(686c) Primary Nucleation Under High Shear Conditions

The influence of external energy on the kinetics of primary nucleation has been investigated under high shear conditions. It is shown in literature, that shear-induced molecular alignment and in particular agitation-enhanced cluster aggregation are mechanisms that appear to deserve further attention [1]. To study this phenomenon further, the induction time has been measured at different supersaturation, and levels of energy input, at various scales using magnetic stir bar and rotor-stator based IKA wet mills.  Since there is a distribution of induction time possible, a statistical view is proposed for the value of induction time at a given condition [2]. There is an overall tendency in the experiments that the primary nucleation is promoted by increased input of shear imparted due to mixing. In small vials agitated by magnetic stir bars and in a larger scale reactor with high shear wet mill, the induction time was found to decrease with increasing wet mill tip speed to the power 0.66, the induction time is inversely related to the shear rate. By fitting the parameters of the classical nucleation theory to experimental data, it is shown that the results can be explained as an influence on the pre-exponential factor. Interfacial tension is estimated between API and solvent. An empirical equation is proposed to quantify the energy input from wet milling, and to predict the induction time.

References:

1. Liu, J.; Rasmuson, A.C. Cryst. Growth Des., 2013, 13 (10), pp 4385–4394
2. Kulkarni, K.A.; Kadam, S.S.; Meekes, H.; Stankiewicz, A.I.; ter Horst, J.H. Cryst. Growth Des., 2013, 13 (6), pp 2435–2440

AbbVie contributed to the design, research, and interpretation of data, writing, reviewing, and approving the publication.  Huayu Li, Moiz Diwan and Fredrik Nordstrom are AbbVie employees at the time that they worked on this project.