(637e) Calcium Stearate Matrix Pellets: Impact of Drying On the Pellet Microstructure and the Ibuprofen Distribution Profiles

Although drying is one of the standard unit operations during manufacturing of solid pharmaceuticals, its potential to modify the final drug and/or dosage form properties is often underrated. Pellets, prepared by wet extrusion/spheronization, contain a certain amount of liquid and need to be dried in a final step. The impact of the drying process may be two-fold: First, the drying process may modify the pellet microstructure by controlling the extent and mechanism of shrinkage. Second, the drying process may alter the active pharmaceutical ingredient´s (API´s) physicochemical properties. APIs that dissolve in the granulation liquid may be subjected to intra-granular (i.e., within a pellet) migration as a function of the drying rate. Once a saturated solution is formed, the API re-crystallizes and may accumulate at certain regions within the pellet and/or undergo changes in its crystal structure.

The current study describes the impact of the drying process on calcium stearate (CaSt) matrix pellets containing ibuprofen as model API. These pellets were previously shown to be spherical in shape and mechanically stable [1]. In a first step the impact of drying on the microstructure was investigated. Therefore, low ibuprofen loadings were used to minimize any effects of dissolved ibuprofen particles on the pellet shrinking behavior. After spheronization pellets were either dried by i) tray drying at 20 °C, ii) fluid-bed drying (FB) at an inlet air temperature of 20 or 50 °C and iii) lyophilization.

We previously showed that CaSt swells in the granulation fluid, i.e., 50% ethanol and is prone to shrinkage during drying [2]. As such, the drying technique determined the pellet porosity, the pore size distribution and the specific surface area [3]. Furthermore, the inlet-air temperature during FB drying modified the pore size distribution and the specific surface area, while keeping the porosity constant. For lower temperatures the specific surface was increased and consequently, the median pore diameter was decreased. FB drying at 50 °C favored the collapse of smaller pores, whereas at 20 °C smaller pores shrunk but still remained intact after drying. Pore collapse was possibly attributed to softening of the material. As soon as the pellets contained dry regions where the temperature exceeded 50 °C, material softening occurred due to formation of a eutectic, which was proven by differential scanning calorimetry (DSC). The ibuprofen in-vitro dissolution rate was a non-linear function of the specific surface area, as the CaSt matrix remained intact and ibuprofen dissolution was diffusion controlled.

In a second step we evaluated the impact of drying on the physicochemical properties of the API. Therefore, pellets were tray dried at 20 and 50 °C. Ibuprofen was applied as dry powder, which was mixed with CaSt and subsequently wetted with ethanol. In a different approach ibuprofen was dissolved in the granulation liquid to ensure that all ibuprofen particles were dissolved and thus, prone to API migration and re-crystallization upon drying. Raman spectroscopy revealed that the final ibuprofen distribution throughout the pellets was inhomogeneous independent on the preparation procedure. Ibuprofen accumulated in regions close to/at the pellet surface. When ibuprofen was applied as solution and drying was performed at 20 °C, the pellet´s interior was entirely depleted from ibuprofen due to a comparatively long constant rate period that promoted transport of dissolved ibuprofen particles towards the surface. When ibuprofen was applied as powder and/or dried at 50 °C, certain amounts of ibuprofen were still found in the pellets´ interior. First, this implies that ibuprofen was not completely dissolved during wetting when applied as powder. Second, increasing the drying temperature to 50 °C elevated the rate of evaporation. Consequently, the constant rate period was shortened and ibuprofen transport towards the surface lowered. In addition, DSC measurements and infrared (IR) spectroscopy highlighted changes in the ibuprofen crystal structure after drying at 50 °C.

Overall, our results indicate that both, the drying technique and the drying conditions may cause severe changes in the final pellet properties and play thus, a crucial role during manufacturing of solid pharmaceutical dosage forms.

[1] E. Roblegg, S. Ulbing, S. Zeissmann, A. Zimmer, Eur. J. Pharm. Biopharm. 75 (2010), 56-62.

[2] S. Schrank, A. Hodzic, A. Zimmer, B. Glasser, J. Khinast, E. Roblegg, AAPS PharmSciTech, 13 (2012), 686-698.

[3] S. Schrank, B. Kann, M. Windbergs, A. Zimmer, J. Khinast, E. Roblegg, submitted.