Featured Excipient: Capsule and Tablet Diluents
Loyd V. Allen, Jr., PhD, RPh
Goal: To provide compounding pharmacists supportive information on the application and
appropriate use of capsule and tablet diluents.
Objectives: After reading and studying the article, the reader will be able to:
1. discuss the purpose and use of diluents in capsules and tablets.
2. select an appropriate diluent based upon the active ingredient(s), the site of application and the
desired therapeutic application.
3. determine whether or not an active ingredient may be incompatible with a selected diluent.
4. suggest an alternative diluent in the event one is not suitable.
5. select a proper storage container for a specific diluent.
Introduction
The presence of excipients in a dosage form can alter the effect obtained by an active drug. The
behavior of the final dosage form is dependent on the preparation variables and inter-relationship
between the excipients and the active ingredient. One such excipient that can have a great influence
on liquid, semisolid and solid dosage forms is the selected diluent. In the case of capsules and tablets,
diluents are commonly used to increase the bulk volume to a reasonable dose size, to assist in dose
preparation and to affect the release rate of the drug.
Official excipients listed as capsule and tablet diluents include calcium carbonate, calcium
phosphate-dibasic, calcium phosphate-tribasic, calcium sulfate, cellulose-microcrystalline, cellulose
powdered, dextrates, dextrin, dextrose excipient, fructose, kaolin, lactitol, lactose, mannitol, sorbitol,
starch, starch-pregelatinized, sucrose, sugar-compressible and sugar-confectioner's.
USP/NF Capsule and Tablet Diluents
Calcium Carbonate, USP
Calcium carbonate (CaCO3, MW 100.09, precipitated calcium carbonate, precipitated
carbonate of lime, precipitated chalk) occurs as a fine, white, odorless, tasteless,
microcrystalline powder that is stable in air. It is practically insoluble in water and insoluble in
alcohol. It dissolves with effervescence in 1 N acetic acid, in 3 N hydrochloric acid and in 2
N nitric acid. When used in tablets containing aspirin, traces of iron may cause discoloration,
which may be overcome by using a suitable chelating agent.1,2
Dibasic Calcium Phosphate, USP
Dibasic calcium phosphate (CaHPO4, MW 136.06) is anhydrous or contains two molecules
of water of hydration. It occurs as a white, odorless, tasteless powder that is stable in air. It is
practically insoluble in water, insoluble in alcohol and soluble in 3 N hydrochloric acid and 2
N nitric acid. They are both used as excipients and as a source of calcium in nutritional
supplements. It should not be used to formulate tetracycline antibiotics and has been reported
to be incompatible with indomethacin, aspirin, aspartame, ampicillin, cephalexin and
erythromycin. The coarse grade material has good flow properties, but is abrasive and
requires a lubricant when used for tableting. The surface of the milled particles is alkaline and
should not be used with drugs that are sensitive to alkaline pH. The surface of the unmilled
particles may be acidic. It is widely used in oral pharmaceutical products, food products and
toothpastes. It should be labeled to indicate whether it is anhydrous or the dihydrate.1,3
Dibasic Calcium Phosphate Dihydrate, USP
Dibasic calcium phosphate dihydrate (CAHPO4.2H2O, MW 172.09) is nonhygroscopic but
can lose its water of crystallization below 100 C.1,4
Tribasic Calcium Phosphate, NF
Tribasic calcium phosphate [Ca5(OH)(PO4)3, MW 502.31, hydroxyapatite, precipitated
calcium phosphate] is not a defined entity but consists of a variable mixture of calcium
phosphates having the approximate composition of 10 CaO.3P2O5.H2O [corresponding to a
molecular formula of Ca5(OH)(PO4)3 or Ca10(OH)2(PO4)6] containing between 34 and
40% of calcium. It occurs as a white, odorless, tasteless powder that is stable in air. It is
practically insoluble in water, insoluble in alcohol, and readily soluble in 3 N hydrochloric acid
and 2 N nitric acid. It is used as an anticaking agent, glidant and tablet/capsule diluent.
Calcium salts are incompatible with tetracycline antibiotics. Tribasic calcium phosphate is also
incompatible with tocopheryl acetate (but not tocopheryl succinate). It can influence the
absorption of vitamin D and may form sparingly soluble phosphates with hormones.1,5
Calcium Sulfate, NF
Calcium sulfate is either anhydrous (CaSO4, MW 136.14, anhydrous gypsum, anhydrous
sulfate of lime) or contains two molecules of water of hydration (CaSO4.2H2O, MW
172.17, alabaster, gypsum, light spar, mineral white, native calcium sulfate, precipitated
calcium sulfate, satinite, satin spar, selenite, terra alba). It occurs as a fine, white to slightly
yellow-white, odorless powder. It is slightly soluble in water (1 in 375) and soluble in 3 N
hydrochloric acid. It should be labeled to indicate whether it is anhydrous or dihydrate. It also
occurs as a hemihydrate form used in the preparation of plaster of paris bandages; this form
should NOT be used in the preparation of tablets or capsules. Calcium sulfate anhydrous is
hygroscopic and the uptake of water can result; it is not recommended for the formulation of
tablets, capsules or powders for oral administration. The dihydrate form is used in oral
preparations.
Calcium salts may be incompatible, in the presence of moisture, with amines, amino acids,
peptides and proteins, which may form complexes. Calcium salts will interfere with
tetracycline antibiotics. Calcium sulfate would be incompatible with indomethacin, aspirin,
aspartame, ampicillin, cephalexin and erythromycin. Calcium sulfate, at high temperatures,
may react violently with phosphorus and aluminum powder.1,6
Microcrystalline Cellulose, NF
Microcrystalline cellulose [(C6H10O5)n where n ~~ 220, MW ~~36,000] is purified,
partially depolymerized cellulose prepared by treating alpha cellulose, obtained as a pulp from
fibrous plant material, with mineral acids. It occurs as a fine, white or almost white powder
consisting of free-flowing, nonfibrous particles. It is insoluble in water, dilute acids and most
organic solvents. It is practically insoluble in sodium hydroxide solution (1 g in 20 mL). It
should be labeled to indicate it's nominal loss on drying, bulk density and degree of
polymerization values. It is used as an adsorbent, suspending agent, tablet disintegrant and
tablet/capsule diluent. It is incompatible with strong oxidizing agents.1,7
Powdered Cellulose, NF
Powdered cellulose [(C6H10O5)n where n = 500, MW ~~243,000] is derived from a
natural polymer, hence it has a variable chain length and variable molecular weight. It is
purified, mechanically disintegrated cellulose prepared by processing alpha cellulose obtained
as a pulp from fibrous plant materials. It occurs as a white or almost white powder that
exhibits degrees of fineness ranging from a free-flowing dense powder to a coarse, fluffy,
nonflowing material. It is insoluble in water, dilute acids and in nearly all organic solvents. It is
slightly soluble in sodium hydroxide solution (1 g in 20 mL). It is used as an adsorbent, glidant,
suspending agent, tablet disintegrant and tablet/capsule diluent. It has also been used in oily
suspension filled capsules to reduce the sedimentation rate of the incorporated powders. It is
incompatible with strong oxidizing agents. It should be labeled to indicate the nominal degree
of polymerization.1,8
Dextrates, NF
Dextrates is a purified mixture of saccharides resulting from the controlled enzymatic
hydrolysis of starch. It is either anhydrous or hydrated and contains between 93 and 99% of
dextrose equivalent, calculated on the dried basis. It is free-flowing, porous, white, odorless,
spherical granules consisting of aggregates of microcrystals. It has a sweet taste and produces
a cooling sensation in the mouth. It may be directly compressed into self-binding tablets; it is
used in the preparation of chewable, nonchewable, soluble, dispersible and effervescent
tablets. Dextrates is freely soluble in water (1 g in 1 mL), insoluble in ethanol, and soluble in
dilute acids and alkalies. It should be labeled to state whether it is anhydrous or hydrated.
Dextrates are incompatible with oxidizing agents and also may react with substances
containing a primary amino group at high temperatures and humidities; the Maillard
reaction.1,9
Dextrin, NF
Dextrin (British gum, canary dextrin, crystal gum, starch gum, yellow dextrin, white dextrin,
[(C6H10O5)n.xH20, MW 162.14--the molecular weight is typically 4,500-85,000
depending upon the number of monomer units] is starch, or partially hydrolyzed starch,
modified by heating in a dry state, with or without acids, alkalies or pH control agents. Its
source is primarily from corn or potatoes; it has different characteristics depending upon its
source and method of preparation. It occurs as a free-flowing, white, yellow or brown
powder. It is also defined as a dextrose polymer. Its solubility in water varies but it is usually
very soluble; it may contain an insoluble portion. It is incompatible with strong oxidizing
agents.1,10
Dextrose Excipient, NF
Dextrose excipient is a sugar usually obtained by hydrolysis of starch, containing one molecule
of water of hydration. It occurs as colorless crystals or as a white, crystalline or granular
powder. It is odorless and sweet-tasting. It is freely soluble in water and very soluble in
boiling water. It is slightly soluble in alcohol. It should be labeled to indicate that it is not
intended for parenteral use. It may cause browning in tablets containing amines.1
Fructose, USP
Fructose (fruit sugar, levulose, C6H12O6, MW 180.16) occurs as colorless crystals or as a
white, crystalline odorless powder with a sweet taste. It is freely soluble in water (1g in 0.3
mL) and soluble in alcohol (1 g in 15 mL). Fructose is incompatible with strong acids or
alkalis forming a brown coloration. When in aldehyde form, it can react with amines, amino
acids, peptides, and proteins; it may cause browning of tablets containing amines.1,11
Kaolin, USP
Kaolin (argilla, bolus alba, china clay, porcelain clay, white bole, hydrated aluminum silicate,
Al2O3.2SiO2.2H20) occurs as a soft, white or yellowish white powder or as lumps. It is a
naturally occurring mineral, has an earthy or clay-like taste and, when moistened with water,
assumes a darker color and develops a marked clay-like odor. It is insoluble in water, cold
dilute acids and in solutions of alkali hydroxides. Kaolin is an adsorbent and may alter the
absorption of orally administered drugs such as amoxicillin, ampicillin, cimetidine, digoxin,
lincomycin, phenytoin, and tetracycline.1,12
Lactitol, NF
Lactitol (C12H24O11, MW 344.31, lactil, lactite, lactobiosit, lactosit) occurs as the
anhydrous, monohydrate (MW 362.34) or the dihydrate (MW 380.35) forms. It is produced
by the catalytic hydrogenation of lactose. It is odorless and has a sweet taste (about one-third
that of sucrose) imparting a cooling sensation in the mouth; it does not promote dental caries.
It is soluble in water (1 g in1.75 mL). It should be labeled to indicate whether it is the
monohydrate, the dihydrate or the anhydrous form.1,13
Lactose Anhydrous, NF
Lactose anhydrous (C12H22O11, MW 342.3, milk sugar, saccharum lactis) is primarily beta
lactose or a mixture of alpha and beta lactose. It occurs as a white or almost white powder
that is freely soluble in water (1 g in 5 mL) and practically insoluble in alcohol.
Lactose Monohydrate, NF
Lactose monohydrate (C12H22O11.H2O, MW 360.31) is a natural disaccharide, obtained
from milk, which consists of one glucose and one galactose moiety. Lactose monohydrate is
widely used as a filler or diluent in tablets, capsules, infant formulas and lyophilized products.
It is available in different grades with varying physical properties such as particle size
distribution and flow characteristics. The dosage form being prepared dictates the type of
lactose to be used. Lactose occurs as a white, free-flowing powder that is freely but slowly
soluble in water (1 g in 4.63 mL) and practically insoluble in alcohol; it is odorless and slightly
sweet-tasting. It should be labeled to state the particle size distribution and if modified, it
should indicate the method of modification. Lactose may undergo a Maillard-type
condensation reaction with compounds containing a primary amine group to form brownish
colored products; this is accelerated in alkaline environments. Lactose is listed as incompatible
with amino acids, aminophylline and amphetamines.1,14
Mannitol, USP
Mannitol (C6H14O6, MW 182.17, manna sugar, mannite) occurs as a white, crystalline
powder or as free-flowing granules. It is odorless and has a sweet taste. It is freely soluble in
water (1 g in 5.5 mL), soluble in alkaline solutions and very slightly soluble in alcohol (1 g in
83 mL). It is commonly used in direct-compression tablets and as an excipient in the
manufacture of chewable tablets due to its negative heat of solution and the resulting cooling
effect. There are no listed incompatibilities of mannitol when in the dry state.1,15
Sorbitol, NF
Sorbitol (C6H14O6, MW 182.17, d-Glucitol) occurs as white, hygroscopic powder,
granules or flakes, with a sweet taste. It is very soluble in water (1 g in 0.45 mL) and slightly
soluble in alcohol (1:25). It is used as a humectant, plasticizer, sweetening agent, and tablet
and capsule diluent. There are no listed incompatibilities of sorbitol in the dry state.1,16
Starch, NF
Starch [(C6H10O5)n where n = 300-1000] consists of the granules separated from the
mature grain of corn, wheat, tubers or tapioca. Starches obtained from different botanical
sources may not have identical properties with respect to their use for specific pharmaceutical
purposes, therefore, types of starch should not be interchanged unless performance
equivalency has been demonstrated. As an example, corn starch contains about 27%
amylose, potato starch about 22% and tapioca starch about 17%; these differences provide
for different physical properties. Starch generally occurs as irregular, angular, white masses or
as a fine powder. It is odorless and has a slight, characteristic taste. It is insoluble in cold
water and in alcohol. It should be labeled to indicate the botanical source from which it was
derived. Corn starch is also known as maize starch and tapioca starch is also known as
cassava starch. Starch has no listed incompatibilities.1,17
Pregelatinized Starch, NF
Pregelatinized starch [(C6H10O5)n, where n = 300-1000)] is starch that has been chemically
and/or mechanically processed to rupture all or part of the granules in the presence of water
and subsequently dried. Pregelatinized starch occurs as a moderately coarse to fine, white to
off-white powder. It is odorless and has a slight, characteristic taste. It is slightly soluble to
soluble in cold water and is insoluble in alcohol. It has no listed incompatibilities.1,18
Sucrose, NF
Sucrose (C12H22O11, MW 342.30, beet sugar, cane sugar, refined sugar, saccharose,
sugar) is obtained from various sources. It occurs as a white crystalline powder or as lustrous,
dry, colorless or white crystals. It is very soluble in water (1 g in 0.5 mL), slightly soluble in
alcohol (1 in 170) and practically insoluble in dehydrated alcohol. Sucrose may be
contaminated with traces of heavy metals that can lead to an incompatibility with active
ingredients as ascorbic acid. It also may contain sulfite from the refining process.1,19
Compressible Sugar, NF
Compressible sugar may contain starch, malto-dextrin or invert sugar and may contain a
suitable lubricant; it contains between 95 and 98% sucrose. It is used in the preparation of
direct compression chewable tablets. It occurs as a practically white, crystalline, odorless
powder with a sweet taste; it is stable in air. The sucrose portion of compressible sugar is
very soluble in water. It is incompatible with dilute acids and can react with alkaline earth
hydroxides to form sucrates.1,20
Confectioner's Sugar, NF
Confectioner's sugar is sucrose ground with corn starch to a fine powder; it contains not less
than 95% sucrose. It has been used in pharmaceutical formulations when a rapidly dissolving
form of sugar is needed for flavoring or sweetening. It occurs as a fine, white, odorless
powder with a sweet taste; it is stable in air. The sucrose portion of confectioner's sugar is
soluble in cold water. Confectioner's sugar is freely soluble in boiling water. It is incompatible
with dilute acids and can react with alkaline earth hydroxides to form sucrates.1,21
References
1. United States Pharmacopeia XXIV/National Formulary 19. Rockville, MD, U.S.
Pharmacopeial Convention, Inc., 1999, pp 277, 290, 754, 943, 1015, 2254-2304, 2423,
2425, 2432, 2433, 2444, 2445, 2469, 2470, 2522, 2524, 2525, 2527, 2528.
2. Armstrong NA. Calcium carbonate. In Kibbe AH (ed). Handbook of Pharmaceutical
Excipients, ed 2. Washington, DC, American Pharmaceutical Association, pp 56-59.
3. Moreton RC. Calcium phosphate, dibasic anhydrous. In Kibbe AH (ed). Handbook of
Pharmaceutical Excipients, ed 3. Washington, DC, American Pharmaceutical Association, pp
60-62.
4. Moreton RC. Calcium phosphate, dibasic dihydrate. In Kibbe AH (ed). Handbook of
Pharmaceutical Excipients, ed 3. Washington, DC, American Pharmaceutical Association, pp
63-67.
5. Daskalakis SA. Calcium phosphate, tribasic. In Kibbe AH (ed). Handbook of
Pharmaceutical Excipients, ed 3. Washington, DC, American Pharmaceutical Association, pp
68-69.
6. Moreton RC. Calcium sulfate. In Kibbe AH (ed). Handbook of Pharmaceutical Excipients,
ed 3. Washington, DC, American Pharmaceutical Association, pp 73-76.
7. Wheatley TA. Cellulose, microcrystalline. In Kibbe AH (ed). Handbook of Pharmaceutical
Excipients, ed 3. Washington, DC, American Pharmaceutical Association, pp 102-106.
8. Aulton ME. Cellulose, powdered. In Kibbe AH (ed). Handbook of Pharmaceutical
Excipients, ed 3. Washington, DC, American Pharmaceutical Association, pp107-109.
9. Armstrong NA. Dextrates. In Kibbe AH (ed). Handbook of Pharmaceutical Excipients, ed 3.
Washington, DC, American Pharmaceutical Association, pp 169-171.
10. Day A. Dextrin. In Kibbe AH (ed). Handbook of Pharmaceutical Excipients, ed 3.
Washington, DC, American Pharmaceutical Association, pp172-174.
11. Fazzi AA, Herbert K, Kibbe AH. Dextrose excipient. In Kibbe AH (ed.) Handbook of
Pharmaceutical Excipients, ed 3. Washington, DC, American Pharmaceutical Association, pp
210-212.
12. Palmieri A. Kaolin. In Kibbe AH (ed). Handbook of Pharmaceutical Excipients, ed 3.
Washington, DC, American Pharmaceutical Association, pp 269-271.
13. Armstrong NA. Lactitol. In Kibbe AH (ed). Handbook of Pharmaceutical Excipients, ed 3.
Washington, DC, American Pharmaceutical Association, pp 274-275
14. Kibbe AH. Lactose monohydrate. In Kibbe AH (ed). Handbook of Pharmaceutical
Excipients, ed 3. Washington, DC, American Pharmaceutical Association, pp 276-285.
15. Armstrong NA, Reier GE. Mannitol. In Kibbe AH (ed). Handbook of Pharmaceutical
Excipients, ed 3. Washington, DC, American Pharmaceutical Association, pp 324-328.
16. Nash RA. Sorbitol. In Kibbe AH (ed). Handbook of Pharmaceutical Excipients, ed 3.
Washington, DC, American Pharmaceutical Association, pp 515-518.
17. Kibbe AH, Rowley G. Starch. In Kibbe AH (ed). Handbook of Pharmaceutical Excipients,
ed 3. Washington, DC, American Pharmaceutical Association, pp 522-527.
18. Lordi NG, Rowley G. Starch pregelatinized. In Kibbe AH (ed). Handbook of Pharmaceutical
Excipients, ed 3. Washington, DC, American Pharmaceutical Association, pp 528-530.
19. Armstrong NA, Fazzi AA, Kibbe AH. Sucrose. In Kibbe AH (ed). Handbook of
Pharmaceutical Excipients, ed 3. Washington, DC, American Pharmaceutical Association, pp
539-543.
20. Wood AW. Sugar compressible. In Kibbe AH (ed). Handbook of Pharmaceutical
Excipients, ed 3. Washington, DC, American Pharmaceutical Association, pp 544-545.
21. Kibbe AH. Sugar confectioner's. In Kibbe AH (ed). Handbook of Pharmaceutical Excipients,
ed 3. Washington, DC, American Pharmaceutical Association, pp 546-547.
Table 1. Physical Properties of USP XXIV/NF 19 Capsule and Tablet Diluents
Substance
Calcium
carbonate
Density
(g/mL)
2.70
Bulk
Density
Tapped
Density
Melting
Point (
C)
pH
Hydroscopic Stable
Container
Yes/No
Yes/No
0.80
1.2
825 (d)
Yes
WC
2.89
0.78
0.82
7.3
(20%)
No
Yes
WC
2.39
0.92
1.17
7.4
(20%)
No
Yes
WC
Calcium phosphate, dibasic
Anhydrous
Hydrate
Calcium
phosphate,
tribasic
3.14
0.80
0.95
1670
6.8
(20%)
Yes
WC
Anhydrous
2.96
0.70
1.28
1450
10.4
(10%)
Yes
Yes
WC
Dihydrate
2.32
0.67
1.12
7.3
(10%)
No
Yes
WC
Cellulose,
1.59
microcrystalline
0.34
0.48
Yes
Yes
WC
Cellulose,
powdered
1.50
0.14-0.39 0.21-0.48
4-7.5
(10%)
Little
Yes
WC
Dextrates
1.54
0.68
0.72
141
3.8-5.8
(20%)
Yes
WC
Dextrin
1.50-1.59 0.80
0.91
178 (d)
Yes
WC
Dextrose
excipient
1.54
1.00
83
3.5-5.5
(20%)
No
Yes
WC
Fructose
1.58
102-105
5.35
(9%)
Yes
Yes
WC
Kaolin
2.60
Yes
WC
Lactitol
1.54
4.5-7
(10%)
No
Yes
WC
Lactose
1.55
0.62
0.94
202
No
Yes
Tight
Mannitol
1.51
0.43
0.73
166-168
No
Yes
WC
Sorbitol
1.50
0.45
0.40
110-112
4.5-7
(10%)
Yes
Yes
Tight
Starch
1.48
0.46
0.66
5.5-6.5
(2%)
Yes
Yes
WC
Starch,
pregelatinized
1.52
0.59
0.88
4.5-7.0
(10%)
Yes
Yes
WC
Sucrose
1.6
0.60
0.82
160-186
(d)
Yes
Yes
WC
Calcium sulfate
0.83
260-270
5-7
(c)
-
Sugar,
compressible
0.49
0.60
Yes
Yes
WC
Sugar,
confectioner's
0.47
0.83
Yes
Yes
WC
d = melts with some decomposition.
c = chars
