Formulation Development of Liquids | Solution & Suspension

Looking for liquid dosage forms? Find a CDMO for the formulation development of syrup, solution, suspension, lotion & other liquids on PharmaCompass.

Q1. What are liquid dosage forms and how are they classified?

Pharmaceutical dosage forms are largely divided into solid dosage forms and liquid dosage forms, as well as semi-solid and gaseous pharmaceutical finished dosage forms. Oral solids include tablets, effervescent tablets, capsules, solid sachets, powders, granules and orally dispersible films, whereas liquid dosage forms are available as liquid oral syrups, pharmaceutical solutions, suspensions, dispersions, etc.

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.

Furthermore, for the preparation of pharma liquid dosage forms, additive ingredients (excipients) are also needed in addition to the Active Pharmaceutical Ingredient (API) or ingredients. These added excipients include vehicles, stabilizers, preservatives, suspending agents, emulsifying agents, solubilizers, colors, flavors, etc.

When developing pharma liquid dosage forms, consideration is first given to the characteristics of the active drug, as the major challenges in oral formulation development & contract 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. The properties of the active pharmaceutical ingredients (APIs) selected for oral administration, therefore, may determine the type of liquid oral formulations that are formed.

Liquid finished dosage forms can be largely divided into two types:

- Monophasic liquid dosage forms such as syrups, linctuses, mixtures, etc. - they have only one phase, the liquid phase.

- Biphasic liquid dosage forms such as suspensions and emulsions - they have two phases, a solid phase and a liquid phase.

Furthermore pharma liquid dosage forms can be classified into the following types:

Oral Liquids - Liquid dosage forms administered orally in the form of pharmaceutical solutions, suspensions and emulsions taken via the oral route of drug administration.

Topical Liquids - Topical liquids are liquid dosage forms administered topically via the dermal route of drug administration.

Sterile/Parenteral Liquids - Sterile liquid products are liquid dosage forms of therapeutic agents that are free from viable microorganisms. Sterile liquids are used as injectable solutions administered parenterally via the subcutaneous, intramuscular, or intravenous route of drug administration.

- Besides topical, parenteral and oral drug delivery, liquids are also used for otic and optic drug delivery.

Liquid dosage forms offer certain benefits over other specialist finished dosage forms such as increased patient compliance, faster absorption, and more flexibility in dosing. Moreover, oral liquid dosage forms are better than tablets or other oral solid dosage forms for patients that have difficulty in swallowing. This makes them the preferred specialist dosage form for pediatric and geriatric patients.

Liquids also absorb faster than oral solids in body fluids and offer flexibility in dosing. Furthermore, liquids are more palatable than oral solid dosage forms. These advantages offered by oral liquids make them an attractive dosage form for oral drug delivery.

Advantages of Liquid Dosage Forms

- Better for patients who have trouble swallowing

- Faster absorption than solids including oral solids

- More flexibility in dosing

- Palatable

- Best choice for geriatric and pediatric patients

Q2. What are oral and topical liquids and what are the different types?

Oral Liquid Dosage Forms

Oral liquids are homogeneous liquid preparations, usually containing a pharmaceutical solution, an emulsion or a pharmaceutical suspension of one or more active ingredients in a suitable liquid base. They are prepared for oral administration either as concentrated pharmaceutical dosage forms or as diluted pharmaceutical dosage forms.

Some Types of Oral Liquid Dosage Forms:

- Solutions

Pharmaceutical solutions are defined as liquid preparations in which active ingredients and various excipients are dissolved in a given solvent. Non sterile solutions are extensively used as dosage forms for the oral drug delivery of therapeutic concoctions.

- Oral Suspensions

In the development of ready-to-use oral dosage forms, oral 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.

- Oral Liquid Syrups

Oral liquid syrups are viscous 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

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

- 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 cough liquid oral syrups.

- 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.

Topical Liquid Dosage Forms

Topical dosage forms are normally presented in the form of topical suspensions, emulsions, lotions, liniments, collodions, paints, etc. They contain one or more active pharmaceutical ingredients (APIs) dissolved or uniformly dispersed in a suitable base with suitable excipients such as emulsifiers, viscosity-increasing agents, antimicrobial agents, antioxidants, or stabilizing agents.

There are several topical solutions available to treat surface wounds which apply directly to damaged tissue. Such formulations facilitate local action, act on the surface of the skin, exert their actions on the stratum corneum, or modulate the function of the epidermis and/or the dermis.

Some Types of Topical Dosage Forms:

- Emulsions

Emulsions are heterogeneous and biphasic, thermodynamically unstable systems containing two immiscible fluids (for e.g. fat and water) stabilized by an emulsifying agent. Emulsions can be administered orally or topically, however, emulsion formulations are not popular for oral ingestion. Instead, they are increasingly used in the preparation of parenteral & topical dosage forms such as ointments, creams, lotions, etc.

- Topical Suspension

Topical suspensions are suspensions for dermatological, cosmetic, and protective purposes. These suspensions are typically colored, and may have some perfume, but they do not contain sweeteners and flavours typically used for oral formulations.

- Lotions

Lotions are usually considered thicker than solutions and more likely to contain oil as well as water or alcohol. A lotion separates into parts with time so it needs to be shaken into a pharmaceutical suspension before use. Lotions are easy to apply to large areas and are also suitable for application to hairy areas.

- Liniments

Liniments are fluid, semi-fluid or, occasionally, semi-solid dosage forms intended for application to the skin. They may be alcoholic or oily solutions or emulsions. Most are massaged into the skin (e.g. counter-irritant).

- Collodion

Collodions are syrupy solutions of nitrocellulose in a mixture of alcohol and ether, used for coating things, chiefly in surgery for cementing dressings and sealing wounds.

- Paints

Paints are liquids for application to the skin or mucous membranes. Skin paints contain a volatile solvent that evaporates quickly to leave a dry resinous film of medicament. Throat paints are more viscous due to a high content of glycerol, designed to prolong contact of the medicament with the affected site.

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

Solutions and pharmaceutical suspensions are the most widely used liquid dosage forms for oral drug delivery. The formulation development of suspension dosage forms involve various steps, explored in detail below.

1. Preformulation development

Preformulation studies primarily help in lead identification during the drug discovery phase. Furthermore, these studies focus on quantifying physicochemical properties of new compounds that may affect drug performance & development of efficacious dosage forms.

The following physicochemical parameters are tested for liquid dosage forms (solutions and suspensions) during the preformulation stage:

- Solubilities of APIs to determine required cosolvents and surfactants.

- pH dependent solution stability.

- Solid form screening for potential poorly soluble salts and hydrates.

- API Particle Size Distribution (PSD) to assess requirements for dose accuracy and physical stability of oral suspensions.

2. Clinical formulation development

Following preformulation development comes clinical formulation development focused on clinical dosage forms. Clinical formulation development pertains to the production of small batches of clinical dosage forms prior to commercial pharmaceutical manufacturing at a full scale.

During the clinical formulation development of solution & suspension liquid oral dosage forms the following is carried out:

- Physical stabilization of suspensions; sedimentation and viscosity, prevention from caking, etc.

- Chemical Stabilization: addition of antioxidants, pH adjustment.

- Dosage form decisions; solution versus suspension.

- Decision on Powder for constitution (PfC) vs. ready to use (RtU) formulations.

3. Commercial formulation development

After the formulation development of clinical dosage forms, comes commercial formulation development. Process definition and development are some of the most crucial parts of commercial formulation development. It is the strategy via which a pharmaceutical contract manufacturing process is identified for a drug substance from an early stage through scale-up and tech transfer to commercial pharmaceutical manufacturing.

During the commercial formulation development of solution & suspension liquid oral dosage forms (liquid orals) the following steps are performed:

- Process definition and scale up.

- Accelerated stability studies to predict shelf life or inuse period.

- Primary stability batches – ICH requirements for stability testing & pharmaceutical manufacturing aspects.

Once the above given formulation development steps are completed, oral liquids such as solutions and suspensions enter the manufacturing stage. Contract manufacturing for oral liquid dosage forms involves the addition of raw materials (excipients and active ingredients) as per the formula, determined during the development stage.

This is followed by the mixing of the raw materials in jacketed vessels with variable mixing speeds. Once all the ingredients are mixed together, filter presses or cartridge filters are employed for the filtration of the medicinal concoction. Finally the liquid dosage forms undergo filling into primary packages after which they are ready for distribution.

There are numerous CDMOs for oral liquids which offer contract development and contract manufacturing for oral liquid dosage forms such as pharmaceutical solutions and suspensions. Some important CDMOs for oral liquid development and manufacturing services are noted in the next question.

Q4. Which are the leading CDMOs offering liquid dosage forms?

There are numerous CDMOs offering pharmaceutical contract development and manufacturing (CDMO) services for liquid dosage forms. Some of the leading CDMOs for oral liquids are listed below.

CDMO for Oral Liquids:

Mission Pharmacal - Formulation development of liquid dosage forms

Mission Pharmacal Company is a privately held pharmaceutical company based in San Antonio, Texas. They offer formulation development for complex oral solid and liquid dosage forms as well as pharmaceutical contract manufacturing for oral liquids.

Mission’s vigorous contract pharmaceutical development and manufacturing services coupled with strategic partnerships enable them to deliver novel healthcare solutions such as topical and oral liquids, topical semi-solids and oral solid dosage forms to the pharmaceutical industry.

JGL d.d - Sterile spray solutions

JGL is an international pharmaceutical company focused on providing pharmaceutical development and manufacturing services for various dosage forms including contract manufacturing for oral liquids .

JGL is a CDMO for oral liquids and sterile drops (for nose & eyes), sterile topical sprays (for nose, throat & ear) and bag on valve technology (for nose, throat, topical application). They also offer formulation development for complex oral solid and liquid dosage forms.

Sai Life Sciences Limited - Liquid oral dosage forms (liquid orals manufacturing)

Sai Life Sciences delivers advanced discovery and contract development and manufacturing (CDMO) services through a broad suite of expert capabilities. They offer formulation development for complex oral solid and liquid dosage forms.

Sai Life Sciences has vast and rich expertise in working across multiple technologies with increasing complexity to develop a variety of specialist dosage forms. They offer contract manufacturing for oral liquids (liquid oral dosage forms) such as non-sterile liquid drug products, solutions and suspensions, emulsions and microemulsions, etc.

Pierre Fabre - Non sterile liquids

Pierre Fabre offers pharmaceutical development and manufacturing services for pharmaceuticals such as non-sterile liquid drug products for customers in France and internationally.

It offers contract development and manufacturing (CDMO) services, from pharmaceutical formulation to commercial pharmaceutical manufacturing for conventional dry forms (tablets, capsules, sachets), lozenges, non-sterile liquid drug products (liquid oral manufacturing for syrups and sprays), paste forms (creams, ointments, gels), etc.

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