Suspension rheology counts
The flow behavior of pharmaceutical suspensions affects production as well as dosage and shelf life

The rheological behavior of pharmaceutical suspensions influences a wide range of process steps. These include the determination of precise dosage, for example in sprays; container filling and other production issues; and storage. During formulation development, questions such as the best methods of dosing and delivery optimization are addressed. After packaging, a stable suspension is required to ensure that ingredients do not separate during storage and transportation.

In addition to the actual medicinal components, which are often present only in milligram quantities, every drug formulation contains a number of additives that give the preparation its required form, such as tablets, solution, gel, or emulsion. Many pharmaceutical products are produced in the form of suspensions to be sold as bottles or sachets. The rheological properties of both liquid and semi-solid pharmaceutical products are important for the dosing format, the bottling process (pumps and dispensers) and the selection of suitable packaging. For example, a nasal spray needs to demonstrate a certain viscosity so that the active ingredient can be applied via an aerosol dispenser. Similarly, products such as eye drops and ear drops must ooze out of the bottle slowly under the effect of gravity.
Storage and transportability are also important issues for suspensions. It is undesirable for solid particles to settle out, and the aim is to keep solids suspended evenly throughout the liquid without the need to shake the bottle. To achieve this, polymer-based stabilizers are often added to suspensions. To determine stability, new drugs are subjected to extensive tests involving agitation and temperature changes.

How rheometry can help
Rheology can help development chemists make reliable predictions about the stability of a new formulation at an earlier stage in the drug development process. In the following example, rheological tests were carried out on two suspensions, one of which was stable and the other unstable. The measurements described [1] require an air-bearing rheometer such as the new Haake Mars rheometer platform
(Figure 1), with a coaxial cylinder measurement geometry (Z40 DIN) at 20 °C.
The Haake Mars features a modular design for quick and flexible adaptation to the requirements of various applications and tests, including temperature control units and measurement geometries. All rheological measurements can be performed in CR (controlled rate), CS (controlled stress) and CD (controlled deformation) modes, in rotation and in oscillation. A new normal force sensor allows
positive and negative normal forces up to 650 N. The design of the rheometer makes it easy to operate, and expansion space and optional adjustments to the base frame allow additional modules to be
connected easily. The design also allows applications such as the simultaneous measurement of optical and rheological properties.
The instrument is designed not only for ease of handling, but also for ease of measurement and evaluation. With user-friendly Haake RheoWin software, measurement and evaluation procedures can be created by drag-and-drop using pre-defined elements. Help tools are available to create suitable “jobs”, and the software can be extended with optional modules.
“21 CFR part 11” tools are available to fulfill stringent FDA requirements. IQ/OQ documentation is also available, and Thermo service engineers can perform IQ/OQ installations.
Practical comparisons
To get a first impression of the two
pharmaceutical products, a flow curve was measured in CR (controlled rate) mode. As neither product demonstrated thixotropy (dependency of the viscosity on the time exposed to certain shear conditions), the flow curve can be plotted as a curve of shear stress t against shear rate (Figure 2).
The fundamental difference between product A (the stable suspension), and product B (unstable), can be recognized by comparing the two flow curves. Product A demonstrates a higher yield stress than product B, and this can be seen at the start of the flow curve. The viscosity of product B is much lower over the whole shear rate range. To determine the yield stress, a CS (controlled stress) ramp is performed with the deformation g as a function of the shear stress t in a double-logarithmic plot (Figure 3). The yield stress taken to be the tangent crossover, as recommended by DIN Technical Report No. 143 (2005). The yield stress of product A is around 4.5 Pa, while that of product B is only 1.5 Pa.
It is also interesting to compare the
viscoelastic properties of both products. This was done by performing an oscillation stress sweep. With a constant oscillation frequency of 1 Hz, the amplitude was increased over three decades. Figure 4 compares the elastic (storage) modulus G’ with the phase shift angle d for both products. The range up to a certain critical amplitude, in which the values of G’ and d (as well as G* and h*) remain constant, is described as the linear viscoelastic region.
Higher stability is generally expected from products with a wide linear viscoelastic region. This can be seen in Figure 4, where the stable suspension A demonstrates higher critical amplitude. If we define the critical amplitude as the
value where d starts to increase, we get
2.5 Pa for product A and only 1 Pa for
product B. Additionally, product A demonstrates greater elasticity than product B, as shown by its smaller phase shift angle d for any given value of the shear stress t. The loss factor tan d is also found from this plot. The loss factor describes the relationship between the elastic and viscous components of the product. Below the critical amplitude, the storage modulus G’ is 9.7 Pa for product A, with a corresponding d value of 24.5°, and 3.6 Pa for product B, with a corresponding d value of 34.7°.
In conclusion, the use of a suitable rheometer such as the Haake Mars helps in the development of pharmaceutical suspensions that must remain stable during storage. Such an instrument can quickly and accurately measure the rheological parameters important in determining stability. To meet the stringent requirements of the FDA, Haake RheoWin measurement and evaluation software can be extended with “21 CFR part 11”-compliant tools.