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Lactose Monohydrate Excipient | Uses, Suppliers, and Specifications
Lactose Monohydrate (also referred to as α-lactose monohydrate, chemical name: α-D-Glucopyranose, 4-O-β-D-galactopyranosyl-, monohydrate) is a highly purified pharmaceutical excipient obtained from milk as a by-product of the dairy sector. Being a disaccharide, each lactose molecule consists of one molecule of glucose and one molecule of galactose linked together via a β-1,4-glycoside bond. Pharmaceutical-grade lactose is manufactured industrially in compliance with pharmacopoeia quality standards and is available in a variety of particle sizes and crystallinities to meet different formulation needs.
Synonyms and Trade Names: Lactose Monohydrate; 4-O-β-D-Galactopyranosyl-α-D-glucose; Milk sugar; β-D-Gal-(1→4)-α-D-Glc; α-Lactose monohydrate; GranuLac; Lactochem; Pharmatose; PrismaLac; Tablettose
Pharmacopoeia Conformance: USP-NF; Ph. Eur; JP; IP; FCC
Uses and Applications: Tablet and Capsule Filler-Diluent; Lyophilisation Aid, and Tablet Coating Extender/Filler
Description
Lactose monohydrate is actually α-Lactose monohydrate, an anomer made up of one molecule of α-D-glucose, and one molecule of D-galactose linked by a β-1,4-glucoside bond. It contains equimolar amounts of Lactose and water. In the pharmaceutical industry, α-Lactose monohydrate is the most commonly used grade of lactose, whether for the formulation tablets and capsules via wet granulation or direct compression, or for use in dry powder inhalers as a carrier.
In the USP-NF, Lactose monohydrate is described as a natural disaccharide sourced from milk, and consists of one galactose and one glucose moiety. The JP and Ph.Eur, on the other hand, describe Lactose monohydrate as the monohydrate of O-β-D-galactopyranosyl-(1,4)-α-D-glucopyranose. It is supplied as a white to off-white crystalline powdered or crystalline material. Upon analysis, it contains between 70-80% anhydrous β-Lactose and 20-30% α-Lactose.
Lactose: Overview, Types and Key Properties
Lactose (IUPAC name of lactose is 4-O-(β-d-galactopyranosyl)-D-glucopyranose) is a naturally occurring disaccharide that consists of one molecule of β-D-galactose and one molecule of β-D-glucose molecules linked through a β1-4 glycosidic linkage. It is produced by the mammary epithelium of all lactating mammals. To date, milk is the only known significant source of lactose.
For pharmaceutical applications, Lactose is produced from whey as a by-product of the dairy industry. The process involves the crystallisation of a saturated whey concentrate. To minimise risk from contamination from Bovine Spongiform Encephalopathy (BSE), additional refining and purification steps are undertaken, the result of a which are a chemically pure excipient that carries no risks arising from being an animal derived raw material.
Lactose exists naturally in the form of two isomers: α-Lactose (i.e β-D-galactopyranosyl-(1,4)-α-D-glucopyranose) and β-lactose (i.e β-D-galactopyranosyl-(1,4)-β-D-glucopyranose). The two forms have specific optical rotations [α]20D of +89.4o and +35o, respectively, dur to their differences in the spatial positioning of a H-atom and the -OH-group on C1 in the glucose moiety.
Conversion between the two anomers occurs via the open chain form of the glucose moiety, and depending on the concentration and temperature, an equilibrium will establish at [α]20D +55.3o, corresponding to ≈37% α-Lactose, and 63% β-Lactose. Changes in concentration or temperature can shift the equilibrium accordingly (for example, an increase in temperature or concentration increases levels of β-Lactose, and vice versa). At typical conditions, however, Lactose in solution is considered to be a mixture of α-, and β-Lactose.
Crystal Forms of Lactose
Lactose crystallises from solution when its equilibrium solubility is exceeded (for instance, through the removal of water or a lowering of temperature). Various Lactose crystal forms can theoretically form. When Lactose is crystallised under standard processing conditions (typically <93.5 oC), the main crystalline form obtained is the α-Lactose monohydrate form, which is also the most stable form. α-Lactose monohydrate forms exist as hard and brittle ‘tomahawk-like’ crystals and is not hygroscopic. In the hydrated form, this form α-Lactose contains one mole of lactose and one mole of water. The water of hydration can be removed if the α-Lactose is heated to above 140 oC which produces anhydrous α-Lactose.
If the crystallisation is conducted at >93.5 oC, anhydrous β-lactose is obtained. This anomer forms small, kite-like brittle crystals that are brittle but also markedly more soluble. It exhibits minimal hygroscopicity, however, it is unstable, and will transform back to the α-Lactose form given the right conditions.
When a solution of Lactose is spray-dried, the rate of water removal is too rapid for crystallisation to occur. Instead, amorphous Lactose is produced which exists in a glassy state. This form also contains some water of hydration. Amorphous Lactose is hygroscopic and can adsorb water causing crystallisation into the α-Lactose monohydrate as a result of molecular mobility.
As a result of the differences in the physicochemical attributes of the different forms of lactose, grades of Lactose exhibit differences in parameters such as melting point, density, and solubility, and ultimately, in their functionalities when it comes to their uses as pharmaceutical excipients.
Lactose Monohydrate Grades
Lactose monohydrate is supplied in a variety of particle sizes and crystallinities to meet different formulation needs. Some manufacturers can even develop customized characteristics on ad hoc basis. On the whole, the different ranges include:
- Crystalline
- Milled, including Fine and Micronised
- Powdered
- Spray dried monohydrate, and
- Anhydrous grades
Commercial grades of Lactose monohydrate and their respective suppliers are shown below:
| D10, D50, D90 | Example | |
| Standard Grade | 9, 70, 190 | Sheffield™ 310 |
| Coarse Crystals | 60, 150, 240 | PHARMATOSE® 100M; PHARMATOSE® 150M |
| Coarse Powder | 15, 100, 210 | Lactochem® Coarse Powder |
| Fine Crystals | 35, 140, 230 | Tablettose® 100 |
| Fine Powder | 3, 20, 50 | PHARMATOSE® 450M; Lactochem Extrafine |
| Micronised | 0, 3, 7 | Lactochem® Microfine |
| Narrow Particle Size | 9, 80, 140 | PHARMATOSE® 125 |
Chemical Structure & Identifiers
| Chemical Name | O-β-D-Galactopyranosyl-(1->4)-α-D-glucopyranose monohydrate |
| CAS Registration Number | [5989-81-1] |
| Empirical Formula | C12H22O11. H2O |
| Molecular weight | 360.32 |
| EC Number | 200-559-2 |
| UNII Code (FDA) | EWQ57Q8I5X |
Regulatory Status
Lactose monohydrate is an approved pharmaceutical excipient. It has official monographs in the USP-NF; Ph.Eur, B.P; I.P and JP. Lactose monohydrate is also GRAS listed and included in the FDA Inactive Ingredients Database for:
- Injections – IM and powder for injections
- Oral – capsules and tablets
- Inhalation preparations
- Vaginal preparations
A specification for lactose is included in the Food Chemicals Codex (FCC).
Lactose is one of the most commonly used excipients today and has been so for over a century. It is available in various grades, all of which differ in physical properties, such as particle size distribution and flow characteristics.
When lactose is intended for specialised formulations, for instance in inhalation and parenteral administration, additional purity requirements apply. For oral products, the most common form of lactose used is crystalline α-lactose monohydrate.
Physicochemical Properties
| Physical form | Solid |
| Appearance | White to off-white crystals or powder |
| pH value | pH=5.0-8.0 for a 2% w/w aqueous solution |
| Compressibility | Highly compressible |
| Bulk density
Tapped density True density |
0.341 g/ml
0.557 g/ml 1.326 g/ml |
| Melting point | Browns at 190-200 oC; Chars at 225 – 230 oC |
| Glass transition temperature | 170 – 180 oC |
| Moisture content | Adsorbs moisture from the atmosphere; the amount adsorbed depends upon the initial moisture content and the temperature and relative humidity of the environment |
| Solubility | Soluble in cold water; practically insoluble in ethanol (95%) but soluble in mixtures of water and alcohol |
| Specific gravity | 1.26 |
| Ash | ≤1.5% |
| Angle of repose | 35-44 |
| Autoignition temperature | 3600C |
Pharmacopeoeal Specifications
| Test | USP-NF | Ph.Eur |
| Official name | Lactose monohydrate | Lactose monohydrate |
| Authorised use | Excipient | specified |
| Definition | specified | specified |
| Identification | A
B C |
A
B C D |
| Characters | White or almost white crystalline powder | White or almost white crystalline powder |
| Acidity of alkalinity | specified | specified |
| Clarity and colour of solution | specified | n/a |
| Appearance of solution | n/a | specified |
| Specific optical rotation | 54.4o – 55.9o | 54.4o – 55.9o |
| Absorbance
210-220nm 270-300nm 400nm |
≤0.25 ≤0.07 ≤0.04 |
≤0.25 ≤0.07 ≤0.04 |
| Heavy Metals | ≤5 µg/g | ≤5ppm |
| Water | ≤4.5 – 5.5% | ≤4.5 – 5.5% |
| Sulphated ash | ≤0.1% | |
| Microbial contamination
Aerobic bacteria Fungi and yeast Absence of E.coli & Salmonella |
100cfu/g 50cfu/g specified |
100cfu/g 50cfu/g specified |
| Protein and light-absorbing impurities | specified | n/a |
| Loss on drying | ≤0.5% | n/a |
| Assay | n/a | n/a |
| Labelling | specified | n/a |
Key: n/a Specification is not listed
*All claims with respect to conformity are subject to our Terms and Conditions. No express or implied warranty is made for specific properties or fitness for any particular application or purpose.
Applications in Pharmaceutical Formulations or Technology
Lactose monohydrate is one of the most widely used excipients in the pharmaceutical industry despite the availability of alternative excipients, such as Mannitol, Fructose, Trehalose, or Microcrystalline cellulose. It functions in multiple capacities as a:
- Filler and Diluent in Solid Dosage Forms
- Lyophilisation Aid in parenteral (biotechnology) products
- Filler and Carrier in Inhalation Products (Dry Powder Inhalers)
- Infant Formula Nutrition Filler and Nutrient
It has remained popular raw material in the manufacture of tablets, capsules, granules, and powders intended for oral administration owing to the various advantages it offers:
Advantages of Lactose Monohydrate as a Pharmaceutical Excipient
- Fully characterised material
- Favourable physicochemical properties, such as solubility and compactability
- Highly cost-effective
- Wide availability
- Odourless and minimal taste impact
- Low hygroscopicity and stability
- Wide compatibility with many active pharmaceutical ingredients and/or other excipients
Lactose Monohydrate Grades and Selection Criteria
Various lactose grades are commercially available that have different physical properties such as particle size distribution and flow characteristics, and hence, functionality. This allows formulators to select the most suitable material for their particular needs, processes or equipment.
Generally, lactose monohydrate grades can be grouped into two main classes:
- Milled lactose monohydrate grades are produced by pulverising lactose monohydrate to obtain powdered products having specific particle size distributions. The milling process produces fine, sharp-edged crystals that are highly cohesive with poor flowability although they retain excellent compactibility.
- Sieved lactose monohydrate grades are obtained by passing crystalline lactose through a series of sieves in order to obtain materials with narrow particle size distribution ranges. These grades typically have optimised compactibility and blending attributes.
Post-production processing of lactose monohydrate creates additional grades, which include the following:
- Agglomerated lactose monohydrate grades are obtained from fine lactose particles in a wet granulation process. The aim is to obtain a grade that possesses the flowability of coarse crystals but with the excellent compressibility of finely milled lactose. It is ideal for direct tableting due to its excellent miscibility and negligible dust content. The narrower the particle size distribution range, the greater the flowability of the lactose product.
- Spray-dried lactose monohydrate grades exhibit narrow size distribution of highly spherical lactose agglomerates that consist of fine crystals in a lattice of amorphous lactose. Spray-dried lactose is highly compactable, with excellent flowability but with very low dusting potential.
- Anhydrous lactose (β lactose) grades are manufactured by crystallising saturated solutions lactose monohydrate at high temperatures (such as a heated rotating drum). This process eliminates the water of hydration to produce β-lactose, albeit with a proportion of a-lactose.
- Micronised lactose monohydrate consists of very fine milled lactose crystals, (90% <10 µm). They are highly cohesive and ideally restricted for formulating dry powder inhalers or pre-blending with micronized active ingredients to minimise blend segregation.
Note that any one of the above grades is supplied in a number of particle sizes and distributions (<10µm to >400µm), leading to a plethora of product types and grades from different manufacturers.
How to Select a Lactose Monohydrate Grade
- Milled lactose particles show poor flow properties but are highly cohesive and compactible. Thus, these grades are mainly used in wet granulation and are known to yield tablets of suitable hardness.
- Sieved lactose monohydrate products exhibit good flow and blending properties. These grades are suitable for encapsulation as well as for dry powders and sachet filling. Larger sizes can be used for direct compression.
| Benefits of Milled Lactose Monohydrate Grades | Benefits of Sieved Lactose Monohydrate Grades |
| Excellent compatibility
Narrow particle size distribution Good blending properties Excellent batch to batch consistency Excellent storage stability |
Excellent flowability
Narrow particle size distribution Good blending properties Excellent batch to batch consistency |
- Spray-dried lactose grades are, due to their high surface areas, ideal for sachet filling, capsules, and for direct tabletting.
- Granulated lactose grades are ideal for direct compression tabletting owing to their excellent compressibility and low dusting attributes.
A number of co-processed excipients which contain lactose are available for direct-compression applications: Co-processed Lactose and Starch (STARLAC®, Meggle/Roquette Freres) lactose and microcrystalline cellulose (MicroceLac®, Meggle); lactose and cellulose powder (CELLACTOSE®, Meggle), and Lactose, Povidone, and Crospovidone (LUDIPRESS®, BASF).
Safety and Precautions
Lactose is widely used in oral pharmaceutical products and may also occasionally be used in intravenous injections. It has been used in pharmaceutical tablets for more than 100 years, thus its safety and toxicity are not in question. Furthermore, pharmaceutical grades of Lactose are required to achieve very high purity levels, including those standards required by the different monographs of the various pharmacopoeia.
Lactose has a clean sweet taste, without any aftertaste. The sweetness profile matches that of sucrose although its intensity is low due to the lower water solubility. Upon ingestion, Lactose is not actively absorbed by the intestine. For absorption to occur, the Lactose molecule needs to be hydrolysed into glucose and galactose. In vivo, the enzyme, lactase, produced by GI tract epithelial cells are responsible for splitting lactose.
In many mammals, the activity of lactase wanes shortly after weaning and then remains constant. However, in some individuals, the level of lactase is very low or non-existent. These individuals are not able to digest lactose (malabsorbers). Lactose that remains in the intestine undigested is transferred into the large intestine where it is fermented by gut flora to produce organic acids, such as lactic acid. This can cause additional symptoms linked to water retention, such as bloating, diarrhoea, and abdominal cramps. Although the majority of malabsorbers can handle lactose, there is a significant number that are intolerant, for whom the ingestion of even a small amount of lactose produces symptoms described above. For these individuals, avoidance of lactose is important.
There some reports that suggest that lactose intolerance may have a role in irritable bowel syndrome. This view, is however, not widely accepted, and more research is needed to fully substantiate it.
Safety of Lactose in Diabetes
The complete limit on sugar in diets of diabetic patients is no longer the conventional approach. The aim of treatment is to achieve and maintain normal blood glucose levels. This can be accomplished by following a normal diet as long as energy intake is controlled and spread evenly throughout the day. For a diet consisting of between 150 and 250g of carbohydrates, the contribution to this by the amount of lactose ingested through tablets is insignificant. Thus, restrictions for diabetic patients to avoid lactose-containing medicines are not warranted.
Lactose and Cariogenicity
Lactose in its non-hydrolysed form is minimally cariogenic compared to sucrose. Streptococcus species that break down carbohydrates to produce organic acids responsible for enamel erosion are much less capable of digesting lactose compared with sucrose. Furthermore, since tablets and capsules are commonly swallowed with water, the rinsing effect leaves little residue for bacteria to work upon.
Transmissible Spongiform Encephalopathies
In the past, there base been concerns over the transmissible spongiform encephalopathies (TSE) contamination of animal-derived 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 TSF contamination; TSE risk is negligible if the calf rennet is produced in accordance with regulations.
Toxicology: LD50 (rat, IP): > 10g/kg; LD50 (rat, oral): > 10g/kg; LD50 (rat, SC): >5g/kg
Stability and Storage Conditions
Lactose is overall a highly stable excipient when stored under ambient conditions. It is also relatively inert from a chemical point of view. It shows little tendency to react with formulation ingredients, including active ingredients or other excipients. However, mould growth may occur under humid conditions (80% RH and above). For this reason, the raw materials should be stored correctly in accordance with recommended storage conditions of the manufacturer.
Lactose may develop a brown coloration on long-term storage, the reaction is accelerated when stored in warm and damp conditions. Tablets formulated with lactose can expand by up to 1.2 times when stored at high temperatures and high humidity (e.g > 80 oC and 80% RH). Lactose anhydrous is a reducing sugar with the potential to interact with primary and secondary amines (Maillard reaction) when stored under conditions of high humidity for extended periods. A Maillard-type condensation reaction may occur when Lactose interacts with compounds having a primary amine group to form brownish by-products.
Lactose should be stored in a well-closed container in a cool, dry place. Observe normal precautions appropriate to the circumstances and quantity of material handled. Excessive generation of dust, or inhalation of dust, should be avoided.
Sustainability and Environmental Impact
Lactose is a natural disaccharide consisting of galactose and glucose and is present in the milk of most mammals. Commercially, it 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; while lactose constitutes 38% of the total solid comment of milk. A naturally-derived substance, lactose is an inert and non-toxic excipient and considered safe for the environment, with minimal long-term impact on ecology or marine life. However, while the dairy industry has faced questions about its long-term sustainability, lactose is a secondary product of the dairy sector and therefore represents a net realisable value. Lactose Monohydrate excipient grade achieved a total score of 72/100 by the Excipients Forum Sustainable Chemistry Score™.
Manufacturers & Suppliers
DFE Pharma markets its lactose products under Pharmatose® and Lactochem® brands.
| Lactochem® Lactose Monohydrate | Pharmatose® Lactose Monohydrate |
|
|
Kerry Group (Sheffield Biosciences)
Kerry manages the lactose business of Foremost Farms and Sheffield Biosciences. Five lactose grades are offered.
- Sheffield™ 200 Mesh
- Sheffield™ 310
- Sheffield™ 312
- Sheffield™ 313
- Sheffield™ 314
- Sheffield™ 80M
- Sheffield™ Capsulating Grade
- Sheffield™ Impalpable
Meggle Pharma markets its lactose grades under the GranuLac®; PrismaLac®, SpheroLac® and CapsuLac® brand names
| Milled Lactose Monohydrate: | Sieved Lactose Monohydrate |
|
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| Milled Lactose Monohydrate: | Sieved Lactose Monohydrate |
|
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Additional Resources (Downloads)
References and Literature Used
[1] H. Ando, S. Watanabe, T. Ohwaki, Y. Miyake, Crystallization of Excipients in Tablets, Journal of Pharmaceutical Sciences, 74 (1985) 128-131. DOI: https://doi.org/10.1002/jps.2600740205. PUBMED
[2] F. Bassam, P. York, R.C. Rowe, R.J. Roberts, Young’s modulus of powders used as pharmaceutical excipients, International Journal of Pharmaceutics, 64 (1990) 55-60. DOI: https://doi.org/10.1016/0378-5173(90)90178-7. Science Direct | Google Scholar
[3] M.D.C.M. Perales, A. Muñoz‐Ruiz, M.V.V. Antequera, M.R.J.C. Ballesteros, Study of the Compaction Mechanisms of Lactose‐based Direct Compression Excipients using Indentation Hardness and Heckel Plots, Journal of Pharmacy and Pharmacology, 46 (1994) 177-181.
[4] J. Du, S.W. Hoag, The influence of excipients on the stability of the moisture-sensitive drugs aspirin and niacinamide: comparison of tablets containing lactose monohydrate with tablets containing anhydrous lactose, Pharmaceutical Development and Technology, 6 (2001) 159-166. DOI: https://doi.org/10.1081/PDT-100000742.
[5] K.M. Nagel, G.E. Peck, Investigating the Effects of Excipients on the Powder Flow Characteristics of Theophylline Anhydrous Powder Formulations, Drug Development and Industrial Pharmacy, 29 (2003) 277-287.
[6] M.B. Heyman, Lactose Intolerance in Infants, Children, and Adolescents, Pediatrics, 118 (2006) 1279-1286. DOI: 10.1542/peds.2006-1721
[7] Y. Takeuchi, M. Amano, Y. Yonezawa, H. Sunada, Evaluation of Lactose Excipients in the Standard Formulation for Direct Tableting Processes, Journal of the Society of Powder Technology Japan, 45 (2008) 819-826.
[8] J.F. Gamble, W.-S. Chiu, V. Gray, H. Toale, M. Tobyn, Y. Wu, Investigation into the Degree of Variability in the Solid-State Properties of Common Pharmaceutical Excipients—Anhydrous Lactose, AAPS PharmScitech, 11 (2010) 1552-1557.
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