(149a) Additives Used for Process Optimization - a Case Study On Ibuprofen

Quality (purity, bio-availability) and processability of crystals generated in a crystallization or precipitation process are of key importance in the pharmaceutical industry. While a high product quality is demanded by both the consumer and federal regulations, a good processability is in the interest of the pharmaceutical company itself, as it makes downstream processing easier and therefore saves costs. Both the quality and the processability largely depend on the crystal size distribution. Therefore, influencing the crystal size distribution to obtain a desirable product is a highly promising approach. To do so, polymeric additives are used in this work to alter nucleation and growth kinetics of the model substance Ibuprofen.

Polymeric additives have two distinct advantages in comparison to tailor-made additives that have been proposed earlier to alter crystallization kinetics[1,2]. First, unharmful and already approved polymers can be used as additives in the crystallization process, such that an expensive and time-consuming approval procedure is avoided. Second, due to the immense size difference between the solute and additive molecules, the additive molecule is unlikely to be incorporated into the crystal lattice of the solute molecule, therefore ensuring crystal purity[3,4].

In this work, metastable zone width measurements and desupersaturation experiments are presented for the solute/additive combination Ibuprofen/Pluronic F127. The experiments are carried out in a 50:50 (w/w) mixture of ethanol and water.The data is obtained with state of the art measurement tools, such as attenuated total reflectance Fourier transform infrared spectroscopy (ATR-FTIR) and focused beam reflectance method (FBRM) measurements. Spectra obtained from the ATR-FTIR measurements are used together with a calibration model and chemometric methods to measure the evolution of the Ibuprofen concentration in solution. FBRM is used to measure nucleation.

By fitting a population balance equation model to the experimental data, the nucleation and growth kinetics are estimated. Knowing the influence of different temperatures, supersaturations and concentrations of Pluronic F127, on the crystallization kinetics of Ibuprofen, the crystallization process can be designed to yield a desirable crystal size distribution.

[1] Weissbuch, I., Addadi, L., Lahav, M., Leiserowitz, L., 1991. Molecular Recognition at Crystal
Interfaces. Science, 253 (5020), 637–645.

[2] Weissbuch, I., Addadi, L., Lahav, M., Leiserowitz, L., 1995. Understanding and Control of
Nucleation, Growth, Habit, Dissolution and Structure OF 2-dimensional and 3-dimensional
Crystals using tailor-made Auxiliaries. Acta Crystallographica Section B-Structural Science,
51, 115–148.

[3] Simonelli, S. P.; Mehta, S. C.; Higuchi, W. I., 1970. Inhibition of Sulfathiazole Crystal
Growth by Polyvinylpyrrolidone. Journal of Pharmaceutical Sciences, 59 (5), 633-637.

[4] Vetter, T.; Mazzotti, M.; Brozio, J., 2011. Slowing the growth rate of Ibuprofen crystals using
the polymeric additive Pluronic F127. Crystal Growth & Design, submitted.