A diluent in medication is one or more inert/inactive ingredients that are added to the API(s) of a drug formulation. Diluents are a subclassification of broader category of excipients. Excipients include all inactive/inert substances added to active pharmaceutical ingredients (APIs) that result in a finished drug formulation.

Diluents (also know as fillers) can be solid, liquid, or specialty forms. In addition to diluents, binders, lubricants, coatings, colorants, emulsifiers and solvents are excipient subcategories. In addition to classification by type of excipient, each subcategory can be categorized by whether they are natural, synthetic or both, and by how they are administered, oral, parenteral or topical.

From an industry perspective, the overall pharmaceutical excipients category holds an estimated 2025 value of 9.6 billion USD Diluents represent the largest share of the category at an estimated 41.2% of market share, at more than 4 billion USD in value. Projected category annual growth rate (CAGR) is forecast at 5.75% through 2034.

Knowing more about the functions and properties of diluents is valuable for everyone involved in new drug discovery, development and optimization.

Key Takeaways

• Why diluents are important components in drug formulations
• The types of diluents and their purposes
• Commonly used solid and liquid diluents
• What to consider when selecting diluents
• How diluents can improve patient experience
  

Why are Diluents Used in Medications?

Diluents enable tablets and capsules, suspensions and syrups to be consistently manufactured to meet volume, size, shape, weight, and patient-centered specifications.  Diluents can perform a variety of purposes in the development of drug formulations. This may call for a combination of diluents with a formula, or in some instances, a single diluent is capable of meeting multiple goals.

• Increase the bulk and uniformity of a formula
• Ensure stability
• Reduce concentration/potency
• Change viscosity
• Deliver and support parenterally administrated formulas
• Improve taste, texture
• Regulate disintegration, dissolution and bioavailability of APIs

Without diluents, many APIs could not be delivered to human patients. There would be no framework or mechanism to ensure drug stability, dosage accuracy, consistency, usability and delivery into the human body, whether oral or parenterally delivered.

Types of Diluents in Pharmaceuticals

Of the three categories solid, liquid, specialty/gas, solid diluents are the most widely used. Their prevalence is due to the sheer scale of orally administrated tablets and capsules marketed, and their versatility.

Liquid diluents are required in the manufacture of both oral and parenterally administered medicines. Liquid diluents can act as fillers in oral suspensions or syrups for oral dosing, but like solid diluents, they can often multitask when required. Parenteral liquid diluents act as reconstituting agents for intravenous infusion or injection.

Specialty diluents are those less frequently used. Specialty diluents are seen primarily in biological and immuno-targeted drugs. Specialty diluents are expected to grow exponentially, due to the new challenges in developing diluents suited to emerging immunotherapies, peptides and biologics. The molecular and living nature of biotech formulations require unique diluents that can ensure uniform dosing, purity and stability without interfering with the biologic active substance or therapeutic peptide/protein.

Common Solid Diluents for Oral Dosage Forms

Solid Diluents

Solid diluents, whether organic or inorganic, can act solely as a filler if needed, or as a multi-function additive. Active ingredients (APIs) often represent the smallest physical part of the whole tablet or capsule/powder that must deliver a consistent dose. Solid diluents are available as organic and inorganic ingredients, with organic solid diluents comprising much of the market. Selecting the optimal diluent for a solid form oral medicine calls for compatibility testing with the API of potentially suited diluents. Diluent factors that could impact patient sensitivities, such as allergen risks, high dosages or long-term are addressed through compatibility studies. Failure to address potential risks could cause consumer or clinician reluctance to use the medicine.

Solid diluents offer many benefits, such as these:

• Volume for mixability and uniform API distribution

• Flowability to manage diversity in particle size and density

• Compressibility for hardness, disintegration, drug release

• Stability during storage and shelf life

• Patient experience (taste, appearance, mouthfeel)

  
  

Solid Diluent Examples

 These are just some of the solid diluents used globally in tablets and capsules (or powdered formulas).

• Lactose—organic. A top contender, both cost effective and versatile. Lactose features excellent compressibility and dissolution. Benefits include consistent, even drug distribution, compatibility with different manufacturing processes. Consider potential patient lactose sensitivity when formulating medicines that require high doses or long-term use.

• Microcrystalline cellulose (MCC)—organic. A preferred organic solid diluent for formulations using direct compression. MCC has superb flowability and high binding performance suited to a variety of hardness specifications. Compatible with many APIs.

• Starches—organic. Made from maize, wheat, potato and even rice, starches are cost effective, biodegradable, versatile and safe. Manufacturing environments must have controlled humidity (30-50% RH).

• Mannitol—organic. Mannitol is a polyol or sugar alcohol. It is common in chewable tablets, orally disintegrating tablets (ODT) and pediatric medicines. It is known for chemical stability and compatibility with amine-inclusive APIs. Its higher cost and poor flowability can be limitations.

• Dibasic Calcium Phosphate (DCP)—Inorganic. The leading inorganic solid diluent is chemically inert, although can affect a formula’s pH. DCP is suited to direct compression formulations and provides stability in moisture-sensitive solid dose drugs.
• Calcium Carbonate—Inorganic. A longstanding and safe diluent, this is an effective, economical and eco-friendly filler. It also improves flow and enhances dissolvability.

Liquid Diluents

Liquid diluents are not used to increase the volume of a liquid medicine. Instead, liquid diluents are a means of transferring APIs into the body via injection, intravenously or other parenteral administration. Since the liquid diluent is the immediate medium that encounters blood (or tissue in an intramuscular injection), the solubility of the API, its chemical stability and compatibility are among multiple critical factors to be tested for safe and effective injectables.

Liquid Diluent Examples

• Sterile water—Inorganic. Known as SWFI (sterile water for injection) SWFI is also non-pyrogenic which means it is free from fever-inducing substances and is hypotonic, which is important in managing tonicity (rapid cellular hydration and rehydration).
• Normal saline—Inorganic. Defined as 0.9% Sodium Chloride Injection, normal saline is isotonic, making it a frequent complement with SWFI in intravenous administration. Both are also used as sole diluents in parenteral formulations for specific therapies.
• Ringer’s solution (Inorganic) and Ringer’s lactate (Inorganic salts and organic lactate). Both Ringer’s solutions contain inorganic salts, with the obvious addition of lactate to the Ringer’s lactate solution. Plain Ringer’s solution is often replaced by normal saline or Ringer’s lactate, though it is still used in certain clinical situations. Ringer’s lactate solution is similar to human plasma, provides electrolytes, buffers acid-base balance and is ideal for fluid replacement and drug delivery.
• Propylene glycol—Organic: A common diluent due to its benefits of high dissolving and absorption properties in IV formulations with insoluble compounds. For parenteral formulations with prolonged doses, propylene glycol can present toxicity risks for certain patients.
• Glycerine/Glycerol—Organic or Inorganic: glycerine or “glycerol” is suited as a liquid diluent for topical, oral and IV drugs. It can be sourced from plants or chemically synthesized. Because of its solubility properties, it is effective with insoluble APIs in parenteral delivery. Glycerine has a higher risk of dangerous contamination than other diluents. Multiple FDA guidance and interventions as well as EU concerns have been published. The risks stem from process impurities during manufacturing, supply chain errors, and improper identity and purity testing.
  

How Diluents Work in Drug Formulation

Diluents could be called “quiet guardians” of APIs and therapeutic efficacy for formulations of all kinds. An area to watch for change is how diluents are used in the biologics and immunotherapies sector. Researchers are beginning to ask questions about longstanding tenets about “inactive” ingredients—diluents, whether organic or inorganic—can be used in the same ways they’ve been used in oral and parenteral medicines.

Studies such as this, evaluate new data about how excipients and diluents work in the body as part of a living formulations. The term “inactive” is predicted to be nuanced, with some diluents and excipients preliminarily showing that they may “directly modulate physiologically relevant targets.” Deeper knowledge through a systematic approach to research will pave the way for state-of-the-art data to confirm or redirect the safe administration, potency and contraindications of living formulations.

Safety and Side Effects of Diluents

• Are diluents safe? Yes, diluents are considered safe. As inactive ingredients, sourcing and supply chain responsibility and compliance with drug development and cGMPs, quality and safety measures protect the resulting drug.
• What about possible side effects or allergic reactions from excipients in a formula? There are many safeguards, such as compatibility testing when a drug is in the development phase, that screen for and identify risks for certain patients and health conditions and side effects. There are also many quality and safety checks performed throughout the development and manufacturing process that protect patients and consumers from harm.
• Are there considerations for sensitive patients such as babies, the elderly or people with certain health conditions? For every medicine, the needs of all patient groups are carefully considered when it comes to the formulation of the active ingredients, the excipients and diluents. The extensive regulatory oversight and internal monitoring and validations support the unique sensitivities of vulnerable people.
  
  

Regulatory Resources related to Excipients and Diluents

• EMA excipients guidelines and excipient applications and GMPs.
• International Pharmaceutical Excipients Council.
• FDA excipients guidance.
• There is also the FDA Inactive Ingredients Database Download that comprehensively catalogs pharmaceutical inactive ingredients.

Diluents vs. Other Pharmaceutical Additives

While “excipients” covers many substances and functions in the formulation of new drugs of all types, each is most known for a certain role, even if it possesses multiple capabilities. Diluents, like all excipients, are inactive substances that are added to drug formulations for a specific purpose or as a vehicle to deliver an active pharmaceutical ingredient (API).  Diluents differ from other excipients in their uniquely suited function as filler and bulk-increasing agents. No APIs could be presented to human medicine without excipients of all kinds to enable consistent, safe, effective medicines to reach the field of human health.

 Summary and Key Takeaways

Diluents are critical inactive ingredients within the excipients market that are available as solid, liquid and specialty forms for many functions. Their foundational purpose is to increase the volume of a formula to optimize the delivery and consistency of the API. The characteristics of solid and liquid diluents are diverse. There are many well-established and effective options that are proven, safe and economical to perfect formulas for modern drugs.

The market for diluents is projected for continued growth of 5.75% through 2034.The growing biologic drug market is expected to drive new diluent discovery opportunities to meet the unique challenges of biologics and targeted immunotherapies.

Relying on established and trusted diluents allows your team to proceed with confidence toward a successful launch and positive response in the field. With many emerging advancements and ongoing innovation, keeping an eye on what is happening in diluent development as a key player in pharmaceutical products can open new doors and help you keep pace with market and regulatory change.

Frequently Asked Questions

• What is a diluent?
  A diluent is an inactive ingredient, generally liquid or solid, that is used to increase the volume of the active ingredient in a medicine. It is a subclassification of the broader excipients category of ingredients for pharmaceutical products.
  
  
• Are diluents the same as fillers?
  A diluent acts as a filler, yes. Fillers and diluents increase the volume of a medicine, whether an oral tablet, capsule, liquid or parenteral drug for injection or intravenous (IV) administration. They could be considered different from a filler in one sense, that many diluents can also act in other roles within a formula.
  
  
• Do diluents affect how well medication works?
  Diluents help ensure that the medicine does work as intended. This is done because diluents enable consistent manufacturing results in size, weight, bioavailability, etc. Diluents support the safe delivery of the exact, often miniscule amount, of the active ingredient (API).
  
  
• Why are some medications reformulated with different diluents?
  A medicine may be reformulated for many reasons. Sometimes, a new diluent is found to increase the stability of a formula. In other cases, there is an opportunity to make a change to avoid allergic reactions or side effects. In other cases, a new formula helps patients manage the medicine more easily, for better compliance and results.