SubscribeRheology is a valuable technology for studying the storage stability of suspensions.
Abstract
Rheology is a valuable technology for studying the storage stability of suspensions. The pharmaceutical industry can benefit greatly by using rheology to rapidly test the storage stability of drug suspensions. Furthermore, "Analytical Rheology" provides insight into the structure of the dispersion, thus giving direction on how to improve the storage stability of a formulation
Introduction
Stability and stability-related issues have been the paramount causes of drug product recalls in the past two years. The manufacture and control of oral solutions and oral suspensions has presented some serious problems to the pharmaceutical industry. Some of the major reasons for recalls are microbiological potency and stability problems.
Select segments of the population who cannot take oral solid drugs forms are newborns, pediatrics, and geriatrics. These groups are most compromised, and placed at much greater risk of not receiving effective treatments.
A liquid product in which the drug is suspended also presents manufacturing and control problems. Specifications for the manufacture of suspensions, as opposed to solution drugs, are far more stringent. Additional important specifications for suspensions include particle size, pH, zeta potential, and viscosity. Good manufacturing practices warrant frequent QC testing during the production process.
Therapeutics based on biomacromolecules, like peptides and proteins, constitute an increasing number of new active ingredients being evaluated in drugs. The fate of these drugs depends upon the physical and chemical stability of proteins in these formulations. These biomacromolecular drugs have a much greater tendency to separate due to their poor solubility in water and therefore present a greater challenge to the drug formulators.
There is an urgent need to have a rapid and informative suspension stability test. Rheology provides this need. Not only is rheological testing fast, but it identifies the ingredients that are responsible for separation. The great sensitivity of rheological testing can observe subtle physical and chemical changes in a formulation.
Understanding Rheology
Rheology is the study of deformation and flow of materials. Most materials are viscoelastic, meaning they behave liquid-like and solid-like depending upon external conditions. "Analytical Rheology" is a study of the microstructure of materials. It relates the structure-processing and end-use behavior of materials. A rheometer measures material functions, which are the shear storage modulus G' and shear loss modulus G". Rheology is contrasted to viscometry which only measures viscosity.
Malvern Instruments is a long-established supplier to the pharmaceutical industry, providing particle characterization systems whose technology has become the industry standard. The company's recent acquisition of Bohlin Instruments has added rheology capabilities and a recognized range of high quality rheometers (shown is the Gemini system).
Combining particle characterization with analytical rheology greatly enhances the support that Malvern can provide to the pharmaceutical and other industries, with ongoing product and applications support playing a crucial role.
Rheology Testing
Oscillatory testing is one of the most suitable techniques for measuring material properties over a range of frequencies and temperatures to produce a viscoelastic spectrum. The spectrum fully characterizes the rheology of a viscoelastic material.
Materials are primarily distinguished from one another by the magnitudes of G' and G" over different ranges of frequency. Radebaugh and Simonelli point out the necessity of measuring the viscoelastic material functions of pharmaceutical products (1).
Rheological Data of Drug Suspensions
Suspensions are viscoelastic fluids. In order to fully understand their rheology, the frequency dependence of their G' and G" material functions must be measured.
The ratio of G"/G', known as tandelta is a predictive parameter for studying the storage stability of suspensions. If the sample has a yield stress, then an additional test should be performed. The creep-recovery test is most suitable for determining a yield stress.
Suspensions can be stabilized in three ways: By producing a network structure; electrostatically; and by adding surfactants. Stable suspensions (stabilized electrostatically or by surfactants) will have an optimum value of tandelta depending upon the concentration of the suspension and the particle interactions.
For network structures the higher the G' value the more stable the suspension. Although, it is undesirable to have too high a G' since it may become solid-like and have too high a viscosity to pour or dispense from a container.
A large body of knowledge exists about the relationship between the interparticle interactions and interphase interactions of suspensions. Tandelta is an important parameter for relating these interactions to suspension stability. For suspension concentrations in the range of 30-40% by volume, the optimum tandelta will range between 2 to 0.8.
The suspension will be unstable when tandelta drops below 0.5 and marginally stable when it is between 0.5 and 0.8. The author has completed extensive studies on the rheology of liquid suspensions pertaining to stabilization - see reference (2) for further details.
An example is given for stable suspensions shown in Figure 1. Here the log of G', G" and tandelta are plotted against the log of frequency. This is only part of the viscoelastic spectrum, but is sufficient for this analysis. The test takes about 10 minutes. This suspension is stable due to the fact that tandelta is between 0.8 and 2 in this range of frequency. This means that the particles have sufficient interactions to maintain a balance between the particle-particle forces and particle-continuous phase force interactions.
Summary
In the example provided, we have shown how a single rheological test can rapidly predict the stability of a drug suspension by monitoring the value of a well-defined parameter (tandelta). The oscillation frequency sweep test also provides further information concerning the structure of the suspension through the magnitudes of the measured viscoelastic properties and therefore allows discrimination of materials for their end use performance characteristics.