ORIGINAL PAPER

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Effect of Fe(III) Impurity on the Antisolvent Crystallization

of Aqueous Ammonium Dihydrogen Phosphate Solutions
Ewa Mielniczek-Brzóska, Keshra Sangwal,* and Jarosław Borc

model compound for the investigation of

Experimental results of a study of the effect of FeCl3 impurity on the the processes of antisolvent crystalliza-
antisolvent crystallization of ammonium dihydrogen phosphate, involving tion in the presence of impurities.
processes of formation of 3D nuclei and growth of these nuclei, from its The authors[6–8] have extensively stud-
aqueous solutions saturated at 30 °C and containing different impurity ied the antisolvent crystallization of
ADP from their aqueous solutions in
concentrations ci from in situ measurements of temperatures of saturated different solvents. These investigations
solutions and pure water as functions of feeding time t of antisolvent ethanol have revealed, among others, that: 1)
at predefined rates RA are described and discussed. The processes of measurements of temperature of aque-
formation of 3D nuclei and growth of these nuclei are studied in terms of the ous solutions during addition of an
maximum antisolvent content 𝚫xmaxN and 𝚫xmaxG , determined from intervals antisolvent is a reliable method for the
determination of the metastable zone
of temperature difference (Ts −Tw ) = 𝚫T < 0 and 𝚫T > 0, respectively,
width (MSZW) from the values of the
obtained from measurements of temperature Ts and Tw of saturated solution, maximum antisolvent content Δxmax ,
without and with impurity, and pure water. It is found that: 1) the processes of and 2) the values of Δxmax , calculated
3D nucleation in antisolvent crystallization from solutions containing from antisolvent feeding time when
impurities can be explained in the framework of theoretical expressions such the difference ΔT = 0 in the tempera-
as a Nývlt-like relation and an approach based on 3D-nucleation theory, and 2) tures Ts and Tw of solution and water,
respectively, for different feeding rates
adsorption of impurity particles accounts for the increase in the values of RA , are reliable for theoretical analysis of
antisolvent contents 𝚫xmaxN and 𝚫xmaxG of solutions during 3D nucleation Δxmax (RA ) data. The maximum volume
and growth of crystallites. fraction Δxmax of the antisolvent in a
saturated solution defines its MSZW and
corresponds to the maximum value of
supersaturation developed in the solu-
1. Introduction tion for the occurrence of 3D nucleation
(see Appendix B). Various factors such as
Trivalent cations like Fe3+ , Cr3+ , and Al3+ are known to have enor-
initial solution concentration, type of antisolvent, antisolvent ad-
mous effect on the growth rate, growth morphology, and qual-
dition rate, location of addition of antisolvent, and solution stir-
ity of KDP-type crystals grown from aqueous solutions.[1–3] At
ring rate are known to affect the value of MSZW during anti-
high pH, NH4 + and PO4 3− ions of ammonium dihydrogen phos-
solvent crystallization.[6–13] Important problems encountered in
phate (ADP), combined with Mg2+ ions, result in struvite which
antisolvent crystallization have been reviewed recently.[14] How-
is the main component of so-called infectious urinary stones.[4,5]
ever, a survey of the literature reveals that the effect of impuri-
At usual temperatures, ADP is moderately soluble in water and
ties on the antisolvent crystallization has been poorly investigated
sparingly soluble in antisolvents. Therefore, ADP is an attractive
so far.
In the present paper the effect of FeCl3 impurity on the anti-
solvent crystallization of ADP from its aqueous solutions satu-
Prof. E. Mielniczek-Brzóska rated at 30 °C as functions of feeding time t of ethanol at pre-
Institute of Chemistry defined rates RA are investigated. The processes of formation
Jan Długosz University of Czestochowa
˛ of 3D nuclei and growth of these nuclei were studied in terms
ul. Armii Krajowej 13/15, 42-200 Czestochowa,
˛ Poland of the maximum antisolvent content ΔxmaxN and ΔxmaxG , de-
Prof. K. Sangwal, Dr. J. Borc termined from intervals of temperature difference (Ts −Tw ) =
Department of Applied Physics
Lublin University of Technology
ΔT < 0 and ΔT > 0, respectively, obtained from in situ mea-
ul. Nadbystrzycka 38, 20-618 Lublin, Poland surements of temperature Ts and Tw of saturated solution, with-
E-mail: k.sangwal@pollub.pl out and with impurity, and pure water. The experimental results
of increase in ΔxmaxN and ΔxmaxG of the solutions with increase
The ORCID identification number(s) for the author(s) of this article in feeding rate RA and impurity concentration ci are discussed
can be found under https://doi.org/10.1002/crat.201900213 in the framework of theoretical approaches advanced in the
DOI: 10.1002/crat.201900213 literature.[14]

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2. Experimental Procedure
The solubility of ADP at 30 °C in the presence of Fe3+ impurity
was determined in water using FeCl3 ⋅6H2 O up to 0.074 wt% (i.e.,
9.2×10−4 mole fraction). All solutions were prepared in 250 mL
flasks from doubly-distilled water and analytical-grade ADP and
FeCl3 ⋅6H2 O (Chempur, Piekary Ślaskie,
˛ Poland). The flask con-
taining the solution was kept at 30 °C using a thermostat JU-
LABO (Poland) with an accuracy of 0.01 °C and was continuously
stirred using a magnetic stirrer. The experimental procedure for
solubility measurements was similar to that used in our earlier
studies.[15]
Using the solubility data of ADP in water reported in the
literature,[16] 85.4 g ADP was first dissolved in 190 mL water in
the 250 mL flask. Then an appropriate amount of FeCl3 ⋅6H2 O
was added to the flask until it was dissolved completely in the
solution. Small portions of known amounts of the solute ADP
were added to the solution containing the impurity after appro-
priate durations with simultaneous observation of the dissolution
of the added solute. When the last portion of the solute added
to the solution was found to remain undissolved at the bottom of
the flask for 36 h, the solution was considered as saturated. From
the total mass the solute dissolved in the solution in the presence
of the impurity of concentration ci , its solubility c0 was calculated.
This procedure for the determination of the solubility of ADP in
the aqueous solution containing a given concentration ci of the
impurity was repeated at least twice.
The experimental setup and the procedure used here for anti-
solvent crystallization have been described earlier.[6,7] Briefly, the
experimental setup consisted of a double-walled crystallizer of
300 mL capacity, a thermostating arrangement, a temperature
meter (accuracy of 0.01 °C), an antisolvent feeding arrangement,
a magnetic stirrer with a predefined rotation rate, and a mechan-
ical stirrer. 220 mL of solution, without and with Fe3+ impurity,
previously saturated at 30 °C was pumped into the crystallizer
in which antisolvent crystallization was carried out by feeding
analytical-grade ethanol (Chempur, Piekary Ślaskie, ˛ Poland) as
an antisolvent at predefined rates RA and the temperature T of
the solution as a function of ethanol feeding time t was recorded
in situ every second.
After the crystallization process, when the temperature of the
solution had reached 30 °C, 3 mL representative sample was with-
drawn from it using a scoop. The mixture sample was then fil-
tered quickly using a low-pressure filter and the ADP crystals
were dried in the laboratory incubator at 50 °C. The crystals ob-
tained in this way were finally observed under optical microscope.
3. Experimental Results
3.1. Solubility Measurements
The results of the solubility c0 of ADP as a function of impurity
concentration ci are presented in Figure 1, where c0 and ci are
expressed in molar fraction. As seen from Figure 1, in this impu-
rity interval the solubility c0 increases linearly with the impurity
concentrations ci according to the relation:
c0 = 6.98 × 10−2 + 0.4312ci (1)
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Figure 1. Solubility c0 (mole fraction) of ADP in water at 30 °C as function
of impurity concentration ci (mole fraction).
with a correlation coefficient R2 = 0.9628. In this relation ci and
c0 are expressed in mole fraction. It may be observed that addi-
tion of the impurity leads to an increase of merely 0.65% in the
ADP solubility in this investigated concentration interval. This
implies that the effect of addition of Fe3+ impurity in the range
of the concentration used in this study on the ADP solubility may
be neglected in the calculation of supersaturation created by the
antisolvent.
3.2. Characteristics of Antisolvent Crystallization of ADP
Solutions in Ethanol
It is well known[6–8] that addition of antisolvents like alcohols and
acetone at a given feeding rate RA to water at a initially maintained
at a constant temperature as well as aqueous ADP solutions sat-
urated at particular temperature leads to a change in their tem-
perature with an increase in the antisolvent feeding duration t.
Examples of plots of the temperature Tw of water from initial
temperature T0 against the feeding duration t of ethanol at dif-
ferent feeding rates RA are shown in Figure 2a, whereas plots
of the temperature Ts of saturated aqueous ADP solutions con-
taining different Fe3+ concentrations with the feeding duration t
at a constant feeding rate RA of 1.0 mL min−1 are illustrated in
Figure 2b. In these figures time t0 indicates the beginning
of ethanol feeding, t1 represents the onset of 3D nucleation,
whereas tmax is the maximum feeding duration when water and
solution attain the highest temperature Tmax and corresponds to
the temperature difference ΔTmax .
As described before for acetone, methanol, and ethanol,[6–8] the
Tw (t) plots of Figure 2a reveal an initial practically linear increase,
followed by a decrease after going through a maximum at tem-
perature TmaxW at feeding duration tmax . Irrespective of the feed-
ing rate RA , the maximum temperature TmaxW is observed prac-
tically at the same value of tmax , but the value of TmaxW increases
with an increase in RA . In aqueous ADP solutions saturated at the
same temperature T0 , the increase in its temperature Ts occurs
with antisolvent feeding duration in two steps. The increase in Ts
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Figure 2. Change in a) temperature Tw of pure water at 30 °C at different antisolvent feeding rates RA [8] and b) solution temperature Ts of ADP solutions
saturated at 30 °C containing different concentrations ci of Fe3+ impurity with ethanol feeding duration t at rate RA of 1.0 mL min−1 . c) Temperature
difference ΔT involved in antisolvent crystallization of ADP from saturated aqueous solutions containing different ci of impurity with ethanol feeding
duration t at rate RA of 1.0 mL min−1 . Time t0 of beginning of antisolvent feeding, t1 corresponding to the onset of 3D nucleation, and tmax corresponding
to the maximum temperature Tmax are indicated in the figures. In the insets of (b) and (c) impurity ci is given in mole fraction.

initially attains a steady value at feeding time t1 and then steeply
increases to the maximum value Tmax at tmax . Moreover, the value
of Tmax increases and that of tmax decreases with an increase in
RA . As seen from Figure 2b, the plots of temperature Ts of aque-
ous ADP solutions containing different concentrations ci of Fe3+
impurity also reveal that the values of feeding times t1 and tmax
increase with an increase in ci , but the value of the maximum
temperature Tmax initially decreases and then increases with an
increase in ci .
It was observed that saturated solutions containing impurity
concentrations ci exceeding 7.01×10−5 mole fraction become tur-
bid even to the naked eye. This turbidity is probably associated
with the precipitation of Fe(PO4 )⋅2H2 O in the solution. However,
even in this case, the crystallization of ADP could be monitored
by measuring the temperature T.
The effect of impurity and its concentration ci on the anti-
solvent crystallization of ADP from its saturated solutions may
be analyzed from the data of the relative change ΔT in the
temperature between Ts and Tw as a function of antisolvent
feeding time t. These data of change ΔT obtained by subtracting
Tw for water from Ts of the solution are shown in Figure 2c as a
function of feeding time t for feeding rate RA of 1.0 mL min−1 .
Obviously, these ΔT(t) data for different impurity concentrations
ci have two antisolvent feeding durations. In the feeding interval
t0 < t < t1 , the temperature difference ΔT < 0. However, in the
interval t1 < t < tmax , ΔT > 0. The feeding duration t0 < t < t1
corresponding to ΔT < 0 is associated with 3D nucleation,
whereas the duration t1 < t < tmax corresponding to ΔT > 0
is associated with the growth of the 3D nuclei formed before
t1 . The maximum decrease in the values of ΔT attained in the
initial antisolvent feeding duration t0 < t < t1 and the maximum
increase in the values of ΔT attained at tmax are denoted in
Figure 2c as ΔTmin and ΔTmax , respectively. These data of ΔTmin
and ΔTmax are presented as a function of impurity concentration
ci for different ethanol feeding rate RA in Figure 3.
From the plots of Figure 3 it may be noted that the values of
both ΔTmin and ΔTmax of solutions containing a given impurity
concentration ci increase with an increase in the ethanol feed-
ing rate RA . These trends are associated with the fact that both
of the processes of 3D nucleation and growth of 3D nuclei in-
volve chemical reactions which occur at increasingly higher rates
with increasing RA . From Figure 3 one also observes that for a
given feeding rate RA the value of ΔTmin shows initially a weak
tendency to increase linearly up to about 5×10−5 mole fraction
and then decreases with an increase in ci . However, the value
of ΔTmax shows an initial decrease followed by an increase with

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Figure 3. Dependence of ΔTmin and ΔTmax , denoted as “Nucl” and “Gro”,
respectively, on impurity concentration ci for different antisolvent feeding
rate RA given in the inset as mL min−1 .
Figure 4. Morphology of ADP crystals obtained from impurity-free aque-
ous solutions at two ethanol feeding rates RA : a) 0.5 and b) 3.0 mL min−1 .
Longer edge of photographs is 0.5 mm long.
increasing ci . This trend is shown for the ΔTmin (ci ) data obtained
at RA = 3.0 mL min−1 by the dashed plot but similar trends
may be discerned for the ΔTmin (ci ) and ΔTmax (ci ) data obtained at
RA = 1.0 mL min−1 .
The above trends of the plots of ΔTmin and ΔTmax against ci
at different ethanol feeding rates RA are due to the effect of Fe3+
impurity on the 3D nucleation and growth processes, and are re-
flected by the morphology and distribution of crystallites growing
in the solution of a given composition. Figure 4 shows examples
of growing crystallites from impurity-free solutions at two differ-
ent ethanol feeding rates RA , whereas Figure 5 from solutions
containing different impurity concentrations ci at a constant rate
RA . It may be seen that the crystals grown from pure solutions are
tapered at RA = 0.5 mL min−1 , but this tapering is suppressed at
RA = 3.0 mL min−1 (Figure 4). In contrast to the pronounced ef-
fect of ethanol feeding rate RA on the tapering of growing crystals,
the crystals growing at a constant RA = 1.0 mL min−1 from solu-
tions containing different ci remain tapered and their size from
solutions containing relatively high ci is reduced (Figure 5).
4. Discussion
It was mentioned above that the feeding duration t0 < t < t1 cor-
responding to ΔT < 0 is associated with 3D nucleation, whereas
the duration t1 < t < tmax corresponding to ΔT > 0 is associated
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with the growth of the 3D nuclei formed before t1 . The maximum
variations in the values of ΔT, denoted as ΔTmin and ΔTmax , are
related to the changes in the energy changes ΔQ due to chem-
ical reactions involved in the formation of 3D nuclei and the
growth of these nuclei during antisolvent crystallization.[6,7] As
seen from Figure 3, the values of ΔTmin and ΔTmax obtained at
a given ethanol feeding rate RA are affected by the concentration
of the Fe3+ impurity. The effects of impurity on the data of ΔTmin
and ΔTmax for 3D nucleation and growth are not analyzed in this
study in view of small changes caused by the impurity and rela-
tively large scatter in their values from solutions containing even
the same impurity concentration ci and at the same antisolvent
feeding rate RA . The main emphasis here is on the analysis of
the data of maximum antisolvent content Δxmax associated with
the antisolvent feeding durations ΔtN = t1 −t0 and ΔtG = tmax −t1
representing 3D nucleation and growth of the 3D nuclei, respec-
tively.
The volume fraction Δxmax corresponding to the above anti-
solvent feeding duration Δt in the initial solution may be given
by
Va
Δxmax = (2)
Vs + Va
where the antisolvent volume Va = RA Δt and the solution volume
Vs = 220 mL. Figure 6 shows plots of antisolvent composition
Δxmax for 3D nucleation and growth at different feeding rates RA
against impurity concentration ci .
It may be seen from Figure 6 that the value of the maximum
antisolvent content Δxmax for 3D nucleation and growth increases
with an increase in both ci and RA . The morphology and the size
of crystals, shown in Figures 4 and 5, in relation to these factors
are mainly associated with the growth of the 3D nuclei formed in
the initial stage of crystallization due to feeding of the antisolvent
at constant RA to the saturated solution containing impurity ci .
Therefore, it is desired to explain the effect of RA and ci on the
processes of 3D nucleation as determined by the value of Δxmax .
4.1. Relationship between Antisolvent Composition 𝚫xmax
and Impurity Concentration ci
It may be seen from Figure 6 that the value of Δxmax for growth
increases linearly with ci but its value for 3D nucleation increases
with ci according to the empirical power-law relation:
q
Δxmax = AN,G + BN,G ci , (3)
where AN,G and BN,G are constants, the exponent q < 1 for 3D nu-
cleation and q = 1 for the growth of the nuclei, and the subscripts
N and G denote the processes of onset of 3D nucleation and the
subsequent growth of 3D nuclei, respectively. The values of the
constants of Equation (3) are listed in Table 1.
As seen from the plots of Δxmax for the onset of 3D nucleation
against ci in the entire impurity concentration interval for the an-
tisolvent feeding rate RA = 1.0 mL min−1 , the empirical power-
law relation is not satisfactory to describe the Δxmax (ci ) data for
3D nucleation at various RA (Figure 6). An alternative approach,
which avoids empirical dependence of the experimental data and
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Figure 5. Morphology of ADP crystals obtained from aqueous solutions containing different FeCl3 impurity concentrations at ethanol feeding rate RA =
1.0 mL min−1 : a) 0.70×10−5 , b) 1.75×10−5 , c) 3.5×10−5 , d) 5.25×10−5 , and e) 8.76×10−5 mole fraction. Longer edge of photographs is 0.5 mm long.

has a sound scientific basis, is to consider the resulting maxi-

mum antisolvent content Δxmax in the presence of the impurity
of concentration ci in terms of contributions of the maximum
antisolvent contents Δxmax 0 and Δxmax i in the absence and pres-
ence of an impurity, respectively, with coverage 𝜃 of adsorption
sites given by Langmuir adsorption isotherm. Then the relation
between Δxmax and ci may be written as: (see Appendix A)
( )
Δxmax
0
1 1
= 1+ (4)
Δxmax − Δxmax
0 𝛼eff KL ci

where the impurity effectiveness coefficient 𝛼 eff ≥ 1 and KL is the

Langmuir constant given by:[3,17]
( )
Qdiff
KL = exp , (5)
RG T
Figure 6. Plots of antisolvent composition Δxmax for 3D nucleation and
growth at different feeding rates RA against impurity concentration ci . Note where Qdiff is the differential heat of adsorption of the im-
linear dependence for growth and power-law dependence for 3D nucle-
purity particles on the surface of the developing 3D nuclei,
ation. Plots are drawn according to Equation (3) with constants given in
Table 1. In the inset, abbreviations “Nucl” and “Gro” denote 3D nucleation RG is the gas constant, and T is the temperature in kelvin.
and growth, respectively, and RA is in mL min−1 . Figure 7 shows the Δxmax (ci ) data for 3D nucleation as plots of
Δxmax 0 /(Δxmax −Δxmax 0 ) against ci −1 for different ethanol feed-
ing rates RA according to Equation (4), with best-fit constants,
Table 1. Constants AN,G , BN,G , and exponent qN for 3D nucleation and goodness-of-the-fit parameter R2 , and Qdiff given in Table 2.
growth at different RA .
The above approach indeed predicts that 𝛼 eff > 1 (Table 2).
However, in view of large scatter in the data it seems that 𝛼 eff ≈ 3
RA [mL min−1 ] 3D nucleation Growth
and the value of Qdiff does not depend on RA .
102 AN 102 BN qN 102 AG 102 BG When KL ci ≪ 1, Equation (4) takes the form:
0.2 2.536 3.996 0.3572 0.434 0.689 Δxmax
= 1 + 𝛼eff KL ci (6)
0.5 3.314 4.210 0.3813 0.680 0.365 Δxmax
0
1.0 4.021 2.544 0.7012 1.017 0.349
4.021 2.586a 0.6440a) This relation explains the Δxmax (ci ) data for the growth of the nu-
2.0 5.281 3.256 0.5566 1.739 0.673 clei (see Figure 6). The values of constants of Equation (6) and
3.0 6.043 3.835 0.5051 2.773 1.249 that of Qdiff , estimated on the assumption that 𝛼 eff = 1, are given
in Table 3. Since the approximation KL ci ≪ 1 in Equation (6) holds
a) All data. for KL ≤ 0.1/ci and the highest ci ≈ 10−4 mole fraction, relation (6)
holds when KL < 103 and Qdiff < 17.4 kJ⋅mol−1 . If the data for the

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Figure 7. Plots of Δxmax 0 /(Δxmax −Δxmax 0 ) against ci −1 for different Figure 8. Dependence of Δxmax on ethanol feeding rate RA for four
ethanol feeding rates RA according to Equation (3), with best-fit constants Fe3+ concentrations ci . Plots are drawn according to empirical power-law
given in Table 2. In the inset RA is given as mL min−1 . relation (7).

two lowest RA are not considered, it seems that here the effec- the empirical relation:
tiveness coefficient 𝛼 eff ≈ 50 and that the value of Qdiff does not
depend on RA . The upper limit of Qdiff mentioned above is com- p
parable with the value of Qdiff ≈ 21 kJ mol−1 estimated for the Δxmax = ARA (7)
adsorption of Fe3+ ions on the (100) face of KDP crystals from
tapering data.[3,18] The high value of 𝛼 eff indicates strong adsorp- where A and p are fitting parameters. As shown in Appendix B,
tion of the impurity in the growth of nucleating crystallites (see when the 3D nucleation rate J at a given saturation concentra-
Equation (A3)). tion c2 of solution containing antisolvent composition Δx dur-
ing antisolvent crystallization is given by an empirical power-law
relation, one may derive an equation of this type, known as the
4.2. Dependence of Antisolvent Composition 𝚫xmax on Ethanol so-called Nývlt-like relation, expressed in the form:
Feeding Rate RA
( ) 1
ln Δxmax = Φ + ln RA (8)
The experimental data of maximum antisolvent content Δxmax m
for 3D nucleation as a function of feeding rate RA to solutions
containing different concentrations ci of Fe3+ impurity are pre- where Φ and 1/m are best-fit constants obtained from the inter-
sented in Figure 8. These Δxmax (RA ) data may be described by cept and the slope of the linear dependence of ln(Δxmax ) on RA .

Table 2. Values of constants 𝛼 eff and KL of Equation (4) and estimated Qdiff .

RA [mL min−1 ] 1/𝛼 eff 1/𝛼 eff KL 𝛼 eff 104 KL Qdiff [kJ⋅mol−1 ] R2

0.2 0.2792 0.403 3.581 6.93 28.09 1

0.5 0.361 ± 0.015 0.649 ± 0.039 2.771 5.56 ± 0.235 27.53 ± 0.11 0.9925
1.0 0.292 ± 0.042 1.278 ± 0.052 3.428 2.28 ± 0.325 25.29 ± 0.34 0.9817
2.0 0.537 ± 0.080 1.481 ± 0.258 1.863 3.62 ± 0.542 26.45 ± 0.35 0.8423
3.0 0.474 ± 0.020 1.742 ± 0.057 2.112 2.72 ± 0.113 25.73 ± 0.10 0.9968

Table 3. Values of constants of Equation (6) and estimated Qdiff .

RA [mL min−1 ] 102 Δxmax 0 102 Δxmax 0 𝛼 eff KL 104 KL Qdiff [kJ⋅mol−1 ] R2

0.2 0.434 ± 0.377 0.689 ± 0.167 15.88 ± 3.84 30.18 ± 0.54 0.8888
0.5 0.680 ± 0.101 0.365 ± 0.038 5.37 ± 0.56 27.44 ± 0.25 0.9492
1.0 1.017 ± 0.120 0.349 ± 0.031 3.43 ± 0.30 26.30 ± 0.21 0.9078
2.0 1.739 ± 0.365 0.673 ± 0.099 3.87 ± 0.57 26.62 ± 0.35 0.8495
3.0 2.773 ± 0.016 1.249 ± 0.080 4.50 ± 0.29 27.00 ± 0.16 0.9877

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Figure 9. Dependence of a) lnΔxmax and b) Δxmax −2 on lnRA according to Equations. (8) and (9), respectively. Plots are drawn with the best-fit parameters,
with the R2 coefficient, given in Tables 4 and 5.

Table 4. Best-fit parameters of Equation (8). such that RA * = RA −ΔRA , is used in the applied antisolvent feed-
ing rate RA . This leads to a lowering of the values of both F and
105 ci [mole −Φ 1/m m R2 −FZ and, consequently, a decrease in the value of −Z. However,
fraction] it may be verified that the value of a2 2 /B obtained from the new
0 3.145 ± 0.021 0.307 ± 0.025 3.257 0.9504 lower values of F and Z remains practically unchanged. There-
1.75 2.435 ± 0.039 0.129 ± 0.044 7.874 0.6879 fore, for the analysis of the a2 2 /B as a function of ci it is immate-
3.50 2.229 ± 0.021 0.144 ± 0.025 6.944 0.8446
rial whether as-applied or corrected feeding rate is considered in
the examination of the Δxmax (RA ) data.
5.25 2.102 ± 0.026 0.158 ± 0.035 6.329 0.7712
The data of the values of constants a2 and F for various ci
may be analyzed using the dependence of nucleation rate J on
Table 5. Values of best-fit constants F and Z of Equation (9) and the pa- impurity concentration ci given by (see Equation (B7)),
rameter a2 2 /B.
( )
105 ci [mole F −FZ −Z a2 2 /B R2 J0 B
J= exp − ( )2 , (10)
fraction] 1 + KL ci a2 Δx
0 627.7 ± 49.4 398.4 ± 57.4 0.645 ± 0.091 973.2 0.8578
1.75 135.1 ± 9.2 32.7 ± 10.3 0.242 ± 0.076 558.3 0.7116 where it is assumed that the impurity particles do not change
3.50 89.5 ± 3.1 25.6 ± 3.6 0.286 ± 0.040 312.9 0.8899 the parameter B due to changes in the interfacial tension 𝛾 (see
5.25 68.0 ± 3.0 19.1 ± 4.0 0.281 ± 0.059 242.0 0.7484 Equation (B8)) but changes the kinetic factor J0 by physically
blocking the existing active sites for the attachment of solute
molecules/ions when the kinetic factor becomes J0 (1−𝜃) and the
The dependence of the nucleation rate J on Δx according to the fraction 𝜃 of blocked sites is given by the Langmuir adsorption
classical 3D nucleation theory gives the relation between Δxmax isotherm of constant KL given by Equation (5). When it is as-
and RA in the form: sumed that fRA is constant in Equation (B4), using the relation
between nucleation rate J and a2 one obtains
( )−2 ( )
Δxmax = F 1 − Z ln RA , (9)
1 ( )
= C 1 + KL ci , (11)
where F and Z are quantities with well-defined physical mean- a2
ing. Equation (9) predicts a linear dependence of Δxmax −2 on RA
with intercept F and slope −FZ. Equations (8) and (9) give sim- where C amalgamates different constants of Equation (10) and
ilar fit when lnF = −2Φ and 1/m = −Z/2, which holds when Equation (B4). Note that the constant C corresponds to the value
ln(1−ZlnRA ) ≈ ZlnRA . of 1/a2 when ci = 0. We denote this value of a2 for the impurity-
Figure 9a,b shows the dependence of lnΔxmax and Δxmax −2 on free solution by a2 0 .
lnRA according to Equations (8) and (9), respectively, whereas the Figure 10 shows the data of a2 (ci ) in the form of plot of a2 −1
linear plots are drawn with the best-fit parameters given in Ta- against ci according to Equation (11), with the best-fit values of
bles 4 and 5. From these tables it may be observed that the values constants C and KL listed in Table 6. The values of a2 −1 were ob-
of −Φ and 1/m of Equation (8) and those of F, −Z, and a2 2 /B of tained from the values of a2 2 /B given in Table 5 taking arbitrarily
Equation (9) decrease with an increase in impurity concentration B = 0.2. This value of B corresponds to the interfacial energy 𝛾 ≈ 5
ci , and that, as expected from the two approaches, lnF = −2Φ and mJ m−2 , which is characteristic of heterogeneous nucleation. The
1/m = −Z/2. values of a2 0 for the impurity-free solution and the differential
It was reported[8] that the fit of the Δxmax (RA ) data according to heat Qdiff of adsorption for the impurity during 3D nucleation
Equation (9) somewhat improves when a small correction ΔRA , are also included in Table 6.

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Table 6. Best-fit parameters of Equation (11).

Data 102 C [−] 102 CKL [−] a2 0 [−] 10−4 KL [−] Qdiff [kJ⋅mol−1 ] R2

a2 (ci ) 7.153 ± 0.352 1.426 ± 0.108 14.0 1.994 24.95 0.9831

F(ci ) 0.225 ± 0.071 0.246 ± 0.022 9.4a) 1.093 23.43 0.9768
F1/2 (ci ) 4.867 ± 0.951 1.507 ± 0.290 9.2a) 3.10 26.06 0.8962

a) Calculated from value of intercept C with B = 0.2.

lower than that obtained from the a2 −1 (ci ) data. However, the val-
ues of Qdiff obtained from the plots of a2 −1 and F−1/2 against ci
are in good agreement with those given in Table 2 from the plots
of Δxmax against ci according to Equation (4), whereas the F−1 (ci )
plot gives somewhat lower value of Qdiff .

Figure 10. Plots of a2 −1 , F−1 , and F−1/2 against impurity concentration
ci . Plots are drawn according to relation (11), with the constants listed in
Table 6.
According to Equation (B11), F is related, among others, to a2
in the form
( ) ( )
1 B B J0 Bf f a2
= 2 ( ) ≈ 2 1− = −1 (12)
F a ln J0 ∕f a2 a2 f a2 a2 J0 J0
2
where we have assumed that ln(J0 /fa2 ) ≈ (1+J0 /fa2 ) ≈ (1−fa2 /J0 )−1 .
Equation (12) represents two extreme situations: 1) when
1 ≫ fa2 /J0 , F ≈ a2 2 /B; 2) when 1 ≪ fa2 /J0 , F ≈ −a2 J0 /Bf. Since
F is related to a2 2 or a2 , depending on whether [ln(J0 /fa2 )]/B or
[(fa2 /J0 )−1] is practically a constant quantity, the F(ci ) data were
also analyzed. These data are shown in Figure 10 as plots of
F−1 and F−1/2 against ci using relations similar to Equation (11)
where, instead of a2 −1 , we take F−1 and F−1/2 as functions of
ci . Then the constant C of Equation (11), with the F−1 (ci ) and
F−1/2 (ci ) data, corresponds to the values of (F−1 )0 and (F−1/2 )0
for impurity-free solution. The values of a2 0 and Qdiff calculated
from the intercept C and the slope CKL of these plots are also
given in Table 6.
It may be noted from Figure 10 that the plots of both a2 −1 and
F−1 against ci follow Equation (11) satisfactorily, but the data of
F−1/2 against ci show poor linear dependence. All the three plots
have positive values of the slope CKL , which implies that the ap-
proximation fa2 /J0 ≪ 1, predicting negative values of a2 , is not
valid here. Therefore, it may be argued that in the F−1 (ci ) plot
the quantity [ln(J0 /fa2 )]/B ∝ a2 −1 but its value increases with im-
purity concentration ci , resulting in a decrease in the slope CKL
of the F−1 (ci ) plot and the value of Qdiff obtained from the corre-
sponding KL . The values of the parameter a2 0 obtained from the
F−1 (ci ) and F−1/2 (ci ) data are comparable but its value is somewhat
5. Conclusions
The experimental results obtained in this study of antisolvent
crystallization of ADP from aqueous solutions containing Fe3+
impurity at 30 °C by feeding ethanol as an antisolvent show that:
1) the value of the maximum antisolvent content Δxmax for both
3D nucleation and growth increases with an increase in ethanol
feeding rate RA as well as impurity concentration ci and 2) the
morphology and the size of crystals are affected by both RA and
ci . These observations are associated with the formation of 3D
nuclei in the initial stage of crystallization and their subsequent
growth.
The maximum antisolvent content Δxmax for 3D nucleation
and growth of crystallites at a given ethanol feeding rate RA in
the presence of the impurity of concentration ci can be explained
in terms of contributions of the maximum antisolvent contents
Δxmax 0 and Δxmax i in the absence and presence of an impurity,
respectively, with coverage 𝜃 of adsorption sites given by Lang-
muir adsorption isotherm and an impurity effectiveness param-
eter 𝛼 eff . Analysis of the Δxmax (ci ) data for processes of 3D nu-
cleation and growth reveals that adsorption of the impurity is
stronger during the growth of crystallites than that during the
formation of 3D nuclei.
The processes of 3D nucleation in antisolvent crystallization
from solutions containing impurities can also be explained in
the framework of known theoretical relationships between Δxmax
and RA given by Nývlt-like relation, Equation (8), and Equation (9)
based on 3D-nucleation theory. In Equation (9) solute−solvent in-
teraction parameter a2 (Equation (B9)) and parameter F describe
the effect of the impurity.
Appendix A: Relationship between 𝚫xmax and
Impurity Concentration ci
If the values of contributions of the maximum antisolvent con-
tents to the MSZW are Δxmax 0 and Δxmax i in the absence and
presence of an impurity, respectively, the resulting maximum an-
tisolvent content Δxmax in the presence of the impurity with cov-
erage 𝜃 of adsorption sites may be written in the form
Δxmax = Δxmax
0
(1 − 𝜃 ) + Δxmax
i
𝜃 (A1)

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or c in the solution. However, when the excess solute concentration

Δc = (c1 −c2 ) generated in a solution saturated at given tempera-
Δxmax
= 1 + 𝛼eff 𝜃 (A2) ture T of initial solution of concentration c1 by feeding an anti-
Δxmax
0
solvent content Δx = (x2 −x1 ) to the solution at a constant rate RA
= Δx/Δt is given by the theory of regular solutions, the relation
where the impurity effectiveness coefficient between supersaturation ratio S and Δx is of the form[14,20]
Δxmax
i
𝛼eff = −1 (A3) Δc
Δxmax
0 ln S ≈ = a2 Δx, (B3)
c2
The impurity effectiveness coefficient 𝛼 eff ≥ 1 because
Δxmax i ≥ Δxmax 0 . Using the Langmuir adsorption isotherm[3,18] where c2 is the saturation concentration of the solution obtained
KL ci by adding Δx and a2 is a parameter related to the solute−solvent
𝜃= (A4) interactions (see Equation (B9)). Then the 3D nucleation rate J
1 + KL ci
due to this generating excess solute concentration Δc by feeding
in Equation (A2), one obtains the antisolvent fraction Δx at constant rate RA = Δx/Δt may be
( ) given by[14,20]
Δxmax
0
1 1
= 1 + (A5)
Δxmax − Δxmax
0 𝛼eff KL ci Δc Δc Δx Δc
J=f =f = f RA = f a2 RA , (B4)
c2 Δt c2 Δx Δt c2 Δx
where KL is the Langmuir constant given by Equa-
tion (5). This relation predicts a linear dependence of
where f is the number of molecules/ions in the initial solution of
Δxmax 0 /(Δxmax −Δxmax 0 ) ≥ Δxmax 0 on ci with intercept 𝛼 eff −1
concentration c1 of antisolvent content x1 . When the nucleation
and slope (𝛼 eff KL ci )−1 , which enable to calculate the values of the
rate J at concentration c2 during the antisolvent crystallization is
effectiveness coefficient 𝛼 eff , the Langmuir constant KL , and the
described by a power-law equation[14,20]
differential heat Qdiff of adsorption of the impurity.
When KL ci ≪ 1, Equation (A5) takes the form ( )m
Δc ( )m
Δxmax J=K = K a2 Δx , (B5)
c2
= 1 + 𝛼eff KL ci (A6)
Δxmax
0

where K and m are empirical constants; upon equating Equations

This relation predicts a linear dependence of Δxmax on ci , with (B4) and (B5) for the occurrence of 3D nucleation corresponding
values of the intercept Δxmax 0 and the slope Δxmax 0 𝛼 eff KL . Note to the maximum antisolvent content Δxmax one obtains Equation
that the approximation KL ci ≪ 1 holds for KL ≤ 0.1/ci . (B2) with the parameter Φ given by

Appendix B: Theoretical Relationships between ( )

1 f 1−m
𝚫xmax and RA Φ=
m
ln
K
+
m
ln a2 . (B6)

The Δxmax (RA ) data for 3D nucleation may be described using

the empirical dependence Δxmax = ARA p , where A and p are fit-
ting parameters. This type of dependence may be derived on the
assumption that the 3D nucleation rate J at a given saturation
concentration c2 of solution containing antisolvent content Δx is
given by an empirical power-law relation of the form[6,9,14,19,20]
J = k(Δx)m (B1)
where k and m are empirical constants. According to this ap-
proach, the final expression relating maximum antisolvent con-
tent Δxmax in the solution as a function of the rate RA has the
form
( ) 1 B
ln Δxmax = Φ + ln RA (B2)
m a2 Δx
where the parameter Φ is a constant.
The above relation is usually known as Nývlt-like equation, but
the form of the parameter Φ depends on the assumptions used
in the expressions of excessive antisolvent composition Δx in dif-
ferent approaches.[6,14] The main problem with Equation (B1) is
that Δx is not directly related to the actual solute concentration
According to Equation (B6), ln(Δxmax ) increases linearly with an
increase in lnRA , with intercept Φ and slope 1/m. Since the con-
stant Φ is related to the values of f, K, m, and a2 , one expects that
the value of Φ depends on factors, such as the solution tempera-
ture and the nature and concentration of impurity, that are likely
to affect the values of the above quantities. The main limitation
of this approach is that K and m are empirical constants without
any physical meaning.
In contrast to the empirical power-law dependences of the nu-
cleation rate J on Δx assumed above, the classical 3D nucleation
theory gives[14,20]
( )
J = J0 exp − ( )2 , (B7)
where J0 is determined by the kinetics of association and dissoci-
ation of monomers to developing nuclei, the parameter
( )3
𝛾Ω2∕3
B=𝜅 (B8)
kB T

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and the solute−solvent interaction parameter Keywords

ΔHsS − ΔHsA ammonium dihydrogen phosphate, antisolvent crystallization, impurity
a2 = . (B9) adsorption, metastable zone width, solution temperature
RG T

In relations (B8) and (B9), Ω is the molecular volume, 𝛾 is the Received: November 18, 2019
Published online:
solute−medium interfacial energy at temperature T, kB is the
Boltzmann constant, 𝜅 is the shape factor for the nuclei (𝜅 =
16𝜋/3 for spherical nuclei), ΔHsS and ΔHsA are the dissolution [1] J. W. Mullin, Crystallization, 4th ed., Butterworth-Heinemann, Oxford,
enthalpies of solvent S and antisolvent A, respectively, and RG is UK 2001.
the gas constant (RG = NA kB , NA is the Avogadro number). From [2] L. N. Rashkovich, KDP-Family Single Crystals, Adam Hilger, Bristol,
Equations (B5) and (B7) to eliminate J and taking Δx = Δxmax for UK 1991.
MSZW, upon rearrangement one obtains the relation between [3] K. Sangwal, Additives and Crystallization Processes: From Fundamentals
Δxmax and RA in the form to Applications, Wiley, Chichester, UK 2007.
[4] Z. Amtul, A. U.Rahman, R. A. Siddiqui, M. I. Choudhary, Curr. Med.
( )−2 ( ) Chem. 2002, 9, 1323.
Δxmax = F 1 − Z ln RA , (B10) [5] J. Prywer, M. Olszynski, J. Cryst. Growth 2013, 375, 108.
[6] K. Sangwal, E. Mielniczek-Brzóska, Cryst. Res. Technol. 2016, 51, 475.
where [7] K. Sangwal, E. Mielniczek-Brzóska, J. Cryst. Growth 2016, 451, 139.
() [8] K. Sangwal, E. Mielniczek-Brzóska, Cryst. Res. Technol. 2017, 52,
a22 J0 1600361.
F= ln , (B11)
B f a2 [9] D. O’Grady, M. Barrett, E. Casey, B. Glennon, Chem. Eng. Res. Des.
( ) 2007, 85, 945.
Z = ln f a2 ∕J0 . (B12) [10] C. T. O’Ciardha, P. J. Frawley, N. A. Mitchell, J. Cryst. Growth 2011,
328, 50.
According to Equation (B10), Δxmax −2 decreases linearly with [11] Y. Zhang, Y. Jiang, D. Zhang, Y. Qian, X. Z. Wang, Chem. Eng. Res. Des.
lnRA with intercept F and slope FZ. As seen from Equations 2015, 95, 187.
(B11) and (B12), F and Z are quantities with well-defined physical [12] K. K. Chaitanya, D. Sarkar, Chem. Eng. Technol. 2014, 37, 1037.
meaning, and F/Z = a2 2 /B. Consequently, from variations in the [13] A. Jaiswal, D. Sarkar, Cryst. Res. Technol. 2015, 50, 347.
[14] K. Sangwal, Nucleation and Crystal Growth: Metastability of Solutions
values of these quantities as functions of solution temperature
and Melts, Wiley, Hoboken, New York 2018.
and impurity concentration, the effects of these parameters
[15] K. Sangwal, E. Mielniczek-Brzóska, Cryst. Res. Technol. 2007, 42, 531.
on the antisolvent crystallization behavior of a system can be [16] O. Söhnel, P. Novotny, Densities of Aqueous Solutions of Inorganic Sub-
discussed. stances, Akademia, Prague 1985.
[17] J. Ościk, Adsorption, PWN-Polish Scientific Publishers, Warsaw,
Poland 1982.
Conflict of Interest [18] K. Sangwal, J. Cryst. Growth 1999, 203, 197.
[19] N. Kubota, J. Cryst. Growth 2008, 310, 4647.
The authors declare no conflict of interest. [20] K. Sangwal, Cryst. Res. Technol. 2010, 45, 909.

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