Within two broad categories, many types of liquid oral doses exist, each best suited to certain types of active pharmaceutical ingredients and target effects.
Pediatric and geriatric patients comprise two of the largest sectors of pharmaceutical consumers. Since patients in both of these demographics may struggle to swallow large capsules and similar dosage forms, liquid oral solutions and other liquid oral forms provide ideal routes of administration.
But while liquid oral dosage forms provide more flexibility in dosage than capsules, and absorb more quickly into bodily fluids and tissues, they are not without their drawbacks. Liquid oral doses are often less stable than solid forms, and are also bulkier. In addition, they typically have shorter lives, and are more susceptible to contamination, than solid oral doses. All these factors make liquid oral doses more challenging to store and transport.
The overall category of liquid oral doses encompasses a wide range of dosage forms, categorized broadly as monophasic and biphasic. While dosage forms in both these categories include at least one active pharmaceutical ingredient (API) in a liquid delivery system, monophasic forms are homogeneous and fully dissolved in the liquid, while biphasic forms are not dissolved in the vehicle.
A wide range of dosage forms within these two broad categories can be suited to various APIs, target patient demographics, and other related factors. In addition to their API(s), liquid oral dosage forms may also include emulsifiers, stabilizers, solubilizers, and agents designed to thicken, sweeten, color and/or preserve the formulation.
This article will analyze the basic criteria used to categorize various types of monophasic and biphasic liquid oral dosage forms. Along the way, it will assess the advantages and disadvantages of oral solutions in many of these categories, providing a clearer picture of a pharmaceutical developer’s options in this sector.
Monophasic liquid oral dosage forms include syrups, spirits, elixirs and extracts.
In a monophasic liquid oral dose, the API is completely dissolved in a solvent, such as water, glycerine, ether or alcohol. One of the most widespread monophasic forms is syrup, a viscous solution containing one or more APIs, along with large amounts of sugar or another sweetening agent. In addition to improving the taste of the formulation, sugars can also help prevent crystallization and stabilize pH. The syrup may also contain some amount of ethanol, which helps preserve the formulation, extending its shelf life.
Because of their saccharine components, which may be supplemented with natural and/or artificial flavorings, syrups frequently taste more palatable than other liquid oral dosage forms. Their high viscosity can also enable the delivery of menthol and other soothing agents directly to mouth and throat tissues, helping ease irritation and coughing. Doses of syrups are also easy to adjust, making these dosage forms ideal for pediatric patients.
A widespread variation on syrup is an elixir, which often contains much higher concentrations of sucrose and ethanol than a typical syrup does. Although elixirs are less effective at masking unpleasant tastes than syrups are, they are better able to preserve APIs that easily degrade in water or diluted ethanol. Spirits represent another common class of monophasic liquid oral dosage forms. In a spirit, a volatile API is dissolved in alcohol or a hydro-alcoholic solution, which may also contain flavorings and/or aromatic components to improve its taste and odor. In some cases, a fluid extract may be best suited to preserving a therapeutic material extracted from plant matter. And if an antiseptic or analgesic is to be administered directly into the patient’s oral cavity, a monophasic mouthwash may be best suited to the task.
Biphasic liquid oral dosage forms include suspensions, emulsions and mixtures.
When the API does not dissolve in the solvent(s), a biphasic liquid oral dosage form is the result. One of the most common types of biphasic oral doses is a suspension, in which the API is suspended in a base. Although particles of the API may gradually settle to the bottom, they will re-disperse throughout the fluid when the dosage container is shaken.
In oral emulsions, meanwhile, solid APIs unstable in water can be stabilized in a dispersion containing both oil and a small amount of water. As in a suspension, particles of the API that settle to the bottom of the container can be re-dispersed by shaking. Emulsions are often highly stable, and can preserve water-soluble APIs over an extended shelf-life.
Mixtures contain one or more APIs suspended or dispersed in a liquid base, to be re-dispersed upon shaking. And in a linctus, the API is suspended in a highly viscous fluid containing a high percentage of sugar, resulting in a cough treatment that can be swallowed directly, without the assistance of water.
Both monophasic and biphasic liquid oral dosage forms involve common concerns.
Whether an oral liquid contains the API in solution, suspension, emulsion, or any other form, its liquid base must be selected carefully to ensure palatable taste, reasonable viscosity, and effective preservation of the API over the product’s intended shelf-life. Excipients such as thickeners, flavorings, sweetening agents and pH stabilizers must also be vetted, in order to ensure they will not interfere with the API’s stability and efficacy. Moreover, if the dosage form is intended for pediatric use, its concentration of any sweetening agent should not exceed 5mg/kg of the body weight.
Throughout the development, manufacturing, packaging, distribution and storage of any liquid oral dosage form, care must be taken to ensure preservation of the API, as well as effective prevention of microbial contamination. The solution should not undergo dilution at any point in the supply chain, unless this is expressly required. And oral solutions stored for any period should be regularly re-assessed for potency and stability, prior to administration.
Pharmaceutical developers who follow these guidelines, and who partner with contract manufacturing organizations (CMOs) who are equally committed to these standards, will be well positioned to produce liquid oral dosage forms that remain shelf-stable, while also providing texture, flavor and aroma that make them pleasant for patients to receive.
