Bruno C. Hancock

Suppression of Intestinal Polyposis in ApcΔ716 Knockout Mice by Inhibition of Cyclooxygenase 2 (COX-2)

Two cyclooxygenase isozymes catalyze conversion of arachidonic acid to prostaglandin H2: constitutive COX-1 and inducible COX-2. To assess the role of COX-2 in colorectal tumorigenisis, we determined the effects of COX-2 gene (Ptgs2) knockouts and a novel COX-2 inhibitor on Apc delta716 knockout mice, a model of human familial adenomatous polyposis. A Ptgs2 null mutation reduced the number and size of the intestinal polyps dramatically. Furthermore, treating Apc delta716 mice with a novel COX-2 inhibitor reduced the polyp number more significantly than with sulindac, which inhibits both isoenzymes. These results provide direct genetic evidence that COX-2 plays a key role in tumorigenesis and indicate that COX-2-selective inhibitors can be a novel class of therapeutic agents for colorectal polyposis and cancer.

The use of solubility parameters in pharmaceutical dosage form design

The use and potential of solubility parameters for pharmaceutical dosage form design are reviewed in this paper. Specific reference is given to the development of the approach, its previous usage and likely future applications. The advantages, assumptions and limitations of this type of approach are also described.

Differential scanning calorimetry: applications in drug development.

Differential scanning calorimetry (DSC) is frequently the pharmaceutical thermal analysis technique of choice because of its ability to provide detailed information about both the physical and energetic properties of a substance. This review provides an up-to-date overview of the applications of DSC in the drug development process. It should serve as a broad introduction to those starting work in this area, and also as a valuable reference for those already practising in this field.

Interpretation of relaxation time constants for amorphous pharmaceutical systems

The molecular mobility of amorphous pharmaceutical materials is known to be a key factor in determining their stability, reactivity, and physicochemical properties. Usually such molecular mobility is quantified using relaxation time constants. Typically relaxation processes in amorphous systems are non-exponential and relaxation time constants are usually obtained from experimental data using a curve fitting procedure involving the empirical Kohlrausch-Williams-Watts (KWW) equation. In this article we explore the possible relationship between the KWW curve fitting parameters (tau(KWW), beta(KWW)) and common statistical measures of the average and the distribution (e.g., median, standard deviation) of the relaxation time values. This analysis is performed for several common statistical distributions (e.g., normal, lognormal, and Lorentzian), and the results are compared and analyzed in the context of pharmaceutical product stability predictions. The KWW function is able to describe relaxation processes stemming from several different statistical distribution functions. Under some circumstances the average relaxation time constant of the KWW equation (tau(KWW)) is significantly different from common statistical measures of the central value of a distribution (e.g., median). Simply knowing the relaxation time constants from the fit of the KWW equation is not sufficient to completely characterize and quantify the molecular mobility of amorphous pharmaceutical materials. An appreciation of the distribution of relaxation times and the resulting effects upon the KWW constants should be considered to be essential when working with amorphous pharmaceutical materials, especially when attempting to use relaxation time constants for predicting their physical or chemical stability.

Water vapour sorption by pharmaceutical sugars

Abstract Sugars are probably the most widely used pharmaceutical excipients in solid and liquid dosage forms, and they can interact strongly with water vapour in their environment due to their hydrophilic nature. Crystalline sugars typically exist in anhydrous and hydrated forms, and these forms primarily interact with water vapour by adsorption and deliquescence mechanisms. Amorphous sugars usually absorb water into their bulk structure, and may experience marked changes in their physicochemical properties as a consequence. This review describes the mechanisms and phenomenology of water vapour sorption by pharmaceutical sugars, and provides an overview of the interaction phenomena that need to be considered when developing sugar-containing pharmaceutical dosage forms.

Micro-scale measurement of the mechanical properties of compressed pharmaceutical powders. 1: The elasticity and fracture behavior of microcrystalline cellulose.

The feasibility of using very small compacts ( approximately 8.0 x 4.5 x 0.4 mm; approximately 20 mg) to determine the elasticity and fracture behavior of compressed pharmaceutical powders using the three-point beam-bending technique was evaluated. Compacts of microcrystalline cellulose with a range of porosities were tested using a thermomechanical analyzer and values for the Youngs modulus and critical stress intensity factor at zero porosity (E(0) and K(IC0)) were determined by extrapolation. The value of E(0) measured at ambient relative humidity on un-notched beams was found to be in close agreement with that reported for much larger samples, and the value of K(IC0) for the small notched compacts was at the lower limit of the accepted range of values for microcrystalline cellulose. The fracture toughness (R) and total energy of fracture (U) for the notched specimens were also determined and used to estimate the apparent surface energies for crack initiation (gamma(i)) and for total fracture (gamma(f)). To further probe the utility of the micro-scale mechanical testing techniques, the effects of humidity on the various mechanical properties of the small microcrystalline compacts were examined and it was found that E(0), K(IC0), R(0), gamma(i0) and gamma(f0) each decreased as the surrounding humidity (and water content of the samples) increased.

A Pragmatic Test of a Simple Calorimetric Method for Determining the Fragility of Some Amorphous Pharmaceutical Materials

AbstractPurpose. To evaluate a simple calorimetric method for estimating the fragility of amorphous pharmaceutical materials from the width of the glass transition region.nMethods. The glass transition temperature regions of eleven amorphous pharmaceutical materials were characterized at six different heating and cooling rates by differential scanning calorimetry (DSC).nResults. Activation energies for structural relaxation (which are directly related to glass fragility) were estimated from the scan rate dependence of the glass transition temperature, and correlations between the glass transition widths and the activation energies were examined. The expected correlations were observed, and the exact nature of the relationship varied according to the type of material under consideration.nConclusions. The proposed method of determining the fragility of amorphous materials from the results of simple DSC experiments has some utility, although calibration” of the method for each type of materials is necessary. Further work is required to establish the nature of the relationships for a broad range of amorphous pharmaceutical materials.

The Effect of Temperature on Water Vapor Sorption by Some Amorphous Pharmaceutical Sugars

To determine the effect of temperature on the water vapor sorption behavior of some amorphous pharmaceutical sugars, aqueous solutions of sucrose, lactose, trehalose, and raffinose were freeze-dried using a conventional laboratory lyophilizer. The amorphous sugars formed were stored for several months at 5, 30, and 50 degrees C and at a range of relative humidities (0-90% RH). After equilibration the extent of water vapor sorption was determined gravimetrically, and the presence of any crystalline material was determined. A significant amount of water was sorbed by each of the amorphous sugars even at moderate humidities. In every system studied, lowering the storage temperature at any given relative humidity caused an increased quantity of water to be sorbed. This indicated the predominance of an exothermic water vapor sorption process. Spontaneous crystallization of all the sugars occurred at elevated RHs, and the onset of crystallization did not necessarily coincide with attainment of the water content of the final crystalline forms(s) or the reduction of the sugars glass transition temperature to ambient conditions. Notably, the amorphous and crystalline forms of some sugars were able to coexist in a quasi-equilibrium state under certain temperature and humidity conditions.

Water vapor sorption by peptides, proteins and their formulations

The interactions of pharmaceutical peptides, proteins and their formulations with environmental water vapor are reviewed. Particular attention is paid to the importance of the physical structure and chemical diversity of peptides and proteins, and comparisons are made with the mechanisms of water vapor sorption by synthetic macromolecular systems. The influences of formulation processes and additives are also considered and suggestions made for future areas of research.

Processing and storage effects on water vapor sorption by some model pharmaceutical solid dosage formulations

Abstract Several excipients and their formulations were equilibrated at relative humidities and temperatures selected to simulate typical pharmaceutical storage and processing conditions. Three different water detection techniques—loss on drying, Karl Fischer coulometry and an automatic moisture balance, were used to determine the moisture content of these systems. The excipients all possessed very different water sorption tendencies, as did their formulations. Isothermal water sorption by the dry blends, granules and tablets of each formulation was identical, suggesting that the processes involved in tablet manufacturing did not affect the water sorption behavior. Accurate water content predictions for the formulations were possible by adding the contribution of water from each excipient. Such predictions may be helpful for defining upper and lower water content specifications and storage conditions for excipients and their formulations.