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Spray-Dried Lactose Excipient | Uses, Suppliers, and Specifications

Spray Dried Lactose is a speciality agglomerated grade of lactose intended for direct compression tabletting applications. It consists of Lactose monohydrate (typically 80-90% by weight), and Amorphous lactose (composed of a 50:50 blend of α-and-β-Lactose). Spray-dried lactose occurs as a white to cream coloured crystalline powder and is available in different size ranges.

Pharmacopoeial Compliance: USP-NF; Ph.Eur; J.P, B.P and I.P

Synonyms and Trade Names: Spray-Dried Lactose; FlowLac®; Lactopress® Spray- Dried; FastFloV; SuperTab®

Uses and Applications: Direct Compression Tablet Filler and Capsule Filling Diluent

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Sheffield™ Spray Dried 315 - KERRY Group

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Lactopress® Spray Dried Lactose - DFE Pharma

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EXCIPRESS™ SD 2L - ARMOR Pharma

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Description

Spray-dried lactose is a grade of agglomerated lactose for use in the pharmaceutical industry as a tabletting aid in direct compression. It is comprised of Lactose monohydrate (80-90 % by weight) and amorphous lactose (10-20 % by weight) in the form of a 50:50 blend α-, and-β-D-galactopyranosly(1,4)-α-D-glucopyranose monohydrate.

The process of producing Spray-dried lactose involves spray drying an aqueous suspension of Lactose monohydrate under controlled conditions to produce spherical agglomerates of crystalline lactose monohydrate in a matrix of amorphous lactose. The resulting product flows and compresses extremely well, making it suitable for use in direct compression applications.

Spray-dried lactose occurs as white to off-white crystalline particles or powder. It is odourless and slightly sweet-tasting.

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.

Grades of Spray-dried lactose 

Spray-dried lactose was first introduced into the pharmaceutical field in the late 1950s and quickly became adopted as a direct compression excipient for mitigating the poor compressibility and flowability of standard crystalline lactose monohydrate. By combining crystalline and amorphous lactose in a unique balance, it was possible to create a grade that had excellent flowability and compressibility compared to either 100% pure amorphous or crystalline α-lactose monohydrate.

Over the years, direct compression characteristics of spray-dried lactose were improved in line with improvements in spray-drying process know-how which allowed the optimisation of the amorphous content, and particle size of the α-lactose monohydrate fraction. As a result, many different grades of spray-dried lactose are now available commercially that are claimed to differentially offer superior flowability, compressibility, compactibility or stability.

Chemical Structure & Identifiers


IUPAC Name
CAS Registration Number [5989-81-1]; [10039-26-6]; [64044-51-5]
Empirical Formula C12H22O11.H2O and C12H22O11
EINECS/EC Number 200-559-2
UNII Code (FDA) EWQ57Q8I5X

Regulatory Status

Spray-dried lactose is an approved pharmaceutical excipient. It is listed in all the major pharmacopoeia, including the USP-NF; Ph.Eur, and the J.P. Lactose is also GRAS listed and included in the FDA Inactive Ingredients Database (IM and SC injections; oral tablets and capsules; and inhalation products). A specification for lactose is included in the Food Chemicals Codex (FCC).

Physicochemical Properties

Physical form Solid
Appearance White to off-white crystalline particles or powder
pH value Not available
Angle of repose 28 – 30 o
Brittle fracture index 0.167 (at compression pressure 54.9 MPa)
Bonding index 0.0044 (at compression pressure 54.9 MPa)
Bulk density 0.50 – 0.75 g/cm3
Tapped density (tapped) 0.65 – 0.85 g/cm3
True density l.545 g/cm3 for α-lactose monohydrate
Melting point
Particle size distribution 99% ≤250 µm
Water content ≤6.0%
Permanent deformation pressure 5648 MPa (at compression pressure 54.9 MPa)
Reduced modulus of elasticity 5648 (at compression pressure 54.9 MPa)
Solubility Soluble in water; sparingly soluble in ethanol
Specific rotation 54.4o to 55.9o
Tensile strength 2.368 MPa (at compression pressure 54.9 MPa)

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
Sulfated ash n/a ≤0.1%
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

Spray-dried lactose is one of the most widely used filler binders for direct compaction. Being an agglomerated lactose grade, it exhibits enhanced flowability, compressibility and compactability, which makes it useful for the manufacture of compressible tablets by direct compression and capsule filling operations. Different grades of spray-dried lactose are commercially available differing in tabletting performance and sensitivity to environmental moisture during storage, and thus many specific performance advantages.

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

The amorphous lactose content in Spray-dried lactose renders the material a highly reactive form of lactose, meaning that it will interact more readily than conventional crystalline grades. Some of the reactions that Spray-dried lactose can participate in include the Maillard reaction (either with primary or secondary amines). For this reason, Spray-dried lactose should be stored in a well-closed container in a cool, dry place.

Workers handling the material should observe adequate precautions commensurate with the quantity of material being processed. Although Spray-dried lactose is less prone to generating excessive dust hazards, a dust mask should be used to minimise the risk of inhalation or contact with mucous membranes and/or skin.

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 GmbH & Co. KG.

  • Lactopress® Spray Dried Lactose
  • Lactopress® Spray Dried Lactose 250
  • SuperTab® 11 SD
  • SuperTab® 14 SD

Kerry Group (Sheffield Biosciences)

  • Sheffield™ Spray Dried 315
  • Sheffield™ Spray Dried 316
  • Reddi Flo AG 80 (Agglomerated Spray Dried Lactose)

Meggle Pharma

  • FlowLac® 90
  • FlowLac® 100

Armor Pharma

  • EXCIPRESS™ SD 2L

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.

[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.

[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.

[5] M.B. Heyman, Lactose Intolerance in Infants, Children, and Adolescents, pediatrics, 118 (2006) 1279-1286.

[6] 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.

[7] M. Vogt, K. Kunath, J.B. Dressman, Dissolution improvement of four poorly water soluble drugs by cogrinding with commonly used excipients, European Journal of Pharmaceutics and Biopharmaceutics, 68 (2008) 330-337.

[8] T. Tanner, O. Antikainen, H. Ehlers, D. Blanco, J. Yliruusi, Examining mechanical properties of various pharmaceutical excipients with the gravitation-based high-velocity compaction analysis method, International Journal of Pharmaceutics, 539 (2018) 131-138.

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