MICRONIZATION OF CALCIUM SALTS BY RAPID EXPANSION OF SOLUTIONS SATURATED WITH SUB AND SUPERCRITICAL CARBON DIOXIDE

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1 MICRONIZATION OF CALCIUM SALTS BY RAPID EXPANSION OF SOLUTIONS SATURATED WITH SUB AND SUPERCRITICAL CARBON DIOXIDE Isabel Mejía and Gustavo Bolaños * School of Chemical Engineering Universidad del Valle P.O. Box 25360, Cali, COLOMBIA gbolano@univalle.edu.co Abstract. The world demand for liquid food products reinforced with calcium is rapidly growing because of an increasing consumer perception on the need for calcium intake to prevent calcium related pathologies such as osteoporosis. For producing calcium-reinforced beverages such as juices and milk, the main technical limitations are the low solubility of calcium compounds and their low bioavailability. The conventional approach has been to reduce the particle size of calcium salts to a few microns (about 10) before incorporating them into the beverage. We have been developing a process based on the rapid expansion of solutions saturated with carbon dioxide. In this process, an aqueous suspension of a suitable salt is saturated with carbon dioxide to increase the salt solubility, and then is expanded through a nozzle, precipitating the salt as fine particles. Our results show that for calcium citrate it is possible to increase the solubility from 0.85 up to 1.60 g/l, and for calcium carbonate from up to 2.25 g/l. Particles with a small size, from 1 to 30 micron can be obtained at temperatures and pressures easily attainable with simple equipment. Keywords: Micronization, calcium carbonate, calcium citrate and supercritical expansion. 1. Introduction Mineral deficiency is one of the nutritional problems that occurs more frequently. Dietary supplements with high bioavailability are necessary to provide these minerals due to the inability of the human body to produce them. The world demand for liquid food products reinforced with calcium is rapidly growing as a result of an increasing consumer perception on the need for calcium intake to prevent calcium related pathologies such as osteoporosis. Of the calcium salts commercially available, citrate provides the greatest calcium bioavailability, although calcium carbonate is also provided, both in solid form [1]. An important technical limitation in manufacturing reinforced calcium products is the low aqueous solubilities of calcium salts: g/l at 20 C for calcium carbonate and 0.85 at 15 C for calcium citrate [2]. There are also difficulties associated with consumer perception of grittiness due to large particle size of these salts in calciumreinforced food products and with possible settlement of the solids in liquid foods during the shelve life of these products in a supermarket. As a result, calcium-reinforced food producers usually require small particle sizes (5 to 10 µm). In a conventional process, calcium citrate is obtained by a reaction between citric acid and calcium hydroxide. The produced particles have and average size of 100 µm and are milled to reduce its size to 8 µm. The energy consumption of the milling process is near to 2500 kj/kg [3]. Smaller sizes required by some food producers are difficult and expensive to obtain by grinding due to the elevated costs associated with energy consumption. The situation for calcium carbonate is not so different. This salt is obtained by reaction between carbon dioxide and calcium hydroxide and also suffers from the high power consumption during milling. Several approaches have been proposed to control the particle size during the production of the calcium salt. For example, Valencia [4] has proposed to carefully control the citric acid/calcium hydroxide ratio. This produces a low particle size but the produced particles are difficult to maintain in suspension during the shelve life of the product. Oneda and Ré [5] proposed a process in which the calcium salt is encapsulated in polymeric microspheres. Such microspheres prevent the aggregation of the salt particles and interactions of calcium with other compounds, which reduces its bioavailability. * To whom all correspondence should be addressed

2 In our group we have been studying the micronization of calcium salts by expanding aqueous solutions saturated with sub and supercritical carbon dioxide [3]. This process has several advantages: (1) It is easy to implement, (2) It requires a low energy consumption, (3) It provides sterile conditions and (4) It reduces the particle size while exerting control over the size distribution. 2. Fundamentals The process we have been studying combines two concepts: (1) increase the calcium salt solubility in water by using compressed carbon dioxide, and (2) then expand the saturated solution through a nozzle. To illustrate, Figure 1 shows the solubility of calcium citrate in water at different ph values. Notice that solubility increases at lower ph, specially at ph below 4.5. This behavior, although not shown here, is common for several calcium salts, carbonate included. A decrease in the ph can be easily obtained by using compressed carbon dioxide. Figure 2 shows the ph of water in equilibrium with supercritical CO 2 [7]. At moderate pressures, carbon dioxide has a low solubility in water (0.036 %mol), while at supercritical conditions (up to 74 atm) it increases up to 2 %mol [6], resulting in acid conditions with ph values below 3.0 [6, 7, 8]. This is a result of the formation of carbonic acid according to the reaction: CO 2 ( g ) + H 2 O H 2 CO 3 ( aq ) H + ( aq ) + HCO 3 (1) Incidentally, notice in Figure 1 that the solubility of calcium citrate in water increases also with decreasing temperature. This temperature dependence is sometimes referred to as inverse solubility, and indicates that a high dissolution can be obtained at high pressures and low temperatures, thus both the supercritical and subcritical regions have to be explored for searching appropriate conditions for this process. 2,00 3,00 Solubility (g/l) 1,80 30 C 1,60 60 C 1,40 90 C 1,20 1,00 0,80 0,60 0,40 0,20 0,00 4,0 4,5 5,0 5,5 6,0 6,5 7,0 7,5 8,0 ph ph 2,95 2,90 2,85 2,80 2,75 25 C 70 C Pressure (atm) Fig. 1. Solubility of calcium citrate in water [6]. Fig. 2. ph variation of water in equilibrium with SC CO 2 [9]. The second concept important in the process is the precipitation that takes place once the saturated solution is expanded through a nozzle. During such a rapid expansion, the carbon dioxide is liberated and the solution becomes supersaturated with the calcium salt, which produces the precipitation. Because the expansion is very rapid, there is no time for the crystals to grow and this results in a precipitate with a small particle size. Except for the fact that the solution is saturated with the calcium salt and carbon dioxide, this step of the process is not different in essence from several other micronization processes discussed in the literature [9,10,11], which have been used to produce micro and nanoparticles for a wide range of materials [12]. There are, however, several questions that have to be answered before a process for producing micron-size calcium salts in an economical way can be developed. In this work, we report on our experiments for determining the solubility of calcium citrate and calcium carbonate in water, when the solutions are saturated with sub and supercritical carbon dioxide. We also report on particle size distributions that can be obtained.

3 3. Materials and methods 3.1 Materials USP-grade calcium citrate was kindly provided by Sucromiles S.A (Cali, Colombia). USP-grade calcium carbonate was obtained from a local supplier. Both of them were stored in a dry environment. CO 2 (purity 99.9%) was obtained from Oxígenos de Colombia S.A (Cali, Colombia). 3.2 Experimental apparatus and procedure The Experimental apparatus that was used for determining the solubility of the calcium salts is shown in Figure 3. This is a laboratory-scale equipment designed and built in our laboratory [3]. In a solubility experiment, a water suspension containing a known concentration of the calcium salt is loaded into a 35 cm 3, magnetically-stirred visual cell that was built in a previous work [13]. The cell is located inside an air isothermal bath capable of controlling the temperature between 5 and 100 C to a ±0.3 C. After obtaining a constant desired value of temperature, carbon dioxide was pumped using a Williams-Milton Roy pneumatic pump (Williams-Milton Roy, model CP250V225, rated for pressures up to 7000 psi). The system was allowed to equilibrate during 2 h. A video system (Maser, LTDA) was used to continuously monitor the presence of solid particles during the equilibration time. The pressure was increased and the system allowed to equilibrate again until the particles were no longer optically detectable. A high-pressure cylinder (HIP, model ) was used for fine tuning the pressure. Temperature inside the cell was measured with a K thermocouple connected to a digital thermometer (Fluke, model 52-II). The thermocouples were calibrated to a NIST-traceable RTD secondary standard. Pressures were measured with a Bourdon-type pressure gage (Ashcroft, model AISI 403, 0 to 7500 psi), and are precise to ±5.0 psi. Isothermal bath Pump Visual cell Camera Ball valve Monitor Nozzle Thermocouple Thermocouple Sample vessel Digital thermometer Carbon dioxide cylinder Fig. 3. Experimental apparatus. After the equilibrium measurements were made, the same basic apparatus was used to produce microparticles at selected conditions of temperature and pressure. The calcium-salt solution saturated with carbon dioxide was suddenly expanded. A ball valve (HIP model 15-16AF2) located on the exit line was opened allowing the solution to pass through a 0.5 µm filtering element (Swagelok, model SS-4F-K4-15) and then through a nozzle. The nozzle is a thin stainless steel 316 plate with a 80 µm pinhole in the center and a length/diameter ratio of The preexpansion temperature is registered by a K thermocuple connected to the Fluke digital thermometer. The thermocuple is located at 2 mm of the nozzle. The exit line was wrapped with an electric resistance (for temperatures above ambient) or a copper tubing with a refrigerant (for temperatures below ambient) to maintain the temperature of the line equal to that in the isothermal bath. The expanded solutions were collected in an erlenmeyer and were analyzed for particle size distribution using a laser granulometer (Malvern 2000).

4 4. Results and discussion Table 1 shows the conditions of temperature and pressure needed for complete solubility of a determined calcium salt concentration. Notice that, as expected, for dissolving a determined calcium salt concentration, higher temperatures require a greater amount of dissolved carbon dioxide (i.e., higher pressure) to compensate for the effect of inverse solubility of the salt with temperature. Concentrations of calcium carbonate as high as 2.2 g/l can be dissolved at 30 C and 1250 psig. This is 200 times the solubility of this salt at 20 C and atmospheric pressure (0.012 g/l). Table 1. Temperature and pressure for complete solubility of calcium salts Calcium carbonate Calcium citrate Concentration (g/l) Temperature ( C) Pressure (psig) Concentration (g/l) Temperature ( C) Pressure (psig) In contrast, for calcium citrate, a solubility of 1.6 g/l was observed at 44.7 C and 960 psig. This value is twice the one observed at 15 C and atmospheric pressure. Curiously, at 30 C citrate does not dissolves completely at any of the pressures we tried (up to 2000 psig). We are interpreting these results by using a thermodynamic model that takes into account the dissociation reactions that take place during the salt dissolution at high pressures. Original material Expanded material Fig 4. Particle size distribution for calcium citrate obtained after expanding a solution saturated at 22.5 C and 490 psig. Figure 4 shows a particle size distribution that was obtained two months after the expansion of a calcium citrate solution saturated at 22.5 C and 490 psig. This time was chosen for simulating the shelve life of a calcium-reinforced liquid. Notice that the average particle size was reduced to 30 µm from 80 µm in the starting material. Important also to notice a small bump at 0.2 µm in the expanded material. Apparently, very fine,

5 submicron particles were produced in the expansion, but after some time those particles formed aggregates with a larger average particle size. This indicates that a mechanism to prevent particle aggregation will be necessary to develop a practical process, but the possibilities for the expansion are important. 5. Conclusions Expansion of solutions saturated with calcium salts and carbon dioxide can be a simple way to produce calcium salts with a reduced particle size, which are important for producers of calcium reinforced foods. An understanding of the phenomena that take place during dissolution and expansion, as well as suitable ways to limit the particle aggregation would be important for developing a new process with a low energy consumption. References [1] BOLDYREV, V. et. al., On the mechanism of solubilization of drugs in the presence of poorly soluble additives. International Journal of Pharmaceutics, 295, 2005, p.177 [2] PERRY, R.H., GREEN, D. Perry s Chemical Engineers Handbook. 6 th edition, Mc Graw Hill, New York, 1984 [3] PAZ, I. A study on micronization of calcium citrate. M.Sc. Thesis. Universidad del Valle, Cali, Colombia, [4] VALENCIA, D., et. al., Powdered beverage mix with rapidly dissolving calcium. US Patent , 2004 [5] ONEDA, F., RÉ., M.I., The effect of formulation variables on the dissolution and physical properties of spray- dried microspheres containing organic salts. Powder Technology, 130, 2003, p.377 [6] ZIEGLER, K. et. al., Producing ph Switches in biphasic water/co2 systems. J. of Supercritical Fluids, , p.109 [7] THIERING, R., DEHGHANI, F., FOSTER, N. Current issues relating to anti-solvent micronization techniques and their extension to industrial scale. J. of Supercritical Fluids, 21, 2001, p.159 [8] TOEWS, K., SHROLL, R., WAI, C. ph defining equilibrium between water and supercritical CO2. Influence on SFE of organics and metal chelates, Anal. Chem., 67, 1995, p.4040 [9] FOSTER, N., et. al., Processing pharmaceutical compound using dense gas technology. Ind. Eng. Chem. Res., 42, 2003, p [10] PERRUT, M., CLAVIER, J.Y., Supercritical fluid formulation: process choice and scale up. Ind. Eng. Chem. Res., 42, 2003, p [11] REVERCHON, E.., CAPUTO, G., DE MARCO, I., Role of phase behavior and atomization in the supercritical antisolvent precipitation. Ind. Eng. Chem. Res., 42, 2003, p.6406 [12] REVERCHON, E., ADAMI, R., Nanomaterials and supercritical fluids. J. of Supercritical Fluids, 37, 2006, p.1 [13] YÉPEZ, B., BOLAÑOS, G. A high-pressure cell for visual observation of equilibrium phenomena. XXII Colombian conference of chemical engineering. Bucaramanga, Colombia, 2003 Acknowledgments The authors thank to Departamento Administrativo de Ciencia Tecnología e Innovación de Colombia (Colciencias) for financial support of this work (project ).

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