(240b) Rational Design of Pharmaceutical Formulations Prepared by High Shear Wet Granulation: Introduction & Evaluation of the Solid-Liquid-Interaction Classification

High shear wet granulation is a process that involves intensive mixing of powders and fluid, which results in the formation of granules. The type and amount of fluid is critical in the preparation of granulations with acceptable processing attributes. Improper granulation causes problems in down-stream processes, which include caking, segregation and poor tableting performance (Iveson et al 2001). It has been observed that different formulations prepared by the same process can require significantly different amounts of fluid to yield product of similar granularity. The central hypothesis of the work described in this abstract is that differences in the sorption potential and solubility of solids are responsible for their different interactions with fluids. The objective was thus to define concepts for the rational selection of fluid levels. One developed concept involved grouping materials according to their solubility and sorption potential and is referred to as Solid-Liquid-Interaction (SLI) classification. The SLI-concept was probed by analysing the data generated for batches prepared as part of a screening design for an internal development program. The design variables were the levels of API, hydroxypropyl methylcellulose (HPMC), croscarmellose sodium (CC Na), microcrystalline cellulose (MCC) and granulating fluid. The Diosna P6 granulator power data for each run was used as a surrogate for the extent of granulation. As shown in Table 1, a low formulation sorption potential (determined by low MCC and CC Na levels) together with a high fluid level correlated to high granulator power, and vice versa, with fluid level modulating the effect of the formulation sorption potential. A more detailed study was then conducted using placebo formulations containing HPMC, CC Na, MCC and lactose. These were granulated with water using a Bohle 1L granulator, oven dried and analysed for particle size using a sonic sifter. The emphasis was on the materials belonging to the (0,1) SLI-class of low solubility and high sorption potential (CC Na, MCC), which were studied over a wide range of fluid levels. The results followed the trends expected from the SLI-concept and showed that the fluid level adjustments required to compensate for differences in ingredient levels could be calculated for the studied system. However, these fluid level adjustments were also found to be a function of the fluid level of the reference formulation, e.g. increasing CC Na from 3 to 5% required fluid level increases of 7.5 versus 2.5% for fluid levels of 20 versus 35%, as used for the reference formulation (3% CC Na). This suggests that fluid level adjustments are difficult to quantify for unstudied systems. Further work will be required to understand this at a more fundamental level. The overall conclusion was that a good understanding of the solid-liquid-interactions has the potential to minimise the need for experimentation and maximise the probability of success of the process. This is of particular relevance in the early stages of development when formulations change frequently.

Table 1 Granulator power end-point for formulations with different sorption potentials granulated at different fluid levels (Note: MCC and CC Na belong to the (0,1) SLI-classification of low solubility and high sorption potential)

MCC / CC Na / Sorption potential / Fluid / Power

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Low / Low / Low / High / 118 W

High / High / High / High / 75 W

High / Low / Medium / Low / 75 W

Low / High / Medium-High / Low / 66 W

Iveson, S.M.; Litster, J.D.; Hapgood, K.; Ennis, B.J. (2001) Nucleation, growth and breakage phenomena in agitated wet granulation processes: a review. Powder Technol., 117, 3-39