Rheological analysis of the stability of pharmaceutical suspensions

Eva-Maria Kutschmann from Thermo Haake discusses use of rheology in determining the stability of drug suspensions

In addition to medicinal components, often present in only milligram amounts, a drug contains a number of additives, which give the preparation its required form. (eg. tablets, solution, gel, emulsion).

Many pharmaceutical compounds are produced in the form of a suspension. A well known example is antacids, which contain magnesium and aluminium hydroxide. Alongside these are sugar substitutes like Sorbitol and Mannitol as well as preserving agents (parabens). Suspensions are usually dispensed in bottles or sachets and are taken from a spoon.

The rheological properties of both liquid and semi-solid pharmaceutical products are important for the bottling process and for the selection of suitable packaging. A nasal spray, for example, needs to demonstrate a certain viscosity so that the active ingredient can be applied via a spray. Similarly, all products that are administered by drops (e.g. eye and ear preparations) must drop out of the bottle slowly under the effect of gravity.

With suspensions there is also the question of storage and transportability. The sinking of solid particles is not usually desirable.

extensive testing

Even without the bottle being shaken prior to use, the solid particles should be evenly distributed throughout the liquid and remain suspended, which is why stabilisers are added to a medicine in the form of polymers to give the product its required properties. During extensive tests, employing the shaking of the products as well as temperature changes, the newly developed medicines were divided into stable and unstable products.

Rheological research can help development chemists make reliable predictions about the stability of a new formulation at an earlier stage.

Rheological tests were carried out on two suspensions (figure 1). One of these suspensions is unstable (sample B) while the second demonstrates the required properties (sample A). The measurements were made using an air bearing rheometer and a cylinder geometry Z40 DIN at 20°C.

In order to gain a first impression of the products, a flow curve was performed in the CR mode. As neither product demonstrated thixotropy (i.e. the dependency of the liquid properties on shear rate and time spent under shear conditions), the flow curve can be produced as a simple, upward curve (in this example, 0 ; 700 s^-1 in three minutes, 200 data points).

The fundamental difference between product A (the stable suspension), and product B (unstable), can be seen from the flow curve. Product A demonstrates a higher yield point - this can be seen at the start of the flow curve.

The viscosity of product B is much lower at the same shear rate. In order to determine the yield point a controlled stress flow curve is constructed (figure 2). The yield point can be established by applying the deformation, γ, as a function of the controlled stress, τ, using a logarithmic axis calculation.

It is also very interesting to compare the viscoelastic properties of both products. This can be seen by performing an oscillation stress sweep (figure 3).

With a constant oscillation frequency of 1Hz the amplitude is increased and the resulting modulus G' (dark blue line), is compared with the phase displacement angle d (light blue) for both products. The area in which the value of G' and δ (as well as G*, η*) remain constant, is described as the linear visco-elastic region.

A higher stability is generally expected from products with a wide linear visco-elastic region. This can be seen in figure 3 where the stable suspension A demonstrates an higher critical amplitude.

stable suspensions

If the point of critical amplitude is defined as where the increase of d is shown, a reading of 2.5Pa for product A will be shown, for B only 1Pa. Additionally product A demonstrated greater elasticity. This can be seen from the smaller phase shift angle δ when compared with suspension B.

The loss factor, Tan δ, is also found here: it describes the relationship between the elastic and viscous components of the product.

The storage modulus G' that was measured for A is higher than that for B. Below the critical amplitude, the values of G' for sample A were 9.7 Pa, when d was at 24.5°. The corresponding values for product B were 3.6 Pa and 34.7°.

The use of an air bearing CS Rheometer with a cylinder geometry is beneficial to the development of a new storage-stable suspension.

With the minimum investment of time, various rheological parameters for stability can be reliably established and reproduced.