(431b) Understanding AUTO-Agglomeration of Dry ACTIVE Pharmaceutical Ingredients

Dry Active Pharmaceutical Ingredient (API) auto-agglomeration is a type of unwanted powder transformation that occurs without any additives. If uncontrolled, formation of hard, i.e. capable to withstand drug manufacturing process, API agglomerates may lead to an inadequate API distribution within the final formulation exhibiting the real risk to safety, efficacy and processability of drug products. Both, the fact that API auto-agglomeration may occur at, almost, any stage of drug manufacturing and/or handling processes as well as that a variety of general powder transformation mechanisms have been previously reported (for instance, mechanical, chemical, and triboelectric modes of bulk powder caking) make API auto-agglomeration phenomenon highly complex and challenging to anticipate and to prevent. However, despite the key role it has in the drug product performance and manufacturing, the number of studies addressing auto-agglomeration is currently limited and its underlying root-causes remain largely unknown. As a result, pharmaceutical industry relies mainly on the cost-ineffective trial and error approach when facing issues related to the unwanted API agglomeration.

The aim of this paper is to explore the correlation between particle properties, its processing/handling conditions and auto-agglomeration phenomenon as well as to establish a method/tool that would allow anticipation and, hence, better control of API auto-agglomeration leading to enhanced product quality, sustainability and cost-effectiveness. The experimental work was carried out to test the following hypothesis: API surface chemistry impacts its auto-agglomeration tendency. Ibuprofen recrystallised in different solvents was used as the main model API. Its auto-agglomeration tendency was tested using mechanical vibration that corresponds to drug handling conditions. Size distribution and particle shape of ibuprofen were analysed using SEM and G3 morphology, FTIR was used to confirm the identification of ibuprofen structure, and Instron to study the strength of the ibuprofen particles before and after the mechanical vibration.

Results and Discussion:

Four batches of ibuprofen of distinct morphologies were recrystallised in order to test the effect of crystal surface chemistry on its auto-agglomeration tendency. Collected FTIR data confirmed the ibuprofen structure in each case. SEM and morphology G3 analyses revealed that the shape regularity of recrystallised ibuprofen decreases with decreasing solvent polarity as follows: ibuprofen recrystalised from methanol (IbuMeth) > ibuprofen recrystalised from ethanol (IbuEth) > ibuprofen recrystalised from acetonitrile (IbuAce) > ibuprofen recrystalised from hexane (IbuHex), in line with previously reported data in the literature. Mechanical vibration experiments resulted in formation of visually detectable, relatively soft agglomerates that differ in size and shape across the batches. In addition, morphology G3 results indicated formation of agglomerates at microscale in the case of IbuEth and IbuHex being vibrated: d10, d50, and d90 of recrystallised IbuEth approximately doubled after mechanical vibration, whereas in the case of IbuHex this shift was less considerable. The strength of both IbuEth d90 as recrystallised and after mechanical vibration was tested using Instron revealing that the latter is approximately ¾ of the former.

Conclusion:

Detection of ibuprofen agglomerates upon mechanical vibration suggests there is a correlation between ibuprofen particle morphology, hence, particle surface chemistry and ibuprofen auto-agglomeration tendency. Further investigations of ibuprofen agglomerates as well as other model APIs agglomerates will include analysis of their strength (Instron, Nanoidenter), internal structure (X-ray micro computed tomography), and their surface chemistry (X-ray photoelectron spectroscopy).