Thursday, April 15, 2021

Excipients Used in the Formulation of Pharmaceutical Suspensions

by | November 10, 2020 0

8. Flocculation modifiers

These are neutral electrolytes that are capable of preventing caking of suspended solids by adjusting the flocculation status of the particles to that which is intended.  Flocculation modifiers are usually the last excipient added to suspension formulations.

The effect of the flocculation modifier on the flocculation behavior of the particles is dependent on the ionic strength in solution and therefore a multivalent salt (e.g. calcium chloride or aluminum chloride ) will have a greater effect than a monovalent salt (e.g. sodium chloride or potassium chloride).

The quantity of flocculation modifier required must be determined last, once the levels and effects of all other functional excipients have been resolved. It is no good, for example, defining the level of the flocculation modifier to give perfect flocculation behavior and then adding a buffer to the system, which will release mobile ions into the diffuse layer and change the flocculation status.

9. Suspending agents/ Viscosity-modifiers

These are excipients that minimize inter-particle attraction and aggregation by functioning as energy barrier thus retarding particle settling. The selection of an appropriate suspending agent is one of the most crucial factors in formulating a pharmaceutical suspension.

The factors considered in the selection of the appropriate suspending or viscosity enhancing agents include desired rheological property, suspending ability in the system, pH stability, chemical compatibility with drug substance and other excipients, reproducibility, hydration time, and cost.

Common suspending agent/ viscosity modifiers used in suspension formulation include cellulose derivatives (e.g., methylcellulose, microcrystalline cellulose, and hydroxypropyl methylcellulose), clays (e.g., bentonite and kaolinite), natural gums (e.g., acacia, guar gum, tragacanth, and xanthan gum), synthetic polymers (e.g., polyvinylpyrrolidone), and miscellaneous compounds (e.g., colloidal silicon dioxide and silicates).

These categories of suspending agents in most cases are used in combination to exert synergistic effects on rheological behavior, as well as, improve the stability of suspensions. A typical example is the use of magnesium aluminum silicate and xanthan gum in the formulation of nystatin oral suspension. The silicate exerts a synergistic effect with xanthan gum, enhancing the thixotropic characteristic of the suspension.

10. Flavoring agents

One problem that can arise with oral suspensions is that suspension may produce a “cloying” sensation in the mouth which is a particular problem with suspensions containing high levels of inorganic components. Though this sensation is not the same as a bitter taste, it can nevertheless cause problems for the patient and affect compliance.

Flavoring agents supplement and complement sweetening agent since only sweetening agents may not be capable of complete taste masking of unpleasant drugs/ formulated suspension. They do so by entrapment of solid particles.

Examples include natural flavoring agents like peppermint, lemon oils, and artificial flavoring agents like butterscotch, ‘tutti-frutti’ flavor.

11. Sweetening agents

Sweetening agents are employed in liquid formulations designed for oral administration specifically to increase the palatability of the therapeutic agent. These agents can be natural or artificial sources.

Examples of sweetening agents from natural sources include

  1. Sucrose: Sucrose is soluble in water, colorless, stable at pH 4-8, and increases viscosity. Sucrose is arguably the best taste/mouthfeel overall but cariogenic and calorific and so should be avoided in pediatrics.
  2. Sorbitol: This is another example of natural sweetener. It is non-cariogenic and non-calorific. Sorbitol is appropriate for pediatric formulations, but lower sweetness intensity than sucrose. This means that more of it is usually added to the formulation and this can cause diarrhea.

The use of artificial sweetening agents in formulations is increasing and, in many formulations, saccharin sodium is used either as the sole sweetening agent or in combination with sugars or sorbitol to reduce the sugar concentration in the formulation. Other examples of artificial sweeteners in addition to saccharin and its salts are Aspartame, Acesulfame –K, and Sucralose (excellent sweetness, non-cariogenic, low calorie, wide & growing regulatory acceptability but relatively expensive).

The use of sugars in oral formulations for diabetic patients and children should be avoided.

12. Colorants

These are added to provide a more aesthetic appearance to the final product. The choice of colorant used in the formulation of pharmaceutical suspensions is usually tied to the choice of flavor, and their choices are also linked to the patient population, such as age group and geographic region, and the therapeutic need. For example, a red colorant is usually used with strawberry flavor for pediatric formulations.

13. Humectants

Humectants are hygroscopic excipients used at ~5% in aqueous suspensions and emulsions for external application. They retard evaporation of aqueous vehicles from dosage forms to prevent

  1. drying of the product after application to the skin
  2. drying of product from the container after first opening
  3. cap-locking caused by condensation onto neck of container-closure after first opening.

Examples include Propylene glycols, Glycerol, Polyethylene glycol, etc.

14. Chelating agents

Chelating agents, also known as sequestrants, are molecules that have the ability to form stable complexes with metal ions, particularly di-valent and tri-valent metal ions including trace metals and heavy metals. They are added to pharmaceutical suspensions to protect drug substance(s) from catalysts that accelerate oxidative reaction.

In addition, certain trace metals are required for microbial growth, and chelation (sequestration) to form complexes can help prevent microbial growth and spoilage, and thus allow lower levels of microbiocidal agents to be used.

Materials used as chelating agents include calcium disodium edetate, disodium edetate, edetic acid (ethylenediaminetetraacetic acid, EDTA), citric acid. While calcium disodium edetate and disodium edetate are soluble in water, the free acid is only slightly soluble. Citric acid may also be used as part of a buffer system to maintain pH.

References

  • Aulton, M. and Taylor, K. (2013). Aulton’s Pharmaceutics: The Design and Manufacture of Medicines, (4th ed.). Edinburgh: Churchill Livingstone.
  • Chaudhari, S. and Patil, P. (2012). Pharmaceutical Excipients: A review. International Journal of Advances in Pharmacy, Biology and Chemistry, 1(1): 21-34.
  • Dash, A., Singh, S. and Tolman, J. (2014). Pharmaceutics: Basic Principles and Application to Pharmacy Practice. USA: Elsevier Inc.
  • Jones D. (2008). Fasttrack Pharmaceutics: Dosage Form and Design of Drugs. London, UK: Pharmaceutical Press.
  • Kulshreshtha A., Singh O. and Wall M. (2010). Pharmaceutical Suspensions: From Formulation Development to Manufacturing.London, New York, Dordrecht Heidelberg: Springer.
  • Mahato, R and Narang, A. (2018). Pharmaceutical Dosage Forms and Drug Delivery (3rd ed.).New York: Taylor & Francis Group, LLC.
  • WHO (2007, October 15-19). Training Workshop on Pharmaceutical Development with focus on Paediatric Formulations. Paper presented at Pharmaceutical Development with focus on Paediatric Formulations, Tallink City Hotel, Tallinn, Estonia. Retrieved June 21, 2020, from http://apps.who.int/prequal/trainingresources/pq_pres/Tallinn-Oct07/Excipients_en.ppt

 

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