Gary A. Nichols

Characterisation of the influence of micronisation on the crystallinity and physical stability of revatropate hydrobromide

Micronised particles of revatropate hydrobromide were observed to agglomerate when stored in uncontrolled conditions. Dynamic vapour sorption (DVS), isothermal microcalorimetry, microscopy and particle size measurement by laser diffraction have been used to study micronised revatropate hydrobromide. The rate and extent of agglomeration were dependent on the energy of the micronisation process, the sampling point for bulk within the mill and the humidity during storage. The agglomeration was attributed to the recrystallisation of disordered regions on the particles of revatropate hydrobromide generated during micronisation. This recrystallisation was assessed qualitatively and quantitatively, compared against spray-dried amorphous material, using DVS and isothermal microcalorimetry, respectively. A correlation was established between the energy of micronisation and the level of disorder within the micronised powder. A comparison of the DVS profiles of freshly prepared and aged micronised revatropate hydrobromide suggests an increased physical stability for the aged material.

Applications of cathodoluminescence spectroscopy and imaging in the characterisation of pharmaceutical materials.

Cathodoluminescence (CL) analysis is a mature technique which utilises the light that is emitted from materials when they are bombarded with a beam of high energy electrons to produce spectra and spectral images of specimens. This technique is used routinely in many industries as a non-destructive way to investigate and characterise inorganic compounds, such as minerals, ceramics and semiconductors, as they are being examined in a scanning electron microscope, but is seldom used to study organic compounds. The discovery that many (up to about 80%) active pharmaceutical ingredients (APIs) and API-like compounds are cathodoluminescent has resulted in the development of CL analysis as a novel technique to rapidly visualise the solid state spatial distribution of APIs in drug products as they are being examined by scanning electron microscopy. Spectral images of API particles dispersed in drug products (a tablet, a multiparticulate bead, and a dry powder inhalation blend) were acquired to illustrate the practical application of CL imaging to support product development or to optimise manufacturing processes. This study has also revealed that CL spectroscopy can distinguish between crystalline and amorphous materials and is sensitive the differences between the solid forms of some organic compounds, such as salts and polymorphs. Up to 80% of commonly used excipients are non-cathodoluminescent and this has the advantage of enabling APIs in formulated products to be imaged without interference. As part of the investigation to explore the use of CL as a way to identify polymorphs and monitor phase transformations, it was discovered that by recrystallising fused carbamazepine, the metastable Form IV was unexpectedly produced.