(527b) Preparation of Calcium Stearate Pellets by Extrusion/Spheronization: Effect of Drying Technique

Pharmaceutical pellets intended for oral dosing are frequently prepared via the wet extrusion/spheronization technique. The last “active” step of this process is drying. Although the drying method and/or the drying conditions applied are considered to highly influence the final pellet characteristics, investigations in this field are rare. Some studies are reported, mostly evaluating the moisture removal from pellets containing microcrystalline cellulose (MCC) [e.g.: 1].

The current study focuses on the drying behavior of calcium stearate (CS) pellets containing ibuprofen as model drug. These matrixpellets were shown to be spherical in shape and mechanically stable before [2]. After spheronization three different drying methods were applied; i) desiccation (D) over silica gel at ambient conditions, ii) drying in a fluid bed (FB) apparatus at an inlet air temperature of 40 °C and iii) lyophilization after freezing the pellets in liquid nitrogen (-196 °C). It was ensured via differential scanning calorimetry (DSC) that no interactions between the primary powders occurred during liquid removal. Furthermore, it was proved by X-ray measurements that neither CS nor ibuprofen underwent changes in their crystal stated during preparation.

The drying profile of the pellets dried via desiccation revealed a non-linear shape, where the rate of drying decreased throughout the process. This is mainly attributed to the shrinking of pellets by 13% during liquid removal causing changes in the surface area. CS was shown to swell in contact with the granulation liquid (i.e., 50% ethanol) and is likely to shrink again during drying. The shrinking of pellets during FB drying was less pronounced due to significantly lower drying times (i.e., by 8%). During lyophilization shrinking was largely suppressed since no liquid was involved resulting in minimal capillary flow. The differences in the shrinking behavior correlated with the pellet size distributions. The shape was not influenced by the drying conditions and the aspect ratio was below 1.2 for all batches.

Drug release studies demonstrated that pellets dried via desiccation liberated the lowest and pellets dried via lyophilization released the highest amount of ibuprofen. However, kinetics were best described by the Higuchi approach (i.e., diffusion based on Fick´s law) for all investigated batches. Differences in drug liberation behavior can occur due to variations in the spatial drug distribution throughout the pellets. It was shown before that for high drying rates (i.e., FB drying in the current study) dissolved components are likely to be transported towards the outer shell [3] where they recrystallize. Therefore, the ibuprofen distribution along the pellet cross sections was investigated using Raman mapping. However, ibuprofen was rather homogeneously distributed throughout all pellets despite the different ways of liquid removal. Although ibuprofen is highly soluble in the granulation fluid (i.e., 48 g/l), only small amounts of drug were expected to be dissolved during pellet preparation. Moreover, it is known from literature that ibuprofen causes phase separation of 50% ethanol at 40 °C [4] (i.e., the applied FB drying temperature). Subsequently, the dissolved ibuprofen crystallized in the water phase due to its poor water solubility [5]. Thus, the active pharmaceutical ingredient was not transported towards the external surface. Another reason for the different dissolution rates may be differences in structure and/or morphology. The crushing strength decreased in the order D, FB and L where FB and L showed similar results. This can be explained by the minimal extent of shrinking during L resulting in different morphological characteristics. During FB drying pellets were exposed to mechanical load. Thereby, cracks were likely to be formed which in turn lead to pellet breakage at lower forces. Moreover, it was found from the He-pycnometer measurements that during FB drying closed pores were more pronounced to be formed. Consequently, the variations in drug release characteristics can be explained by drying induced changes in the pellet morphology.

[1] B. Song, S.L. Rough, D.I. Wilson, Int. J. Pharm. 332 (2007), 38-44.

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

[3] A. Lekhal, B.J. Glasser, J. G. Khinast, Chem. Eng. Sci. 59 (2004), 1063-1077.

[4] J. Manrique, F. Martinez, Lat. Am. J. Pharm. 26 (2007), 344-354.

[5] M. Jbilou, A. Ettabia, A.M. Guyot-Hermann, J.C. Guyot, Drug Dev. Ind. Pharm. 25 (1999), 297-305.