Lactose in Pharmaceutical Applications

INTRODUCTIONLactose is a naturally occurring simple carbohydrate, or sugar, found only in the milk of mammals. For this reason, it is also commonly referred to as “milk sugar.” All commercial lactose is obtained from the milk of cows as a by-product of the dairy industry. Chemically, lactose is the disaccharide of the simple sugars D-galactose and D-glucose (Figure 1). In other words, the lactose molecule comprises one molecule of D-galactose chemically linked to one molecule of D-glucose. Lactose exists in two isomeric forms, known as alpha and beta (designated a-lactose and b-lactose).

Pharmaceutical-grade lactose is highly pure lactose specifically produced to meet the standards of identity and purity set down in the lactose monographs of the various pharmacopoeia, including the United States Pharmacopoeia/National Formulary (USP/NF). Lactose is widely used as a filler or diluent in tablets and capsules, and to a more limited extent in lyophilized products, infant feed formulas, and a diluent in dry-powder inhalations.^1-9

GENERAL PROPERTIES OF LACTOSE AS AN EXCIPIENT

Lactose is widely used as a filler or filler-binder in the manufacture of pharmaceutical tablets and capsules. The general properties of lactose that contribute to its popularity as an excipient are its:

• cost effectiveness;
• availability;
• bland taste;
• low hygroscopicity;
• compatibility with active ingredients and other excipients;
• excellent physical and chemical stability; and
• water solubility

Various lactose grades are commercially available that have different physical properties, such as particle size distribution and flow characteristics. The most common form of lactose used in pharmaceutical formulation is crystalline a-lactose monohydrate. This form is available in a range of milled and sifted pharmaceutical grades differing in physical properties, such as flowability, bulk density, and particle size distribution (Figure 2).

Lactose is also available in modified forms for use as a filler-binder in the production of tablets by the direct compression method. The two most important forms for this application are spray dried lactose and anhydrous lactose (Figure 3). These forms have the key property that they are inherently compactable, that is, they are able to form a solid compact (ie, tablet) under compression.

PHARMACEUTICAL APPLICATIONS OF LACTOSE

In order to make tablets or capsules, a blend of excipients and active ingredients must first be prepared. In its final form, as the tablet press or capsule filling feed material, this blend is referred to as the running powder. Three major processes are used to prepare the running powder from its components; these are:

• wet granulation;
• dry granulation or slugging; and
• dry mixing.

For wet granulation, the binder can be added dry to the powder blend, or as a solution in the solvent. The solvent is usually ethanol, water, or a mixture of both. The actual granulation is performed in either a high-shear, or low-shear type mixer. Low-shear granulation requires cheaper equipment and produces a more porous granule. High-shear granulation is faster and affords good control over particle size.

The finer milled grades are commonly used as fillers in the production of tablets by the wet granulation, or in applications in which a small particle size is required. The coarser sifted grades are used when flowability is important, for example, as diluents in capsule and sachet filling applications, and as a flow improver. Some sifted grades are also used as fillers in granulation and direct compression formulations, although they must be used with a binder, as crystalline a-lactose monohydrate has little inherent compactability.

Fluid bed wet granulation is another
variation of the process in which the granulation and drying is carried out in the same vessel (a fluid bed granulator). The powder mix is fluidized by dry air inside a chamber. The binder solution is sprayed onto the fluidized powder to form the agglomerates. Air fluidizing continues until the agglomerates are dry. The process requires expensive equipment, but is simpler and produces a very porous low-density granule, which can result in faster drug dissolution. Slow drug dissolution is sometimes a problem associated with wet granulation, as the active ingredient is locked into the granule, and initial tablet disintegration liberates the granules rather than the primary drug particles.

In dry granulation, particle size enlargement is achieved by aggregating the powder particles under high pressure (ie, by compaction) then milling the compressed material to the desired size. Fines generated by milling are recycled back through the compactor. The compression step is typically carried out in a roller compactor in which the powder is compressed between two rollers.

In direct compression, the key running powder requirements (principally blend homogeneity, consistent bulk density, flow, and compactability) must be met by the dry blend of excipients as there is no further physical or chemical modification before tableting. Thus, the physical and functional properties of the excipients, particularly the filler-binder, are very important and must be consistent from batch to batch.

Anhydrous lactose for direct compression is usually produced by drying a lactose solution on the surface of a heated drum. This results in a product composed of agglomerated small crystals of anhydrous b-lactose, with some anhydrous a-lactose present. The anhydrous product has excellent compactability and high solubility due to its high b-lactose content. Tables 1 through 4 are examples of direct compression tablet formulations that use a highly compactable lactose powder composed of agglomerated micro-crystals of anhydrous beta-lactose and stable anhydrous alpha-lactose as a filler-binder.

SUMMARY

Generally, the grade of lactose chosen is dependent on the type of dosage form being developed. In addition to the general properties of lactose, several characteristics of lactose will be beneficial to the pharmaceutical formulations if the lactose could offer BSE-free status, very high purity / low protein residue, excellent functionality, special modified forms for direct compression applications, and Calf Rennet Free pharmaceutical lactose.

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REFERENCES

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