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CHAPTER TWO

Calcium Carbonate
M.M.H. Al Omari*, I.S. Rashid*, N.A. Qinna†, A.M. Jaber{,
A.A. Badwan*
*The Jordanian Pharmaceutical Manufacturing Co., Amman, Jordan

Petra University, Amman, Jordan
{
Philadelphia University, Amman, Jordan

Contents
1. Description 32
1.1 Nomenclature 32
1.2 Formulae 33
1.3 Elemental Analysis 33
1.4 Appearance 34
2. Methods of Preparation 34
2.1 Existence in Nature 34
2.2 Preparation of Crystalline Form 38
2.3 Preparation of Amorphous Form 46
2.4 Factors Affecting Preparation 47
2.5 Inhibitors of Precipitation 53
3. Physical Characteristics 54
3.1 Ionization Constant 54
3.2 Solubility Characteristics 54
3.3 Partition Coefficient 56
3.4 Optical Property 56
3.5 Polymorphism 56
3.6 Particle Morphology 57
3.7 Hygroscopicity 59
3.8 Molecular Modeling 59
3.9 Crystallographic Properties 61
3.10 Thermal Analysis 68
3.11 Spectroscopy 72
4. Methods of Analysis 79
4.1 Compendial Methods 79
4.2 Titrimetric Methods 87
4.3 Gravimetric Method 95
4.4 Spectroscopic Methods 95
4.5 Electrochemical Methods 99
4.6 Calcimetric Method 102
4.7 Chromatographic Methods 102

Profiles of Drug Substances, Excipients, and Related Methodology, Volume 41 # 2016 Elsevier Inc. 31
ISSN 1871-5125 All rights reserved.
http://dx.doi.org/10.1016/bs.podrm.2015.11.003
32 M.M.H. Al Omari et al.

5. Stability 104
5.1 Crystal Phase Transformation 104
5.2 Solid-State Stability 105
5.3 Stability in Solution 106
5.4 Interaction with Complexing Agents 106
6. Uses, Applications, and Pertinent History 107
7. Pharmacology 108
7.1 Pharmacokinetics 108
7.2 Mechanism of Action 109
7.3 Pharmacodynamics 110
7.4 Toxicities 110
7.5 Drug Interactions 111
References 112

1. DESCRIPTION
1.1 Nomenclature
1.1.1 Systematic Chemical Names
Calcium carbonate [1,2].
Carbonic acid calcium salt (1:1) [1].

1.1.2 Nonproprietary Names


Recommended international nonproprietary name: Calcium carbonate
[3].
Synonyms: E 170, calcite, aragonite, vaterite, chalk, CI pigment white 18
[4], drop chalk, prepared chalk, whiting, English white, Paris white [5].

1.1.3 Proprietary Names


Caltrate (Pfizer Consumer Healthcare), Maalox Quick Dissolve (Novartis
Consumer Healthcare), Maalox Regular Strength (Novartis Consumer
Healthcare), Os-Cal (Glaxo SmithKline), Alka-Seltzer (Bayer), Alcalak
(Medique Products), Oyster Shell Calcium (Swanson Health Products),
Oysco (Rugby), Cal-Gest (Rugby), Icar Prenatal Chewable Calcium (Haw-
thorn Pharmaceuticals), Oyster Shell Calcium (Swanson Health Products),
Children’s Pepto (Procter & Gamble), Rolaids Soft Chew (Johnson & John-
son), Adcal 1500 Chewable (Biokirch), Ostocal (Hikma Pharm.) [6], Cal-
cichew (Takeda), Calcichew 500 mg purutabletti (Takeda), Calcichew
Spearmint 500 mg purutabletti (Takeda), Calcimagon 500 mg (Takeda),
Calcioral (Takeda), Mastical (Takeda), Calcitugg (Takeda) [3], Boots
Calcium Carbonate 33

Indigestion Relief (The Boots Company Plc), Cacit (Warner Chilcott UK


Ltd), Remegel (SSL International Plc), Setlers Antacid (Thornton & Ross
Ltd), Tums Assorted Fruit Antacid (GlaxoSmithKline Consumer
Healthcare) [7], Calcidia (Bayer Healthcare) [5], Adcal 500 (JPM), Oystercal
(United Pharma) [8].

1.2 Formulae
1.2.1 Empirical Formula, Molecular Weight, Identification Numbers
Information of empirical formula, molecular weight, and different identifi-
cation numbers of CaCO3 are listed in Table 1 [4].

1.2.2 Structural Formula


The chemical structure of CaCO3 is shown in Fig. 1.

1.3 Elemental Analysis


The theoretical values of elemental compositions of CaCO3 are listed in
Table 2 [5].

Table 1 The Empirical Formula, Molecular Weight, and Identifications Numbers of


CaCO3
Empirical Molecular
Name Formula Weight CAS No. CI No. EEC No. INS No.
Calcium CaCO3 100.09 [471-34-1] [77220] [207-439-9] 170(i)
carbonate

O
Ca2+

O O–

Figure 1 Chemical structure of CaCO3.

Table 2 The Theoretical Elemental Compositions of CaCO3


%
Compound Molecular Formula C Ca O
Calcium carbonate CaCO3 12.00 40.04 47.96
34 M.M.H. Al Omari et al.

1.4 Appearance
According to the United States Pharmacopeia (USP), CaCO3 is fine, white,
odorless, tasteless, and microcrystalline powder [9], while it is described as a
white or almost white powder in the European Pharmacopeia (Eur. Ph.) [2].

2. METHODS OF PREPARATION
2.1 Existence in Nature
CaCO3 is one of the most abundant materials found in earth’s crust and
forms the rock types like limestone and chalk [10]. Moreover, it is the most
abundant chemical sediment in modern and most ancient oceans, making up
roughly 10% of sediments [11]. CaCO3 can be a dominant sedimentary con-
stituent in virtually any environment, at any latitude, and in any depth of
water. However, it is most prevalent in warm, tropical, and subtropical seas
where the organisms that produce carbonate sediments can thrive [12]. On
the other hand, carbonates are forming extensively in many regions in the
western margins of large oceans, in both the southern and northern hemi-
spheres, at seawater temperatures ranging from about 2 to 40°C [13,14].
Nearly all the CaCO3 that makes up carbonate platforms is derived from
marine organisms. CaCO3 is also an important component in biological sys-
tems, such as shells of marine organisms, pearls, and egg shells [15]. Some of
these systems, eg, Oyster shells, have enjoyed recent recognition as a source
of dietary Ca, but are also a practical industrial source [16]. While not prac-
tical as an industrial source, dark green vegetables such as Broccoli and Kale
contain dietarily significant amounts of CaCO3 [17].
Carbonates are largely made up of skeletal remains and other biological
constituents that include fecal pellets, lime mud (skeletal), and microbially
mediated cements and lime muds. Chemical constituents, including coated
grains such as ooids and pisoids, cements, and lime mud, are common in
carbonates but are absent in most siliciclastics. Clastic grains exist in carbon-
ates, as they do in siliciclastics. In carbonates, however, these grains are
mainly clasts of intraformational, lithified sediment (intraclasts) or of
reworked, older rock (lithoclasts). Carbonates have four main components:
(1) grains, (2) matrix, (3) cement, and (4) pores.
There are many classification schemes for carbonate rocks [18–23].
Classifications for detrital carbonates were developed by Folk [18,19] and
Dunham [20]. Classifications for reef rocks were developed by Embry
and Klovan [21] and Riding [22]. A scheme to include depositional,
Calcium Carbonate 35

Figure 2 Dunham's classification of carbonate rocks.

diagenetic, and biological aspects of carbonates in one classification system


was proposed by Wright [23]. Fig. 2 represents Dunham’s classification,
where it includes detrital carbonates as mudstones through grainstones, bio-
genic (reef ) carbonates as boundstones, and diagenetically altered carbonates
as crystalline carbonate [20].
Furthermore, there is a genetic classification of porosity linked to the com-
plete geological history of reservoir rocks as an alternative. It is based on the
idea that there are three end-member pore types in carbonate reservoirs:
depositional, diagenetic, and fracture pores. These different processes impart
distinctive characteristics to both rock matrix and pores. Because the distinc-
tive characteristics were imparted to pores and rocks at the same time and by
the same processes, key rock properties may act as “markers” or proxies for
pore types that can be identified and traced at stratigraphic scale. To the extent
that the proxies are identifiable and mappable, so will be the accompanying
pore types and, of capital importance, their petrophysical attributes [24].
In nature, exposure of CaCO3 (calcite or aragonite) to water containing
high Mg/Ca ratio and high absolute concentration of Mg may produce
dolomite (CaMg(CO3)2) [11]. Also the use of calcite and aragonite for shell
production and other metabolic needs in animal decreases the carbonate ions
in ocean leading to increase in its acidity [25]. Caldeira and Wickett showed
through their geochemical model that with no reduction in fossil fuel
emission of CO2 into the atmosphere, there may be a rapid decline in
pH in surface ocean water over the next 100 years of as much as 0.4 units
(a doubling of H+ ion concentration) [26]. Andersen et al. studied the effects
of ocean acidification on embryos and unfed larvae of the great scallop
36 M.M.H. Al Omari et al.

(Pecten maximus Lamarck), at various pCO2 until 7 days after fertilization.


They showed that ocean acidification affected both survival and shell growth
negatively [27]. Such high sensitivity of bivalve larvae may be connected to
the carbonate composition of the larval shell as the larval shell contains
mainly aragonite, the most soluble form of crystalline CaCO3 [28–30].
The predicted undersaturation of aragonite in the world’s oceans may have
a great negative impact on these calcifying organisms [31,32].
Furthermore, it was assumed that diagenesis [33] alters aragonite-rich
sediments into calcitic limestones and elevated CO2 level initiates aragonite
dissolution and reprecipitation of the CaCO3 as calcite cement [34]. Diagen-
esis of carbonates in the deep sea almost exclusively involves the dissolution
of CaCO3, where only 20–30% of the flux to the seafloor is preserved [35].
The major factors influencing CaCO3 preservation can be summarized as
follows: weight percent of CaCO3 in deep-sea sediments, the input of ter-
rigenous material which leads to more rapid burial and to better preservation
of carbonates [36], higher productivity in overlying water, often in upwell-
ing areas, can also lead to more rapid carbonate deposition and to higher car-
bonate concentrations in sediments, and the relative CaCO3 to organic
carbon rain rate ratio.
Generally, oxidation of sedimentary organic matter can decrease the sat-
uration of pore water with respect to CaCO3 by increasing pCO2 [37]. The
approach that has generally been used is to estimate carbonate dissolution
rates via diagenetic models [38], incorporating organic matter oxidation
by oxygen (assuming a C:O ratio) that produces undersaturated conditions
considered. A relationship is then established between the calcite dissolution
rate and the pore-water saturation state. The general kinetic equation for
calcite introduced by Morse and Berner for calcite dissolution in seawater
has been most commonly used [39]. Many investigators, eg, Morse [40],
Keir [41], and Hales and Emerson [42], have modeled rates of carbonate dis-
solution from deep-sea sediment. It is clear that diagenetic factors that con-
trol the partial or complete dissolution of deep-sea carbonates are dependent
on scale [43]. At the scale of the major ocean basins, it is clear that the pri-
mary variable is the saturation state of water at a given depth. This is largely
controlled by its potential pCO2.
Over 60 different minerals have been identified in organisms [44]. Living
organisms like photosynthetic microalgae can induce the precipitation
of CaCO3 through biomineralization. CaCO3 precipitation in the ocean
is almost exclusively due to an enzymatically controlled intracellular biomin-
eralization process [45], and even the carbonate rocks and caves are mainly
Calcium Carbonate 37

formed biogenically, by microorganisms and plants [46]. The level of bicar-


bonate in solution is crucially important for the rate of carbonate mineral
precipitation [47]. Bicarbonate is reversibly formed by hydration of CO2,
a reaction which represents the rate-limiting step in the process of CaCO3
precipitation in the presence of Ca cations. The conversion of CO2 and
water to HCO3 can be drastically upregulated by the carbonic anhydrase
(CA), a Zn-containing enzyme (EC 4.2.1.1). The cofactor in this enzyme
is involved in the attack of bound OH to CO2 molecule that is loosely
bound in the active center of the enzyme, a reaction during which the coor-
dinated HCO3 ion is displaced from the metal ion by water [48]. The CA,
one of the fastest catalyzing enzymes for the fixation of CO2, allows an
increased deposition of CaCO3 in this biomineralization process [49].
Fig. 3 shows the pathway of CaCO3 formation for CA-mediated enzy-
matic synthesis of calcitic spicular elements in calcareous sponges as proposed

Figure 3 The light microscopic images show (A) the initial calcitic pat-like deposits, (B)
the maturated calcitic crystals, (C) the organized piling up of the calcitic crystals on S.
raphanus spicules (Sr-s), and (D) the tight interaction of three cells within the tissue of S.
raphanus; into which the gaps between the cells the spicules are formed.
38 M.M.H. Al Omari et al.

by Müller et al. [50]. It is outlined that the CA reversibly interconverts CO2


and water into HCO3, a reaction which is followed by CaCO3 mineraliza-
tion in the presence of Ca. Finally, amorphous CaCO3 is synthesized and is
transformed to the different crystal forms of calcite.
Gebauer et al. described stable prenucleation CaCO3 clusters [51], and
Pouget et al. revealed the initial stages of template-controlled CaCO3
formation by cryo-TEM [52]. Jacob et al. found that membrane-coated
amorphous CaCO3 was deposited on the organic layer in pearls and
suggested a new growth mechanism beginning from amorphous CaCO3
[53]. All these investigations support the proposition that amorphous
CaCO3 is initially formed as a precursor and then transforms into calcite
or aragonite [54]. Finally, it is sketched that the growing spicules are formed
by a layer-by-layer apposition of calcitic bricks into a preformed collagenous
mold [50].

2.2 Preparation of Crystalline Form


CaCO3, upon precipitation, is capable of forming an amorphous phase com-
prising colloidal systems of amorphous primary particles. The colloidal sta-
bility of these systems is not sufficient to prevent aggregation. Due to the
high number density of primary particles and the high ionic strength of
the solution, the aggregation process leads to a gelation of the reaction mix-
tures. The gel is bound by van der Waals forces only. Therefore, the gel is
colloidally less stable and undergoes a quick morphological collapse. The
recrystallization to vaterite, aragonite, or calcite takes place simultaneously
with the dissolution of the gel (Fig. 4) [55].
The sequence of reactants directly affects the morphological structure of
CaCO3 upon precipitation. For example, if Na2CO3 solution is first intro-
duced into the reactor and then CaCl2 solution is fed to this solution under
standard conditions, the product consists almost entirely of vaterite. The
increase in particle size is due to spherulitic growth mechanism of vaterite
caused by multiple passages of the particle through the region of maximum
supersaturation at the feed inlet [56]. For the reversed sequence case (ie, the
CaCl2 solution is first introduced into the reactor and then Na2CO3 is fed to
this solution) a larger percentage of calcite (c.10% is formed). The calcite
cubes are aggregated to form larger irregular particles and are partly over-
grown by clusters of vaterite. This may be due to the same mechanism as
in the standard experiment (first case), with the vaterite nucleating on the
calcite surface. When MgCl2 is introduced into CaCl2 solution to avoid
Calcium Carbonate 39

Educt A Mixing Educt B

Supersaturation

Nucleation

CaCO3: Growth
Van der Waals
bonds Primary
particles
Gelation
Aggregation
Reorganization

Fragmentation

Recrystallization

Growth

Vaterite Aragonite Calcite

Figure 4 The formation mechanisms of CaCO3 under high supersaturation conditions.

premature precipitation, some calcites are formed but all the particles are
mainly vaterite. The vaterite particles of various shapes are aggregated and
of various shapes. When KOH is introduced into Na2CO3 solution for
the same purpose, large calcite particles and smaller aragonite needles, which
are attached to the calcite cubes, are formed [55].
The kinetics of CaCO3 precipitation is a significant tool to understand
because they relate the CaCO3 saturation, pH, and the alkalinity to the
CaCO3 precipitation potential. All of the aforementioned parameters rep-
resent key aspects which specifically affect the morphology of CaCO3 crys-
tals [57,58]. C€olfen and Qi noted that the HCO3/CO3 rate, coupled with a
change in the solution supersaturation, leads to a change in the nucleation
rate of CaCO3 [59].
Generally, the precipitation of CaCO3 is accompanied by a drop in pH
and a reduction in hardness and in total alkalinity for each mole of precip-
itated CaCO3. The CaCO3 precipitation potential increases with saturation
index and buffer intensity. Buffer intensity in turn is a function of pH and
total alkalinity. Because buffer intensity decreases with increasing pH, the
CaCO3 precipitation potential also decreases as pH is increased [60]. The
detailed kinetics of such precipitation dependence is described by
Wojtowicz [60] and Plummer and Busenberg [61].
40 M.M.H. Al Omari et al.

It has been found that supersaturation is critical in determining the pre-


cipitation of CaCO3 [62]. At high degrees of supersaturation, where spon-
taneous precipitation occurs, vaterite forms predominantly even at 25°C.
On the other hand, organic matrices are considered to play a principal role
in biomineralization.
It is known that many fresh water algae build calcite crystals when they
live in an environment supersaturated with Ca [63,64]. This is a result of the
influence of the algae’s metabolism on their aqueous environment through
photosynthesis, whereby the algae assimilate CO2 and/or HCO3, and
release OH [65,66]. This leads to an increase in the pH and the concentra-
tion of carbonate within the solution [67,68]. With increasing pH, more
functional groups, such as COOH or NH groups, are exposed, which
increases the biosorption of metal ions on the negatively charged cell walls.
In the first step, Ca binds to the cell wall, followed by accumulation of car-
bonate anions and extracellular precipitation of CaCO3 [65].

2.2.1 Calcium Acetate and Carbon Dioxide


The hierarchical monodispersed aragonite microspheres can be prepared by
carbonating Ca(CH3COO)2 aqueous solution with CO2 gas at a high pres-
sure of 40 bar and a high temperature of 80°C after 60 min of reaction [69].
Ca(CH3COO)2 aqueous solution is introduced into a reactor under atmo-
spheric pressure. Pure CO2 gas is then continuously introduced until it
reaches the setting pressure. During the experiments, the CO2 pressure in
the reactor is kept constant by continuous supplying of CO2 from the cyl-
inder using a pressure controller. After a given time, the stirring is stopped.
The obtained precipitates are collected from the man-made filter and
washed several times with water as well as anhydrous ethanol then air dried.
The reaction between CO2 and Ca(CH3COO)2 in an aqueous solution
was first proposed by Kakizawa et al. [70] for the fixation of the greenhouse
gas CO2 into solid CaCO3. Generally, CaCO3 can be dissolved in an
CH3COOH solution at atmosphere conditions [71,72]. Therefore,
CH3COOH is replaced by H2CO3 in this carbonation crystallization pro-
cess, resulting in precipitating CaCO3 particles. Moreover, it is reported that
the reaction between CO2 and Ca(CH3COO)2 is endothermic and occurs
spontaneously at temperatures above 45°C at atmospheric pressure [73].

2.2.2 Calcium Hydroxide and Carbon Dioxide


CaCO3 can be precipitated by mixing Ca(OH)2 and H2CO3 solutions, the
latter solution being prepared by bubbling a high-grade CO2 stream into
Calcium Carbonate 41

water until saturation was achieved [74]. Using the aforementioned princi-
ple, fine particles of calcite with controlled morphology can be synthesized
by using hydrothermal carbonation of Ca(OH)2 at high CO2 pressure (initial
pCO2 ¼ 55 bar) and at moderate and high temperatures (30 and 90°C). A
specific volume of high-purity water with electrical resistivity of
18.2 MΩ cm containing Ca(OH)2-portlandite material (7.4 g/100 mL)
with purity of 96% is placed in a titanium reactor (autoclave with internal
volume of 2 L). The Ca(OH)2 particles are immediately dispersed with
mechanical agitation. The dispersion is then heated to 90°C with a heating
system adapted to the reactor. When the dispersion temperature is reached,
CO2 gas is injected in the reactor and the total pressure in the system is
adjusted to 90 bar by Ar injection. Under these preparation conditions,
the vapor phase consists mainly of an Ar and CO2 mixture with the CO2
in a supercritical state. At the end of the experiment, the autoclave is
removed from heating system and immersed in cold water. The reaction cell
is depressurized during the water-cooling period. After water cooling at
35°C (about 15 min), the autoclave is disassembled and the solid product
is carefully recovered and separated by centrifugation. Finally, the solid
product is dried directly in the centrifugation flasks for 48 h at 60°C and
consecutively for 12 h at 110°C in order to eliminate the adsorbed water.
The metastable crystalline phases of CaCO3 (initial P ¼ 90 bar, T ¼ 90°C
after 4 h), such as vaterite and aragonite, cannot be identified during the Ca
(OH)2 carbonation process, except when the reactor is depressurized after
the water-cooling stage at 35°C. For this case, crystalline aragonite can be
also detected. However, the carbonation of Ca(OH)2 in the presence of
supercritical or gaseous CO2 led to the precipitation of submicrometric iso-
lated particles (<1 μm) and micrometric agglomerates (<5 μm) of calcite.

2.2.3 Calcium Chloride and Sodium Bicarbonate


The preparation of calcite hollow microspheres, at room temperature, onto
which aragonite needles are attached using Mg as a crystal growth modifier
has been reported [75]. 0.5 M CaCl2 and 2.0 M MgCl2 solutions are added
into water at the Mg/Ca molar ratio of 2 and the pH is adjusted to 7. Then
0.5 M Na2CO3 solution is injected quickly into the above mixed solution
under vigorous stirring by using a magnetic stirrer. This produces a solution
containing a final CaCO3 concentration of about 8 mM. The mixed disper-
sion is stirred for 1 min, and then the solution is kept under static conditions
at room temperature for 24 h before the precipitates are collected and dried.
The obtained product mainly consists of mixed phases of calcite and
42 M.M.H. Al Omari et al.

aragonite in addition to a small amount of vaterite. It consists of well-defined


spheres with attached bundles of needles on their surfaces. The spheres with
needle bundles can be broken by a simple ultrasonic method, clearly reveal-
ing the hollow nature of the spheres. It is important to note that the molar
ratio [Mg]/[Ca] and pH value of the solution play an important role in the
formation of special superstructure. A dissolution–growth mechanism could
account for the formation of hierarchical assemblies of calcite hollow spheres
and aragonite bundles.
Furthermore, different CaCO3 phases were prepared using a self-
designed crystallization apparatus [76,77]. Calcite was prepared by rapidly
mixing 2 M CaCl2 (pH 2.7) and 0.05 M Na2CO3 (pH 11.4) at 40°C,
followed by stirring for 6 h. Aragonite was prepared by rapidly mixing
0.1 M CaCl2 (pH 4) and 0.1 M Na2CO3 (pH 11.4) at 80°C, followed by
immediate filtration. Vaterite was prepared by rapidly mixing 2 M CaCl2
(pH 2.7) and 0.05 M Na2CO3 (pH 11.4) at 1°C, followed by immediate
filtration. Calcite, aragonite, and vaterite were all dried at 70°C in the air.
Monohydrocalcite (CaCO3H2O) was prepared according to the precip-
itation from artificial seawater (containing NaCl, MgCl2, CaCl2, SrCl2, and
K2CO3) and dried at room temperature in the air [78].

2.2.4 Calcium Acetate and Ammonium Carbonate


The most common crystallization method to produce CaCO3 is carried out
by preparing 0.5 M solutions of (NH4)2CO3 and Ca(CH3COO)2 followed
by mixing [79]. (NH4)2CO3 solution is tightly sealed with parafilm paper to
minimize the loss of NH3 and the introduction of CO2 from the atmo-
sphere. All solutions are stirred moderately until the reactants are completely
dissolved. The measured pH values before and subsequent to mixing are
8.39 for the (NH4)2CO3 solution and 8.26 for the Ca(CH3COO)2 solution.
After mixing the two solutions together, the pH equilibrated to 8.36. The
(NH4)2CO3 is then poured into beakers containing Ca(CH3COO)2 solu-
tion while being stirred, producing CaCO3. The precipitated CaCO3 slurry
is filtered using filter paper in a filtration system operated under vacuum.
Immediately after the precipitate is recovered, it is rinsed in water and dried
in a furnace at 105°C.

2.2.5 Calcium Chloride, Gelatin, and Urea


Wang et al. prepared nonagglomerated calcite (trigonal), vaterite (spherical),
and aragonite (needlelike) particles by the decomposition of urea in CaCl2-
containing aqueous solutions at a temperature range of 50–90°C [80]. CaCl2
Calcium Carbonate 43

is added to water to prepare a solution containing 0.4 M Ca. Gelatin powder


is then dissolved in the Ca solution until reaching a gelatin content of 0.2 g/
100 mL. Finally, the urea powder is added to the aforementioned solution
up to a concentration of 0.5 M. For preparation of trigonal prismatic CaCO3
(calcite) crystals, portion of the solution is taken into a bottle in which one
piece of microscope cover glass is dropped. The bottle should be tightly
capped and placed in a microprocessor-controlled oven preheated to 70°
C, and kept undisturbed for 24 h. The bottle is then opened; the white-
coated cover glass is removed, and washed with an ample supply of water,
followed by rinsing with ethanol. The cover glass is dried in an oven at 37°C
overnight in air.
For the preparation of CaCO3 microtablets, a portion of the Ca-con-
taining gelatin–urea solution is refrigerated. The pH of the refrigerated solu-
tion is measured to be 6.5 (at 6°C). One piece of microscope cover glass is
dropped into the bottle. The bottle is capped and placed in a microproces-
sor-controlled oven preheated to 70°C, and kept undisturbed for 24 h. At
the end of 24 h, the bottle is opened and the white-coated cover glass is
removed, and washed with an ample supply of water, followed by rinsing
with ethanol. The cover glass is dried in an air atmosphere oven at 37°C,
overnight. For further analyses, the white powder material coating the cover
glass is gently scraped off using a clean and sharp razor blade [80].
Prerefrigerated solutions, on the other hand, produce vaterite microtablets
contaminated with a minor amount of the calcite phase [81].

2.2.6 Carbon Dioxide Sequestration


Carbon sequestration involves the intake/injection of carbon CO2 emitted
from stationary sources by deep underground reservoirs instead of being
released to the atmosphere. A geological seal, or caprock, prevents the
CO2 from leaking out of the reservoir and migrating toward the surface.
Modeling studies [82–84] and laboratory and field-scale experiments [85–
87] on CO2 injection show that carbonate minerals are the first minerals
to react. Precipitation can be abiotic (independent of biological activity)
or biologically induced (ie, bioremediation). Precipitation reactions involve
Ca, Mg, and CO2 and occur at the mixing interface between two advecting
fluids. Relevant scenarios in the subsurface include the mixing interface
between a plume of injected CO2 and the surrounding brine, or the mixing
interface between injected nutrients and surrounding groundwater that is
contaminated. In these cases, mixing is controlled by diffusion in the direc-
tion of and transverse to flow. Different carbonate may precipitate along this
44 M.M.H. Al Omari et al.

mixing zone in the forms of CaCO3, ie, calcite, aragonite, and vaterite; mag-
nesite (MgCO2); and dolomite (CaMg(CO)3)2.
Precipitation of carbonate minerals can cause pore blockage and lead to
decreased porosity and permeability. This is beneficial within the caprock
and may increase the integrity of the injection. Moreover, carbonate precip-
itation can impact in situ remediation of groundwater contaminants (Sr, Pb,
Cd, Cu, and UO2) through coprecipitation of carbonates and contaminants
[88–90].

2.2.7 Cockle Shell and Dodecyl Dimethyl Betaine


Initially, micron-sized cockle shell powders (Anadara granosa) are extracted
by washing, boiling, and then are cooled at room temperature, washed thor-
oughly with water and dried in the oven for 7 days, ground, and finally
sieved. A slurry is formed by adding and mixing water. CaCO3 nanoparticles
are prepared by adding dodecyl dimethyl betaine into the slurry under
vigorous stirring at 1000 rpm at room temperature for 90 min using a
mechanical hot plate and magnetic stirrer bar. The obtained sample is sep-
arated from the mother liquid using a double ring filter paper of 18.0 cm size.
The final product is dried at 100°C and packed in a polyethylene plastic bag
[91]. Pure crystalline aragonite nanoparticles were produced in the presence
of dodecyl dimethyl betaine which has most likely acted as a biomineraliza-
tion catalyst. The obtained crystals were small sized, agglomerated, clumped,
and homogenized.

2.2.8 Dolomite and Sucrose


Dolomite (CaMg(CO3)2) can be used to prepare precipitated CaCO3 by the
separation of Ca and Mg components. One of the difficulties in the separa-
tion of Ca and Mg components in dolomite is the low solubility of both
materials [92]. However, usage of sucrose solution to separate these compo-
nents from dolomite has been proven to be an exceptionally successful
method [93]. When calcined dolomite (CaOMgO) is dissolved in a sucrose
solution, CaO will be converted into soluble calcium sucrate [94], while
MgO remains unreacted and presents in the precipitated form [93]. The
purified MgO by-product provides an additional value to dolomite in many
applications, whereas the calcium sucrate solution can be used to prepare
precipitated CaCO3.

2.2.9 Quicklime or Hydrated Lime


Limestone is converted to CaO by heat, followed by formation of milk
of lime (Ca(OH)2) either by slaking quicklime or by dispersing hydrated
Calcium Carbonate 45

lime in water. Finally, Ca(OH)2 is combined with CO2 to form precipitated


CaCO3 [95,96].

2.2.10 Wollastonite
The direct dry (gas–solid phase) carbonation of wollastonite (CaSiO3) can be
carried in a continuously stirred tank reactor at 25°C and atmospheric pres-
sure for 0–600 h. The main drawback of this method is the slow rate at ther-
modynamically set temperatures [97].
CaCO3 can be prepared by direct wet carbonation by: (1) leaching
of Ca, (2) dissolution of CO2 and subsequent conversion of bicarbonate
species, and (3) nucleation and growth of CaCO3. The main disadvantage
related to aqueous carbonation is the high energy consumption and cost
[97].
CaCO3 can be also prepared indirectly by dissolving wollastonite in HCl
to form CaCl2. The Ca(OH)2 produced (via CaCl2) is then dissolved in
water and then reacted with CO2 to produce CaCO3. The major drawbacks
of such method are the energy demand for the acid recycling stage and the
very large water demand for the carbonation stage [97].
Another indirect method to prepare CaCO3 is by extracting Ca ions
from wollastonite using CH3COOH [70,97]. CO2 is then injected into
the solution, which causes CaCO3 to crystallize.

2.2.11 Dolomite
The thermal decomposition of dolomite occurs in air in two steps from
CaCO3 and CaO, respectively [98]. The process can be controlled precisely
only at a temperature of 800°C due to the two-step reaction of dissociation.
The main drawback of this method is the adsorption and precipitation of
AsCO3 and AsO.

2.2.12 Gypsum Waste


The gypsum waste can be thermally reduced into CaS, which is then
subjected to a direct aqueous carbonation step for the generation of
H2S and CaCO3 [99]. CaS can be successfully converted into CaCO3;
however, the reaction may yield low-grade carbonate products (<90%
as CaCO3) which comprise a mixture of calcite and vaterite, as well as
trace minerals originating from the starting material. Thus, indirect aqueous
CaS carbonation processing for the production of high-grade CaCO3
(>99% as CaCO3) or precipitated CaCO3 can be developed and
optimized.
46 M.M.H. Al Omari et al.

2.3 Preparation of Amorphous Form


2.3.1 Calcium Chloride and Sodium Carbonate
CaCl2 and Na2CO3 solutions, equimolar in Ca and carbonate ions, are rap-
idly mixed [100]. For example, 106 mg of solid Na2CO3 is added to 20 mL
of a 0.5 M NaOH solution and 30 mL of water. This solution is combined
with 50 mL of a 20 mM CaCl2 solution and stirred rapidly, followed imme-
diately by vacuum filtration and rinsing with acetone to dry the solid.

2.3.2 Calcium Chloride and Dimethyl Carbonate


Amorphous CaCO3 can be prepared by initially preparing dilute solutions
(0.01 M) of CaCl2 in water and an excess of (CH3)2CO3. When a 0.5 M
solution of NaOH is added, the solution starts to become turbid after 90 s at
25°C. The reaction solution is stirred for 1 min at room temperature and pH
of the solution is about 12. The resulting precipitate is separated rapidly by
centrifugation (4000 rpm) and washed with ethanol and acetone once sep-
arately, and dried under vacuum at 35°C for 48 h [101].

2.3.3 Dolomitic Marble with the Aid of Poly(Acrylic Acid)


Amorphous CaCO3 can be prepared using extensively distributed impure
dolomitic marbles and poly(acrylic acid) as stabilizer, whereby a bubbling
column can be used to enhance the yield. The best conditions are temper-
ature of 40°C, pH of 4.5, and poly(acrylic acid) concentration of 102 M.
The prepared amorphous CaCO3 nanoparticles with high purity and quality
are suitable for industrial applications [102].

2.3.4 Calcium Hydroxide and Carbon Dioxide


Precipitates of pure amorphous CaCO3 can be obtained by bubbling CO2
through a saturated Ca(OH)2 solution at 0°C. The precipitation is stopped
when the pH reaches 8 and the precipitate is filtered and rinsed with cold
acetone. The precipitate dried under high vacuum at 0°C for 36 h and stored
under phosphorous pentoxide in a desiccator. Ikaite (CaCO36H2O) is pre-
pared in the same way as the amorphous, but the precipitate is not dried in a
vacuum after washing with acetone, instead, it is immediately placed in a
freezer at 20°C [103].

2.3.5 Calcium Chloride and Sodium Bicarbonate by Sono Atomization


Amorphous CaCO3 can be prepared by sono atomization upon reactive
mixing whereby aqueous equimolar solutions of CaCl2 and Na2CO3 along
with a 20% methanol aqueous solution are inserted in containers each having
Calcium Carbonate 47

a small window opening. An ultrasonic generator of 2.4 MHz frequency is


immersed in each of the solutions. At this frequency, the droplet size is about
3 μm. The fine droplets are formed by atomization of the suspension, and a
hollow material is obtained by subsequent removal of the water from the
formed droplet. In this method, droplets produced by atomization are used
as a reaction field for synthesis of CaCO3 [104].

2.4 Factors Affecting Preparation


2.4.1 Temperature, pH, and Pressure
The influence of temperature on CaCO3 polymorph formed from
(NH4)2CO3–Ca(CH3COO)2 system was investigated. At 25 and 80°C,
the predominant form was found to be vaterite, while calcite form was
obtained at 50°C. Less than 5% aragonite was observed at 70°C [79]. In
CaCl2–Na2CO3 system, vaterite with specific morphologies was formed
at 2–35°C, whereas needle-shaped aragonite crystals were obtained at 50–
70°C [105].
The effect of pH on the polymorphic phase and crystal growth upon
precipitation of CaCO3 was investigated by using gas diffusion method.
At pH 0.5, calcite and aragonite crystals are obtained. When the pH value
was higher than 5.5, the precipitates are calcite crystals with different mor-
phologies and particle sizes [105]. It was also reported that calcite preci-
pitation in water was favored in alkaline conditions [106]. Han et al. also
reported that higher pH value tended to induce calcite crystals [107]. Cheng
et al. [57] and Yu et al. [58] also reported that greater morphology control can
be afforded by low supersaturation as pH is decreased. This means that the
induction time of CaCO3 precipitation increases considerably with de-
creasing pH [105].
The effect of pressure on transition of calcite forms was first studied by
Bridgman [108]. It was observed a transition to a slightly denser phase (cal-
cite II) at 1.44 GPa and a transition to a significantly denser phase (calcite III)
at 1.77 GPa. Singh and Kennedy [109] and Merrill and Bassett [110] placed
the calcite I–calcite II transformation at 1.45 and 1.5 GPa and the calcite II–
III transformation at 1.74 and 2.2 GPa, respectively. Moreover, the phase
transition of metastable calcite III–postcalcite III initiates at a pressure of
15.5 GPa and is completed between 25 and 30 GPa [111]. In addition to
the aforementioned calcite form, there exists a denser calcite VI form that
can be formed using shock compression experiments [112]. The phase dia-
gram of calcite is further complicated by the appearance of the calcite II and
calcite III intermediates at high-pressure phases in the range from 1.0 to
48 M.M.H. Al Omari et al.

2.5 GPa [108,113]. At higher pressures, calcite is known to undergo yet


another phase transition; this high-pressure phase, known as calcite IV,
occurs at pressures in excess of 10 GPa and is usually observed in impact
experiments in the form of a somewhat anomalous rarefaction shock.
None of the intermediate phases of calcite is stable under equilibrium con-
ditions [114–116]. Kerley developed a theoretical model for the equation
of state of CaCO3 that includes phase transitions and melting. As noted,
calcite IV is assumed to have the same properties as aragonite except for
a shift in the energy [117]. Different CaCO3 phases have been deter-
mined by using a combination of advanced ab initio simulation techni-
ques and high-pressure experiment. The crystal structure of postaragonite
phase in CaCO3 at a pressure of 40 GPa was identified in addition to a
number of energetically competitive structures (stable phase I and meta-
stable phases II–IV). Above 137 GPa, phase I with a pyroxene-type
structure with chains of CO44 tetrahedra becomes more stable than pos-
taragonite [118].

2.4.2 Calcium and Carbonate Ion Concentration


The effect of Ca/CO3 concentration ratio on CaCO3 particles’ size and
shape, prepared from CaCl2 and Na2CO3 system, was investigated [119–
121]. It was found that particles’ shape changed from squared, spherical,
to oblong by increasing the concentration (g/L) ratio of Ca/CO3 from
0.21 to 1.22. On the other hand, the average particle size changed from
3.5 to 1.8 μm [119,120]. It was explained by formation of soluble complexes
Cax(CO3)y at excess CO3 anions, which lowers the supersaturation and,
accordingly, the primary nucleation rate [121].

2.4.3 Magnesium
It has been reported that the precipitated CaCO3 polymorphs are related
to the Mg/Ca ratio [122–124] whereby low-Mg calcite, then high-Mg
calcite and aragonite, then aragonite, are the sequence of phases com-
monly precipitated from fluids with increasing Mg/Ca ratio. Furthermore,
Mg/Ca ratio of about five was considered as the threshold of the forma-
tion of low-Mg calcite to high-Mg calcite and aragonite [123]. Sandberg
[125] and Milliken and Pigott [126] attributed the inferred differences
in cortical mineralogies in Phanerozoic seas to the variations in marine
Mg/Ca ratio.
With respect to CaCO3 morphology, calcite progresses from angular
to spherical with increasing Mg concentration in solution, while by
Calcium Carbonate 49

decreasing the concentration, aragonite progresses from needlelike to spher-


ical [127]. It has been reported that the presence of Mg ions at high concen-
trations leads to a transformation process with multiple-step self-assembly
from amorphous into aragonite [128]. In both natural and most synthetic
monohydrocalcite, the presence of high concentrations of Mg relative to
Ca in the precipitating solution (0.17  Mg/Ca < 65) is a prerequisite for
its formation [129].

2.4.4 Organic and Inorganic Additives


Organic modifiers decrease the size of CaCO3 crystalline particles (<1 μm)
upon preparation. Inorganic modifiers (eg, NH4Cl, PbCl2) favor an increase
in the size of CaCO3 crystals by a factor of 1.52 [119].

2.4.5 Antiscalants
Synthetic antiscalants including pentasodium salt of aminotrimethylene
phosphonic acid, and hepta-sodium salt diethylenetriamine pentamethylene
phosphonic acid, in addition to a copolymer containing acrylic acid,
methacrylic acid, and itaconic acid were found to be better suited for adsorp-
tion and prevention of CaCO3 precipitation [130].

2.4.6 Polysilicic Acid


The effect of polysilicic acid on the precipitation of CaCO3 from supersat-
urated solutions was investigated under pH 9 and room temperature. The
decrease in turbidity of the CaCO3 solution in the presence of polysilicic
acid indicated that the polysilicic acid inhibits the precipitation of CaCO3
[131].

2.4.7 Polyelectrolytes
Anionic polyelectrolytes were found to lengthen the induction time and
to reduce the size of CaCO3 nanocrystals precipitated from super-
saturated solution. The extent of time depends on the interaction efficiency
between the polymer anionic repeating units and the Ca ions [132]. Further,
nanocrystals having vaterite structure give spherical CaCO3, while nano-
crystals having calcite structure lead to either acicular or flower shapes
of CaCO3.
Poly(allylamine HCl) as a cationic polyelectrolyte strongly influences
CaCO3 precipitation and induces the formation of calcite thin films and
fibers by counterion-induced phase separation [133]. Furthermore, CaCO3
50 M.M.H. Al Omari et al.

is precipitated, in the presence of poly(allylamine HCl) and Mg ions, as thin-


ner and smoother films, together with fibers with more polycrystalline, gran-
ular structures.

2.4.8 Metal Ions


Aragonite appears to be a favored form in the presence of cationic impu-
rities such as Mg, Ni, Co, Fe, Zn, and Cu, whereas Cd ions showed no
significant effect [134]. It appears that the presence of such impurities can
result in a prolonged induction period leading to slower precipitation
[135]. It has been reported that the trace amounts of Zn ions can slow down
the nucleation rate of CaCO3 and also encourage its crystallization in
aragonite form, even under conditions favoring calcite [136]. Meyer
suggested that Zn ions can significantly reduce the crystal growth of calcite
[137]. Cu ions are much less effective than Zn ions [138,139]. Only a high
concentration of Cu ions in comparison to Zn ions is necessary to achieve a
similar effectiveness.
Divalent cations have been given some attention in CaCO3 precipitation
(eg, Mg, Mn, Cu, Sr, Cd) [140]. When vaterite and calcite crystals are pre-
pared by spontaneous precipitation under defined conditions, followed by
doping with foreign cations, all cations, except Cu, are incorporated in
vaterite. The uptake of Mn is about the same in the presence or absence
of cations [141,142]. Furthermore, the presence of Mn and Mg stimulates
the incorporation of Pb and the uptake of Mn, Cd, and Pb by vaterite is
much larger than that by calcite.

2.4.9 Surfactants
In the presence of cetyltrimethylammonium bromide (CTAB), crystal
agglomeration of CaCO3 increases and the irregular calcite rhombohedral
crystals are numerous. At high concentrations of CTAB (8.5 mM), the
number of spherical particles is smaller and the majority of the particles is
rhombohedral and consists of calcite crystals [143].
In the case of sodium dodecyl sulfate (SDS), at low concentrations
(5 mM), which is greater than the critical micellar concentration of SDS
in 0.1 M NaCl (1.5 mM at 25°C) [144], the crystals are primarily flower
shaped and only few rhombohedral and spherical particles are obtained.
When the concentration is increased, eg, 10 times, very small crystals result.
At very high SDS concentration, the aspect of the crystals and their magni-
tude are changed dramatically, but not the polymorphism of CaCO3 because
even in the presence of SDS the form obtained is calcite [143].
Calcium Carbonate 51

It has been reported that addition of sodium dodecylbenzene-


sulfonate improves the formation of vaterite, while SDS enhances the
formation of calcite and the presence of poly(N-vinyl-1-pyrrolidone)
affects the crystal shape [145,146]. When trichloroacetic acid and
hydroxyethylidene-1,1-phosphonic acid are present in the sonically
mixing solutions at 95°C, vaterite is stably formed [147].
2.4.10 Media Viscosity
Gels, in general, can effectively reduce the ion activities and diffusion rates so
that the crystallization process in the gel is totally different from that occur-
ring in aqueous solution [148,149]. It has been reported that the morphol-
ogy of CaCO3 can be controlled in the presence of double-hydrophilic
block polymers in a mixture of solvents [150–152]. These studies suggest
that the reaction medium has a great effect on the crystallization process.
It was reported that the transformation of amorphous CaCO3 to crystal-
line form is affected by solvent viscosity [54]. The solid transition from
amorphous to calcite is only observed in ethanol/water and the reaction
is suppressed in both ethylene glycol/water and diethylene glycol/water.
Furthermore, the resulting crystals always have different morphologies
and size distributions although they all have the calcite structure.
2.4.11 Proteins
CaCO3 crystal forms, the chemical composition, morphology, and texture
of the deposited mineral can be easily controlled by the type of proteins
[153]. For example, in the presence of glycine, L-alanine, or L-aspartic acid,
vaterite are produced when mixing the two salt solutions, CaCl2 and
Na2CO3 [154–157].
Furthermore, CaCO3 form selectivity in organisms is controlled by spe-
cific glycoproteins in the presence of particular substrates [158]. For exam-
ple, oriented crystallization of vaterite occurs in uniaxially deformed gelatin
films containing poly-L-aspartate [159]. No orientation of the mineral phase
can be observed with entrapped poly-L-glutamate, suggesting that the ori-
ented crystallization is controlled by the β-sheet structure assumed by poly-
L-aspartate in the presence of Ca ions.
Nucleation of calcite instead of aragonite in situ preparation in
immobilized bovine serum albumin was obtained due to the difference in
the charge distribution on the surface and faster reaction kinetics at the inter-
face [160].
Belcher et al. showed that a controlled phase transition between arago-
nite and calcite in nacre could be obtained in the laboratory with the use of
52 M.M.H. Al Omari et al.

soluble polyanionic proteins [161]. This was directly observed by Thomp-


son et al. through atomic force microscopy [162]. Mann et al. explained the
role of soluble proteins as effective agents to the reduction of interfacial ener-
gies on the surface of the inorganic. An increase in hydrophobicity of the
additive reduces its ability to control morphology and phase transition dur-
ing crystallization [163].

2.4.12 Sucrose/Bovine Serum Albumin System


The sucrose/bovine serum albumin system in biological organisms has been
investigated on changes in the form and morphology of CaCO3 [164]. The
results revealed that low concentration of sucrose (5%) leads to the formation
of calcite and vaterite, while high concentration (20%) leads to the formation
of vaterite.
Moreover, the activation energy of nucleation is decreased by interfacial
molecular recognition leading to form easily vaterite [165]. Also, glucan has
been used as a template to control preparation of aragonite CaCO3 [166] and
its morphology has been controlled by β-cyclodextrin [167].

2.4.13 Algae–Metal Ions System


The effect of metal ions bound to cell surfaces of living organisms on the
precipitation of CaCO3 has been investigated [168]. Calcite and aragonite
are formed in the absence or presence of low Zn amount (3.27 mg/L); how-
ever, at higher Zn concentration (6.53 mg/L), pure aragonite crystals can be
formed. In contrast, in the inorganic, algae-free solutions without Zn, pure
calcite is precipitated. Both inorganic solutions with Zn show major calcite
precipitation.

2.4.14 Mixing Equipment


When CaCO3 is prepared by slowly pouring CaCl2 solution into an equi-
molar solution of K2CO3, using a double-cylinder-type homogenizer or an
ultrasonic homogenizer to another solution agitated using the homogenizer,
vaterite particles are produced. On the other hand, the same particle type is
produced when one of the two salt solutions is added at once to another
solution agitated using the ultrasonic homogenizer [169].

2.4.15 Ultrasound Waves


The nucleation of crystals, from type, particle size, and shape of CaCO3, can
be affected by the presence of ultrasound waves [170–173]. Sonawane et al.
[170] obtained only calcite form using sonochemical carbonization method.
Calcium Carbonate 53

Kojima et al. [174] have also investigated the effect of frequency and
amplitude on the morphological of vaterite at high supersaturation without
additives. Kirboga et al. [175] showed that the higher amplitude, the higher
relative vaterite fraction. Moreover, specific surface area increases gradually
with the increase in the sonicator amplitude in the presence of biopolymer
carboxymethyl inulin. The presence of biopolymer affects the specific sur-
face area of CaCO3 crystals prepared not only with magnetic stirring [176]
but also with ultrasound waves [175].

2.5 Inhibitors of Precipitation


There are many inhibitors for CaCO3 precipitation reported in the litera-
ture. A summary list of these inhibitors is presented in Table 3. A list of var-
ious inhibitors for the crystal growth of CaCO3 with their affinity constants
(Kd/Ka) is also given in Table 4. The inhibitory effect of these substrates is
mainly due to adsorption and subsequent blocking of the active growth site
[189,190]. The variation on the affinity constant values for the same inhib-
itor (eg, sodium alginate or phosphate) is most probable due to the difference
in the experiments parameters such as the form of CaCO3 used, pH, con-
centration of inhibitor, and ions (Table 4).

Table 3 List of Inhibitors for CaCO3 Precipitation


Name of Inhibitor References
Synthetic polyacrylic acid [177]
Carboxymethyl inulin [178]
Modified palygorskite by maleic anhydride and styrene sulfonic sodium [179]
Perlinhibin (19.5% cysteine-, 17% histidine-, and 14.6% arginine-rich [180]
miniprotein from Abalone (Haliotis Laevigata) Nacre)
Fulvic acid and Mg ions [181]
Cysteine-rich Mdm2 peptide [182]
Aqueous extract of Paronychia argentea [183]
Xanthan gum [184]
Acrylic acid/2-acrylamido-2-methylpropanesulfonic [185]
acid/2-hydroxypropyl acrylate and orthophosphate
A synthetic polyacrylic acid-allyloxy poly(ethylene glycol) polyglycerol [186]
carboxylate block copolymer
54 M.M.H. Al Omari et al.

Table 4 Comparative Data on the Inhibition of CaCO3 Precipitation


CaCO3 Kd/Ka × 1024
Form Inhibitor (mol/dm3) References
Calcite Mg 0.42 [187]
Calcite Glycerophosphate 6 [188]
Vaterite Sodium alginate 19.3 [189]
Calcite Sodium alginate 999.8 [190]
Calcite Phosphate 50 [188]
Calcite Phosphate 5842 [191]
Calcite Mellitic acid (benzenehexacarboxylic acid) 200 [192]
Calcite Ethylenediamine-tetra-bis-methylene 1000 [193]
phosphonic acid
Vaterite 2-Dihydroxyphosphonyl-2-hydroxyl- 1350 [194]
propionic acid
Vaterite 1,3-Bis[(1-phenyl-1-dihydroxy-phosphonyl) 1588 [194]
methyl]-2-imidiazolidenon
Ka and Kd are the specific rate constants for adsorption and desorption, respectively.

3. PHYSICAL CHARACTERISTICS
3.1 Ionization Constant
Chemical equilibria of CaCO3 in aqueous solution can be described as
H2CO3 undergoing dissociation to give H+, HCO 2
3 , and CO3 ionic spe-
cies [195]. The corresponding dissociation constants pKa1 and pKa2 are 6.35
and 10.32 at 25°C, respectively [61]. Fig. 5 shows the distribution of carbon-
ates species (H2CO3, HCO 2
3 , and CO3 ) as a function of pH. However, the
presence of Ca ions leads to the formation of CaHCO+3 , CaCO3, and
CaOH+ in solution with association constants pKCaHCO3 + , pKCaOH + , and
pKCaCO3 of 1.26, 1.49, and 3.22 at 25°C, respectively [61,196].

3.2 Solubility Characteristics


According to the USP, it is practically insoluble in water. Its solubility in
water is increased by the presence of any ammonium salt or of CO2. The
presence of any alkali hydroxide reduces its solubility. It is insoluble in
Calcium Carbonate 55

1.00

0.75
Mole fraction

CO32–
0.50 H2CO3 –
HCO3

0.25

0.00 pK1 pK2


2 4 6 8 10 12 14
pH
Figure 5 The distribution of carbonate species as a fraction of total dissolved carbonate
in relation to solution pH.

alcohol. It dissolves with effervescence in 1 N CH3COOH, in 3 M HCl,


and in 2 M HNO3 [9]. The solubility of CaCO3 (conventional) in water
is 16.6 mg/L (20°C, pH 9–9.4), while that of the aragonite and calcite forms
is 6.6 mg/L (20°C) and 11 mg/L (20°C) for the vaterite form. The amor-
phous form of CaCO3, with particles predominately in the nanoscale range,
is approximately 10 times more soluble than crystalline CaCO3 [4].
The solubility products (log pKsp) of various solid forms and hydrate
forms are listed in Table 5. In general, the solubility of the hydrate forms
of CaCO3 was found to be higher than those of anhydrous forms calcite,
aragonite, and vaterite [197].
The pH solubility of CaCO3 in water was measured as a function of pH
of solution. The pH was adjusted with HCl or NaOH depending on the pH
needed [198]. As shown in Fig. 6, the solubility decreases with the pH of

Table 5 Solubility Products (log pKsp) for the Various Forms of CaCO3 at 25°C [197]
Form Structure 2log pKsp
Amorphous (monohydrate) — 6.40
Ikaite (hexahydrate) Monoclinic 6.62
Vaterite (anhydrous) Hexagonal 7.91
Aragonite (anhydrous) Orthorhombic 8.34
Calcite (anhydrous) Rhombohedric 8.48
56 M.M.H. Al Omari et al.

80

Solubility as elemental Ca (mg/mL)


Calculated
Measured
60

46
40

20

3.8 0.005
0.13
0
2 4 6 8 10 12 14
pH
Figure 6 The calculated and measured solubility of CaCO3 as a function of pH of solu-
tion open to the atmosphere at room temperature. The pH of aqueous solutions
adjusted with HCl or NaOH (0.1–10 M) depending on the pH needed.

solution [198,199]. The measured solubility [198] is in agreement with that


calculated using the dissociation and solubility product constants [199].

3.3 Partition Coefficient


The octanol–water partition coefficient (log P) of CaCO3 at pH 7 and 20°C
was reported as 0.81 [200].

3.4 Optical Property


Carbonates can easily be recognized in soil thin sections, as their birefrin-
gence is extreme resulting in upper-order creamy white interference colors.
They are also characterized by high relief generally from strongly negative to
strongly positive depending upon their orientation. Table 6 represents some
optical properties of different forms of CaCO3 [201]. As shown in the table,
the optical properties of the various CaCO3 forms are quite similar.

3.5 Polymorphism
CaCO3 exists naturally in six different forms: three crystalline polymorphs,
calcite, aragonite, and the metastable vaterite; two hydrate phases,
monohydrocalcite and ikaite; in addition to amorphous CaCO3 [202].
Calcium Carbonate 57

Table 6 Optical Properties of Different Forms of CaCO3


Form Crystal System Refractive Index Birefringence (δ) Uniaxial/Biaxial
Calcite Trigonal ne: 1.486; 0.172 U
no: 1.658
Aragonite Orthorhombic nx: 1.530; ny: 0.156 B
1.682; nz: 1.686
Vaterite Hexagonal ne: 1.550; no: 1.650 0.100 U+

3.6 Particle Morphology


Calcite typically displays the rhombohedral habit. Aragonite typically
appears as prisms or needlelike crystals, and vaterite tends to form polycrys-
talline spherulites. They are metastable phases and, especially the
latter, may play a role as a precursor in calcite formation. The amorphous
CaCO3 typically appears as small spheres less than 1 μm in diameter [203].
The morphological modifications in the absence and presence of L-
aspartic acid as organic template that induce the nucleation of CaCO3
were investigated [157]. In the absence of L-aspartic acid in the reaction
system, only calcite can be observed and the precipitate is bulky amor-
phous crystal with irregular shape (Fig. 7A). While in the presence of
the acid with a concentration of 0.25 mg/mL, the precipitate contains
calcite which appears layered and rhombohedral shape (Fig. 7B). At high
acid concentration (>1 mg/mL), nearly all the precipitate becomes
spherical vaterite crystal (Fig. 7C). Beck and Andreassen described differ-
ent morphologies of the calcite form [204]. For example, the plate-like
morphology with hexagonal features for calcite could only be obtained
under the influence of significant levels of Li ions at 45°C. The spheru-
litic, cube-shaped crystals of calcite are produced at 10°C. Precipitation at
room temperature resulted in smooth calcite polyhedra, but the
unwanted extent of agglomeration is much higher at that temperature.
Needle-shaped particles (Fig. 7D) could be obtained at low supersatura-
tion and high temperature (90°C). In this experiment, low supersatura-
tion during the crystallization process was obtained by a slow addition of
Ca ions.
The different crystalline polymorphic phases of CaCO3 possess different
particle morphology, shape, porous structure, and density (Table 7). The
foregoing properties are further dependent on whether CaCO3 exists as nat-
ural or synthetically prepared via the various synthetic routes.
58 M.M.H. Al Omari et al.

A B

C D

Figure 7 The SEM images of CaCO3 forms: (A) amorphous calcite, (B) layered and rhom-
bohedral calcite, (C) spherical vaterite, and (D) needle aragonite.

Table 7 Reported Particle Size, Specific Surface Area, and Pore Size of CaCO3
Specific Surface
Form Particle Size (μm) Area (m2/g) Pore Size (cm3/g) References
Calcite — 0.99 0.068 [205,206]
0.1 30 — [207]
Aragonite — 3.6 0.16–3.8 nm [208,209]
Vaterite 5 77 0.068 [206]
3–5 9–15 10 nm [62,210]
Amorphous 0.04 65 — [104]
0.086–0.31 12–42 — [205]
0.19–0.41 9–19 — [205]
Natural 1–3 4–10 — [211]
Precipitated 0.07 17–25 2.5 [212,213]
Calcium Carbonate 59

With regard to specific gravity and Mohs scale of CaCO3, all crystalline
forms showed similar values recorded as 2.54–2.95 and 3–4, respectively
[214,215].

3.7 Hygroscopicity
Amorphous and ikaite forms of CaCO3 exist as mono- and hexahydrate,
respectively, while vaterite, aragonite, and calcite exist as anhydrous.
According to USP and Eur. Ph. [1,2], CaCO3 does not loss more than
2% upon drying at 200°C, while in Japanese Pharmacopeia (JP) [216], it does
not loss more than 1% upon drying at 180°C.

3.8 Molecular Modeling


Molecular modeling studies of calcite and aragonite have been carried by
molecular dynamics (MD) simulations approach [217]. In this study, con-
stant volume and constant stress simulations were performed using the
force-field parameters of Dove et al. [218]. The reported crystallographic
data were used to build the initial configurations of calcite and aragonite
[219,220]. The calcite simulation cell was composed of 20 unit cells, four
unit cells along the a-axis, five along b, and one along c, while the aragonite
simulation cell included 27 unit cells, three along each of the a, b, and c axes.
In the case of calcite, the constant volume MD simulations show little
difference between the initial (Fig. 8A) and final structures (Fig. 8B), apart
from some thermally induced positional and rotational disorder. For arago-
nite, there is apparently very little rearrangement of the structure after the

A B C

Figure 8 The molecular dynamic simulation of calcite: (A) the initial, (B) the final with
a constant volume simulation (298K and density of 2.71 g/cm3), and (C) the final with a
constant stress simulation (298K and 1 bar pressure). Carbonate ions are shown with
a stick representation for the bonds between carbon and oxygen atoms. The projection
is along the b-axis.
60 M.M.H. Al Omari et al.

A B C

Figure 9 The molecular dynamic simulation of aragonite: (A) the initial, (B) the final
with a constant volume simulation (298K and density of 2.944 g/cm3), and (C) the
final with constant stress simulation (298K and 1 bar pressure). Carbonate ions are
shown with a stick representation for the bonds between carbon and oxygen atoms.
The projection is along the a-axis.

simulation (Fig. 9B) in comparison with the initial configuration (Fig. 9A).
The agreement between experimental and simulated pair distribution func-
tions would suggest that the force field reproduces the structural features of
calcite and aragonite when using constant volume simulations. However,
the constant volume/shape constraints may have had the effect of stabilizing
metastable structures [217].
Fig. 8C shows the final system configuration of the constant stress sim-
ulation for calcite. Comparing this with the starting configuration (Fig. 8A),
it is evident that the calcite structure is not greatly altered by relaxation in the
simulation constraints. The final and initial configurations of aragonite
(Fig. 9C and A, respectively) do show some differences. The equilibrated
structure from the constant stress simulation indicates that the carbonate ions
had rotated through an angle of c.60 degree, although the Ca and carbon
center-of-mass positions did not change appreciably. The differences in
the simulation outcomes can be associated with differences in the carbonate
anion geometries between the calcite and aragonite natural crystalline forms.
Furthermore, the equilibrium unit cell parameters of calcite calculated from
the constant stress simulation show a close agreement with the X-ray crys-
tallographic values. Aragonite, however, shows greater differences in the
unit cell dimensions. All three lengths, a, b, and c, were longer so that the
density was lower, in fact quite close to the calcite, suggesting that the ara-
gonite phase is tending toward this structure in an attempt to relieve stress on
the system [217].
Calcium Carbonate 61

Atomistic simulation techniques, based on the Born model of solids,


have been used to investigate the effect of molecular adsorption of water
on the low-index surfaces of calcite, aragonite, and vaterite [221]. For
calcite, the results showed that {1014} surface is the most stable surface
of calcite and exhibits the same 1  1 symmetry and structural features of
the surface oxygen ions. Also the presence of partially hydrated surfaces
has equivalent surface carbonate groups, while the {1011} surface and also
the {1120} plane both exhibit bulk-like termination of the surface with only
some rotation of surface carbonate groups. In the case of aragonite, the sta-
bility and regularity of the hydrated {010} surface confirms the needs to be
stabilized by an ordered water layer to be able to fit well onto hydrated gyp-
sum (010). In the case of vaterite, the calculated equilibrium morphology of
the hydrated vaterite crystals has a disk shape, while the unhydrated and
growth morphologies are elongated and perhaps more needlelike.
The bulk lattice energies of the three forms (Table 8) reflect their ther-
modynamic stability, in that the stability of calcite over aragonite is due to its
higher entropy content at elevated temperatures rather than its bulk lattice
energy, which favors aragonite. The relative surface contributions of the
forms show that in the crystal nucleation stage, calcite is the most stable form,
while aragonite becomes more stable when the crystal is large enough for the
bulk lattice energy to outweigh the surface energy terms [219].

3.9 Crystallographic Properties


3.9.1 Single-Crystal Structure
3.9.1.1 Calcite
Calcite has a rhombohedral crystal structure as determined by Bragg [222].
The hexagonal unit cell of calcite, with space group R3c, has
a ¼ b ¼ 4.990 Å, c ¼ 17.061 Å, α ¼ β ¼ 90 degree, and γ ¼ 120 degree
(Fig. 10) [219,223,224].

Table 8 Calculated Lattice Energies of Calcite, Aragonite,


and Vaterite
Form Bulk Lattice Energy ×108 (kJ/m3)
Calcite 1.6867
Aragonite 1.7851
Vaterite 1.6577
62 M.M.H. Al Omari et al.

A B

Figure 10 The hexagonal representation of a calcite unit cell: (A) side view and (B) top
view (Ca ¼ green (light gray in the print version), O ¼ red (dark gray in the print version),
C ¼ gray).

A B

Figure 11 The orthorhombic double cells of aragonite: (A) side view and (B) top view
(Ca ¼ green (light gray in the print version), O ¼ red (dark gray in the print version),
C ¼ gray).

3.9.1.2 Aragonite
Aragonite has an orthorhombic crystal structure with space group Pmcn. The
experimental structure parameters found by Dickens and Bowen are:
a ¼ 4.960 Å, b ¼ 7.964 Å, c ¼ 5.738 Å, and α ¼ β ¼ γ ¼ 90 degree, containing
four CaCO3 molecules [220]. The theoretical crystal parameters a
(5.0192 Å), b (8.0393 Å), and c (5.7952 Å), as obtained by USPEX simula-
tion method are almost close to the experimental values [118].
The Ca ion (green (light gray in the print version) spheres in Fig. 11) is
very close to the limiting value for transition making aragonite’s
orthorhomobic structure fairly easy to shift into the thermodynamically
Calcium Carbonate 63

stable rhombohedral structure, though depending on approach the activa-


tion energy ranges from 159 to 452 kJ/mol [225–227].

3.9.1.3 Postaragonite and Phases I–IV


It was reported by Santillán and Williams that CaCO3 postaragonite phase
has a trigonal structure [228], while Ono et al. showed that it has an ortho-
rhombic structure [229]. Furthermore, a combination of advanced ab initio
simulation techniques (USPEX) and high-pressure experiment was used to
determine the crystal structure of the postaragonite phase in CaCO3, in
addition to different stable (phase I) and metastable phases (phases II–IV)
at high-pressure conditions [118]. Fig. 12 shows the best structure of these
phase produced by USPEX, where the structure optimizations were per-
formed at a series of pressures between 0 and 100 GPa.
It was found that the postaragonite structure is characterized by the pres-
ence of 12-coordinate Ca atoms (in aragonite Ca is 9-coordinate) and can be
viewed as hexagonal close packing of Ca2+ and O2 ions with small C4+ ions
in triangular voids (Fig. 12A). Furthermore and for postaragonite, theoret-
ical and experimental lattice parameters are in excellent agreement with each
other. Also it was found that at 50 GPa, all crystal structures contain

A B

C D E

Figure 12 The crystal structures of CaCO3: (A) postaragonite, (B) phase I, (C) phase II, (D)
phase III, and (E) phase IV (Ca ¼ red (dark gray in the print version), O ¼ green (gray in the
print version), C ¼ blue (dark gray in the print version)).
64 M.M.H. Al Omari et al.

triangular CO2 3 carbonate ions, whereas at 80 GPa, many structures also


contained CO4 4 tetrahedra (eg, phase I, Fig. 12B), indicating that such
structures become competitive well within the experimentally reachable
pressure range. The most stable structure identified at both 50a and
80 GPa is the postaragonite structure, but several metastable structures turn
out to be almost stable in this pressure range [118].
The orthorhombic crystal structure with space group C2221
(a ¼ 5.544 Å, b ¼ 6.926 Å, and c ¼ 3.213 Å) pyroxene-type structure (phase
I, Fig. 12B) appeared as metastable at 80 GPa, but at 150 GPa it became as
the most stable one. Thus, the limit for the enormous stability field of pos-
taragonite was obtained at the pressure range of 42–137 GPa. Additionally,
several energetically competitive structures, but always metastable phases II
(triclinic, space group P1, 10 atoms in the unit cell), III (trigonal, space
group R3m, 5 atoms in the rhombohedral cell), and IV (monoclinic, space
group P21, 10 atoms in the cell), all contain carbon only in the form of CO2
3
ions (Fig. 12C–E) [118].

3.9.1.4 Vaterite
Its crystal structure differs from those of calcite and aragonite in terms of
symmetry, orientation of CO3 ions, and coordination environment of Ca
ions. There is general agreement that the carbonate planes are parallel to
the c-axis and that the Ca atoms are in eightfold coordination with oxygen
atoms. In contrast, the CO3 ions in calcite and aragonite are perpendicular to
the c-axis, and the Ca atoms have sixfold coordination in calcite and ninefold
in aragonite [81,230,231].
Meyer first reported an orthorhombic unit cell with a space group Pbnm
and Z ¼ 4 (Fig. 13A) for vaterite crystal structure derived from single-crystal
X-ray diffraction experiments [232]. On the other hand, Kamhi [81] found a
structure with hexagonal symmetry and space group P63/mmc using the
same XRD technique (Fig. 13B).
Later, Meyer [232] provided a structure mainly consistent with Kamhi’s
structure [81], which has the same space group but different carbonate site
symmetry. Furthermore, Lippmann [225] developed an idealized structure
from the vaterite-type high-temperature phase of YbBO3 [233] with space
group P6322. Spectroscopic methods have been applied to resolve the con-
troversy on the vaterite structure and focused on space group and site sym-
metry. However, the results are inconsistent, often due to impurities in the
samples, mode assignments, and differences of group theory analysis. For
example, Sato and Matsuda’s infrared spectra [234] support Kamhi’s
Calcium Carbonate 65

A B

Figure 13 Crystal structures of vaterite: (A) orthorhombic structure with space group
Pbnm and (B) hexagonal structure with space group P63/mmc (Ca ¼ black, O ¼ light gray,
C ¼ gray).

structure [81]. Behrens et al. [235] argued that none of the proposed struc-
tures, P63/mmc or P6322, is consistent with the Raman spectra, while
Gabrielli et al. [236] show that Meyer’s structure [232] is consistent with
the Raman spectra. On the other hand, Anderson [237] favors both Kamhi’s
[81] and Lippmann’s [225] structures. Deer et al. [223] reported that vaterite
is hexagonal with space group P63 and a ¼ b ¼ 4.13 Å, c ¼ 8.48 Å, α ¼ β ¼ 90
degree, and γ ¼ 120 degree.
Wang and Becker used MD simulation with temperature annealing to
study the structure and carbonate orientation of vaterite, in addition to esti-
mate the relative stability of the structures proposed in the literature [238].
The investigation revealed that the orthorhombic crystal structure of vaterite
proposed by Meyer [232] cannot be confirmed by quantum-mechanical cal-
culations and by the experiments by Kamhi [81]. Thus, partial occupancy
and disordering are unavoidable for correctly describing the vaterite
structure.
Subsequently, the temperature-annealing MD simulation of vaterite
structure at the end of the annealing cycle at room temperature (300K) shows
that the orientations of CO3 ions are disordered (Fig. 14A) and there are three
preferred orientations with an angle of 120 degree between CO3 planes.
However, the structure lacks long-range orientational order [238]. This
disordered structure (Fig. 14A), when taking a space average, is consistent with
Kamhi’s structure [81], in which each lattice site of the CO3 ion is partially
occupied and all atoms of the CO3 ions are randomly distributed among three
positions. An ordered hexagonal superstructure with space group P6522 or
P3221 appeared at the end of about 7 ns of simulated annealing with a final
66 M.M.H. Al Omari et al.

A B

Figure 14 Snapshots of the molecular dynamic computations projected onto (001)


plane for vaterite: (A) at the end of the annealing cycle at 300K, where CO3 ions are dis-
ordered and (B) at the end of the annealing cycle at 1500K, where they are ordered
(Ca ¼ black, O ¼ light gray, C ¼ gray).

A B

Figure 15 The structure of monohydrocalcite (CaCO3H2O) viewed down {001}: (A) the
P3121 subcell structure showing the disordered carbonate groups and (B) the super-
structure P31 model (Ca ¼ large gray, O ¼ large black, C ¼ small black, H ¼ small gray).

annealing temperature of 1500K (Fig. 14B). The different crystal structures of


vaterite energetically follow the order: the ordered superstructure > the disor-
dered superstructure > orthorhombic structure [238].

3.9.1.5 Monohydrocalcite
The generally accepted structure of monohydrocalcite is that of Effenberger
et al. [219]. The structure from single-crystal diffraction is solved in P3121
(Fig. 15A) with cell parameters a ¼ 6.0931 Å and c ¼ 7.5446 Å, which
requires orientationally disordered carbonate groups. A superstructure that
determines the orientation of water oxygen, one carbonate oxygen, and the
hydrogen atoms is solved in P31 (Fig. 15B) with a ¼ 10.5536 Å and
c ¼ 7.5446 Å, on the basis of weak super-lattice reflections, in which the car-
bonate groups are orientationally ordered. The positions are mapped from
Calcium Carbonate 67

the P3121 substructure, and the ordered orientations of the carbonate groups
are refined using rigid bodies.
Monohydrocalcite consists of eightfold coordinated Ca2+ ions, in which
some of the oxygen coordination is direct to carbonate groups and some
to water molecules. The eightfold Ca coordination consists of bonding to
four neighboring carbonate groups and two water molecules. Two of the
carbonate groups are involved in two bonds from Ca to two separate O
atoms, and two others are involved in one bond from Ca.

3.9.1.6 Ikaite
Ikaite tends to form very steep or spiky pyramidal crystals, often radially
arranged, of varied sizes from thumbnail size aggregates to gigantic salient
spurs. Upon synthesis, CaCO3H2O crystallizes in well-defined rhombohe-
dral crystals in the size range 10–40 mm. It crystallizes in the monoclinic
crystal system in space group C2/c with lattice parameters a  8.87 Å,
b  8.23 Å, c  11.02 Å, and β  110.2 degree [239]. The structure of ikaite
consists of an ion pair of (Ca2+CO2 0
3 ) surrounded by a cage of hydrogen-
bonded water molecules which serve to isolate one ion pair from another
(Fig. 16) [240].

3.9.2 X-Ray Powder Diffraction Pattern


Different anhydrous and hydrate CaCO3 forms were prepared and tested by
a Siemens D500 diffractometer operating with Cu Kα radiation
(λ ¼ 1.5406 Å) at 40 kV and 20 mA in Bragg-Brentano mode with a step size

Figure 16 Ion pair (Ca2+CO2 0


3 ) and hydration cage. Ca is in dodecahedral coordination
with O atoms of the carbonate and water molecules, while hydrogen bonds (dotted)
between H atoms of the water molecules to the O atoms of the carbonate ion exist
(Ca ¼ blue (light gray in the print version), O ¼ red (dark gray in the print version),
CO3 ¼ black planar, H ¼ yellow (white in the print version)).
68 M.M.H. Al Omari et al.

Figure 17 XRPD patterns of different CaCO3 forms including calcite, vaterite, aragonite,
monohydrocalcite (CaCO3H2O), ikaite (CaCO36H2O), and amorphous.

of 0.02 degree 2θ and a counting time of 1 s per step [76,77]. XRPD patterns
of these prepared CaCO3 were shown in Fig. 17 and their corresponding
crystallographic data including 2θ, d-spacing, hkl indices [241,242], and %
intensity are listed in Tables 9 and 10. The interplaner d-spacing is calculated
from the Bragg equation (2d sin θ ¼ nλ), where λ (¼1.5406 Å) is the wave-
length of the X-ray (Cu Kα radiator).
As shown in Fig. 17, the XRPD patterns of the three crystalline forms of
CaCO3 (calcite, aragonite, and vaterite), prepared according to the above
conditions, represent their pure phases with no other crystalline phases
detected. Also monohydrocalcite can be clearly identified by XRPD in a
phase-pure form. Ikaite form has only one major and sharp peak at 2θ of
about 17 and 2 minors around 35. However, amorphous can be distin-
guished from other forms by a halo broad peak (Fig. 17).

3.10 Thermal Analysis


3.10.1 Melting Point
The reported melting points of CaCO3 are 825 and 1339°C for aragonite
and calcite, respectively [243].

3.10.2 Differential Scanning Calorimetry


The differential scanning calorimetry (DSC) thermogram of CaCO3 calcite
form was recorded using an STA S-1500 instrument at a heating rate of
10°C/min in an air flow (Fig. 18A) [102]. From the DSC results, calcite
has an endothermic peak at 726°C, which reveals the decomposition of
Calcium Carbonate 69

Table 9 The Crystallographic Data from the X-Ray Powder Diffraction Patterns of
Anhydrous Crystalline CaCO3 Forms Calcite, Aragonite, and Vaterite
Scattering Angle (2θ) d-Spacing (Å) hkl Indices Relative Intensity (%)
Calcite
23.0 3.8637 {012} 10.0
29.4 3.0356 {104} 100.0
35.9 2.4995 {110} 15.0
39.5 2.2796 {113} 20.0
43.1 2.0971 {202} 17.5
47.5 1.9126 {024} 17.5
48.5 1.8755 {018} 20.0
57.5 1.6015 {112} 7.5
Aragonite
21.1 4.2071 {110} 12.2
26.3 3.3834 {111} 100.0
27.3 3.2618 {021} 51.2
31.2 2.8689 {002} 4.9
33.2 2.6931 {012} 29.3
36.2 2.4821 {200} 34.1
37.3 2.4076 {031} 34.1
37.9 2.3708 {112} 22.0
38.5 2.3394 {130} 39.0
41.3 2.1833 {221} 17.1
43.0 2.1036 {220} 36.6
46.0 1.9722 {221} 87.8
48.3 1.8821 {202} 41.5
50.2 1.8159 {132} 24.4
52.5 1.7425 {113} 22.0
53.1 1.7233 {231} 17.1
Continued
70 M.M.H. Al Omari et al.

Table 9 The Crystallographic Data from the X-Ray Powder Diffraction Patterns of
Anhydrous Crystalline CaCO3 Forms Calcite, Aragonite, and Vaterite—cont'd
Scattering Angle (2θ) d-Spacing (Å) hkl Indices Relative Intensity (%)
Vaterite
21.0 4.2269 {004} 11.4
24.9 3.5730 {110} 75.0
27.0 3.2997 {112} 100.0
32.7 2.7364 {114} 84.1
44.5 2.0343 {211} 79.5
49.0 1.8575 {304} 25.0
50.0 1.8227 {300} 45.5
56.0 1.6408 {224} 22.7

Table 10 The Crystallographic Data from the X-Ray Powder Diffraction Patterns of
Hydrate CaCO3 Forms Monohydrocalcite (CaCO3H2O) and Ikaite (CaCO36H2O)
Scattering Angle (2θ) d-Spacing (Å) Relative Intensity (%)
Monohydrocalcite
20.8 4.2671 46.7
29.0 3.0765 46.7
32.0 2.7946 100.0
36.0 2.4927 13.3
38.0 2.3660 20.0
42.0 2.1495 40.0
45.5 1.9919 60.0
47.0 1.9318 53.3
52.0 1.7572 20.0
56.0 1.6408 20.0
Ikaite
17.5 5.0637 100.0
34.0 2.6347 40.0
34.5 2.5976 40.0
Calcium Carbonate 71

A
10

Heat flow (mV)


–10

–20

–30

–40

–50
400 500 600 700 800
Temperature (°C)
B
100

90
Weight (%)

80

70

60

50

40
200 400 600 800 1000
Temperature (°C)
Figure 18 (A) The DSC and (B) TGA thermograms of CaCO3 calcite form recorded at a
heating rate of 10°C/min in an air flow.

CaCO3 into CaO. Both aragonite and vaterite forms show almost similar
DSC patterns to calcite with endothermic peaks at around 800 (heating rate
of 10°C/min per Ar gas) and 775°C (heating rate of 5°C/min per air flow),
respectively [244,245]. In the case of vaterite, two additional exothermic
peaks obtained at 481 and 488°C are unambiguously attributed to the trans-
formation of vaterite into calcite [245].

3.10.3 Thermogravimetric Analysis


The thermogravimetric analysis (TGA) thermogram of CaCO3 calcite form
was recorded using an STA S-1500 instrument at a heating rate of 10°C/min
in an air flow (Fig. 18B) [102]. From the TGA results gave 43% weight loss
in the temperature range of 680–780°C, which attributed to the
72 M.M.H. Al Omari et al.

100 Exo 15

99 10

98 5
0

Heat flow (mV)


97
Weight (%)

–5
96
–10
95
–15
94
–20
93 –25
92 Step 1 Step 2 –30

50 100 150 200 250 300 350


Temperature (°C)
Figure 19 TGA and DSC thermograms of amorphous CaCO3, showing the steps of water
loss prior to crystallization to form calcite.

decomposition of CaCO3 to CaO. Both aragonite and vaterite forms show


almost similar TGA patterns to calcite [244,245]. Fig. 19 represents the
TGA–DSC of amorphous CaCO3 prepared by bubbling of CO2 and by
mixing of Ca and carbonate solutions [103]. Water is lost in two distinct
steps. From 50 to 100°C, a first step is assigned to loosely bound water.
In the second step from 100 to 250°C, structural water is lost with a begin-
ning crystallization to calcite as indicated by DSC.

3.11 Spectroscopy
3.11.1 Ultraviolet/Visible Spectroscopy
The ultraviolet/visible (UV/VIS) spectrophotometry was used for direct
measurement of carbonate ions (CO2 3 ) concentration. For example,
CO23 absorbs light at wavelengths of less than 250 nm, this facilities
acidimetric titration with UV detection of most carbonate-containing nat-
ural waters and observe an increase in % transmittance [246]. Ariponnammal
reported that CaCO3 has three characterized wavelengths at 233.42, 254.91,
and 356.52 nm [247]. Furthermore, Nangare described direct UV/VIS
method for simultaneous determination of CaCO3 and aspirin in tablet dos-
age form [248]. Fig. 20 represents the UV/VIS spectrum of CaCO3 in 0.1
NaOH, recorded by a Shimadzu model 1700 double beam UV/VIS spec-
trophotometer, which shows a maximum at about 240 nm.
Calcium Carbonate 73

Figure 20 The UV/VIS absorption spectrum of CaCO3 (20 μg/mL) in water.

3.11.2 Vibrational Spectroscopy


3.11.2.1 Fourier Transform Infrared Spectroscopy
The Fourier transform infrared spectroscopy (FTIR) absorption spectra of
different CaCO3 forms were recorded using Shimadzu IRAffinity-1 FTIR
spectrophotometer (Fig. 21) [128]. Carbonate ions and similar molecules
have four normal modes of vibration peaks: υ1 symmetric stretching, υ2
out-of-plane bending, υ3 doubly degenerate planar asymmetric stretching,
and υ4 doubly degenerate planar bending [249]. As shown in Fig. 21, ara-
gonite has two characteristic absorption bands at υ2 856 cm1 and υ4
713 cm1 along with a weak 700 cm1 absorption peak, and also a υ3
absorption band at 1490 cm1, and these can be considered as the com-
mon characteristic features of the CO2 3 ions in CaCO3 and are the funda-
mental modes of vibration for this molecule [250]. Vaterite’s characteristic
absorption bands are υ2 875 cm1 and υ4 745 cm1 and a split peak of υ3 at
1440 and 1490 cm1. For calcite, there are two absorption bands at υ2
875 cm1 and υ4 713 cm1 and an absorption peak at 1420 cm1.
Monohydrocalcite shows weak absorption bands at υ4 700 and
727 cm1, at υ2 873 cm1, at υ1 1068 cm1, and a split peak of υ3 at
1418 and 1488 cm1 [78,251]. Amorphous CaCO3 has a characteristic
broad υ2 absorption band at 866 cm1, and a split peak at 1418 and
1475 cm1.
From the earlier results, the characteristic carbonate υ2 band of aragonite
is at 856 cm1; whereas that of both calcite and vaterite is at 875 cm1. The
74 M.M.H. Al Omari et al.

1490 856

713 700 Aragonite


1490 875
1440

1487 745 Vaterite


1408
875
Monohydrocalcite
700

1420 875

713 Calcite

1475 1418
866 Amorphous

00 00 0 0 0 0 0 0 0 0
90 85 80 75 70 65 60 55 50
0
20 15
Wavenumber (cm-1)
Figure 21 The FTIR spectra of different CaCO3 forms.

characteristic carbonate υ4 band of aragonite is at 700 and 713 cm1,


whereas that of calcite is at 713 cm1 and vaterite at 744 cm1 [252].

3.11.2.2 Raman Spectroscopy


The Raman absorption spectra of CaCO3 were obtained with a Jobin-Yvon
T64000 Raman spectrometer. The Raman spectra were excited by the laser
line having a wavelength of 514.5 nm, provided by an Ar laser [253]. The
Raman spectra of three crystalline forms of CaCO3 (calcite, aragonite, and
vaterite) are shown in Fig. 22 and the assignments of distinctive Raman
bands are given in Table 11 [236]. Three zones can be used to distinguish
the three forms. The selection of the appropriate bands for quantitative anal-
ysis is a difficult task since there is a strong overlapping. Unfortunately, the
strongest bands of CaCO3 forms at 1000 cm1 overlap and cannot be used
for analytical purposes. Vibration modes 700 cm1 are very weak, and par-
ticularly undetectable for vaterite. The most intense Raman bands are
observed in the low frequencies region (50–400 cm1), corresponding to
the lattice mode vibrations. For this reason, the range chosen for the quan-
titative analysis is situated between 50 and 400 cm1.
The Raman spectra of monohydrocalcite are shown in Fig. 23A. The
spectrum is dominated by the symmetric stretching vibration (υ1) of
the CO3 group, which occurs at 1069 cm1. The only other features in
Calcium Carbonate 75

10,000

Raman intensity (a.u.)

Calcite

Aragonite

Vaterite

200 400 600 800 1000 1200 1400 1600


Wavenumber (cm-1)

B
Raman intensity (a.u.)

Calcite

Aragonite

Vaterite

50 100 150 200 250 300 350 400


Wavenumber (cm-1)
Figure 22 The Raman spectra of different CaCO3 forms in the ranges of (A) 50–1600 and
(B) 50–400 cm1.

the spectrum are a weak lattice vibration at 212 cm1 and traces of ν1 at
880 cm1 [254]. For amorphous CaCO3, the typical Raman spectrum is
shown in Fig. 23B. The amorphous character is initially confirmed by the
low intensity for all Raman bands when compared to other crystalline forms.
Furthermore, the main Raman band of the carbonate ion (ν1 at 1085 cm1)
is shifted toward lower wavenumbers (1079.87 cm1) and is broader than
for well-crystallized forms [255,256].
76 M.M.H. Al Omari et al.

Table 11 The Wavenumbers (cm1) and Vibrational Mode of the Raman Absorption
Bands of Different CaCO3 Forms
Form Wavenumber (cm21)
υ1 υ2 υ3 υ4
Lattice Symmetric Out-of-Plane Asymmetric In-Plane
Mode Stretching Bending Stretching Bending
Calcite 284 1086 — 1434 1747
Aragonite 151, 206, 275 1085 853, 910 1460, 1570 —
Vaterite 267, 300, 325 1074, 1090 874 1445, 1485, 1749
1550, 1595

Figure 23 The Raman spectra of (A) monohydrocalcite (CaCO3H2O) and (B) amorphous
CaCO3. The wavenumbers at 914.90 and 1371.26 cm1 correspond to Ne emission lines,
(C and D) ikaite (CaCO3 6H2O) at pressures from 0.14 to 4.08 GPa in a diamond anvil cell
in the ranges of 200–1100 and 2800–4000 cm1, respectively.
Calcium Carbonate 77

The Raman spectra of a single crystal of ikaite over a range of pressures in


a diamond anvil cell are shown in Fig. 23C and D [257]. The spectrum at
1.32 GPa shows eight peaks, four corresponding to Eg external vibrations of
1
CO2 3 ions at 228, 240, 280, and 308 cm , two corresponding to internal
vibrations of CO2
3 ions, namely, the Eg (internal) and A1g (internal) vibra-
tions at 729 and 1081 cm1, respectively, and two peaks related to water at
3207 and 3403 cm1 [258]. Ikaite has a spectrum similar to the other CaCO3
forms [259,260], but with water peaks visible between 3000 and 3600 cm1.
The peaks become more intense as the pressure increases and the pressure
shifts become larger for the external (lattice) modes than for the internal
vibrations.

3.11.3 Nuclear Magnetic Resonance Spectrometry


3.11.3.1 1H MAS NMR Spectrum
Solid-state proton NMR spectroscopy was performed on a Bruker ASX 400
spectrometer with a 400.132 MHz resonance frequency. For all solid-state
spectra, magic angle spinning (MAS) was applied at a frequency of
15,000 Hz in a 4-mm rotor and direct excitation of the protons was induced
by a single 90 degree pulse [76].
The use of 1H MAS NMR technique is mainly aimed to analyze the
incorporated molecular water. Vaterite, monohydrocalcite, and amorphous
forms contain molecular water as the main hydrogen component and only
traces of hydroxide. A signal at around 5 ppm is observed for the aforemen-
tioned forms (Fig. 24). Such signal is assigned to incorporated molecular

* * Vaterite
Intensity

* *
Monohydrocalcite

* * Amorphous

100 80 60 40 20 0 –20 –40 –60 –80


Chemical shift (ppm)
Figure 24 1H MAS NMR spectra of vaterite, monohydrocalcite (CaCO3H2O), and amor-
phous forms. *Spinning side bands.
78 M.M.H. Al Omari et al.

water. The peaks between 1.5 and 2.5 for the amorphous are due to traces of
a mobile water fraction containing hydroxide ions.

13
3.11.3.2 C MAS NMR Spectrum
Solid-state carbon NMR spectroscopy was performed on a Bruker ASX 400
spectrometer with a 100.623 MHz resonance frequency. For all solid-state
spectra, MAS was applied at a frequency of 4000 Hz in a 7-mm rotor and
direct excitation of 13C nuclei was induced by a single 30 degree pulse of
5.75 μs duration [76].
The 13C MAS NMR spectra of all hydrated and anhydrous CaCO3
forms are shown in Fig. 25. All samples show carbonate or hydrogen carbon-
ate peaks in the range of 156–174 ppm. The crystalline, water-free phases
calcite and aragonite show very narrow NMR peaks, whereas the water-
containing phases all showed broad peaks [76,261]. The linewidth of the
amorphous peak is large due to the disordered structure. There is a clear dis-
tinction between the regions of carbonate peaks (about 166–174 ppm) and
hydrogen carbonate peaks (below 166 ppm). The foregoing indicates that
the majority of the carbon atoms in amorphous are present as carbonate
and not as hydrogen carbonate, with some similarity of the chemical envi-
ronment to the highly hydrated phase ikaite.

Calcite
* *

* * Aragonite

* * Vaterite
PTFE
Monohydrocalcite
* *
Intensity

Ikaite
*
Amorphous
* *

250 200 150 100 50 0


Chemical shift (ppm)
Figure 25 13C MAS NMR spectra of anhydrous forms of CaCO3 (calcite, aragonite,
and vaterite) and hydrated forms (monohydrocalcite, ikaite, and amorphous). *Spinning
side bands.
Calcium Carbonate 79

For aragonite, there is a single peak at 169.9 ppm; for calcite, there is a
single peak in the range of 167.4–167.9 ppm with a full width at half max-
imum (fwhm) of 1–1.1 ppm; for vaterite containing 9% calcite, there is a
single peak at 168.7 ppm (fwhm 1.9 ppm). Ikaite shows a slow decomposi-
tion during the NMR experiment, even if it is carried out at 20°C as it
partially converts to calcite (confirmed by X-ray powder diffraction) [76].

4. METHODS OF ANALYSIS
4.1 Compendial Methods
4.1.1 Calcium Carbonate
CaCO3 monograph is listed in the Eur. Ph. [2], United States Pharmaco-
peia–National Formulary (USP–NF) [1], and JP [216]. Table 12 shows a
summary of its specifications and methods of analysis.

4.1.2 Calcium Carbonate Tablets


CaCO3 tablets monograph is listed in the USP-NF [262]. Table 13 shows a
summary of its specifications and methods of analysis.

4.1.3 Chewable Calcium Carbonate Tablets


Chewable CaCO3 tablets monograph is listed in the British Pharmacopeia
(BP) [263]. Table 14 shows a summary of its specifications and methods of
analysis.
Combination of CaCO3 with heavy MgCO3 in chewable tablets, as ant-
acid, is also listed in BP [264].

4.1.4 Calcium Carbonate Oral Suspension


CaCO3 oral suspension monograph is listed in the USP-NF [265]. Table 15
shows a summary of its specifications and methods of analysis.

4.1.5 Calcium Carbonate Lozenges


CaCO3 lozenges monograph is listed in the USP-NF [266]. Table 16 shows
a summary of its specifications and methods of analysis.
Different combinations with aluminum hydroxide and magnesium
hydroxide [267], with magnesium hydroxide and simethicone [268], with
magnesium hydroxide [269], with aluminum hydroxide, magnesium
hydroxide and simethicone [270], and with magnesium carbonate
[271,272] monographs are listed in USP.
Table 12 The Summary of the Compendial Methods of CaCO3
Test Eur. Ph. USP-NF JP

Definition CaCO3 CaCO3 Precipitated CaCO3


98.5–100.5% (dried substances) 98.5–100.5% (dried substances) Not less than 98.5% (dried substances)
Characters A white or almost white powder. It is practically A fine, white, odorless, tasteless, microcrystalline powder. A white, fine crystalline powder. It is
insoluble in water It is stable in air. Practically insoluble in water. Its solubility odorless and tasteless. It is practically
in water is increased by the presence of ammonium salt or insoluble in water, but its solubility is
of CO2. The presence of any alkali hydroxide reduces its increased in the presence of CO2. It is
solubility. Insoluble in alcohol. Dissolves with practically insoluble in ethanol (95%) and
effervescence in 1 N acetic acid, in 3 N HCl, and in 2 N in diethyl ether. It dissolves with
HNO3. NF category: Diluent; pH modifier (acidifying effervescence in dilute acetic acid, in
agent/alkalizing agent/buffering agent); coating agent; dilute HCl, and in dilute HNO3
wet binder
Identification It gives the reaction of carbonates The addition of acetic acid to it produces effervescence It responds to the Quantitative test h1.09i
A (carbonate) (see Section 2.3.1) for carbonate
Identification 0.2 mL of solution S gives the reactions of Ca The resulting solution in identification A, after boiling, Dissolve 0.5 g in 10 mL of dilute HCl,
B (Ca) (see Section 2.3.1) meets the requirements of Ca test h191i boil, then cool, and neutralize with
Solution S: Dissolve 5.0 g in 80 mL of dilute ammonia TS (the solution responds to
acetic acid R. When the effervescence ceases, the Quantitative test h1.09i (1) for
boil the solution for 2 min, allow to cool, dilute carbonate.)
to 100 mL with dilute acetic acid R and filter, if
necessary, through a sintered-glass filter (see
Section 2.1.2)
Insoluble Wash any residue obtained during the Mix 5.0 g with 10 mL water and add HCl, dropwise, with To 5.0 g add 50 mL of water, then 20 mL
substances preparation of solution S with four quantities, agitation, until it ceases to cause effervescence, then add of HCl dropwise with stirring, boil for
each of 5 mL, of hot water R, and dry at 100– water to make 200 mL, and filter. Wash the insoluble 5 min, cool, add water to make 200 mL,
105°C for 1 h (NMT 0.2%) residue with water until the last washing shows no and filter. With filter paper for
chloride, and ignite and weigh the residue (NMT 0.2%) quantitative analysis. Wash the residue
until the last washing shows no turbidity
with silver nitrate TS, and ignite the
residue together with the filter paper and
weigh (NMT 0.2%)
Chloride Dilute 3 mL of solution S to 15 mL with — —
distilled water R (see Section 2.4.4) (NMT
330 ppm)
Sulfates 1.2 mL of solution S diluted to 15 mL with — —
distilled water R complies with the limit test for
sulfates (see Section 2.4.13) (NMT 0.25%)
Arsenic 5 mL of solution S (see Section 2.4.2, Slowly dissolve 1.0 g in 15 mL of HCl and dilute with Moisten 0.40 g with 1 mL of water, then
Method A) (NMT 4 ppm) water to 55 mL (arsenic, method I, omit the addition of dissolve in 4 mL of dilute HCl, use this
20 mL of 7 N H2SO4) (NMT 3 ppm) solution as the test solution, and perform
the Arsenic test h1.11i (NMT 5 ppm)
Barium To 10 mL of solution S add 10 mL of calcium A platinum wire, dipped in the filtrate obtained in the test Mix 1.0 g with 10 mL of water, add
sulfate solution R. After at least 15 min (any for insoluble substances and held in a nonluminous flame dropwise 4 mL of HCl with stirring, boil
opalescence in the solution is not more intense (does not impart a green color) for 5 min, cool, add water to make
than that in a mixture of 10 mL of solution S and 40 mL, and filter. With the filtrate,
10 mL of distilled water R) perform the Flame Coloration test h1.04i
(1) (no green color appears)
Iron Dissolve 50 mg in 5 mL of dilute HCl R and 40 mg in 5 mL of 2 N HCl. Transfer to a beaker with the —
dilute to 10 mL with water R (see Section 2.4.9) aid of water and dilute with water to 10 mL (sample
(NMT 200 ppm) solution). Transfer 4.0 mL of the standard iron solution
h241i to a beaker and dilute with water to 10 mL (standard
solution). Add separately to the sample solution and
standard solution 2 mL of citric acid solution (1 in 5) and 2
drops of thioglycolic acid, adjust with ammonia TS to a pH
of 9.5  0.1, dilute with water to 20 mL, and allow to stand
for 5 min. Dilute with water to 50 mL. Measure the
absorbances of the solutions from the sample solution and
the standard solution at 530 nm h851i (NMT 0.1%; the
absorbance of the solutions from the sample solution does
not exceed that of the standard solution)
Lead — To 1.0 g in 5 mL of water, slowly add 8 mL of 3 N HCl, —
evaporate on a steam bath to dryness, and dissolve the
residue in 5 mL of water h251i (NMT 3 ppm)
Continued
Table 12 The Summary of the Compendial Methods of CaCO3—cont'd
Test Eur. Ph. USP-NF JP

Magnesium Dissolve 1.0 g in 12 mL of dilute HCl R. Boil Mix 1.0 g with 35 mL of water. Carefully add 3 mL of Dissolve 1.0 g in 20 mL of water and
and alkali the solution for about 2 min and add 20 mL of HCl, heat the solution, and boil for 1 min. Rapidly add 10 mL dilute HCl, boil, neutralize with
metals water R, 1 g of ammonium chloride R and 40 mL of oxalic acid TS and stir vigorously until ammonia TS, and add ammonium
0.1 mL of methyl red solution R. Add dilute precipitation is well established. Add immediately to the oxalate TS until precipitation of calcium
ammonia R1 until the color of the indicator warm mixture 2 drops of methyl red TS and then 6 N oxalate is completed. Heat the mixture
changes and then 2 mL in excess. Heat to ammonium hydroxide, dropwise, until the mixture is just on a water bath for 1 h, cool, dilute with
boiling and add 50 mL of hot ammonium alkaline. Cool to room temperature, transfer to a 100-mL water to 100 mL, shake well, and filter.
oxalate solution R. Allow to stand for 4 h, dilute graduated cylinder, dilute with water to 100 mL, mix, and To 50 mL of the filtrate add 0.5 mL of
to 100 mL with water R, and filter through a allow to stand for 4 h or overnight. Filter, and to 50 mL of H2SO4, evaporate to dryness, and ignite
suitable filter. To 50 mL of the filtrate add the clear filtrate in a platinum dish add 0.5 mL of H2SO4, at 600°C to constant mass (the mass of the
0.25 mL of H2SO4 R. Evaporate to dryness on a and evaporate the mixture on a steam bath to a small residue is not more than 5 mg)
water bath and ignite to constant mass at 600°C. volume. Carefully heat over a free flame to dryness and
The residue weighs not more than 7.5 mg continue heating to complete decomposition and
(NMT 1.5%) volatilization of ammonium salts. Finally, ignite the
residue to constant weight (NMT 1.0%; the weight of the
residue is NMT 5 mg)
Heavy metals 12 mL of solution S complies with limit test A Mix 1.0 g with 5 mL of water, slowly add 8 mL of 3 N Mix 2.0 g with 5 mL of water, slowly add
for heavy metals. Prepare the standard using lead HCl, and evaporate on a steam bath to dryness. Dissolve 6 mL of dilute HCl, and evaporate on a
standard solution (1 ppm Pb) R the residue in 20 mL of water, filter, and add water to the water bath to dryness. Dissolve the
(see Section 2.4.8, Test A) (NMT 20 ppm) filtrate to make 25 mL h231i (NMT 20 ppm) residue in 50 mL of water, and filter. To
25 mL of the filtrate add 2 mL of dilute
acetic acid, 1 drop of ammonia TS and
water to make 50 mL, and perform the
test using this solution as the test solution.
Prepare the control solution as follows:
evaporate 3 mL of HCl on a water bath
to dryness, add 2 mL of dilute acetic acid,
2.0 mL of standard lead solution and
water to make 50 mL h1.07i
(NMT 20 ppm)
Mercury — Mercury stock solution and Standard Mercury solution: Proceed —
as directed in Mercury h261i
Standard solution: Proceed as directed in Mercury h261i,
except use 3 mL of HCl instead of 3 mL of H2SO4
Sample stock solution: 4.0 g in a 100-mL beaker, and
cautiously dissolve in 14 mL of 6 N HCl
Sample solution: Proceed as directed in Mercury h261i
using the Sample stock solution, except use 3 mL of HCl
instead of 3 mL of H2SO4
Analysis samples: Standard solution and sample solution
proceed as directed in Mercury h261i method IIa
(NMT 0.5 ppm)
Fluoride — [Prepare and store all solutions in plastic containers] —
Solution A: 294 mg/mL of sodium citrate dentate in water
Standard solution: Combine 20.0 mL of the standard stock
solution (1.11 mg/mL of USP NaF RS in water) with
50.0 mL of solution A, and dilute with water to 100.0 mL
Electrode system: Use a fluoride-specific ion—indicating an
electrode and a silver–silver chloride reference electrode
connected to a pH meter capable of measuring potentials
with a minimum reproducibility of 0.2 mV h791i
Standard response line: Transfer 50.0 mL of solution A and
4.0 mL of HCl to a beaker, and add water to make
100 mL. Add a plastic-coated stirring bar, insert the
electrodes into the solution, stir for 15 min, and read the
potential (mV). Continue stirring, and at 5-min intervals
add 100, 100, 300, and 500 μL of the standard solution,
reading the potential 5 min after each addition. Plot
the logarithms of the cumulative fluoride ion
concentrations (0.1, 0.2, 0.5, and 1.0 μg/mL)
vs potential (mV)
Analysis: Transfer 2.0 g to a beaker containing
a plastic-coated stirring bar, add 20 mL of
water and 4.0 mL of HCl, and stir until dissolved.
Continued
Table 12 The Summary of the Compendial Methods of CaCO3—cont'd
Test Eur. Ph. USP-NF JP

Add 50.0 mL of solution A and sufficient water to make


100 mL of test solution. Rinse and dry the electrodes,
insert them into the sample solution, stir for 5 min, and
read the potential (mV). From the standard response line
(NMT 50 ppm)
Loss on Determined on 1.000 g by drying in an oven at Dry the sample at 200°C for 4 h h731i (NMT 2.0%) Dry the sample at 180°C for 4 h h2.41i
drying 200°C (NMT 2.0%) (NMT 1.0%)
Assay Dissolve 0.150 g in a mixture of 3 mL of dilute Transfer 0.200 g, previously dried at 200°C for 4 h to a Transfer 0.12 g, previously dried, and
HCl R and 20 mL of water R. Boil for 2 min, 250-mL beaker. Moisten thoroughly with a few milliliters dissolve in 20 mL of water and 3 mL of
allow to cool, and dilute to 50 mL with water R. of water, and add, dropwise, sufficient 3 N HCl to dilute HCl. Add 80 mL of water, 15 mL
Carry out the complexometric titration of Ca. dissolve. Add 100 mL of water, 15 mL of 1 N NaOH, and of KOH (1 in 10), and 0.05 g of NN
1 mL of 0.1 M EDTA is equivalent to 10.01 mg 300 mg of naphthol blue. Titrate with 0.05 M EDTA VS indicator, and titrate with 0.05 mol/L
of CaCO3 to change the color to distinct blue h541i. 1 mL of 0.05 M EDTA VS to change the color from red-
EDTA disodium is equivalent to 5.005 mg of CaCO3 purple to blue h2.50i. 1 mL of 0.05 mol/
L EDTA is equivalent to 5.004 mg of
CaCO3
Storage — Preserve in well-closed containers Tight containers
Calcium Carbonate 85

Table 13 The Summary of the USP-NF Compendial Methods of CaCO3 Tablets


Test USP-NF
Definition CaCO3 tablets contain NLT 90.0% and NMT 110.0% of the
labeled amount of CaCO3. For tablets labeled for any indication
other than, or in addition to, antacid use, the tablets contain NLT
90.0% and NMT 115.0% of the labeled amount of CaCO3
Identification Ca h191i: The addition of 6 N acetic acid to the tablets produces
effervescence, and the resulting solution, after being boiled to
expel CO2 and neutralized with 6 N ammonium hydroxide,
meets the requirements
Assay Sample solution: Finely powder NLT 20 tablets. Transfer a portion
of the powder, equivalent to 200 mg of CaCO3, to a suitable
crucible. Ignite to constant weight. Cool the crucible, add 10 mL
of water, and dissolve the residue by adding sufficient 3 N HCl,
dropwise, to achieve complete solution
Blank: 150 mL of water and 15 mL of 1 N NaOH
Titrimetric system (see Titrimetry h541i)
Mode: Direct titration
Titrant: 0.05 M EDTA VS
Indicator: 300 mg of hydroxy naphthol blue
Endpoint detection: Visual, change to distinct blue
Analysis: Transfer the sample solution completely to a suitable
container and dilute with water to 150 mL. Add 15 mL of
1 N NaOH and 300 mg of hydroxy naphthol blue. Titrate
with the titrant
Calculation: Calculate the percentage of CaCO3 in the sample
taken:
Result ¼ [(VS  VB)  M  F  100]/W. VS ¼ volume of the
titrant consumed by the sample solution (mL). VB ¼ volume
of the titrant consumed by the blank (mL). M ¼ titrant molarity
(mmol/mL). F ¼ equivalency factor, 100.09 mg/mmol.
W ¼ weight of CaCO3 taken (mg)
Dissolution [Note: For tablets labeled for any indication other than, or
h711i in addition to, antacid use]
Medium: 0.1 N HCl; 900 mL, Apparatus 2: 75 rpm, time: 30 min
Lanthanum chloride solution: 50 mg/mL of lanthanum chloride
in 0.1 N HCl
Standard stock solution: 100 μg/mL of Ca in 0.1 N HCl
Standard solutions: Into separate 100-mL volumetric flasks
containing 10.0 mL of lanthanum chloride solution, pipet 3-, 4-,
5-, and 6-mL portions of standard stock solution and dilute each
with 0.1 N HCl to volume to obtain solutions with Ca
concentrations of 3, 4, 5, and 6 μg/mL, respectively
Continued
86 M.M.H. Al Omari et al.

Table 13 The Summary of the USP-NF Compendial Methods of CaCO3 Tablets—cont'd


Test USP-NF
Sample solution: Filter a portion of the solution under test. Pipet a
volume of the filtrate, estimated to contain 1 mg of Ca, into a
250-mL volumetric flask. Add 25.0 mL of lanthanum chloride
solution and dilute with 0.1 N HCl to volume
Instrumental conditions: (See Spectrophotometry and Light
Scattering h851i)
– Mode: Atomic absorption spectrophotometry
– Analytical wavelength: 422.8 nm
– Lamp: Ca hollow cathode
– Flame: Air-acetylene
– Blank: Lanthanum chloride solution and 0.1 N HCl (1:9)
– Samples: Standard solutions and sample solution
– Concomitantly determine the absorbances of the standard
solutions and the sample solution against the blank. Construct
a standard curve by plotting absorbances vs Ca concentrations
of the standard solutions, then from it obtain the
concentration, C (μg/mL) of Ca, of the sample solution
Calculation: Calculate the percentage of the labeled amount of
CaCO3 (CaCO3) dissolved:
Result ¼ (Mr/Ar)  (C  D  V/L)  100. Mr ¼ molecular
weight of CaCO3, 100.09. Ar ¼ atomic weight of Ca, 40.08.
C ¼ measured concentration of Ca in the sample solution
(mg/mL). D ¼ dilution factor for the sample solution.
V ¼ volume of medium, 900 mL. L ¼ label claim (mg/tablet)
Tolerances: NLT 75% (Q) of the labeled amount of CaCO3
(CaCO3) is dissolved
Acid- [For tablets labeled for antacid use]
neutralizing Analysis: Proceed as directed in the chapter h301i
capacity h301i Acceptance criteria: NLT 5 mequiv. of acid is consumed by the
minimum single dose recommended in the labeling, and NLT
the number of mequiv. calculated as follows:
Result ¼ (C  ANC)  F. C ¼ quantity of CaCO3 in the sample
(mg), based on the labeled amount. ANC ¼ theoretical
acid-neutralizing capacity of CaCO3, 0.02 mequiv./mg.
F ¼ acceptance factor for the lower limit of the required
acid-neutralizing capacity, 0.9
Uniformity Meets the requirements
of dosage units
h905i
Storage Preserve in well-closed containers
Calcium Carbonate 87

Table 14 The Summary of the BP Compendial Methods of Chewable CaCO3 Tablets


Test BP
Definition Chewable CaCO3 tablets contain NLT 95.0% and NMT 105.0%
of the stated amount of Ca. The tablets may be flavored. They
comply with the general requirements stated under tablets
Identification A. Ca: The powdered tablets yield reaction B characteristic
of Ca salts
B. The powdered tablets yield the reactions characteristic
of carbonates
Disintegration The requirement for disintegration does not apply to chewable
CaCO3 tablets
Assay Weigh and powder 20 tablets. To a quantity of the powder
containing the equivalent of 0.25 g of Ca, add 50 mL of water
and 5 mL of HCl. Heat the dispersion gently to boiling and
continue to boil for about 2 min. Allow to cool, add sufficient water
to produce 250 mL, and filter, if necessary. To 50 mL of this
solution add 50 mL of 0.05 M EDTA VS. Neutralize the solution
using 2 N NaOH and add 10 mL of ammonia buffer pH 10.9 and
50 mL of water. Titrate the excess of EDTA with 0.05 M zinc
chloride VS using mordant black 11 solution as indicator. 1 mL
of 0.05 M EDTA is equivalent to 2.004 mg of Ca
Storage Chewable CaCO3 tablets should be protected from moisture

The analytical methods reported for Ca and carbonate ions, summarized


in the following sections, are not necessary used for CaCO3, but they are
general methods used for measuring Ca and carbonate individually. It is
worth mentioning that these methods may require some verification prior
to their use for analyses of CaCO3 (eg, sample treatment, using suitable sol-
vents, pH adjustment, and changes in method parameters).

4.2 Titrimetric Methods


4.2.1 Aqueous Acid–Base
About 500 mg of CaCO3, accurately weighed, is dissolved in exactly 50 mL
of 0.5 N HCl VS and gently swirled. The sample was heated gently to boil
for exactly 5 min to remove the H2CO3. The sample was then removed
from the heat and allowed to cool. Then, about two to three drops of phe-
nolphthalein indicator solution and 75 mL of water were added and swirled.
Then, the exact amount of CaCO3 was calculated using back titration with
0.5 N NaOH VS. Each milliliter of 0.5 N HCl is equivalent to 25.02 mg of
CaCO3 [273].
88 M.M.H. Al Omari et al.

Table 15 The Summary of the USP-NF Compendial Methods of CaCO3 Oral


Suspension
Test USP-NF
Definition CaCO3 oral suspension contains NLT 90.0% and NMT 110.0%
of the labeled amount of CaCO3
Identification Ca h191i: The addition of acetic acid to it produces effervescence
(presence of carbonate). The resulting solution, after boiling,
meets the requirements
Assay Sample solution: Transfer a portion of oral suspension, equivalent
to 1 g of CaCO3, previously well shaken in its original container,
to a beaker with the aid of 25 mL of water. Add 20 mL of 1 N
HCl. Heat on a steam bath for 30 min. Allow to cool, and transfer
with the aid of water to a 100-mL volumetric flask. Dilute with
water to volume. Mix and filter
Blank: 100 mL of water, 15 mL of 1 N NaOH, and 5 mL of
triethanolamine
Titrimetric system (see Titrimetry h541i)
– Mode: Direct titration
– Titrant: 0.05 M EDTA VS
– Indicator: 100 mg of hydroxy naphthol blue
– Endpoint detection: Visual, change to distinct blue
Analysis: Transfer 20.0 mL of the sample solution to a suitable
container. Dilute with water to 100 mL. Add 15 mL of 1 N
NaOH, 5 mL of triethanolamine, and 100 mg of hydroxy
naphthol blue. Titrate with the titrant
Calculation: Calculate the percentage of the labeled amount of
CaCO3 in the sample taken:
Result ¼ [(VS  VB)  M  F  100]/W. VS ¼ volume of the
titrant consumed by the sample solution (mL). VB ¼ volume of
the titrant consumed by the blank (mL). M ¼ titrant molarity
(mmol/mL). F ¼ equivalency factor, 100.09 mg/mmol.
W ¼ nominal amount of CaCO3 taken
Fluoride [Note: Prepare and store all solutions in plastic containers]
Solution A: 294 mg/mL of sodium citrate dihydrate in water
Standard stock solution: 1.1 mg/mL of USP sodium fluoride RS in
water
Standard solution: Combine 20.0 mL of the standard stock
solution with 50.0 mL of solution A, and dilute with water to
100.0 mL. [Note: Each milliliter of this solution contains 100 μg
of fluoride ion]
Sample solution: Transfer a portion of oral suspension, equivalent
to 2.0 g of CaCO3, to a beaker containing a plastic-coated
stirring bar. Add 20 mL of water and 4.0 mL of HCl. Stir until
Calcium Carbonate 89

Table 15 The Summary of the USP-NF Compendial Methods of CaCO3 Oral


Suspension—cont'd
Test USP-NF
dissolved. Add 50.0 mL of solution A and sufficient water to
make 100.0 mL.
Electrode system: Use a fluoride-specific ion—indicating an
electrode and a silver–silver chloride reference electrode
connected to a pH meter capable of measuring potentials with a
minimum reproducibility of 0.2 mV (see pH h791i)
Standard response line: Transfer 50.0 mL of solution A and 4.0 mL
of HCl to a beaker. Add water to make 100.0 mL. Add a
plastic-coated stirring bar, insert the electrodes into the solution,
and stir for 15 min. Read the potential (mV). Continue stirring,
and at 5-min intervals add 100, 100, 300, and 500 μL of the
standard solution, reading the potential 5 min after each addition.
Plot the logarithms of the cumulative fluoride ion concentrations
(0.1, 0.2, 0.5, and 1.0 μg/mL) vs potential (mV)
Analysis: Rinse and dry the electrodes, and insert them into
the sample solution. Stir for 5 min and read the potential (mV).
From the measured potential and the standard response line,
determine the concentration, C (μg/mL), of fluoride ion in the
sample solution.
Calculation: Calculate the content of fluoride in the sample taken:
Result ¼ (V  C)/W. V ¼ volume of the sample solution (mL).
C ¼ determined concentration of fluoride in the sample solution
(μg/mL). W ¼ nominal weight of CaCO3 taken (g)
Acceptance criteria: 50 μg/g, with respect to the labeled amount
of CaCO3
Arsenic h211i, Test preparation: Slowly dissolve a portion of oral suspension
Method I equivalent to 1.0 g of CaCO3 in 15 mL of HCl. Dilute with
water to 55 mL
Analysis: Proceed as directed in the chapter h211i, except omit
the addition of 20 mL of 7 N H2SO4 specified under Procedure
Acceptance criteria: NMT 3 μg/g, with respect to the labeled
amount of CaCO3
Lead h251i Test preparation: Mix a portion of oral suspension equivalent
to 1.0 g of CaCO3 in 5 mL of water
Analysis: To the test preparation slowly add 8 mL of 3 N HCl.
Evaporate on a steam bath to dryness, and dissolve the residue
in 5 mL of water
Acceptance criteria: NMT 3 μg/g, with respect to the labeled
amount of CaCO3
Continued
90 M.M.H. Al Omari et al.

Table 15 The Summary of the USP-NF Compendial Methods of CaCO3 Oral


Suspension—cont'd
Test USP-NF
Heavy metal Test preparation: Mix a portion of oral suspension equivalent
h231i to 1.0 g of CaCO3 with 5 mL of water. Slowly add 8 mL of 3 N
HCl, and evaporate on a steam bath to dryness. Dissolve the
residue in 20 mL of water. Filter and add water to the filtrate
to make 25 mL.
Acceptance criteria: NMT 20 μg/g, with respect to the labeled
amount of CaCO3
Microbial The total aerobic microbial count is NMT 102 cfu/mL. It meets
enumeration the requirements of the tests for the absence of Escherichia coli
tests h61i and and Pseudomonas aeruginosa
tests for specified
microorganisms
h62i
pH 7.5–8.7 h791i
Storage Preserve in tight containers, and avoid freezing

Previously, back-titration technique has been used for the analysis of Ca


in the presence of strontium in blood serum [274], Mg, phosphate, and sul-
fate in urine [275]. Pretreatment of the samples was done by precipitating Ca
as the oxalate, followed by converting to the carbonate or oxide by heating.
The content of the later is then determined by back titration using methyl
red as indicator. In the presence of relatively large amounts of Mg, calcium
oxalates are isolated by double precipitation instead of a single precipitation
to reduce the interference [275].
Bundy and Bremner described a simple titration method of determining
inorganic carbon in soils [276]. The sample is treated with 2 N HCl at room
temperature for 16–24 h in a stoppered bottle containing 2 N KOH in a
small beaker, and the CO2 released from carbonates is determined by titra-
tion of the KOH solution with standard HCl. El Mahi et al. reported that the
acid neutralization method suffers from the reaction of the acid with soil
constituent other than carbonates and the consumption of protons by the
exchange complex. The latter error was corrected by assuming that protons
occupied the entire exchange complex [277,278]. The values of carbonate
equivalent estimated by acid neutralization were corrected for cation
exchange capacity (CEC) as
CaCO3 equivalent ¼ acid neutralization % CaCO3  0:05 CEC
Calcium Carbonate 91

Table 16 The Summary of the USP-NF Compendial Methods of CaCO3


Lozenges
Test USP-NF
Definition CaCO3 lozenges contain NLT 90.0% and NMT 110.0% of the
labeled amount of CaCO3
Identification Ca h191i: The addition of 6 N HCl to a lozenge produces
effervescence, and the resulting solution, after being boiled to
expel CO2 and then neutralized with 6 N ammonium
hydroxide, meets the requirements of the tests
Assay [Note: The standard solutions and the sample solution may be
modified, if necessary, to obtain solutions of suitable
concentrations adaptable to the linear or working range of the
instrument]
Lanthanum chloride solution: Transfer 10 g of potassium chloride
and 20 g of lanthanum chloride to a 2000-mL volumetric flask.
Add 1000 mL of water and 40 mL of HCl, mix, and allow to
cool. Dilute with water to volume
Standard stock solution: Transfer 250 mg of chelometric standard
CaCO3, previously dried at 110°C for 2 h and then cooled in
a desiccator, to a 500-mL volumetric flask. Add 100 mL of
water and 12 mL of 1 N HCl, swirl to dissolve the CaCO3, and
allow to cool. Dilute with water to volume. This stock
solution contains about 500 μg/mL of CaCO3
Standard solutions: To three separate 100-mL volumetric flasks
add 2.0, 3.0, and 4.0 mL of the standard stock solution, and dilute
each with lanthanum chloride solution to volume. These
standard solutions contain 10, 15, and 20 μg/mL of CaCO3,
respectively
Sample stock solution: Transfer the equivalent to 3000 mg of
CaCO3, from powdered lozenges, to a 1000-mL volumetric
flask. Add 100 mL of 1 N HCl and 300 mL of water, and sonicate
to dissolve the powder. Dilute with water to volume
Sample solution: Transfer 5.0 mL of sample stock solution to a
1000-mL volumetric flask, and dilute with lanthanum chloride
solution to volume
Instrumental conditions: (See Spectrophotometry and Light
Scattering h851i) Mode: Atomic absorption spectrophotometry
– Lamp: Ca hollow cathode, Flame: Nitrous oxide-acetylene,
Analytical wavelength: Ca emission line at 422.7 nm
Blank: Lanthanum chloride solution
– Samples: Standard solutions, sample solution, and blank
Continued
92 M.M.H. Al Omari et al.

Table 16 The Summary of the USP-NF Compendial Methods of CaCO3


Lozenges—cont'd
Test USP-NF
– Plot the absorbances of the standard solutions vs their
concentrations of CaCO3 (μg/mL), by drawing a straight line
best fitting the three plotted points. From the graph determine
the concentration, C (μg/mL), of CaCO3 in the sample
solution.
Calculation: Calculate the percentage of label claim of CaCO3 in
the portion of lozenges taken:
Result ¼ (C/CU)  100. C and CU ¼ measured and nominal
concentrations of CaCO3 in the sample solution (μg/mL)
Sodium Standard stock solution: Transfer 2.542 g of sodium chloride,
(If so labeled) previously dried at 105°C for 2 h, to a 1000-mL volumetric flask.
Dissolve in and dilute with water to volume. Transfer 10.0 mL
of this solution to a 100-mL volumetric flask, and dilute with
water to volume
Standard solutions: To three separate 100-mL volumetric flasks,
add 1.0, 3.0, and 5.0 mL of the standard stock solution, and dilute
each with water to volume. These standard solutions contain 1.0,
3.0, and 5.0 μg/mL of sodium, respectively
Sample stock solution: Prepare as directed in the Assay. Pass a
portion of it, if necessary, through a filter of 0.5 μm or finer
pore size, and use the clear solution
Sample solution: Transfer 10.0 mL of the sample stock solution
to a 25-mL volumetric flask, and dilute with water to volume
Instrumental conditions: (See Spectrophotometry and Light
Scattering h851i)
– Mode: Atomic absorption spectrophotometry, Lamp: Sodium
hollow cathode, Flame: Air-acetylene, Analytical wavelength:
Sodium emission line at 589.6 nm, Blank: Water
– Samples: Standard solutions, sample solution, and blank
– Plot the absorbances of the standard solutions vs their contents
of sodium (μg/mL) by drawing a straight line best fitting the
three plotted points. From the graph determine the quantity,
C (μg), of sodium in each milliliter of the sample solution
Calculation: Calculate the percentage of label claim of sodium in
the portion of lozenges taken:
Result ¼ (C/CU)  100. C ¼ measured concentration of sodium
in the sample solution (μg/mL), as calculated earlier.
CU ¼ nominal concentration of sodium in the sample solution
(μg/mL)
Acceptance criteria: NMT 115.0% of the labeled amount
Calcium Carbonate 93

Table 16 The Summary of the USP-NF Compendial Methods of CaCO3


Lozenges—cont'd
Test USP-NF
Uniformity Meet the requirements
of dosage units
h905i
Acid- Analysis: The acid consumed by the minimum single dose
neutralizing recommended in the labeling is NLT 5 mequiv. of acid and NLT
capacity h301i the number of mequiv. calculated by: Result ¼ (FC  C)  0.9.
FC ¼ theoretical acid-neutralizing capacity of CaCO3,
0.02 mequiv. C ¼ quantity of CaCO3 in the sample tested (mg),
based on the labeled quantity
Storage Preserve in well-closed containers

Maulood et al. used back titration for CaCO3 determination in soil sam-
ples using 0.5 N HCl to dissolve the samples, followed by back titration with
0.2 N NaOH [279]. The results were found to be comparable with those
obtained using calcimetric method.

4.2.2 Complexometry
Ethylenediaminetetraacetic acid (EDTA) is used as a complexing agent to
determine CaCO3 in its pure form [1,2,216] or in different dosage forms
including tablets [262], chewable tablets [263], and oral suspension [265].
Full detailed procedures are mentioned in Tables 12–15.
Previously, micro- and macrodeterminations of serum Ca by direct titra-
tion with EDTA with ammonium purpurate as the indicator [280,281]. The
end point is determined by changing the indicator color to purple [280] or
graphically from spectrophotometric readings at 620 nm taken during the
titration [281]. Also Beale and Bostrom used a microtitration of Ca in the
presence of Mg in serum and urine, with EDTA as titrant and Corinth
Ca (Plasmocorinth B) as indicator [282].
Garvey et al. analyzed Ca in dietary supplements using complexometric
titration with EDTA and then, following ion exchange of the Ca ion present
for hydronium ion, by acid–base titration with NaOH [283]. Also statistical
comparison of both methods was adopted.
94 M.M.H. Al Omari et al.

4.2.3 Oxidometry
In direct oxidometric determination of Ca in solution containing also Mg,
phosphates and small amounts of Fe, or in the ash of food or feces has been
reported [284]. The method is based upon the formation of calcium oxalate,
followed by immediate titration of oxalate in acid media with standard
K2MnO4. The microdetermination of Ca in whole blood, plasma, serum,
urine, and stools was also performed by direct precipitation of calcium oxa-
late and then titration with 0.01 N K2MnO4 [285,286]. Furthermore, an
improvement in the method by using new washing solution for calcium
oxalate precipitation of 2% NH3 in equal parts of alcohol, ether, and water
is introduced to prevent flotation and permit washing of the precipitate
without appreciable loss of Ca [287].

4.2.4 Amperometry
Indirect amperometric titration of Ca using dropping mercury electrode has
been reported [288]. The method is based upon the precipitation of Ca as
picrolonate and followed by back titration of excess picrolonate with meth-
ylene blue.

4.2.5 Spectrophotometry
Sweetser and Bricker were the first to use spectrophotometric measurements
to determine the end points of EDTA titrations, which they applied to Ca
and Mg in two stages of analysis [289].

4.2.6 Coulometry
Caughey and Barcelona used this technique for the determination of total
inorganic carbon (TIC) using 2 N HClO4 with the UIC 5130/5011 mod-
ules coulometer [290].
Coulometry is still used, more than 25 years later, by the Integrated
Ocean Drilling Program for shipboard analysis of CaCO3 concentration
[291]. M€ orth and Backman described a practical approach for acquiring
accurate measurements of the carbonate content in sediments by using an
UIC Inc. coulometer [292]. The coulometer readings are absolute; ie, the
total amount of available carbon is converted by HCl to CO2 gas and the
output reading (counts) of the instrument is in μg C. In this work, they
investigated the effect of sample weight, sampling tool, preparation proce-
dure, and use of a multipoint regression analysis on the precision of the
method.
Calcium Carbonate 95

Dabke et al. used the coulometric back-titration method for the deter-
mination of CaCO3 in antacid tablets [293]. The sample was dissolved in
excess acid and the remaining acid was back titrated against the coulomet-
rically generated OH ions. The amount of acid neutralized by CaCO3 was
determined from the difference in the anodic and cathodic charge.

4.3 Gravimetric Method


Determination of Ca in solution containing also Mg, phosphates, and small
amounts of Fe, or in the ash of food or feces, has been reported [284]. The
method is based upon the formation of calcium oxalate, followed by burning
in a platinum crucible to CaO and brought to constant weight by heating in
a blast lamp.
Another direct gravimetric analysis of Ca has been also reported by
complete precipitation at pH 3 as calcium oxalate at pH 3, followed by
simple drying of the precipitate at 105°C and weighing [294]. Another
approach for quantitative determination of CaCO3 is based on the reac-
tion of HCl with carbonate and then the loss of CO2 is measured gravimet-
rically [295].

4.4 Spectroscopic Methods


4.4.1 UV/VIS Spectrophotometry
Nangare described direct UV/VIS method for simultaneous determination
of CaCO3 and aspirin in tablet dosage form [248]. The determination is
based on the use of simultaneous equations and Q-absorbance ratio method
by using 240 and 230 nm as absorbance maxima for CaCO3 and aspirin,
respectively, and 290.5 nm (isoabsorptive point). A 0.1 M NaOH was used
as solvent. Linearity was observed in the concentration range of 2–24 μg/mL
for CaCO3 and 5–25 μg/mL for aspirin.
Direct spectrophotometric method for the measurement of CaCO3 sat-
uration states in seawater has been reported [296,297]. Easley et al. used the
measurements of pH and carbonate ion concentrations in the seawater to
determine CaCO3 saturation states. The spectrophotometric method is
based upon the measurement of the ratio of absorbances at 250 and
234 nm using Pb(II) as a complexing agent [297].

4.4.2 Colorimetry
An indirect colorimetric method for measuring blood Ca has been devel-
oped, which is based upon the precipitation of Ca as phosphate, and the
determination of the latter by the MoO3 colorimetric procedure [298].
96 M.M.H. Al Omari et al.

Further improvement of the proposed method, microlevel determination,


and minimizing the interference of other cations such as Mg were carried
out [299].
A colorimetric method using N-hydroxy-naphthalene-1,8-dicarboxylic
acid imide in the presence of ethylenediaminetetraacetic acid has been
developed for convenient and rapid estimation of 5–15 μg Ca in 0.1 mL
of blood serum at wavelength of 338 nm [300]. Tartaric acid, low concen-
trations of citric acid, phosphate, Mg, zinc, and ferrous or ferric ions will not
interfere in the determinations of Ca. However, higher concentrations of
citric acid as well as the presence of Mn, Sr, and Ba must be avoided.
Radin and Gramza described a colorimetric method using Eriochrome
Blue SE to measure the concentration of Ca in serum and urine [301]. The
study indicated that at pH value above 13.7, Ca will complex and cause a
change of dye absorbance, while Mg does not complex with the dye.
Prokopov described a direct colorimetric method for determination of
Ca in the range of 2 mg to 0.002 mg/mL by using sodium rhodizonate as
reagent. The proposed procedure is not laborious and easily eliminates all
interfering ions [302]. A modified flow-through colorimeter for the deter-
mination of Ca, Mg, and phosphate in a pmol level has been described by
Adkinson and Evans [303]. Methylthymol and 8-quinolinol, which is the
Mg-complexing agent, polylectrolite, and a monoethanolamine–sodium
sulfite buffer were used in the analysis of Ca.
Blanco et al. have described a simultaneous flow injection spectrophoto-
metric method for Ca and Mg with Arsenazo III based on the use of diode-
array detector and merging zones [304]. Quantitation is based on the normal
absorbance and first-derivative absorbance spectra. The method is applied to
0.2–1.5 μg/mL for Ca and 0.1–1.0 μg/mL for Mg. Another simultaneous
determination of Ca and Mg in different types of water by colorimetric
method has been reported [305]. The determination is based on the formation
or their complexes with 4-(2-pyridylazo)resorcinol and measuring the absor-
bances over the wavelength range 470–650 nm (λmax ¼ 490 and 502 nm for
Mg and Ca, respectively). To minimize the overlapping, the absorbance band
yielded by the mixture was resolved by applying a computer multilinear
regression program to the corrected, standardized spectrum of each metal
ion as standard. The proposed method is straightforward and rapid and
provides a linear determination range of 0.10–4.0 μg/mL for Ca and 0.15–
2.5 μg/mL for Mg. Shanahan and Kapustin measured the level of Ca in blood
samples by using o-cresolphthalein as complexing agent. The Ca concentra-
tion is quantified by measuring the absorbance at 450 nm [306].
Calcium Carbonate 97

Colorimetric methods for determination of Ca and Mg in mineral water


[307] and pharmaceuticals [308] were proposed. The determination in both
methods is based on the blue color developed by the reaction of Ca and Mg
with methylthymol blue (MTB) at pH 11. The first proposed method used
the multivariate partial least-squares regression and adapted as a portable
(static mode) or automatic (flow injection) method [307]. The JOB method
was used in the second method to determine the ratio combination of com-
plex ions Ca-MTB and Mg-MTB [308].

4.4.3 Atomic Absorption Spectrophotometry


In 1950, Severinghaus and Ferrebee determined Ca in serum, urine, and
other fluids by flame photometry [309]. In the case of serum, proteins are
precipitated in 4% trichloroacetic acid, and the supernatant solution, effec-
tively a 1:10 dilution of the serum electrolytes, is nebulized into a constant
flame. The intensity of the flame light at 556 nm is compared with that pro-
duced by standard solutions containing Ca.
Welch et al. study the effect of phosphate on the determination of Ca in
urine with lanthanum–air/acetylene and potassium–nitrous oxide/acetylene
methods [310]. The 20 g/L La-air/acetylene method was the most nearly
accurate, followed by the 2 g/L K-nitrous oxide/acetylene method, 10 g/
L La-air/acetylene, and finally 5 g/L La-air/acetylene.
The determination of Ca in cereal with flame atomic absorption spec-
troscopy has been reported [311]. A cereal sample is crushed and dry-ashed
at 600°C in a silica crucible. The residue is treated with 5 mL of 6 M HCl,
diluted to volume, and aliquots taken and prepared for analysis using the
two-increment standard addition approach. The prepared solutions are aspi-
rated into a nitrous oxide–acetylene flame and the absorbance measurements
are made using the resonance line of Ca at λ ¼ 422.7 nm, 0.5-nm slit width,
and 5.0-mA lamp current. The results for the determination of Ca in two
brands of cereal showed good precision with the majority (72%) of the data
having RSD  5%.
Furthermore, atomic absorption spectroscopy was used to measure the
Ca content in analgesic tablets [312], in hydroethanolic extracts of propolis
[313], and in dissolution test for CaCO3 tablets [262], CaCO3 lozenges
[266], and CaCO3 gallstones [314].

4.4.4 Fluorometry
Lerga and O’Sullivan reported a fluorometric method for a simultaneous
combined determination for Ca and Mg (water hardness) using a
98 M.M.H. Al Omari et al.

double-labeled synthetic oligonucleotide as a fluorescent molecular aptamer


beacon [315]. The fluorescent emission of the beacon was measured
(λex. ¼ 494 nm; λem. ¼ 518 nm). Interference of different cations (eg, K)
was eliminated by increasing the temperature beyond the melting point
of the potassium-stabilized quadruplex. The detection limit of the aptamer
beacon is 0.04 mmol/L, with a dynamic linear range of 0–0.5 μM, and is
very reproducible, with an RSD ¼ 8%, n ¼ 3. An excellent correlation
was obtained when the performance of the proposed method compared
to that of the standard method of complexometric titration and atomic
absorption spectroscopy.

4.4.5 FTIR Spectroscopy


Analysis of ternary mixtures of CaCO3 forms (calcite, aragonite, and
vaterite) was quantitatively performed using the FTIR spectra of pure cal-
cite, aragonite, and vaterite powders with KBr [316]. The absorptivities, a,
of the absorption bands at 713 cm1 for calcite, 745 cm1 for vaterite, and
713 and 700 cm1 for aragonite were determined. Analysis of a known ter-
nary mixture of CaCO3 forms tested the validity of the method.
oke et al. used the same technique for the quantitative analysis method
B€
for mixtures of CaCO3, calcium sulfite hemihydrate (CaSO3 1/2H2O),
and gypsum (CaSO4 2H2O). The method involves the FTIR analysis of
powder mixtures of several compositions on KBr disc specimens. Inten-
sities of the resulting absorbance peaks for CaCO3, CaSO31/2H2O, and
CaSO42H2O at 1453, 980, and 1146 cm1, respectively, were used in
the analysis [317].
Recently, Changwen et al. applied the infrared photoacoustic spec-
troscopy as an alternative to conventional infrared reflectance spectroscopy
for rapidly estimating a wide array of soil properties [318]. Principal com-
ponent analysis, partial least-squares regression, and generalized regression
neural network (GRNN) models were used to calibrate and validate soil car-
bonate analysis. Significant relationships were observed between carbonate
content and FTIR–PAS spectral components, particularly in the range of
1000–2000 cm1.
Attenuated total reflectance–Fourier transform infrared spectroscopy
(ATR–FTIR) has been used to determine the content of CaCO3 and
styrene–butadiene (SB) latex in the coating layer of coated paper [319].
The GRNN model can be used to estimate the CaCO3 and SB latex con-
tents in coatings of coated papers. The maximum errors for CaCO3 and SB
latex were only 3.32% and 3.39%, respectively.
Calcium Carbonate 99

4.4.6 LA-ICP Mass Spectroscopy


A precise and accurate laser ablation inductively coupled plasma mass spec-
trometry (LA-ICP-MS) microanalysis of speleothems and biogenic analysis
of CaCO3 to improve the understanding of past climatic conditions has been
reported [320]. Isotopes for interference-free measurements at low (M/ΔM
300) and medium (M/ΔM 4000) mass resolution have been identified.
Analytical reproducibility (RSD) is a factor of 2 better using the 193 nm
laser than the 213 nm laser. The LA-ICP-MS method was applied for the
determination of trace element concentrations in calcite and aragonite layers
of a stalagmite and found large variations for Mg, Zn, Sr, and U. In ostracod
shells, the concentrations of some trace elements (eg, Sr and Ba) vary signif-
icantly, indicating the potential for paleoclimate research.

4.4.7 Raman Spectroscopy


Quantitative analysis by Raman spectroscopy has been mainly reported for
binary mixtures [236,321,322]. When three forms are present in the mix-
ture, treatment of the spectra becomes difficult due to overlapping bands.
Dandeu et al. investigated the possibility of using the Raman spectroscopy
for quantitative analysis of CaCO3 forms (calcite, aragonite, and vaterite) in
ternary mixtures. It was found that quantitative analysis is a difficult task
since there is a strong overlapping, where the strongest bands of CaCO3
forms at around 1000 cm1 overlap and the vibration modes around
700 cm1 are very weak, and particularly undetectable for vaterite. The
low frequencies region (50–400 cm1), which corresponds to the lattice
mode vibrations, was chosen for the quantitative analysis. The partial least
squares (PLS) method was used for mathematical treatment, which takes into
account the intensity of the whole spectral range, and not the intensity of a
specific wavelength [253]. Wang et al. used this technique to measure Mg
content in amorphous CaCO3 [256].

4.5 Electrochemical Methods


4.5.1 Ion-Selective Electrode
Deoxy-3,12-bis(TFAB)CA-based electrode was used as a carbonate-selec-
tive electrode to measure CO2 in seawater [323]. The method was evaluated
and compared with Severinghaus-type CO2 gas sensor and the traditional
potentiometric titration methods. The results showed that the carbonate-
selective electrode provides accurate measurement for CO2 comparable
to that obtainable with the other two methods. The proposed method does
not require any sample pretreatment and extra reagents other than the
100 M.M.H. Al Omari et al.

standard calibration solutions, while providing the measured results directly


and immediately.
Ca ion-selective electrode method was used to study Ca–soy protein
interactions [324]; to determine Ca-binding constants of caseins, pho-
sphoserine, citrate and pyrophosphate [325], and phytase-aided release of
bound Ca in soymilk [326]; and to study the complexation of Ca ions with
[(UO2)(CO3)3]4 [327] and the transport of Ca ions across the hydrogel
membrane [328]. Kabagambe et al. described an ultrasensitive ion-selective
electrode of subnanomolar level measurements based on stripping
voltammetry [329]. An acrylic acid-grafted PVC [330], polyindole-cam-
phorsulfonic acid composite [331], PVC containing attapulgite/
thioacetamide as ionophore [332], graphene as ionophore [333], schiff base
[334], lactate enzyme [335], plasticized PVC incorporating ester as an ion-
ophore [336], vinyl acetic acid-grafted PVC [337], and PVC with and with-
out ETH129 as Ca ionophore [338,339]-based membrane ion-selective
electrodes containing dioctyl phthalate (plasticizer) and sodium tetraphenyl
borate (anion excluder) were used as an indicator electrode in potentiomet-
ric titration of Ca with EDTA [340] and determination of Ca in milk [341]
and water samples. Stoodley et al. used Ca ion-selective electrode for field
Ca measurement in seawater and compared the other techniques such as
potentiometric and colorimetric titration with EDTA [342]. Kuwamoto
et al. proposed a system to perform pretreatment before measuring Ca ion
in a sample solution with a Ca ion-selective electrode by an acid and
base-adding mechanism [343].

4.5.2 Polarography
Cohn and Kolthoff used picrolonic acid to precipitate Ca as calcium
picrolonate and then the excess of the acid is determined polarographically
without filtering the solutions. The method yields good result in the pres-
ence of relatively large amounts of Na, K, NH3, Mg, sulfate, and phosphate
in the solutions [344]. Another indirect polarographic determination of
Ca by chloranilic acid has been also reported [345]. Ca was determined
by precipitating as chloranilate complex, followed by measuring the polar-
ographic diffusion current of the residual chloranilic acid without need of
separation of the solid complex. The interference of different cations as a
function of their concentration has been investigated. Fleet et al. also
reported indirect polarographic method based on the decrease in the height
of the anodic polarographic waves of EDTA and ethylene glycol-bis-(β-
aminoethylether)-NNN 0 N 0 -tetraacetic acid [346]. Different complexing
Calcium Carbonate 101

agents were investigated in a DC polarographic determination of Ca in


aqueous solutions [347]. A dropping mercury electrode was applied to get
peak-shaped waves for Ca in tetrabutylammonium hydroxide supporting
electrolyte. The square root of the peak height is directly proportional to
the Ca concentration over the range 0.1–1.0  103 M. In the presence of
the sequestrants EDTA, nitrilotriacetic acid (NTA), and tripolyphosphate
(TP), indications of distinct Ca complexes were seen by noting the positions
of slope changes in plots of peak height vs mole ratio of Ca to sequestrant. The
species found were CaEDTA, Ca(3)(NTA)(2), Ca(2)(TP)(3), and Ca(3)TP.

4.5.3 Voltammetry
In direct measurement of Ca by differential pulse stripping voltammetry has
been achieved by using hanging electrolyte drop electrode [348]. The
method is based on the transfer of Ca ions from water to nitrobenzene facil-
itated by the complex formation with the macrocyclic polyether
diamide,7,19-dibenzyl-2,3-dimethyl-7,19-diazo-1,4,10,13,16-pentaoxacy-
cloheneicosane-6,20-dione. Wang et al. described a sensitive adsorptive
stripping procedure for trace measurement Ca using their chelates with
the dihydroxyazo dye solochrome violet RS [349].
Kim used a water-soluble calix[4]arene-diquinone-diacid (CDA) to
quantify Ca in aqueous solution by forming a complex with Ca ions
[350]. Fig. 26 shows the redox changes of CDA as a function of Ca concen-
tration in aqueous buffered solution of pH 7.4.

Potential/V vs Ag/AgCl
–0.6 –0.4 –0.2 0.0 0.2 0.4 0.6

2 µA

Increase of [Ca2+]

Figure 26 Squarewave voltammograms of calix[4]arene-diquinone-diacid as a function


of Ca concentration (0.01–1.5 mM).
102 M.M.H. Al Omari et al.

Furthermore, Almeida et al. used a squarewave voltammetry and a glassy


carbon electrode in a solution containing EDTA to determine Ca ions in real
biodiesel samples [351].

4.6 Calcimetric Method


This method depends upon the conversion of carbonate ions into CO2 gas
by adding diluted HCl to the sample and the pressure of the released CO2
was measured by manometer [352]. Dreimanis described a quantitative
determination of calcite and dolomite by measuring the content of the
CO2 evolved in the Chittick gasometric apparatus [353].
The analysis of CO2 by pressure-calcimetric method is also described by
Loeppert and Suarez [354]. It is a direct, accurate, and inexpensive method,
but the complexity of the pressure calcimeter apparatus makes large sample
runs impractical [355]. Wagner et al. described a modified volumetric analysis
system of the pressure-calcimeter apparatus by utilizing a pressure transducer,
which is monitored by a data acquisition card connected to a personal com-
puter [356]. Furthermore, modifications of the pressure-calcimetric method
by using Wheaton serum bottles (20 and 100 mL) sealed with butyl rubber
stoppers and aluminum tear-off seals as the reaction vessel and a pressure
transducer monitored by a digital voltmeter [355]. This method was used
for CaCO3 determination in soil samples [279]. The results were found
to be comparable with those obtained using back-titration method.

4.7 Chromatographic Methods


4.7.1 High-Performance Liquid Chromatography
A sensitive and selective high-performance liquid chromatography (HPLC)
method for the separation of Mg and Ca in complex saline matrices has been
reported [357]. The mobile phase contains the selective metallochromic
chelating ligand, o-cresolphthalein complexone, and the separation is done
at a reversed-phase porous graphitic carbon column using a spectrophoto-
metric detector at 575 nm. Detection limits of 0.05 mg/L for Mg and
0.10 mg/L for Ca were obtained in samples containing in excess of
2300 mg/L of Na, without interference.

4.7.2 Ion-Exchange Chromatography


Fritz and Waki described an anion exchange chromatographic separation
for Ca and Mg using 0.5 M HNO3 in 90% of water-miscible isopropyl
alcohol as the eluent. The separation was performed using Amberlyst
XN-1002 resin [358]. Moreover, Fritz and Story proposed a forced-flow
Calcium Carbonate 103

chromatography on partially sulfonated macroreticular resin beads to rapid


separate several metal ions using strong acid of moderate concentration as
the eluent [359]. Separation of Ca and Mg from each other and from
several other cations by ion-exchange chromatography was proposed
also by Argiiello and Fntz [360]. They used a sulfonated macroporous resin
of 1.8–2.0 mequiv./g capacity and 1 M NH4Cl or 0.03 M ethylenediam-
monium chloride as the eluent. A sensitive continuous metal ion detection
system based on the use of 2-(pyridylazo)resorcinol-Zn-EDTA was devel-
oped and employed in a liquid chromatographic separation [361].
Trace enrichment and HPLC have been examined for the determination
of metal ions in the low pg/mL range. The metal ions are enriched on a short
bonded-phase ion exchanger and then separated on a 13 μm styrene
divinylbenzene resin [362,363]. The use of ion-exchange chromatography
was also used to determine Ca in dietary supplement tablets [364].

4.7.3 Gas Chromatography


Amundson et al. reported a rapid and sensitive method of soil carbonate
analysis, utilizing gas chromatography [365]. The results of analysis by gas
chromatography and the Chittick methods are comparable (r ¼ 0.96,
slope ¼ 1.11). The proposed method was the most sensitive and had the
lowest possible detection limit (0.008 mg CaCO3). However, low and high
concentrations should be avoided to get accurate results.
A continuous-flow isotope ratio mass spectrometry (CF-IRMS) coupled
online with gas chromatography (GasBench II) sample preparation and with
multiloop injection procedures was applied for the analysis of carbonates
(calcite and aragonite). The method showed precise and accurate measure-
ments at high sample throughput [366]. Ishimura et al. developed a CF-
IRMS system to determine stable isotopic compositions (δ13C and δ18O)
of submicrogram quantities of CaCO3 for the purpose of analyzing individ-
ual foraminiferal shells [367]. The system consists of a microvolume CaCO3
decomposition tube, stainless steel CO2 purification vacuum line with a
quantity-regulating unit, helium-purged CO2 purification line, gas chro-
matograph, and a CF-IRMS system. Fiebig et al. described a method for
the precise measurement of carbonate samples in the range 10–30 μg for
the GasBench II [368]. However, their method requires a modification of
the hardware and the use of liquid nitrogen, which increases the costs
and the complexity of the measurements. Skrzypek and Paul used the same
IRMS technique coupled online with gas chromatography (GasBench II)
and an elemental analyzer system to measure stable carbon isotopic
104 M.M.H. Al Omari et al.

composition (δ13C) of carbonates or carbonate-rich soils [369]. The δ13C


analyses of CaCO3 samples by using both techniques showed high precision.
However, the results suggested that the δ13C of pure CaCO3 samples can
also be analyzed using the elemental analysis technique. Technical mo-
dification of the conventional method for the δ13C and δ18O analysis of
10–30 μg carbonate samples was described by Velivetskaya et al. [370].
The method has been used successfully for the analyses of the oxygen and
carbon isotopic composition of the planktonic and benthic foraminifera
in detailed paleotemperature reconstructions of the Okhotsk Sea. Also
the method has been used to determine the content and isotopic composi-
tions of minor amounts of carbonate in silicate rocks [371]. Further technical
improvements have been achieved in carbonate samples analysis, as small as
20 μg can be analyzed routinely, using a GasBench II continuous-flow
IRMS setup, with standard deviations smaller than 0.07% for both δ18O
and δ13C [372].

5. STABILITY
5.1 Crystal Phase Transformation
Calcite, stable anhydrous form of CaCO3, undergoes a series of structural
transitions toward denser of calcite II–IV phases with increasing pressure
[108,110,111]. In addition to the aforementioned calcite forms, there exists
a denser form calcite VI that can be formed using shock compression exper-
iments [112]. At even higher pressures (>100 kbar), calcite is known to
undergo yet another phase transition, known as calcite IV [114–116].
However, monohydrocalcite, the hydrate form of calcite, is not stable
thermodynamically and will transform into other crystal phases upon the loss
of crystalline water (eg, calcite and aragonite) [78,240]. In addition, low con-
tent of Mg in aqueous solution will lead to its transformation to aragonite
over 25 days at ambient temperatures [373,374].
Aragonite, metastable anhydrous form of CaCO3, will remain unaltered
for tens of millions of years in dry conditions at temperatures below 400°C.
If water is present, however, aragonite will convert to calcite in a matter of
months due to its greater solubility in water. The difference in solubility is
one of the reasons why aragonite is not as common in geological beds and is
rarely found outside of organically controlled systems [225]. At standard
temperature and pressure, aragonite is thermodynamically unstable and
tends to alter to calcite [375]. At high pressure, it becomes the stable phase
[117]. A postaragonite phase in CaCO3 at a pressure of 40 GPa and a number
Calcium Carbonate 105

of energetically competitive structures (stable phase I and metastable phases


II–IV) were identified [118]. Above 137 GPa, phase I with a pyroxene-type
structure with chains of CO4 4 tetrahedra becomes more stable than
postaragonite.
Vaterite is also a metastable anhydrous form of CaCO3 at ambient con-
ditions, and once it is exposed to water, it converts to aragonite or calcite
[376]. It is a rare mineral in geologic settings, though it may be an important
precursor in several carbonate-forming processes [238].
The amorphous form of CaCO3 is unstable solid phase, which undergoes
a rapid transformation to more stable anhydrous forms, while the two
hydrated forms monohydrocalcite and ikaite can be kept unchanged for a
few days at temperatures below 0°C before they undergo transformation
into calcite. As a result, preparation of ikaite was carried out at temperatures
below 10°C [62]. Mg ions were noticed to further enhance the form trans-
formation of amorphous CaCO3 into aragonite [128]. Bentov et al.
improved the stability of amorphous CaCO3 by phosphate-rich organic
matrix proteins and by single phosphoamino acids [377]. Such stable form
showed an improvement in solubility and bioavailability in comparison with
the crystalline form [378,379].
Ikaite, hydrate form of CaCO3, is thermodynamically stable at moderate
pressures near the earth’s surface. It has been found in deep sea and conti-
nental shelf sediments, and in groundwater discharge sites in lakes, glacial
environments, coastal waters, and sea ice [380–383]. It decomposes rapidly
by losing most of its water content once removed from near-freezing water
[239]. Both amorphous and ikaite forms are metastable in the environment
and change easily to the more stable form calcite [223,375].

5.2 Solid-State Stability


CaCO3 decomposes upon heating (>650°C) to CaO and CO2. This endo-
thermic process is called calcination [384,385]:
CaCO3ðsÞ ! CaOðsÞ + CO2ðgÞ ΔH ¼ + 182:1kJ=mol
The reaction is favored by higher temperatures and will proceed only if
the partial pressure of CO2 in the gas above the solid surface is less than the
decomposition pressure of the CaCO3 [384]. Furthermore, evaluation of
the kinetics of calcination is complicated by: (1) CO2 atmosphere and its
concentration, which inhibits the reaction; (2) sample weight and particle
size, which may introduce both thermal and mass transfer limitations;
106 M.M.H. Al Omari et al.

(3) catalysis/inhibition by impurities; (4) the applying pressure and inert


atmosphere; (5) the use of isothermal or nonisothermal method; and (6)
the rate of temperature increase [384–390].
L’vov studied the mechanism and kinetics of CaCO3 decomposition and
showed that the effect of self-cooling of reactant is of primary importance in
the explanation of many controversial results obtained by different researchers
in investigations of the kinetics of carbonate decomposition [391].
Gabal et al. also studied the effect of different atmosphere (air, N2, and
N2–H2 mixture) on the thermal decomposition of CaCO3. It was found that
changing of the applied atmosphere affects the carbon content of the ash,
which results in different thermal decomposition behaviors [392]. Effect
of tartaric, succinic, and citric acids on the decomposition of CaCO3 has
been studied [393]. The decomposition temperature of CaCO3 is not
decreased, and at the same time, particle size distribution and morphology
of CaO are changed.
Rodriguez-Navarro et al. studied the mechanism of CaO nanocrystals
formation and their texture during the decomposition of calcite [394]. It
was found that the thermal decomposition of calcite is homogeneous and
topotactic in nature, and does not depend on the experimental conditions
(eg, CO2 pressure, crystal size, or type of energy used for the activation
of the reaction). Their findings may help establishing conditions to achieve
the best properties in terms of crystal size, surface area, porosity, and
reactivity. The proposed model may also help establishing crystallographic
constraints for possible relationships between reactant and product, in order
to interpret textural relationships found in natural samples (eg, Martian
meteorites).

5.3 Stability in Solution


CaCO3 has a very low solubility in water, but in saturated with CO2, its
solubility increases due to the formation of more soluble calcium bicarbon-
ate (Ca(HCO3)2). However, like all metal carbonates, CaCO3 reacts with
acidic solutions to produce CO2 gas [395].

5.4 Interaction with Complexing Agents


Interaction of some complexing agents such as EDTA, oxalate, phosphate,
picrolonic, rhodizonic, arsenazo, and resorcinol derivative with Ca is widely
used for analysis of pharmaceutical and biological samples. These studies are
fully discussed in Section 4.
Calcium Carbonate 107

6. USES, APPLICATIONS, AND PERTINENT HISTORY


CaCO3 is authorized as a food color in the European Union (EU)
under Directive 94/36/EC and is also authorized as an additive generally
permitted in foodstuffs under Directive 95/2/EC. It is also included in
Directive 2001/15/EC on substances that may be added for specific nutri-
tional purposes in foods for particular nutritional uses, and in Directive
2002/46/EC relating to food supplements, and it can be used in fortified
foods according to Regulation 1925/200626 on the addition of vitamins
and minerals and of certain other substances in food. CaCO3 has been eval-
uated by Joint FAO/WHO Expert Committee on Food Additives ( JECFA)
in 1965, when the Committee established an acceptable daily intake (ADI)
not limited. The EU Scientific Committee of Food (SCF) evaluated CaCO3
as part of a group of carbonates and assigned a group ADI not specified.
CaCO3 together with other carbonates has also been reviewed by
TemaNord, who concluded that there was no need for a reevaluation.
The SCF allocated a tolerable upper intake level (UL) for Ca of
2500 mg/person per day as a nutrient and also established a population ref-
erence intake of 700 mg Ca/day (range 400–1200 mg/day depending on
age and physiological status) [4].
CaCO3 is included in Commission Decision 2006/257, establishing an
inventory of ingredients in cosmetic products. In pharmaceuticals, CaCO3
is used as an excipient and as an active ingredient of antacids. It is also in-
cluded in Directive 91/41428 concerning the placing of plant products on
the market. CaCO3 has been registered under the Reach Regulation
1907/2006 [4].
CaCO3 is included in the Food and Drug Administration (FDA) list of
food additives that are generally recognized as safe (GRAS) for use in
nutrient and dietary supplements, and is also certified by the FDA for use
in amounts consistent with good manufacturing practice to color drugs gen-
erally [396].
CaCO3, both natural and precipitated, is widely used as a major filler in
paper, paint, adhesives and sealants, and polymers. Also CaCO3 meets the
pharmacopeia requirements as a therapeutic source in antacids, as Ca supple-
ments, and as a tableting excipient [397,398]. As a pharmaceutical excipient,
it is mainly used as diluents, coating agent, and wet binder in solid dosage
forms, as a base for medicinal and dental preparations, and as buffering
and dissolution aid in dispersible tablets, as well as food additive [9,398].
108 M.M.H. Al Omari et al.

CaCO3 is also used as a fire extinguisher foam filler, as an abrasive in


household cleaners, as a flux in welding rod coatings, as a diluent in agricul-
tural pesticide dusts, and as a dusting agent in mines, in the manufacture of
Portland cement, lime, glass, and metallurgical fluxes, as well as in flue gas
desulfurization processes and as a soil amendment [397].

7. PHARMACOLOGY
7.1 Pharmacokinetics
7.1.1 Absorption
Ca is endogenously occurring substance within the body. It is actively
absorbed into the body and its level is controlled by various Ca homeostasis
mechanisms [399]. After oral administration, 18–40% of Ca is absorbed from
the small intestine by active transport and passive diffusion. Active absorp-
tion of Ca is highly dependent on vitamin D, and vitamin D deficiency
decreases the absorption of Ca [399,400]. Absorption of Ca is dose depen-
dent, with fractional absorption being highest when at doses up to 500 mg.
Absorption of Ca is also dependent on pH (reduced in alkaline), body size,
estrogen status, vitamin D status, age, and genetic polymorphisms. The
absorption of Ca from CaCO3 is increased when taken with food [399,400].
Different Ca salts show different levels of absorption. For example,
calcium citrate is more bioavailable than CaCO3 [401–403]. Hanzlik et
al. showed that calcium formate is clearly superior to both CaCO3 and cal-
cium citrate in ability to deliver Ca to the blood stream after oral adminis-
tration [404].
Zhao et al. compared the Ca bioavailability from CaCO3-fortified
soymilk (CCSM) and tricalcium phosphate-fortified soymilk (TCPSM)
with cow’s milk in young healthy women using ICP-MS technique
[405]. They found that the fractional Ca absorption in CCSM did not differ
from that of cow’s milk, but both were higher than that of TCPSM.
Ayed and Thannoun studied the effect of phosphorus on the bioavail-
ability of Ca [406]. They concluded that CaCO3-based diet containing
0.19% Ca with 1.5:1 Ca to phosphorus ratio may give high Ca bioavailability
for growing rats which was considered as standard (control) diet for other
diet supplement. Kressel et al. showed that calcium lactate citrate and cal-
cium lactate malate may offer a very good choice for the fortification
of beverages to increase the daily Ca intake comparing with CaCO3 and
calcium gluconate [407]. The two former salts have higher water
solubility with a satisfactory Ca content and availability comparing with
the later salts.
Calcium Carbonate 109

Mueller et al. showed that daily intake of 1200 mg of Ca, as CaCO3, and
800 IU of vitamin D3, with a new chewable tablet increased the intestinal
Ca absorption compared to the results from the placebo [408].
Meiron et al. compared the solubility and fractional absorption of a
stabilized amorphous CaCO3 without and with the presence of chitosan
and crystalline CaCO3 [378]. The results demonstrated that the amorphous
is more soluble than the crystalline form. Fractional absorption was evaluated
by intrinsically labeling CaCO3 preparations with 45Ca, orally administrated
to rats using gelatin capsules. The results revealed that Ca absorption
from the amorphous preparations is up to 40% higher than from the crys-
talline form.
It was reported that Ca from nanoparticulate CaCO3 is more readily
absorbed than the microparticulate form in mice study. A slight increase
in bioavailability (by 38%) of the nanosized CaCO3 by comparison with
the micronized form in humans indicates that the absorption levels of
Ca from both forms are almost similar [4].

7.1.2 Distribution
Skeletal Ca accounts for 99% of the Ca in the body. Of the remaining 1%,
40–45% is bound to proteins, primarily albumin. About 5–10% is
complexed to phosphate, citrate, or other anions. Approximately 50% of
Ca in the serum is in the physiologically active ionized form [399,400].

7.1.3 Metabolism
As an endogenously occurring substance, Ca is not metabolized in the
traditional pharmacokinetic sense [399].

7.1.4 Elimination
Unabsorbed Ca from the small intestine is excreted in the feces. Renal
excretion depends largely on glomerular filtration and Ca tubular
reabsorption with more than 98% of Ca reabsorbed from the glomerular
filtrate, with only 2% lost as obligatory Ca loss. This process is regulated
by active vitamin D and parathyroid hormone (PTH) [399,400]. Excess
carbonate is excreted as CO2 via respiration [4].

7.2 Mechanism of Action


Antacid: Neutralizes gastric acidity.
Dietary supplement: Prevents or treats negative Ca balance; oral Ca sup-
plements may protect against renal calculi formation by chelating with
oxalate in gut and preventing its absorption.
110 M.M.H. Al Omari et al.

Phosphate binder: Binds with dietary phosphate to form insoluble calcium


phosphate, which is excreted in feces [409].

7.3 Pharmacodynamics
Ca administration decreases the elevated rate of bone turnover typically
seen in postmenopausal women with osteoporosis. In randomized, pla-
cebo-controlled studies in postmenopausal women, Ca administration
(500–1600 mg) decreased biochemical markers of bone turnover, including
urine N-telopeptide, urine-free pyridinoline (markers of bone resorption),
alkaline phosphatase, and osteocalcin (markers of bone formation) relative to
placebo-treated women. Ca administration may transiently increase levels of
serum Ca with compensatory reductions in serum PTH and an increase in
urinary Ca. However, urinary and serum Ca levels usually remain within the
normal reference range [400].

7.4 Toxicities
Different toxicity studies have been carried out with CaCO3 in rats, mice,
and cats. They have overall not demonstrated any evidence of toxicity attrib-
utable to CaCO3 [4].
Recommendations for daily dietary Ca intake that range from 400 to
1200 mg/day depending on age and gender have been issued by governmen-
tal and nongovernmental organizations in many countries [4,399,400,404].
Total daily intake of Ca above 1500 mg has not demonstrated additional bone
benefits, while daily intake above 2000 mg has been associated with increased
risk of adverse effects, including hypercalcemia and kidney stones [399,400].
However, intake of dietary Ca equivalent to 250 or 500 mg/kg bw/day
in rats leaded to nephrocalcinosis, while in Beagle dogs at the same doses did
not show any signs of nephrocalcinosis [4]. Nephrocalcinosis was also not
observed in a recent combined repeat dose oral toxicity/reproduction/
developmental toxicity screening study with CaCO3 (having a particle size
of 60–100 nm) carried out in Wistar rats at dose levels of up to 1000 mg/kg
bw/day for up to 48 days. The only changes seen in this study were slight but
statistically significant hematological and biochemical effects in males receiv-
ing 1000 mg/kg bw/day, and significant reductions in plasma phosphate
levels in all male-treated groups. No evidence of toxicity was reported in
a study in which mice were administered CaCO3 (described as nano
CaCO3) by oral gavages at dose levels up to 1300 mg/kg bw/day [4].
Calcium Carbonate 111

Evidence of fetotoxicity of Ca (as CaCO3) was observed when admin-


istered during pregnancy at levels in the diet greater than 1500 mg/kg bw/
day CaCO3. Overall, it was noted that in rodents high doses of CaCO3
(>1500 mg/kg bw/day) causing hypercalcemia during gestation can result
in adverse effects on reproduction, fetotoxicity, and elemental imbalances in
the offspring [4].
No data are available indicating that CaCO3 has allergenic properties or
can invoke sensitivity or intolerance reactions in exposed individuals [4].
CaCO3 (including CaCO3 having a particle size of 60–100 nm) has
given negative results in a range of in vitro genotoxicity assays. No data
are available on the chronic toxicity or carcinogenicity of CaCO3. How-
ever, it is very unlikely that CaCO3 has carcinogenic potential, given that
both Ca and carbonate are natural constituents of the body and normal
metabolites of man, animals, and plants and have a long history of safe
use as a source of Ca supplementation for humans [4].
Furthermore, there are reports which indicated health associated
problems with Ca intake upon the presence of other compounds. For
example, Picolos and Orlander reported the presence of Ca with antacids
can lead to milk-alkali syndrome, which is a common cause of hypercalce-
mia [410].

7.5 Drug Interactions


Ca may reduce the absorption of bisphosphonates (such as risedronate,
alendronate, etidronate, ibandronate, pamidronate), thyroid hormones
(levothyroxine), fluoroquinolones (such as ciprofloxacin, moxifloxacin,
and ofloxacin), tetracyclines (such as doxycycline, minocycline, and tetracy-
cline), and omeprazole [399,400,410]. There is a report, which describes
antagonism of the antiarrhythmic effects of oral verapamil due to the use
of oral Ca and calciferol [399].
Ca absorption is reduced when CaCO3 is taken concomitantly with
systemic glucocorticoids and thiazide diuretics reduced urinary excretion
of Ca during concomitant use with CaCO3 [400].
Absorption of Ca may be increased when CaCO3 is given concomitantly
with vitamin D analogues (such as calcitriol, doxercalciferol, and
paricalcitol). Also Ca may interfere with the absorption of iron. Patients
being treated for iron deficiency should take iron and Ca at different times
of the day [400]. Certain foods (eg, those containing oxalic acid, phosphate,
or phytanic acid) may reduce the absorption of Ca [399].
112 M.M.H. Al Omari et al.

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