Thursday, June 24, 2021

Excipients Used in the Formulation of Pharmaceutical Suspensions

Pharmaceutical excipients by definition are substances other than the prodrug or active pharmaceutical ingredient which are added in the manufacturing process or are contained in a finished dosage form. In the formulation of pharmaceutical suspensions, excipients are generally added along with the active pharmaceutical ingredients in order to:

  1. Protect, support or enhance the stability of the formulation
  2. Bulk up the formulation in case of potent drug for assisting in the formulation of an accurate dosage form.
  3. Improve patient acceptance
  4. Help improve bioavailability of active drugs
  5. Enhance overall safety and effectiveness of the formulation during its storage and use.

Excipients used in the formulation of pharmaceutical suspension are sub-divided into various functional classifications, depending on the role they intend to play in the resultant formulation. Some excipients can have different functional roles in different formulation types and in addition, individual excipients can have different grades, types, and sources depending on those different functional roles.

The possible types of excipients commonly used in the formulation of pharmaceutical suspensions include:

1. Solvents/ Vehicle

Solvents (or vehicles) are used as a base in which drugs and other excipients are dissolved or dispersed. The most commonly used vehicle for the formulation of pharmaceutical suspensions is purified water. This is due to its lack of toxicity, physiological compatibility, and good solubilizing power (high dielectric constant).

In a few instances, viscous nonaqueous solvents, such as propylene glycol and polyethylene glycols, are used as vehicles to impart stability to suspended drug particles. The choice of solvent used depends on the nature and physicochemical properties of the drug substance and the intended use of the formulation.

Other examples of solvents used in suspension formulation include alcohol, acetic acid, acetone, ethyl acetates, etc.

2. Co-solvent

Co-solvent is used to increase the solubility of solute in solvents and they act by reducing the interfacial tension between predominantly aqueous solutions and hydrophobic solutes. Sorbitol, dextrose, etc. are often added as solubilizers, as well as base sweeteners. Other examples of co-solvents include Ethanol, Sorbitol, Glycerin, Propylene glycol, etc.

3. Buffering agents

Buffers are mixture of a weak acid or base and one of its salts which when dissolved in a solvent will resist any change in pH when an acid or base is added. Buffering agents/ pH modifiers are added to suspensions to

  1. Ensure physiological compatibility
  2. Maintain/ optimize chemical stability
  3. Maintain/ optimize anti-microbial effectiveness
  4. Optimize solubility (or insolubility if taste is an issue).

Generally, the pH of pharmaceutical suspension should be kept between 7.0 – 9.5 preferably between 7.4 – 8.4. Substances commonly used buffering agents in pharmaceutical suspensions include salts of week acids such as carbonates, citrates, gluconates, phosphate, and tartrates.

Amongst these, citrates and phosphates with their respective pharmaceutically accepted salts are commonly used in pharmaceutical suspensions. Citrate buffers are used to stabilize suspensions in the pH range of 3 – 5, while phosphate buffers are used in the pH range of 7 – 8.

Read Also: Excipients Used In the Formulation of Liquid Dosage Forms

4. Preservatives

Preservatives are agents that protect pharmaceutical formulations against microbial spoilage and prevent increased risk of contamination by opportunistic microbial pathogens from excipients or introduced externally, resulting in potential health consequences. A range of potential preservatives is available, including sorbic acid, benzoic acid, parabens, chloroform, sucrose, and benzalkonium chloride.

Some ionic preservatives such as sodium benzoate may interact or form complexes with other suspending ingredients thus reducing their preservative efficacy. For this reason, effective aqueous concentration of the preservative must be monitored and controlled.

Solvents, such as alcohol, glycerin, and propylene glycol, may also have some preservative effect depending on their concentration. Sucrose has a preservative action at concentrations greater than or equal to 67% w/v. It is unlikely to be used in commercial products due to its cariogenic potential but may be encountered in extemporaneous products, albeit more likely in solution formulations.

5. Antioxidants

Antioxidant molecules which themselves are preferentially oxidized can be included in pharmaceutical suspension to reduce or delay the degradation of some components of pharmaceutical suspensions that are susceptible to oxidative degradation. The type of antioxidant will depend on the nature of the formulation and different antioxidants will be required for aqueous and non-aqueous formulations.

The Efficacy of these antioxidants can be affected by:

  1. Compatibility with other excipients
  2. Partitioning into micelles (from surfactants)
  3. Adsorption onto surfaces (container, thickening agent and suspended particles)
  4. Incompatibilities, e.g. with metal ions.

Examples of antioxidants used in pharmaceutical suspension include ascorbic acid, sodium bisulfate, thiourea, Butyl Hydroxy Toluene (BHT), tocopherols, etc.

6. Wetting agents/ surfactants

Surfactant or surface-active agent is a general name for materials that possess surface activity; in solution, they tend to orient at the surface of the liquid. These agents aid wetting and dispersion of hydrophobic active pharmaceutical ingredients and they usually act by reducing interfacial tension between solids and liquids in suspensions.

Depending on the nature of the polar area, surfactants can be anionic (e.g., Sodium lauryl sulfate, docusate sodium), cationic (e.g., benzalkonium chloride, phosphatidylcholine), amphoteric (e.g., betaines or sulfobetaine and natural substances such as amino acids and phospholipids) and nonionic (e.g., polyoxyethylene sorbitan fatty acid esters). Among these, the most commonly used ones are the anionic and non-ionic surfactants.

Nonionic surfactants, rather than ionic surfactants, are generally considered to be more suitable for pharmaceutical suspensions, not only because of their lower toxicity but also because the surfactant’s shell can confer stealth properties to the micelle, avoiding uptake by macrophages of the reticular endothelial system (RES), thus, prolonging their lifetime in blood circulation. Since many of the surfactants in this group are esters, they are usually susceptible to hydrolysis under conditions of high or very low pH.

7. Anti-foaming agents

The formation of foams during manufacturing processes or when reconstituting powder for suspension can be undesirable and disruptive. Anti-foaming agents discourage the formation of stable foam and they do so by lowering the surface tension and cohesive binding of liquid phase. Examples of anti-foaming agents include simethicone, organic phosphates, alcohols, paraffin oils, stearates, and glycols.

It is worthy to note that foam is also a very valid dosage form option for certain situations, e.g. for topical administration and in wound dressings and in addition, granulation using a foam rather than aqueous granulation fluid is gaining popularity.

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