Cellulose, Microcrystalline

Pharmaceutical diluents/ Fillers

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Pharmaceutical diluents/ Fillers

Diluents or fillers are materials that are added to bulk up a dosage form when the active ingredient is not present in sufficient quantity to make a compressible tablet or fill a capsule shell. In the case of direct compression, use of the term “filler-binders” is more appropriate because they not only bulk up a dosage form but also provide binding property by imparting strength to a dosage form.

In addition, diluents play an important role in imparting manufacturability by impacting properties such as powder flow, compactability, compressibility, and homogeneity by locking active pharmaceutical ingredient (API) in granules. They also impact quality and performance of the dosage form with respect to tablet friability, content uniformity, dissolution, and stability among other properties.

A mixture of diluents is generally used to circumvent a shortcoming of a single diluent. For example, if lactose is the only diluent used in a formulation, the blend will have a sharp granulation endpoint. By adding some microcrystalline cellulose (MCC), the granulation endpoint is more forgiving due to its high water absorption capacity.

Mixture of diluents may also be used for economical reasons where an expensive diluent may be partially replaced by an inexpensive diluent without impacting the performance of a dosage form. In general, the nature of materials used as diluents generally falls in the broad category of cellulosic materials, sugars, or inorganic salts. Some of the more commonly used diluents are highlighted as follows.

Types of Diluents

Microcrystalline Cellulose

MCC is a purified, partially depolymerized cellulose derived from α-cellulose. MCC is a versatile excipient with application as a diluent, binder, and disintegrant in oral solid dosage forms. It is primarily used as a diluent/binder in direct compression and wet granulation process. As a diluent, it is used in tablet formulations in the range of 20–90% w/w. MCC undergoes plastic deformation and shows good compactability even at low compression pressures.

However, it has poor flow characteristics. It is available in different particle sizes and densities, with larger particle size and higher bulk density helping in the flow characteristics of blends but at the cost of reduced compactability. In direct compression process, it is often used with other excipients due to its comparatively high cost. In dry granulation, MCC is often combined with a diluent such as lactose with brittle compaction property to complement the plastic deformation behavior of MCC. Wet granulation has been known to reduce the compactability of MCC due to change in structure and loss of bonding surfaces.

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Dibasic Calcium Phosphate

Anhydrous and dihydrated forms of dibasic calcium phosphate (DCP) are used as fillers for oral solid dosage forms. It is more commonly used as a source of calcium in nutraceuticals than in the pharmaceutical industry. The popularity of DCP in the pharmaceutical industry is due to its excellent flow and compaction properties. Comparison between the two forms of DCP shows that anhydrous form has better intraparticular porosity, mean yield pressure, and better compressibility than the dihydrate form. In addition, due to higher intraparticular porosity, disintegration of anhydrous DCP is better than the dihydrate form.

However, both forms of DCP do not generate good disintegration force and needs a swelling-type disintegrant in the formulation when used. Different grades of DCP are available, with coarse grade used for direct compression and milled grade for roller compaction or wet granulation. The milled grade has an alkaline pH and cannot be used with API incompatible with high pH. Being an inorganic salt, DCP can be abrasive on the tablet tooling. However, compared to MCC, it is less sensitive to magnesium stearate levels.

Lactose

Lactose is one of oldest and most widely used diluents in an oral solid dosage form. It is commonly used as a diluent and is known to exist in four different forms: α-lactose monohydrate, anhydrous α-lactose, anhydrous β-lactose, and amorphous lactose. Even though pure forms are present, some of the commercially available lactose may be a mixture of multiple forms. α-Lactose monohydrate is prepared by crystallization of a supersaturated solution of lactose below 93.5 ∘C. α-Lactose monohydrate is primarily used in wet granulation process. Even though α-lactose monohydrate contains 5% water of crystallization, the water is unavailable for reaction even if used with moisture-sensitive materials.

Mannitol

It is a widely used diluent in both pharmaceutical and food industries. It is nonhygroscopic and a good choice of diluent for moisture-sensitive drugs. Mannitol also gives up moisture when dried after wet granulation. Due to its negative heat of solution, it provides a cooling sensation and as a result of its good mouth feel, it is a preferred diluent in chewable tablets. It is present in different polymorphic forms and they have different compression characteristics.

Crystalline grades are generally used for wet granulation with the spray-dried grades being used for direct compression. Without spray drying, mannitol has poor flow and binding properties to be used as direct compression excipient. Higher lubricant levels are needed for mannitol-containing granulations than granulations made with other diluents.

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2 thoughts on “Pharmaceutical diluents/ Fillers”

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