Calcium Phosphate Excipients - Innophos

Calcium
Phosphate
Excipients

Calcium
Phosphate
Excipients

TABLE OF CONTENTS
Page Number
Clinical trials
demonstrate the
positive effect
of calcium and
phosphorus
supplimentation
in osteoporosis
sufferers who
receive bone
building therapy.
SECTION 1: THE LEADER IN CALCIUM PHOSPHATES
The Leader in Calcium Phosphate Excipients ...............1
An Introduction to Calcium Phosphates .........................1
Manufacture of Calcium Phosphates ...............................2
SECTION 2: METHODS FOR THE PREPARATION OF TABLETS
Methods for the Preparation of Tablets...........................3
SECTION 3: PHYSICAL AND CHEMICAL PROPERTIES
Physical and Chemical Properties.....................................5
Formulas and Nomenclature ..............................................5
Calcium and Phosphorus Content....................................6
Scanning Electron Photomicrographs..............................7
Particle Size Distributions.....................................................9
Adsorption Isotherm..............................................................9
Moisture ..................................................................................10
Compatibilities and Stability .............................................10
Thermal Behavior .................................................................11
Solubility..................................................................................11
Density .....................................................................................12
SECTION 4: TABLETING PROPERTIES
Calcium Phosphates in Direct Compression ...............13
Direct Compression with A-TAB ® .....................................13
Direct Compression with DI-TAB ® ...................................15
Direct Compression with TRI-TAB ® .................................16
Direct Compression Tableting with TCP-DC ...............17
Disintegration of Calcium Phosphate Tablets .............18
Consolidation of Calcium Phosphates ..........................18
Flow of Calcium Phosphates............................................18
Lubrication of Tablets with Calcium Phosphate
Formulations ..........................................................................19
Tooling Phosphate Formulations.....................................20
Loading Capacity of Calcium Phosphates ....................20
SECTION 5: COMPLETE SERVICE SUPPORT
Complete Service Support.................................................21
Units of measurement, definition of terms .................23
Bibliography ...........................................................................24

THE LEADER IN CALCIUM PHOSPHATES
Innophos is well positioned to meet all your needs for high-quality calcium phosphates. We have been
manufacturing calcium phosphates at our Chicago Heights, Illinois manufacturing plant since the 1930s.
Because of our high commitment to meeting the pharmaceutical industry's need for high performance
excipients, we have continually made improvements in our products and our plant's manufacturing
capability. We also have continued to add to our product line to establish our positions
as the market leader in calcium phosphates.
1
Uncompromising Quality
Each product is manufactured under carefully
controlled processing conditions to minimize
lot-to-lot variations in pharmaceutical tableting.
These products are manufactured under the Food
and Drug Administration and Good Manufacturing
Practice guidelines for bulk pharmaceuticals. A drug
master file (DMF) is available for each product.
Complete Technical Support
Our laboratories and technical staff can provide
you with ongoing support in your pharmaceutical
application of calcium phosphate excipients.
Why we prepared this guide.
The information on the following pages has been
compiled to offer you an overview of the general
chemical, physical and tableting properties of
calcium phosphates.
We encourage you to use this guide as reference
for your own product line, as well as a technical
resource for calcium phosphates in general. If you
have questions about an existing product or a
potential application, please do not hesitate to
call our technical information number.
This guide, our product quality and our ongoing
product development programs are all evidence
of our commitment to meeting the needs of
customers who use calcium phosphates as
pharmaceutical ingredients.
An Introduction to Calcium Phosphates
Calcium phosphates have a number of fundamental
properties which make them ideal for solid dosage
formulations with a wide range of actives:
◆ white color
◆ stability
◆ insolubility
◆ will not case harden
◆ excellent disintegration with disintegrants
◆ compatible with a wide range of actives
◆ provide a source of calcium and phosphorus
Calcium phosphates are often used in
pharmaceutical tableting...
◆ with soluble drugs
◆ to improve flow
◆ to densify a blend
◆ in ordered mixing
◆ to reduce production cost
◆ in direct compression formulations
◆ in wet granulations for ease of handling
Calcium phosphates find wide application as
excipients in direct compression and wet
granulation tableting. They're used as flow
agents, as a source of calcium and phosphorus
and are used extensively in the food, feed and
pharmaceutical industries.
We offer a complete line of calcium phosphates,
unmatched by any other calcium phosphate
supplier. With a wide variety for both wet
granulation and direct compression tableting,
we can supply you with the calcium phosphate
excipient that best meets the needs of your
particular application.

For Direct Compression
DI-TAB ® : Dicalcium phosphate, dihydrate,
unmilled, USP/FCC grades. The most well-known
of Innophos's directly compressible excipients, it is
used in major vitamin and mineral formulations, in
over-the-counter drugs and in prescription drugs.
TRI-TAB ® : Tricalcium phosphate, anhydrous, granular,
NF/FCC grade. TRI-TAB ® has the highest percentage
of calcium and is used in calcium supplements.
A-TAB ® : Dicalcium phosphate, anhydrous, granular,
USP/FCC grade. It is anhydrous (giving it good
storage stability), very compressible and provides
a high level of calcium and phosphorus.
Our calcium phosphates are most effectively used
in direct compression tableting. This three-step
procedure - which consists of weighing (actives and
excipients), mixing and compressing - is all that is
required to manufacture a wide variety of tablets.
Both wet and dry granulation take more steps.
Eu and JP grades are available upon request.
For Wet Granulation
Calipharm-D ® : Dicalcium phosphate, dihydrate,
powder, USP/FCC.
Calipharm-T ® : Tricalcium phosphate, anhydrous,
powder, NF/FCC.
Calipharm-A ® : Dicalcium phosphate, anhydrous,
powder, USP/FCC.
The powder forms of calcium phosphates can
be used in a wet granulation with a variety of
commonly used binders, starches, gums, cellulosics
and other polymers. Their water and solvent
insolubility make the calcium phosphates ideal
for wet granulation.
Manufacture of Calcium Phosphates
H 3
PO 4
+ Ca(OH) 2
Ca(H 2
PO 4
) 2
Monocalcium Phosphate
H 3
PO 4
+ Ca(OH) 2
Manufacture
Ca(H 2
PO 4
) 2
•H 2
O
Monocalcium Phosphate
Monohydrate
H 3
PO 4
+ Ca(OH) 2
CaHPO 4
Dicalcium Phosphate
Anhydrous
H 3
PO 4
+ Ca(OH) 2
Figure 1
CaHPO 4
•2H 2
O
Dicalcium Phosphate
Dihydrate
Ca(OH) 2
+ H 3
PO 4
Ca 5
(OH)(PO 4
) 3
Tricalcium Phosphate
To manufacture calcium phosphates, very pure
foodgrade phosphoric acid is used. The phosphoric
acid is reacted with calcium hydroxide, Ca(OH) 2
,
which comes from limestone (CaCO 3
). The
products are precipitated from solution.
When Ca(OH) 2
is added to phosphoric acid in the
appropriate ratio, the products are monocalcium
phosphate or dicalcium phosphate. When acid is
added to the calcium hydroxide, the precipitate is
tricalcium phosphate. As defined in the USP/NF,
tricalcium phosphate is a variable mixture of
calcium phosphates, having the approximate
composition 10CaO•3P 2
O 5
•H 2
O. This composition
corresponds to the formula Ca 5
(OH)(PO 4
) 3
or
Ca 10
(OH) 2
(PO 4
) 6
. TRI-TAB ® is this material in the
granular form. The manufacturing process general
equations are shown in Figure 1.
2

METHODS FOR THE PREPARATION OF TABLETS
Wet Granulation
Wet granulation continues to be a widely used
method. In this process, granules are formed
from wetted mixtures of the preblended tablet
ingredients, dried, screened and compressed into
tablets. This method is often employed in tablets
that have either a low dose active or a very high
degree of actives. See Figure 2.
Dry Granulation
The dry granulation method is often used with
ingredients which are moisture or heat sensitive.
Dry granulation utilizes dry, preblended mixtures
of ingredients which are compacted into large
granules ("slugs"). The granules are then crushed,
screened and compressed into tablets. This
method is useful in the granulation of aspirin
and effervescent tablets. See Figure 3.
Direct Compression
In the direct compression process, tablets are
compressed directly from blends of the active
ingredients and suitable excipients. These blends
include all appropriate fillers, disintegrants,
lubricants and require no further pretreatment
prior to tableting. See Figure 4.
Direct compression has become widely accepted
and continues to grow in popularity because it
offers several major advantages...
◆ economy (reduced labor costs, manufacturing
time, less equipment, energy and space)
◆ elimination of heat and moisture
◆ optimization of tablet disintegration
◆ stability
DI-TAB ® , TRI-TAB ® , A-TAB ® and TCP-DC are
direct compression excipients.
3

Figure 2: Wet Granulation
DRUG
EXCIPIENT
LIQUIDS
PELLET
GRIND
COMPRESS
BLEND
LUBRICANT
AGGLOMERATE
TABLET
BLEND
SCREEN
DRY
Figure 3: Dry Granulation
DRUG
EXCIPIENT
2
CRUSH
GRIND
COMPRESS
BLEND
LUBRICANT
PELLET
TABLET
BLEND
SCREEN
Figure 4: Direct Compression
DRUG
A-TAB ® , DI-TAB ® ,
TRI-TAB ® , TCP-DC ,
AND OTHER
EXCIPIENTS
COMPRESS
TABLET
GRIND
BLEND
4

PHYSICAL AND CHEMICAL PROPERTIES
Formulas
The chemical formulas and molecular weights
of dicalcium phosphate dihydrate, dicalcium
phosphate anhydrous and tricalcium phosphate are
listed in Table 1. As shown, dicalcium phosphate
(or dibasic calcium phosphate) is produced as
either the dihydrate or the anhydrous salt.
Commercial tricalcium phosphate is primarily
hydroxyapatite, with a general formula of
Ca 5
(OH)(P0 4
) 3
. It can also be referred to as
tribasic calcium phosphate since during preparation
from phosphoric acid, all of the three hydrogens are
replaced by calcium. In nature, hydroxyapatite is the
primary inorganic structural material in bones and
teeth. It is different from the mineral whitlockite,
with a formula of Ca 3
(P0 4
) 2
.
TCP-DC is Innophos’ patented (US Patent
7,226,620) directly compressible ingredient
designed to make high calcium load tablets
easier to make. It is a granulated product made
from tricalcium phosphate, NF/FCC and povidone
USP, with an elemental calcium content of
approximately 35%.
Table 1
DCPD DCPA TCP
Name ◆ Dicalcium Phosphate ◆ Dicalcium Phosphate, ◆ Tricalcium Phosphate
Dihydrate Anhydrous ◆ Tribasic Calcium Phosphate
◆ Dibasic Calcium ◆ Dibasic Calcium ◆ Tricalcium Orthophosphate
Phosphate Dihydrate Phosphate, Anhydrous ◆ Hydroxyapatite
CAS 7789-77-7 7757-93-9 12167-74-7
Number
Formula CaHPO 4
•2H 2
O CaHPO 4
Ca 5
(OH) (PO 4
) 3
or
Ca 10
(OH) 2
(PO 4
) 6
or
10CaO•3P 2
O 5
•H 2
O
Molecular 172.09 136.06 1004.7
Weight
5

Calcium and Phosphorus Content
Typical calcium and phosphorus contents of the
calcium phosphates are listed in Table 2 as the
percent by weight for each element. The Ca/P
weight ratios and mole ratios are also given for
comparison. Of the calcium phosphates, tricalcium
phosphate contains the highest calcium content
(38%) and the highest Ca/P weight ratio, 2.2/1.
Table 2
Typical Chemical Analysis
DI-TAB ® A-TAB ® TRI-TAB ® TCP-DC
% Ca (wt) 23.3 29.0 38.0 34.5 – 37.5
% P (wt) 18.1 22.2 17.3 15.6 – 17.4
Ca/P (wt) 1.3/1 1.3/1 2.2/1 2.2/1
Ca/P (mole) 1.0/1 1.0/1 1.7/1 N/A
U.S. RDA: Ca: 800 – 1200 mg, Ca/P wt. ratio 1/1.
6

Scanning Electron Photomicrographs
The scanning electron photomicrographs of
DI-TAB ® , A-TAB ® and TRI-TAB ® illustrate the
surface roughness of these granules which can
be important in ordered blending operations. Fine
particles of active ingredients can adhere more
readily to the large, rough surface of the calcium
phosphates to enhance effective mixing.
The granular excipients can be seen to be
aggregates of crystalline particles.
DI-TAB ® and A-TAB ® compact via a brittle fracture
mechanism, forming clean surfaces for good
bonding. TRI-TAB ® compacts primarily by
plastic deformation.
7

SCANNING ELECTRON PHOTOMICROGRAPHS
OF DI-TAB ® , A-TAB ® , TRI-TAB ®
Figure 5a: DI-TAB ® , 100x magnification
Figure 5b: DI-TAB ® , 300x magnification
100µm
Figure 6a: A-TAB ® , 100x magnification
100µm
Figure 6b: A-TAB ® , 250x magnification
100µm
Figure 7a: TRI-TAB ® , 75x magnification
100µm
Figure 7b: TRI-TAB ® , 200x magnification
100µm
100µm
8

Table 3
Particle Size Distributions
Figure 8 shows typical particle size distributions
for Dl-TAB ® , A-TAB ® and TRI-TAB ® . These granular
products are designed for excellent flow with over
95% of the granules between 40 and 325 US sieve
mesh (420 to 44µm). Sieving data are obtained
using a 25.0-g sample, RO-TAP Sieve Tester and 20,
60, 100, 200 and 325 US Series Standard Sieves.
The powdered calcium phosphates are all less than
about 44µm in particle size (325 mesh). Typical
average diameters are shown in Table 3.
Name
Average Particle Diameters (µm)
DI-TAB ®
A-TAB ®
TRI-TAB ®
TCP-DC
TRICAL-WG
Powder Dicalcium
Phosphate Dihydrate
Powder Dicalcium
Phosphate Anhydrous
Powder Tricalcium
Phosphate
Typical Average
Diameter (µm)
180 (a)
180 (a)
350 (a)
125 (a)
180 (a)
9 (b)
15 (b)
5 (b)
(a) By sieving; (b) By laser granulometer.
% Weight Less Than Diameter
100
90
80
70
60
50
40
30
20
Figure 8:
Typical Particle Size Distributions
A-TAB ® DI-TAB ® TRI-TAB ®
Adsorption Isotherms
As shown in Figure 9, dicalcium phosphate
dihydrate and dicalcium phosphate anhydrous
are not hygroscopic. This equilibrium moisture
adsorption isotherm shows only minimal
moisture uptake by the dibasic salts. TRI-TAB ® ,
hydroxyapatite, is a slightly hygroscopic material
and will pick up some moisture at higher relative
humidities. For example, at 25°C, TRI-TAB ® will
hold about 4% moisture at 60% R.H. at
equilibrium. It can take several weeks to
reach equilibrium depending on bed depth
and exact experimental conditions.
10
0
10
Diameter
in Microns
Sieve Numbers
100 1000
325 200 100 60 20
9

% Water
15
10
5
Moisture
Figure 9:
Equilibrium Moisture Isotherms, 25°C
0
0 20 40 60 80 100
% Relative Humidity
TRI-TAB ®
A-TAB ®
DI-TAB ®
Equilibrium moisture adsorption isotherm at 25°C expressed as %
water on an anhydrous basis vs. relative humidity. Moisture determined
for A-TAB ® and TRI-TAB ® at 105°C; for DI-TAB ® at 60°C.
While TRI-TAB ® is slightly hygroscopic and may
pick up surface moisture or contain moisture
in small pores, it does not form a well-defined
crystalline hydrate, and surface moisture can be
readily removed in an oven. The moisture content
of TRI-TAB ® can be determined by drying at 105°
and is typically about 0.2%. High temperatures
(>100°C) can also be used to determine the
surface moisture of A-TAB ® , because A-TAB ® is
an anhydrous material. Unlike A-TAB ® , moisture
determination or weight loss-on-drying for DI-TAB ® ,
dicalcium phosphate dihydrate, is done at 60°C.
At higher temperatures, some of the waters of
hydration of DI-TAB ® are removed, leading to
incorrect high surface moisture values.
When DI-TAB ® or powdered dicalcium phosphate
dihydrate is dehydrated, it cannot be rehydrated
again to form the dihydrate. Thus, a formulation
exposed to high temperatures, say 50° or 60°C,
can irreversibly lose water.
The anhydrous dicalcium phosphate salt will not
pick up water to form the dihydrate because it
is a thermodynamically stable material. In a wet
granulation, the anhydrous remains anhydrous
as shown by its X-ray diffraction powder pattern.
Compatibilities and Stability
A well-known incompatibility for calcium salts
is with the tetracycline antibiotics. These drugs
should not be taken within two hours of eating
dairy products such as milk, yogurt or cheese,
or taking calcium or iron supplements.
Hydroxyapatite is incompatible with tocopheryl
acetate (but not with tocopheryl succinate). The
reason is attributed to the large number of hydroxyl
groups on the hydroxyapatite surface and the large
surface area of this excipient.
DI-TAB ® , which contains waters of crystallization,
is stable during storage under normal conditions
(20° – 40°C). However, some of this water can be
lost during storage at higher temperatures and
may interact with water-sensitive ingredients in a
formulation. Accelerated stability testing of tablets
containing DI-TAB ® Should not be done at high
temperatures of 50° – 60°C, as they will yield
erroneous results. This can give rise to some
apparent incompatibilities at higher temperatures,
where the released moisture may interact with
drugs, vitamins and other excipients. To extrapolate
such findings to room temperature would be
erroneous, since dicalcium phosphate dihydrate
does not dehydrate at this temperature.
Arrhenius plots should not be done for dicalcium
phosphate dihydrate dosage forms which have
been stored under high temperature conditions
because the dihydrate may no longer be present.
10

Figure 10:
Differential Scanning Calorimetry Curves
TRI-TAB ®
Tricalcium Phosphate (open pan)
ENDO ∆T EXO
A-TAB ®
DI-TAB ®
0 100 200 300 400 500
˚C
Thermal Behavior
Dicalcium Phosphate Anhydrous (open pan)
Dicalcium Phosphate Dihydrate (open pan)
Dicalcium Phosphate Dihydrate
(closed pan)
The thermal behavior of dicalcium phosphate,
anhydrous shows no differential scanning
calorimetry (DSC) pattern until it reaches very
high temperature (where molecular dehydration to
pyrophosphate takes place). For the dihydrate, there
are three distinct events. As shown in Figure 10, the
first, between 85 and 100˚C, is presumably loss of
surface moisture, although the amount (judging
from the area under the peak), would imply at least
10 layers of moisture. The second loss corresponds
to a loss of 0.5 mole of water, and the third peak to
the remaining 1.5 moles of water.
There are distinct differences between DSCs of
dicalcium phosphate dihydrate in closed and open
pans. These types of thermograms demonstrate the
fact that moisture catalyzes the dehydration of
dicalcium phosphate dihydrate, a statement which,
at first, may seem self-contradictory.
The DSC curve for dicalcium phosphate anhydrous
confirms that it has no water of hydration. The
endotherms exhibited by dicalcium phosphate
dihydrate and dicalcium phosphate anhydrous
(at temperatures greater than 400°C) correspond
to condensation of the orthophosphate groups to
4-
form pyrophosphate, P 2
O 7
groups.
The DCS curve for tricalcium phosphate shows
that it is anhydrous.
Solubility
Dicalcium phosphate dihydrate, dicalcium
phosphate anhydrous and tricalcium phosphate
are insoluble in water, by USP definition. They are
all soluble in 0.1 N hydrochloric acid because
they react with the acid and dissolve. Table 4
lists the chemical solubility constants for
dicalcium phosphate dihydrate and dicalcium
phosphate anhydrous.
This table also lists the aqueous slurry pH for 20%
wt/wt slurry for the direct compression calcium
phosphates. Both the powdered and granular forms
of dicalcium phosphate dihydrate or of tricalcium
phosphate have the same slurry pH, but the
powdered form of dicalcium phosphate
anhydrous has a pH of 7.4.
11

Table 4
Typical Properties Of Calcium Phosphates In Tableting
DI-TAB ® A-TAB ® TRI-TAB ®
Formula CaHPO 4
•2H 2
O CaHPO 4
Ca 5
(OH) (PO 4
) 3
Water Solubility No No No
K SO
(25˚C) 2.5 x 10 -7 ** 4.7 x 10 -59
K SO
(37˚C) 1.9 x 10 -7 ** 2.3 x 10 -59
HCl Solubility Yes Yes Yes
pH (20% slurry) 7.4 5.1 6.8
Surface Area (m 2
/g) 1-2 20-30 70-80
Disintegration
Without Disintegrant No No No
With Disintegrant Rapid Rapid Rapid
Compressibility Good Good Acceptable
Primary Bonding Brittle Fracture Brittle Fracture Plastic Deformation
Mechanism
**Same as for Dicalcium Phosphate Dihydrate.
Density
The calcium phosphates are inherently
dense materials. This contributes to
the excellent flow of the granular
phosphates. Table 5 lists the loose
and tapped bulk densities of these
materials together with the true, or
crystallographic, density values.
Table 5
DI-TAB ® A-TAB ® TRI-TAB ® TCP-DC
Loose Bulk 0.87 0.78 0.80 .58
Density a (g/cc)
Tapped Bulk 0.93 0.82 0.95 .65
Density b (g/cc)
Crystallographic 2.31 2.89 3.15 N/A
(true) Density
(g/cc)
a. Weight of a known volume loosely poured into a graduated cylinder.
b. Weight of a measured volume in a graduated cylinder after tapping to constant volume.
12

TABLETING PROPERTIES
Calcium Phosphates
in Wet Granulations
The powdered calcium phosphates have been
traditionally used in wet granulation processes.
They are blended, size enlarged through the use of
a binder and dried and sized for compression. The
calcium phosphates can be granulated with a large
variety of commonly used binders, including starch,
pregelatinized starch, acacia, locust bean and
guar gums, cellulosics such as methylcellulose,
ethylcellulose, hydroxypropyl methylcellulose
and polyvinylpyrrolidone.
Some special facts to remember about the
calcium phosphates are:
◆ Tricalcium phosphate will dry to its
anhydrous form.
◆ Dicalcium phosphate anhydrous will
remain anhydrous.
◆ Dicalcium phosphate dihydrate can lose some
or all of its waters of hydration irreversibly
during drying.
Often, a granular calcium phosphate is used in a
wet granulation process because of the advantages
of granular over powdered products: ease of
handling, smoother unit operation due to higher
bulk densities, fewer fine particles and therefore
less dust. A special grade of tricalcium phosphate,
TRI-CAL-WG, which is a densified tricalcium
phosphate, is designed for wet granulation
(WG) use.
Direct Compression Tableting
with A-TAB ®
A-TAB ® is also directly compressible to give hard
compacts at moderate applied forces. Using
tableting conditions like those used for DI-TAB ® ,
Figure 11 shows a compressibility profile for A-TAB ®
slightly greater than for DI-TAB ® at the higher
applied forces. A-TAB ® , like DI-TAB ® , is also
compatible with microcrystalline cellulose.
Figure 12 shows the expected increase in
tablet hardness or crushing strength in A-TAB ®
formulations containgin AVICEL ® PH-101.
A-TAB ® tablets do not change in thickness or
hardness after 1 month storage at room
temperature or 50˚C. The data in Table 6 shows
modest softening and a slight increase in
disintegration time when tablets are stored in
a desiccator over 75% relative humidity. This is
most likely due to moisture uptake by the
disintegrant at the high humidity.
Tablet Hardness (kp)
35
30
25
20
15
10
Figure 11 Figure 12
40
35
30
25
A-TAB 20
®
5
5 10 15 20 25 30 35
Compaction Force (kN)
Tablet Hardness (kp)
A-TAB ® +
20% AVICEL ® A-TAB ® +
10% AVICEL ®
A-TAB ®
15
10
5
5 10 15 20 25 30 35
Compaction Force (kN)
COMPRESSIBILITY PROFILE FOR A-TAB ®
Data for 750 mg. tablets, 7/16-in. standard cup, Manestry B3B rotary
tablet press. Vertical bars indicate standard deviation of tablet hardness.
COMPRESSIBILITY PROFILE FOR A-TAB ® containing 10 and 20% AVICEL ®
PH-101 microcrystalline cellulose.
13

Table 6
Properties Of Aged A-TAB ® Tablets
Aging Conditions Hardness Weight Thickness Disintegration
(kp) (mg) (mm) (min.)
Initial 31 751 5.26 0.6
1 Month R.T., Closed 31 752 5.28 0.7
1 Month 50˚, Closed 29 751 5.27 0.9
1 Month, R.T., 75% R.H. 25 763 5.27 1.8
Tablets made at 30kN applied force; 7/16-in. standard cup tooling.
14

Table 7
Representative Formulations
Used For Tablets In Profiles
% wt % wt % wt
A-TAB ® 97.0 – 87.0
DI-TAB ® – 97.0 –
AC-DI-SOL ® 2.0 2.0 2.0
Magnesium
Stearate
1.0 1.0 1.0
AVICEL ® PH101 – – 10.0
Direct Compression Tableting
with DI-TAB ®
DI-TAB ® shows good compressibility, as shown
in Figure 13. These data, like all other rotary press
data in this brochure, were obtained on a Manesty
B3B rotary tablet press, instrumented to measure
compression force. Nominal tablet weight was
750 mg and 7/16-in., standard concave IPT tooling
was used. Typical tablet formulations are given in
Table 7.
DI-TAB ® is compatible vvith microcrystalline
cellulose. Figure 14 illustrates the typical increase
in tablet hardness, or crushing strength, observed
upon addition of microcrystalline cellulose, in this
case AVICEL ® PH-101*, to the formulation.
Properties of DI-TAB ® tablets are shown in Table 8.
Initial tablet properties are excellent. A total of 2%
croscarmellose sodium (AC-DI-SOL ® )* disintegrant
was used in these tablets together with 1%
magnesium stearate lubricant.
*AC-DI-SOL ® and AVICEL ® are registered trademarks of
FMC Corporation, Philadelphia, PA 19103.
Tablet Hardness (kp)
Tablet Hardness (kp)
35
30
25
20
15
10
Figure 13
DI-TAB ®
5
5 10 15 20 25 30 35
Compaction Force (kN)
COMPRESSIBILITY PROFILE FOR DI-TAB ®
Data for 750 mg. tablets, 7/16-in. standard cup, Manestry B3B rotary
tablet press. Vertical bars indicate standard deviation of tablet hardness.
Figure 14
40
35
30
25
DI-TAB ®
20
15
10
5
5 10 15 20 25 30 35
Compaction Force (kN)
DI-TAB ® +
20% AVICEL ®
DI-TAB ® +
10% AVICEL ®
COMPRESSIBILITY PROFILE FOR DI-TAB ® containing 10 and 20%
AVICEL ® PH-101 microcrystalline cellulose.
DI-TAB ® tablets are hard initially and maintain
their hardness under a variety of storage conditions.
However, after storage in closed glass jars at 50˚C
for one month, significant tablet weight loss is
observed. This is due to the loss of some of the
water of hydration of the dicalcium phosphate
dihydrate at this high temperature. There also
appears to be a slight increase in disintegration
time at this condition. Thus testing after storage
at 50˚C is not valid for DI-TAB ® . These data are
listed in Table 8.
15

Table 8
Properties Of Aged DI-TAB ® Tablets
Aging Conditions Hardness Weight Thickness Disintegration
(kp) (mg) (mm) (min.)
Initial 19 751 4.94 0.3
1 Month R.T., Closed 19 751 4.91 0.3
1 Month 50˚, Closed 18 661* 4.92 1.2
1 Month, R.T., 75% R.H. 17 752 4.92 0.6
Tablets made at 30kN applied force; 7/16-in. standard cup tooling.
*Weight loss is due to loss of DI-TAB ® water of hydration at high temperature.
Direct Compression Tableting with TRI-TAB ®
A typical compressibility profile for TRI-TAB ® is shown in Figure 15. Data is listed in Table 9. The addition of
microcrystalline cellulose (AVICEL ® PH-101) increases tablet hardness and extends the capping point to
higher compression forces, as shown in Figure 16.
Figure 15 Figure 16
Tablet Hardness (kp)
20
16
12
8
4
0
8
TRI-TAB ®
10 12 14 16 18 20 22
Compaction Force (kN)
Tablet Hardness (kp)
20
16
12
8
4
TRI-TAB ® +
20% AVICEL ® TRI-TAB ® +
10% AVICEL ®
TRI-TAB ®
0
8 12 16 20 24 28 32
Compaction Force (kN)
COMPRESSIBILITY PROFILE FOR TRI-TAB ® COMPRESSIBILITY PROFILE FOR TRI-TAB ® containing 10 and 20%
AVICEL ® PH-101 microcrystalline cellulose.
Table 9
TRI-TAB ® Tablet Properties
Force Hardness Weight Disintegration (minutes)
(kp) (mg)(%RSD) (mm) Initial 1 Month 2 Months
15.3 7.6 731.6 (0.41) 0.3 0.4 0.4
20.1 9.8 734.2 (0.30) 0.7 0.5 0.4
14.9 7.0 752.5 (0.18) 0.4 0.4 0.4
20.9 9.3 755.3 (0.23) 1.1 0.8 0.5
13.4 6.6 748.9 (0.40) 0.4 0.6 –
17.7 9.0 754.0 (0.33) 0.8 0.9 –
16

Direct Compression Tableting
with TCP-DC
A directly compressible grade of Tricalcium
Phosphate
TCP-DC is a spray dried directly compressible
product that is a perfect choice for use in
manufacturing calcium supplements. TCP-DC is an
excellent source for both calcium and phosphorus
needed to maintain bone health.
Compression
25 Kp harness was achieved at 2.5 tons of
pressure. This could be extended with no
observation of capping.
Supplement Formula
By combining TCP-DC with Tri-Tab ® you can
formulate a calcium supplement that takes
advantage of the growing scientific evidence
linking the requirement of both calcium and
phosphorus to better bone health.
Table 10
Supplement Formula
Mg/Tablet
Tablet
% by
Weight
TRI-TAB ® (38% Ca) 819 46.5
TCP-DC (36% Ca) 819 46.5
Microcrystalline
Cellulose
71 4
Vit D3 100 IU/mg
(150% xs)
3 0.2
Croscarmellose
Sodium
36 2
Sodium Lauryl
Sulfate
4 0.3
Magnesium
Stearate
8 0.5
Totals 1760 mg 100%
Label claim: Ca = 600mg. P = 275mg. Vitamin D = 200 IU/mg.
Benefits
◆ TCP-DC exhibits a high level of calcium
with improved compressibility
◆ Delivery of both calcium and phoshorus in one
directly compressible product
◆ Higher compressibility Lower compression
force Harder tablets
◆ Small tablet size and high performance
◆ Meets Prop 65 requirements for lead levels
◆ Tablet hardness significantly higher
than regular TRI-TAB ® used alone
◆ Manufactured under nutritional GMP’s
Advantages
TCP-DC is made from Tricalcium Phosphate NF and
Povidone USP. The combination provides increased
compressibility relative to TRI-TAB ® alone, but more
importantly for chewable tablets, it exhibits a greatly
improved taste profile and mouthfeel, with the
virtual elimination of grittiness and chalkiness
often associated with calcium products.
Figure 17
Compressibility of TCP-DC with TRI-TAB ® (1:1)
30
Tablet Hardness (kp)
25
20
15
10
5
0
0 0.5 1 1.5 2 2.5 3 3.5
Compaction Force (tons)
17

Relative A.N.C. (%)
Figure 18
Antacid Properties of Calcium Phosphates
100
90
80
70
60
50
40
30
20
10
0
37
DI-TAB ®
Disintegration
43
A-TAB ®
Acid Neutralization Capacity Relative to CaCO 3 .
Antacid Properties of
Calcium Phosphates
TRI-TAB ® TCP-DC
The calcium phosphates, when tableted, do not
disintegrate readily. They are quite water insoluble
69
73
100
CaCO3
Often overlooked are the significant antacid
properties accessible from formulating with the
calcium phosphates. As the graph demonstrates
(Figure 18), the tricalcium phosphates have
approximately 70% the acid neutralization capacity
of CaCO 3
. TCP-DC in a chewable tablet can offer
the same antacid properties as leading brands in
a gentle, non-bloating formula with the additional
benefit of phosphorus to better support bone health.
Tapped Volume (cc/g)
2.0
1.0
Figure 19
10 20 30 40
Number of Taps
Consolidation Volume (cc/g) as a function of number of taps.
A-TAB ®
DI-TAB ®
TRI-TAB ®
Excipient CV (%RSD) Flow (g/sec)
A-TAB ® 0.4 28
DI-TAB ® 0.2 33
TRI-TAB ® 0.3 39
and dissolve in dilute hydrochloric acid by erosion.
All of the calcium phosphate tablets do disintegrate
rapidly with the use of appropriate disintegrants.
Both the traditional starch and the newer
superdisintegrants, such as croscarmellose sodium,
crospovidone and sodium starch glycolate, can
be formulated with calcium phosphates. The
appropriate use level is, of course, dependent
on the formulated blend. Because the calcium
phosphate tablets contain void volume (in which
the disintegrant can reside), the wetting and
swelling pressure generated by the disintegrant
is especially effective.
Consolidation
Rapid consolidation of an excipient in a rotary
press die is an advantage, especially in high-speed
rotary presses which allow minimal time for die fill,
formulation consolidation and tablet compression.
The excellent consolidation properties of the
granular calcium phosphates are illustrated in
Figure 19, which describes consolidated bed
volume as a function of tapping.
Flow
Table 11
Coefficient of Variation of Tablet Weights of A-TAB ® , DI-TAB ® and TRI-TAB ®
indicating excellent flow properties.
DI-TAB ® , A-TAB ® , and TRI-TAB ® exhibit excellent
flow rates. The flowing excipients exhibit no
bridging or ratholing in a hopper. Good flow is also
demonstrated by the low coefficient of variation of
tablet weight (% relative standard deviation) typical
of tablets, These flow properties are illustrated in
Table 11.
18

Tablet Hardness (kp)
35
30
25
20
15
10
Lubrication
Figure 20
A-TAB ® , 0.5% Magnesium Stearate
A-TAB ® , 1.0% Magnesium Stearate
A-TAB ® , 2.0% Magnesium Stearate
A-TAB ® , 1.0% Magnesium Stearate
20 minutes
5
5 10 15 20 25 30 35
Compaction Force (kN)
The same compressibility profile is obtained for A-TAB ® formulations
containing magnesium stearate blended for five minutes at 0.5%,
1.0%, 2.0% and 1.0% blended for 20 minutes.
Like DI-TAB ® , A-TAB ® is not especially sensitive to
lubrication. Tablets remain hard and disintegrate
rapidly, even when an A-TAB ® formulation is
blended with high levels of magnesium stearate or
is overblended with lubricant for long time periods.
This is illustrated in Figure 20 by the similarity in
compressibility profiles for A-TAB ® blended with
magnesium stearate for 5 minutes, or 1%
magnesium stearate for 20 minutes. Normally,
A-TAB ® formulations are blended with 1.0%
magnesium stearate for 2 to 5 minutes
Disintegration times for tablets formulated
with excess magnesium stearate remain short,
as shown in Table 12. This is often indicative of
an excipient which undergoes brittle fracture
during compression.
The relative insensitivity of A-TAB ® to lubrication
is an advantage to both the formulator and
production staff.
When TRI-TAB ® compacts, the primary bonding
mechanism is plastic deformation. Thus a TRI-TAB ®
blend is sensitive to both lubricant level and
blending time. Overcoating of the TRI-TAB ® granules
with a hydrophobic lubricant can lead to softer
tablets and increased disintegration times. Figure
21 shows that a low level of magnesium stearate
lubricant such as 0.5% should be used with
TRI-TAB ® . Figure 22 shows that minimally short
blending times, such as 2 or 5 minutes, and
gentle techniques are recommended.
Table 12
Properties Of A-TAB ® Tablets Formulated
With Selected Lubricant Levels & Blending Times
Magnesium Stearate
Level Blending Time Hardness Weight Friability Disintegration
(%) (min) (kp) (mg) (%) (min.)
0.5 5 32 758 0.03 0.7
1.0 5 31 751 0.06 0.6
2.0 5 31 759 0.1 0.8
1.0 25 33 773 0.06 0.6
Tablets made at 30kN applied force; 7/16-in. standard cup tooling. Formulations contain 2.0% AC-DI-SOL*.
19

Figure 21 Figure 22
20
20
Tablet Hardness (kp)
16
12
8
4
0
8
0.5% Mg Stearate
1.0% Mg Stearate
(2.0% Mg Stearate gave no tablets)
10 12 14 16 18 20 22
Compaction Force (kN)
Tablet Hardness (kp)
16
12
8
4
0
8
2-Minute blend
30-minute blend
10 12 14 16 18 20
Compaction Force (kN)
22
COMPRESSIBILITY PROFILE OF TRI-TAB ®
Lubricant Level Effect
Tooling
Because they are inorganic materials, the calcium
phosphates are, in general, more abrasive than
the softer organic materials. Interestingly, calcium
phosphates are also used as polishing agents in
toothpaste, because they clean and polish yet do
not abrade a tooth surface. When tableting a
formulation containing calcium phosphates, each
press production group will optimize the choice of
tooling to achieve maximum tool life. Depending
on the formulation, the press, production conditions
and the size and shape of tooling, a given set of
tools of a specified steel will be selected. Often
premium steel or tungsten carbide tooling is
recommended. Calcium phosphates have long
been used in direct compression formulations on
standard presses and tooling by the multivitamin/
mineral manufacturers. Interestingly, A-TAB ® ,
Table 13
COMPRESSIBILITY PROFILE OF TRI-TAB ®
Lubricant Blend Time Effect with 0.5% Magnesium Stearate
the granular dicalcium phosphate anhydrous,
has been specially manufactured to be less
abrasive than the powdered dicalcium phosphate
anhydrous. This may prove beneficial in reducing
the potential for tool wear.
Loading Capacity
The loading capacities of DI-TAB ® , TRI-TAB ® and
A-TAB ® are shown in Table 13. Here, blends of
excipients were formulated with a poorly
compressible, fine granular Vitamin C. Blends
were tableted on a laboratory hydraulic press
(Carver press). The hardness of A-TAB ® tablets
was very similar to, or slightly better than, that
of DI-TAB ® and TRI-TAB ® tablets, indicating the
ability of all three excipients to act as compressible
carriers. The addition of microcrystalline cellulose
will increase the loading capacity of a formulation.
Loading Capacity With Fine Granular Vitamin C
% Fine Granular Vitamin C Tablet Hardness (kp)
In Formulation A-TAB ® DI-TAB ® TRI-TAB ®
0 20 14 20
10 15 11 13
25 10 10 8
50 5 5 3
Carver press, 1/2-in. die, 3 seconds dwell at 2 metric tons force, 1% Mg stearate for A-TAB ® and DI-TAB ® , 0.5% Mg stearate for TRI-TAB ® .
20

COMPLETE SERVICE SUPPORT
Innophos is the culmination of over a century of advancement in phosphate
technology. Our phosphate technologies have provided texture, mineral
fortification, enhanced color and flavor to a wide variety of foods, including
baked goods, beverages, cereals, meats, seafood, poultry, dairy products
and pharmaceuticals.
With over 50 years experience in calcium phosphate excipients, Innophos has
become the recognized leader in the field. We offer you the sales and service
support of a worldwide resource for quality pharmaceutical ingredients. Our
extensive sales, service and distribution channels are your assurance of fast,
efficient delivery of the ingredients you need, with technical support that's
second to none.
Our ongoing research and development ensures that each batch meets our
standards for the highest level of purity and consistency, for all grades and
applications. We supply a Certificate of Analysis with each and every shipment,
as well as documentation of each transaction to simplify record keeping.
Above all, we provide you with an unsurpassed level of technical expertise and
support - to maximize the application benefits of our products and minimize
potential processing and product problems. We provide you with the technical
support you can get only from the leader in calcium phosphate excipients.
21

Appendix
Units of Measurement
(from Scientific Tables, K. Diem and C. Lentner, eds., Ciba-Geigy Corp., Ardsley, NY 10502, 1970).
FORCE (F) (= mass x acceleration)
International System of Units: newton (N) = m kg s -2
ft-lb-s System: poundal (pdl) = ft Ib s -2 = 0.13825N
Conversion of noncoherent units of force (g n
= standard acceleration due to gravity = 9.80665 ms -2 =
32.174048 ft s-2)
1A unit= (b) B units (b in table)
A
B
Name Symbol Definition pdl N
pond p g n
x (1g) 7.09316 x 10 -2 9.80665 x 10 -3
gram-force
gf
pound-force lbf g n
x (1lb) 3.21740 x 10 4.44822
kilopond kp g n
x (1kg) 7.09316 x 10 9.80665
kilogram-force
kgf
short ton-force sh tonf g n
x (1sh tn) 6.43481 x 10 4 8.89644 x 10 3
long ton-force tonf g n
x (1ton) 7.20699 x 10 4 9.96402 x 10 3
10kN = 2250 lbf (pound force) = 1.12 tons (U.S.)
}
}
PRESSURE (p) (=force/area)
International System of Units: newton per square
meter (Nm -2 = m -1 kg s -2 (Nm -2 = Pascal (Pa))
ft-lb-s System: poundal per square foot
(pdl ft -2 ) = ft -1 Ib s -2 = 1.48816 Nm -2
Conversion of noncoherent units of pressure
1A unit = bB units (b in table)
Standard Deviation: (s.d. or s)
s.d. = √Σ(x i
- _ x) 2
n - 1
Coefficient of Variation: (c.v.) =
% relative standard deviation (%RSD)
c.v. = s.d. (100)
_
x
Porosity (∈): tablet void volume/tablet volume
Tablet Crushing Strength: Tablets should break across the diameter.
Crushing strength, commonly called tablet hardness, is measured in units of force.
1 kp = 1 kgf 1 kilopond = 1 kilogram-force
1kg = 1kgf ÷ gn 1 kilogram = 1 kilogram-force/acceleration due to gravity
1 S.C.U. = 1 Strong-Cobb Unit = 0.71 kiloponds
A
B
Name Symbol pdl ft -2 Nm -2
kilogram force per square meter kgf m -2 6.58976 9.80665
pound force per square inch lbf in -2 4.63306 x 10 3 6.89476 x 10 3
23

Bibliography
Carstensen, J.T., Alcorn, G.J., Hussain, S.A. and
Zoglio, MA, J. Pharm. Sci. 74, 1239 (1985).
Cartensen, J.T., "Solid Pharmaceutics: Mechanical
Properties and Rate Phenomena," Academic Press,
N.Y., 1980, p.187-189.
Skotnicky, J., Czech. J. Phys., 3, 225 (1953).
DeBoer, A.H., Bolhuis, O.K. and Lerk, C.F,
Powder Tech., 20, 75 (1978).
McDowel, H., J. Res. Nat. Bur. Stds., 81 A, 273
(1977).
Marshall, R., Ph.D. Thesis, SUNY/Buffalo, 1970.
Toy, A.D.F, "Inorganic Phosphorous Chemistry,"
Chapter 20 in “Comprehensive Inorganic
Chemistry," Eds. Bailar, J.C., Emeleus, H.J., Nyholm,
R. and Trotman-Dickenson, A.F., Pergamon Press,
London, 1973, p. 502.
Patent and Warranty Disclaimers
Innophos believes all information given in this
manual is accurate. It is offered in good faith,
but supplied without consideration or guarantee.
Innophos assumes no obligation or liability for the
accuracy or sufficiency of the information given or
the results obtained, all such information being
given or accepted at user's risk. The use(s) referred
to are listed for purposes of illustration only and
the user is urged to investigate and establish
the suitability of application of such uses(s) in
every case.
Nothing herein contained is to be construed as
a recommendation for uses which infringe valid
patents or as extending a license under valid
patents or as advising or authorizing practice
of any patents or patent applications owned
by Innophos or others.
Toy, A.D.F. and Walsh, E.N., "Phosphorous Chemistry
in Everyday Living," ACS, Washington, D.C, 1987,
p. 64.
VanWazer, J.R., “Phosphorous and Its Compounds,”
Vol. 1, Interscience Publishers, Inc., N.Y, 1958,
p. 511-520.
24

Our name says it all…
Innophos is the culmination of over a century of advancement in phosphate technology. Although our name
may be new to you, our phosphate technologies have provided texture, mineral fortification, enhanced color
and flavor to a wide variety of foods, including baked goods, beverages, cereals, meats, seafood, poultry and
dairy products for over 100 years.
The applications for phosphate technologies are limitless. As manufacturers develop new products,
Innophos will set industry standards with solutions and products designed to enhance the qualities of life.
Innophos is your source for specialty phosphate applications worldwide.
Manufacturing Facilities
◆ Chicago Heights, Illinois
◆ Chicago, Illinois (Waterway)
◆ Geismar, Louisiana
◆ Nashville, Tennessee
◆ Port Maitland, Ontario, Canada
◆ Coatzacoalcos, Veracruz, Mexico
Research and Development/
Technical Centers
North America
◆ Cranbury, New Jersey
North American Headquarters
US/Canada
Innophos, Inc.
259 Prospect Plains Road
Cranbury, New Jersey
P.O. Box 8000
08512-8000 USA
Tel: (609) 495-2495
Fax: (609) 860-0138
email: spcustomerservice@innophos.com
Canada
Innophos Canada, Inc.
3265 Wolfedale Road
Mississauga, Ontario L5C 1V8 Canada
Tel: (800) 465-9035
Fax: (905) 566-9778
Export Sales
Asia/Pacific/Europe/Mexico
Central America/South America
Innophos, Inc.
259 Prospect Plains Road
Cranbury, New Jersey
P.O. Box 8000
08512-8000 USA
Tel: (609) 495-2495
Fax: (609) 860-0138
email: exportsales@innophos.com
For more information, please
visit our website: innophos.com
The above application information is provided in good faith, and is primarily based upon on our current
knowledge. It is the user’s responsibility to determine the suitability of Innophos’ products for any
application. In no event should such information be used as a substitute for applications testing or
other evaluations to determine product suitability. The above information is provided without warranty
or obligation of any kind, including its completeness or accuracy, infringement of intellectual property
rights, legal or regulatory requirements, or results obtained from use of the information. Innophos
warrants solely to meet standard manufacturing specifications for its products, subject to the limitations
set forth in its standard terms and conditions of sale, or those set forth in a written contract between
Innophos and its customer.
©2007 Innophos, Inc. All rights reserved. 9/07