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Dushman protocols for mixing performance in microchannels: Effect of geometry on micromixing characterization and size reduction
Chemical Engineering and Processing 85 (2014) 178–186
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Chemical Engineering and Processing: Process Intensification journal homepage: www.elsevier.com/locate/cep
LASP and Villermaux/Dushman protocols for mixing performance in microchannels: Effect of geometry on micromixing characterization and size reduction Masoud Rahimi a, *, Peyvand Valeh-e-Sheyda a,b , Mohammad Amin Parsamoghadam a , Neda Azimi c , Hadi Abidi c a
CFD Research Center, Chemical Engineering Department, Razi University, Taghe Bostan, Kermanshah, Iran Chemical Engineering Department, Kermanshah University of Technology, Kermanshah, Iran c Novel Drug Delivery Research Center, Faculty of Pharmacy, Kermanshah University of Medical Sciences, Kermanshah, Iran b
A R T I C L E I N F O
A B S T R A C T
Article history: Received 10 May 2014 Received in revised form 17 July 2014 Accepted 4 September 2014 Available online 15 September 2014
The paper reports an experimental investigation on the effect of geometrical design of double jet impingement microchannels on mixing efficiency. Three arrangements of microchannel reactors (MCRs) were designed with 800 mm in diameter by 30 mm in length in various confluence angles of 45 , 90 , and 135 . Mixing performance of the microchannels was first evaluated via competitive parallel reactions of Villermaux/Dushman. The mixing quality was then described under various total liquid flow rates and initial acid concentration using segregation index (XS). In the second protocol, mixing performance was further investigated via complicated liquid anti-solvent precipitation (LASP) process for nanodrug production. Curcumin was utilized as a model of an insoluble drug in water and particle size and SEM imaging were then employed to characterize the produced nanosuspentions. The whole results show that despite considerable differences in nature of these two processes, the microchannel with confluence angle of 135 works more efficiently in both protocols, due to its higher mixing quality. ã 2014 Elsevier B.V. All rights reserved.
Keywords: Microchannel Villermaux/Dushman LASP Curcumin Nanoparticle Nanodrug
1. Introduction Microchannels can perform chemical reactions in tiny channels using continuous-flow processes. Together with other microfluidic components, they enable lab-on-a-chip devices to be fabricated where sample preparation for assays, drug delivery, etc. is carried out on the same chip [1]. Owing to the low volume of reagents needed and the higher speed of the analysis [2–4], this technique has advantages such as minimal environmental hazards and enhanced safety over the standard bench-top method [5]. Microchannels are portable, automated, and parallelizable. They have also generated a considerable activity at economic and scientific levels, and their relative low material cost has made an enormous progress in recent years [6]. Due to the small characteristic dimension of the conduit, the flow is usually laminar in microchannels. Thus, the slow diffusive mass transfer governs the extent of the chemical reactions taking place in the reactor, which in turn is proportional to the interfacial area between the reacting phases.
* Corresponding author. Tel.: +98 8314274530; fax: +98 8314274542. E-mail addresses: [email protected], [email protected] (M. Rahimi). http://dx.doi.org/10.1016/j.cep.2014.09.001 0255-2701/ ã 2014 Elsevier B.V. All rights reserved.
Mass transfer via diffusion is enhanced by the reduction in the channel width, as the path for diffusion (striation thickness) is minimized and increased the shear rate [7]. Considering this, mixing is a very important issue in MCRs design [8]. In micromixers, fluid deformation through convection is generated by variations in the geometry of a channel, e.g., channel confluence, bend, and twist can influence the mixing performance [8–10]. During the last decade, some experimental and computational studies were performed using microchannel technology [11–17]. Nevertheless, due to a lack of knowledge or even of data, the field uncovers a number of scientific challenges that researchers are just beginning to tackle. The other main challenges in microchannel is mixing, where more than one fluid comes together. Few reports have discussed the conditions under which a two-phase system can be effective in improving the selectivity of a desired product. It was investigated that compared to the microchannel diameter, the channel geometry plays a more important role in micromixing performance [18]. In order to leverage the effects of channel geometries, Ansari et al. [19] designed a T-joint micromixer relying on the unbalanced splits and cross collisions of fluid streams. It was illustrated that the interface in the curved sub-channels can enhance mixing performance of the micromixer. Besides, some numerical
M. Rahimi et al. / Chemical Engineering and Processing 85 (2014) 178–186
Nomenclature API As/S Ci DI g(t) h [H+]0 I ID k L LASP MCR NPs PI DP Q rj R t tm V Vacid V Y YTS
active pharmaceutical ingredients anti-solvent/Solvent concentration of tracer at time ti, mol/L deionized Growth function of incorporation law Hour Initial concentration of H+ ion, mol/L Ionic strength, mol m3 Internal diameter Constant in Eq.id=6#(12) Length liquid anti-solvent precipitation Microchannel reactor Nanopatricles polydispersity index Pressure drop difference, Pa volume flow rate, mL/min and m3/s total producing rate of the total producing rate of the types j in the reaction, mol/m3.s Flow rate ratio, dimensionless Time, s Characteristic micromixing time, s volume,m3 volume of acid at t, m3 0id=6#Initial of volume of acid, m3 Selectivity of iodide, dimensionless Selectivity of iodide for segregation, dimensionless
Greek letters e specific power dissipation,w/kg n liquid kinematic viscosity, m2/s u( ) degree
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methods in the pharmaceutical process, are more complicated. They always involve with both aqueous and organic solutions. Utilization of the two independent protocols including Villermaux–Dushman method and liquid anti-solvent precipitation (LASP) process can play a significant role in illustrating the mixing phenomenon in microchannels. The Villermaux–Dushman, also known as iodide–iodate test reaction system, is a suitable parallel reaction for making quantitative comparisons with different microchannels. In order to be able to characterize the mixing, the reaction time for the system must be less than the characteristic time for mixing. In LASP, precipitation of a solid solute is achieved by increase in a molar volume of solution and hence a decrease in solvent power for solute by addition of a non-solvent (anti-solvent) [26]. It mainly involves nucleation due to supersaturation attained by mixing [27] and simultaneous growth of nuclei by coagulation and condensation [28]. Higher nucleation rates result in low or negligible growth and hence can potentially produce nanoparticles (NPs). In this direction, serious poor delivery characteristics of drugs may be significantly improved by increasing their bioavailability. Considering the two proposed protocols, fast and homogenous mixing is the basic requirement for nanosuspension preparation, as well as high mixing efficiency. In the present work, the impact of confluence inlet angles of MCRs on mixing performance was investigated for two different applications. It has been tried to show that change in mixing performance proved by a classic competitive-parallel reaction, is also valid for a practical precipitation process. In order to evaluate mixing efficiency of MCRs, dissipation rate and mixing time were estimated in different confluence angles. The particle size of produced nanodrug particle was also used as a criterion for mixing efficiency in the precipitation process. The similarities in the mixing observations of two protocols were found to improve the geometrical conditions of MCRs and enhance the selectivity of desired products. 2. Experimental methods
study undertook indicating the effect of geometric parameters of micromixers on mixing and fluid flow, for a wide range of Reynolds number [8,20–23]. Among the available literatures, Aoki et al. [24] discussed the combination effects of fluid collision and channel bend after the confluent flow. Subsequently, it was revealed that the bend geometry improves mixing performance and larger confluence angle leads to a rapid mixing [25]. In literature, studies on mixing performance mostly focus on liquid systems, as a single component system, i.e., water–water system. From these studies, it is convenient to understand the flow patterns, energy consumption, etc. In order to investigate the proper evaluation of the flow patterns and mixing behaviors, it is necessary to monitor the extent of the mixing in different solvents. However, practical systems, such as nanodrugs’ preparation by anti-solvent
2.1. Materials The chemical materials used in the iodide–iodate test reaction containing KIO3, H3BO3, KI, and NaOH powders were supplied by Merck Inc. Sulfuric acid with a purity of 98% was provided by Fluka. Moreover, the reagents used were of analytical grade, and used as received. In the other hand, in LASP experiments, raw curcumin (C21H20O6) was obtained with a mean particle size of 28.9 mm (95%) from Merck–Schuchardt, and used without further purification. Ethanol (99.4%) was selected as an organic solvent for the curcumin. The organic solvent was purchased from Mojallali chemical laboratories, Iran. The sodium dodecyl sulfate (SDS) was also obtained from Merck–Schuchardt, Germany. Table 1
Table 1 (a) Materials used in LASP experiments (b) Reactant concentrations and flow rates used for Villermaux–Dushman reaction test. a) LASP material
Function
Mol. wt. (g/mol)
Curcumin > 90% Ethanol > 99.4% Sodium dodecyl sulfate (SDS)
API Solvent Stabilizer
368.39 46.07 288.4
b) Iodide–iodate reactant
Concentration (mol /L)
Q (mL/min)
R = Q/QH+
H3BO3 NaOH KIO3 KI H2SO4 IO3I-
0.1818 0.0909 0.00233 0.0116 0.0251, 0.053, 0.08 – –
Oct-50 – – – – Oct-50 Oct-50
10, 20, 30 – – – – 10, 20, 30 10, 20, 30
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summarizes the materials used in LASP experiments to produce curcumin nano-suspension. 2.2. Solution preparation 2.2.1. Villermaux–Dushman In Villermaux–Dushman test, the used chemical materials, their initial concentrations and flow rates are listed in Table 1. For preparation of the base solution, boric acid (H3BO3) and sodium hydroxide solutions (NaOH) were first dissolved in (deionized) DI water in a separate vessel. The as-prepared solutions were then mixed to obtain an equimolar buffer solution mixture of H2BO3/ H3BO3 (pH 9.14). Similarly, powders of KI and KIO3 were dissolved in DI water in a separate container. KI and KIO3 solutions were then added to the buffer solution in sequence. This sequence of mixing operation must be carefully followed so that iodide and iodate ions coexist in a basic solution which prevents thermodynamic iodine formation. The concentrated solutions were mixed as required [29–31]. 2.2.2. LASP process In order to prepare macro-suspension of the drug, 89.1 mg curcumin was dispersed in 20 mL ethanol (4.455 g/L) using mechanical stirring. At this concentration, the curcumin dissolved
completely in the solvent. Then, it was filtered through a 0.45 mm syringe filter, and sonicated (bath sonicator, Tecno-Gaz) for 2 min. The anti-solvent solution was prepared by dissolving 1 mg of water-soluble surfactant, SDS, in 100 mL of DI water to make antisolvent solution with 0.001% w/v. It is of noted that a small amount of surfactant will change the wetting property and help achieve formation of fine particles of poorly water soluble curcumin [32]. The aqueous solution of surfactant was homogenized continuously in a mixer at the room temperature. The agitation was stopped after 1 h in order to settle the mixture. Before processing, the supernatant was filtered through a 0.22 mm syringe filter to remove any possible particulate impurities. 2.3. Experimental setup Both LASP and Villermaux–Dushman test reaction experiments were performed in the schematic diagram of the experimental setup, illustrated in Fig. 1a. The key part in the diagram is the MCR. The diameters and lengths of the three MCRs are approximately 800 mm and 30 mm, respectively. Details of the fabricated microchannels were displayed in Fig. 1b–d. As illustrated in the figure, the solution A and B are pumped through a set of MCRs with different inlet angles (45 , 90 and 135 ). Since different flow rates of solutions A and B are introduced into the MCR, a constant flow
Fig. 1. Experimental setup for the iodide-iodate test reaction system and LASP process (a) Schematic diagram of experimental setup. (b) Scheme of MCR: u = 45 (c) u = 90 (d) u = 135 .
M. Rahimi et al. / Chemical Engineering and Processing 85 (2014) 178–186
rate of A is symmetrically provided by dividing the feed A into two jets. Subsequently the impinging point is located just at the crossing of the two channels. Directly after emerging from the MCR, the resulting dispersion is introduced to the analysis chamber. The analysis chamber for LASP test, is a flask (40 mm ID 60 mm L) stirring at 1500 rpm with a propeller mixer. It brings about the mixing of the drug solution and the anti-solvent to allow complete crystal growth. In iodide and iodate reaction experiments, the downstream of the outlet capillary is further attached to an online spectroscopic analysis system comprising of a cuvette, a UV–vis spectrometer (UVmini1240, SHIMADZU). A BD sensors model DMP-321 pressure transducer (accuracy: 0.25%) was used for all pressure testing. An analysis of the repeatability of the measurements was performed in order to ensure reliable and repeatable results.
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by the following scheme: [36–39]. þ H2 BO 3 þ H ! H3 BO3
quasi-instantaneous (I)
5I þ IO3 þ 6Hþ ! 3I þ 3H2 O I2 þ I $I 3
very fast (II)
(III)
The reaction rates are reported as follows: r1 ¼ k1 ½Hþ ½H2 BO 3
(1)
2 r1 ¼ k2 Hþ ½I 2 IO 3
(2)
2.4. Experimental procedure
þ r3 ¼ r þ 3 ¼ k3 ½I ½I2 k3 I3
(3)
2.4.1. Villermaux–Dushman test reaction system In the first step, solutions A and B were prepared. The procedure for preparation of solution A and B was described before. The mixture of KI, KIO3 and buffer solution is called solution A, while a dilute sulfuric acid solution (H2SO4) is called B. The test procedure consists of adding a small quantity of solution B (in stoichiometric deficiency) and A into the MCR, simultaneously. The feed (A) flow rate was varied in the range of 10–50 mL/min and the acid (B) was injected at flow rates of 0.33–5 mL/min. An online UV spectrophotometer (UVmini1240, SHIMADZU) was placed just at the outlet of the microchannel to measure I3 concentration using spectrophotometry at 353 nm. For each test, the measurements of samples continued until the I3 concentration reached to a stable value.
In which k1,k2 and k3 values were reported in our previous works [30,31].The redox reaction (II) is very fast, in the same range of the micromixing process, however it is much slower than the neutralization reaction (I), which is quasi-instantaneous. In perfect micromixing conditions, I 3 cannot be produced [31], whereas in partial or total segregation conditions, I 3 can be produced according to reaction (III). In order to quantify the micromixing performance, the segregation index (XS) is defined as follows [36,40,41]:
2.4.2. LASP system For LASP process, the syringe was filled with 5 mL of the prepared curcumin solution (B) and placed on a syringe pump. Next, 30 mL of DI water containing the corresponding surfactant (A), was loaded in the syringe pump, as the anti-solvent. The antisolvent and drug solution were then dropped from the solution injector into the microchannel with a vigorous mixing, so that the two media could contact immediately. Based on the syringe pump capacity, the total flow rate of anti-solvent and curcumin solution were adjusted at 40 and 4 mL/min, respectively. During 2 min of emerging the drug solution and the aqueous phase in the MCR, the resultant suspension was immediately transferred to the analysis chamber at constant room temperature of 25 C, as necessary. In the next step, the resulting fresh precipitates were immediately frozen in the liquid nitrogen and then freeze dried for 48 h to remove water and organic solvent and keep dispersed nanopowders. The samples were stored at room temperature in a glass desiccators till further. The experiments were also repeated twice in order to ensure reliable results.
Xs ¼
Y YTS
(4)
Where Y is the ratio of the H+ mole that is consumed by reaction (II) to the total injected mole of H+. YTS is this ratio in total segregation conditions. For continuous flow MCRs, these parameters are as follow equations [42,43]: Y¼2
ðnI2 þ n13 Þ nHþ
(5)
0
6 IO 3 0 Y TS ¼ 6 IO3 0 þ H2 BO3 0
(6)
In which, subscript 0 represents the initial concentration of the component in the solutions. The concentration of I3 is determined by spectrophotometery method, whereas the mole number of I2 can be calculated in terms of mass balance of iodine atoms and chemical equilibrium reactions [44,45]. It is also of noted that the value of the XS is within the range of 0
3. Characterization tests
3.2. Particle size measurements
3.1. Micromixing characterization in Villermaux–Dushman test reaction system
The particle size of the produced dispersed system was determined by using a Zetasizer nanoparticle (Nano-ZS, Malvern Instruments, Malvern, UK) based on dynamic light scattering principle technique, yielding the mean particle diameter of the suspension. All samples were measured in the formed suspension after particle preparation without further dilution. The measured parameters are the average particle size diameter (Z-Average) and the polydispersity index (PI). The refractive index of the suspension medium was also measured in 25 0.1 C in a refractometer, Model RE4OD (Metter
There are high numbers of papers concerned with competitive parallel test reaction for characterizing micromixing efficiency in several kinds of MCRs. The competitive parallel reactions are affected by the micromixing level, since their product distribution depends on the degree of segregation [33–35]. The reaction between iodide and iodate, coupled with a neutralization reaction, is one of the well-known parallel competing reactions namely the Villermaux/Dushman reaction. The reaction formula is described
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Toledo) with a precision of 0.0001 refractive index units. The obtained value was then applied in the particle size calculations.
with the angle of 135 . Therefore, the large confluence angle is favorable for enhancing mixing performance.
3.3. Scanning electron microscopy (SEM)
4.1.2. Effect of volumetric flow ratio on XS in various confluence angles In order to investigate the effect of the volumetric flow ratio, R (R is defined as QA/QB) on XS in three designed microchannels, the volumetric flow rates of acid solution, QB, was changed at a fixed flow rate of base solution, QA. By increasing the flow ratio R (meaning decrease in QB), the concentration of acid CB increased to maintain a given stoichiometric ratio (keeping mole ratio of bulk ions in A solution to acid ions in B solution constant), according to Eq. (7): nA Q A C A ¼ (7) nB Q B C B
The particle size and morphology of samples were observed using a scanning electron microscope (AIS 2100 microscope 86, Seron). The freeze-dried samples were spread on a SEM stub and sputtered with gold, before the SEM observations. The sample was placed in an evacuated chamber and scanned in a controlled pattern by an electron beam. Interaction of the electron beam with the specimen produces a variety of physical phenomenon used to form images and provide information about the specimens. 4. Results and discussions As mentioned earlier, to make a direct comparison between the mixing performances of three microchannels, the same hydraulic diameter (800 mm) and total geometric length of 30 mm was employed for the three fabricated microchannels. 4.1. Villermaux–Dushman test reaction system 4.1.1. Effect of basic liquid flow rates on XS in various confluence angles Segregation indexes in MCRs (XS) characterize the micromixing performances. In other words, low XS close to 0 means good micromixing performance, while high XS close to 1 means poor micromixing performance. In the experiments, the flow rates of basic incoming fluids were changed in the range of 10–50 mL/min and segregation index was obtained for each microchannel. Fig. 2 exhibits the results of segregation index in different basic solution flow rates. The general trend of the figure indicates that for the three channels, segregation index values decreases substantially, with the increase in the shearing velocity at constant flow ratio. That is, the mixing performance (XS) is enhanced at higher incoming flow rate of the shearing fluid, due to the more intensive impinging between A and B in the confluence region. Furthermore, the performance is improved with increasing confluence angle. In other words, to achieve a desired mixing performance, for instance XS = 0.01, the basic liquid flow rate of 50 mL/min is required for the channel with the confluence angle of 45 , while 30 mL/min for that
Fig. 2. Mixing performance of microchnannels with variousconfluence angles in different flow rates of basic solution (R = 10, [H+]0 = 0.16 mol/L).
Accordingly, R = 10, 20 and 30 corresponds to [H+]0 = 0.053, 0.106 and 0.16, respectively. Fig. 3 illustrates the segregation index (XS) values for each three micromixers in three values of flow rate ratios. As shown in this figure, the segregation index substantially increased by increasing the R-value and corresponding acid concentration. This phenomenon may be ascribed to the following two reasons. Firstly, the order of reaction rate (II) is more sensitive to acid concentration than that of reaction (I), since its reaction order is higher with respect to acid. In other words, a higher local concentration of acid directs the reaction (II) toward more iodine production. Secondly, at a fixed flow rate of A, QB will be decreased with further increase in the flow ratio (R), resulting in less intensive impinging between A and B, at the confluence area, so increasing XS. However, depending on the flow rate, mixing process is mainly controlled by the molecular diffusion and convection in the microchannels. The change in segregation index could be also attributed to the molecular diffusion [24,25]. In order to evaluate the influence of the microchannel confluence angle on the mixing rate, the obtained values of XS for u = 45 were compared with u = 90 and u = 135 . From Fig. 3, it is obvious that the angle between two adjoining inlet channels (u ) has a significant influence on the mixing performance. As can be seen, the mixing performance steeply enhances with increasing the angle of confluence, confirming the desirable effect of a large confluence angle for streams of two adjoining microchannels. The mechanism is that an increase in the angle of confluence causes an increase in the exerted force to the fluid at the confluence, which it previously reported by other authors [25]. In fact, increasing the applied force results in a reduction in the diffusion length between the fluids and hence can improve the mixing quality.
Fig. 3. Mixing performance of microchnannels in different flow rate ratios (QA = 30 mL/min).
M. Rahimi et al. / Chemical Engineering and Processing 85 (2014) 178–186
4.1.3. Effect of confluence angle on Mixing time (tm) To get a better understanding of the micromixing efficiency in microreactors, mixing time, was calculated as a useful parameter for assessing the mixing. It is well known that whenever fast reactions occur in reactors, the characteristic micromixing time (tm) is in competition with the characteristic reaction time (tR). When tm of reactants is comparable to tR, unequal molar ratios exists locally during the reaction and the reaction conversion is controlled by micromixing [39]. The micromixing time depends on hydrodynamic conditions and it only can be evaluated for each experiment using micromixing models. Several authors have developed an “incorporation model” to calculate tm from the segregation index, in many kinds of reactors including MCRs. This model is relatively simple and previously developed by Fournier et al. [47]. According to this model, the injected acid solution is divided into a series of aggregates that have an initial volume of Vacid,0. The aggregates are progressively invaded by the outside fluid containing iodide and iodate in basic medium. The characteristic time of incorporation is assumed to be equal to the micromixing time. The isolated aggregates grow gradually by incorporating the surrounding fluid, as Reactions (I) and (II) take place. The acid volume grows according to the equation [18]: V acid ¼ V acid;o gðtÞ
(8)
Where, Vacid,o is the initial volume and g(t) is growth function. The growth law of aggregates is a function of tm and can be expressed as follows [18]: gðtÞ ¼ 1 þ
t tm
(9)
Finally, the rate of concentration change of each species in the incorporation model is defined as given in the following [18,39] dcj 1dg þ rj ¼ ðC j;s cj Þ g dt dt
(10)
Where, Cjs, is surrounding fluid concentration of main solution and rj is the net production rate of species j for the reaction. The set of equations generated from (8) to (10) can be easily solved via the Runge–Kutta method and components concentrations and XS can be calculated on the basis of our experimental conditions. Applying the results of Fig. 2, the calculated micromixing time, tm, was demonstrated based on the incorporation model for designed micromixers in Fig. 4. From the results presented, the values of XS generally increased with increasing of tm. Moreover, when the XS was plotted versus tm for whole data a linear relation was obtained as shown in Fig. 4. According to the experimental values of XS, it was observed that for most of flow rates, the tm is in the range of 0.001–0.01 s. As illustrated, for angle of confluence
Fig. 4. Segregation index (XS) against micromixing time (tm) in various confluence angles (R = 10, [H+]0 = 0.16 mol/L).
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u = 90 , the value of tm is at the same order of tm for u = 135 . However, for confluence angle of u = 45 , tm is one order of magnitude higher in comparison with that of other micromixers. When all microchannels are compared, the microchannel with the large confluence angle, u = 135 , demonstrates lower tm indicating excellent micromixng performance, compared to other layouts. 4.2. Anti-solvent precipitation of drug using MCR As described earlier, the best mixing performance was obtained by employing the microchannel with the largest confluence angle, u = 135 . This part aims to confirm the results of confluence angles in MCRs in a complicated practical process, LASP, far away from a simple parallel-competitive reaction. It indeed contributes further information on the innovation and performance evaluation of MCRs. In LASP process, ethanolic solution of curcumin and aqueous surfactant were simultaneously injected into the double impingement microchannels and the precipitated particles were characterized. 4.2.1. Effect of confluence angle on size of precipitated particles The mean particle size of the raw curcumin was measured around 28.9 mm with PI of 1, which is outside the nanoparticle size range. Fig. 5 presents the mean particle size of curcumin in three configurations of micromixer at As/S = 10. Based on the figure, the size of the particles was found to increase from 181 nm to 265 nm upon decrease in the contact angle from 135 to 45 . Comparing the values, one can note that at a constant experimental condition, the agglomeration caused by non-uniform mixing plays a significant role in determining the size and stability of the precipitated particles. The possible reason is that in the smallest angle of confluence (u = 45 ), the impingement generates lower mixing intensity leading to relatively larger precipitated particles, while at u = 135 the impingement is relatively stronger, which is beneficial to the formation of smaller particles. In this regard, by reducing the particle size, the dissolution rate of curcumin can be improved in u = 135 according to the Noyes–Whitney equation, [48] as particles’ surface area increase. This reveals the significance of the particle size reduction. However, the particle growth depends on the meta-stable concentration region that exists between solubility and spontaneous nucleation. For a given solute, this varies from solvent to solvent [49]. The size of precipitated particles after 24 h from the experiments allows qualitative judgment about the short-term stability of the nanosuspension. For that, the nanosuspensions were divided into two parts; one part was stored at 25 C and the particle size was monitored after a period of 24 h. The results were also exhibited in Fig. 5. The general trend of the results reveals that after this period, an increase in mean particle size was observed nearly
Fig. 5. The mean particle size of curcumin nanosuspension in various angles of confluence.
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Fig. 6. Scanning electron micrographs of (a) raw curcumin as-received, (b) the freeze dried particles precipitated at u = 135 ; scale bar represents 1 mm.
in all samples. Agglomeration, crystal growth due to Ostwald ripening or both may be the contributing factors [27]. Besides, the microchannel with u = 45 does not perform well and produces unstable particles whose size significantly changes up to 24 h. The PI is also an important parameter in nanosuspension technology, as it gives an indication about the width of particle size distribution as well as the long-term stability of nanosuspension. A PI value of 0.1–0.25 indicates a narrow size distribution whereas a PI value greater than 0.5 indicates a very broad distribution [50]. For the prepared curcumin nanosuspensions, the corresponding PI was found to be 0.188, 0.138, and 0.225, respectively indicating a good distribution profile. 4.2.2. Scanning electron microscopy (SEM) To obtain dry powders of NPs, freeze drying process was applied. In freeze drying processes, water is removed from frozen nanoparticle suspensions by sublimation and desorption under high vacuum. Fig. 6 portrays the SEM image of unprocessed (aspurchased) and the finest processed curcumin powder obtained in selected MCR. The SEM image illustrates the irregular shape of raw curcumin particles in different sizes. Interestingly, the fine amorphous freeze dried NPs do not show aggregation or adhesion among the NPs. In addition, compact crystalline structures cannot be formed in microchannels, due to insufficient time available for crystal growth. However, the authors believed that increase in stabilizer concentration provides more dispersing medium, which plays an important role during dissolution study. 4.2.3. Specific energy dissipation calculations in different confluence angles For further understanding of mixing phenomena at micro-scale level, the specific energy dissipation was investigated inside the
Fig. 7. Effect of confluence angle on dissipation rate in various directions of micromixer.
fluid. For that, the pressure drops across the channel were measured using pressure transducers. The values for specific power dissipation (e) were calculated according to the following equation:
e¼
Q Dp rV
(11)
In this equation, Dp denotes the pressure loss over the control volume, with corresponding volume of the focused space, V, and volumetric flow Q [18,51]. According to Eq. (11), the specific power dissipation is proportional to the pressure drop and flow rate. Besides, by increasing the volumetric flow rate, the specific power dissipation will be increased, that is generally caused micromixing enhancement.Fig. 7 reveals the calculated values for specific power dissipation. Based on this figure, it is apparent that increase in the power dissipation rate is considerably noticeable at higher flow rates. However, keeping the flow rate constant, the power dissipation directly relates to the confluence angle of inlet streams. As an illustration, at constant flow rate of 21 mL/min, as the confluence angle increases from 45 to 135 , the dissipation rate increases from 33.10 to 42.23 w/kg. Another interesting result is that the energy dissipation depends more strongly on the flow rates than on the geometry. In other words, the data suggests that higher values of energy dissipation can be obtained at relatively higher flow rates with larger confluence angles. The characteristic micromixing time (tm) is mainly influenced by the energy dissipation based on following equation:
y 1=2 Þ e
tm ¼ kð
(12)
where k is a constant, n is the kinematic viscosity, and e is the energy dissipation rate [52]. The k value has been frequently reported in literatures reporting LASP process [53,54]. According to Eq. (12), it is clear that large confluence angles of MCRs can significantly reduce mixing time (tmix) resulting in production of NPs with narrower size distribution.Finally, on the basis of experimental observations in above section, it is found that depending upon the angle of confluence in inlet streams, the size of the resultant particles is different. The results of LASP experiments are clearly in agreement with the results given in iodide–iodate test reaction. It suggests that a large confluence angle is favorable for decreasing the segregation index, XS, and size of nanosuspensions in MCRs. It is only due to the increase in the degree of fluid deformation with the angle, as a rapid mixing and large energy dissipation will be achieved.
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5. Conclusion Homogeneous mixing in three different impingement jet microfludic mixers was characterized by adopting the LASP technique and iodide–iodate test reaction, known as Villermaux–Dushman reaction. Studies of the mixing effects on NP formation and Villermaux–Dushman reaction strongly suggest that the quality of target products were greatly influenced by confluence geometry of the streams in microchannels. In the first series of experiments, the micromixing efficiency of the microchannels was studied in terms of segregation index (XS), under various total flow rates and initial concentration of acid solution. The results show that because of decrease in volumetric flow rate ratio, segregationindex decreases with decreasein acid concentration. For comparative purposes, the reduction in XS values was more considerable, at larger confluence angles. In particular, upon application of the MCR with confluence angle of (135 ), the segregation indexes (XS) were found in the range of 0.001–0.1, indicating that this geometry of micrormixer can establish higher micromixing efficiency. In the second series of experiments, mixing performance was evaluated in terms of size reduction of precipitated curcumin nanoparticles and their short-term physical stability. Among fabricated microchannels, the most effective confluence angle was satisfactorily observed in u = 135 . As a result of this study, nanoparticles with least average diameters of 181 nm were obtained in the selected microchannel, compared with 28.9 mm original size of purchased raw curcumin particles. Considering both iodide–iodate reaction and LASP process, superior performance of MCRs with large contact angle is clearly due to their large energy dissipation in the center of micromixer. This causes a higher momentum exchange, which is primarily responsible for its more efficient mixing. From this study, it can be concluded that change in mixing performance proved by a classic competitiveparallel reaction, is also valid for a complicated LASP nanodrug production process. References [1] S.H. Wong, M.C.L. Ward, C.W. Wharton, Micro T-mixer as a rapid mixing micromixer, Sens. Actuators B. 100 (2004) 359–379. [2] T. Fujii, PDMS-based microfluidic devices for biomedical applications, Microelectron. Eng. 61–62 (2002) 907–914. [3] C.T. McClain, S.C. Culbertson, Nancy, L.C.E. Sims, J.M. Ramsey, Microfluidic devices for the high-throughput chemical analysis of cells, Anal. Chem. 75 (21) (2003) 5646–5655. [4] M.Y. Ye, et al., DNA separation with low-viscosity sieving matrix on microfabricated polycarbonate microfluidic chips, Anal. Bioanal. Chem. 381 (2005) 820–827. [5] S. Ferrouillat, P. Tochon, H. Peerhossaini, Micromixing enhancement by turbu lence: application to multifunctional heat exchangers, Chem. Eng. Process. 45 (2006) 633–640. [6] R. Krger, CFD for Microfluidics, Fluent Deutschland GmbH, 2006. http://scai. fraunhofer.de/fileadmin/download/fsi-biomedical/FSI-Bio-FluentKroeger.pdf (accessed 20.02.08). [7] R.B. Bird, W.E. Stewart, E.N. Lightfoot, Transport Phenomena, second ed., Wiley, New York, 2001, pp. 846–848. [8] A.G. Kanaris, A.A. Mouza, Numerical investigation of the effect of geometrical parameters on the performance of a micro-reactor, Chem. Eng. Sci. 66 (2011) 5366–5373. [9] M. Faryadi, M. Rahimi, S. Safari, N. Moradi, CFD Effect of high frequency ultrasound on micromixing efficiencyin microchannels, Chem. Eng. Process. 77 (2014) 13–21. [10] N. Kockmann, M. Gottsponer, D.M. Roberge, Scale-up concept of singlechannel microreactors from process development to industrial production, Chem. Eng. J. 167 (2011) 718–726. [11] W. Ehrfeld, V. Hessel, H. Löwe, Microreactors-New Technology for Modern Chemistry, Wiley/VCH, Weinheim, 2000. [12] V. Hessel, H. Löwe, Mikroverfahrenstechnik: Komponenten-Anlagen- konzeption-Anwenderakzeptanz-Teil 1, Chemie Ingenieur Technik 74 (2002) 17–30. [13] V. Hessel, H. Löwe, Mikroverfahrenstechnik: Komponenten-Anlagen- konzeption-Anwenderakzeptanz-Teil 3, Chemie Ingenieur Technik 74 (2002) 381– 400.
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Contents lists available at ScienceDirect
Chemical Engineering and Processing: Process Intensification journal homepage: www.elsevier.com/locate/cep
LASP and Villermaux/Dushman protocols for mixing performance in microchannels: Effect of geometry on micromixing characterization and size reduction Masoud Rahimi a, *, Peyvand Valeh-e-Sheyda a,b , Mohammad Amin Parsamoghadam a , Neda Azimi c , Hadi Abidi c a
CFD Research Center, Chemical Engineering Department, Razi University, Taghe Bostan, Kermanshah, Iran Chemical Engineering Department, Kermanshah University of Technology, Kermanshah, Iran c Novel Drug Delivery Research Center, Faculty of Pharmacy, Kermanshah University of Medical Sciences, Kermanshah, Iran b
A R T I C L E I N F O
A B S T R A C T
Article history: Received 10 May 2014 Received in revised form 17 July 2014 Accepted 4 September 2014 Available online 15 September 2014
The paper reports an experimental investigation on the effect of geometrical design of double jet impingement microchannels on mixing efficiency. Three arrangements of microchannel reactors (MCRs) were designed with 800 mm in diameter by 30 mm in length in various confluence angles of 45 , 90 , and 135 . Mixing performance of the microchannels was first evaluated via competitive parallel reactions of Villermaux/Dushman. The mixing quality was then described under various total liquid flow rates and initial acid concentration using segregation index (XS). In the second protocol, mixing performance was further investigated via complicated liquid anti-solvent precipitation (LASP) process for nanodrug production. Curcumin was utilized as a model of an insoluble drug in water and particle size and SEM imaging were then employed to characterize the produced nanosuspentions. The whole results show that despite considerable differences in nature of these two processes, the microchannel with confluence angle of 135 works more efficiently in both protocols, due to its higher mixing quality. ã 2014 Elsevier B.V. All rights reserved.
Keywords: Microchannel Villermaux/Dushman LASP Curcumin Nanoparticle Nanodrug
1. Introduction Microchannels can perform chemical reactions in tiny channels using continuous-flow processes. Together with other microfluidic components, they enable lab-on-a-chip devices to be fabricated where sample preparation for assays, drug delivery, etc. is carried out on the same chip [1]. Owing to the low volume of reagents needed and the higher speed of the analysis [2–4], this technique has advantages such as minimal environmental hazards and enhanced safety over the standard bench-top method [5]. Microchannels are portable, automated, and parallelizable. They have also generated a considerable activity at economic and scientific levels, and their relative low material cost has made an enormous progress in recent years [6]. Due to the small characteristic dimension of the conduit, the flow is usually laminar in microchannels. Thus, the slow diffusive mass transfer governs the extent of the chemical reactions taking place in the reactor, which in turn is proportional to the interfacial area between the reacting phases.
* Corresponding author. Tel.: +98 8314274530; fax: +98 8314274542. E-mail addresses: [email protected], [email protected] (M. Rahimi). http://dx.doi.org/10.1016/j.cep.2014.09.001 0255-2701/ ã 2014 Elsevier B.V. All rights reserved.
Mass transfer via diffusion is enhanced by the reduction in the channel width, as the path for diffusion (striation thickness) is minimized and increased the shear rate [7]. Considering this, mixing is a very important issue in MCRs design [8]. In micromixers, fluid deformation through convection is generated by variations in the geometry of a channel, e.g., channel confluence, bend, and twist can influence the mixing performance [8–10]. During the last decade, some experimental and computational studies were performed using microchannel technology [11–17]. Nevertheless, due to a lack of knowledge or even of data, the field uncovers a number of scientific challenges that researchers are just beginning to tackle. The other main challenges in microchannel is mixing, where more than one fluid comes together. Few reports have discussed the conditions under which a two-phase system can be effective in improving the selectivity of a desired product. It was investigated that compared to the microchannel diameter, the channel geometry plays a more important role in micromixing performance [18]. In order to leverage the effects of channel geometries, Ansari et al. [19] designed a T-joint micromixer relying on the unbalanced splits and cross collisions of fluid streams. It was illustrated that the interface in the curved sub-channels can enhance mixing performance of the micromixer. Besides, some numerical
M. Rahimi et al. / Chemical Engineering and Processing 85 (2014) 178–186
Nomenclature API As/S Ci DI g(t) h [H+]0 I ID k L LASP MCR NPs PI DP Q rj R t tm V Vacid V Y YTS
active pharmaceutical ingredients anti-solvent/Solvent concentration of tracer at time ti, mol/L deionized Growth function of incorporation law Hour Initial concentration of H+ ion, mol/L Ionic strength, mol m3 Internal diameter Constant in Eq.id=6#(12) Length liquid anti-solvent precipitation Microchannel reactor Nanopatricles polydispersity index Pressure drop difference, Pa volume flow rate, mL/min and m3/s total producing rate of the total producing rate of the types j in the reaction, mol/m3.s Flow rate ratio, dimensionless Time, s Characteristic micromixing time, s volume,m3 volume of acid at t, m3 0id=6#Initial of volume of acid, m3 Selectivity of iodide, dimensionless Selectivity of iodide for segregation, dimensionless
Greek letters e specific power dissipation,w/kg n liquid kinematic viscosity, m2/s u( ) degree
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methods in the pharmaceutical process, are more complicated. They always involve with both aqueous and organic solutions. Utilization of the two independent protocols including Villermaux–Dushman method and liquid anti-solvent precipitation (LASP) process can play a significant role in illustrating the mixing phenomenon in microchannels. The Villermaux–Dushman, also known as iodide–iodate test reaction system, is a suitable parallel reaction for making quantitative comparisons with different microchannels. In order to be able to characterize the mixing, the reaction time for the system must be less than the characteristic time for mixing. In LASP, precipitation of a solid solute is achieved by increase in a molar volume of solution and hence a decrease in solvent power for solute by addition of a non-solvent (anti-solvent) [26]. It mainly involves nucleation due to supersaturation attained by mixing [27] and simultaneous growth of nuclei by coagulation and condensation [28]. Higher nucleation rates result in low or negligible growth and hence can potentially produce nanoparticles (NPs). In this direction, serious poor delivery characteristics of drugs may be significantly improved by increasing their bioavailability. Considering the two proposed protocols, fast and homogenous mixing is the basic requirement for nanosuspension preparation, as well as high mixing efficiency. In the present work, the impact of confluence inlet angles of MCRs on mixing performance was investigated for two different applications. It has been tried to show that change in mixing performance proved by a classic competitive-parallel reaction, is also valid for a practical precipitation process. In order to evaluate mixing efficiency of MCRs, dissipation rate and mixing time were estimated in different confluence angles. The particle size of produced nanodrug particle was also used as a criterion for mixing efficiency in the precipitation process. The similarities in the mixing observations of two protocols were found to improve the geometrical conditions of MCRs and enhance the selectivity of desired products. 2. Experimental methods
study undertook indicating the effect of geometric parameters of micromixers on mixing and fluid flow, for a wide range of Reynolds number [8,20–23]. Among the available literatures, Aoki et al. [24] discussed the combination effects of fluid collision and channel bend after the confluent flow. Subsequently, it was revealed that the bend geometry improves mixing performance and larger confluence angle leads to a rapid mixing [25]. In literature, studies on mixing performance mostly focus on liquid systems, as a single component system, i.e., water–water system. From these studies, it is convenient to understand the flow patterns, energy consumption, etc. In order to investigate the proper evaluation of the flow patterns and mixing behaviors, it is necessary to monitor the extent of the mixing in different solvents. However, practical systems, such as nanodrugs’ preparation by anti-solvent
2.1. Materials The chemical materials used in the iodide–iodate test reaction containing KIO3, H3BO3, KI, and NaOH powders were supplied by Merck Inc. Sulfuric acid with a purity of 98% was provided by Fluka. Moreover, the reagents used were of analytical grade, and used as received. In the other hand, in LASP experiments, raw curcumin (C21H20O6) was obtained with a mean particle size of 28.9 mm (95%) from Merck–Schuchardt, and used without further purification. Ethanol (99.4%) was selected as an organic solvent for the curcumin. The organic solvent was purchased from Mojallali chemical laboratories, Iran. The sodium dodecyl sulfate (SDS) was also obtained from Merck–Schuchardt, Germany. Table 1
Table 1 (a) Materials used in LASP experiments (b) Reactant concentrations and flow rates used for Villermaux–Dushman reaction test. a) LASP material
Function
Mol. wt. (g/mol)
Curcumin > 90% Ethanol > 99.4% Sodium dodecyl sulfate (SDS)
API Solvent Stabilizer
368.39 46.07 288.4
b) Iodide–iodate reactant
Concentration (mol /L)
Q (mL/min)
R = Q/QH+
H3BO3 NaOH KIO3 KI H2SO4 IO3I-
0.1818 0.0909 0.00233 0.0116 0.0251, 0.053, 0.08 – –
Oct-50 – – – – Oct-50 Oct-50
10, 20, 30 – – – – 10, 20, 30 10, 20, 30
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summarizes the materials used in LASP experiments to produce curcumin nano-suspension. 2.2. Solution preparation 2.2.1. Villermaux–Dushman In Villermaux–Dushman test, the used chemical materials, their initial concentrations and flow rates are listed in Table 1. For preparation of the base solution, boric acid (H3BO3) and sodium hydroxide solutions (NaOH) were first dissolved in (deionized) DI water in a separate vessel. The as-prepared solutions were then mixed to obtain an equimolar buffer solution mixture of H2BO3/ H3BO3 (pH 9.14). Similarly, powders of KI and KIO3 were dissolved in DI water in a separate container. KI and KIO3 solutions were then added to the buffer solution in sequence. This sequence of mixing operation must be carefully followed so that iodide and iodate ions coexist in a basic solution which prevents thermodynamic iodine formation. The concentrated solutions were mixed as required [29–31]. 2.2.2. LASP process In order to prepare macro-suspension of the drug, 89.1 mg curcumin was dispersed in 20 mL ethanol (4.455 g/L) using mechanical stirring. At this concentration, the curcumin dissolved
completely in the solvent. Then, it was filtered through a 0.45 mm syringe filter, and sonicated (bath sonicator, Tecno-Gaz) for 2 min. The anti-solvent solution was prepared by dissolving 1 mg of water-soluble surfactant, SDS, in 100 mL of DI water to make antisolvent solution with 0.001% w/v. It is of noted that a small amount of surfactant will change the wetting property and help achieve formation of fine particles of poorly water soluble curcumin [32]. The aqueous solution of surfactant was homogenized continuously in a mixer at the room temperature. The agitation was stopped after 1 h in order to settle the mixture. Before processing, the supernatant was filtered through a 0.22 mm syringe filter to remove any possible particulate impurities. 2.3. Experimental setup Both LASP and Villermaux–Dushman test reaction experiments were performed in the schematic diagram of the experimental setup, illustrated in Fig. 1a. The key part in the diagram is the MCR. The diameters and lengths of the three MCRs are approximately 800 mm and 30 mm, respectively. Details of the fabricated microchannels were displayed in Fig. 1b–d. As illustrated in the figure, the solution A and B are pumped through a set of MCRs with different inlet angles (45 , 90 and 135 ). Since different flow rates of solutions A and B are introduced into the MCR, a constant flow
Fig. 1. Experimental setup for the iodide-iodate test reaction system and LASP process (a) Schematic diagram of experimental setup. (b) Scheme of MCR: u = 45 (c) u = 90 (d) u = 135 .
M. Rahimi et al. / Chemical Engineering and Processing 85 (2014) 178–186
rate of A is symmetrically provided by dividing the feed A into two jets. Subsequently the impinging point is located just at the crossing of the two channels. Directly after emerging from the MCR, the resulting dispersion is introduced to the analysis chamber. The analysis chamber for LASP test, is a flask (40 mm ID 60 mm L) stirring at 1500 rpm with a propeller mixer. It brings about the mixing of the drug solution and the anti-solvent to allow complete crystal growth. In iodide and iodate reaction experiments, the downstream of the outlet capillary is further attached to an online spectroscopic analysis system comprising of a cuvette, a UV–vis spectrometer (UVmini1240, SHIMADZU). A BD sensors model DMP-321 pressure transducer (accuracy: 0.25%) was used for all pressure testing. An analysis of the repeatability of the measurements was performed in order to ensure reliable and repeatable results.
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by the following scheme: [36–39]. þ H2 BO 3 þ H ! H3 BO3
quasi-instantaneous (I)
5I þ IO3 þ 6Hþ ! 3I þ 3H2 O I2 þ I $I 3
very fast (II)
(III)
The reaction rates are reported as follows: r1 ¼ k1 ½Hþ ½H2 BO 3
(1)
2 r1 ¼ k2 Hþ ½I 2 IO 3
(2)
2.4. Experimental procedure
þ r3 ¼ r þ 3 ¼ k3 ½I ½I2 k3 I3
(3)
2.4.1. Villermaux–Dushman test reaction system In the first step, solutions A and B were prepared. The procedure for preparation of solution A and B was described before. The mixture of KI, KIO3 and buffer solution is called solution A, while a dilute sulfuric acid solution (H2SO4) is called B. The test procedure consists of adding a small quantity of solution B (in stoichiometric deficiency) and A into the MCR, simultaneously. The feed (A) flow rate was varied in the range of 10–50 mL/min and the acid (B) was injected at flow rates of 0.33–5 mL/min. An online UV spectrophotometer (UVmini1240, SHIMADZU) was placed just at the outlet of the microchannel to measure I3 concentration using spectrophotometry at 353 nm. For each test, the measurements of samples continued until the I3 concentration reached to a stable value.
In which k1,k2 and k3 values were reported in our previous works [30,31].The redox reaction (II) is very fast, in the same range of the micromixing process, however it is much slower than the neutralization reaction (I), which is quasi-instantaneous. In perfect micromixing conditions, I 3 cannot be produced [31], whereas in partial or total segregation conditions, I 3 can be produced according to reaction (III). In order to quantify the micromixing performance, the segregation index (XS) is defined as follows [36,40,41]:
2.4.2. LASP system For LASP process, the syringe was filled with 5 mL of the prepared curcumin solution (B) and placed on a syringe pump. Next, 30 mL of DI water containing the corresponding surfactant (A), was loaded in the syringe pump, as the anti-solvent. The antisolvent and drug solution were then dropped from the solution injector into the microchannel with a vigorous mixing, so that the two media could contact immediately. Based on the syringe pump capacity, the total flow rate of anti-solvent and curcumin solution were adjusted at 40 and 4 mL/min, respectively. During 2 min of emerging the drug solution and the aqueous phase in the MCR, the resultant suspension was immediately transferred to the analysis chamber at constant room temperature of 25 C, as necessary. In the next step, the resulting fresh precipitates were immediately frozen in the liquid nitrogen and then freeze dried for 48 h to remove water and organic solvent and keep dispersed nanopowders. The samples were stored at room temperature in a glass desiccators till further. The experiments were also repeated twice in order to ensure reliable results.
Xs ¼
Y YTS
(4)
Where Y is the ratio of the H+ mole that is consumed by reaction (II) to the total injected mole of H+. YTS is this ratio in total segregation conditions. For continuous flow MCRs, these parameters are as follow equations [42,43]: Y¼2
ðnI2 þ n13 Þ nHþ
(5)
0
6 IO 3 0 Y TS ¼ 6 IO3 0 þ H2 BO3 0
(6)
In which, subscript 0 represents the initial concentration of the component in the solutions. The concentration of I3 is determined by spectrophotometery method, whereas the mole number of I2 can be calculated in terms of mass balance of iodine atoms and chemical equilibrium reactions [44,45]. It is also of noted that the value of the XS is within the range of 0
3. Characterization tests
3.2. Particle size measurements
3.1. Micromixing characterization in Villermaux–Dushman test reaction system
The particle size of the produced dispersed system was determined by using a Zetasizer nanoparticle (Nano-ZS, Malvern Instruments, Malvern, UK) based on dynamic light scattering principle technique, yielding the mean particle diameter of the suspension. All samples were measured in the formed suspension after particle preparation without further dilution. The measured parameters are the average particle size diameter (Z-Average) and the polydispersity index (PI). The refractive index of the suspension medium was also measured in 25 0.1 C in a refractometer, Model RE4OD (Metter
There are high numbers of papers concerned with competitive parallel test reaction for characterizing micromixing efficiency in several kinds of MCRs. The competitive parallel reactions are affected by the micromixing level, since their product distribution depends on the degree of segregation [33–35]. The reaction between iodide and iodate, coupled with a neutralization reaction, is one of the well-known parallel competing reactions namely the Villermaux/Dushman reaction. The reaction formula is described
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Toledo) with a precision of 0.0001 refractive index units. The obtained value was then applied in the particle size calculations.
with the angle of 135 . Therefore, the large confluence angle is favorable for enhancing mixing performance.
3.3. Scanning electron microscopy (SEM)
4.1.2. Effect of volumetric flow ratio on XS in various confluence angles In order to investigate the effect of the volumetric flow ratio, R (R is defined as QA/QB) on XS in three designed microchannels, the volumetric flow rates of acid solution, QB, was changed at a fixed flow rate of base solution, QA. By increasing the flow ratio R (meaning decrease in QB), the concentration of acid CB increased to maintain a given stoichiometric ratio (keeping mole ratio of bulk ions in A solution to acid ions in B solution constant), according to Eq. (7): nA Q A C A ¼ (7) nB Q B C B
The particle size and morphology of samples were observed using a scanning electron microscope (AIS 2100 microscope 86, Seron). The freeze-dried samples were spread on a SEM stub and sputtered with gold, before the SEM observations. The sample was placed in an evacuated chamber and scanned in a controlled pattern by an electron beam. Interaction of the electron beam with the specimen produces a variety of physical phenomenon used to form images and provide information about the specimens. 4. Results and discussions As mentioned earlier, to make a direct comparison between the mixing performances of three microchannels, the same hydraulic diameter (800 mm) and total geometric length of 30 mm was employed for the three fabricated microchannels. 4.1. Villermaux–Dushman test reaction system 4.1.1. Effect of basic liquid flow rates on XS in various confluence angles Segregation indexes in MCRs (XS) characterize the micromixing performances. In other words, low XS close to 0 means good micromixing performance, while high XS close to 1 means poor micromixing performance. In the experiments, the flow rates of basic incoming fluids were changed in the range of 10–50 mL/min and segregation index was obtained for each microchannel. Fig. 2 exhibits the results of segregation index in different basic solution flow rates. The general trend of the figure indicates that for the three channels, segregation index values decreases substantially, with the increase in the shearing velocity at constant flow ratio. That is, the mixing performance (XS) is enhanced at higher incoming flow rate of the shearing fluid, due to the more intensive impinging between A and B in the confluence region. Furthermore, the performance is improved with increasing confluence angle. In other words, to achieve a desired mixing performance, for instance XS = 0.01, the basic liquid flow rate of 50 mL/min is required for the channel with the confluence angle of 45 , while 30 mL/min for that
Fig. 2. Mixing performance of microchnannels with variousconfluence angles in different flow rates of basic solution (R = 10, [H+]0 = 0.16 mol/L).
Accordingly, R = 10, 20 and 30 corresponds to [H+]0 = 0.053, 0.106 and 0.16, respectively. Fig. 3 illustrates the segregation index (XS) values for each three micromixers in three values of flow rate ratios. As shown in this figure, the segregation index substantially increased by increasing the R-value and corresponding acid concentration. This phenomenon may be ascribed to the following two reasons. Firstly, the order of reaction rate (II) is more sensitive to acid concentration than that of reaction (I), since its reaction order is higher with respect to acid. In other words, a higher local concentration of acid directs the reaction (II) toward more iodine production. Secondly, at a fixed flow rate of A, QB will be decreased with further increase in the flow ratio (R), resulting in less intensive impinging between A and B, at the confluence area, so increasing XS. However, depending on the flow rate, mixing process is mainly controlled by the molecular diffusion and convection in the microchannels. The change in segregation index could be also attributed to the molecular diffusion [24,25]. In order to evaluate the influence of the microchannel confluence angle on the mixing rate, the obtained values of XS for u = 45 were compared with u = 90 and u = 135 . From Fig. 3, it is obvious that the angle between two adjoining inlet channels (u ) has a significant influence on the mixing performance. As can be seen, the mixing performance steeply enhances with increasing the angle of confluence, confirming the desirable effect of a large confluence angle for streams of two adjoining microchannels. The mechanism is that an increase in the angle of confluence causes an increase in the exerted force to the fluid at the confluence, which it previously reported by other authors [25]. In fact, increasing the applied force results in a reduction in the diffusion length between the fluids and hence can improve the mixing quality.
Fig. 3. Mixing performance of microchnannels in different flow rate ratios (QA = 30 mL/min).
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4.1.3. Effect of confluence angle on Mixing time (tm) To get a better understanding of the micromixing efficiency in microreactors, mixing time, was calculated as a useful parameter for assessing the mixing. It is well known that whenever fast reactions occur in reactors, the characteristic micromixing time (tm) is in competition with the characteristic reaction time (tR). When tm of reactants is comparable to tR, unequal molar ratios exists locally during the reaction and the reaction conversion is controlled by micromixing [39]. The micromixing time depends on hydrodynamic conditions and it only can be evaluated for each experiment using micromixing models. Several authors have developed an “incorporation model” to calculate tm from the segregation index, in many kinds of reactors including MCRs. This model is relatively simple and previously developed by Fournier et al. [47]. According to this model, the injected acid solution is divided into a series of aggregates that have an initial volume of Vacid,0. The aggregates are progressively invaded by the outside fluid containing iodide and iodate in basic medium. The characteristic time of incorporation is assumed to be equal to the micromixing time. The isolated aggregates grow gradually by incorporating the surrounding fluid, as Reactions (I) and (II) take place. The acid volume grows according to the equation [18]: V acid ¼ V acid;o gðtÞ
(8)
Where, Vacid,o is the initial volume and g(t) is growth function. The growth law of aggregates is a function of tm and can be expressed as follows [18]: gðtÞ ¼ 1 þ
t tm
(9)
Finally, the rate of concentration change of each species in the incorporation model is defined as given in the following [18,39] dcj 1dg þ rj ¼ ðC j;s cj Þ g dt dt
(10)
Where, Cjs, is surrounding fluid concentration of main solution and rj is the net production rate of species j for the reaction. The set of equations generated from (8) to (10) can be easily solved via the Runge–Kutta method and components concentrations and XS can be calculated on the basis of our experimental conditions. Applying the results of Fig. 2, the calculated micromixing time, tm, was demonstrated based on the incorporation model for designed micromixers in Fig. 4. From the results presented, the values of XS generally increased with increasing of tm. Moreover, when the XS was plotted versus tm for whole data a linear relation was obtained as shown in Fig. 4. According to the experimental values of XS, it was observed that for most of flow rates, the tm is in the range of 0.001–0.01 s. As illustrated, for angle of confluence
Fig. 4. Segregation index (XS) against micromixing time (tm) in various confluence angles (R = 10, [H+]0 = 0.16 mol/L).
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u = 90 , the value of tm is at the same order of tm for u = 135 . However, for confluence angle of u = 45 , tm is one order of magnitude higher in comparison with that of other micromixers. When all microchannels are compared, the microchannel with the large confluence angle, u = 135 , demonstrates lower tm indicating excellent micromixng performance, compared to other layouts. 4.2. Anti-solvent precipitation of drug using MCR As described earlier, the best mixing performance was obtained by employing the microchannel with the largest confluence angle, u = 135 . This part aims to confirm the results of confluence angles in MCRs in a complicated practical process, LASP, far away from a simple parallel-competitive reaction. It indeed contributes further information on the innovation and performance evaluation of MCRs. In LASP process, ethanolic solution of curcumin and aqueous surfactant were simultaneously injected into the double impingement microchannels and the precipitated particles were characterized. 4.2.1. Effect of confluence angle on size of precipitated particles The mean particle size of the raw curcumin was measured around 28.9 mm with PI of 1, which is outside the nanoparticle size range. Fig. 5 presents the mean particle size of curcumin in three configurations of micromixer at As/S = 10. Based on the figure, the size of the particles was found to increase from 181 nm to 265 nm upon decrease in the contact angle from 135 to 45 . Comparing the values, one can note that at a constant experimental condition, the agglomeration caused by non-uniform mixing plays a significant role in determining the size and stability of the precipitated particles. The possible reason is that in the smallest angle of confluence (u = 45 ), the impingement generates lower mixing intensity leading to relatively larger precipitated particles, while at u = 135 the impingement is relatively stronger, which is beneficial to the formation of smaller particles. In this regard, by reducing the particle size, the dissolution rate of curcumin can be improved in u = 135 according to the Noyes–Whitney equation, [48] as particles’ surface area increase. This reveals the significance of the particle size reduction. However, the particle growth depends on the meta-stable concentration region that exists between solubility and spontaneous nucleation. For a given solute, this varies from solvent to solvent [49]. The size of precipitated particles after 24 h from the experiments allows qualitative judgment about the short-term stability of the nanosuspension. For that, the nanosuspensions were divided into two parts; one part was stored at 25 C and the particle size was monitored after a period of 24 h. The results were also exhibited in Fig. 5. The general trend of the results reveals that after this period, an increase in mean particle size was observed nearly
Fig. 5. The mean particle size of curcumin nanosuspension in various angles of confluence.
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Fig. 6. Scanning electron micrographs of (a) raw curcumin as-received, (b) the freeze dried particles precipitated at u = 135 ; scale bar represents 1 mm.
in all samples. Agglomeration, crystal growth due to Ostwald ripening or both may be the contributing factors [27]. Besides, the microchannel with u = 45 does not perform well and produces unstable particles whose size significantly changes up to 24 h. The PI is also an important parameter in nanosuspension technology, as it gives an indication about the width of particle size distribution as well as the long-term stability of nanosuspension. A PI value of 0.1–0.25 indicates a narrow size distribution whereas a PI value greater than 0.5 indicates a very broad distribution [50]. For the prepared curcumin nanosuspensions, the corresponding PI was found to be 0.188, 0.138, and 0.225, respectively indicating a good distribution profile. 4.2.2. Scanning electron microscopy (SEM) To obtain dry powders of NPs, freeze drying process was applied. In freeze drying processes, water is removed from frozen nanoparticle suspensions by sublimation and desorption under high vacuum. Fig. 6 portrays the SEM image of unprocessed (aspurchased) and the finest processed curcumin powder obtained in selected MCR. The SEM image illustrates the irregular shape of raw curcumin particles in different sizes. Interestingly, the fine amorphous freeze dried NPs do not show aggregation or adhesion among the NPs. In addition, compact crystalline structures cannot be formed in microchannels, due to insufficient time available for crystal growth. However, the authors believed that increase in stabilizer concentration provides more dispersing medium, which plays an important role during dissolution study. 4.2.3. Specific energy dissipation calculations in different confluence angles For further understanding of mixing phenomena at micro-scale level, the specific energy dissipation was investigated inside the
Fig. 7. Effect of confluence angle on dissipation rate in various directions of micromixer.
fluid. For that, the pressure drops across the channel were measured using pressure transducers. The values for specific power dissipation (e) were calculated according to the following equation:
e¼
Q Dp rV
(11)
In this equation, Dp denotes the pressure loss over the control volume, with corresponding volume of the focused space, V, and volumetric flow Q [18,51]. According to Eq. (11), the specific power dissipation is proportional to the pressure drop and flow rate. Besides, by increasing the volumetric flow rate, the specific power dissipation will be increased, that is generally caused micromixing enhancement.Fig. 7 reveals the calculated values for specific power dissipation. Based on this figure, it is apparent that increase in the power dissipation rate is considerably noticeable at higher flow rates. However, keeping the flow rate constant, the power dissipation directly relates to the confluence angle of inlet streams. As an illustration, at constant flow rate of 21 mL/min, as the confluence angle increases from 45 to 135 , the dissipation rate increases from 33.10 to 42.23 w/kg. Another interesting result is that the energy dissipation depends more strongly on the flow rates than on the geometry. In other words, the data suggests that higher values of energy dissipation can be obtained at relatively higher flow rates with larger confluence angles. The characteristic micromixing time (tm) is mainly influenced by the energy dissipation based on following equation:
y 1=2 Þ e
tm ¼ kð
(12)
where k is a constant, n is the kinematic viscosity, and e is the energy dissipation rate [52]. The k value has been frequently reported in literatures reporting LASP process [53,54]. According to Eq. (12), it is clear that large confluence angles of MCRs can significantly reduce mixing time (tmix) resulting in production of NPs with narrower size distribution.Finally, on the basis of experimental observations in above section, it is found that depending upon the angle of confluence in inlet streams, the size of the resultant particles is different. The results of LASP experiments are clearly in agreement with the results given in iodide–iodate test reaction. It suggests that a large confluence angle is favorable for decreasing the segregation index, XS, and size of nanosuspensions in MCRs. It is only due to the increase in the degree of fluid deformation with the angle, as a rapid mixing and large energy dissipation will be achieved.
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5. Conclusion Homogeneous mixing in three different impingement jet microfludic mixers was characterized by adopting the LASP technique and iodide–iodate test reaction, known as Villermaux–Dushman reaction. Studies of the mixing effects on NP formation and Villermaux–Dushman reaction strongly suggest that the quality of target products were greatly influenced by confluence geometry of the streams in microchannels. In the first series of experiments, the micromixing efficiency of the microchannels was studied in terms of segregation index (XS), under various total flow rates and initial concentration of acid solution. The results show that because of decrease in volumetric flow rate ratio, segregationindex decreases with decreasein acid concentration. For comparative purposes, the reduction in XS values was more considerable, at larger confluence angles. In particular, upon application of the MCR with confluence angle of (135 ), the segregation indexes (XS) were found in the range of 0.001–0.1, indicating that this geometry of micrormixer can establish higher micromixing efficiency. In the second series of experiments, mixing performance was evaluated in terms of size reduction of precipitated curcumin nanoparticles and their short-term physical stability. Among fabricated microchannels, the most effective confluence angle was satisfactorily observed in u = 135 . As a result of this study, nanoparticles with least average diameters of 181 nm were obtained in the selected microchannel, compared with 28.9 mm original size of purchased raw curcumin particles. Considering both iodide–iodate reaction and LASP process, superior performance of MCRs with large contact angle is clearly due to their large energy dissipation in the center of micromixer. This causes a higher momentum exchange, which is primarily responsible for its more efficient mixing. From this study, it can be concluded that change in mixing performance proved by a classic competitiveparallel reaction, is also valid for a complicated LASP nanodrug production process. References [1] S.H. Wong, M.C.L. Ward, C.W. Wharton, Micro T-mixer as a rapid mixing micromixer, Sens. Actuators B. 100 (2004) 359–379. [2] T. Fujii, PDMS-based microfluidic devices for biomedical applications, Microelectron. Eng. 61–62 (2002) 907–914. [3] C.T. McClain, S.C. Culbertson, Nancy, L.C.E. Sims, J.M. Ramsey, Microfluidic devices for the high-throughput chemical analysis of cells, Anal. Chem. 75 (21) (2003) 5646–5655. [4] M.Y. Ye, et al., DNA separation with low-viscosity sieving matrix on microfabricated polycarbonate microfluidic chips, Anal. Bioanal. Chem. 381 (2005) 820–827. [5] S. Ferrouillat, P. Tochon, H. Peerhossaini, Micromixing enhancement by turbu lence: application to multifunctional heat exchangers, Chem. Eng. Process. 45 (2006) 633–640. [6] R. Krger, CFD for Microfluidics, Fluent Deutschland GmbH, 2006. http://scai. fraunhofer.de/fileadmin/download/fsi-biomedical/FSI-Bio-FluentKroeger.pdf (accessed 20.02.08). [7] R.B. Bird, W.E. Stewart, E.N. Lightfoot, Transport Phenomena, second ed., Wiley, New York, 2001, pp. 846–848. [8] A.G. Kanaris, A.A. Mouza, Numerical investigation of the effect of geometrical parameters on the performance of a micro-reactor, Chem. Eng. Sci. 66 (2011) 5366–5373. [9] M. Faryadi, M. Rahimi, S. Safari, N. Moradi, CFD Effect of high frequency ultrasound on micromixing efficiencyin microchannels, Chem. Eng. Process. 77 (2014) 13–21. [10] N. Kockmann, M. Gottsponer, D.M. Roberge, Scale-up concept of singlechannel microreactors from process development to industrial production, Chem. Eng. J. 167 (2011) 718–726. [11] W. Ehrfeld, V. Hessel, H. Löwe, Microreactors-New Technology for Modern Chemistry, Wiley/VCH, Weinheim, 2000. [12] V. Hessel, H. Löwe, Mikroverfahrenstechnik: Komponenten-Anlagen- konzeption-Anwenderakzeptanz-Teil 1, Chemie Ingenieur Technik 74 (2002) 17–30. [13] V. Hessel, H. Löwe, Mikroverfahrenstechnik: Komponenten-Anlagen- konzeption-Anwenderakzeptanz-Teil 3, Chemie Ingenieur Technik 74 (2002) 381– 400.
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