(481e) Modeling of Crystallization of Melt-Based Oral Dosages in a Drop-on-Demand Manufacturing System

Under the NSF supported Engineering Research Center for Structured Organic Particulate Systems (NSF ERC-SOPS), a dropwise additive manufacturing process for solid oral drug production has been developed as an alternative to conventional pharmaceutical manufacturing methods [1]. This mini manufacturing process for the production of pharmaceuticals utilizes drop on demand printing technology for automated and controlled deposition of melt-based drug formulations onto edible substrates [2]. A supervisory control system, including on-line monitoring, automation and closed-loop control, is implemented on the process, in order to produce individual dosage forms with the desired dosage amount and crystal morphology [3].

The temperature of the deposited drops is controlled indirectly by controlling the temperature of the substrate using a Peltier device placed beneath the substrate on the xy-stage. This allows control of the rate of solidification of melts and thus control of nucleation and crystallization phenomena. Precise control of the drop solidification process occurring on the substrate is very important since the crystallization temperature profile has a strong effect on product solid-state characteristics, influencing the dissolution properties and hence the bioavailability of the drug [3]. Recently, Içten et al. [3] reported that applying a fast cooling rate of 10 °C/min to the deposits containing naproxen results in faster dissolution profiles compared to a slow cooling rate of 1 °C/min, indicating that the crystallization temperature profiles can be used to enhance the solubility of dissolution limited drugs such as naproxen.

This paper presents a model based on the non-isothermal Avrami kinetic equation [4] for the solidification and crystallization processes of the drug deposits produced using the dropwise additive manufacturing process. Temperature dependent crystallization kinetics is monitored under different cooling profiles via an optical microscopy with a hot-stage. Using the proposed model, the temperature profiles leading to the desired solid-state parameters such as the mean feature size can be optimized, which allows achievement of the desired product quality, in this case, dissolution rate.

1. L. Hirshfield, A. Giridhar, L. S. Taylor, M. T. Harris, G. V. Reklaitis, “Dropwise Additive Manufacturing of Pharmaceutical Products for Solvent-based Dosage Forms,” Journal of Pharmaceutical Sciences, vol. 103, issue 2, pages 496-506, 2014.
2. E. Içten, A. Giridhar, L. Taylor, Z.K. Nagy, G.V. Reklaitis, 2014, Dropwise Additive Manufacturing of Pharmaceutical Products for Melt-based Dosage Forms, Journal of Pharmaceutical Sciences, DOI 10.1002/jps.24367.
3. E. Içten, Z. K. Nagy, G.V. Reklaitis, 2014, Supervisory Control of a Drop on Demand Mini-manufacturing System for Pharmaceuticals, Comp. Aided Process Eng., 33, 535-540.
4. M. Avrami, 1939, Kinetics of phase change I General Theory, Journal of Chemical Physics, 7, 12, 1103-1112.