Monday, May 17, 2021

Excipients Used In the Formulation of Liquid Dosage Forms

Liquid dosage forms in addition to drug substance also contain excipients which serve different and specialized pharmaceutical purposes in the formulation. These excipients in most cases are present in a greater proportion with regards to the drug substance as it forms the bulk of the formulation. It is, therefore, essential to ensure that all excipients used in the formulation of liquid dosage forms are physically and chemically compatible with the drug substance and every other component of the formulation.

Excipients used in the formulation of pharmaceutical liquid dosage forms include:

1. Vehicles/ Solvents

In liquid pharmaceutical formulations, vehicles are major components used as a base in which drugs and other excipients are dissolved or dispersed. They function by breaking of bond and reducing effective charge on ions thus, increasing solute-solvent forces of attraction which are eventually greater than solute-solute and solvent-solvent forces of attraction.

Vehicles used in the formulation of liquid dosage forms may be aqueous (e.g., water, polyhydric alcohols, hydro-alcoholic solutions and buffers) or oily (e.g., vegetable or mineral oils, organic oily bases, emulsified bases etc). The choice of vehicle used depends on the nature and physicochemical properties of the active pharmaceutical ingredient (API) and the intended use of the formulation.

a. Water as a solvent

Water is the most widely used solvent in pharmaceutical formulations. In routine use, it lacks toxicity, is compatible with bodily fluids, and can dissolve most compounds that are used as pharmacologic agents (due to its high dielectric constant) but likely to cause instability of hydrolytically unstable drugs and provides suitable media for microbial growth.

The compendial requirement for water used in the formulation of liquid dosage forms is Purified Water, USP, except for those intended for parenteral administration (injections) for which water for injection is used. Water used for compounding oral solutions and the reconstitution of oral suspensions must meet official standards.

It is worthy of note that drinking water, bottled or from the municipal tap, is not covered by a compendial monograph and therefore cannot be used in the formulation of liquid dosage form obviously due to the possible incompatibility of formulation components with dissolved impurities in water.

b. Alcohol as a solvent

Alcohol frequently referred to as ethyl alcohol or ethanol is the most commonly used solvent in liquid pharmaceutical formulation next to water. It is a clear, colourless, mobile, and volatile liquid with a slight, characteristic odour and burning taste.

Alcohol USP contains ethanol, C2H5OH, not less than 92.3% and not more than 93.8%, by weight, which corresponds to not less than 94.9% and not more than 96.0%, by volume. Ethanol is miscible with water, glycerine, propylene glycol, and polyethylene glycol 400. It is used as a primary solvent for many organic compounds. Water–alcohol mixtures can be very effective in solubilizing poorly soluble drugs.

c. Glycerin, USP (Glycerol) as a solvent

This is a clear, colourless, odourless, viscous, hygroscopic liquid with sweet taste, approximately 0.6 times as sweet as sucrose. It is a triol alcohol without the central nervous system depressant activity of ethanol.

Glycerin is miscible with water, alcohol, propylene glycol, and polyethylene glycol 400.  As a solvent, the solubilizing properties of glycerin are comparable to alcohol but because of its viscosity, solutes are slowly soluble in it unless it is rendered less viscous by heating. Also, the increased viscosity imparted to the final product may be an undesired outcome of the use of this solvent.

Glycerol is used in both internal and external preparations. It serves as an excellent solvent for a range of substances such as alkalis, neutral salts, tannins etc.

d. Propylene Glycol as a solvent

Propylene glycol USP is a clear, colourless, viscous, practically odourless liquid, with a sweet, slightly acrid taste resembling that of glycerin. It is a diol and like glycerin, it has no central nervous system activity.

Propylene glycol has become widely used as a solvent, extractant and preservative in a variety of pharmaceutical formulations. It is used more often in modern formulations, possibly replacing glycerin as it dissolves a wide variety of materials, such as corticosteroids, phenols, sulpha drugs, barbiturates, vitamins (A and D), most alkaloids, and many local anaesthetics.

e. Polyethylene Glycol 400 as a solvent

Polyethylene glycol 400 (PEG 400) is a low-molecular-weight grade of polyethylene glycol. It is a clear, colourless, viscous liquid. PEG 400 is a liquid at room temperature, and it is the most common polyethylene glycol used in drug product formulations.

In concentrations up to approximately 30% v/v, PEG 400 has been used as the vehicle for parenteral dosage forms. Like glycerin and propylene glycol, PEG 400 is miscible with water and alcohol.

2. Co-solvents

Co-solvents are primarily liquid components often used to increase the water solubility of drugs which do not contain ionisable group(s) and whose solubility can thus not be increased by pH adjustment. They work by reducing the interfacial tension between predominantly aqueous solutions and hydrophobic solutes.

Co-solvents are partially polar due to the presence of hydrogen bond donors and/or acceptors, thus ensuring miscibility with water. The selection of a co-solvent depends on a number of factors, including the solubility and stability of drug substance in the vehicle and toxicity of the vehicle. Most water-miscible organic liquids are however toxic and only a few are used as co-solvents in pharmaceutical solutions.

Each co-solvent is characterized by an acceptable concentration range, which cannot be exceeded without incurring biological damage. The use of co-solvents in parenteral formulations has been limited by the uncontrolled precipitation of the drug substance upon dilution in aqueous/biological media which results in embolism or necrosis at the injection site. In vitro and in vivo models are available to evaluate the safety of co-solvent excipients.

Examples of excipients used as co-solvents include glycerol, propylene glycol, ethanol, the low molecular weight PEGs etc.

3. Surfactants

Surfactants or surface-active agents are molecules with well-defined polar (hydrophilic) and non-polar (hydrophobic) regions that associate in aqueous media to form dynamic aggregates, known as micelles. Non-polar drugs can partition into these micelles and be solubilized.

Depending on the nature of the polar area, surfactants can be anionic (e.g., sodium dodecyl sulfate), cationic (e.g., trialkylammonium), zwitterionic (e.g., glycine and proteins) and nonionic (e.g., polyethylene glycol). 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 applications, 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 the process of solubilization occurs due to the presence of micelles, generally high concentrations of surfactants are needed to significantly improve drug solubility. The concentration at which the micelles form in appreciable numbers is called the critical micelle concentration (CMC). Depending on surfactant concentration, normal micelles can be spherical, cylindrical, or lamellar in shape.

Examples of surfactants used in pharmaceutical liquid dosage forms are shown in the table below.

Examples of Surfactants Used in Liquid Dosage Forms

Range of HLB Value Surfactant Category Examples Applications
1 – 3 Anti-foaming agents Dimethicone, simethicone ethylene glycol distearate, sorbitan tristearate Creams, lotions
3 – 6 W/O emulsifier Propylene glycol monostearate, glyceryl monostearate, propylene glycol monolaurate, sorbitan stearate (Span 60), diethylene glycol monostearate, sorbitan monooleate (Span 80) Creams, lotions
6 – 8 Wetting agent Diethylene glycol monolaurate, sorbitan monopalmitate, sucrose dioleate Suspensions
8 – 13 O/W emulsifier Polyethylene glycol monooleate, sorbitan monolaurate (Span 20), polyoxyethylene sorbitan monostearate, polyoxyethylene sorbitan tristearate O/W emulsions
13 – 14 Detergent Polyethylene glycol (400) monolaurate, polyoxyethylene sorbitan monolaurate, triethanolamine oleate, PEG-8 laurate Lotions
15 – 18 Solubilizer Polyoxyethylene sorbitan monooleate (Tween 80), polyoxyethylene sorbitan monopalmitate (Tween 60), sodium oleate, polyoxyethylene stearate, potassium oleate Solutions, O/W

emulsions, lotions

4. Preservatives

Preservatives are chemical compounds that are added to formulations to protect them from microbial contamination. An ideal preservative should be

  1. effective at low concentrations against all possible microorganisms
  2. non-toxic, non-sensitizing, soluble and compatible with the API, other excipients, and the container system
  3. stable for the shelf-life of the product.

Microbial contamination presents a significant health hazard in aqueous-based liquid dosage forms. Therefore, the use of preservatives becomes unavoidable in such cases to prevent the growth of microorganisms during production and over storage time. Although it may be most desirable to develop a “preservative-free” formulation to address the increasing concerns about the biological activity or unwanted effects of these excipients, most formulations require some kind of preservative to ensure no microbial growth.

The majorities of preservatives are of both acid and non-acid types and are bacteriostatic rather than bactericidal. Among the acidic types are phenol, benzoic acid, boric acid, chloro-cresol, 9-phenyl phenol, alkyl esters of para-hydroxybenzoic acid, sorbic acid, and their respective salts. Neutral preservatives include chlorobutanol, benzyl alcohol, and beta-phenylethyl alcohol.

Read Also: Excipients Used In the Manufacture of Tablets

Under alkaline conditions, it is generally regarded that microbial growth is insignificant and at these pH values, the need for a preservative is not generally recommended.

Preservatives often contain reactive functional groups, which are responsible for their antimicrobial activity but lead to unwanted reactions. Therefore, in addition to the excipient’s antimicrobial activity, other parameters should be evaluated during the formulation development for its compatibility with the API, other excipients, and the container system. The table below shows common preservatives used in liquid dosage forms and their typical concentration level.

Common preservatives used in liquid pharmaceutical dosage forms and their typical concentration levels
Antimicrobial Preservatives Typical Usage Level (% w/w) Antifungal Preservatives Typical Usage Level (% w/w)
Benzalkonium Chloride 0.002–0.02% Butyl Paraben 0.1–0.4%
Benzethonium Chloride 0.01–0.02% Methyl Paraben 0.1–0.25%
Benzyl Alcohol 3.0% Ethyl Paraben 0.1–0.25%
Bronopol 0.01–0.1% Propyl Paraben 0.1–0.25%
Cetrimide 0.005% Benzoic Acid 0.1–0.5%
Cetylpyridinium chloride 0.0005–0.0007% Potassium sorbate 0.1–0.2%
Chlorhexidine 0.002–0.5% Sodium Benzoate 0.1–0.2%
Chlorobutanol 0.5% Sodium Propionate 5–10%
Chlorocresol 0.2% Sorbic Acid 0.05–0.2%
Chloroxylenol 0.1–0.8%
Cresol 0.15–0.3%
Ethyl Alcohol 15–20%
Glycerin 20–30%
Hexetidine 0.1%
Imidurea 0.03–0.5%
Phenol 0.1–0.5%
Phenoxyethanol 0.5–1.0%
Phenylethyl Alcohol 0.25–0.5%
Phenylmercuric nitrate 0.002–0.01%
Propylene Glycol 15–30%
Thimerosal 0.1%

5. Viscosity modifiers/ Suspending agents

Viscosity modifiers also known as suspending agents are excipients that minimize interparticle 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. Other 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 viscosity modifiers used in liquid pharmaceutical dosage forms include cellulose derivatives (e.g., methylcellulose, microcrystalline cellulose, carboxymethylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropyl cellulose and hydroxypropyl methylcellulose etc), clays (e.g., hectorite, bentonite, aluminium and/or magnesium silicate), natural gums (e.g., acacia, guar gum, tragacanth, xanthan gum, alginates, carrageenan and locust bean gum), synthetic polymers (e.g., carbomers, polyvinyl pyrrolidone, polyvinyl alcohol and poloxamer), and miscellaneous compounds (e.g., colloidal silicon dioxide and silicates). In many cases, these excipients are used in combination.

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