Microencapsulation of Aqueous Compounds Using

Preparation of Polyphthalamide Microcapsules Chem. Pharm. Bull. 1969, 17, 804. [Crossref], [CAS]. 22. Microcapsules. II. Preparation of polyphthalamid...
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Microencapsulation of Aqueous Compounds Using Hexamethylenediamine and Trimesoyl Chloride: Monodisperse Capsule Formation and Reaction Conditions on Membrane Properties Long Chen and Robert K. Prud’homme* Department of Chemical and Biological Engineering, Princeton University, Princeton, New Jersey 08544, United States ABSTRACT: Efficient microencapsulation of aqueous compounds for dispersion in aqueous media remains challenging. To prepare aqueous microcapsules, we employed interfacial polymerization with hexamethylenediamine (HMDA) and trimesoyl chloride (TMC), which are commonly used for the formation of impermeable reverse-osmosis membranes. We employed an emulsification technique based on a high-viscosity external phase and uniform shear fields to produce monodisperse aqueous drops on the order of 10 μm. The effects of shear stress and HMDA concentration on the drop sizes were studied. The HMDA amount and emulsion drop size were both found to be important for subsequent capsule formation. The stoichiometric ratios of amine to acid chloride affected both the redispersibility of the microcapsules and the release rates of Coomassie Brilliant Blue (Coomassie Blue). Although high encapsulation efficiencies were achieved, the release rate varied with the sizes of the encapsulated molecules/ions. Optimum capsule formation and control of release were obtained with a stoichiometric ratio [c(NH2)/c(COCl)] of 5.

1. INTRODUCTION Microencapsulation1,2 has been widely applied since its introduction to encapsulate ink for carbonless copies in the 1950s.3 Various techniques have been found to be effective, such as coacervate formation,4,5 polymerization/precipitation,6 and interfacial polymerization.7−9 Coacervate encapsulation often requires thick membranes to create impermeable capsules, and membranes made by this means are often susceptible to swelling and permeability if used in aqueous media.10 In our research, we are interested in encapsulating aqueous systems for use in aqueous environments. This is the most challenging of encapsulation applications. Interfacial polymerization11,12 is the most appropriate approach for this application because defects in the encapsulating membrane are self-healing.13 Interfacial polymerization has been successfully used in the application of reverse-osmosis membranes,14,15 which have similar requirements of functioning in aqueous environments and providing defect-free membranes. With interfacial polymerization, one water-soluble monomer is dissolved in an aqueous medium, one oil-soluble monomer is dissolved in an oil medium, and a rapid reaction takes place at the interface between the two phases. In many reports on interfacial polymerization, the desired final microcapsule contains a nonaqueous internal phase into which an active ingredient of interest has been dissolved.16−19 Versatile microencapsulation systems have been reported to effectively encapsulate oil-soluble active ingredients. For example, Su et al.18 reported encapsulation of phase-change material through interfacial polymerization of toluene diisocyanate and diethylenetriamine. Dexter and Benoff20 synthesized microcapsules with hexamethylenediamine (HMDA) and trimesoyl chloride (TMC) that encapsulated pendimethalin. However, far less work has been done on inverse systems that encapsulate water© 2014 American Chemical Society

soluble compounds in an aqueous core. Although there have been studies on the preparation of inverse microcapsules using interfacial polymerization,21−25 few have focused on release rates for small molecules and the interplay of processing, isolation of the capsules, and release. In particular, HMDA− TMC microcapsules that contain aqueous active ingredients and their isolation and release characteristics have not been reported. The relationship between the microcapsule size and the concentration of reactants is especially important in interfacial polymerization because the total interfacial area depends on drop size. Therefore, statements about reaction chemistry can be made with confidence only when the drop size is known and preferably when the drop size distribution is narrow. A uniform drop size ensures that the membrane thickness is uniform over the entire population. With very polydisperse systems, the smaller aqueous drops might not contain adequate amine reactants to form adequate membranes, and larger drops might contain an excess of amine, which could lead to unacceptably high pH levels in the larger drops. Therefore, the preparation of narrowly dispersed microcapsules is of interest in this study. Monodispersity of microcapsules requires monodispersity of the emulsion drops. The process of drop breakup is controlled by shear and elongational flows.26 Nonuniform shear and elongational fields in conventional dispersion equipment lead to polydisperse emulsions. Mabille et al.27 showed that applying a uniform shear field with Taylor−Couette flow28 and using a specific value for the ratio of the viscosity of the continuous Received: Revised: Accepted: Published: 8484

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Scheme 1. Reaction Formula of Interfacial Polymerization between Hexamethylenediamine (HMDA) and Trimesoyl Chloride (TMC)

phase to that of the dispersed phase can lead to the production of very narrow drop size distributions. Their work showed that, in an oil-in-water emulsion, the viscosity ratio for the best monodisperse emulsion was ∼10.29 We previously used this method to prepare gel particles for drug delivery.30 In this study, the same principle is applied to create emulsions of uniform sizes to enable a better understanding of processing conditions and encapsulation efficiency of active ingredients. In this article, we present an efficient two-step procedure for the encapsulation of water-soluble active ingredients using interfacial polymerization between HMDA and TMC as shown in Scheme 1. The first step is the preparation of a monodisperse water-in-oil (W/O) emulsion using Taylor−Couette flow. The second step is the reaction at the drop surface to encapsulate an aqueous dye. The dye is used as a model active ingredient and has the added feature that, because it is a pH-indicating dye, the pH of the aqueous internal phase can be monitored before and after the reaction. Techniques to isolate the polymerized microcapsules from the external oil phase and to disperse them in an aqueous medium are presented. Finally, we report on how reaction stoichiometry affects encapsulation efficiency and the integrity of the microcapsules.

emulsified using a rotor−stator shear cell to create a uniform shear flow (Figure 1, discussed below). The rotational speed

2. EXPERIMENTAL SECTION 2.1. Materials. Hexamethylenediamine (HMDA) and trimesoyl chloride (TMC) were purchased from Sigma-Aldrich. Poly(ethylene glycol) with a molecular weight of 20000 g/mol (PEG 20000) was purchased from Fluka. Sodium carbonate (Na2CO3) and sodium dodecyl sulfate (SDS) were products of J.T. Baker Co. Silicone oil with viscosities of 10, 100, and 500 cSt were supplied by Sigma-Aldrich. Xiameter 749 dispersant was kindly supplied by Dow Corning. Coomassie Brilliant Blue, sodium salicylate, and Thymol Blue were obtained from BioRad, Fluka, and Aldrich, respectively. Toluene and hexane were purchased from Fisher Scientific. All materials were used as received without further purification. 2.2. Preparation of Microcapsules. 2.2.1. Water-in-Oil Emulsion. HMDA and equimolar Na2CO3 were dissolved in deionized water. PEG 20000 was added to adjust the viscosity of the aqueous phase. In addition, Coomassie Blue, Thymol Blue, or sodium salicylate was added to the aqueous phase to enable quantification of encapsulation efficiency and subsequent release. Xiameter 749 dispersant was dissolved in silicone oil at 5 wt % to form the oil phase. The aqueous phase was added to the oil phase in a single injection at a water/oil weight ratio of 1/50. The water-in-oil (W/O) dispersion was then

Figure 1. Schematic of the rotor−stator shear cell used for emulsification. Specifications of sizes are included. Two rotors of different sizes are available to allow a choice of gap size δ of either 1.5 or 3 mm.

was first set to 50−100 rpm and maintained for 1 min to create a crude emulsion. Then, the speed was stepwise increased by ∼150 rpm and maintained for 30 s, until the final speed at which the emulsion was sheared was reached. This final speed was maintained for 15 min for the drop size to reach a steady state. 2.2.2. Rotor−Stator Shear Cell. Figure 1 presents a schematic of the rotor−stator shear cell used to apply Taylor−Couette flow. The rotor was driven by an overhead motor (Caframo BDC 3030 stirrer, Georgian Bluffs, Canada) with a maximum rotational speed of 3000 rpm. Two rotors of different sizes were available, allowing a choice for the gap δ of either 1.5 or 3 mm. The shear rate was calculated as πdω/60δ, where d is the diameter of the rotor and ω is the rotational speed in rpm. The shear stress was obtained from the product of the shear rate and the viscosity of the continuous oil phase. 2.2.3. Postemulsification Processing. Figure 2 presents a schematic of the postprocessing of the emulsion for the 8485

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Figure 2. Schematic of postemulsification processing in the preparation of HMDA−TMC microcapsules.

A low PDI (0.25 or lower) is regarded as a narrow drop size distribution.29 2.3.2. Morphology of Microcapsules. A drop of the microcapsule dispersion was placed on a glass slide and observed using an optical microscope under wet conditions. Coverslips were not used because silicone oil does not evaporate and samples were observed immediately after the emulsion was prepared. Microcapsules that had been exchanged into hexane and air-dried on a silicon wafer were observed using an FEI Quanta 200 Environmental Scanning Electron Microscope (SEM) to show the morphological features in a low vacuum mode with an LFE detector. The microcapsules were not coated. The voltage was set to 15.0 kV, and the spot size was 3.0. 2.4. Measurement of Encapsulation Efficiency and Release Profile. Because some microcapsules might not form complete shell structures, the active ingredient dissolved in these open capsules will be released upon redispersion into the SDS solution. UV−vis spectroscopy was used to measure the amount of the unencapsulated active ingredient and the subsequent release profile over time. Given the mass of the aliquot (maliquot) taken from the emulsion (which had a total mass of mtotal), prior to capsule formation, the mass of the active ingredient to be encapsulated (ma) is given by

preparation of the polyamide microcapsules. The W/O emulsion was diluted with 10 cSt silicone oil at a 1:1 ratio so that the emulsion could be stirred under gentle agitation with a magnetic stir bar. Decreasing the external phase viscosity reduced the stress on the droplet surface. A defined amount of TMC dissolved in toluene was added dropwise to the emulsion at 0.5 mL/min. The stoichiometric ratio Rc was calculated based on the concentration of amine groups in HMDA relative to the concentration of acid chloride groups in TMC. The reaction was allowed to continue for 5 min after all TMC was added, and the mixture was then diluted with more toluene at a 1:1 ratio. The density of the diluted reaction suspension was lowered by further dilution with hexane to a final hexane-todiluted reaction suspension ratio of 2:1 by volume. This decreased the density of the oil phase from ∼0.9 to ∼0.75 g/ mL and also significantly decreased its viscosity so that the microcapsule suspension could be centrifuged at 20 rcf (relative centrifugal force) for 2 min to concentrate the microcapsule phase. The microcapsules were washed with hexane and centrifuged again. After collection by centrifugation, the microcapsules were placed under an air stream to evaporate the residual hexane for 1 min, and they were finally redispersed into a 0.02 M SDS solution. The volume fraction of microcapsules in the final dispersion could be up to 10%, with the assistance of low-intensity sonication (Jeken PS-20A Digital Ultrasonic Cleaner, Guangdong, China). 2.3. Characterization Methods. 2.3.1. Drop Size Distribution of Emulsion. The W/O emulsion sizes were measured from digital images taken on a Bausch & Lomb Balplan microscope in monochrome mode and analyzed using ImageJ software. The function of FFT filters enabled elimination of drops that were out of focus, so that image analysis was accurate and reliable. Surface average mean sizes and standard deviations were used to display the size distribution of each emulsion sample. At least 500 drops were analyzed for each sample. The polydispersity index (PDI) is defined as the ratio of the standard deviation to the mean size.

ma = ma,total

maliquot mtotal

(1)

where ma,total is the total mass loading of the active ingredient. The unencapsulated fraction of ma or its release when dispersed in SDS solution can be obtained with its cumulative concentration (CUV) in the dispersion by calculation with a calibration curve following Beer’s law (the molar extinction coefficient of Coomassie Blue was measured to be 1.628 × 105 M−1 cm−1). Then, the encapsulation efficiency (EE) or remaining active ingredient after release is available as 8486

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c UV cmax

Article

(2)

where cmax is the concentration in SDS solution if all of the ingredient (ma) were unencapsulated. In our release study, the active-ingredient-loaded microcapsules were always dispersed in the same amount of SDS solution when the active-ingredientcontaining SDS solution was withdrawn for measurement, thus ensuring reliability of cumulative summation of the mass of the released active ingredient.

3. RESULTS AND DISCUSSION 3.1. Emulsification. A stable and monodisperse W/O emulsion is essential to the preparation of narrowly dispersed microcapsules. With the rotor−stator apparatus, the aqueous phase undergoes a uniform shear history. A number of crucial factors associated with this process determine the sizes and distributions of the aqueous droplets, including (1) shear stress, (2) surface tension, and (3) viscosity of the continuous phase relative to the dispersed phase. The drop breakup is determined by the balance between the viscous stress from the shear forces, ηcγ̇, and the characteristic Laplace pressure, σ/r,31 where ηc is the viscosity of the continuous oil phase, γ̇ is the applied shear rate, σ is the surface tension, and r is the radius of the drop. This balance is represented by the capillary number Ca = ηcγr/ ̇ σ

Figure 3. Emulsion drop size as a function of shear stress at various HMDA concentrations. Emulsions were sheared for 15 min. The symbols are the mean sizes, and error bars show the standard deviations. The symbols are for samples of HMDA at concentrations of 0.6 M (squares), 0.4 M (circles), and 0.2 M (upright triangles) and DI water (inverted triangles). The viscosity ratios of the continuous oil phase to the dispersed aqueous phase for the same samples were ηc/ηd = 50, 50, 50, and 100, respectively.

stresses were ∼150 and ∼100 Pa, respectively. The polydispersity of emulsion drops is also shown in Figure 3, where one standard deviation is shown by the bars around the average size, indicated by the symbols. We tested three different viscosity ratios (28, 50, and 84) and found that a ratio of 50 is the best for this system, leading to PDIs of 0.228 for the sample with 0.4 M HMDA and 0.214 for the sample with 0.6 M HMDA, both of which are quite narrowly dispersed. As a contrast, the sample without HMDA and PEG (DI water sample in Figure 3) showed large variations, with a viscosity ratio of 100. Figure 4 shows a representative micrograph of a W/O emulsion with a size of 10.1 ± 2.3 μm. The aqueous drops contain 0.6 M HMDA. The oil phase is 100 cSt oil containing 5 wt % Xiameter 749, and the viscosity ratio is 50. The size distribution of the emulsion did not change over 2 days, but we usually started the reaction less than 4 h after emulsification. The stability of the emulsion is due to the relatively small

(3)

The capillary number must exceed a critical number (of order ∼1) to allow drop elongation.26 Because the critical capillary number is of order unity, the drop size scales with the surface tension and inversely with the shear rate.28 However, this scaling assumes steady state and neglects the effects of the viscosity ratio and transient elongation and rotation on the breakup process.26,32 Recently, Mabille et al. described a technique to exploit transient elongation of large drops to produce emulsions of exceptionally narrow polydispersity.27,29 If the external fluid viscosity is significantly higher than the internal phase viscosity, in transient shear flow, large drops are deformed into elongated filaments. The filament diameter is relatively insensitive to the size of the initial large drop size. Therefore, large polydisperse drops are elongated into filaments of different lengths but approximately similar diameters. These filaments break into smaller drops by the classical Rayleigh instability.33 The result will be a final drop size distribution that is generally narrow. To tune the drop size, the shear stress is controlled by varying the rotor−stator gap, the rotational speed, and the viscosity of the continuous phase. The surface tension can be varied by the concentrations of HMDA in the aqueous phase and Xiameter 749, the interfacial stabilizer, in the oil phase; however, the Xiameter 749 concentration was held at 5 wt % throughout this study. Figure 3 shows the drop size as a function of shear stress and HMDA concentration. The comparison between samples with different HMDA concentrations demonstrates a clear size differentiation. It was found that, as the concentration of HMDA increased, the drop size at the same shear stress decreased. HMDA is amphiphilic; it can reside at the interface of the two phases, thus changing the surface tension, which leads to a change in drop sizes. As a result, the shear stress needed to produce drops of ∼10 μm in size varies with HMDA concentration. The required shear stress was ∼180 Pa for the sample that contained 0.2 M HMDA. For the sample with 0.4 and 0.6 M HMDA, the shear

Figure 4. Optical micrograph of a W/O emulsion containing 0.6 M HMDA. Emulsification was conducted at 111 Pa shear stress for 15 min. The external phase was 100 cSt silicone oil containing 5 wt % Xiameter 749, and the viscosity ratio of the continuous phase to the dispersed phase was 50. 8487

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TMC is added to the oil phase, the HMDA reacts rapidly and begins membrane formation, possibly followed by continuing membrane growth if there are remaining reactants in both phases. Based on the dye-release data presented below, the HMDA inside the core can diffuse through the membrane and continue polymerization. By loading Thymol Blue into the aqueous phase as a pH indicator, we found that, a few seconds after TMC was added, Thymol Blue changed its color from deep blue to yellow, which indicates a transition from an alkaline environment (pH > 9) to a nearly neutral environment (pH < 8). This shows that only negligible amounts of free HMDA were left in the microcapsules after polymerization. Assuming pH = 8, the residual HMDA in neutral or ionized forms was calculated to be less than 10−6 M, given that the pKa values of HMDA are 11.86 and 10.76.35 Therefore, the reaction between HMDA and TMC is near completion. This is true for all of the concentrations of HMDA and the size range of microcapsules in this study. Table 1 summarizes the morphologies of the microcapsules prepared under different reaction conditions. The interfacial polymerization starts with oligomers formed by HMDA and TMC. These oligomers cross-link and form a polyamide membrane at the interface. We observed that, when the emulsion drops were large (34.9 ± 6.6 μm), an HMDA concentration of 0.2 M was sufficient for the formation of individual capsules, although we obtained aggregates at some stoichiometric ratios (Rc = 1.25 or Rc ≥ 25). Aggregation arises from capsule−capsule adhesion; the capsules do not disperse back to individual spheres. At very high external TMC concentrations, secondary acid chloride reactions might cause cross-linking between incomplete microcapsules. At very low external TMC concentrations, interfacial membrane formation might be restricted by low molecular weight. When the mean drop size is smaller (12.5 ± 3.9 μm), 0.2 M HMDA is not adequate for capsule formation. This is consistent with the increased surface-to-volume ratio for smaller drops. A drop of 12.5 μm in diameter and 0.2 M HMDA contains 1.64 × 10−9 mmol of HMDA. Assuming complete polymerization of HMDA with TMC and a polymer density of 1 g/mL, the average membrane thickness would be 244 nm, if uniformly polymerized. This is to be contrasted to the membrane thickness of 13−32 μm obtained by Laguecir et al.24 for much larger 200-μm microcapsules. Heterogeneity of the film formation or incomplete reaction apparently leads to incomplete encapsulation. In contrast, when the HMDA

density difference between the aqueous phase and the oil phase and the efficient Xiameter dispersant. In addition, the viscosity of the oil phase slows the sedimentation and coalescence of aqueous drops.34 When the 100 cSt silicone oil was replaced with 10 cSt silicone oil, which has a larger density difference with the aqueous phase and is less viscous, the aqueous drops settled and coalesced within 24 h. 3.2. Formulation of Microcapsules. Figure 5a shows the polyamide microcapsules prepared with 0.6 M HMDA using a

Figure 5. (a) Optical micrograph of narrowly sized polyamide microcapsules dispersed in 0.02 M SDS solution and (b,c) SEM images of dried microcapsules. The microcapsules were made from a W/O emulsion containing 0.6 M HMDA, with drop sizes of 10.0 ± 2.0 μm. TMC was added at a stoichiometric ratio Rc = 10 for the interfacial reaction.

W/O emulsion of 10.0 ± 2.0 μm drops. TMC was added at a stoichiometric ratio Rc = 10. The microcapsules could be dispersed in 0.02 M SDS solution. However, they cracked or became flat if dried in air (as shown in Figure 5b,c). The interfacial polymerization between HMDA and TMC is a very fast process.12 The locus of polymerization is in the oil phase because the solubility of HMDA in the oil is much greater than the solubility of TMC in the aqueous phase. When

Table 1. Summary of Capsule Morphologies under Different Reaction Conditions (HMDA Concentrations and Emulsion Drop Sizes) capsule morphology Rc = c(NH2)/c(COCl) 1.25 2.5 5 10 20 25 40 50

0.2 M HMDA 34.9 ± 6.6 μm

0.2 M HMDA 12.5 ± 3.9 μm

aggregatesa individual capsulesc individual capsules individual capsules

piecesb pieces pieces pieces pieces

0.4 M HMDA 16.2 ± 3.7 μm

0.4 M HMDA 11.2 ± 3.3 μm

individual capsules individual capsules

pieces/capsules

0.6 M HMDA 10.1 ± 2.3 μm individual individual individual individual

capsules capsules capsules capsules

aggregates pieces

individual capsules

aggregates

a

Aggregates are fused microcapsules that cannot be dispersed by SDS solution. bPieces are polyamide membranes that do not form a spherical shell structure. cIndividual capsules are microcapsules that can be dispersed and have independent membrane shells (shells might have defects). 8488

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allow a higher release rate. At this point, we cannot differentiate between the two possible mechanisms. 3.4. Effects of Stoichiometric Ratio. We have discussed the importance of HMDA concentration and drop size for the formation of the polyamide microcapsules. Another key factor for interfacial polymerization is the stoichiometry. It has been reported36,37 that the interfacial reaction between polyamine and polyacyl chloride is controlled by the diffusion of polyamine from the aqueous phase to the oil phase, and the solubility of polyamine in oil is much smaller than that in water.12 Therefore, for the best membrane formation, the concentration of amine groups in the aqueous phase should be higher than that of acid chloride groups to balance the fluxes to the interface.12 3.4.1. Encapsulation Efficiency. Figure 7a shows the encapsulation efficiency of Coomassie Blue for microcapsules prepared at different stoichiometric ratios in the range Rc = 2.5−40. The emulsion for the preparation of these microcapsules had a mean size of 10.1 ± 2.3 μm with an HMDA concentration of 0.6 M. The stoichiometric ratio was varied by varying the concentration of TMC in the external phase. At least 90% of Coomassie Blue was encapsulated over the entire range of Rc values. The stoichiometry did not seem to affect the encapsulation efficiency of Coomassie Blue. This is because the encapsulation and release of Coomassie Blue have different time scales (encapsulation by interfacial polymerization takes seconds, whereas release takes days, as can be seen in section 3.4.2). The reactant was sufficient to provide membrane coverage across various stoichiometries, so the encapsulation efficiency was consistently high. 3.4.2. Release Rate. We investigated these microcapsules containing Coomassie Blue over a longer time and recorded their release profiles. In Figure 7b, it can be seen that the microcapsules synthesized at intermediate Rc values had the lowest release rates (see data for Rc = 5, 10, and 20). However, at higher and lower Rc values, the membranes were leakier. These results are consistent with formation of linear chains rather than tightly cross-linked membranes when the acid chloride concentration is too high (Rc = 2.5). Conversely, when the acid chloride groups are too dilute (Rc = 40), the acid chloride groups are capped with excess diamine, resulting in the failure to form high-molecular-weight polyamide. The differences in membrane properties are reflected in the release

concentration was increased to 0.6 M for a sample of emulsion drops of similar size (10.1 ± 2.3 μm), capsules were formed with excellent encapsulation efficiency (data shown below). 3.3. Effects of Drop Size on Shell Permeability. The color change of the encapsulated Thymol Blue dye indicates that the HMDA is, essentially, completely consumed during the reaction. If the polymerization is quantitative in the limiting HMDA reactant, the membrane thickness should be directly proportional to the drop size; that is, it should scale as volume/ area. In our study, two emulsion samples of different drop sizes (10.0 ± 2.0 and ∼6 μm) containing 0.6 M HMDA were investigated. The sample with smaller drops was prepared by raising the shear to a very high speed, which somewhat increased the polydispersity. We found that the initial encapsulation efficiencies of Coomassie Blue using these two samples were similar (>90%), but the release rate of Coomassie Blue from the smaller microcapsules was significantly higher (see Figure 6). This is consistent with a thinner membrane

Figure 6. Encapsulation efficiency and release rate of Coomassie Blue (CBB) for microcapsules of different sizes. The microcapsules were synthesized at Rc = 10. The symbols are for prereaction emulsion drops of 10.0 ± 2.0 μm (squares) and ∼6 μm (circles).

leading to faster release kinetics, whether by diffusion through the membrane or defects in the membrane. Here, defects refer to openness or ultrathinness due to locally insufficient reactants as a result of nonuniform membrane formation; therefore, they

Figure 7. (a) Encapsulation efficiency and (b) release profile of Coomassie Blue for microcapsules synthesized at different stoichiometric ratios ranging from 2.5 to 40. The W/O emulsion containing 0.6 M HMDA prepared for the interfacial polymerization had a mean size of 10.1 ± 2.3 μm. The symbols in panel b are for stoichiometric ratios of 2.5 (squares), 5 (circles), 10 (upright triangles), 20 (inverted triangles), and 40 (diamonds). 8489

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The relatively rapid exchange with H+ and OH− is expected because this polyamide is used in the formation of reverseosmosis membranes,38 and such membranes are not impermeable to these small ions. The observed faster diffusion of H+ than OH− might be due to negative charges on the membrane surface causing ionic repulsion to the transport of the negative hydroxyl ions. These carboxyl groups might arise from the hydrolysis of unreacted acid chlorides.

profiles. Release runs were duplicated twice, and two samples were taken at each time point. 3.5. Membrane Selectivity. The results above were obtained with Coomassie Blue (Mw = 826 g/mol) as the model solute for encapsulation. The selectivity of the membrane for solutes of other molecular weights was studied by using a smaller molecule: sodium salicylate (Mw = 160 g/ mol). The UV−vis absorbance data (not shown) indicated that sodium salicylate diffused out of the microcapsules in 1−2 h. In addition, the pH dependence of the color of Coomassie Blue enabled a qualitative assessment of the kinetics of H+ and OH− diffusion through the membrane. The kinetics of OH− diffusion was assessed by adding 0.4 mL of 1 M NaOH to 0.6 mL of microcapsule dispersion containing 2.6 × 10−3 mg of Coomassie Blue. Once OH− was added to the external phase, its diffusion into the microcapsules caused Coomassie Blue to lose its blue color. This was quantified through UV−vis spectroscopy (see Figure 8). It can be seen that the sample

4. SUMMARY AND CONCLUSIONS In this study, we investigated the preparation of polyamide microcapsules with low polydispersity through interfacial polymerization of HMDA and TMC. The success of membrane formation depends on a combination of conditions for this very reactive acid chloride−amine system: (1) There must be an adequate reservoir of HMDA in the emulsion drop to form the polymer membrane, and (2) the ratio of HMDA and TMC must be correct to allow full cross-linking of the reactive sites. The first condition requires a correct combination of drop volume and HMDA concentration. Processing of uniformly sized drops aids in producing capsules with similar membrane properties for all drops. We showed that processing emulsions in high external phase viscosity fluids and using uniform Couette shear fields yields narrow size distributions. Drops with sizes of 10.0 ± 2.0 μm were produced by this means. The membrane porosity was illustrated through release studies of microcapsules with mean sizes of ∼10 and ∼6 μm. It was also found that microcapsules made through this protocol encapsulate more than 90% of Coomassie Blue, and membranes synthesized with stoichiometric ratios Rc between 5 and 20 are less leaky than those made with Rc = 25 and 40. At TMC concentrations that are too low, excess HMDA in the drop phase appears to lead to incomplete membrane formation through capping of TMC with excess amine. At the other extreme, TMC concentrations that are too high cause capping of HMDA by excess acid chloride and also increases the likelihood of forming linear chains instead of cross-linked polymer. In either case, membranes with more rapid release of the active ingredients were observed. In addition, a membrane selectivity study showed that both H+ and OH− can exchange through the membrane very quickly, on the order of minutes. Sodium salicylate tends to be released from the microcapsules in 1−2 h, whereas the higher-molecular-weight Coomassie Blue is released in a very slow manner, with a modest loss of less than 20% of encapsulated Coomassie Blue in ∼90 h. One challenge in preparing microcapsules to encapsulate an aqueous core for application in an aqueous medium is that the capsules must be isolated from the initial highly viscous organic phase and exchanged into an aqueous phase. These interfacially synthesized shells produce thin membranes, which present challenges in this isolation step. Stresses from the viscous phase were observed to damage the integrity of the microcapsules during isolation. We developed an isolation protocol that obviated this problem. First, the high-viscosity oil was diluted with low-viscosity oil, so that stress was transferred less efficiently to the capsule surface. Then, the densities were tuned to enable centrifugal separation without placing too great a stress on the microcapsules. Finally, there should be no further reaction occurring in the isolation steps to avoid fusing particles during processing. Although we successfully produced microcapsules with this chemistry, there are several unanswered questions and challenges. Direct measurement of membrane thickness using

Figure 8. UV−vis absorbance of encapsulated Coomassie Blue as a function of time upon addition of NaOH. The sample of microcapsule dispersion contained 2.6 × 10−3 mg of Coomassie Blue and 0.4 M NaOH at the start of the measurements. The Coomassie Blue absorption peak disappeared within 15 min as OH− diffused into the microcapsules to interact with Coomassie Blue.

color change occurred in ∼15 min, showing the time for OH− to diffuse through the membrane. We added HCl in an equimolar amount to the original OH− to neutralize the sample. With gentle shaking, the microcapsule dispersion returned to blue again. This recovery happened very quickly, more rapidly than the base-driven color change. Table 2 summarizes the method of studying the membrane selectivity and the different permeation rates of molecules/ions. Table 2. Summary of Membrane Selectivity of HMDA− TMC Microcapsulesa molecule/ion H+ OH− sodium salicylate Coomassie Blue a

molecular weight (g/mol) 1 17 160 826

diffusion direction external to internal external to internal internal to external internal to external

performance fast recovery of Coomassie Blue color Coomassie Blue color change within ∼15 min full release in 1−2 h