Oral Liquids | Non-Sterile Solutions & Suspensions

Looking for oral liquid dosage forms? Find a CMO offering pharmaceutical oral solutions, syrups, suspensions & other liquid orals on PharmaCompass.

Q1. What are pharmaceutical liquid dosage forms?

Liquid dosage forms are prepared by dissolving active pharmaceutical ingredients (API) in aqueous and nonaqueous solvents, suspending the API in appropriate mediums, or by incorporating the drug substances into oil or water phases. Pharmaceutical liquids therefore come in a variety of formulations.

Liquid dosage forms are available as monophasic and biphasic formulations. While monophasic liquid dosage forms are true (single phase) or colloidal solutions, liquids which consist of two phases are known as biphasic liquids.

Liquids may also be classified as non-sterile and sterile liquid dosage forms. Sterile liquid products are liquid dosage forms of therapeutic agents that are free from viable microorganisms. Sterile liquids are administered parenterally via the subcutaneous, intramuscular, or intravenous route of drug administration.

Meanwhile, non-sterile liquids are prepared in environments which are clean, but not completely free of microorganisms. These non-sterile liquid drug products are meant for internal or external use. Once a non-sterile liquid dosage form is prepared it can be administered by the oral or topical route of drug administration.

When developing pharmaceutical liquid dosage forms, such as liquid oral dosage forms, consideration is first given to the characteristics of the active drug or drugs selected for administration. APIs thus play an important role in determining the type of liquid pharmaceutical formulations that are formed.

Consideration is first given to the characteristics of the active drug, as the major challenges in contract development and manufacturing services for liquid dosage forms are (i) the stability of a drug in a solution, (ii) the solubility of a drug at the required level, and (iii) acceptable taste.

For the preparation of liquid dosage forms, such as liquid oral dosage forms, a lot of additive ingredients are also needed. Pharmaceutical excipients used in liquid dosage forms may include vehicles, stabilizers, preservatives, suspending agents, emulsifying agents, solubilizers, colors, flavors, etc.

Furthermore, liquid dosage forms offer certain benefits over other specialist dosage forms such as increased patient compliance, faster absorption, and more flexibility in dosing. Some other important advantages of pharmaceutical liquid dosage forms (LDFs) include:

- Very useful for those patients who have trouble swallowing complex oral solid dosage forms.

- Increases patient convenience and patient compliance (e.g. liquid oral dosage forms as compared to oral solid dosage forms).

- Flavors (sweetening agents/sugar) can be added to mask the bitter or unpleasant taste and odor.

- Rate of absorption of a liquid oral dosage form is faster than an oral solid dosage form.

- Liquid dosage forms enable dosing flexibility.

- It is suitable for use by infants, geriatric patients, and those suffering from mental health problems.

- It can be designed for many routes of administration.

Q2. What are the different types of oral non-sterile liquid dosage forms?

Liquid dosage forms serve as drug delivery solutions for both oral drug delivery as well as parenteral routes of drug delivery. However, oral liquids are non sterile, whereas liquids administered by the parenteral route are available as sterile pharmaceutical formulations.

Non-Sterile Liquid Dosage Form

Non-sterile manufacturing involves creating a medication in a clean environment, but does not require the environment to be completely free from all microorganisms.

Liquid dosage forms administered orally are usually available as non-sterile preparations such as oral suspensions, oral solutions, oral syrups, etc. Some topical specialist dosage forms are also present as non-sterile liquid medications including topical solutions, lotions and liniments.

Some Types of Oral Non-Sterile Liquid Dosage Forms:

- Suspensions

Suspensions are a widely used pharma liquid dosage form. They may be defined as preparations containing finely divided drug particles distributed somewhat uniformly throughout a medium in which the drug exhibits a minimum degree of solubility. Non-sterile suspensions facilitate oral drug delivery.

- Solutions

Solutions are defined as liquid preparations, meant to be taken orally, in which active ingredients and various excipients are dissolved in a given solvent. Non sterile solutions are extensively used as oral drug delivery solutions.

- Syrups

Liquid syrups are viscous oral solutions that contain one or more active ingredients. The base contains large amounts of sugar such as sucrose or sorbitol, which can inhibit crystallization, or change taste, base properties and/or modify solubilization.

- Elixirs

They are clear, sweetened hydro-alcoholic oral solutions and are usually flavored to enhance palatability. They are not as sweet syrups and are significantly less viscous than them.

- Drops

Drops are liquid preparations for oral use that are intended to be administered in small volumes with the aid of a suitable measuring device. They may be available in the form of oral solutions, suspensions or emulsions.

- Oral Linctuses

Linctuses are syrupy or sticky solution preparations containing medicaments exerting local action on the mucous membrane of the throat. Oral linctuses are often used to formulate liquid oral syrups for treating coughs.

- Mouth Washes/Gargles

Oral mouthwashes or gargles are solutions designed to treat infections and inflammations of the oral cavity. They are not meant to be swallowed.

Q3. What are the steps involved in the manufacturing of oral solutions and suspensions?

Whether it is a suspension or a solution, the non-sterile manufacturing (offered by CDMOs and CMOs with non-sterile processing capabilities) of oral liquid dosage forms offer a number of advantages: They allow for individual dosing, are easy to swallow and are suitable for pediatric or geriatric applications.

On the other hand, formulators face considerable challenges concerning solubility, API stability in aqueous systems, or taste during the drug product development (pharmaceutical product development) and pharmaceutical manufacturing of liquid orals. If that’s the case, it’s beneficial to outsource drug product development and manufacturing of oral liquids to contract manufacturers, CMOs and CDMOs.

Various CDMOs and CMOs carry out the following steps for the clinical and commercial manufacturing of oral solutions and suspensions:

Step 1: Selecting raw materials

Excipient selection is one of the most important steps in the drug product development (pharmaceutical product development) & pharmaceutical contract manufacturing of oral solutions and suspensions. In suspensions suspending mediums and suspending agents are selected and in solutions suitable solutes and solvents are selected, at this stage.

Step 2: Regulating particle size distribution

The particle size distribution in oral solutions and suspensions development and manufacturing is a critical parameter that significantly impacts the bioavailability and pharmacokinetics of the pharmaceutical product.

Step 3: GMP Manufacturing Process

The following steps are carried out during the non-sterile contract manufacturing for oral solutions and suspensions.

- Manufacturing for Oral Suspensions

1. Grinding insoluble ingredients into a smooth paste with a vehicle containing the wetting agent.

2. Dissolving soluble ingredients in the same portion of the vehicle, adding to paste created in step 1, and making a slurry.

3. Transferring the slurry to a graduated cylinder and rinsing the mortar with successive portions of the vehicle.

4. Adding the vehicle containing the suspending agent (or) flocculating agent to the slurry.

5. Making the dispersion up to the final volume.

- Non-sterile manufacturing for oral solutions

1. Preparing the raw materials, solutes and solvents, for use in the GMP manufacturing process.

2. Preparing the continuous phase of the liquid solutions.

3. Preparing the dispersed phase of the solution.

4. Preparing the finished liquid solution product by dissolving the solutes in the solvents or the dispersed phase in the continuous phase.

Step 5: Scale-Up

Scale-up is generally defined as a manufacturing process which enables increasing batch sizes. In suspension and solution scale-up, a formula is transformed into a viable, robust pharmaceutical product by the development of reliable and practical methods of pharmaceutical manufacturing or contract manufacturing, that affect the orderly transition from laboratory to full-scale production.

Step 6: Packaging

After scale-up, suitable pharmaceutical packaging materials are selected. Once an oral solution or suspension is prepared at a large scale it can be filled into bottles or other packaging materials. Finally, after primary and secondary packaging is complete, the non-sterile liquid drug products are ready for commercialization.

Step 7: Regulatory compliance

All of this pharmaceutical formulation design and drug product development (pharmaceutical product development) work should ultimately culminate into a regulatory filing in accordance with regulatory guidelines for the liquid solution or suspension dosage form.

Q4. What are the different packaging materials available for non sterile liquids?

Primary & Secondary Packaging Contract Services

The packaging presentation of pharmaceutical non-sterile liquid dosage forms (specialist dosage forms) is a critical step in maintaining chemical and physical stability, compliance, adherence, and it facilitates proper handling by the target patient population, caregivers, and health-care professionals

The most common packaging presentations for commercial non-sterile liquid drug products are glass bottles, plastic bottles, practical single-dose sachets, liquid stick packs, etc. Some of these primary packaging materials for liquid dosage forms are explored in detail below.

Primary Packaging

- Glass and plastic bottles

Glass and plastic bottles are primary packaging materials available for the pharmaceutical contract packaging of non-sterile liquid dosage forms. A bottle is defined as a container with a more or less pronounced neck and usually a flat bottom, which is done to protect medicines from superfluous materials. Depending on the material used to prepare the primary packaging bottles, they may be classified into glass bottles or plastic bottles.

- Aluminium caps or plastic stoppers

Aluminium caps or plastic stoppers are primary packaging materials which serve as closures. Closures are defined as any materials used for closing medicinal products in their primary packaging vessels so that the products are properly contained and protected. Closures may be re-opened or closed depending upon a consumer's requirements.

- Liquid stick packs

While glass or plastic bottles are not ready-to-use liquid packaging, liquid stick packs are a type of flexible pouch which serves as a ready-to-use liquid medical primary packaging. The packs themselves are sealed on two shorts ends and have a seal down the back. Ready-to-use liquid stick packs can be emptied almost completely, easily consumed and transported, and are eco-friendly making this type of packaging increasingly popular with consumers.

Secondary packaging

After the oral formulations (pharmaceutical non-sterile liquid dosage forms) are packaged into their primary containers, they undergo secondary packaging offered by contract packagers before they can be distributed. Secondary pharmaceutical contract packaging services provide the packaging that holds together the individual units of a good (primary packaged goods), often grouping them into multipacked units.

It is not designed to hold the drugs (that is the job of primary packaging services), but to deliver mass quantities of the primary packaged drugs to the point of sale or end user. Secondary packaging may include cartons, boxes, trays, bundles, pouches, etc.

Full Service Serialization & Labelling

Full service serialization and labelling activities come into play in both primary and secondary packaging contract services.

- During primary packaging, pharmaceutical serialization serves to assign a unique serial number or serialization code to each saleable unit of a prescription drug product linked to information about the product's origin, batch, and expiration date via the company’s serialization equipment.

- Secondary packaging also undergoes pharma serialization and aggregation. While pharma serialization in itself adds a unique identifier to each product in a serialization line setup, an aggregation solution adds codes to the outside of secondary medical packagings all the way up to cases and pallets. This makes it easier to track medicinal products throughout the supply chain.

Once these primary and secondary packaging activities along with proper serialization and aggregation of the primary and secondary packaging is complete, these goods are ready for distribution. There are many contract packagers or co-packers that enable the outsourcing of primary and secondary packaging contract packaging services as well as full service serialization.

Q5. Which are the leading pharmaceutical contract manufacturers offering liquid dosage forms?

There are numerous CDMOs and CMOs offering integrated pharmaceutical development and manufacturing services and stand alone pharmaceutical contract manufacturing (clinical and commercial manufacturing) for liquid dosage forms. Similarly, there are various contract packagers offering pharmaceutical contract packaging services for non sterile liquids.

Fermion Oy - Liquid drug product manufacturing

Fermion, through its mother company Orion, has manufacturing capabilities for liquids, solutions, suspensions, gels, creams and ointments with potent OEB4-5 APIs. Fermion offers contract development and manufacturing services for hormonal and non-hormonal semi-solids and liquids.

Sharp - Clinical manufacturing services for liquids

Sharp is engaged in manufacturing services for the development of ethical, over-the-counter products including liquids, suspensions, tablets (immediate and controlled release), powders, solid and liquid combination fills, etc.

Wasdell Group - Pharmaceutical contract manufacturing for oral liquids

The Wasdell Group is a fast-growing contract service partner offering end-to-end supply chain services. It also supports customers from clinical to commercial manufacturing, with a particular focus on flexible, small batch packaging & liquid oral or oral liquid manufacturing.

Wasdell’s contract manufacturing team offers agile drug delivery solutions for non-sterile manufacturing requirements. They offer clinical and commercial manufacturing of oral liquid dosage forms.

AMRI - Liquid contract development and manufacturing services

Albany Molecular Research Inc. (AMRI) is a global contract research and manufacturing organization offering integrated pharmaceutical development and manufacturing services, that has been working with the Life Sciences industry to improve patient outcomes for more than two decades.

AMRI offers specialized aseptic development and non-sterile contract manufacturing for oral solutions and other liquid dosage forms for early-stage clinical trials. They have non-sterile processing capabilities offering both sterile and non-sterile contract manufacturing services along with clinical manufacturing for oral solutions.

JGL d.d - Manufacturing of non sterile solution

JGL offers contract development and manufacturing services for non sterile solutions. They have a fully automated filling and packaging line for syrups and drops, for outdoor use, which are dosed in glass or plastic bottles of 10 to 150 ml.

JGL also offers sterile clinical and commercial manufacturing services. They provide a complete suite of integrated pharmaceutical development and manufacturing services for complex oral solid and liquid dosage forms as well as all sterile dosage forms — routinely handling nearly every category of sterile liquid, suspended or lyophilized biological or pharmaceutical product. They also provide commercial and clinical manufacturing for oral solutions and topical solutions.

Quotient Sciences - Phase III clinical supply for suspensions

Quotient Sciences is a global player in commercial drug product manufacturing of small molecule products (oncology, orphan drugs) as well as complex oral solid and liquid dosage forms. They have non-sterile processing capabilities and commercial batch size capabilities for complex oral solid and liquid dosage forms up to 500kg & up to 350L respectively.

Quotient offers contract development and manufacturing services along with clinical manufacturing for oral solutions. They offer manufacturing & testing services for major dosage forms such as solutions, suspensions, capsules, tablets, etc.