Article pubs.acs.org/Langmuir
Hydrogelation and Crystallization of Sodium Deoxycholate Controlled by Organic Acids Guihua Li, Yuanyuan Hu, Jianfei Sui, Aixin Song, and Jingcheng Hao* Key Laboratory of Colloid and Interface Chemistry & Key Laboratory of Special Aggregated Materials, Ministry of Education, Shandong University, Jinan 250100, China S Supporting Information *
ABSTRACT: The gelation and crystallization behavior of a biological surfactant, sodium deoxycholate (NaDC), mixed with L-taric acid (LTA) in water is described in detail. With the variation of molar ratio of LTA to NaDC (r = nL‑TA/nNaDC) and total concentration of the mixtures, the transition from sol to gel was observed. SEM images showed that the density of nanofibers gradually increases over the sol−gel transition. The microstructures of the hydrogels are three-dimensional networks of densely packed nanofibers with lengths extending to several micrometers. One week after preparation, regular crystallized nanospheres formed along the length of the nanofibers, and it was typical among the transparent hydrogels induced by organic acids with pKa1 value 27 mmol L−1). Figure 1c shows that the gelation behavior of the NaDC/L-TA system is closely related to pH value of the solution. The initial pH value of 100 mmol L−1 NaDC solution was 8.1 due to the sodium carboxylate group of tail chain.45 With an increase of L-TA, the pH decreases gradually to about 7.0 at cL‑TA = 20 mmol L−1, and the sample solution does not flow when the vial was inverted, indicating that gels were formed. A significant pH drop was observed at the gelation to precipitation point, as the value decreased to 4.5. 3.2. Microstructures. SEM was used to visualize the selfassembled nanostructures. As shown in Figure 2, the density of nanofibers gradually increases with the transition from sol to gel. Moreover, with the increase in the total concentration of the mixtures (shown in Figure 2a−c), the fragments of
2. EXPERIMENTAL SECTION 2.1. Chemicals and Materials. Sodium deoxycholate (NaDC), acid, (L,D-TA), and L-malic acid (MA) were purchased from J&K Chemical Company (China, purity >98%). L-Glutamic acid (Glu), citric acid (CA), and terephthalic acid (TPA) were purchased from Sinopharm Chemical Reagent Co., Ltd., and were of pro analysis quality. L-Aspartic acid (Asp) was purchased from Tokyo Chemical Industry Company, Ltd. (TCI, purity >98%). All chemicals were used without further purification. Ultrapure water with a resistivity of 18.25 MΩ·cm was obtained using a UPH-IV ultrapure water purifier (China). 2.2. Sample Preparation. Stock solutions of NaDC and organic acids were prepared by dissolving appropriate amounts in ultrapure water. The solutions were mildly stirred at room temperature until all solids dissolved. A series of sample solutions with desired concentrations of each component were prepared by mixing different amounts of each stock solution to a final volume of 5 mL. All samples were equilibrated at 25.0 ± 0.5 °C for at least 4 weeks before the phase behavior was inspected. 2.3. Transmission Electron Microscopy (TEM). About 5 μL of sample solution was placed on carbon-coated copper grids (400 mesh) and then freeze-dried. The morphologies of samples were studied on a JEOL JEM-1400 TEM (acceleration voltage, 120 kV) with a Gatanmultiscan CCD for collecting images. 2.4. Field-Emission Scanning Electron Microscopy (FE-SEM) Observations. For SEM observations, 4 μL of gel sample was coated L,D-tartaric
B
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composed of much denser nanofibers, and some nanofibers can be found to aggregate into bundles. When the L-TA concentration was high (cL‑TA > 27 mmol L−1), the hydrogels were destroyed to form precipitates (Figure 2d) which are short nonflexible fragments of nanofibers. We consider that at high LTA concentration with the pH value of the solution lower 4.0. In this case, a large amount of precipitates of insoluble deoxycholic acid are produced and most of them do not participate in the gelation process.45 Curiously, irregular semicrystals, nanospheres, were found to be pendant on the surface of the nanofibers several days after being prepared. Figure 3a shows the necklace-like morphology of the pendant nanospheres, formed by 100 mmol L−1 NaDC/ 10 mmol L−1 L-TA. One can see that almost all the nanospheres grow on the same side of the nanofibers. It is considered that the surface of nanofibers is negatively charged because of the deprotonated carboxylate species (−COO−) of NaDC,38 which tend to concentrate the cations (Na+ or H+) and create the local supersaturation followed by nucleation and growth of the crystals. Thus, the interfacial electrostatic attraction between the carboxylate and positively charged species (Na+ or H+) is the driving force for the nucleation of the crystallization,47 and the nanospheres with roughly the uniform interparticle spacing can be obtained. Moreover, the diameters of these fibers and nanospheres could be controlled by tuning the total concentration of the mixtures. For hydrogels formed by 100 mmol L−1 NaDC/10 mmol L−1 L-TA, the diameter of the nanospheres ranged from 20 to 65 nm, with an average diameter of 42 nm (Figure 3b), which is smaller than the thickness of nanofibers that range from 25 to 100 nm. While for 300 mmol L−1 NaDC/30 mmol L−1 L-TA, the average diameter of these nanospheres along nanofibers decreased to 30 nm (Figure 3c,d). The dynamic process of
Figure 2. SEM images of typical NaDC/L-TA nanofibers formed under different conditions after 1 day: (a) 10 mmol L−1 NaDC/1 mmol L−1 L-TA, (b) 100 mmol L−1 NaDC/10 mmol L−1 L-TA, (c) 100 mmol L−1 NaDC/25 mmol L−1 L-TA, and (d) 100 mmol L−1 NaDC/30 mmol L−1 L-TA.
nanofibers gradually become longer. In Figure 2b,c it can be seen that these fragments link together to gradually form the dense networks of nanofibers. The microstructures of the hydrogels are three-dimensional networks consisting of densely stacking nanofibers with lengths extending to several micrometers. Their different appearance is probably ascribed to the increasing number of nanofibers. Compared with the transparent gels at lower L-TA concentrations, the turbid gels are
Figure 3. SEM images of NaDC/L-TA nanofibers with pendant nanospheres: (a) 100 mmol L−1 NaDC/10 mmol L−1 L-TA and (c) 300 mmol L−1 NaDC/30 mmol L−1 L-TA (room temperature, 7 days). Respective size distribution diagrams (b) 100 mmol L−1 NaDC/10 mmol L−1 L-TA and (d) 300 mmol L−1 NaDC/30 mmol L−1 L-TA of pendant nanospheres. C
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Figure 4. (a) Stress sweep and (b) frequency sweep of sols and gels formed at varied total concentration (r = 0.1).
the formation of nanospheres displayed in Figure S1 indicates that the amount of the nanospheres gradually increases with increasing incubation time. After 4 days, the nanospheres with uniform interparticle spacing along the nanofibers can be obtained, and the diameter of these nanospheres keeps unchangeable during the incubation time. 3.3. Rheological Properties. Before oscillatory frequency sweep, the applied stress should be checked to ensure that it is within the linear viscoelastic region, within which the elastic modulus (G′) is independent of the yield stress.48 When the yield stress is above a critical value (τ*), G′ will decrease quickly due to the destruction of gel microstructures. The τ* value reflects the strength of the network structures.49 As shown in Figure 4a, at a constant molar ratio of L-TA to NaDC (r = nL‑TA/nNaDC), r = 0.1, the τ* value is about 5 Pa, which is independent of the total concentration of the mixtures. Moreover, upward trend in G′ values indicates that increasing the total concentration of the mixtures can make the nanofibers arrange more tightly. From the oscillatory measurement (Figure 4b), it was found that for sols formed by 10 mmol L−1 NaDC/1 mmol L−1 L-TA and 50 mmol L−1 NaDC/5 mmol L−1 L-TA, G′ is higher than G″ at low frequency, representing an elastic dominant property. Above a critical frequency, 0.5 and 1.2 Hz, for 10 mmol L−1 NaDC/1 mmol L−1 L-TA and 50 mmol L−1 NaDC/5 mmol L−1 L-TA, respectively, G″ exceeds G′, indicating that the systems were now more viscous than elastic. For sols formed with 100 mmol L−1 NaDC/10 mmol L−1 L-TA, with increasing frequency, both G′ and G″ increase, and G′ is higher than G″ within the whole range of frequency. With a further increase of the total concentration of the mixtures (200 mmol L−1 NaDC/20 mmol L−1 L-TA), hydrogels were formed and exhibited typical solidlike rheological behavior, in which G′ and G″ are nearly independent of the oscillatory frequency, and G′ exceeds G″ over the investigated frequency range. Finally, one can see that with an increase in concentration G′ and G″ increase significantly, along with an appearance change from sols to gels, indicating a remarkable enhancement in the strength of network structures. 3.4. Effect of Different Organic Acids. To detect the role of organic acids in gelation and formation of the irregular nanospheres, 20 mmol L−1 organic acids with different pKa values were introduced to 100 mmol L−1 NaDC aqueous solutions. Hydrogels with almost the same appearance as those formed by L-TA were obtained. As shown in Figure 5, the pKa1 values of the four organic acids are 2.0, 2.19, 3.46, and 3.54 for Asp, Glu, MA, and TPA, respectively, indicating the acidity in the sequence of Asp > Glu > MA ≈ TPA. SEM was used to
Figure 5. Structures of Asp, Glu, MA, and TPA. The pKa of the organic acids is also included.
detect whether irregular nanospheres were formed and located at the surface of the nanofibers 7 days after hydrogel preparation. From Figure 6, the remarkable differences in gelation and formation of irregular nanospheres demonstrate the significant role of pKa value of organic acids in the process. For the hydrogels formed in the NaDC/HCl system, the
Figure 6. SEM images of hydrogels formed by (a) 100 mmol L−1 NaDC/HCl (pH = 7.0) or 100 mmol L−1 NaDC/20 mmol L−1 organic acid: (b) Asp, (c) Glu, and (d) TPA. D
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organic acids with similar chemical structures. Stress sweep measurements (Figure S3) also showed that at a fixed concentration of 20 mmol L−1 organic acids/100 mmol L−1 NaDC, for hydrogels induced by TPA and Asp, τ* and the elastic modulus (G′) are about 10 and 1000 Pa, respectively. Values larger than those observed in Glu, MA, or HCl systems, with τ* and (G′) around 1 and 3 Pa, respectively. The results above demonstrate that the structure of the organic acids influences the interactions between NaDC and organic acids, thus affecting the arrangement of nanofibers. For the organic acids with similar chemical structures, the mechanical strength of the hydrogels depends on the sample solution pH value because the aggregation number will increase by ∼10% when the pH is reduced from 7.0 to 6.8.42 3.5. Proposed Mechanism. NaDC is a well-known facial amphiphile composed of a rigid steroid backbone with a polar face and a nonpolar face.44 Two hydroxyl groups and a carboxyl group were directed to polar face and two methyl groups to the nonpolar face. Owing to the hydrogen bond between hydroxyl groups, NaDC can assemble into a unique bilayer structure.50 FT-IR spectra were used to detect the formation of hydrogen bonding, which usually exhibited intense and continuous absorption peaks within the region of 3500−1000 cm−1. The presence of sharp peaks above 3500 cm−1 is characteristic of unassociated −OH groups, while broad peaks below this wavenumber range arise from associated forms of OH moieties.51 As shown in Figure 8, all the samples show a
system pH value was located at 7.0. SEM investigation (Figure 6a) showed that nanospheres with the diameter ranged from 45 to 80 nm are pendants along nanofibers. Moreover, these nanospheres whether inpairs, triplets, or large clusters were directed by the structure of nanofibers. As for the hydrogels formed in NaDC/Asp and NaDC/Glu systems (Figure 6b,c), randomly distributed and nicely separated nanofibers were observed, and the nanospheres aligned with the long axes of the fibers are solitary. It was observed that the average diameter of nanospheres was about 30 nm in the NaDC/Asp and NaDC/ Glu systems, which is much smaller than the nanospheres formed in NaDC/HCl system. Morphologic measurements showed that no nanospheres were formed in NaDC/TPA and NaDC/MA systems (Figure 6d and Figure S2a), in which entangled nanofibers with an average diameter of about 120 nm were obtained. Other organic acids, CA (pKa1 = 3.13) and DTA (pKa1 = 3.03) were also studied in 100 mmol L−1 NaDC aqueous solutions. As shown in Figures S2b and S2c, it can be observed that the deposition of nanospheres appeared on structures of nanofibers in these systems. According to these results, we conclude that the pKa value of organic acids seems to play a significant role in the formation of nanospheres. For organic acids with pKa1 values above 3.4, nanospheres were not found in hydrogels of these systems even after a month. Moreover, nanospheres were not formed, even if the organic acids (pKa1 > 3.4) concentration reached to 25 and 30 mmol L−1 when precipitates were obtained (pH < 5). The mechanical properties of the hydrogels formed in NaDC/HCl and NaDC/organic acids systems were also investigated by the dynamic rheological technique. As shown in Figure 7, all the hydrogels predominantly exhibit elastic
Figure 8. FT-IR spectra of NaDC (a) and hydrogels of 100 mmol L−1 NaDC with varied amounts of L-TA: (b) 10, (c) 15, (d) 20, and (e) 25 mmol L−1. Figure 7. Frequency sweep of hydrogels formed with 100 mmol L−1 NaDC and 20 mmol L−1 organic acid or HCl (pH = 7.0).
wide peak at the region of 3483−3354 cm−1, indicating the formation of intermolecular hydrogen bond between the −OH groups on the concave α-face. For pure NaDC (curve a), there is no peak around 1710 cm−1 (the symmetric stretching vibration of −COOH), indicating the existence of deprotonated form, −COO−, in NaDC molecules. For the hydrogels formed by 100 mmol L−1 NaDC with varied amount of L-TA (curves b−e), the peaks appearing at 1600 cm−1 is assigned to the antisymmetric stretching vibration of −COO−.51,52 The bands at 1712, 1600, and 1382 cm−1 indicate that the carboxyl and carboxylate species coexist in aggregates solutions,53 proving the existence of O−H···O hydrogen bonding between NaDC and deoxycholic acid molecules (or between NaDC and L-TA). Detailed information on the microstructure was revealed by small-angle X-ray diffraction (SXRD) patterns. According to Bragg’s law, we can get d values from the reflection peaks, which are considered to be related to some cycled units
properties, for which G′ exceeds G″ over the investigated frequency range. Both G′ and G″ increase in the order of TPA > Asp > Glu > MA > HCl. For hydrogels formed by NaDC with TPA, G′ and G″ are about 104 Pa and 600 Pa, respectively. That is much larger than the values for hydrogels induced by NaDC and HCl, with G′ and G″ around 2 Pa and 0.2 Pa, respectively, although the two samples were both at pH = 7.0. The result may be ascribed to hydrophobic and steric effects between hydrophobic moieties of the NaDC and TPA molecules and by hydrogen bonding between the −OH and the −COO− groups. Thus, the nanofibers formed by NaDC and TPA may be arranged more tightly. As for hydrogels formed by NaDC with Asp, Glu, and MA, the system pH values were 6.8, 6.9, and 7.0, respectively. The mechanical strength of the hydrogels decreased with the increasing pH value for the E
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Scheme 1. Schematic Representation of Organic AcidInduced NaDC Gel and Nanospheres along Nanofibers: (a) Deoxycholate Pairs Linked Together by Hydrogen Bonds with an Opened Angle; (b) Transparent Hydrogels; (c) Nanospheres along the Nanofibers; (d) Antiparallel Oriented Deoxycholate Pairs Stacked Together with Hydrogen Bonds; (e)Turbid Hydrogel
Figure 9. Small-angle XRD patterns of transparent and turid hydrogels. T = 25.0 ± 0.1 °C.
and turbid gels. For hydrogels formed by 100 mmol L−1 NaDC/10 mmol L−1 L-TA and 200 mmol L−1 NaDC/20 mmol L−1 L-TA (transparent gels), at 2θ = 2.4, a strong peak appears, from which the d spacing distance calculated is 3.68 nm, slightly larger than twice of the deoxycholate (bile salt) backbone length (1.5 nm × 2).41 The arrangement patterns of pure nanofibers without nanospheres were also investigated by SXRD. As shown in Figure S4, compared with the samples of nanospheres on the nanofibers, the d value of pure nanofibers almost does not change (3.52 nm), indicating that the cycled units induced by the arrangement of DC− species remain the same style at different times after preparation. This result is consistent with helical deoxycholate complexes reported by Rich et al.,45 for which the XRD studies of fibers show that the molecules are assumed an elongated helical configuration of 3.6 nm in diameter. This diameter increases if other molecules such as amino acids or peptides are in the solution during the formation of the complexes. However, for the hydrogels formed by NaDC/NaBr/Lys,43 the predominating peaks at the 2θ value of 8.14 and 17.48 correspond to the d spacing of 1.09 and 0.51 nm, respectively. It might be ascribed to the combination of several NaDC molecules through the hydrophobic interaction in each unit of the arrays. This suggests the different molecular packing mode between the two systems. For hydrogels formed by 100 mmol L−1 NaDC/25 mmol L−1 L-TA and 200 mmol L−1 NaDC/60 mmol L−1 L-TA (turbid gels), two well-resolved reflection peaks at 2θ = 6.0 and 8.7 occur, which correspond to d spacing of 1.45 and 1.0 nm, being comparable with a deoxycholate backbone length and twice the width of deoxycholate skeleton, respectively. The presence of two peaks suggests that NaDC may form cylindrical aggregates, with the first and second peaks corresponding to the length and diameter, respectively.54,55 The patterns and thus the molecular packing are different between transparent and turbid gels, indicating the amounts of organic acids possibly change the hydrogen bond mode,56 which promote different arrangement models of NaDC species. Based on above results, the mechanism of the formation of fibers in hydrogels and nanospheres along the nanofibers was proposed and was shown in Scheme 1. For transparent hydrogels with low concentrations of L-TA, the deoxycholate anions and organic acids may adopt a lamellar type of arrangement, for which the hydrogen-bonded deoxycholate pairs are stacked together at their hydrophilic edges, allowing
an opening angle between the planes of the two ring systems (a).50 As for turbid hydrogels with a lower pH value and high ionic strength, the antiparallel oriented deoxycholate pairs stacked together more tightly with three hydrogen bonds (d). In both of the patterns, the two connected deoxycholate species formed the continuous hydrophilic cavities,51 and such interior cores acted as the pocket in which water molecules were held through interfacial tension. McGown et al. reported that the hydrophobic interaction plays an important role in the aggregation.57 All results above indicate that the formation of nanofibers is driven by the balance of hydrogen bonding, hydrophobic interaction, steric effect, and van der Waals force. The controlled nucleation and growth of crystals from organic templates has been demonstrated by in vitro experiments in a number of natural biomineralizing systems.58−61 These reports on template crystal growth suggest that nucleation occurs on surfaces which expose repetitive patterns of anionic groups. As for the irregular nanospheres formed in our system, a similar model can be established. The negatively charged nanofiber surface could concentrate the inorganic cations (Na+ or H+) and creating local supersaturation followed by nucleation and growth of the crystals (c). Because of the formation of low soluble deoxycholic acids (0.0436 mmol L−1 at 308.2 K),62 the local supersaturation and nucleation easily happen on the surface of aggregates. The interfacial electrostatic attraction between the negatively charged carboxylate species and positively charged Na+ or H+ is the driving force of the nucleation in the crystallization. The atomic ratio of C to O to Na in the nanospheres was determined by energy-dispersive spectroscopy (EDS) to be roughly 79.3:17.6:3.1 (Figure S5). For pure NaDC and deoxycholate acid, the atomic ratios of C to O to Na were 81.8:18.2:0 and 76.8:17.0:6.13, respectively, indicating the formation of the nanospheres with the possible coexistence of NaDC and DCA. Moreover, the acidic moieties play a key role in promoting growth of the crystals.61
4. CONCLUSIONS In conclusion, we reported the hydrosols and hydrogels formed by NaDC with different organic acids at appropriate concentrations. The driving forces of the gelation were F
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considered to be the synergistic effect of hydrogen bonding, electrostatic interaction, hydrophobic interaction, and other weak interactions. SXRD results proved that the molecular packing are different between transparent and turbid gels, indicating the amounts of organic acids could change the hydrogen bond mode, which promote different kinds of NaDC self-assembly. The microstructures of the hydrogels were threedimensional networks of densely stacking nanofibers with the length extending to several micrometers. For the transparent hydrogels formed by organic acids with the pKa1 value below 3.4, some irregular nanospheres were formed along the nanofibers 1 week after preparation. The surface of nanofibers formed in our systems was negatively charged, and this promotes nucleation by concentrating the inorganic cations creating local supersaturation. Dynamic rheological determination proved that the mechanical strength of the hydrogels depends on the pH value and the structures of the organic acids. We hope our results will provide useful information in understanding the self-assembly of bile salts and their applications in drug delivery systems, material science, and other related areas.
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ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.langmuir.6b00019. SEM images of NaDC/L-TA nanofibers with pendant nanospheres formed by 10 mmol L−1 NaDC/1 mmol L−1 L-TA at various time intervals; SEM images and stress sweep of hydrogels formed by 100 mmol L−1 NaDC with 20 mmol L−1 MA, CA, and D-TA; EDS spectrum of pendant nanospheres; small-angle XRD patterns of transparent hydrogels after 1 day preparation (PDF)
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AUTHOR INFORMATION
Corresponding Author
*E-mail
[email protected]; Tel +86-531-88366074; Fax +86531-88364750 (J.H.). Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS This work is financially supported by the NSFC (Grants 21420102006 and 21273134) and NSF for distinguished young scholars of Shandong province (JQ201303).
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REFERENCES
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DOI: 10.1021/acs.langmuir.6b00019 Langmuir XXXX, XXX, XXX−XXX
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DOI: 10.1021/acs.langmuir.6b00019 Langmuir XXXX, XXX, XXX−XXX
