desiccants based on their moisture sorption isotherms to provide an estimate of the instantaneous relative humidity (RH) within the packaging. This time-based RH is calculationally combined with a moisture-sensitive Arrhenius equation (determined using the accelerated stability assessment program, ASAP) to predict the drug products chemical stability over time as a function of storage conditions and packaging options. While physical stability of dosage forms with respect to moisture has been less well documented, a process is recommended based on the threshold RH at which changes (e.g., dosage form dissolution, tablet hardness, drug form) become problematic. The overall process described allows packaging to be determined for a drug product scientifically, with the effect of any changes to storage conditions or packaging to be explicitly accounted for.

Improved Protocol and Data Analysis for Accelerated Shelf-Life Estimation of Solid Dosage Forms

PurposeTo propose and test a new accelerated aging protocol for solid-state, small molecule pharmaceuticals which provides faster predictions for drug substance and drug product shelf-life.Materials and MethodsThe concept of an isoconversion paradigm, where times in different temperature and humidity-controlled stability chambers are set to provide a critical degradant level, is introduced for solid-state pharmaceuticals. Reliable estimates for temperature and relative humidity effects are handled using a humidity-corrected Arrhenius equation, where temperature and relative humidity are assumed to be orthogonal. Imprecision is incorporated into a Monte-Carlo simulation to propagate the variations inherent in the experiment. In early development phases, greater imprecision in predictions is tolerated to allow faster screening with reduced sampling. Early development data are then used to design appropriate test conditions for more reliable later stability estimations.ResultsExamples are reported showing that predicted shelf-life values for lower temperatures and different relative humidities are consistent with the measured shelf-life values at those conditions.ConclusionsThe new protocols and analyses provide accurate and precise shelf-life estimations in a reduced time from current state of the art.

Extrudable core system : Development of a single-layer osmotic controlled-release tablet

A new controlled-release, extrudable core system (ECS) tablet has been developed which osmotically delivers high doses of low solubility active pharmaceutical ingredients (APIs). The tablet has a single core formed in a modified oval shape with a semi-permeable coating. The core contains hydroxyethylcellulose, which serves to entrain the API particles as they are extruded out a hole in the coating at one end of the tablet, and a sugar, which provides the osmotic driving force for water imbibing. The dosage form has been successfully shown to control delivery of API over a range of delivery rates even with 50% of the tablet being API (up to about 500 mg).

Use of Activated Carbon in Packaging to Attenuate Formaldehyde-Induced and Formic Acid–Induced Degradation and Reduce Gelatin Cross-Linking in Solid Dosage Forms

Formaldehyde and formic acid are reactive impurities found in commonly used excipients and can be responsible for limiting drug product shelf-life. Described here is the use of activated carbon in drug product packaging to attenuate formaldehyde-induced and formic acid-induced drug degradation in tablets and cross-linking in hard gelatin capsules. Several pharmaceutical products with known or potential vulnerabilities to formaldehyde-induced or formic acid-induced degradation or gelatin cross-linking were subjected to accelerated stability challenges in the presence and absence of activated carbon. The effects of time and storage conditions were determined. For all of the products studied, activated carbon attenuated drug degradation or gelatin cross-linking. This novel use of activated carbon in pharmaceutical packaging may be useful for enhancing the chemical stability of drug products or the dissolution stability of gelatin-containing dosage forms and may allow for the 1) extension of a drug products shelf-life when the limiting attribute is a degradation product induced by a reactive impurity, 2) marketing of a drug product in hotter and more humid climatic zones than currently supported without the use of activated carbon, and 3) enhanced dissolution stability of products that are vulnerable to gelatin cross-linking.

Modeling of in-use stability for tablets and powders in bottles

Abstract A model is presented for determining the time when an active pharmaceutical ingredient in tablets/powders will remain within its specification limits during an in-use period; that is, when a heat-induction sealed bottle is opened for fixed time periods and where tablets are removed at fixed time points. This model combines the Accelerated Stability Assessment Program to determine the impact on degradation rates of relative humidity (RH) with calculations of the RH as a function of time for the dosage forms under in-use conditions. These calculations, in a conservative approach, assume that the air inside bottles with broached heat-induction seals completely exchanges with the external environment during periods when the bottle remains open. The solid dosages are assumed to sorb water at estimable rates during these openings. When bottles are capped, the moisture vapor transmission rate can be estimated to determine the changing RH inside the bottles between opening events. The impact of silica gel desiccants can also be included in the modeling.

The Humidity Exposure of Packaged Products

Abstract 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.