6578
Ind. Eng. Chem. Res. 2005, 44, 6578-6582
KINETICS, CATALYSIS, AND REACTION ENGINEERING Evaluating the Effect of the Antimonium Pentachloride Feed Rate to Ensure Safer Conditions During the Synthesis of Meglumine Antimoniate Amaro G. Barreto, Jr.,‡ Luciana R. M. Esteva˜ o,† Evaristo C. Biscaia, Jr.,‡ Alcione S. de Carvalho,§ Silvio L. Duarte,§ Jorge C. S. Costa,§ Marcus V. N. Souza,§ Jorge de S. Mendonc¸ a,§ and Joa˜ o F. Cajaiba da Silva*,† Po´ lo de Xistoquı´mica, Departamento de Quı´mica Orgaˆ nica, Instituto de Quı´mica, Universidade Federal do Rio de Janeiro 21494-900, Rio de Janeiro, Brazil, Programa de Engenharia Quı´mica, COPPE, Universidade Federal do Rio de Janeiro, and Instituto de Tecnologia em Fa´ rmacos, Fundac¸ a˜ o Osvaldo Cruz
Pentavalent antimony derivatives, among them meglumine antimoniate, are widely used in antileishmanial therapy. The production of meglumine antimoniate involves an extremely exothermic reaction with antimony pentachloride, which can lead to hazardous situations. Simulation of temperature profiles of highly exothermic reactions is an efficient means of determining optimal experimental conditions that lead to reduced energy consumption and increased safety. The reaction involving SbCl5 addition to an aqueous meglumine solution was studied using an RC1 reaction calorimeter. A mathematical model was developed on the basis of energy balances. The model was used to simulate temperature profiles and to determine optimal operating conditions. The excellent correspondence between the experimental and theoretical results indicates that the mathematical model developed can adequately simulate the temperature profile of highly exothermic reactions. Introduction Leishmaniasis is a widespread parasitic disease transmitted by the bite of infected female sand flies. This is a major worldwide health issue, continuously increasing in incidence, and can occur in several different forms, notably cutaneous, mucocutaneous, and visceral Leishmaniasis.1,2 According to the World Heath Association, Leishmaniasis currently threatens 350 million people worldwide, found in approximately 90 countries around the world. It occurs in the tropics, subtropics, and southern Europe, in settings ranging from rain forests in Central and South America to deserts in West Asia.2 More than 90% of the world’s cases of cutaneous Leishmaniasis are in Afghanistan, Algeria, Brazil, Iran, Iraq, Peru, Saudi Arabia, and Syria and, although it has been well-known for hundreds of years, the complexities of the disease still require further study. For the past sixty years, pentavalent antimony derivatives, among them meglumine antimoniate (Glucatime; Rhoˆne-Poulenc Rorer), have remained the mainstay of antileishmanial therapy.2-4 The production of meglumine antimoniate involves an extremely exothermic reaction, which can give rise to a * To whom correspondence should be addressed. Phone/ Fax: 55 21 25900990. E-mail:
[email protected]. † Instituto de Quı´mica, Universidade Federal do Rio de Janeiro. ‡ Programa de Engenharia Quı´mica, Universidade Federal do Rio de Janeiro. § Instituto de Tecnologia em Fa ´ rmacos.
number of safety issues. A major hazard in its production is loss of thermal control, and for safer handling, identification and evaluation of the risks involved are necessary. The main purpose of this work is to determine the effect of the feed rate of SbCl5 on the reaction temperature profile during the synthesis of meglumine antimoniate. Extreme reaction conditions were considered to establish safe parameters in high-risk situations. A mathematical model based on the energy balance in the reaction system was developed and used to predict the reaction temperature profile and to evaluate the cooling capacity of the system. To obtain valid theoretical data, an accurate knowledge of the overall heattransfer coefficient of the reaction is required. Calorimetric studies were carried out in a Mettler Toledo RC1 reaction calorimeter whose principles have been amply described in the literature.5 The RC1 has been previously used to provide the experimental data and process information needed to optimize safety and economy in scaling-up processes.6,7 Hazards of thermal runaway scenarios in a chemical plant can be simulated, and once they are known, a procedure for the safe operation of a particular plant can be defined. The RC1 consists of a double-walled reaction vessel where both the jacket temperature (Tj) and the temperature of the reaction medium (Tr) can be accurately measured when properly calibrated. The heat flow through the double-wall reactor jacket (Qf) can be expressed as
Qf ) UA(Tr - Tj)
10.1021/ie0503038 CCC: $30.25 © 2005 American Chemical Society Published on Web 07/19/2005
Ind. Eng. Chem. Res., Vol. 44, No. 17, 2005 6579
Figure 1. Schematic representation of the batch reaction system: (1) Reaction medium, (2) cooling jacket, (3) heat exchanger for control action, (a) coolant, and (b) electrical resistance.
where Tr - Tj is the temperature gradient formed between the reaction mixture and the jacket, U is the overall heat transfer coefficient, and A is the area in the reactor wetted by the liquid phase. The heat production rate (W/kg) and the reaction enthalpy (J/kg) are mass related values that do not depend on the volume of the reactor. Hence, the same values should be always obtained, whether the reaction is carried out in a laboratory or in a large scale reactor, considering the reaction mechanism is maintained. Experimental Section Addition of SbCl5 Over an Aqueous Solution of Meglumine. Water (0.21 L) was manually introduced into the 2.0 L RC1 vessel at 20 °C, followed by the addition of diethylamine (0.29 L) and meglumine (120 g). The reaction mixture was stirred during the experiment at 150 rpm using an anchor agitator. An electrical calibration heater was used to apply a known heat generation rate to the reactor. On the assumption that no reaction occurs, the applied calibration power (20 W) can only be dissipated through the wall. This allows the global heat transfer coefficient (U) to be determined. The specific heat capacity of the reaction mass was determined by performing temperature ramps. The reaction temperature was kept at 23 °C. SbCl5 (177 g, 0.227 L) was added to the reactor through a pump, during a period of 40 min. A final set of U and Cp determinations was carried out to calculate the heat of reaction. This experimental procedure corresponds to the results presented in Figure 2. The only modification for the other syntheses was the times taken for SbCl5 addition. Mathematical Modeling The mathematical model used was developed from the energy balance involving (1) the reaction medium, (2) the jacket, (3) the heat exchanger, and the temperature control restrictions, as shown in Figure 1. Equations 1, 2, and 3 describe the temperature dynamics in the reaction medium, in the jacket and in the heat exchanger, respectively. Equation 4 corresponds to the energy balance in the interior of the heat exchanger (cold current, Figure 1) and describes the influence of coolant flow on temperature control. Two temperature control systems are presented in the mathematical model. In the Tj mode, the jacket’s set point is fixed and its temperature is controlled by manipulating coolant flow rate and the electrical resistance (eqs 6 and 7). In the Tr mode, the temperature in the reaction medium is controlled by manipulating the coolant flow rate and the electrical resistance in a cascade control system (eqs 5, 6, and 7). Both modes are feedback control systems.
Figure 2. Thermochemical profile SbCl5 addition (40 min). Mass of the SbCl5 (kg) and the heat of reaction (Qr, W).
Energy balance in the reactor
dTr Qdos - Qflow + Qr ) dt Cpr
(1)
Energy balance in the jacket
dTj Qflow - Qhj ) dt Cpj
(2)
Energy balance in the heat exchanger
-Q*flow + Qhc + Qh dTc ) dt Cpc
(3)
Energy balance in the coolant spiral
0 ) Qhe - Q*flow
(4)
Temperature control actions on the medium and jacket SP SP TSP j ) Tr + (Tr - Tr)Pcontrolr
(5)
Fc ) - (TSP j - Tj)Pcontrolj
(6)
where 0 e Fc e Fcmax
Qh ) (TjSP - Tj)Pcontrolj
(7)
where 0 e Qh e Qhmax. The heat generated during the reaction (Qr) was represented in eq 1 as that of a reaction controlled by reagent feed. By having no SbCl5 accumulation in the system, the heat generation becomes proportional to the mass fraction of the reagent added, as represented in eq 8.
Qr )
dR ∆Hr dt
(8)
where the empiric parameter R expresses a relationship between the heat conversion measured by the RC1 and the mass fraction of reagent feed. The differential algebraic system, obtained from eqs 1-4 and from the restrictions 5-7, was integrated using
6580
Ind. Eng. Chem. Res., Vol. 44, No. 17, 2005
Figure 3. Heat conversion as a function of the fraction of SbCl5 added. Table 1. Physical Characteristics of the Reaction System mi mdos Tstart Treag
0.72 0.18 23 30 1342 3471 2103 1350 159 154
∆H Cpi Cpf Cpreag Ui Uf
Thermochemical Parameters enthalpy of the reaction (kJ/kg) initial specific heat of the reaction medium (J/kgK) final specific heat of the reaction medium (J/kgK) specific heat of the reagent (J/kgK) initial global heat-transfer coefficient (W/Km2) final global heat-transfer coefficient (W/Km2) Control System Parameters 10 proportional parameter in the control system 10 proportional parameter in the control system 23 set point temperature (°C)
Pcontrolr (Tr mode) Pcontrolj (Tj mode) Trsetpoint Ai Af Tci Cpj Cpc Cpe UAc UAe Fj Fc Qh
Operating Parameters initial mass in the reactor (kg) mass of SbCl5 added (kg) initial temperature in the reaction medium (°C) initial temperature of the reagent (°C)
0.0348 0.0355 -20 1440 8400 1770 3 2 5 × 10-4 5 × 10-4 2000
Heating and Cooling Parameters initial heat transfer area in the reactor (m2) final heat transfer area in the reactor (m2) temperature of the cooling fluid (°C) heat capacity of the jacket (J/K) heat capacity in the heat exchanger (J/K) heat capacity of the coolant (J/K) heat exchange capacity in the heat exchanger (J/K) heat exchange capacity through the wall of the coolant spiral (J/K) flow in the jacket (103 x m3/s) maximum flow rate of the coolant (103 x m3/s) heating power of the electrical resistance (W)
the DASSL computational code.8 The computational code was developed in Fortran. Results and Discussion The reaction studied involves the addition of SbCl5 to an aqueous meglumine solution. Antimony pentachloride reacts violently with water to give antimonic acid, which in turn reacts with meglumine. Figure 2 shows the typical heat release profile observed during the reaction involving SbCl5 and the aqueous meglumine solution. Heat flux ceased as the reagent addition came to an end, indicating that the kinetics of the process is determined by the SbCl5 feed rate. The enthalpy of the reaction was calculated as the area underneath the Qr curve, giving -241 ( 15 kJ, which corresponds to -1365 ( 85 kJ/kg of SbCl5. Considering that all the heat generated in the reaction is immediately removed by the jacket and that the reaction rate is controlled by reagent feed rate, the heat release profiles do not depend on the temperature of the reaction mixture, hence making it possible to correlate
heat release with reaction progress. This procedure generated the data given in Figure 3, which were used to validate the mathematical model. The regression curve that fits the data given in Figure 3 permits relating calorimetric conversion (R) with the SbCl5 fraction added (dos), as shown in eq 9.
R(dos) ) 0.2375dos2 + 0.7443dos
(9)
The quadratic relationship shown in eq 9 can be attributed to the thermochemical effects that influence the assessment of heat conversion, such as changes in Cp throughout the reaction. To simulate the temperature in the reaction mixture (Tr) and the average temperature in the jacket (Tj) with various SbCl5 feeding rates, eqs 1-8 were used in combination with the empiric parameters, estimated from Figure 3 and shown in eq 9. The reaction enthalpy, measured from the profile shown in Figure 2, and the physical characteristics of both the reactor and the reaction mixture, given in Table 1, were also used for the simulations.
Ind. Eng. Chem. Res., Vol. 44, No. 17, 2005 6581
Figure 4. Safe-operation region obtained by simulation using a Tr mode temperature control.
Figure 4 shows the theoretical relationships between the maximum and minimum temperatures in the reaction mixture and the jacket, respectively. The curves were obtained by considering the addition of 177 g of SbCl5 during different time periods (1 to 80 min) and a Tr mode temperature control. The dotted line in Figure 4 represents the limit operating temperature of the system being studied. This limit is imposed by the maximum operating pressure in the reactor. Temperatures higher than those of the operating limit cause solvent volatilization, pressurizing the reaction system and leading to potentially hazardous situations. According to Figure 4, to minimize the risk and make it manageable, the minimum SbCl5 addition time should be 15 min. However, for immediate removal of the generated heat, to avoid Tr increase, the addition time should not be less than 25 min. The results in Figure 4 are clearly valid for the system described in Table 1, given that the operating region depends on the heat capacity of the coolant circulating in the heat exchanger of the reaction system (Figure 1) and on the maximum operating power of the cryostat. Hence, mathematical models based on the RC1 data, may also be used, in conjunction with data from the industrial reactor,9 to calculate the best feed time and ensure safer operation conditions when developing or optimizing processes. Comparing Simulated and Experimental Results. Two experiments were carried out in the Tr mode to evaluate the accuracy of the simulated results obtained by using the mathematical model developed. Figures 5 and 6 show the dynamic profiles of heat generation per unit time (Qr) and the temperatures of the reaction medium (Tr) and the jacket (Tj) for reactions conducted using addition times of 45 and 15 min, respectively. The results from the simulations, using eqs 1-8, show excellent agreement with the experimental data. The fluctuations in Tj and Qr shown in Figure 5 are the result of the pulsating flow of SbCl5 from the positive displacement piston pump used in the experiment. The fluctuations decrease with the time taken for reagent addition. Higher feed rates involve faster piston displacement, resulting in a somewhat steadier flow rate. This is clearly observed in Figure 6, where very little Tj and Qr fluctuation is detected. It should be noted that simulations using only eqs 1, 5, and 8 have been previously reported in the literature.9 These simulations have adequately represented the experimental data when conducted in the Tj mode. However, they have failed to reproduce the experimental results in the Tr mode, by not taking into consideration the cooling dynamics of the systems, represented by eqs 2-4, 6, and 7. Because of the inherent potential risk of this reaction, an experiment simulating an uncontrolled SbCl5 addi-
Figure 5. Comparison of the experimental and simulated results for the 45 min dosing of SbCl5.
Figure 6. Comparison of the experimental and simulated results for the 15 min dosing of SbCl5.
Figure 7. Comparison of the experimental and simulated results for the 1 min dosing of SbCl5.
tion was carried out with the intent of observing possible hazards in a runaway scenario. The results obtained in Figure 7 show that, regardless of the fast addition of the reagent, no mass accumulation was observed. This
6582
Ind. Eng. Chem. Res., Vol. 44, No. 17, 2005
indicates that the reaction is still controlled by reagent feed because Qr returned to its initial value as soon as the addition ceased. The excellent relationship observed between the theoretical and experimental results indicates that the mathematical model developed can adequately simulate the temperature profile for this reaction.
) heat transferred to the coolant per unit time Q* flow ((UA)c(Teo - Tc)) Tc ) average temperature of the fluid in the heat exchanger ((Tco + Tci)/2) Tj ) average temperature of the fluid in the jacket ((Tjo + Tji)/2)
Conclusion The mathematical model developed has been able to accurately reproduce experimental results for the reaction being studied under varying conditions; it is a promising means to determine temperature profiles. Assessment of the experimental hazards through simulation has made it possible to determine safe operation conditions for the extremely exothermic reaction involving SbCl5 addition to an aqueous medium, when performed in a RC1 reaction calorimeter. It has been demonstrated that it is possible to keep the reaction temperature within the operating limits by controlling the reagent feed rate, hence preventing thermal runaway.
Literature Cited
Nomenclature Cpc ) heat capacity of the fluid in the heat exchanger (FcVccpc) Cpj ) heat capacity of the fluid in the jacket (FjVjcpj) Cpr ) heat capacity of the fluid in the reaction medium (mrcpr) Qdos ) added heat per unit time (Fdoscpreag(Treag - Tr)) Qhc ) enthalpy of the fluid in the heat exchanger per unit time (FcFccpc(Tco - Tci)) Qhe ) enthalpy of the coolant per unit time (FeFecpe(Teo - Tei)) Qhj ) enthalpy of the fluid in the jacket per unit time (FjFjcpj(Tjo - Tji)) Qflow ) heat transferred through the reactor wall per unit time ((UA)j(Tr - Tj))
(1) Uzun, S.; Durdu, M.; Culha, G.; Allahverdiyev, A. M.; Memisogiu, H. R. Clinical Features, Epidemiology, and Efficacy and Safety of Intralesional Antimony Treatment of Cutaneous Leishmaniasis: Recent Experience in Turkey. J. Parasitol. 2004, 90, 853. (2) Herwaldt, B. L. Leishmaniasis. Lancet 2004, 354, 1191-1199. (3) Hepburn, N. C. Cutaneous Leishmaniasis. Clin. Exp. Dermatol. 2000, 25, 363-370. (4) Davidson, R. N. Visceral Leishmaniasis in Clinical Practice. J. Infection 1999, 39, 112-116. (5) Crevatin, A.; Mascarello, F.; Lenthe, B.; Minder, B.; Kikic, I. Kinetic Investigations of a Ketonization Reaction Using Reaction Calorimetry. Ind. Eng. Chem. Res. 1999, 38, 4629. (6) Roche, D.; Sans, D.; Girgis, M. J.; Prasad, K.; Repic, O.; Blacklock, T. J. Optimization and Scale-Up of a Novel Process for 2-Aminoindan Hydrochloride Production. Org. Process Res. Dev. 2001, 5, 167. (7) Zogg, A.; Stoessel, F.; Fischer, U.; Hungerbuhler, K. Isothermal Reaction Calorimetry as a Tool for Kinetic Analysis. Thermochim. Acta 2004, 419, 1. (8) Petzold, L. R. DASSL, version 1989; Computing and Mathematics Research Division, Lawrence Livermore National Laboratory: Livermore, CA, 1989. (9) Barozza, A.; Verlardi, F.; Fornaroli, M. Thermochemical Scale-Up of a Mesylation Reaction. Org. Process Res. Dev. 2003, 7, 599.
Received for review March 3, 2005 Revised manuscript received May 5, 2005 Accepted June 20, 2005 IE0503038
