LACTOSE, MONOHYDRATE

Chemical Properties

In the solid state, lactose appears as various isomeric forms, depending on the crystallization and drying conditions, i.e. alactose monohydrate, b-lactose anhydrous, and a-lactose anhydrous. The stable crystalline forms of lactose are a-lactose monohydrate, b-lactose anhydrous, and stable a-lactose anhydrous.
Lactose occurs as white to off-white crystalline particles or powder. Lactose is odorless and slightly sweet-tasting; a-lactose is approximately 20% as sweet as sucrose, while b-lactose is 40% as sweet.

Chemical Properties

White or almost white, crystalline powder.

Uses

Excipient.

Production Methods

Lactose is a natural disaccharide consisting of galactose and glucose, and is present in the milk of most mammals. Commercially, lactose is produced from the whey of cows’ milk; whey being the residual liquid of the milk following cheese and casein production. Cows’ milk contains 4.4–5.2% lactose; lactose constitutes 38% of the total solid content of milk.
a-Lactose monohydrate is prepared by crystallization from supersaturated solutions below 93.5°C. Various crystalline shapes are prism, pyramidal, and tomahawk; these are dependent on the method of precipitation and crystallization. Direct compression grades of a-lactose monohydrate are prepared by granulation/ agglomeration and spray-drying.

Pharmaceutical Applications

Lactose is widely used as a 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; seeLactose, Inhalation. Various lactose grades are commercially available that have different physical properties such as particle size distribution and flow characteristics. This permits the selection of the most suitable material for a particular application; for example, the particle size range selected for capsules is often dependent on the type of encapsulating machine used. Usually, fine grades of lactose are used in the preparation of tablets by the wet-granulation method or when milling during processing is carried out, since the fine size allows better mixing with other formulation ingredients and utilizes the binder more efficiently.
Other applications of lactose include use in lyophilized products, where lactose is added to freeze-dried solutions to increase plug size and aid cohesion. Lactose is also used in combination with sucrose (approximately 1 : 3) to prepare sugar-coating solutions. It may also be used in intravenous injections.
Lactose is also used in the manufacture of dry powder formulations for use as aqueous film-coating solutions or suspensions. Direct-compression grades of lactose monohydrate are available as granulated/agglomerated a-lactose monohydrate, containing small amounts of anhydrous lactose.
Direct-compression grades are often used to carry lower quantities of drug and this permits tablets to be made without granulation.
Other directly compressible lactoses are spray-dried lactose and anhydrous lactose; see Lactose, Spray-Dried and Lactose, Anhydrous.

Safety

Lactose is widely used in pharmaceutical formulations as a filler and filler-binder in oral capsule and tablet formulations. It may also be used in intravenous injections. Adverse reactions to lactose are largely attributed to lactose intolerance, which occurs in individuals with a deficiency of the intestinal enzyme lactase. This results in lactose being undigested and may lead to cramps, diarrhea, distension, and flatulence. In lactose-tolerant individuals, lactase hydrolyzes lactose in the small intestine to glucose and galactose, which are then absorbed. Lactase levels are normally high at birth, and levels decline rapidly in early childhood. Malabsorption of lactose (hypolactasia) may occur at an early age (4–8 years) and varies among different ethnic groups. Lactose is excreted unchanged when administered intravenously.
The symptoms of lactose intolerance are caused by the osmotic effect of the unabsorbed lactose, which increases water and sodium levels in the lumen. Unabsorbed lactose, upon reaching the colon, can be fermented by colonic flora, which produces gas, causing abdominal distension and discomfort. A lactose tolerance test has been developed based on the measurement of blood glucose level and the hydrogen level in the breath. However, its usefulness has been questioned as the test is based on a 50 g dose of lactose. Approximately 10–20% of lactose-intolerant individuals, in two studies, showed clinical symptoms of intolerance after ingestion of 3–5 g of lactose. In one of the studies, 75% of the subjects had symptoms with 12 g of lactose (equivalent to 250 mL of milk). In another, eight out of 13 individuals developed diarrhea after the administration of 20 g of lactose, and nine out of 13 after the administration of 25 g.
Lower doses of lactose produce fewer adverse effects, and lactose is better tolerated if taken with other foods. As a result, there is a significant population with lactose malabsorption who are still able to ingest normal amounts of lactose, such as that in milk, without the development of adverse side effects.
Most adults consume about 25 g of lactose per day (500mL of milk) without symptoms. When symptoms appear, they are usually mild and dose-related. The dose of lactose in most pharmaceuticals seldom exceeds 2 g per day. It is unlikely that severe gastrointestinal symptoms can be attributed to the lactose in a conventional oral solid-dosage form, especially in adults who have not previously been diagnosed as severely lactose-intolerant. However, anecdotal reports of drug-induced diarrhea due to lactose intolerance have been made following administration of pharmaceutical preparations containing lactose.
It has also been suggested that lactose intolerance may have a role in irritable bowel syndrome, but this role is currently unclear.
In the past, there have been concerns over the transmissible spongiform encephalopathies (TSE) contamination of animalderived products. However, in the light of current scientific knowledge, and irrespective of geographical origin, milk and milk derivatives are reported as unlikely to present any risk of TSE contamination; TSE risk is negligible if the calf rennet is produced in accordance with regulations.
LD50 (rat, IP): >10 g/kg
LD50 (rat, oral): >10 g/kg
LD50 (rat, SC): >5 g/kg

storage

Mold growth may occur under humid conditions (80% relative humidity and above). Lactose may develop a brown coloration on storage, the reaction being accelerated by warm, damp conditions. The purities of different lactoses can vary and color evaluation may be important, particularly if white tablets are being formulated. The color stabilities of various lactoses also differ. Solutions show mutarotation.
Lactose should be stored in a well-closed container in a cool, dry place.

Incompatibilities

A Maillard-type condensation reaction is likely to occur between lactose and compounds with a primary amine group to form brown, or yellow-brown-colored products. The Maillard interaction has also been shown to occur between lactose and secondary amine. However, the reaction sequence stops with the formation of the imine, and no yellow-brown coloration develops.
Lactose is also incompatible with amino acids, amfetamines, and lisinopril.

Regulatory Status

GRAS listed. Included in the FDA Inactive Ingredients Database (IM, IV, and SC: powder for injections; oral: capsules and tablets; inhalation preparations; vaginal preparations). Included in nonparenteral and parenteral medicines licensed in the UK. Included in the Canadian List of Acceptable Non-medicinal Ingredients.