From Molecule to Material to Medicine: A Case Study on the Sticking Propensity of Ibuprofen

Purpose.This study aims to combine small scale experimental tools along with the emerging field of computational pharmaceutical solid-state chemistry to begin to understand the elusive mechanisms of active pharmaceutical ingredient punch sticking. Punch sticking is a challenge for drug product manufacture and there are many complex mechanisms thought to be involved [1-5]. As well as this, sticking is often not discovered until late in development or during full scale manufacture due to lack of predictive tools.

In order to address this technology gap, a small scale tablet press will be utilised to investigate the effect of ibuprofen particle habit on punch sticking. To further understand the mechanisms of punch sticking, computational tools will be utilised to explore the crystal chemistry of the ibuprofen molecule and how the materials properties can be linked to punch sticking.

Methods.The crystal chemistry, morphology and surface energy of ibuprofen were interrogated using Materials Studio and Habit98. In the attempt to generate ibuprofen particles with diverse morphology cooling crystallisation was performed using solvents with varying polarity. A suite of materials characterisation tools were used to examine the physico-chemical, surface and mechanical properties of these batches.

Results.Computationally the effect of solvent on ibuprofen crystal habit can be explained by the disruption of a directionally important centrosymmetric carboxylic acid moiety. Crystallisation from non-polar solvents, such as hexane, results in needle-like particle habit however polar solvents, such as ethanol, are able to hydrogen bond resulting in a more regular shape and higher presence of side faces.

Ibuprofen batches with four particle habits were produced and it was confirmed that as solvent polarity increases shape regularity increases. The surface energy of these particles was determined both experimentally and computationally and it was found that the most regular shaped particles exhibited the highest surface energy due to the greater exposure of the side faces.

The sticking propensity of these batches was measured and it was revealed that the batch with the highest surface energy exhibited the highest degree of punch sticking.

Conclusions.The crystal chemistry of ibuprofen has been explored and the effect of solvent on habit has been explained. Particles with a higher exposure of the side faces exhibit a higher surface energy and in turn this results in a higher sticking propensity.

Roberts, M., et al., Effect of punch tip geometry and embossment on the punch tip adherence of a model ibuprofen formulation. Journal of Pharmacy and Pharmacology, 2004. 56(7): p. 947-950.
Danjo, K., et al., Effect of Water Content on Sticking during Compression. CHEMICAL & PHARMACEUTICAL BULLETIN, 1997. 45(4): p. 706-709.
Roberts, M., et al., Effect of lubricant type and concentration on the punch tip adherence of model ibuprofen formulations. Journal of Pharmacy and Pharmacology, 2004. 56(3): p. 299-305.
Lam, K.K. and J.M. Newton, Influence of particle size on the adhesion behaviour of powders, after application of an initial press-on force. Powder Technology, 1992. 73(2): p. 117-125.
Abdel-Hamid, S. and G. Betz, A novel tool for the prediction of tablet sticking during high speed compaction. Pharmaceutical Development and Technology, 2012. 17(6): p. 747-754.