Raymond C Rowe

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.

Crystal chemistry and solvent effects in polymorphic systems: Sulfathiazole

Sulfathiazole, a compound that forms four known crystal structures, has been examined with a view to understanding its polymorphism. A graph set approach was used to classify the structural differences and similarities of the polymorphs, the results of which indicated packing motifs common to three of the four structures. By combining this analysis with experimental morphological data, it has been possible to examine the origins of the observed solvent dependence of polymorph appearance in this system. In particular, the possible link between the observed hydrogen-bond motifs of each form and the associated processes of nucleation and crystal growth from n-propanol, nitromethane, ethanol, water and ammonia solution, have been considered.

Young's modulus of powders used as pharmaceutical excipients

The Youngs modulus (E) of 15 representative tableting excipient powders has been measured for compressed rectangular beam specimens over a range of porosities using a four-point beam bending technique. Calculated values of Youngs modulus at zero porosity (E0) provide a means of categorising the mechanical characteristics in terms of elasticity and rigidity (stiffness) and brittleness on a quantitative scale. The order of increasing stiffness for the studied materials was starch < microcrystalline celluloses < sugars < inorganic fillers (calcium carbonate, calcium phosphate), with values of E0 ranging from 3.71 to 88.28 GPa. Differences in E0 for alternative sources of similar materials are discussed in terms of manufacturing pretreatment and crystallo-graphic structure.

Disappearing polymorphs and the role of reaction by-products: the case of sulphathiazole

Abstract A combined modelling and experimental strategy has been applied to the problem of reaction by-product influence on the appearance of sulphathaizole polymorphs from aqueous solution. From pure aqueous solution after 24 h the most stable phase, form IV was isolated. This work shows for the first time that a reaction by-product, ethamidosulphathiazole, from the final hydrolysis stage at concentrations as low as 1 mol.% stabilises the metastable modification, form I. In the presence of 1.0–0.5 mol.% forms II and III are stabilised. Only at concentration below 0.5 mol.% does the transformation proceed to form IV as in the pure solution. The role of the impurity was accounted for from an analysis of the respective hydrogen bond networks and crystal morphologies of each phase.

The relationship between the fracture properties, tensile strength and critical stress intensity factor of organic solids and their molecular structure

Abstract For a variety of pharmaceutical solids it has been shown that both tensile strength, σ T , and critical stress intensity factor, K IC , determined by beam bending are related to cohesive energy density by a simple factor. The equations allow the prediction of both mechanical properties from a knowledge of the chemical structure of the material.

Examples of successful crystal structure prediction: polymorphs of primidone and progesterone.

The field of crystal structure prediction and its potential value to the pharmaceutical industry is described. The process of structure prediction employed here is summarized and the results of its application to primidone and progesterone are reported. It is shown that the process successfully generates the known polymorphs of these molecules, starting from the molecular structure alone. Observations related to the application of the structure prediction process are reported.

FRACTURE MECHANICS OF MICROCRYSTALLINE CELLULOSE POWDERS

A fracture mechanics approach has been successfully applied to determine KIC, the critical stress intensity factor and a measure of brittleness of materials, using notched beam specimens in four point flexure testing. Seven chemically equivalent microcrystalline cellulose samples have been examined and, based on determined values of KIC, all samples have been classified as semi-brittle with respect to crack propogation and fracture mechanics. The generally minor differences found in KIC values between different suppliers and grades are attributed to alternative processing conditions and variations in solid-state properties.

The Poisson's ratio of microcrystalline cellulose

The Poissons ratio of microcrystalline cellulose has been found to be 0.30 (as determined by independent measurements of shear and Youngs modulus). This value compares well to aspirin (v = 0.29 - calculated from single-crystal elastic constants), a material with similar yield and elastic properties to microcrystalline cellulose.

An assessment of substrate-binder interactions in model wet masses. 1: Mixer torque rheometry

Abstract Recent work has shown the importance of physical interactions between materials during size enlargement processes (e.g., wet granulation). In this study several model substrates and binder solutions were selected, their particulate, solution and energetic properties determined and the potential physical interactions of the solid and liquid phases assessed. Considerable differences were noted in the wetting, spreading and adhesion tendencies of the various substrate-binder combinations. The rheological properties of the wet massed solid-liquid systems were then measured using an instrumented mixer torque rheometer. The results confirmed that solid-liquid physical interactions (especially spreading) are important in determining wet massing behaviour. The most important influences appeared to be on the stability of the wet masses at elevated liquid levels and theories were developed to explain this observation in terms of the accepted models of wet granule structure.

The mechanical properties of two forms of primidone predicted from their crystal structures

Molecular modelling is used to predict the mechanical properties of aspirin and forms A and B of primidone. It is shown that the predictive method gives values which are in good agreement with the experimental ones. The method is therefore of great potential value to those interested in the compaction characteristics of pharmaceutically active compounds, as it obviates the need for measurements which can be difficult to make.