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Quality control of pharmaceutical products using rotational viscometry

Quality control by means of rotational viscometry is a crucial part in the production of pharmaceuticals, for example in the preparation of suspensions. Incoming raw materials and production processes like the stirring, pumping, and filling of pharmaceuticals have to be controlled by performing regular viscosity checks with a viscometer. The end product also needs to be tested to ensure e.g. proper storage stability or application. Parameters such as the viscosity of medicines have to be adapted to match customers’ expectations so that customer satisfaction is ensured. This article introduces and describes important basic rotational viscosity test methods and analyses that enhance quality control. 

Groups of liquid pharmaceuticals

Pharmaceuticals can be roughly divided into three main groups:

  • Pharmaceutical solutions: These are homogeneous mixtures which do not show sedimentation of particles. Solutions consist of a soluble material which is dissolved in a liquid/solvent and looks clear. A typical example is a sugar/water solution. Solutions can be further divided into aqueous solutions like douches, mouthwash, and nasal wash, non-aqueous solutions like elixirs, spirits, and collodions, and sweet or viscid solutions like cough syrup and honey.[1]
  • Pharmaceutical emulsions: These are biphasic systems consisting of two immiscible liquids. They are thermodynamically unstable and must be stabilized by the addition of an emulsifying agent. Examples are preparations for the treatment of skin conditions and for skin care. An advantage of emulsions compared to solutions is that they can deliver water-insoluble drugs via oral administrations.[2]
  • Pharmaceutical suspensions: These are heterogeneous mixtures containing solid particles (>1000 nm) that settle down. A good suspension must be stable during storage, should settle slowly, and re-disperse readily upon gentle shaking of the container. Drugs that have very low solubility are usually formulated as suspensions. A suspension may prolong the action of a drug by preventing rapid degradation in the presence of water, improve chemical stability of certain drugs (e.g. penicillin G), and mask an unpleasant taste of a drug.[3][4]

Quality control of cough syrup with rotational viscometry

Syrup is a concentrated, aqueous solution of sugar or a sugar substitute with or without flavors. It contains one or more active ingredients in the solution. Such a solution is called a syrup if the sucrose concentration is 85 %, which also prevents bacterial growth.[5]

The viscosity of cough syrup should be preferably as high as possible but it should still be drinkable in order to smoothly flow past the digestive tract. To evaluate the flow behavior of cough syrup with a rotational viscometer it is useful to perform a speed/shear rate ramp test and analyze the flow behavior with e.g. the mathematical regression model “Power Law”. With this mathematical model two parameters can be obtained: the consistency index and the flow index.[6]

  1. Consistency index k: This parameter represents the product’s viscosity at one reciprocal second, which means at rest in the bottle.
  2. Flow index n: This parameter determines the flow behavior of the cough syrup. When n < 1 the product shows shear-thinning behavior. This means that the apparent viscosity decreases as the shear rate increases. The closer n is to 0, the stronger the shear-thinning behavior of the material is. When n > 1 the product shows shear-thickening behavior. Its apparent viscosity increases as the shear rate increases. When n = 1 the product shows Newtonian flow behavior. This means the viscosity is independent of the shear rate.

To guarantee customer satisfaction and consistent quality from batch to batch the flow index and consistency index need to be properly adjusted.

Example: 7.5 mL of a cough syrup sample were analyzed with a rotational viscometer using a double-gap measuring system at different shear rates (Figure 1). According to the mathematical model “Power Law” the syrup has a relatively high viscosity of 94.93 Pa·s at rest (1 s-1). Also during swallowing the preferred high viscosity of the syrup does not change as it shows Newtonian flow behavior of n = 1 (flow index).

Figure 1: Flow curve diagram of cough syrup and Power Law analysis

Quality control of ointments and lotions with rotational viscometry

The viscosity of ointments and lotions, for example, has an impact on several stages in the production: It must be possible to pump them, pack them, and squeeze them out of the packing easily, and also to apply them on the target body areas. To be able to forecast the viscosity during production and at application, the viscosity at different speeds/shear rates has to be determined with a rotational viscometer. Ointments have to show shear-thinning flow behavior, because the viscosity has to decrease when a force is applied, e.g. during squeezing it out of a tube or applying it to the skin. In order to prevent liquids like ointments from flowing out of the tube when no force is applied, the yield point has to be analyzed. On rotational viscometers, the yield point is often calculated from flow curves measured with a linear increase of the speed using mathematical regression models. Once the desired emulsion and emulsifiers have been chosen, a consistency that provides the desired stability and yet has the appropriate flow characteristics must be attained. Generally, an increase in viscosity minimizes creaming, rising, or sedimentation of particles. A change in the globule size or number or migration of emulsifying agent during aging may be detected by a change in viscosity. Further, flocculation of oil-in-water emulsions results in an immediate increase in viscosity.[7]

Example: After carrying out a speed ramp test the yield point of an ointment was analyzed using the mathematical regression model Herschel-Bulkley (Figure 2). The Herschel-Bulkley model gives the product’s yield stress (τo) as well as the product’s flow index and consistency index.[8] The tested ointment does not flow immediately out of the tube. 90.75 N/m² need to be applied on the tube to make the ointment flow. Based on this data, formulators are able to modify the ingredients accordingly. Once a formulation is established, multi-point tests and e.g. analyses using the Herschel-Bulkley model can be performed for quality control to check batches before and after processing.

Figure 2: Flow curve diagram of an ointment and Herschel-Bulkley analysis

Conclusion

Simple viscosity checks with a rotational viscometer ensure the correct consistency of the end product to meet customers’ expectations. Measurements of the viscosity at different speeds give insight into the flow behavior of pharmaceutical products. Yield point analysis helps to figure out the force required for e.g. pumping, filling, and application of pharmaceuticals. The viscosity, the flow behavior, and the yield point can be controlled through the formula of the product and addition of thickening agents. More complex tests to analyze the structure of pharmaceutical products can be performed with a rheometer.

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References

  1. Mobley, W. C. Amiji M. M. Cook T. J. (2019). Applied Physical Pharmacy. 3rd ed. New York: McGraw-Hill Education.
  2. Khan, B. Akhtar, N. Khan, H. Waseem, K. Mahmood, T. Rasul, A. Iqbal, M. Khan, H. (2011). Basics of pharmaceutical emulsions: A review. African Journal of Pharmacy and Pharmacology, [online] Vol. 5(25), 2715-2725. Available at academicjournals.org/journal/AJPP/article-full-text-pdf/1DFCEB237386 [Accessed 10 Dec. 2019]
  3. Santosh Kumar, R. and Naga Satya Yagnesh, T. (2016). Pharmaceutical Suspensions: Patient compliance oral dosage forms. World Journal of Phramacy and Pharmaceutical Sciences, [online] Vol. 5(12), 1471-1537. Available at www.researchgate.net/publication/326293246_PHARMACEUTICAL_SUSPENSIONS_PATIENT_COMPLIANCE_ORAL_DOSAGE_FORMS [Accessed 10 Dec. 2019]
  4. Kulshreshtha, A. Singh, O. and Wall, M. (2010). Pharmaceutical Suspensions. New York: Springer.
  5. Gaud, R. S. Yeole, P. G. Yadav. A. V. and Gokhale, S. B. (2008). Pharmaceutics. 10th ed. Pune: Nirali Prakashan
  6. Mezger, T. (2011). The Rheology Handbook. 3rd revised ed. Hanover: Vincentz Network.
  7. Mastropietro, D. Nimroozl R. and Omidian, H. (2013). Rheology in Pharmaceutical Formulations-A Perspective. Journal of Developing Drugs, [online] Vol. 2(2), ISSN: 2329-6631. Available at www.longdom.org/open-access/rheology-in-pharmaceutical-formulationsa-perspective-2329-6631.1000108.pdf [Accessed 10 Dec. 2019]
  8. Mezger, T. (2011). The Rheology Handbook. 3rd revised ed. Hanover: Vincentz Network.