Improving the stability of a suspension - Pharmaceutical Technology

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Improving the stability of a suspension
Feb 1, 2006
By: Bas Moorthaemer, Joris Sprakel
Pharmaceutical Technology Europe

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A suspension is a dispersion of a particulate solid in a liquid matrix. The solid phase is usually the drug substance, which is insoluble or very poorly soluble in the matrix. The liquid matrix is commonly an aqueous solution that contains several additives; for example, a surfactant for powder wetting, a thickening agent to control the matrix viscosity and salt to regulate the osmolarity. Sometimes preservatives are added to multiple-dose containers to prevent microbial growth.

The main problem dealt with in this article is preventing the aggregation of particles in a suspension — extensive aggregation can lead to 'caking'. This is the process in which almost all particles in the sediment become interconnected, making it impossible to resuspend. Two main causes can be pointed out (see sidebars "Particle interactions" and "Crystal bridging"):

  • energetic bonding
  • bonding through shared material.


Particle interactions
Many different aspects were investigated in our efforts to improve the physical stability of a suspension. One of the most commonly mentioned ways to influence the behaviour of a suspension is changing the salt concentration. This method is based on the DLVO theory1,2 (see sidebar Particle interactions). By decreasing the salt concentration it should be possible to increase the repulsive interactions between the particles, preventing them from aggregating. In our studies, we found, however, that salt had no influence whatsoever on the physical behaviour of the suspension, probably because the particles were outside the colloidal range (<1 μm) with a size of 10 μm.3 This indicates that factors such as particle size strongly influence the effect of this method. This is also the first indication of the complexity of this problem; many of the factors involved have a strong influence on each other. If salt concentration does provide a useful basis for improvement, additives such as sorbitol can be used to regulate the osmolarity of the suspension.

Next to the influence of salt, a variety of other possibilities were investigated; for example excipient concentrations; unit operations in the process; origin and synthesis of the drug substance; polymorphic behaviour of the drug substance crystals; and other particle characteristics. From these explorations it was decided to focus on the particle properties and the surfactant.

Particle size


Figure 1 The relationship between PSD and compactness of sediment packing in a suspension.
The main characteristic of suspension particles is their size. As powders almost never consist of particles of the same size (monodisperse), but of a large variety of different sizes (polydisperse), they are often characterized by a size distribution. The particle size distribution (PSD) is of great importance on the aggregation behaviour because of its influence on the packing of the particles in the sediment. Figure 1 illustrates that a system with a wide distribution (yellow) gives more compact packing than a system with a narrower distribution (red). Compact packing leads to more contact points between particles, in turn increasing the chances for aggregation.4 This means that the physical stability of a suspension can be improved by controlling the PSD.

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Source: Pharmaceutical Technology Europe, 2/1/2006
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