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Understanding the effect of API changes in pharmaceutical processing
There is, of course, the natural curiosity of the scientist to understand what they are working with, and how the molecule’s journey influences its performance. The regulators who control medicines for the benefit of the patients who take them also require an understanding of what is happening to the drug molecules and particles. These two interests combine in Quality by Design (QbD) initiatives, where scientists and regulators come together to provide a thorough understanding of the manufacturing process of a dosage form, to ensure that it is effective and fit for purpose.
Over the past few years there have been significant scientific advances in understanding how a molecule joins, and is incorporated into, the crystal that is its home until it reaches the gastric intestinal (GI) tract. Despite the fact that the instant of nucleation remains a moment of magic or mystery, the growth of a crystal can be followed, understood and modelled and the process of isolating and drying formed crystals has been closely studied.
The milling process has opened itself to greater understanding in recent years, such that the mechanism and extent of crystal fracture can be followed, and the properties of the resultant particles predicted with greater accuracy. We can characterise the end material, with its single particles, agglomerates or aggregates by size, shape and surface area, and examine them in detail using microscopy techniques. At the end of the particles’ journey to the dosage form we can follow the disintegration of the dosage form and the dissolution of the particles in a range of model media. This data can be combined with other observations to develop models of how drugs will reach the bloodstream and eventually be eliminated.
The use of chemical imaging to investigate the distribution of single components with a formulated sample have previously been reported2. However, due to limitations in the optical resolution of such systems, the individual particle sizes cannot be directly measured; pixels often contain more than one of the constituents. Pixels are instead colour coded to indicate the relative concentration of each constituent, thus enabling identification of ‘domains’ (areas of high component concentration). The relationship between domain size and particle size can be affected by multiple factors such as homogeneity, aggregation and morphology.
The challenge of characterising the primary particle characteristics of single components within multi-component systems has recently been addressed through the application of image-based particle characterisation with integrated Raman capability. This approach enables the characterisation of particles in terms of both size and shape. Utilising the Raman probe, the components within a blended sample can be sub-classified in terms of their chemistry, thus enabling the actual particle size distribution of individual components to be determined rather than the domain size.
Examples of this approach have recently been reported; Gamble3 demonstrated the process-induced attrition of a formulated API. It was demonstrated that blending and cone milling process steps had little impact on the primary particle size of the API, whilst a powder feed system, associated to a roller compactor, was observed to significantly reduce particle size. Such attrition could impact the processability of the material, both positively and negatively. This work highlighted that the powder feeding step, a hitherto overlooked sub-process, has a significant impact on the API/blend properties, and therefore requires consideration when selecting sources of process variation.
In addition to size, changes to the particle shape were also investigated. The combination of the two datasets provides insight into the attrition mechanisms within the unit processes. For the milling process, minor shifts in both size and shape could suggest a surface abrasion mechanism where the elongated particles undergo ‘chipping’. For the powder feed system, however, more significant shifts in both size and shape were proposed to suggest a bulk fracture mechanism where the particles undergo more complete fracture.
The work not only demonstrates that the input API size was impacted by the process, but that by characterising the API particle characteristics one could understand the mechanism of the change. This improved understanding of the intermediate API/blend characteristics could be applied to subsequent processing steps, removing the requirement to rely on the input particle characterisation data.