Diluents and fillers in pharmaceuticals

Diluents and fillers are a ubiquitous class of materials in formulated products, including pharmaceuticals, medical devices, vaccines, nutraceuticals, cosmetics and industrial goods. But what exactly are diluents and fillers? Do they perform any function beyond filling up space? This technical note provides an introductory review of pharmaceutical diluents and fillers. The information will be particularly relevant to anyone interested in learning more about fillers and diluents.

Definition of Pharmaceutical Diluents and Fillers

For the vast majority of medical products in current use, the active pharmaceutical ingredient is rarely administered in its basic form. Often, this is because it is present in much lower amounts relative to the weight of the dosage form unit.

A specific type of excipients known as bulking agents are therefore added to product formulations to provide bulk and render the product convenient to process, manufacture or administer.

Alternative names for fillers and diluents are:

carriers

fillers

diluents

extenders

voluminising agents

Not every formulation requires a diluent – in product formulations where the active ingredient or other functional excipients are already added in sufficient proportions, for instance, greater than 70 – 90% a bulking agent may not be required.

When added, however, and despite their humble name, pharmaceutical fillers do a lot more than just fill space. Here are some of their functions: add structure aid application e.g., mouth feel impact appearance influence many quantifiable properties that are important to a product’s performance.

In solid dosage forms, fillers and diluents are almost always required as they provide the foundation upon which the formulation is constructed.

For convenience of administration (holding and swallowing, for instance), a tablet should weigh no less 50mg, and where the active ingredient is present in very low quantities, a diluent with high carrying capacity is absolutely essential. This is an important consideration, particularly today given the increasingly high percentage (and growing) demographic of seniors across the world. Click here to read about the importance of applying empathy in new drug development.

Diluents and fillers are not limited solid dosage forms only – their usage also applies to many other product types, including topical creams and lotions, parenteral products, dusting powders, aerosols, suppositories, and suspensions.

Types of Pharmaceutical Diluents and Fillers

Pharmaceutical fillers are very diverse group of excipients. They may be:

organic chemicals

mineral substances

metal oxides

polymers

simple inorganic chemicals,

liquids,

gases (aerosols)

They may be classified on the basis of

source (natural, mineral or synthetic)

dosage form in which they are used

physical and chemical properties and functionality

A more practical approach is to classify fillers as either functional or non-functional.

Functional fillers are those excipients that extend the property gamut of the formulation, opening up new performance qualities and functionalities. For example, silica is frequently added to elastomers and rubbers to provide to the topical medical device strength and structure without compromising drug delivery properties.

Non-functional fillers, as the name suggests, only serve one thing – to provide bulk and fill void volume in the formulation, which is still an important requirement in the formulation for the reasons outlined previously.

The image galery below shows fillers that may be encountered in the pharmaceutical industry:

Ideal Properties of a Pharmaceutical Filler and Diluent

When it comes to pharmaceutical formulations, there are a number of fundamentals properties that formulators seek in fillers:

Physiological inertness

Filler concentration

Particle size and size distribution of the filler

Shape and aspect ratio

Bulk density/carrying capacity

Low API binding capacity

Processability

Physical and chemical stability

Strength (low impact)

Cost-effectiveness

For solid dosage forms (tablets and capsules), the following factors (in no particular order) are the most important considerations when selecting a material to use:

Compressibility and compactibility

Flowability

Particle size and distribution

Moisture content and type of interactions

Bulk density

Compatibility

Solubility and effect on bioavailability

Abrasiveness (lubricity)

Stability

Physiological inertness

Cost and availability

Regulatory acceptance

The 10 Most Popular Filler-Diluents in Solid Dosage Forms

The following fillers are consistently the most commonly used materials in solid dosage forms:

Lactose

Lactose is a natural disaccharide obtained from milk. It consists of one galactose and one glucose moiety. It is listed in the USP-NF, JP and PhEur and is also GRAS listed and included in the FDA Inactive Ingredients Database (IM, and SC: powder for injections; oral: capsules and tablets: inhalation preparations; vaginal preparations).

Lactose is one of the most widely used filler and diluent in tablets and capsules, and to a more limited extent in lyophilized products and infant formulas. Lactose is also used as a diluent in dry-powder inhalation.

Microcrystalline cellulose

Microcrystalline cellulose is purified, partially depolymerized cellulose and one of the most widely used ingredients in the pharmaceutical industry. It is used in many types of dosage forms, including as filler, binder, flow aid, lubricant, texturiser, among others.

Microcrystalline cellulose is listed in all major pharmacopoeia, including the USP-NF, Ph.Eur, BP, JP and IP. It is also GRAS listed and accepted for use as a food additive in Europe and the United States and included in the FDA Inactive Ingredients Database (oral: powders, suspensions, syrups and tablets; topical & vaginal products).

Starch

Starch is a polysaccharide consisting of two polymers: a linear polymer known as amylose and a branched polymer known as amylopectin. Both polymers are made up of glucose residues.

Pharmacopoeia have individual monographs for different starch derivatives, including native starch, pregelatinised starch, tapioca starch, pea starch and rice starch. Starch is also co-processed with lactose and microcrystalline cellulose.

Generally, as a material, starch is a highly versatile material, finding application in many different dosage forms. It is widely used as filler and diluents in solid dosage forms. It is also added to dusting powder and also in topical products and film coatings.

Calcium phosphate

Calcium phosphate is actually a family of chemical substances made up of calcium ions and phosphate anions. These include anhydrous dibasic calcium phosphate, hydrated dibasic calcium phosphate, and tribasic calcium phosphate. All the three grades are listed in the main pharmacopoeia, are GRAS listed and included in the FDA Inactive Ingredients Database.

Calcium carbonate

Calcium carbonate is the calcium salt of carbonic acid. It is listed in all the major pharmacopoeia and is GRAS listed. The FDA Inactive Ingredients Database lists calcium carbonate as an excipient for chewing gum, capsules and tablets.

It is one of the main fillers used in compressed tablets. Other uses are as a bulking agent in tablet sugar-coating processes and as an extender and opacifier in tablet film-coatings.

Sucrose

Sucrose is a naturally-occurring disaccharide made up of a glucose molecule joined to a fructose molecule. Pharmaceutical grade sucrose is currently obtained from sugar cane and sugar beet, and is listed in all the major pharmacopoeia and the FDA Inactive Ingredients Database (parenterals, tablets, capsules, syrups and topical products). It is a highly compressible filler in tablets and selected for its sweetness, low reactivity, safety profile and cost-effectiveness.

Maltodextrin

Maltodextrin is a saccharide consisting of mixture of polymers of D-glucose units. It is prepared by the partial hydrolysis of a starch. It is a non-sweet, odourless, white powder or granules.

Maltodextrin is used as a coating agent, tablet and capsule diluent, tablet binder and viscosity- increasing agent. Maltodextrin is also widely used in confectionery and food products, as well as personal care applications.

Mannitol

Mannitol (D-mannitol) is a polyol and an isomer of sorbitol. It occurs as a white, crystalline powder, or free-flowing granules, with a sweet taste. It is noted for its cooling, sweet sensation in the mouth. It is official in multiple pharmacopoeia as a filler diluent as well as a therapeutic agent.

Mannitol is used as a diluent (10 – 90% w/w) in tablet formulations. It’s specific advantage is its low hygroscopicity and high compressibility. However, it is a costly filler compared with lactose and selected for use where mouthfeel is important, for example, chewable tablets.

Sorbitol

Sorbitol is a polyol and an isomer of mannitol. It is supplied as a white or almost colourless, crystalline, hygroscopic powder. It is available in a wide range of grades and polymorphic forms, such as granules, powders and pellets for use in solid and liquid oral and topical products.

Sorbitol is used as a diluent in tablet formulations prepared by either wet granulation or direct compression. It is especially useful in chewable tablets owing to its pleasant, sweet taste and cooling sensation.

Sodium Chloride

Sodium chloride is an inorganic chloride salt having sodium as the exchangeable ion. It is listed in all the major pharmacopoeia, is GRAS and included in the FDA Inactive Ingredients Database (injections, inhalations, nasal, ophthalmic, oral, otic, rectal and topical products). It occurs as a white, crystalline powder with a saline taste.

Sodium chloride is used widely in parenteral products to produce isotonic solutions. In oral products, it functions as a diluent (capsules and direct compression tablets), and a porosity modifier in controlled-release coatings.

Material	Reason for Popularity	Usage
Lactose (all grades)	Highly compactible	Up to 60% w/w in tablets & capsules
Microcrystalline cellulose	Versatile, inert and low cost	Optimum level is 15-20% w/w in tablets & capsules
Starch (all grades)	Versatile, inert and low cost	Up to 40% w/w as a filler in tablets & capsules
Calcium phosphates	Low moisture content. Source of Calcium	Up to 60% w/w in tablets & capsules
Sucrose	Highly compactible & Sweet tasting	Highly compressible grades up to 90% w/w in tablets, capsules & oral liquids
Maltodextrin	Highly compactible	Up to 50% w/w/ in tablets & capsules
Mannitol	Mouthfeel & highly compactible and inert	Up to 60% w/w in tablets & capsules
Sorbitol	Mouthfeel & highly compactible and inert	Up to 60% w/w in tablets, capsules & oral liquids

Summary about pharmaceutical Fillers and Diluents

Despite their ordinary name, pharmaceutical fillers do much more than simply fill up space. They provide structure, influence appearance, and impact many other measurable properties that ultimately determine product’s end uses.

For solid dosage forms, lactose and microcrystalline cellulose are the most commonly used diluents. Mannitol is used as a substitute for lactose, however it is costly and its use is only justified when other functional properties are sought in a formulation.