Characterisation of Mechanical Properties of Pharmaceutical Crystals by Nanoindentation: Hardness, Young's Modulus and Fracture Toughness

Principal Investigator: Prof. M. Ghadiri
Co-Investigator(s): Mr P.A. Arteaga
Sponsor(s): EPSRC (GR/J 72233), Pfizer Ltd., Roche Products Ltd, SmithKline Beecham Ltd.
Status: Completed (1994 - 1997)

Abstract

In developing an understanding of the compaction and breakage behaviour of pharmaceutical particulate solids, the knowledge of mechanical properties of the particles is essential. In tabletting, the elastic and plastic characteristics of a material play important roles on the quality of resulting compacts. The strength of the tablet and its elastic and plastic behaviour depends on the properties of the individual particles. Hardness and yield stress of the particles are good measures of their plastic deformation stress. Furthermore, the fracture characteristics such as failure mode, fracture toughness and slip planes controlling fracture of crystals will influence whether the material can be formed into stable compacts. In grinding and milling, the hardness and fracture toughness of the particles are key parameters in determining the ease with which the particles will break down.

Previous work on the characterisation of the mechanical properties of pharmaceutical particulate solids has been commonly performed by measuring properties on compacts of different porosities and extrapolating the data to zero porosity or with instrumented compression equipment. Although the usefulness of these methods has been widely justified for some materials, their applicability is limited to materials which can be formed into beam specimens in a die or tablets in a compaction simulator, and to materials which do not work-harden. Furthermore, a major drawback of these methods is that they are likely to be unsuitable during the early stages of tablet formulation as only a small quantity of drug may be available. More recently, in an attempt to overcome these limitations, microindentation with a Vickers diamond indenter has been used to measure the mechanical properties of pharmaceutical crystals. However, this technique requires that the crystals have the size of a few millimetres. This generally means that the crystallisation conditions at which this larger crystal has to be grown will be different from those required by the process in which a particular drug will be produced.

The nanoindentation technique (also referred to as ultra-microindentation), on the other hand, has been developed to measure the material properties of small crystals by applying very small loads, making it particularly suitable for performing indentations on particles below 100 µm in size. Therefore, the shortcomings of the techniques outlined above are overcome by the use of this technique. This device produces a continuous recording of the load and displacement during a complete cycle of loading and unloading of an indenter (typically, a Berkovitch diamond) into the surface of a specimen and then deduces the hardness and Young's modulus from these data by the use of well-established methods. In our work, nanoindentation in paracetamol and a -lactose monohydrate crystals performed with a Berkovitch diamond has shown that well-developed cracks are produced at loads as low as 5 mN. Recent work on crystals of these materials in the sieve size range 300-600 µm has shown that the indentation fracture mechanics method can be used to determine the fracture toughness. Figure I shows a nanoindentation in a 500 µm crystal of lactose.

In our work the hardness, Young's modulus and fracture toughness measured with the nanoindentation technique is coupled with impact mechanics to analyse the extent of breakage.

Publications

Bentham, A.C., Arteaga, P.A., and Ghadiri, M. (1996), "Measurement of the Mechanical Properties and Fragmentation of Pharmaceutical Powders", IChemE Research Event 2, 1039-1041 Leeds, UK, 2-3 April.

Bentham, A.C., Arteaga, P.A. and Ghadiri, M. (1997), "Impact Breakage of Pharmaceutical Powders". First European Congress on Chemical Engineering, Florence, Italy, 4-7 May.

Fagan, P.G., Harding, V.D., Norman, G.T., Arteaga, P.A. and Ghadiri, M. (1996), "Comparative Study of the Mechanical Behaviour of Alpha-Lactose from Measurements on Compacted Beam Specimens, Controlled Powder Compression and Single Crystals". 5th World Congress of Chemical Engineering 5, 590-595 San Diego, USA, 14-18 July.