Rational design of pharmaceutical formulations prepared by high shear wet granulation:Introduction evaluation of the Solid-Liquid-Interaction classification

摘要

High shear wet granulation is a process that involves intensive mixing of powders and fluid, whichresults in the formation of granules. The type and amount of fluid is critical in the preparation ofgranulations with acceptable processing attributes. Improper granulation causes problems in downstreamprocesses, which include caking, segregation and poor tableting performance [1]. It has beenobserved that different formulations prepared by the same process can require significantly differentamounts of fluid to yield product of similar granularity. The central hypothesis of the work describedhere is that differences in the sorption potential and solubility of solids are responsible for theirdifferent interactions with fluids. The objective was thus to define concepts for the rational selection offluid levels. A concept has been developed, which involves grouping materials according to theirsolubility and sorption potential and is referred to as the Solid-Liquid-Interaction (SLI) classification.The SLI-concept was probed by analysing the data generated for batches prepared as part of a screeningdesign for an in-house development program. The design variables were the levels of drug,hydroxypropyl methylcellulose (HPMC), croscarmellose sodium, microcrystalline cellulose andgranulating fluid. The granulator power data for each run was used as a surrogate for the extent ofgranulation and it was found that the combination of low formulation sorption potential and high fluidlevel correlated to high granulator power, and vice versa, with fluid level modulating the effect of theformulation sorption potential. A more detailed study was then conducted using placebo formulationscontaining HPMC, croscarmellose sodium, microcrystalline cellulose and lactose. These formulationswere granulated with water, dried in a vacuum oven and analysed for particle size. The focus was onthe (0,1) SLI-class materials croscarmellose sodium and microcrystalline cellulose, which arecharacterised by low solubility and high sorption potential and were studied over a wide range of fluidlevels. The results followed the trends expected from the SLI-concept and showed that the fluid leveladjustments required to compensate for differences in ingredient levels could be calculated for thestudied system. However, these fluid level adjustments were also found to be a function of the extent ofgranulation, e.g. for granulations with coarse fractions (>1000 μm) of 15 versus 44% an increase in thecroscarmellose sodium level from 3 to 5% required fluid level increases of 7.1 versus 2.5%. Thissuggests that fluid level adjustments are difficult to estimate for unstudied systems. Further work willbe required to understand this at a more fundamental level.The overall conclusion was that a good understanding of the solid-liquid-interactions has the potentialto minimise the need for experimentation and to maximise the probability of success of the process.This is of particular relevance in the early stages of development when formulations change frequently.