Understanding Pharmaceutical Liquid Dosage Forms

Liquid dosage forms are pourable pharmaceutical formulations which contain a mixture of active drug components and nondrug components (excipients) dissolved or suspended in a suitable solvent or mixtures of solvents. They are pharmaceutical preparations designed to provide the maximum therapeutic response in a target population with difficulty swallowing solid dosage forms and/or to produce rapid therapeutic effects.

Liquid dosage forms can be supplied as ready-to-use liquids or powders for reconstitution. They are administered by oral and parenteral (injectable, inhalation, ophthalmic, otic, nasal, and topical) routes. Oral liquids are nonsterile, whereas liquids administered by the parenteral route are available as sterile and nonsterile formulations.

This article details the various classifications of liquid dosage forms, excipients used in the formulation of liquid dosage forms, packaging and labelling of liquid dosage forms, quality control and assurance of liquid dosage forms as well as the advantages and disadvantages of liquid dosage forms.

Classification of Liquid Dosage Forms

Liquid dosage forms are broadly classified into two groups:

1. Monophasic liquid dosage forms
2. Biphasic liquid dosage forms

1. Monophasic liquid dosage forms

This is the simplest form of presenting medication for rapid and high absorption of medicinal products. It is a one-phase system consisting of two components, solute (the component that gets dissolved) and the solvent (the medium in which solute dissolves).

The monophasic liquid dosage forms are further classified into

1. Liquids for oral use e.g., mixtures, linctuses, draughts, elixirs, syrups, and drops
2. Liquids for external use e.g., lotions, liniments and collodions
3. Liquids for special use e.g. gargles, mouthwashes, throat paints, eye drops, eye lotions, ear drops, nasal drops and sprays, douches, enemas, inhalations and aerosols.
4. Parenteral solutions (injections)

i. Monophasic liquid dosage forms for oral use

This class of monophasic liquid dosage form comprises one phase pourable pharmaceutical formulations intended for oral use. Examples include mixtures, linctuses, draughts, elixirs, syrups, and drops.

a. Mixtures

Pharmaceutical mixtures are liquid oral preparation consisting of one or more medicaments dissolved, suspended or diffused an aqueous vehicle. They are usually freshly or recently prepared and are used fairly quickly, usually within a month for short term therapy like cough, diarrhoea, constipation etc.

Mixtures are further classified into five different groups

1. Simple mixtures containing soluble substances
2. Mixtures containing diffusible solids; that is, solids which do not dissolve in water, but may be mixed by shaking. As a result, it is evenly distributed throughout the liquid for sufficient time.
3. Mixtures containing indiffusible solids; that is, solids which are not dissolved in water and do not remain uniformly distributed in the solvent for sufficiently long time.
4. Mixtures containing precipitate forming liquids and
5. Mixtures containing slightly soluble liquids

Note:  The term ‘mixture’ may also be applied to a suspension.

b. Linctuses

Linctuses are viscous oral liquids containing one or more medicament dissolved in a vehicle that usually contains high proportion of sucrose or other sugars. They are chiefly used as demulcent, expectorant or sedative principally in the treatment or relief of cough. As such, linctus is intended to be sipped slowly in small doses and allowed to trickle down the throat in an undiluted form. This gives maximum and prolonged effect of medicament in the throat.

c. Draughts

A draught is an older term used to describe liquid oral preparations which contain only one or two large doses. The volume of the formulation is usually larger than that generally utilised in traditional mixture formulations and each dose is supplied in separate bottles.

d. Elixirs

Elixirs are clear, flavoured, sweetened, hydroalcoholic liquid oral preparations that usually contain either potent or unpleasant-tasting drugs. They may be medicated or nonmedicated. Compared to syrups, elixirs are usually less sweet and less viscous because they contain a lesser amount of sugar. Because of their hydroalcoholic character, elixirs are better able than are syrups to maintain both water-soluble and alcohol-soluble components in solution.

e. Syrups

Syrups are concentrated aqueous solutions containing one or more sugar components, chiefly sucrose, or sugar substitute. The concentration of sugar in syrup is 66.7 % W/W. Syrups may be medicated or nonmedicated. The nonmedicated often referred to as simple syrups are used as vehicles for medicinal substances to be added later, either in the extemporaneous compounding of prescriptions or in the preparation.

f. Drops (Paediatric drops)

Drops are liquid preparations of potent drugs usually in solution that are intended to be administered in small volumes with the aid of a suitable measuring device (calibrated dropper) to paediatric patients.

ii. Monophasic liquid dosage forms for external use

This class includes liquid preparation such as lotions, liniments and collodions

a. Lotions

Lotions are solutions, but may also be suspensions or emulsions, intended for external application to the skin. They are rubbed on the skin without friction with the help of some absorbent material such as cotton, wool or gauze soaked in it. In some cases, lotions are applied to the scalp, where the vehicle for the medication is alcohol based, allowing for rapid drying of the hair and thus making the product more acceptable to the patient (e.g. Salicylic Acid Lotion 2% BPC). In these cases, problems of flammability are addressed by suitable labelling.

b. Liniments

Liniments are liquid preparation intended to be rubbed with friction and massaged onto unbroken skin to obtain analgesic, rubefacient or generally stimulating effects. They are usually solutions of oils, alcohols or soaps, but may be formulated as emulsions.

c. Collodions

Collodions are principally solutions of pyroxylin in a vehicle of ether and alcohol that are intended to be painted onto the skin using a brush or rod and left to dry. When dry, the collodion leaves a protective film covering the site. Collodions are highly volatile and highly flammable and care should be taken to label any preparation appropriately.

iii. Monophasic liquid dosage forms for special use

These include

a. Gargles

Gargles are aqueous solutions containing antiseptics, antibiotics, and/or anaesthetics that are intended for prevention or treatment of throat infections. They are generally formulated in a concentrated form.

b. Mouthwashes

These are aqueous solutions with pleasant taste and odour intended for local treatment of the membranous lining of the mouth and gums. They generally contain antibacterial agents, alcohol, glycerine, sweetening agents, flavouring agents and colouring agents.

c. Throat paints

Throat paints are viscous liquid preparations that are applied with the help of a brush to the mucosa of the mouth or throat. Glycerine is commonly used as a base in throat paints because it possesses a sweet taste and it adheres to mucous membrane for a long period.

d. Eye drops

These are sterile solution or suspensions of drugs that are instilled into the eye with a dropper. The eye drops are usually made in aqueous vehicle. It should be isotonic with lachrymal secretions, buffered and free from foreign particles to avoid irritation to the eye.

e. Eye lotions

Eye lotions are sterile aqueous solutions used for washing the eye. They are supplied in concentrated form and are required to be diluted with warm water immediately before use. Eye lotions are generally used to remove foreign substances from the eye.

f. Ear drops

These are medicated solutions of drugs that are instilled in to the ear with a dropper. These are generally used for cleaning the ear, softening the wax and for treating the mild infections.

g. Nasal drops and sprays

Nasal drops are solutions of drugs that are instilled into the nostrils with the help of a dropper. Nasal sprays are the same preparations as nasal drops but instilled into the nostrils in the form of a spray. Both formulations intended for administration to the nasal cavities to obtain a systemic or local effect.

h. Douches

Douches are liquid preparations used to cleanse deodorize, soothe or medicate wounds, body orifices or cavities.

i. Enemas

Enemas are liquid preparations often formulated as solutions (though they may be presented as an emulsion or suspension) and are intended for rectal administration. They are used for cleansing, therapeutic or diagnostic purposes.

j. Inhalations

They are preparations containing volatile substances. They are used to relieve congestion and inflammation of the respiratory tract. They are added to hot water and the vapours are inhaled.

k. Aerosols

Aerosols are liquid preparations dissolved in a solvent. The solvent is a gas. It is delivered in the form of a spray. It is mainly used for treating asthma and also for migraine.

iv. Parenteral Solutions (Injections)

Parenteral solutions are sterile drug solutions intended for administration by needle or pressure syringe. Drugs may be injected into most any vessel or tissue of the body, but the most common routes are intravenous (IV), intramuscular (IM), and subcutaneous (SC).

Parenteral solutions may be small-volume injections, packaged in ampules for single-dose administration, or vials for multiple-dose injections. Large-volume parenterals containing 100 mL to 1 litre of fluid, are intended for the slow intravenous administration (or infusion) of medications and/or nutrients in the institutional or home care setting

2. Biphasic liquid dosage forms

Biphasic liquid dosage form is one which contains two phases. A good example of such liquid dosage form is suspensions and emulsions.

i. Suspensions

Suspensions are biphasic liquid dosage forms containing essentially insoluble finely divided solid particles or drug(s) suspended with the help of a suspending agent(s) in a liquid medium. The solid particles act as disperse phase whereas liquid acts as a continuous phase.

ii. Emulsions

An emulsion is a biphasic liquid preparation containing two immiscible liquids (usually oil and water) one of which is dispersed as minute globules into the other and rendered homogeneous by the addition of an emulsifying agent. The liquid which is converted into minute globules is called the disperse phase and the liquid in which the globules are dispersed is called the continuous phase.

Emulsions are of two types

1. Oil in water type (O/W): Emulsion in which oil is in the dispersed phase whereas water is in the continuous phase.
2. Water in oil type (W/O): Emulsion in which water is in the dispersed phase whereas oil is in continuous phase.

Excipients used in the formulation of liquid dosage forms

Liquid dosage forms are prepared by combining drug substance(s) with different excipients. These excipients serve a variety of function in the liquid formulation; however, several excipients behave differently at different concentration and one excipient can be used for multiple purposes depending upon the need of the dosage form.

When formulating liquid medicines, it is essential to ensure that all the different excipient used is physically and chemically compatible with the drug substance and every other component of the formulation. Below is a list of common excipients generally used in the formulation of liquid dosage forms.

Excipients	Role	Example(s)
Solvents/ vehicles	Liquid in which drugs and other excipients are dissolved or dispersed.	Purified water, alcohol, acetic acid, acetone, vegetable or mineral oils, organic oily bases, emulsified bases etc.
Co-solvents	Enhance solubility of drug substance in the vehicle	Ethanol. glycerol, propylene glycol etc
Surfactant	Enhance solubility of drug substance in the vehicle	Cetrimide, sodium lauryl sulphate, triethanolamine
Preservatives	Prevents microbial growth in the formulation	Parabens, phenylmercuric nitrate, sodium benzoate, benzalkonium chloride
Viscosity modifiers	Control the viscosity of the formulation	Cellulose polymers, polyvinyl pyrrolidone, alginic acid, xanthan gum
Buffers	Regulate the pH of the formulation	Phosphate buffers, Acetate buffers, Citric acid Phosphate buffers etc
Antioxidants	Control oxidation	Sodium bisulphite, ascorbic acid, butylated hydroxytoluene etc
Thickening agents.	Prevent settling/sedimentation, modify viscosity.	Methylcellulose, Hydroxyethylcellulose, Microcrystalline cellulose etc.
Chelating agents	Enhance stability of drug substance	Disodium edetate, phosphoric acid
Sweeteners	Enhance the palatability of oral liquid formulations	Sucrose, saccharin, aspartame, sorbitol
Flavouring agents	Enhance the palatability of oral liquid formulations	Lemon oil, orange oil, peppermint, menthol
Colourants	Enhance the aesthetic appearance of the formulation	Amaranth, Erythrosin, Eosin, Tartarazine etc.
Antifoaming agents	Discourage formation of stable foam	Simethicone, Organic phosphates, Alcohols, Paraffin oils, Sterates and glycols.
Humectants	Retard evaporation of aqueous vehicles from dosage forms	Propylene glycols, Glycerol, Polyethylene glycol etc.
Emulsifying agents	Prevent coalescence of the dispersed globules	Sodium Lauryl Sulphate, Cetrimide, Macrogol esters, Sorbitan esters etc.
Flocculating agents	Prevent caking	Starch, Sodium alginate, Carbomer.etc.
Excipient used in aerosol Propellant	Developing pressure in container which expels the product	Trichloromonofluoromethane, Dichlorodifluoromethane, etc.

Manufacture of liquid dosage forms

Most liquid dosage forms are prepared:

1. by simply dissolving the solutes (active pharmaceutical ingredient and excipients) in an aqueous or nonaqueous solvent or solvent mixture;
2. by suspending the solutes in appropriate medium;
3. by incorporating the solutes into an oil or water phase.

On an industrial scale, they are prepared in large mixing vessels with ports for mechanical stirrers. The vessels are generally thermostatically controlled to maintain a certain temperature if desired. The order of addition of components is fixed through product development and scale-up exercises.

Packaging of liquid dosage forms

Liquid dosage forms vary widely both physically and chemically, and in the ways they are distributed and used. Consequently, the materials from which the containers and packaging components are made also vary considerably and these containers are usually in direct contact with the formulation. For stability concerns, the container must not physically or chemically interact with the product so as to alter the strength, quality, or purity of the product beyond the official requirements.

Liquid dosage forms that contain light-sensitive active ingredients should be supplied in containers that are light resistant. If the preparation contains volatile ingredients, the liquid preparation should be kept in a tightly closed container. Except where indicated in the individual monograph, containers used in packaging liquid preparations for parenteral and oral use should be made from material that is sufficiently transparent to permit the visual inspection of the contents.

Labelling of liquid dosage forms

Every pharmaceutical preparation must comply with the labelling requirements established under Good Manufacturing Practice. The label should include:

1. The name of the pharmaceutical product
2. The name(s) of the active ingredients; International Nonproprietary Names (INNs) should be used wherever possible
3. The amount of active ingredient in a suitable dose-volume
4. The name and concentration of any antimicrobial preservative and the name of any other excipient
5. The batch (lot) number assigned by the manufacturer;
6. The expiry date and, when required, the date of manufacture;
7. Any special storage conditions or handling precautions that may be necessary
8. Directions for use, warnings, and precautions that may be necessary
9. The name and address of the manufacturer or the person responsible for placing the product on the market.

If the Liquid preparation is supplied as granules or powder to be constituted just before issue for use, the label should include:

1. That the contents of the container are granules or powder for reconstitution
2. The strength as the amount of the active ingredient in a suitable dose-volume of the constituted preparation
3. The directions for preparing the liquid including the nature and quantity of liquid to be used
4. The storage conditions and shelf-life of the constituted preparation.

Quality assurance and quality control/ Evaluation of liquid dosage form

Like any other dosage form, liquid dosage forms have specifications for drug substance and drug products. To ascertain batch to batch uniformity and to ensure stability of the products over the recommended shelf life, manufacturers follow those specifications. An established and validated stability-indicating assay method is the key to quality control/quality assurance. Some of the parameters that are routinely monitored for liquid dosage forms are content uniformity, viscosity, pH, colour, and odour. The efficacy of the preservative over the shelf life also should be monitored. For suspensions and emulsions, the effect of storage on flow properties and particle size also should be monitored.

Advantages of liquid dosage forms

1. Liquid dosage forms (for oral use) are the most suitable dosage form for patients who have difficulty taking tablets or capsules, as might be the case with paediatric or geriatric patients.
2. They are attractive in appearance and gives beneficial psychological effects.
3. Drugs with bitter and unpleasant taste can be given in sweetened, coloured and flavoured vehicles.
4. There is higher flexibility in dosing when compared to solid dosage forms like tablet and capsules. The dose of the drug substance can be easily and conveniently adjusted by measuring a different volume.
5. If given orally, liquid dosage forms are rapidly available for absorption than tablets and capsules.
6. Hygroscopic and deliquescent medicaments which are not suitably dispensed in solid dosage forms can easily be given in liquid dosage form.
7. The products like adsorbents and antacids are more effective in liquid dosage form.
8. The liquid dosage form is expected for certain types of products like cough medicaments

Disadvantages of liquid dosage forms

1. Liquid dosage forms are usually more susceptible to chemical degradation when compared to solid dosage forms.
2. They are bulky and therefore inconvenient to transport and store.
3. Accidental breakage of the container results in loss of whole dosage form.
4. The shelf-life of a liquid dosage form is often much shorter than that of the corresponding solid preparation due to low stability.
5. Solution often provides suitable media for microbial growth and may, therefore, require the incorporation of a preservative.
6. Liquid dosage forms e.g., vaccines may require special storage conditions
7. The taste of a drug which is usually unpleasant is always more prominent when in solution than in a solid form.
8. There is a higher chance of dose variability since the delivery of the dose depends upon the patient measuring the proper volume. This can be significant issue for vision-impaired patients, patients with arthritis, or patients unable to read the numbers on an oral dosing syringe or medicine cup.

References

• Ansel, H. (2010). Pharmaceutical Calculations, (13th ed.). London: Wolters Kluwer Health and Lippincott Williams & Wilkins.
• Chaudhari, S. and Patil, P. (2012). Pharmaceutical Excipients: A review. International Journal of Advances in Pharmacy, Biology and Chemistry, 1(1): 21-34.
• Denton, P. and Rostron, C (2013). Pharmaceutics: The Science of Medicine Design. United Kingdom: Oxford University Press.
• Gautami, J. (2016). Liquid Dosage Forms. Nano Science & Nano Technology, 10(3):1-9.
• https://www.who.int/medicines/services/expertcommittees/pharmprep/QAS07_191_rev1monoOralliquidsOct07.pdf
• Marriott, J., Wilson, K., Langley, C., and Belcher, D.(2010). Pharmaceutical Compounding and Dispensing (2nd ed.). UK: Pharmaceutical Press.