Tablet formulation design starts with a predetermined value, which is the dose size. The amount of drug in a tablet can be a limiting step in formulation design. Tablet excipients can be classified based on their functionality as listed below:
Excipients Used in Tablet Formulation
- Buffering agents
- Wetting agents
- Coating agents
- Matrix formers
Fillers are used to arriving at a tablet of reasonable size when a drug forms a small portion of the formula, as in the case of 25 mg estradiol vaginal tablets. Depending on the physiological conditions and formulation, one needs a tablet of around 100 mg for ease of handling and administration, and therefore, fillers are used to increase bulk. Usually, a lactose monohydrate is the first material to be considered. This water-soluble disaccharide is obtained from whey by crystallization and drying after cheese production. Lactose is a water-soluble diluent, 216 mg dissolving in 1-mL water. Using three different drying techniques, fluidized-bed methods, roller drying, and spray drying, a-lactose monohydrate, anhydrous b-lactose, and spray-dried lactose are obtained, respectively. The three different lactose grades differ considerably in their mechanical properties about tableting. For instance, anhydrous b-lactose shows a steep compression force–tablet crushing strength relation. On the other hand, a-lactose monohydrate and even spray-dried lactose are inferior grades in this respect. Spray drying of lactose forms partial amorphous structures, and that contributes to its better compressibility. Spray-dried lactose flows well because of its spherical granule shape.
Therefore, the mechanical properties and the size distribution of lactose types must be known before making a selection out of many lactose grades. A partial list of excipients used in tablet manufacturing is following:
Fillers/Diluents Used in Tablet Formulations are:
- Lactose (a-lactose monohydrate, anhydrite b-lactose, spray-dried lactose)
- Microcrystalline cellulose (Avicel PH 101, Avicel PH 200, Emcocel)
- Starch (Corn starch, partially hydrolyzed starch)
- Dibasic calcium phosphate (Emcompress, Di-Tab)
- Mannitol (Parteck, Delta M)
- Sorbitol (Neosorb 60)
- Calcium sulfate (Delaflo)
- Compressible sucrose (Di-Pac, Des-tab, Nu-Tab)
1. Starch: Starch has been used as a tablet/capsule excipient for a long time. Unlike lactose, starch has a multifunctional use in solid dosage forms. It serves as a filler/diluent as well as a disintegrant, and also as a binder in the form of starch paste. Depending on the region, starch can be obtained from corn, potatoes, wheat, or rice. It contains amylase and amylopectin units. Starch is not water-soluble. For pharmaceutical purposes, starch does not flow well and cannot be compressed into strong compacts. Hence, partially pregelatinized starch is obtained by mechanical means such as rupturing the starch granules between hot rollers to render it partially water-soluble. This contributes to its binding properties because of about 15% free amylopectin, 5% free amylose, and 80% unmodified starch. Starch normally has the highest equilibrium moisture content among all pharmaceutical excipients, that is to say, about 11% to 14%. In general, starch or modified starch does not have good mechanical properties for tableting processes without the contribution of other plastic deformationshowing materials. On the other hand, starch is a good disintegrant in tablets, especially in the form of its semisynthetic derivative such as sodium carboxymethyl starch, which is extremely important. Its abundance and low cost make it a major pharmaceutical excipient.
2. Microcrystalline Cellulose: Since its introduction to the pharmaceutical industry in 1964 by FMC, microcrystalline cellulose (MCC) has revolutionized tablet formulation. MCC forms very strong compacts under even low compression pressures. It is obtained from the wood pulp after controlled acid hydrolysis, which produces a high degree of crystallinity to the cellulose chains. After neutralization, filtering, and spray drying a white granular powder is obtained.
MCC has at least nine different commercial grades (Avicel PH grades, FMC, U.S.A.) according to its average particle size (20 –180 mm), moisture content (1.5–5.0%), bulk density (0.25–0.44 g/ml), and volumetric flow (1.5–5.0 lit/min) for applications ranging from wet granulation to direct compression. MCC shows a strong plastic deformation under pressure and a high dilution potential. Therefore, good compressibility can be matched with good flow only by selecting the right grade or making a wet granulation to a certain size and shape. As a diluent, it is used in combination with spray-dried lactose or dicalcium phosphate dihydrate during the DC tableting to balance the cost or flow properties. In a compression force–crushing strength plot, MCC shows the steepest line among all excipients reaching 20- kg tablet crushing strength at about 750 kg force. MCC is not water-soluble but absorbs water. In a fluidized-bed granulation process, MCC requires the highest amount of water for the same granule size when compared to starch and lactose monohydrate.
3. Dicalcium Phosphate Dihydrate: This water-insoluble material is among the top five excipients in modern tablet formulations. The true density of dicalcium phosphate dihydrate is 2.3 g/ml, which makes it one of the heaviest pharmaceutical excipients per volume with a reported tapped density of 0.7 g/ml. Dicalcium phosphate anhydrous is also available. At 2000 kg-f compression, tablet crushing strength reaches a maximum of 100 N with this excipient.
Therefore, its binding properties are inferior to those of MCC. The main mechanism of compaction of dicalcium phosphate is a brittle fracture, creating new surfaces, which therefore shows much less lubricant sensitivity: This can be an advantage over plastically deforming materials such as MCC or some starches. Dicalcium phosphate dihydrate, like other inorganic salts, has a detrimental effect on tablet tooling.
4. Mannitol: Mannitol in various polymorphic forms is the main excipient of chewable tablets due to its negative heat of solution, which results in a pleasant mouthfeel. A new mannitol grade, namely, d-mannitol (Partick, Delta M) has been reported to be superior to the other polymorphs such as a or b-mannitol in terms of mechanical properties and chemical reactivity. Hence, tablets with higher crushing strengths can be manufactured. Mannitol is nonhygroscopic and shows a low reactivity with drug substances. Therefore, it has the potential to be utilized more in future tablet formulations.
5. Coprocessed Excipient Products: Some flexibility is necessary for the design of tablet formulations. Selecting each excipient depends on the physical and chemical properties of the drug, the drug dose, and the required final form and function of the tablet. There are however aids for the formulator. Some co-processed excipients are containing usually a diluent and binder, and sometimes, even a disintegrant in a readymade granulation. LudipressTM (BASF, Germany) contains a-lactose monohydrate, polyvinylpyrrolidone (PVP), and Kollidon CL. Cellactose 80TM (Meggle, Germany) contains a-lactose monohydrate and cellulose powder, ProsolvTM SMCC (JRS Pharma, Germany), silicified MCC, contains 98% MCC and 2% colloidal silicon dioxide, which provides a better granule flow and an opportunity for smaller and denser tablets upon direct compression. There are also processed actives like ascorbic acid, thiamine, riboflavin, pyridoxine, paracetamol, and acetylsalicylic acid. For those drugs that are manufactured in huge volumes, the use of co-processed excipients is efficient, since the small capacity of many pharmaceutical manufacturing plants for wet or dry granulation cannot deal with huge volumes.
Materials that contribute to plastic deformation, which means stronger compacts upon compression or forming a matrix such as a methylcellulose (MC), HPMC, hydroxypropyl cellulose (HPC), cellulose powder, gelatine, and mannitol are used. Coprocessed products are so designed that by the simple addition of the drug, compressed tablets may be produced. Using co-processed activity allows minimum excipient addition and manipulation.
Binders used in Tablet Formulation are:
- Polyvinylpyrrolidone (PVP)
- Sodium carboxymethyl cellulose
- HPMC (Low molecular weight, 5 cps)
- Starch paste
- Simple syrup
Binders in tablet technology serve the purpose of binding small drug or excipient particles together to impart cohesiveness, and to form a granulate of a designed size range, usually larger than the initial material that flows freely and is also compressible, and eventually to be compressed into tablets or to be filled into capsules. A binder will help the tablet to remain intact after compression. Binders can be added as dry powders to form a matrix that will include the drug, as in the case of dry granulation or direct compression. Sometimes, the binders are dissolved in liquids such as water or alcohol and then sprayed onto the powder mixture as with wet granulation. Materials such as MCC act as a binder/ diluent in the case of direct compression. However, a polymer such as PVP is solely used as a binder. One of the commercial products of PVP is KollidonTM (BASF), which has grades based on the molecular weight of the polymer: Kollidon K 25 (MW 28,000– 34,000), K 30 (MW 44,000–54,000), and K 90 (MW 1,000,000–1,500,000) contain PVP of increasing molecular weights. PVP has some advantages over other binders: it is used in relatively small concentrations such as 1% to 5% to prepare a binder solution, it is soluble to above 10% in water, ethanol, and glycerol, which provides an opportunity for water-free granulation. One of the most significant advantages of PVP is its low viscosity (5–10 mPa.sec) even up to concentrations as high as 20% (w/v). A low-viscosity solution can easily be sprayed using peristaltic pumps during a fluidized-bed granulation. Starch paste has been a traditional binder, at concentrations between 5% and 10%. Starch is dispersed in cold water, and then slowly heated up to boiling with constant stirring. When a translucent paste is formed, it can be diluted with cold water. On the other hand, preparing a starch paste with modified starch will not require boiling, since it dissolves in warm water because of the free amylopectin. In modern granulation processes using high shear mixers, starch paste finds few applications. HPMC, MC, HPC, and ethylcellulose can be used as binders in tablet formulations. These cellulose-based binders perform as well as PVP in modern granulation processes. Hydrophilic polymers, especially of low molecular weight, for instance, HPMC E6 (6 CP viscosity grade), can be dissolved in water to obtain a low-viscosity solution, and they bind well and contribute to plastic deformation during tableting. The high-molecular-weight grades of these cellulose-based materials can be used as matrix formers, and incorporated into formulations as dry binders. Ethylcellulose is not water-soluble, so it is used as an alcoholic solution. Materials such as PVP and HPMC have largely replaced other binders such as gelatine, sucrose, simple syrup, or acacia.
Disintegrants serve the purpose of facilitating the disintegration of tablets into their components either after administration in the GI tract or just before administration, such as in the case of the fast-disintegrating tablets. Disintegrants may play an important role in the bioavailability of a drug in tablet dose forms. When disintegrants come into contact with water, they usually swell, as their cross-linked molecular structure, such as in amylose in starch or cross-linked PVP, imbibes water and swells, providing the force to disperse the tablet. Depending on the formulation design, some tablets containing higher percentages of MCC may disintegrate readily during disintegration tests without an additional disintegrant. The addition of starches externally to the final granulation before tableting is best justified for disintegration purposes. Starch is a “mild” tablet disintegrant. In the past, there was concern that tablet compression forces should not exceed certain limits or tablet crushing strengths 70 to 80 N because of the probability of prolonged disintegration times. However, with the advent of modern excipients, mechanically strong tablets with 200 to 300 N crushing strengths can be produced, and these tablets will disintegrate within five minutes or less using the super-disintegrants. Super-disintegrants are materials added to tablet formulations in a range of 1% to 5% to assure disintegration within 1 to 10 minutes. Among these are sodium carboxymethyl starch (ExplotabTM, Mendell, U.S.A.), cross-linked sodium carboxymethyl cellulose (PharmacelTM XL, DMV, Netherlands), and cross-linked PVP (KollidonTM XL, BASF). The rank order of the degree of swelling in water in two minutes for those disintegrants has been reported to be sodium carboxymethyl starch > sodium carboxymethyl cellulose > L-HPC 11 > cross-linked PVP > starch > MCC.
Lubricants and Glidants used in Tablet Formulations are:
- Magnesium stearate
- Stearic acid
- Sodium stearyl fumarate
- Hydrogenated vegetable oil
- PEG 4000, 6000
- Hexagonal boron nitride
- Sodium lauryl sulfate
- Glyceryl behenate
- Sodium benzoate
- Colloidal silicon dioxide
- Super disintegrants
- Sodium starch glycolate (Explotab)
- Cross-linked PVP (Polyplasdone XL)
- Cross-linked carboxymethyl cellulose (Ac-Di-Sol)
Pharmaceutical lubricants are materials used in tablet formulations to reduce the friction between the lower punch and the die and the tablet. Friction damages both the tablet and the tablet press during the ejection cycle. Lubricants are a mechanical necessity, without which modern tablet manufacturing would be impossible. Glidants are materials that reduce interarticular friction, covering the particle surfaces with a thin layer, and as a result, helping in better granule flow. Colloidal silicon dioxide, talc, and starch can be used as glidants; colloidal silicon dioxide is effective as low as 0.5% as a glidant. Lubricants are added to pharmaceutical granules just before the tableting stage. Mixing the main granule mass with a lubricant has been an intensively investigated subject. Prolonged mixing with a surfacecovering lubricant such as magnesium stearate negatively affects the binding capacity of a granule mass. Hence, tablet formation might be inhibited, unless the granule mass undergoes brittle fracture and creates new clean surfaces. Especially, materials exhibiting plastic deformation with a limited surface area would show a strong sensitivity to lubricants. Therefore, the specific surface area of a lubricant as well as the surface area of the granule mass is both important parameters in selecting lubricant type, concentration, and mixing times. Boundary lubricants will adhere on the metal surfaces of the tablet press, die, and punches and will form a boundary layer with the tablet. Alkaline stearates such as magnesium stearate are an example of a boundary lubricant. Magnesium stearate is still the most effective pharmaceutical lubricant. Its usual concentration range is between 0.1% and 2%, and its effectiveness shows a biphasic profile, a region of a fast reduction in friction up to 1 %, and a slower friction-reducing effect after 1%. Magnesium stearate reduces not only the lower punch ejection force by about 70% but also tablet tensile strength. Stearic acid is the second most important lubricant. It is not as effective as magnesium stearate, the minimum effective stearic acid concentration is about 1%, and it reduces the lower punch ejection force by no more than 30%. This fatty acid is however useful when an alkaline ingredient in a tablet formula is undesirable. The hexagonal form of boron nitride (HBN) has been reported as a potential tablet lubricant. HBN is similar to graphite, which is soft and lubricious. This inorganic solid powder retains its ability to lubricate in extreme cold or heat.
It was reported that boron nitride reduced the lower punch ejection force as efficiently as magnesium stearate, but its ability to reduce the tablet tensile strength is less than magnesium stearate. The result is mechanically stronger tablets. Therefore, there is a good potential for HBN to be used as a tablet lubricant. For effervescent tablets, water-soluble lubricants are required since insoluble alkaline lubricants would accumulate on the surface of the final solution or form a cloudy solution with an alkaline taste, all of which is undesirable. Sodium lauryl sulfate, DL-leucine, or various PEGs can be used as water-soluble lubricants. Liquid paraffin and hydrogenated vegetable oil are also among the lubricants, but their effectiveness is lower than that of magnesium stearate and stearic acid.
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