Thursday, June 24, 2021

Rheologic Considerations for Pharmaceutical Suspensions

by | September 9, 2020 0

Rheologic consideration is of great importance in the study of the stability of pharmaceutical suspensions. This is because the viscosity of a suspension can modify the sedimentation rate.

The viscosity of a liquid is a measure of its resistance to flow. Greater viscosity of dispersion medium offers the advantage of slower sedimentation; but on the other hand, it may compromise other desirable properties such as ease of redispersibility, syringability for parenteral suspensions, spreadability for topical suspensions, and ease of administration for oral suspensions.

From the manufacturer’s point of view, low viscous products are more productive. Rheology can affect the manufacturing process of suspensions since highly viscous mixture produces excessive frictional drag on the mixing vessel and other machinery accessories, thereby resulting in wasted energy.

Factors affecting rheology of a suspension

The ease of manufacture and the stability of a pharmaceutical suspension depends on the desired viscosity of the product. A formulator should have exact knowledge of the factors that affect the viscosity to enable him change the rheological behavior of suspension products.

Along with the physical factors, there are some chemical parameters that affect the particle interactions and, thereby, the effective dispersed phase fraction, which, in turn, changes the viscosity of the product.

The most important physical parameters that influence the rheological properties of pharmaceutical suspensions include:

1. Dispersed phase content

The content of the dispersed phase φ is the most important physical parameter that affects the viscosity of dispersions. It is generally considered as either the ratio (in fraction or percentage) of volume of the dispersed phase to the total volume of the dispersion or as weight fraction or weight percentage or weight by weight concentration.

The viscosity of a suspension has a direct relationship with the content of the dispersed phase. As the viscosity increases, the content of the dispersed phase also increases. The contribution of the solid phase content to the overall viscosity can be understood by Einstein equation as shown below

ηs= ηo (1+ 2.5 φ)

Where ηs is the viscosity of the suspension and ηo is the viscosity of the dispersion medium.

The lower the value of φ (i.e., the less the solid content), the closer is the overall viscosity of the suspension to the viscosity of the dispersion medium. The Einstein equation gives good results of the overall viscosity for very dilute solutions (φ <0.02).

In practice, most pharmaceutical suspensions are more concentrated, and inter-particular attractions are more prominent. In such cases, particles remain as aggregates of two or more particles, and the dispersion medium is trapped within the aggregate.

This situation reduces the effective volume of the dispersion medium and, thereby, increases the effective volume of the dispersed phase.

Read Also: Stability Considerations for Pharmaceutical Suspensions

2. Particle shape

Particle shape can affect the rate of sedimentation as well as the viscosity of suspensions. As the particles deviate from spherical shape, the suspension becomes more viscous. The maximum volume fraction of the dispersed phase decreases as the particles become increasingly irregular in shape.

Under high shear, non-spherical particles generally show dilatant flow as they have higher contact area among themselves. However, shear-thinning behavior is also possible with the non-spherical particles.

A common example is the dispersion of natural or synthetic polymers.

3. Particle size and size distribution

The particle size of any suspension is critical and must be reduced within the range as determined during the preformulation study since it is necessary to ensure that the drug to be suspended is of a fine particle size prior to formulation as this will ensure a slow rate of sedimentation of the suspended particles.

In dilute dispersions, viscosity is independent on particle size. However, in concentrated suspension, the effect of particle size on viscosity depends on the counterbalance of hydrodynamic and Brownian forces. An increase in particle size increases the shear thickening property of a levodopa injectable suspension.

Particle size can also have an effect on thixotropy. In dispersions, smaller particles aggregate at a faster rate than larger particles. Particle size distribution can also play an important role in determining the viscosity of dispersion. Suspension with a wide particle size distribution shows lower viscosity than the one with narrow particle size distribution. The broadening of the particle distribution span was also found to lower shear-thickening property.

A suspension with too many smaller particles, tend to occupy themselves within larger particles and, thus, reduce the interactions between the latter. In this way, smaller particles and the dispersion medium act as a pseudo-continuous phase that carries the larger particles suspended. Therefore, the effective dispersed phase content is reduced, which reduces the viscosity.  Bimodal particle distributions were also found to reduce shear thickening behavior.

Read Also: Theoretical Considerations for Pharmaceutical Suspensions

4. Temperature

Apart from crystal growth, which results from temperature fluctuations, changes in temperature can also affect the viscosity of the dispersion medium and thus that of the dispersion. Generally, a rise in temperature causes a decrease in viscosity. Apparent viscosities of suspensions containing suspending agents, sodium starch glycolate, and modified corn starch, were found to decrease progressively with increase in temperature over 10–50°C.

Temperature can also affect the viscosity of a suspension by

  • modifying interfacial properties and thus inducing or reducing flocculation. Flocculation increases viscosity.
  • increasing the Brownian movement.

In addition, temperature causes volume expansion in both the dispersion medium and the solid. However, liquid medium expands more than the solid, leading to a decrease in φ value and a decrease in viscosity.

References

  • Aulton M. and Taylor  (2013). Aulton’s Pharmaceutics: The Design and Manufacture of Medicines (4th ed.). Amsterdam, Netherlands: Churchill Livingstone Elsevier.
  • Briceño M. (2000). Rheology of Suspensions and Emulsions, In: Nielloud F and Marti-Mestres (Eds), Pharmaceutical Emulsions and Suspensions, (pp 557–607). New York, NY: Marcel Dekker Inc.
  • Hiemenz P. and Rajagopalan R. (1997). Principles of Colloid and Surface Chemistry (3rd ed.). New York, NY: Marcel Dekker Inc.
  • Illing A. and Unruh T. (2004). Investigation on the Flow Behavior of Dispersions of Solid Triglyceride Nanoparticles. International Journal of Pharmaceutics, 284: 123-131.
  • Sabra K. and Deasy P. B. (1983). Rheological and Sedimentation Studies on Instant Clearjel® and Primojel® Suspensions. Journal of Pharmacy and Pharmacology, 35: 275–278.

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