Interactions of salicylic acid derivatives with calcite crystals

Journal of Colloid and Interface Science 365 (2012) 296–307

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Journal of Colloid and Interface Science www.elsevier.com/locate/jcis

Interactions of salicylic acid derivatives with calcite crystals Marko Ukrainczyk a, Matija Gredicˇak b, Ivanka Jeric´ b, Damir Kralj a,⇑ a b

- Boškovic´ Institute, Bijenicˇka cesta 54, P.O. Box 180, HR-10002 Zagreb, Croatia Laboratory for Precipitation Processes, Ruder - Boškovic´ Institute, Bijenicˇka cesta 54, P.O. Box 180, HR-10002 Zagreb, Croatia Laboratory for Carbohydrate, Peptide and Glycopeptide Research, Ruder

a r t i c l e

i n f o

Article history: Received 27 July 2011 Accepted 7 September 2011 Available online 12 September 2011 Keywords: Calcium carbonate Calcite Salicylic acid derivatives Crystal growth kinetics Adsorption Drug delivery

a b s t r a c t Investigation of basic interactions between the active pharmaceutical compounds and calcium carbonates is of great importance because of the possibility to use the carbonates as a mineral carrier in drug delivery systems. In this study the mode and extent of interactions of salicylic acid and its amino acid derivates, chosen as pharmaceutically relevant model compounds, with calcite crystals are described. Therefore, the crystal growth kinetics of well defined rhombohedral calcite seed crystals in the systems containing salicylic acid (SA), 5-amino salicylic acid (5-ASA), N-salicyloil-L-aspartic acid (N-Sal-Asp) or N-salicyloil-L-glutamic acid (N-Sal-Glu), were investigated. The precipitation systems were of relatively low initial supersaturation and of apparently neutral pH. The data on the crystal growth rate reductions in the presence of the applied salicylate molecules were analyzed by means of Cabrera & Vermileya’s, and Kubota & Mullin’s models of interactions of the dissolved additives and crystal surfaces. The crystal growth kinetic experiments were additionally supported with the appropriate electrokinetic, spectroscopic and adsorption measurements. The Langmuir adsorption constants were determined and they were found to be in a good correlation with values obtained from crystal growth kinetic analyses. The results indicated that salicylate molecules preferentially adsorb along the steps on the growing calcite surfaces. The values of average spacing between the adjacent salicylate adsorption active sites and the average distance between the neighboring adsorbed salicylate molecules were also estimated. Ó 2011 Elsevier Inc. All rights reserved.

1. Introduction In the recent years, much attention has been paid to the development of various systems that could be used for the controlled introduction and/or release of active pharmaceutical compounds in living organisms and tissues. In particular, the studies of basic interactions between the active compounds and the specific drug carriers, which predominantly affect their pharmacodynamic properties and therapeutic efficacy, are of great importance. Even though the organic drug delivery systems, like liposomes or micelles, are commonly used, some inorganic carriers, in the form of micro- and nano-sized particles, have been recently proposed for modulating the delivery of active pharmaceutical compounds [1,2]. However, among the mineral drug delivery systems, silica particles have been the most frequently studied, in spite of its evident drawback for clinical and biomedical applications – poor biodegradability. On the contrary, due to the recognized biocompatibility, nontoxicity and low price of calcium carbonate, it is a potential candidate for the use as mineral carrier of pharmaceutical substances. Moreover, due to its demonstrated ability to dissolve in a controlled manner, calcium carbonate has a great potential as the next generation of drug delivery system [3–6]. ⇑ Corresponding author. E-mail address: [email protected] (D. Kralj). 0021-9797/$ - see front matter Ó 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.jcis.2011.09.009

Calcium carbonate appears in the form of different hydrates (monohydrate, hexahydrate and amorphous calcium carbonate) and three anhydrous polymorphic modifications (calcite, aragonite, vaterite). Calcite is thermodynamically stable modification under standard conditions and it appears in various morphologies, typically as rhombohedral crystals bounded by the most stable calcite surfaces, the {1 0 4} faces [7,8]. When in contact with aqueous solutions, calcite presents complex heterogeneous system because of a vast number of dissolved ionic species or surface complexes, which are in dynamic equilibrium with crystal surface(s). In addition, it is known that the calcite surfaces chemisorb the layer of dissociated water molecules as well as lattice ions [9–11]. When the dissolved organic compounds are in contact with the calcite crystals, they can adsorb onto the calcium sites on the surface, thus competing with other ions present in the solution, mainly hydroxide or carbonate ions. Calcite exhibits exceptional chemical affinity for organic molecules having polar functional groups, such as carboxyl and hydroxyl groups. Most extensively studied organic molecules are fatty acids, as the oleic and stearic acids are, which are used to control the hydrophobicity of calcite when it is applied as filler in the polymer matrices. Thus, it was found that stearic acid molecules chemisorb on the calcium sites on its surface by means of the carboxyl groups and that the molecules are vertically oriented in relation to the surface, forming a monolayer [12–14]. However, the presence of a

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hydrophobic group enhances the adsorption of fatty acid molecules on the crystal surfaces. Apart from the fatty acids, the interaction mechanisms of other organic molecules with the calcite surface are still poorly understood. Mann et al. studied the changes of calcite, caused by the addition of an a,x-dicarboxylic acid, and found a correlation between the morphology of the crystals and the number of carbon atoms in the main chain of the molecules that preferentially adsorb onto the surfaces [15]. Geffroy et al. also attempted to clarify the adsorption mechanism of carboxylic acids having different numbers of functional groups [16] and concluded that the molecules with two carboxyl groups form a ring-structured surface complex with the calcium ions. In addition, they found that the five-membered chelate ring, consisting of surface calcium ions and dicarboxylate, is the most stable one, followed by six- and seven-membered chelate rings. The presence of a-hydroxyl groups (a-hydroxycarboxylates) could additionally enhance the adsorption. A vast number of studies described in literature have been motivated by finding the effective additives for the scale prevention. It was shown that the degree of inhibition of calcite crystal growth, being a consequence of the adsorption of molecules on the surface, depends on the number and the orientation of stereochemicaly functional carboxyl groups, as well as on the flexibility of the adsorbing molecules [17]. Recently, an advanced kinetic model, describing the crystal growth inhibition in the presence of additives [18–20], was applied for studying the interaction of calcium complexing substances, carboxylic acids like citric acid or EDTA, with calcite and aragonite crystals [21]. It was shown that the complexing agents have more pronounced interaction with aragonite than with calcite, as a consequence of different surface structures of the two polymorphs. Crystal growth kinetic approach has also proved to be a useful method to study the extent and mode of calcite/polypeptide interactions, involved in biomineralization processes [22]. In the present work, the mechanism of interactions between the salicylic acid and its functional derivates, used as the models for active pharmaceutical substances (non-steroidal anti-inflammatory drugs), with well defined rhombohedral calcite seed crystals, was studied. The data on the kinetics of calcite seeds grown in the presence of either, salicylic acid, 5-amino salicylic acid, N-salicyloil-L-aspartic acid or N-salicyloil-L-glutamic acid, carried out at relatively low initial supersaturation and moderate pH, were compared with the appropriate spectroscopic, electrokinetic and adsorption measurements, in order to set up a consistent model of interactions at the solid–liquid interfaces.

washed with saturated NaCl solution and water, and purified by HPLC. Yields of 83% of N-Sal-Asp and 78% of N-Sal-Glu were obtained. Physical and chemical constants, as well as the NMR shifts of thus prepared compounds were compared with standards in order to confirm their purity. The molecular structures of SA, 5-ASA, N-Sal-Asp and N-Sal-Glu are given in Table 1. The calcite crystals used in seeding experiments were prepared by semicontinuous carbonation method [23,24], which enables the preparation of pure and well defined precipitate. The total dissolved calcium concentration was maintained apparently constant at ctot = 2.0 mmol dm3, by controlling the addition of Ca(OH)2 suspension (c(Ca(OH)2) = 100 g dm3) into the thermostated bench-scale glass reactor of V = 6.0 dm3. As a measure of the dissolved calcium concentration, the electrical conductivity of the reacting mixture was continuously monitored: the concentration and the conductivity were experimentally correlated. The concentration of total dissolved calcium was determined by means of an ion chromatography system ICS-1000 (Dionex) fitted with a CS16 Analytical Column. Gas mixture with approximately 20% CO2/and 80% N2 (Messer) was introduced at a constant flow rate, Q = 1.0 dm3 min1, into the reactor through the nozzles at the bottom of baffles. The temperature, h = 50 °C, and the stirring rate, n = 1100 min1, were kept constant during the semicontinuous carbonation process that lasted for 3 h. The precipitate was separated by filtration through a membrane filter, thoroughly washed with deionised water, resuspended in 6 dm3 of deionised water and allowed to age at room temperature for 2 months. Finally, the crystals were filtered and dried at 105 °C. The mineralogical composition of the precipitate was determined by FT-IR spectroscopy (FT-IR Mattson spectrometer, Genesis Series) using KBr pellet technique and by X-ray powder diffraction (Philips PW1830 with a Cu Ka radiation). The composition was identified according to the ICDD Powder Diffraction File and/or by comparing the spectra with

Table 1 Molecular structure of SA, 5-ASA, N-Sal-Asp and N-Sal-Glu, corresponding dissociation and calcium complexation constants. Molecular structure

OH

pKa3

pK CaHL2n

–

0.4a

5.8b

12.0b

(0.4)c

–

–

–

2.73 ± 0.12d

–

–

–

2.61 ± 0.09d

pKa1

O

pKa2

a

3.0

13.8

2.0b

a

OH

SA

OH

O OH

5-ASA

2. Experimental 2.1. Materials Analytically pure chemicals, CaCl2, NaHCO3, HCl, NaOH Ca(OH)2, salicylic acid (SA) and 5-amino salicylic acid (5-ASA) (Merck) and deionized water of high quality (conductivity <0.055 lS cm1), were used in experiments. N-salicyloil-L-aspartic acid (N-Sal-Asp) and N-salicyloil-L-glutamic acid (N-Sal-Glu) were prepared according to the following procedure: salicylic acid (10 mmol) and N-hydroxysuccinimide (11 mmol) were dissolved in dimethylformamide (DMF) and placed in an ice bath. N,N0 -dicyclohexylcarbodiimide (12 mmol) was dissolved in DMF, added dropwise into the initial solution, stirred for 30 min at 0 °C and afterwards at room temperature, overnight. The solution was filtered and the mother liquor was added dropwise into the suspension of the selected amino acid (H-Asp-OH or H-Glu-OH) (11 mmol) and KHCO3 (11 mmol), and stirred at room temperature for 2 h. The reaction mixture was filtered and the filtrate was acidified by means of citric acid to pH = 2–3. The product was extracted with ethyl acetate,

NH2 O N-SalAsp

OH O

OH OH

N H

O O

N-SalGlu

OH

O N H

a b c d

Ref. [25]. Ref. [26]. Estimated. This work.

OH

OH O

298

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the appropriate FT-IR standards. The morphology and the size distribution of the precipitate were observed by scanning electron microscopy (SEM, Philips XL20 and Philips XL30), while the specific surface area was determined by the multiple BET method (Micromeritics, Gemini), using liquid nitrogen. 2.2. Determination of calcium complexation constants The stability constants of the calcium complexes with derivatives of salicylic acid (ASA, N-Sal-Asp and N-Sal-Glu), which are not reported in the literature, were estimated by using a calcium selective electrode and calomel reference electrode, type K401. Potentiometric measurements were made by means of pH/ion meter (pHM 240, Radiometer) at 25 ± 0.1 °C. Titrations were carried out by adding portions (0.20 cm3) of salicylate derivative stock solution (c = 0.0153 mol dm3) into 20 cm3 of an aqueous CaCl2 solution, co = 1.04  104 mol dm3. Relatively low concentration range of salicylate derivatives (1.53  104 < co < 1.53  103) was used in order to avoid possible interferences of calcium electrode with organic acid molecules at higher concentrations. The pH of the standard solutions and titrated systems (pH = 7.3) was adjusted by adding NaOH solution, c = 1.0 mol dm3. Ionic strength was adjusted by the addition of 0.01 mol dm3 NaCl solution. The calcium complexation constant, K, was calculated by using the expression:

K¼

½CaHL2n   cð2nÞ ½Ca2þ   c2 ½HLn   cn

:

ð1Þ

In the above expression the square brackets denote molar concentrations of the ionic species, while the cz is the activity coefficient of z-valent ions, calculated by using the Davies’ modification of the Debye–Hückel equation [27]. The salicylate concentration, [HLn], and the complex concentration, [CaHL2n], were defined as:

½CaHL2n  ¼ ½Ca2þ o  ½Ca2þ 

ð2Þ

½HLn  ¼ ½HLn o  ½CaHL2n 

ð3Þ

where [Ca2+]o and [HLn]o are the initial concentrations of calcium and salicylate, while [Ca2+] is the calcium concentration obtained by titration, using calcium selective electrode. 2.3. Crystal growth kinetics 2.3.1. Experimental procedures The kinetic experiments of the seeded growth of calcite were performed in a thermostated double-walled glass vessel (400 cm3). The vessel was tightly closed by a Teflon cover in order to minimize the exchange of carbon dioxide between the reaction system and the air. The sodium bicarbonate solution was always freshly prepared by dissolving NaHCO3 in water while the calcium chloride solution was made by appropriate dilution of a stock solution. The supersaturated calcium carbonate solutions were prepared by mixing equal volumes of CaCl2 and NaHCO3 solutions: the initial concentrations of both reactant solutions were identical, 3 3 ci ðCa2þ Þ ¼ ci ðCO2 3 Þ ¼ 5:0  10 moldm . The initial pH of the system was adjusted to pH0 = 7.61, by adding an appropriate amount of HCl solution (1.7  104 mol dm3) into CaCl2 solution. The final pH of the systems dropped to about pHeq = 7.1, which is an apparent equilibrium for calcite. The experiments were started by introducing 250 mg dm3 of calcite seed crystals in the system immediately after mixing reactant solutions. Seed was previously suspended in 0.5 cm3 of ethanol and homogenized by means of an ultrasonic bath for 40 s. Preliminary measurements showed that the addition of 0.5 cm3 of ethanol did not change the pH of the system. An appropriate amount of salicylic acid or one of its

derivatives (SA, 5-ASA, N-Sal-Asp, N-Sal-Glu), previously neutralized with NaOH, was added to the calcium solution. The concentrations of the salicylic acid derivates used in experiments varied in the range 0.7 mmol dm3 < ci(SA, 5-ASA) < 7.2 mmol dm3 and 0.05 mmol dm3 < ci(N-Sal-Asp, N-Sal-Glu) < 1.2 mmol dm3. All experiments were carried out at 25 °C and the systems were continuously stirred at a constant rate by means of a Teflon-coated magnetic stirring bar. The propagation of the precipitation process was followed by measuring pH of the solution using a combined glass-calomel electrode (GK 2401C), connected to a digital pH meter (PHM 290, Radiometer). Samples of the suspension were periodically taken from the system, filtered through the 0.22 lm membrane filters, and analyzed by ion chromatography system ICS-1100 (Dionex) fitted with CS16 Analytical Column, in order to determine the concentration of total dissolved calcium. At the end of each experimental run, the total suspension volume was filtered through a membrane filter, washed with small volume of water, and dried at 105 °C. After separation, the solid phase (calcite with adsorbed salicylate molecules) was analyzed by means of the diffuse reflectance UV/VIS spectroscopy (Ocean Optics). Spectral reflectance of the calcite samples were measured relative to a blank calcite sample and were shown as Kubelka–Munk functions. The morphology of the calcite crystals was examined by scanning electron microscopy (Philips XL20). 2.3.2. Treatment of data Calculations of the solution composition at any moment of the calcite crystal growth process were based on continuous pH measurements. The total CaCl2, NaHCO3, HCl, NaOH, salicylates (i.e. SA (H2Sal), 5-ASA (H2ASal), N-Sal-Asp (H3SalAsp) or N-Sal-Asp (H3SalGlu)) concentrations, that were initially added to the system, were used for calculating the molar concentrations and activities of relevant ionic species (see Appendix A). The crystal growth rate, R, was calculated by numerical differentiation of the total dissolved calcium concentration, Catot, as a function of time, t, and normalized with respect to the surface area of the precipitate, A, at a particular moment:

R ¼ dCatot =ðdt  AÞ:

ð12Þ

During the growth of calcite crystals, the total surface area increases. This increase was also considered in calculations. Thus, the total surface area of calcite at time t was calculated by using the data on the concentration of precipitated total calcium carbonate, cppt:

 2=3 cppt  M A ¼ Ai 1 þ ; mi

ð13Þ

where Ai is the initial surface area of calcite seed, mi is the initial mass concentration of calcite seed and M is the molar mass of calcium carbonate. 2.4. Adsorption experiments The solutions of SA, 5-ASA, N-Sal-Asp and N-Sal-Glu were prepared by dissolving the appropriate amount of the acids neutralized with NaOH, in the previously prepared saturated calcite solution (equilibrated at pH  7.34). The calcite suspensions were prepared by dispersing 2.5 g of calcite in 5.0 cm3 of saturated calcite solutions and additionally homogenized by means of an ultrasonic bath for 30 s. The suspensions were kept in the tightly closed flasks and shacked for 8 h in a thermostated water bath (Haake, SWB 20) at 25 °C. Calcite was separated by centrifugation at nc = 4000 min1 for 20 min. The amount of acids adsorbed was calculated from the difference between the measured initial and final concentrations in solution and the specific surface area of the

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calcite applied. The concentration of salicylates in supernatant solution was determined spectrophotometrically (Perkin Elmer, Lambda 35). The absorbance was measured at kmax = 298 nm, which is a characteristic band for the protonated benzene ring [28]. The final pH of the solutions was measured. However, no significant effect of the pH, in the range of 7.0 < pH < 8.0, on the spectra of the used organic acids were observed. 2.5. Measurements of zeta potential A zeta potential of respective calcite samples was measured by electroacoustic spectrometer (Dispersion Technology, DT 1200) with a titration unit built in. The calcite samples (m = 3.0 g) were dispersed in 60 cm3 of saturated calcite solutions (equilibrated at pH  7.0) and left for 12 h to equilibrate in tightly closed flasks. Suspensions were homogenized by means of an ultrasonic bath for 30 s before measurements. Suspensions were continuously stirred at a constant rate by means of a Teflon-coated magnetic stirring bar and titrated with previously neutralized solutions of SA, 5-ASA, N-Sal-Asp or N-Sal-Glu. Equilibration time for each titration point was 15 min. The pH and temperature of the suspensions were continuously monitored during analyses and were found to be about pH = 7.38 ± 0.27 and h = 24.5 ± 0.5 °C. 3. Results and discussion In order to ensure a satisfying reproducibility and comparison of the results of somewhat different type of experiments, like crystal growth kinetics, spectroscopy, adsorption or electrophoretic mobility measurements, the same batch of calcite seed was used. Thus, possible errors caused by minute difference in the physical–chemical properties of solid phase, could be avoided and reliable deduction on interaction mechanisms are possible. The seed material prepared by semicontinuous carbonation procedure in the Ca(OH)2(s)–H2O(l)–CO2(g) precipitation system, aged for 2 months, was found to consist of pure calcite crystals of regular rhombohedral morphology, having a typical size of 1 lm and a specific surface area of s = 2.20 ± 0.09 m2 g1. 3.1. Crystal growth kinetics The calcite crystal growth experiments performed in model systems, as well as in systems containing the salicylic acid derivatives, were initiated at relatively low driving force (initial supersaturation, S  1 = 1.52) and at practically neutral pH. At such conditions the precipitation proceeds through the crystal growth of calcite seed and no spontaneous nucleation in the bulk could be expected. Actually, it was found that the systems were stable for at least 10 h. In addition, a possible degradation of salicylic acid derivatives, that could take place at higher pH, particularly degradation of 5-ASA [26], was avoided. Fig. 1 shows typical progress curves of calcite growth, ctot versus time, obtained in the model systems (bold lines), as well as in the systems containing different concentrations of SA, 5-ASA, N-SalAsp or N-Sal-Glu. It is evident that calcite started to grow as soon as the seed was introduced into the reactant solution. It is also evident that, in comparison to the model systems, the crystal growth in the additive containing systems is progressively reduced by increasing salicylate concentration, while in the presence of the N-Sal-Asp the growth apparently terminates at a specific concentration level. In order to conclude on the controlling growth mechanism of calcite in the model system, at given experimental conditions, the kinetic data were analyzed by carrying out the appropriate tests [29,30]. Thus, Fig. 2 shows the test plots for: (a) spiral growth

299

(R = ks(S  1)lnS) and (b) surface nucleation (R = keS7/6(S  1)2/3 (lnS)1/6exp[Ke/lnS]  keF(S)exp[Ke/lnS)] mechanisms; the sets of at least three independent experiments are shown. The obtained linearity for the spiral growth test indicates that at given conditions calcite growth is controlled by surface reaction, that is, the growth predominantly proceeds by the addition of constituting ions into the spiral step emerging from the surface dislocation [29,30]. From the slope of the straight line, the rate constant, ks = 2.20 ± 0.03 lmol dm3 m2 s1, was obtained. The spiral growth mechanism obtained from our results, is consistent with some previous studies in which the growth of calcite at low supersaturation was investigated as well [22,31–34]. However, by using the constant composition technique, Reddy and Hoch [17] have experimentally determined the growth rate of R = 1.65 ± 0.02 lmol dm3 m2 s1 for calcite at S = 2.1 and pH = 8.5, which is comparable with growth rate at the identical supersaturation, R = 1.80 ± 0.03 lmol dm3 m2 s1, found in this study. The observed inhibition of the calcite growth in the presence of salicylate derivatives, seen as lowering of the slope of the respective curves, as well as the appearance of the dead zone in the case of N-Sal-Asp, could be explained by the action of two possible mechanisms. The growth rate reduction can be caused, either by the adsorption of salicylate molecules on the crystal surfaces and blocking the active growth sites, or by complexation of Ca2+ in solution, thus causing a lowering of the supersaturation1. In order to reveal the dominating mechanism and to investigate a mode of interactions between the selected model molecules and calcite, the crystal growth rates, R = dc/(dtA), calculated from the progress curves, were correlated with the solution supersaturation, as well as with the concentrations of salicylates. Fig. 3 shows the growth rates obtained for different salicylate derivatives of different concentrations, plotted as a function of relative supersaturation. To make a comparison, the growth rates of calcite obtained in the systems without additives are also shown and indicated as bold lines. It is evident that in the system containing N-Sal-Glu, and particularly N-Sal-Asp, the inhibition is significantly stronger than in the SA or 5-ASA systems, at the same additive concentration. Actually, the growth rate reductions in the SA and 5-ASA systems are weak, so the estimate of kinetic parameters is rather unreliable. It is also evident that different N-Sal-Asp concentrations caused the termination of calcite growth (dead zone) at the well defined values of critical supersaturation, S⁄. According to the generally accepted models that describe the impact of impurities on the crystal growth kinetics [20,35], the critical supersaturation is a value below which a crystal does not grow. That is, when the advancing step of the growing crystal contacts the adsorbed additive, it will be stopped at a supersaturation value at which the distance between the adsorbed molecules is smaller than the diameter of the respective critically sized surface nucleus. On the contrary, when the distance is larger than the diameter, the step will curl around the additive molecules and slow down the growth. Since it was found that in the model system the growth proceeds at the spiral steps, described by the expression, R0 = ks(S  1)lnS, the expression for the growth rate as a function of reduced (critical) supersaturation, in the presence of additives, can be derived by considering the terms related to the size of critical surface nucleus and average spacing between the active sites available for adsorption of additive molecules at the crystal surface [18,19,36]:

R ¼ ks ðS  1Þðln S  ln S Þ:

ð14Þ

1 The calculations of solution speciation showed that in the systems of the highest calcium and N-Sal-Asp concentrations, (c(Ca)i = 5.0  103 mol dm3, c(N-SalAsp) = 1.2  103 mol dm3) approximately 9.8% of the total calcium is in the form of Ca-N-Sal-Asp complex. Consequently, the supersaturation is lowered to the value of S  1 = 1.38.

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Fig. 1. Progress curves, ctot versus time, of the seeded calcite growth in the systems containing different concentrations of SA, 5-ASA, N-Sal-Asp and N-Sal-Glu). Control systems, not containing salicylates are also indicated (bold lines).

The solid lines drawn through the experimental points shown in Fig. 3 are obtained by fitting the Eq. (14) by using the least-squares method. The values of kinetic parameters, S⁄ and ks, are summarized in Table 2. It is evident that the critical supersaturation continuously increases with increasing the additive concentration and that the effect of additive concentration on critical supersaturation is more pronounced for N-Sal-Asp than for N-Sal-Glu. The obtained relatively low values of S⁄ indicate that the number of active adsorption sites available for N-Sal-Asp molecules are limited and that they are located along the steps (including kink sites) [19], rather than the effective adsorption occur at the surface terraces. On the other hands, it can be said that the N-Sal-Asp molecules are rather mobile upon the arrival at the surface so they could easily diffuse along the terraces and attach at the step lines, thus blocking the integration of solute molecules into the growth active sites. Our assumptions are consistent with the results of computational analysis of the interactions of organic molecules containing carboxyl functional groups that show their stronger interactions with the calcium ions at the step edges, rather than with the ions at the terraces of the calcite surfaces [37–39]. Fig. 4 shows a possible model of interactions between N-Sal-Asp with rhombohedral calcite surface at the step edge sites. Each calcium ion at the step position (=Ca) has two broken bonds that resulted with the unsaturated coordination, z = 2/3+. The addition of increasing concentrations of N-Sal-Asp or N-SalGlu causes a slight decrease of the values of rate constants, ks, which is somewhat surprising because these two parameters are not supposed to be correlated, as indicated by the respective expression for crystal growth kinetics (Eq. (14)). According to

explanation given by Sangwal [18,19], the decrease of experimentally obtained growth rate constants is a consequence of the increasing activation energy for integration of calcium carbonate ions into the crystal lattice. The activation energy increase is associated with increasing competition between N-Sal-Asp or N-SalGlu molecules and constituent ions for their integration into the kink positions during the growth. The extent of interactions of different additives with mineral surface can be estimated by means of Kubota and Mullin’s model [20], which postulate that the overall reduction of the crystal growth rate, R/R0, is determined by both, the coverage of adsorption-active sites by the additive, heq, and by the additive effectiveness factor, a:

R=R0 ¼ 1  aheq :

ð15Þ

In the above expression the concentration of the additive in solution is derived by applying the appropriate adsorption isotherm (e.g. Langmuir isotherm), so the model is described by equation:

R=R0 ¼ 1  a½K ad c=ð1 þ K ad cÞ;

ð16Þ

in which c is the additive concentration and Kad is the Langmuir constant. Fig. 5 shows the plots of the relative growth rate reduction for calcite seeds at different relative supersaturations (R/R0) as a function of different concentrations of SA, 5-ASA, N-Sal-Asp or N-Sal-Glu (R is the growth rate in the additive containing system and R0 is the growth rate in the control system, at given supersaturation). In the case of SA, 5-ASA or N-Sal-Glu the relative growth rates, R/R0, gradually decrease with increasing the respective salicylate concentrations and asymptotically approach certain nonzero

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301

decrease with increasing the supersaturation. This indicates the existence of numerous active sites for adsorption and the separation of impurities that is smaller than the size of critical surface nucleus at the given supersaturation [20]. In order to additionally verify the proposed model of interaction between the different salicylate derivatives and the calcite crystals, some thermodynamic parameters were calculated by using the experimentally determined kinetic data of the additive effectiveness factor, a. At that, it was considered that the effectiveness of an additive at the given growth conditions (supersaturation and temperature) can be related to the radius of the critically sized surface nucleus, r 2D , and the average spacing, L, between the adsorption active sites through the expression [19,20,40]:

a¼

r 2D : L

ð17Þ

Radius of the critically sized surface nucleus was defined by GibbsThompson equation, adjusted for the two-dimensional nucleus:

r2D ¼

Fig. 2. Test plots for the spiral growth (a) and surface nucleation (b) mechanisms for the calcite crystals grown in the model precipitation system (system without salicylates).

values.2 On the other hand, N-Sal-Asp causes a significant reduction of relative growth rates and a dead zone can be observed even at relatively low additive concentration. It should be noted that the data are complementary to the results shown in Fig. 3. The solid lines drawn through the experimental points in Fig. 5 are obtained by fitting the respective set of data with the function given by Eq. (16). However, thus obtained values of Kad (Table 3) were used for verification of interaction mechanisms of respective salicylate with calcite surfaces by comparing with data obtained in distinct set of adsorption measurements. The calculated, relatively low, values of Kad for SA and 5-ASA, indicate their weak affinity for the adsorption sites at the calcite surface, while the Kad values of N-Sal-Asp and N-Sal-Glu (Kad(NSal-Asp) > Kad(N-Sal-Glu)) are significantly higher, indicating higher attraction, respectively. The values of effectiveness factor, a, obtained by fitting the experimental data sets of SA, 5-ASA and N-Sal-Glu (Fig. 5, insets) are found to be lower than 1. According to the applied Kubota & Mullin’s model, the reduction, but not a complete prevention of the calcite crystal growth in the presence of relatively high concentrations of SA, 5-ASA or N-Sal-Glu, points out to the complete surface coverage and the separation between adsorbed molecules, which is larger than the size of the critical surface nucleus. On the other hand, the values of a (N-Sal-Asp) are higher than 1 and

2 It should be emphasized that the applied concentration range of SA and 5-ASA is about 6 times higher than in the case of respective Asp or Glu derivatives.

ca2 : kB T m ln S

ð18Þ

In the above expression c is the edge free energy of the step, a is the size of the growth unit, kB is the Boltzmann constant, T is the temperature and m is the number of ions in the formula unit of the growing crystal (for CaCO3 m = 2). The values of the effectiveness factor, a, determined from growth experiments and presented as a function of the reciprocal of supersaturation, 1/lnS, are shown as the insets in Fig. 5. As could be expected (Eq. (18)), a increases linearly with 1/lnS and with the slope equal to ca2/kBTmL. Consequently, if the values of the edge free energy, c, and a are known, the average spacing between the adsorption active sites located on the step lines, L, can be estimated. The values presented in Table 3 are calculated by taking c = 35.4 pJm1 and a = 0.450 nm [34]. Since the average spacing, L, is a parameter related to the adsorption characteristics of adsorbate and is specific for each combination of additive and crystal surface, the estimated values of L, shown in Table 3, seem to be realistic, although direct experimental verification is impossible. The minimum value should be about the dimension of the growth unit size, a, but it can be even larger. 3.2. Adsorption In order to support the growth kinetic data and further investigate the mode and extent of selected salicylates interactions with calcite, the equilibrium adsorption measurements in salicylates/ calcite systems were performed and compared. Fig. 6 shows the adsorption isotherms of SA, 5-ASA, N-Sal-Asp and N-Sal-Glu obtained by equilibration with calcite seed, in the system of saturated calcite solution at pH = 7.34 ± 0.21. The shape of the isotherms is typical for the Langmuir model of adsorption, described by the expression:

C¼

Cm K ad ceq
: 1 þ K ad ceq

ð19Þ

In the above expression C is the respective surface concentration of adsorbate, Cm is the saturation surface concentration of adsorbate, ceq is the concentration of adsorbate in solution in equilibrium with the solid phase and Kad is the adsorption constant. Analysis of the adsorption data by applying Eq. (19), allows the simultaneous determination of the adsorption constant, Kad and the saturated surface concentration, Cm. The values are given in Table 3. Since, Kad reveals the affinity of particular salicylates molecules for the adsorption sites, a reasonable agreement between thus obtained values and those obtained by analysis of kinetic data, additionally supports the validity of the kinetic model described by Eq (16). Actually, the values obtained from the kinetic data are slightly low-

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Fig. 3. Crystal growth rate of calcite as a function of relative supersaturation in the systems containing different concentrations of SA (a), 5-ASA (b), N-Sal-Asp (c) and N-SalGlu (d). The lines are fitted according to Eq. (14). Model systems are shown as solid bold lines. The values of calcite growth rate constans, ks, obtained in N-Sal-Asp (j) and NSal-Glu (h) systems are shown as a function of respective concentrations of the additives (e).

er, but such discrepancy may be ascribed to the fact that significantly higher mass concentrations of calcite in suspensions were used in equilibrium adsorption experiments [41]. It is also evident (Fig. 6 and Table 3) that the Cm values for SA, 5-ASA and N-SalGlu (0.49 lmol m2 > Cm > 0.56 lmol m2) are similar, while for N-Sal-Asp Cm is significantly higher (Cm = 0.73 lmol m2). The obtained results for Cm (N-Sal-Asp N-Sal-Glu > SA/5-ASA) are consistent with some previous investigations in which the structure

of carboxylic acids was correlated with their ability to form surface complexes with calcite [16,21]. According to the authors, the adsorption occurs by complexation of two carboxylic groups from the same molecule, with a single –Ca+ surface site, so a surface complex of chelate-like structure is formed (Fig. 4). At that, the fivemembered rings are the most stable, just like in the case of bonding the carboxylic groups of aminoacidic part of N-Sal-Asp, while the stability of six-membered ring (like in the case of N-Sal-Glu) is sig-

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303

Table 2 Kinetic parameters (critical supersaturations, S⁄ and rate constant, ks) obtained for the crystal growth of calcite in the presence of different N-Sal-Asp and N-Sal-Glu concentrations. c (mmol dm3)

S⁄

ks (lmol dm3 m2 s1)

N-Sal-Asp

0.05 0.11 0.2 0.4 0.6 0.8 1.2

1.05 1.12 1.21 1.31 1.39 1.52 1.60

2.12 2.07 2.10 1.92 1.71 1.66 1.69

N-Sal-Glu

0.11 0.4 1.0 1.2

1.05 1.08 1.10 1.12

2.18 2.13 1.87 1.85

Fig. 4. Model of interaction of N-Sal-Asp with calcium ion at the step position of calcite {1 0 4} crystal face. Each calcium ion at the step position (=Ca) has two broken bonds that resulted with the unsaturated coordination. Partial charge, z = 2/3+, felt in the vacant site above the surface Ca atoms.

nificantly lower. However, the formation of chelate-like surface complexes, in which hydroxyl groups (a-hydroxycarboxylates) are involved, is likely as well, but in the particular case of SA and 5ASA, OH group is in the b position. The intramolecular hydrogen bonding hinders additionally such mechanism of adsorption. In addition, it should be noted that the absolute values of Cm are relatively low, thus indicating the absence of typical monolayer and complete surface coverage. Since the selected salicylate molecules can cover an area of 0.5 nm2 (SA and 5-ASA) or 0.7 nm2 (NSal-Asp and N-Sal-Glu) and by assuming their parallel orientation,3 it can be concluded that about 19%, 20%, 22% and 31% of the surface area is accessible for the adsorption of SA, 5-ASA, N-Sal-Glu and N-Sal-Asp molecules, respectively. Since one of the objectives of the research performed in this work was to explore the possibility of using calcium carbonate as the mineral carrier in a drug delivery system, salicylic acid (SA) and 5-aminosalicylic acid (5-ASA) have been chosen as relatively simple models of anti-inflammatory drug compounds. In order to increase the adsorption of selected model salicylates onto calcite surface, it was necessary to introduce a suitable substituent that would serve as a binding agent. Due to the known tendency of amino acids and peptides to accumulate on surfaces, they were considered to be a suitable choice. However, a number of earlier studies clearly showed that calcite growth is inhibited by polyaspartic and

3 A parallel orientation of molecules is a plausible assumption for a low surface coverage [42].

polyglutamic acids even at very low concentrations, thus indicating strong additive-mineral interactions [22], the aspartic and glutamic acids are used as binding agents for promotion of drugcalcite interaction. In addition to the obtained strong impact of selected substituents on adsorption, a convenient advantage of their use is that they can be easily cleaved by hydrolysis after being set free from the calcite surface: the products of hydrolysis are salicylic acid (drug) and biologically compatible amino acids (binding agent). In spite of the fact that the exact mechanism of N-salicyloilL-aspartic acid (N-Sal-Asp) or N-salicyloil-L-glutamic acid (N-SalGlu) adsorption onto the calcite surface is a complex process with a large number of dynamic constrains, the obtained adsorption and kinetic results can contribute to the understanding of the basic interactions between the amino acid functional groups and the inorganic material. Consequently, the obtained data can also contribute to the practical use of such drug delivery systems. 3.3. Diffuse reflectance spectroscopy The presence of SA and respective derivatives (5-ASA, N-Sal-Asp and N-Sal-Glu) at the calcite surfaces are directly confirmed by diffuse reflectance UV/VIS spectroscopy (DR-UV/VIS) of the samples isolated after the crystal growth experiments. Fig. 7 shows the typical DR-UV/VIS spectra of the dried calcite samples that were in contact with solutions of different SA (spectra A) and N-Sal-Asp (spectra B) concentrations. In addition, the spectra of the calcite samples that were mechanically blended with about 1% (w/w) of

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Fig. 5. Relative growth rate of calcite seed crystals as a function of salicylate concentrations: SA (a), 5-ASA (b), N-Sal-Asp (c) and N-Sal-Glu (d) at different supersaturations. The curves are fitted according to Eq. (16). Insets show effectiveness factor of the corresponding additives as a function of the reciprocal supersaturation. The lines are fitted according to Eq. (18).

Table 3 Adsorption parameters obtained from the crystal growth kinetic data and from equilibrium adsorption data. L is the active growth site separation and l is a distance between the adsorbed molecules. For comparison, L and l are additionally given as a function of the calcite growth unit size (a = 0.450 nm [34]). Growth kinetic data 3

Kad (dm mol SA 5-ASA N-Sal-Glu N-Sal-Asp a b c

150 ± 21 173 ± 14 813 ± 55 1633 ± 91

1 a

)

Adsorption data L (nm) 4.95 ( 11a) 4.5 (10a) 2.7 ( 6a) 1.35 ( 3a)

l (nm)

c

28.8 ( 64a) 28.35 ( 63a) 5.4 ( 12a) 1.8 ( 4a)

Kad (dm3 mol1) b

204 ± 65 204 ± 65 905 ± 139 1723 ± 198

Cm (lmol m2)b 0.530 ± 0.08 0.530 ± 0.08 0.488 ± 0.03 0.729 ± 0.02

Means ± standard deviations of at least three determinations. Values ± standard errors obtained by the fitting. Given for additive concentration of c = 1.2 mmol dm3.

the powdered SA or N-Sal-Asp (dotted line) are used as standards. The spectra exhibited the UV absorption band at about ka = 303 nm, typical for the protonated phenol, while the observed bathochromic shift is a consequence of the interaction of salicylate molecules with the solid surface. In spite of the fact that the shown Kubelka–Munk diffuse reflectance spectra are not appropriate for quantitative determination, the increasing absorbance at ka = 303 nm of SA and N-Sal-Asp samples, isolated from the systems of increasing initial concentration of salicylates, indicate their enhanced adsorption on the calcite surface. However, by comparing the spectra of calcite/N-Sal-Glu and calcite/N-Sal-Asp samples, obtained from the system containing the identical concentration of additive molecules (Fig. 7 B, inset; c(salicylate) = 0.6 mmol dm3),

calcite/N-Sal-Asp system shows significantly stronger absorption for aspartic acid derivatives. The observation is consistent with the crystal growth kinetics and the adsorption measurements, which demonstrated stronger interactions of Asp derivatives with calcite seed. On the other hand, the DR spectrum of mechanically blended (standard) calcite/SA or calcite/N-Sal-Asp samples, exhibited not only the typical absorption band of salicylate (ka = 299 nm), but also the fluorescence bands with maximum at about kemR = 330 nm and kemP = 440 nm. The observed two bands correspond to appearance of rotamers P and R (shown as insets in the spectrum) that exist in the ground state of SA molecules, as well as their derivatives [43].

M. Ukrainczyk et al. / Journal of Colloid and Interface Science 365 (2012) 296–307

Fig. 6. Adsorption isotherms of SA (j), 5-ASA (h), N-Sal-Asp () and N-Sal-Glu (e) obtained for calcite seed crystals at pH = 7.34 ± 0.21. Fitted curves are drawn in accordance to the theoretical Langmuir isotherm, Eq. (19).

305

Fig. 8. Zeta potential (f) of calcite crystals at pH = 7.38 ± 0.27 and different concentrations of SA (j), 5-ASA (h), N-Sal-Asp (), N-Sal-Glu (e). Inset shows the zeta potentials of calcite crystals as a function of pH for the systems without salicylates.

3.4. Zeta potential

Fig. 7. Diffuse reflectance spectra of calcite samples isolated after crystal growth experiments at different concentrations of (A) SA: c(SA)/mmol dm3 = (a) 0, (b) 0.7, (c) 3.6, (d) 5.4 and (B) N-Sal-Asp, c(N-Sal-Asp)/mmol dm3 = (a) 0, (b) 0.045, (c) 0.11, (d) 0.6 and (e) 1.2. Spectra of samples containing about 1%, (w/w) of corresponding salicylates that are mechanically blended with calcite (standards) are presented as dotted lines. Inset in (B) shows spectra of calcite samples isolated after crystal growth experiments in the presence of N-Sal-Asp and N-Sal-Glu, c = 0.6 mmol dm3. Diffuse reflectance spectra are plotted as F(R), the Kubelka– Munk function.

The electrokinetic measurements of calcite samples were carried out with the purpose to additionally support the proposed mechanism of interactions between the selected salicylic acid derivatives and calcite crystals, obtained by the crystal growth kinetics and adsorption measurements. Fig. 8 shows f-potentials of calcite samples suspended in saturated solution at pH = 7.38 ± 0.27, as a function of different SA, 5-ASA, N-Sal-Asp or N-Sal-Glu concentrations. At the applied pH, but in the absence of salicylates, the f-potential of calcite is found to be, f = 15.02 ± 0.21 mV. However, by changing pH of the system in the range 7.0 < pH < 8.0, the f-potential decreases just slightly (15.0 mV < f < 14.2 mV). It should be pointed out that in the typical model kinetic experiments, the pH drops for about 0.5 units: pHi  7.6, while pHeq  7.1. Similar values of positive zeta potential for aqueous suspensions of calcite, in the systems closed to atmosphere and at about neutral pH, were also reported by some other authors [44–46]. Since calcite is a sparingly soluble salt-type mineral, which reacts with the solvent molecules (water), the potential determining species could be either ions resulting from the protolytic dissociation of water molecules, the lattice ions or their complexes [44]. In particular, it was shown for calcium carbonate that Ca2+ and CO2 3 ions are the main potential-determining ions, and that H+ and OH also affect the surface potential by changing the distribution of species in the entire system, and/or by adsorbing directly to the mineral surface. At the relatively low H+ concentration, as it is the case in this study, Ca2+ ions are supposed to be responsible for the positive values of zeta potential. On the other hand, in the presence of dissociated organic species, like SA, 5ASA, N-Sal-Asp or N-Sal-Glu, a shift of zeta potential of calcite to less positive values is caused by the electrostatic interactions of the respective anionic salicylate species with the positive sites at the calcite surface. The observed tendency of zeta potential decrease in the presence of SA and 5-ASA is significantly lower than in the presence of N-Sal-Glu and N-Sal-Asp (Fig. 8). The effect is assumed to be caused by the difference in intensity of interactions between the calcite surface and the specific salicylate molecules, as well as by the different net charge of the two groups of salicylate molecules. Like this, N-Sal-Glu and N-Sal-Asp anions have additional negative charges originating from dissociation of two carboxyl groups at amino acid substituent, while their respective

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Fig. 9. Scanning electron micrographs of calcite crystals used for overgrowth experiments (a). The calcite seed isolated from the system containing 0.4 mmol dm3 N-Sal-Glu (b) and N-Sal-Asp (c).

two-carboxyl group chelate complexes, with the single calcium ion at crystal surface are known to form strong bonds [16,21]. 3.5. Morphology The morphological changes of calcite seed, that occurred during crystal growth in the absence and in the presence of selected salicylates were observed by SEM and are shown in Fig. 9. The calcite seed used for the overgrowth experiments was of high monodispersity, with a typical dimension of 1 lm and exhibited welldefined rhombohedral {1 0 4} faces of the uniform distribution of growth planes and sharp edges. However, the calcite crystals grown in the presence of selected salicylates clearly differ from the control system. The changes of growth morphology are even more pronounced for the N-Sal-Asp systems (Fig. 9c). The overgrown layers exhibit curved, broken or discontinuous edges, thus suggesting the appearance of new crystalline faces different from the stable {1 0 4} faces. Actually, the observed faces are, probably, the specifically oriented steps of the original {1 0 4} family of faces. The morphological observations are consistent with conclusions based on the growth kinetic analysis and the applied model of crystal growth in the presence of impurities. Accordingly, the model suggests the formation of regular straight steps in the additivefree systems, while the adsorption of additive molecules reduces the growth rate by blocking the propagation of growth steps and causes formation of jagged and discontinuous surfaces.

4. Conclusions The mode and extent of interactions of dissolved additives, used as models of active pharmaceutical substances, with well defined rhombohedral calcite crystals, were studied by analyzing the crystal growth kinetics of calcite seed in the presence of salicylic acid (SA), 5-amino salicylic acid (5-ASA), N-salicyloil-L-aspartic acid (N-Sal-Asp) and N-salicyloil-L-glutamic acid (N-Sal-Glu). The kinetics was studied in the systems of relatively low initial supersaturation and moderate pH. The N-Sal-Asp and N-Sal-Glu showed a significantly enhanced crystal growth inhibition in comparison to SA and 5-ASA. The obtained data on intensity of interactions (N-Sal-Asp N-Sal-Glu > SA and 5-ASA) were additionally supported with the appropriate electrokinetic, spectroscopic, and particularly, adsorption measurements. The results are correlated with the structural properties of derivatives studied, which affect the stability of the supposed chelate-like surface complexes. The results indicate that the aspartic acid–based moieties can be useful binding agents for the adsorption of drugs onto the calcium carbonate surfaces. Due to the promising binding affinity, the additional aspartic acid–based linkers, particularly their structural and conformational properties, are investigated in order to increase the adsorbtivity of host molecules on calcium carbonate.

Acknowledgments The authors thank to Dr. Sc. Damir Ivekovic´ for his assistance with the DR-UV/VIS analysis and Dr. Sc. Ljerka Brecˇevic´ for reading the manuscript and helpful suggestions. This research has been supported by the Ministry of Science, Education and Sports of the Republic of Croatia (Project Nos. 098-0982904-2951 and 0980982933-2936). Appendix A Fifteen ionic species are assumed to be present in solution in   considerable amounts: Hþ ; OH ; CO2 3 ; HCO3 ; H2 CO3 ; NaCO3 ; þ 2n + + ; CaOH ; CaHL (i.e. CaHSal , CaHASal , NaHCO03 CaCO03 ; CaHCOþ 3 0 0 n   2 (i.e. HSal , HASal , HSalAsp CaHSalAsp or CaHSalGlu ), HL or HSalGlu2) Ca2+, Na+, Cl. According to the pH range examined in this study, SA and 5-ASA predominantly existed in their monovalent form with deprotonated carboxyl group, HSal and HASal (Table 1, pKa values). However, dissociation constants for N-SalAsp and N-Sal-Glu are not reported in the literature, but the results of potentiometric titrations indicate that only HSalAsp2 or HSalGlu2 ionic species are present in solution at the pH range investigated. By considering the fact that the carboxyl group is much more acidic than the hydroxyl group, it is reasonable to assume that both carboxyl groups are deprotonated. It was also confirmed by UV spectra (not shown here), obtained in the range 2.6 < pH < 7.9, that only absorbance peak at kmax = 298 nm characteristic for protonated benzene ring was exhibited, while in the range 8.7 > pH > 10.4 the absorbance peak at kmax = 330 nm, characteristic for deprotonated benzene ring, was detected [28]. The following mass balance equations:

ctot ¼ ½Ca2þ  þ ½CaCO03  þ ½CaHCOþ3  þ ½CaOHþ  þ ½CaHL2n   0 þ ¼ ½CO2 3  þ ½HCO3  þ ½H2 CO3  þ ½CaCO3  þ ½CaHCO3 

þ ½NaCO3  þ ½NaHCO03 ;

ð4Þ



½Cl  ¼ 2½CaCl2 i þ ½HCl;

ð5Þ

½Natot ¼ ½Naþ  þ ½NaCO3  þ ½NaHCO03  þ ½NaOH;

ð6Þ

½Ltot ¼ ½HLn  þ ½CaHL2n ;

ð7Þ

and the charge balance equation:

½Hþ  þ 2½Ca2þ  þ ½CaHCOþ3  þ ½CaOHþ  þ ½Naþ  þ ð2  nÞ½CaHL2n  

  n ¼ ½OH  þ 2½CO2 3  þ ½HCO3  þ ½NaCO3  þ ½Cl  þ n½HL ;

ð8Þ

as well as the respective equilibrium constants ([47,48], Table 1) were considered in calculations of solution speciation. However, the calcium complexation constant of 5-ASA was not obtained by potenciometric titration, because of the complex low stability, but it was assumed that the complexation ability was similar (relatively

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low) to that of SA. The activity coefficients of z-valent ions, cz, were calculated by using a modification of the Debye–Hückel equation as proposed by Davies [27]. Supersaturation was expressed as relative supersaturation, S  1, the saturation ratio, S, being defined as the square root of the quotient of the calcite activity product:

S  1 ¼ ½ðaCa  aCO3 Þ=K sp 1=2  1;

ð9Þ CO2 3

2+

where aCa is the Ca activity, aCO3 is the activity, and Ksp is the solubility product of calcite. The concentration of precipitated calcium carbonate, cppt, was determined by subtracting the calculated total concentration, ctot, of calcium or carbonate species in the closed system from the known initial calcium chloride or sodium carbonate concentration ([CaCl2]i or [Na2CO3]i):

cppt ¼ ½CaCl2 i  f½Ca2þ  þ ½CaCO03  þ ½CaHCOþ3  þ ½CaOHþ  þ ½CaHL2n g; ð10Þ or 2



0

þ

cppt ¼ ½NaHCO3 i  f½CO3  þ ½HCO3  þ ½H2 CO3  þ ½CaCO3  þ ½CaHCO3  þ½NaCO3 

þ

0 ½NaHCO3 g;

ð11Þ

In the above expressions, the square brackets denote molar concentrations of the ionic species. References [1] M. Fujiwara, K. Shiokawa, K. Morigaki, Y. Zhu, Y. Nakahara, Chem. Eng. J. 137 (2008) 14. [2] C. Wang, C. He, Z. Tong, X. Liu, B. Ren, F. Zeng, Int. J. Pharm. 308 (2006) 160. [3] Y. Ueno, H. Futagawa, Y. Takagai, A. Ueno, Y. Mizushima, J. Controlled Release 103 (2005) 93. [4] D. Ogomi, T. Serizawa, M. Akashi, J. Controlled Release 103 (2005) 315. [5] K. Gopal, Z. Lu, M.M. de Villiers, Y. Lvov, J. Phys. Chem. B 110 (2006) 2471. [6] A.I. Petrov, D.V. Volodkin, G.B. Sukhorukov, Biotechnol. Prog. 21 (2005) 918. [7] F.C. Meldrum, H. Cölfen, Chem. Rev. 108 (11) (2008) 4332. [8] Lj. Brecˇevic´, D. Kralj, Croat. Chem. Acta 80 (3–4) (2007) 467. [9] P. Fenter, P. Geissbühler, E. DiMasi, G. Srajer, L.B. Sorensen, N.C. Sturchio, Geochim. Cosmochim. Acta 64 (2000) 1221. [10] S.L.S. Stipp, Geochim. Cosmochim. Acta 63 (1999) 3121. [11] O.S. Pokrovsky, J.A. Mielczyrski, O. Barres, J. Schott, Langmuir 16 (2000) 2677. [12] E. Fekete, B. Pukanszky, A. Toth, I. Bertoti, J. Colloid Interface Sci. 135 (1990) 200. [13] P. Fenter, N.C. Sturchio, Geochim. Cosmochim. Acta 63 (1999) 3145. [14] M. Ukrainczyk, J. Kontrec, D. Kralj, J. Colloid Interface Sci. 329 (2009) 89.

307

[15] S. Mann, J.M. Didymus, N.P. Sanderson, B.R. Heywood, E.J.A. Samper, J. Chem. Soc., Faraday Trans. 86 (1990) 1873. [16] C. Geffroy, A. Foissy, J. Persello, B. Cabane, J. Colloid Interface Sci. 211 (1999) 45. [17] M.M. Reddy, A.R. Hoch, J. Colloid Interface Sci. 235 (2001) 365. [18] K. Sangwal, Additives and Crystallization Processes: From Fundamentals to Applications, John Willey & Sons, Chichester, 2007. [19] K. Sangwal, J. Cryst. Growth 203 (1999) 197. [20] N. Kubota, J.W. Mullin, J. Cryst. Growth 152 (1995) 203. [21] K.-J. Westin, A.C. Rasmuson, J. Colloid Interface Sci. 282 (2005) 359. [22] B. Njegic´-Dzˇakula, Lj. Brecˇevic´, G. Falini, D. Kralj, Cryst. Growth Des. 9 (5) (2009) 2425. [23] J. García-Carmona, J. Gómez-Morales, R. Rodríguez-Clemente, J. Colloid Interface Sci. 261 (2003) 434. [24] M. Ukrainczyk, J. Kontrec, V. Babic´-Ivancˇic´, Lj. Brecˇevic´, D. Kralj, Powder Technol. 171 (2007) 192. [25] A.E. Martel, R.M. Smith, Critical Stability Constants, Other Organic Ligands, vol. 3, Plenum Press, New York, 1977. [26] N. Zerrouk, J.M.G. Dorado, P. Arnaud, C. Chemtob, Int. J. Pharm. 171 (1998) 19. [27] C.W. Davies, Ion Association, Butterworths, London, 1962. 41. [28] E. Pretsch, P. Bühlmann, M. Badertscher, Structure Determination of Organic Compounds: Tables of Spectral Data, Springer-Verlag, Berlin Heidelberg, 2009. 401–420. [29] A.E. Nielsen, J. Cryst. Growth 67 (1984) 289. [30] Lj. Brecˇevic´, D. Kralj, Interfacial dynamics. in: N. Kallay, (Ed.), Surfactant Science Series, vol. 88, Marcel Dekker, New York, 2000, pp. 435–474 (Chapter 12). [31] Y. Zhang, R. Dawe, Appl. Geochem. 13 (1998) 177. [32] D. Kralj, Lj. Brecˇevic´, J. Kontrec, J. Cryst. Growth 177 (1997) 248. [33] E. Dalas, A. Chalias, D. Gatos, K. Barlos, J. Colloid Interface Sci. 300 (2006) 536. [34] S. Rosa, H.E. Lundager Madsen, J. Cryst. Growth 318 (2011) 99. [35] N. Cabrera, D. A. Vermilyea, in: R.H. Doremus, B.W. Roberts, D. Turnbull, (Eds.), In Growth and Perfection of Crystals, Wiley, New York, 1958. [36] N. Kubota, M. Yokota, J.W. Mullin, J. Cryst. Growth 182 (1997) 86. [37] C.A. Orme, A. Noy, A. Wierzbicki, M.T. McBride, M. Grantham, H.H. Teng, P.M. Dove, J.J. DeYoreo, Nature 411 (2001) 775. [38] N.H. de Leeuw, T.G. Cooper, Cryst. Growth Des. 4 (2004) 123. [39] U. Aschauer, D. Spagnoli, P. Bowen, S.C. Parker, J. Colloid Interface Sci. 346 (2010) 226. [40] N. Kubota, H. Otosaka, N. Doki, M. Yokota, A. Sato, J. Cryst. Growth 220 (2000) 135. [41] J.J. Taylor, W.M. Sigmund, J. Colloid Interface Sci. 341 (2010) 298. [42] L. Madsen, C. Gron, I. Lind, J. Engell, J. Colloid Interface Sci. 205 (1998) 53. [43] K. Suyal, N.K. Joshi, R. Rautela, H.C. Joshi, S. Pant, J. Photochem. Photobiol., A – Chem. 216 (2010) 51. [44] F. Heberling, T.P.J. Lützenkirchen, P. Eng, M.A. Denecke, D. Bosbach, J. Colloid Interface Sci. 354 (2011) 843. [45] R. Eriksson, J. Merta, J.B. Rosenholm, J. Colloid Interface Sci. 313 (2007) 184. [46] P. Virtanen, Precipitated Calcium Carbonate and Method for the Production Thereof, 2003. US Patent 6602,484 B1. [47] L.N. Plummer, E. Busenberg, Geochim. Cosmochim. Acta 46 (1982) 1011. [48] R.M. Garrels, M.E. Thompson, Am. J. Sci. 260 (1962) 57.