Lubricants in pharmaceutical development process

Lubricants are commonly added excipients to many pharmaceutical tablet formulations. Following compression, a tablet must be ejected out of the tablet press die. Lubricants reduce the friction between the tablet and the die metal surface which reduces the ejection force and helps to ensure that the tablet is completely ejected. High friction during tableting can cause a series of problems, including inadequate tablet quality from capping or even fragmentation during ejection. One class of functional excipients that are essential in most solid oral dosage forms is “lubricants”.

There are two main mechanisms by which lubrication is achieved:

1)Fluid lubrication.

2)Boundary lubrication.

In fluid lubrication, the lubrication forms a thin, continuous fluid layer between the tablet and metal dies surface. Fluid lubricants are seldom used in tablet formulations. However, liquid paraffin has been used in formulations for effervescent tablets. Lubricants utilizing the boundary lubrication mechanism are the most common.

In boundary lubrication, the sliding surfaces are separated by a very thin film of lubricant. The nature of the tablet and die surface properties will thus frictional forces present.

There are six categories of boundary lubricants commonly used for pharmaceutical tableting:

(i) Metallic salts of fatty acids,

(ii) Fatty acids, hydrocarbons and fatty alcohols,

(iii) Fatty acid esters.

(iv) Alkyl sulfates,

(v) Polymers, and

(vi) Inorganic materials

Magnesium stearate, a metallic salt boundary lubricant, is probably the most commonly used lubricant for pharmaceutical tableting, it is comparatively cheap, provides high lubrication, has a high melting point and is chemically stable.

Common lubricants and classification are summarized their Lubricant classification 

A.Metallic salts of fatty acids :

Magnesium stearate, aluminum stearate, calcium stearate, sodium stearate, zinc stearate.

B.Fatty acids, hydrocarbons and fatty alcohols :

Stearic acid, decanoic, dodecanoic, docosanoic, octadecanoic, eicosanoic

C.Fatty acid esters :

Sodium stearyl fumarate, sodium lauryl sulfate, magnesium lauryl sulfate, Glyceryl behenate, dodecanoic triglyceride, samarium stearate, sucrosemonopalmitate

D. Alkyl sulfates :

Magnesium lauryl sulfate, sodium lauryl sulfate

E.Polymers :

PEG 4000, PEG-6000, polyoxyethylene & p olyoxyproprylene copolymer, poly-tetrafluoroethylene

F.Inorganic materials :

Magnesium silicate, aluminum silicate

As magnesium stearate is the most commonly used boundary layer lubricant, it has been the most extensively studied. It has been hypothesized that the film formed by magnesium stearate around other excipient particles could be:

(i) As a monomolecular film of magnesium stearate particles bound to the other excipient’s by their polar heads.

(ii) As a monoparticulate film of magnesium stearate particles covering the surface of the other excipients, and

iii) As layers of magnesium stearate particles first filling any cavities of the other excipients before forming a  continuous layer.

The third hypothesized mechanism of first filling any cavities is the most popular. With this mechanism, magnesium stearate would improve flow by minimizing any surface irregularities of the excipients which reduces contact points between excipients, decreasing friction forces.

Effect on tablet properties

Besides reducing friction and cohesion, lubricants may cause undesirable changes in the properties of the tablet. The presence of lubricant in a powder is thought to interfere in a destructive way with the bonding between particles during compaction, thus reducing final tablet strength. Lubricant type, concentration, method of lubrication, and the manner of incorporating the lubricant all affect the tablet compression. It is generally accepted that magnesium stearate has more negative effect on the hardness and tensile strength of the tablets with more deformable materials than brittle ones conducted a study using dibasic calcium phosphate as an example of a material that is susceptible to brittle fracture during compaction. Results showed that the tablet strength showed no change when magnesium stearate up to 3%wt was present. Other lubricants, such as stearic acid and talc, showed no effect on the interparticle bonding, and thus tablet strength, of dibasic calcium phosphate dehydrate up to 8%wt. Alternatively, when microcrystalline cellulose, an example of a plastic material, was mixed with magnesium stearate, the tablet strength  was weakened significantly as the amount of added lubricant increased. Similar results were obtained when other lubricants (stearic acid, talc, and15PEG) were mixed with microcrystalline cellulose. The adverse impact of magnesium stearate on lactose and starch, excipients that also deform plastically, was also observed.

Because many lubricants are hydrophobic, tablet disintegration and dissolution are  often retarded by the addition of lubricant. Multiple studies have led to the theoretical conclusion that the deleterious effects observed are a cause of the combination of the large surface area and hydrophobicity of the lubricant. Many research showed that the powder form of magnesium stearate have more adverse effects on tablet hardness and disintegration than the granular form. A decrease in the magnesium stearate level from 1.7-0.85 mg in a tablet comprised of mostly calcium phosphate dibasic reduced the disintegration time from 10 to 4.5 min (Bavitzetal., 1986 & Strickland et al.1956) showed that disintegration time increased substantially more for increases of magnesium stearate than other lubricants stearic acid and stearyl alcohol.

Magnesium stearate

Magnesium stearate, also called octadecanoic acid, magnesium salt, is a white substance, powder which becomes solid at room temperature. It has the chemical formula Mg(C18H35O2)2. It is a salt containing two equivalents of stearate (the anion of stearic acid) and one magnesium cation (Mg2+). Magnesium stearate melts at about 120 °C, is not soluble in water, and is generally considered safe for human consumption at levels below 2500 mg/kg per day. In 1979, the FDA's Subcommittee on GRAS (generally recognized as safe) safe) Substances (SCOGS) reported, "There is no evidence in the available information on stearate that demonstrates, or suggests reasonable grounds to suspect, a hazard to the public when they are used at levels that are now current and in the manner now practiced, or which might reasonably be expected in the future.

Magnesium stearate is often used as a diluent in the manufacture of medical tablets, capsules and powders. In this regard, the substance is also useful, because it has lubricating preventing ingredients from sticking to manufacturing equipment during the compression of chemical powders into solid tablets; magnesium stearate is the most commonly used lubricant for tablets. Studies have shown that magnesium stearate may affect the release time of the active ingredients in tablets, etc., but not that it reduces the overall bioavailability of those ingredients.

Magnesium Stearate and Calcium Stearate:

Water Solubility: Insoluble Conc. Use Range: 0.25 - 1.5% Magnesium stearate is the most commonly used and most effective of all lubricants. It is also the most likely to cause compression & dissolution problems. Concentration, grade and mixing parameters must be carefully controlled. These stearates are alkaline in reaction and cannot be used with some acidic drugs like ASA. Magnesium stearate has good glidant and anti-adherent properties.

Stearic acid:

Water Solubility: Insoluble Conc. Use Range: 1 - 4% Not as effective a lubricant as Magnesium Stearate. Mixing times not as critical. Incompatibilities include some alkaline salts such as sodium saccharin and sodium phenobarbital. Hydrogenated Vegetable Oil(Sterotex, Lubritab, Cutina): Water Solubility: Insoluble Conc. Use Range: 2 - 5% Solid at room temperature, these materials melt at compression pressures and temperatures to impart a lubricating effect. 

Hydrogenated Vegetable Oil(Sterotex, Lubritab,Cutina):

Water Solubility: Insoluble Conc. Use Range: 2 - 5% Solid at room temperature, these materials melt at compression pressures and temperatures to impart a lubricating effect. 

Mineral Oil:

Water Solubility: Insoluble

Conc. Use Range: 1 - 3%

Light mineral oil is an efficient lubricant. But since it must be finely sprayed onto granules and powders to be used, it also can cause noticeable mottling or spotting on tablet surfaces. For these reasons, it is not commonly used anymore. But can still be found in some formulations

Polyethylene Glycol 4000 -6000 (PEG):

Water Solubility: Soluble

Conc. Use Range: 2 - 5%

Has been used as a water-soluble lubricant for some water soluble and effervescent tablet formulations. Fairly high concentration and low particle size needed to be moderately effective as a lubricant. It has no glidant or anti-adherent properties. 

Sodium Lauryl Sulfate (SLS):

Water Solubility: Soluble

Conc. Use Range: 2 - 3%

Effective at reducing ejection forces but does not help much for sticking to punch faces. Therefore, it must be used in conjunction with an anti-adherent.

Sodium Stearyl Fumarate 

In addition to stearic acid, sodium stearyl fumarate is another alternative lubricant to be used in solid dosage forms. Since sodium stearyl fumarate is often supplied in a purer form, it can provide an option when the less pure stearate-type lubricants (stearic acid and magnesium stearate) are unsuitable due to chemical incompatibility. Sodium stearyl fumarate has a usage rate of four out of 200 drugs as a lubricant in formulations. It is less hydrophobic and has a less retardant effect on tablet dissolution than magnesium stearate. As reported by Arne W. Hölzer, et al., compared with magnesium stearate, sodium stearyl fumarate has the same lubrication efficiency, and about the same influence on tablet strength and disintegration [55]. However, due to the importance of the particle size of sodium stearyl fumarate, prolonged mixing improved its lubricating effect and had no effect on tablet disintegration. Therefore, sodium stearyl fumarate appears to be a good alternative to magnesium stearate in certain solid dosage formulations.

OTHER LUBRICANTS:

Glyceryl Palmitostearate (Precirol) & Glyceryl Behenate (Compitrol 888):

Water Solubility: Insoluble

Conc. Use Range: 2 - 5%

Sodium Benzoate:

Water Solubility : Soluble

Conc. Use Range: 1 - 4%

Sodium Stearyl Fumarate (Pruv):

Water Solubility: Soluble

Conc. Use Range: 0.5 - 2%

ANTIADHERANTS & GLIDANTS:

Talc:

Water Solubility: Insoluble

Conc. Use Range: 1-10%

Not particularly effective on its own as a tablet lubricant or glidant. But very effective with lubricants in the role of an anti-adherent in that it effectively prevents sticking to surfaces. When using talc, it should always be blended into the formulation first followed by the lubricant (i.e. magnesium stearate).

Fumed Silicon Dioxide (Cab-o-sil):

Water Solubility: Insoluble

Conc. Use Range: As anti-adherent, 1-2% As

glidant, 0.1 - 0.5%

Fumed Silicon Dioxide has no lubricant properties. It is commercially available as very fine particles (approx. 0.014 microns), which tend to agglomerate into “balls”. It functions by coating granules, etc. and reducing interparticulate friction of these thereby improving flow characteristics. For processing, this material must be screened into a batch. However, due to the extremely fine particle size, it should be pre-blended with another component to facilitate screening and distribution.It is an extremely effective glidant at low concentrations, and has antiadherent properties at higher concentrations. However at higher concentrations, flow characteristics may actually be impeded resulting in an increase in weight variation.

Unfortunately the “ideal” lubricant for use in all occasions and with all formulations does not yet exist. However, by understanding how this important class of Excipients functions is solid oral dosage manufacturing; lubricants can be made to work for you and not against you.

CONCLUSION

Tablet lubricants are those vital ingredients of oral solid dosage form which avoid adhering of granules to die wall. Lubricants also assists tablet to get free of

various flaws like amination, sticking, chipping. Mode of action of lubricants follow unlike behavior but here in this review article it has been explained with the help of Surface lubrication and boundary lubrication. Lubricants create a film layer in between die wall and granules. In this review, the basic conditions on lubrication are introduced, in which the relationships between lubrication and friction/adhesion forces are discussed. Then, the application of lubrication in the growth of pharmaceutical products and manufacturing processes is discussed with an emphasis on magnesium stearate.