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Preparation of Monodisperse Calcium Alginate Micro-/Nanospheres via Shirasu Porous Glass Membrane Emulsification Followed by Classification Using Microfiltration Membranes Kazuki Akamatsu,*,† Yusuke Ide,† Takuya Inabe,† and Shin-ichi Nakao†,‡ †
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Department of Environmental Chemistry and Chemical Engineering, School of Advanced Engineering, Kogakuin University, 2665-1 Nakano-machi, Hachioji-shi, Tokyo 192-0015, Japan ‡ Research Institute for Science and Technology, Kogakuin University, 2665-1 Nakano-machi, Hachioji-shi, Tokyo 192-0015, Japan ABSTRACT: Monodisperse calcium alginate micro-/nanospheres were developed via ionic cross-linking of alginate polymers in water-in-oil emulsion droplets prepared using a direct membrane emulsification technique with Shirasu porous glass (SPG) membranes. By changing the concentration of the alginate polymers in the dispersed phase and the pore size of the membrane, we obtained monodisperse calcium alginate micro-/nanospheres with tunable sizes because each micro-/nanosphere was formed in each droplet. However, the monodispersity decreased when SPG membranes with pores of smaller than 0.5 μm were used because they contained larger microspheres from the coalescence of the emulsion droplets. To remove such larger microspheres for achieving an excellent monodispersity, classification using microfiltration membranes was performed. After serial classifications with membranes of 1.2, 0.8, and 0.45 μm pore sizes, the resulting fraction showed an average diameter of 0.22 μm and CV of 21%, starting from an original with an average diameter of 0.35 μm and CV of 59%.
1. INTRODUCTION Alginate is one of the best known linear polysaccharides and is composed of (1−4)-linked β-D-mannuronic acid (M) and α-Lguluronic acid (G) residues.1,2 Due to its biodegradability, low toxicity, and low-cost properties, alginate has been studied for biomedical applications, mainly in the form of hydrogels.3,4 Alginate hydrogels are often prepared through ionic crosslinking using divalent cations such as Ca2+, and these divalent cations work as cross-linking points for intermolecular crosslinking.5,6 Only the G-blocks of alginate can capture these divalent cations to form hydrogels; thus, the length of the Gblocks and the contents of G-residues, which generally depends on the sources from which alginates are extracted, affect the physical properties of the hydrogels.7,8 Among the alginate hydrogels used as biomaterials, microspheres have been extensively developed for the applications of cell encapsulation and drug delivery systems (DDS).9−14 In such applications, size-controllability and monodispersity of the microspheres are required. The simplest preparation method to meet the requirements is to add aqueous solution containing sodium alginate polymers dropwise to a solution bath containing such divalent cations. The droplets can be formed one-by-one by extruding the alginate solution through syringes or needles, and the ionic cross-linking occurs inside each droplet.15,16 The sizes of the droplets are determined by the diameter of the syringes or needles; thus, the sizes of the resultant alginate spheres are often larger than 500 μm. The droplets can be also prepared using microfluidic devices.17,18 © XXXX American Chemical Society
These methods are favorable for achieving excellent monodispersity, and the sizes of the droplets are smaller than those formed with syringes or needles. The sizes of the resultant microspheres range from 50 to 500 μm. However, micro-/ nanospheres having much smaller sizes are often required, especially for the applications of DDS. In order to obtain smaller-sized micro-/nanospheres with diameters in the single micron range or less than 1 μm, the sizes of the droplets need to be further decreased. One of the candidates is to employ a membrane emulsification technique. In particular, the direct membrane emulsification method using Shirasu porous glass (SPG) membranes is favorable for preparing monodisperse, size-controlled, and small-sized single emulsion droplets.19−21 In this method, the dispersed phase is pressurized through the membrane to the continuous phase to form emulsions droplets. The direct membrane emulsification offers a stable emulsion, regardless of water-in-oil (W/O) or oil-in-water (O/ W) types, and the sizes become around three times as large as the pore sizes of the membranes used. There are many reports on the preparation of monodisperse and size-controlled emulsion droplets with a wide range of diameters from submicron to several tens of microns.22,23 In addition, there are reports on the preparation of the alginate microspheres with Received: Revised: Accepted: Published: A
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2, 2018 24, 2018 26, 2018 26, 2018 DOI: 10.1021/acs.iecr.8b02473 Ind. Eng. Chem. Res. XXXX, XXX, XXX−XXX
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Industrial & Engineering Chemistry Research
Figure 1. FE-SEM micrographs of the calcium alginate micro-/nanospheres prepared via emulsion droplets containing 2 wt % sodium alginate formed with SPG membrane pore sizes of (a) 0.2, (b) 0.5, (c) 1.1, (d) 2.6, and (e) 5.5 μm.
and used without further purification. Tetraglycerol-condensed ricinoleate (TGCR) was kindly supplied by Sakamoto Yakuhin Kogyo Co., Japan, and it was used without further purification. 2.2. Preparation of Calcium Alginate Micro-/Nanospheres via SPG Membrane Emulsification. An external pressure type micro kit (SPG Techno Co. Ltd., Japan) was used as the membrane emulsification apparatus, and SPG membranes with pore sizes of 5.5, 2.6, 1.1, 0.5, 0.3, and 0.2 μm after modification with a silicone resin (KP-18C, Shin-Etsu Chemical Co., Ltd., Japan) to make the surface hydrophobic were used. A 0.1, 1, or 2 wt % aqueous sodium alginate solution was used as the dispersed phase and poured into the dispersion tank. Using nitrogen gas, the dispersed phase was pressurized into the continuous phase consisting of kerosene with 1 wt % of TGCR as a surfactant, which produced W/O emulsion droplets containing the sodium alginate. The stirring speed of the continuous phase was 280 rpm. W/O emulsion consisting of 4 wt % calcium chloride solution as the dispersed phase and the same continuous phase were also prepared by the mechanical stirring for the results shown in section 3.1 or by membrane emulsification with a hydrophobic SPG membrane having 0.5 μm pore sizes for the results shown in section 3.2. The W/O emulsions were mixed together for 17 h to proceed the reaction for micro-/nanosphere formation. After centrifugation and washing with hexane, acetone, and deionized water, the obtained micro-/nanospheres were freezedried. A field emission scanning electron microscope (FESEM, JSM-6701F; JEOL, Japan) was used for observing the obtained micro-/nanospheres, and the average diameter of the micro-/nanospheres was determined by analysis of more than 100 particles in the FE-SEM pictures in each preparation condition. 2.3. Classification of Calcium Alginate Micro/Nanospheres Using Microfiltration Membranes. The calcium alginate micro-/nanospheres prepared via emulsion droplets containing 2 wt % sodium alginate formed with a membrane having 0.3 μm pore sizes were dispersed in pure water with a concentration of 100 or 1000 ppm. The dispersion was poured into a syringe and then filtered with a mixed cellulose membrane (Millipore) having 1.2 μm pore sizes using a syringe pump (CX07100, ISIS Co., Ltd., Japan) at a flux of 6.0 × 10−6 m3 m−2 s−1. The effective membrane area was 3.46 cm2. The membranes were replaced by new ones after 1 mL of the
diameters of a single micron to several tens of microns using this method.24,25 However, there is no report on the preparation of monodisperse and size-controlled calcium alginate nanospheres having diameters of less than 1 μm by the direct membrane emulsification probably because of the difficulty in emulsifying such viscous polymer solutions with the membranes having smaller pores. The development of a preparation method of such calcium alginate nanospheres is strongly required now. In this study, we demonstrate that monodisperse calcium alginate micro-/nanospheres can be prepared by utilizing the direct membrane emulsification method, and the diameters of the micro-/nanospheres can be tuned by changing the concentrations of sodium alginate in the dispersed phase and the pore sizes of the SPG membranes. However, the monodispersity decreases because there are larger micro-/ nanospheres present when the pore sizes of the SPG membranes for preparing the droplets are smaller than 0.5 μm. Thus, we suggest removing these larger micro-/nanospheres by classification using microfiltration membranes as a post-treatment. This post-treatment is also essential for removing other contaminants, in particular in pharmaceutical field. Due to the sieving effect of the pores of microfiltration membranes, only the micro-/nanospheres whose diameters are smaller than the pore size can permeate through the membranes. However, simple microfiltration procedures would result in failure because even the micro-/nanospheres that are smaller than the pore size cannot permeate through the microfiltration membrane once the membrane surface is completely covered by the rejected micro-/nanospheres. Thus, we devise a better procedure: the microfiltration membranes are replaced prior to the occurrence of fouling by the larger micro-/nanospheres. This seems simple, but very important for the stable classification. It is demonstrated this procedure enables the improvement of size-uniformity for obtaining smaller sized calcium alginate nanospheres.
2. EXPERIMENTAL SECTION 2.1. Materials. Sodium alginate (viscosity of the 1% aqueous solution at 20 °C is 80−120 mPa s), calcium chloride, kerosene, hexane, acetone, and sodium tripolyphosphate were purchased from Wako Pure Chemical Industries Ltd., Japan, B
DOI: 10.1021/acs.iecr.8b02473 Ind. Eng. Chem. Res. XXXX, XXX, XXX−XXX
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Industrial & Engineering Chemistry Research dispersion was filtered. The collected permeate solution was then filtered with a mixed cellulose membrane having 0.8 μm pore sizes in a similar manner. This collected permeate solution was filtered with a mixed cellulose membrane having 0.45-μm pore sizes. The obtained micro-/nanospheres at each step were observed with the FE-SEM. At the same time, rejection at each step was determined with a total organic carbon analyzer (TOC-VCSH; Shimadzu Corp., Japan) after the addition of 3 wt % aqueous tripolyphosphate solution into the collected permeate solution to solubilize the micro-/ nanospheres completely by capturing calcium ions.26
using 2 wt % sodium alginate. The average diameter of the micro-/nanospheres decreased with the pore size of the SPG membranes used for emulsification, and the size uniformity was worse due to the presence of larger particles when an SPG membrane having 0.2 μm pore sizes was used. We also tried preparing the calcium alginate micro-/nanospheres via emulsion droplets containing 0.1 wt % sodium alginate; however, almost no spherical particles were obtained. The similar phenomenon where the lower concentration of sodium alginate resulted in the failure of the formation of calcium alginate particles was also reported by other groups,24,25 even though the pore size of the SPG membranes used were larger than 1 μm in their cases. Figure 3 shows the relationships between the pore size of the SPG membrane used for preparing emulsion droplets
3. RESULTS AND DISCUSSION 3.1. Effects of the Concentration of Sodium Alginate and the Pore Size on the Diameter of the Micro-/ Nanospheres. Figure 1 shows FE-SEM micrographs of the calcium alginate micro-/nanospheres prepared via emulsion droplets containing 2 wt % sodium alginate formed with SPG membranes with pore sizes 0.2−5.5 μm. The microspheres prepared with a SPG membrane having 5.5 μm pore sizes were monodisperse with an average diameter of 3.8 μm. The average diameter of the micro-/nanospheres decreased with the pore size of the SPG membranes used for emulsification, and the size-uniformity of the micro-/nanospheres was maintained. However, when a SPG membrane having 0.2 μm pore sizes was used, some of the micro-/nanospheres were much larger and the size-uniformity worsened, although most of the nanospheres showed diameters around 0.2 μm. In the direct membrane emulsification method using SPG membranes, the proper operation condition is determined by the pore size. When the emulsification is not carried out under the proper conditions, the size distribution of the emulsion droplets becomes broader. In addition, it is more difficult to optimize the operation condition when the pore size becomes smaller and the viscosity of the dispersed phase becomes higher.27 In fact, the relationship between pore size and diameter of emulsion droplet was usually discussed only when the pore size was not smaller than 1 μm. Another reason would be the coexistence of the smaller droplets containing sodium alginate and the larger droplets containing calcium chloride during the micro-/nanosphere formation. These instable effects induced the coalescence of the emulsion droplets, resulting in the loss of the size-uniformity when the SPG membrane having 0.2 μm pore sizes was used. Figure 2 shows FE-SEM micrographs of the calcium alginate micro-/nanospheres prepared via emulsion droplets containing 1 wt % sodium alginate formed with SPG membranes having 0.2 and 0.5 μm pore sizes. The trend was similar in the case of
Figure 3. Relationships between the pore size of the SPG membrane used for preparing emulsion droplets containing 2 wt % sodium alginate and the average diameter of the calcium alginate micro-/ nanospheres. Solid line represents prediction by the eq 3.
containing sodium alginate and the average diameter of the calcium alginate micro-/nanospheres. The data for the SPG membrane having 0.2 μm pore sizes were not included because of the poor size uniformity as mentioned above. The average diameter of the micro-/nanospheres decreased with decreasing pore size, and it was successfully tuned from 0.43 to 3.8 μm by changing the pore size of the SPG membranes ranging from 0.5 to 5.5 μm when the concentration of sodium alginate in the dispersed phase was 2 wt %. The average diameter of the calcium alginate micro-/ nanospheres can be predicted with the assumption that one micro-/nanosphere is generated in one emulsion droplet as follows 3 4 ji Dw zy 4 i y y3 π jj zz C = π jjj zzz ρ 3 k2 { 3 k2{
(1)
where ρ is the density of a calcium alginate micro-/nanosphere, y is the diameter of the micro-/nanosphere, Dw is the diameter of the W/O emulsion droplet, and C is the concentration of sodium alginate polymers in the emulsion droplet, which is regarded the same as that in the dispersed phase. This equation is based on the mass balance concept. It is difficult to estimate the exact ρ value in the micro-/nanospheres; thus, we used 1.6 g/cm3, which is the reported density of calcium alginate from Wako Pure Chemical Industries, Ltd. When the direct membrane emulsification with SPG membranes is employed, Dw is dependent on the pore size of SPG membrane, Dm, as follows.
Figure 2. FE-SEM micrographs of the calcium alginate micro-/ nanospheres prepared via emulsion droplets containing 1 wt % sodium alginate formed with SPG membrane pore sizes of (a) 0.2 and (b) 0.5 μm. C
DOI: 10.1021/acs.iecr.8b02473 Ind. Eng. Chem. Res. XXXX, XXX, XXX−XXX
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Industrial & Engineering Chemistry Research Dw = 3Dm
(2)
By combining eqs 1 and 2, y can be derived as
iC y y = 3jjjj zzzz Dm (3) k ρ{ As shown in Figure 3, the prediction using eq 3 is successful, and the average diameters obtained experimentally by changing the pore sizes of the SPG membranes and the concentrations of the sodium alginate polymers in the emulsion droplets are in good agreement with the prediction lines. In addition, when an aqueous solution containing 1 wt % sodium alginate was emulsified with the SPG membrane of a 0.5-μm pore size, the smallest nanospheres with sizeuniformity showed an average diameter of 0.35 μm were obtained in this study. And the diameter predicted by eq 3 in this case was 0.28 μm, showing a good agreement also in this case. This mass balance concept was examined when chitosan microspheres were prepared via W/O emulsion droplets containing chitosan polymers in our previous study, and the concept was demonstrated to predict the average diameter of the chitosan microspheres in the range of submicrometer to 10 μm.28 In this study, this mass balance concept is also demonstrated in preparing the calcium alginate micro-/ nanospheres. The mass balance concept is not dependent on the difference in polymers; thus, successful predictions are obtained. 3.2. Classification of Calcium Alginate Micro-/Nanospheres using Microfiltration Membranes. As discussed in the previous section, we can prepare monodisperse calcium alginate micro-/nanospheres with average diameters tunable in the range from 0.35 to 3.8 μm by changing the pore sizes of the SPG membranes from 0.5 to 5.5 μm and the concentrations of sodium alginate polymers from 1 to 2 wt %. However, when the pore sizes of the SPG membranes were smaller than 0.5 μm, the size-uniformity of the micro-/nanospheres worsened. This was because of the presence of a portion of larger particles, which were not predicted from the mass balance concept. These larger particles may have been formed by the coalescence of the emulsion droplets, and most of the nanospheres were small in the range predicted. Thus, we examined the removal of the larger micro-/nanospheres by classification using microfiltration membranes as a posttreatment to achieve an excellent size uniformity of smallsized calcium alginate nanospheres. Figure 4a shows the FE-SEM micrograph of the calcium alginate nanospheres prepared via emulsion droplets containing 2 wt % sodium alginate formed with SPG membrane having 0.3 μm pore sizes. From the prediction using eq 3, the average diameter should be 0.21 μm. However, larger micro-/ nanospheres were observed, which was the similar tendency discussed in the previous section. The average diameter of the nanospheres was 0.35 μm with a coefficient of variation (CV) of 59%. We performed the classification of the micro-/ nanospheres. Total permeation, which was estimated with the rejection, after each step is shown in Figure 5. When the concentration of the micro-/nanospheres was 1000 ppm, the rejection at the step using membrane with a 1.2-μm pore size was 0.64, and accordingly, the permeation was 0.36, which means that a high proportion of the micro-/nanospheres were rejected. In contrast, when the concentration was 100 ppm, the rejection was 0.28, and accordingly, the permeation was 0.72. The 1/3
Figure 4. (a) FE-SEM micrographs of the calcium alginate nanospheres prepared via emulsion droplets containing 2 wt % sodium alginate formed with SPG membrane having a 0.3 μm pore size and those after the classification using microfiltration membranes with pore sizes of (b) 1.2, (c) 0.8, and (d) 0.45 μm.
Figure 5. Total permeation after the classification using microfiltration membranes with pore sizes of 1.2, 0.8, and 0.45 μm.
rejection even at the same step strongly depended on the concentration of the micro-/nanospheres. This was because of the difference in the extent of the coverage of the effective pore sizes by the rejected micro-/nanospheres. In both cases, membranes were replaced to new ones after filtering 1 mL of the dispersion under the same flux conditions, as described in the Experimental Section. This means that the number of the micro-/nanospheres accessing the pores of the membrane surface in the case of 1000 ppm was 10 times as many as that in the case of 100 ppm because the number of the micro-/ nanospheres accessing each pore within a certain time was regarded to be proportional to the feed concentration in the dead-end mode. Thus, the pores of the membrane surface would be completely covered by the rejected micro-/ nanospheres when the concentration was high. Once the membrane surface enters such a situation, micro-/nanospheres that are smaller than the pore size should be able to pass through the membranes, but instead, become trapped by the larger micro-/nanospheres covering the membrane surface.29 Consequently, the rejection becomes larger, and this is what occurred in the situation of 1000 ppm. However, when the concentration was 100 ppm, a number of the pores were not covered by the rejected micro-/nanospheres and active as “sieves”, and accordingly, the nanospheres that are smaller than D
DOI: 10.1021/acs.iecr.8b02473 Ind. Eng. Chem. Res. XXXX, XXX, XXX−XXX
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Industrial & Engineering Chemistry Research
each droplet. Because each micro-/nanosphere is generated in each droplet containing alginate polymers, the total mass of the alginate polymers in each droplet, which can be estimated by the concentration of sodium alginate and the pore size of the SPG membrane, determines the diameter of the micro-/ nanospheres. The effects of these parameters by changing the sodium alginate concentration from 1 to 2 wt % and the SPG membrane pore size from 0.2 to 5.5 μm were examined. The results show that the diameter decreases with decreasing concentration and decreasing the pore size. The average diameter of the micro-/nanospheres was successfully tuned from 0.43 to 3.8 μm by changing the pore size of the SPG membranes from 0.5 to 5.5 μm using 2 wt % of sodium alginate as the dispersed phase. However, monodispersity worsened when the SPG membrane pores were smaller than 0.5 μm because there were some larger micro-/nanospheres present formed by the coalescence of the emulsion droplets. The classification of micro-/nanospheres with microfiltration membranes to remove such larger micro-/nanospheres was performed. Aqueous dispersions of 100 or 1000 ppm of the calcium alginate micro-/nanospheres prepared from 2 wt % of sodium alginate as the dispersed phase and SPG membrane pores of 0.3 μm were filtered through the microfiltration membranes in successively decreasing pore sizes from 1.2, 0.8, to 0.45 μm. The microfiltration membranes were replaced after each filtering 1 mL of dispersion, which was an important point because even the micro-/nanospheres that were smaller than the pore size could not permeate through the microfiltration membrane once the membrane surface was completely covered by the rejected micro-/nanospheres. After the serial classifications, monodisperse calcium alginate nanospheres with an average diameter of 0.22 μm and a CV of 21% were obtained from an original solution of micro-/nanospheres with an average diameter of 0.35 μm and a CV of 59% by removing larger micro-/nanospheres at every step. If we carry out the classification by using an ideal microfiltration membrane, whose pore size distribution would be quite sharp and its average pore size would be a little larger than the size predicted by the eq 3 derived from the mass balance concept, the monodispersity of the micro-/nanospheres would be better, which is a future issue.
the pore sizes easily passed through the membrane. In this study, we just used the membranes with small effective areas as a lab-scale apparatus; however, a larger volume of the dispersion would be treated at one time when a membrane with larger effective area was used, and the volume would be proportional to the effective membrane area. This means that the frequency of the replacement of the membranes would be less. At the second and third classifications using membrane of 0.8− and 0.45-μm pore sizes, respectively, similar tendencies were observed. Rejection at the lower feed concentration (100 ppm) was smaller than at the higher concentration (1000 ppm). The reason was the same as that discussed above. After the three steps, 63% of the nanospheres were recovered when the initial feed concentration was 100 ppm, whereas only 18% of the nanospheres were recovered when the initial feed concentration was 1000 ppm. Parts b−d of Figure 4 show FE-SEM micrographs of the calcium alginate nanospheres obtained after classification with the membranes of 1.2, 0.8, and 0.45 μm pore sizes. Micro-/ nanospheres that were larger than the pore sizes were steadily removed at each step. As shown in Figure 6, the average
Figure 6. Average diameter and CV before and after the classification using microfiltration membranes with pore sizes of 1.2, 0.8, and 0.45 μm.
diameter and CV before the classification were 0.35 μm and 59%, respectively, and those became 0.32 μm and 35%, respectively, after the classification using a membrane of 1.2 μm pore size. The average diameter and CV were 0.31 μm and 25%, respectively, after using a membrane of 0.8 μm pore size, and 0.22 μm and 21%, respectively, after using a membrane of 0.45 μm pore sizes. The average diameter steadily decreased and became consistent with the prediction value after a threestep classification using microfiltration membranes was performed. The monodispersity, represented by the CV value, steadily improved. These results demonstrate that the classification as a post-treatment is effective to obtain monodisperse calcium alginate nanospheres by removing micro-/nanospheres that are larger than the prediction values when using SPG membranes with small pore sizes.
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AUTHOR INFORMATION
Corresponding Author
*Tel: +81-42-628-4584. Fax: +81-42-628-4542. E-mail:
[email protected]. ORCID
Kazuki Akamatsu: 0000-0002-2865-1580 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS TGCR was kindly provided by Sakamoto Yakuhin Kogyo Co., Japan.
4. CONCLUSION Monodisperse and size-controlled calcium alginate micro-/ nanospheres were successfully prepared by utilizing the direct membrane emulsification technique with SPG membranes. W/ O emulsion droplets containing sodium alginate polymers were prepared by the membrane emulsification, and mixed with W/ O emulsion droplets containing Ca2+, which induced ionic cross-linking to form calcium alginate micro-/nanospheres in
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DOI: 10.1021/acs.iecr.8b02473 Ind. Eng. Chem. Res. XXXX, XXX, XXX−XXX
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