Study on the thermoresponsive two phase transition processes of hydroxypropyl cellulose concentrated aqueous solution: from a microscopic perspective
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- Jing, Y. & Wu, P. Cellulose (2013) 20: 67. doi:10.1007/s10570-012-9816-z
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In this paper, it was discovered that during the heating process from 35 to 63 °C, hydroxypropyl cellulose (HPC) concentrated aqueous solution (20 wt%) would first go through coil-to-globule transition and then sol–gel transition with temperature elevation. The microdynamic mechanisms of the two phase transitions were thoroughly illustrated using mid and near infrared spectroscopy in combination with two-dimensional correlation spectroscopy (2Dcos) and perturbation correlation moving window (PCMW) technique. Mid infrared spectroscopy is an effective way to study the hydrophobic interactions in HPC molecules. And near infrared spectroscopy is a potent method to study hydrogen bonds between HPC molecules and water molecules. Boltzmann fitting and PCMW could help determine the exact transition temperatures of each involving functional groups in the two processes. Moreover, 2Dcos was used to discern the sequential moving orders of the functional groups during the two phase transitions. Depending on the structure of HPC and the thermodynamic conditions, the dominating associative elements in either process might vary. During the coil-to-globule transition, HPC molecules precipitated to form an opaque system with mobility.It was discovered that the driving force of the coil-to-globule transition process in microdynamics could only be the dehydration and hydrophobic interactions of C–H groups. However, in the sol–gel transition, the system crosslinked to form a physical network with no mobility. The driving force of this process in microdynamics was primarily the self-assembly behavior of O–H groups in HPC “active molecules”.
KeywordsHydroxypropyl celluloseTwo-dimensional correlation spectroscopyCoil-to-globule transitionSol–gel transitionHydrophobic interactionsHydrogen bonding
Large interests have been aroused in associative water soluble polymers during the past decades (Clasen and Kulicke 2001). Such polymers usually contain hydrophilic and hydrophobic moieties (block or pendent groups) which self-associate in aqueous media. These peculiar systems can be used in a wide range of applications such as food, pharmaceutical, biomedical and cosmetic industries (Klouda and Mikos 2008). In the context of these applications, the conception of smart system responding strongly under slight and precise stimulus is a great challenge (Kobayashi et al. 1999). Temperature is one of the most important stimuli for such applications, and polymers having response to temperature are often named in the literature with the generic term “thermosensitive polymers” (Carotenuto and Grizzuti 2006). These thermosensitive polymers tend to self-associate above the lower critical solution temperature (LCST) and/or below the upper critical solution temperature (UCST) via intra and/or intermolecular interactions (Mori et al. 2010). Most of the water soluble thermosensitive polymers are from synthetic origin, such as poly(N-isopropylacrylamide) (PNIPAM) (Wei et al. 2009) or poly(ethylene oxide)-b-poly(propylene oxide)-b-poly(ethylene oxide) triblock copolymers (Alexandridis and Hatton 1995) or poly(ethylene glycol)-biodegradable polyester copolymers (Du et al. 2007). However, for biocompatibility, environmental friendliness, and renewability, development of systems based on natural or semi-natural polymers, mainly polysaccharides, is in expansion.
Cellulose derivatives exhibiting a clear thermosensitive behavior in aqueous solution greatly satisfy the urgent demand mentioned above. Hydroxypropyl cellulose (HPC), one of the water soluble cellulose derivatives, has been approved by the united states food and drug administration in biomedical and pharmaceutical applications for its nontoxicity, biocompatibility and biodegradability. It is soluble in water and a range of organic solvents, convenient for structural modification. In addition, it undergoes phase transitions upon changes of both temperature and concentration (Suto and Suzuki 1997; Mustafa et al. 1993). It has been well studied in many works that HPC will precipitate from its aqueous solution above its LCST (~45 °C) (Lu et al. 2002), which is known as the coil-to-globule transition. This phenomenon has been studied in dilute HPC solutions using various experimental techniques like turbidimetry, viscometry, rheology, laser light scattering and differential scanning calorimetry (DSC) from a macroscopic scale (Bumbu et al. 2004; Carotenuto and Grizzuti 2006; Gao et al. 2001). However, few works have concentrated on this coil-to-globule transition in molecular level. In addition to the coil-to-globule transition, Carotenuto etal. found that concentrated HPC solution (>20 wt%) would subject to another sol–gel transition at even higher temperature using rheological method (Carotenuto and Grizzuti 2006). The phenomenon of transition from a solution to a gel is commonly referred to as the sol–gel transition and hydrogel is thus formed. Thermoresponsive hydrogels especially from natural origin, for example cellulose derivatives, chitosan, dextran, xyloglucan, and gelatin, are of particular interest in the fields of injectable drug delivery and tissue engineering recently. In cellulose derivatives, the most extensively investigated one for biomedical applications is methylcellulose because of its remarkable spontaneous gelation behavior simply due to hydrophobic interactions between 60 and 80 °C in a wide concentration range (Li et al. 2002). However, the sol–gel transition temperature of HPC is much lower than that of methylcellulose and its transition mechanisms are more complicated. In this paper, both the coil-to-globule transition and the sol–gel transition at different temperatures in the same HPC solution (20 wt%) were well studied using both middle (MIR) and near infrared (NIR) spectroscopy. Near infrared spectroscopy has long been employed as a unique tool for investigating hydrogen bonding and hydration of self-associated molecules (Adachi et al. 2002). In this work, NIR spectroscopy can trace the spectral variations of both HPC and water in the dynamic phase transition processes. Additionally, two-dimentional correlation infrared spectroscopy (2Dcos) in combination with perturbation correlation moving window (PCMW) technique is used to further illustrate the microdynamic mechanisms of the two processes.
Two-dimentional correlation infrared spectroscopy is a mathematical method whose basic principles were first proposed by Noda in 1986. So far, 2Dcos has been widely used to study the spectral variations of different chemical species under various external perturbations (e.g.Temperature, pressure, concentration, time, pH, etc.) (Noda 2008). By spreading peaks along a second dimension, 2Dcos can sort out complex or overlapped spectral features and get an enhanced spectral resolution. Due to the different responses of different species to external variables, additional information about molecular motions or conformational changes can be obtained which can not be extracted directly from one-dimensional spectra. Further, 2Dcos can provide the specific order occurring under a certain physical variable.
Perturbation correlation moving window is a technique proposed by Morita in 2006 to give much wider applicability through introducing the perturbation variable into the correlation equation (Morita et al. 2006; Thomas and Richardson 2000). Perturbation correlation moving window has the ability in determining transition points along with monitoring complicated spectral variations along the perturbation direction.
Hydroxypropyl cellulose was purchased from Sigma Aldrich (average Mw ~80,000, average Mn ~10,000, MS 3–3.5, DS 2.2–2.8. Fourier transform infrared spectroscopy spectrum is shown in Fig. S1. 1HNMR spectrum is shown in Fig. S2. The calculated DS is 2.1). 20 wt% HPC D2O and H2O solutions were prepared and kept for one week before experiments in order to ensure the complete dissolution of HPC.
Instruments and measurements
Differential scanning calorimetry
Calorimetric measurements for the prepared samples (20 wt% HPC H2O and D2O solutions) were performed on a Mettler-Toledo differential scanning calorimeter thermal analyzer. All the experiments were carried out in a nitrogen atmosphere. The temperature range was 25–65 °C, and the heating rate was 10 °C min−1.
Fourier transform infrared spectroscopy
The sample of 20 wt% HPC D2O solution for MIR detection was prepared by being sealed between two pieces of microscope CaF2 windows which have no absorption bands in MIR region. The sample of 20 wt% HPC H2O solution for NIR detection was prepared by being sealed in the sample cell (quartz glass, 1 mm width) which has no absorption bands in NIR region. The FTIR measurements were performed on a Nicolet Nexus 470 spectrometer with a spectral resolution of 4 cm−1 and 32 scans were accumulated to obtain an acceptable signal-to-noise ratio. Variable-temperature spectra were collected between 35 and 63 °C for MIR, and between 35 and 60 °C for NIR with an increment of 0.5 °C (accuracy: 0.1 °C). Manual method was used to change the temperature, and IR spectrum was collected for each temperature point. The baseline correct processing was performed by the software of OMNIC 8.0. To guarantee data reproducibility, both MIR and NIR experiments were taken for more than three times for a valid result.
Two-dimensional correlation analysis (2Dcos)
Mear infrared and NIR spectra recorded at an interval of 0.5 °C were selected in certain wavenumber ranges and 2D correlation analysis wascarried out using the software 2D Shige ver. 1.3 (©ShigeakiMorita, Kwansei-Gakuin University, Japan, 2004–2005), andwas further plotted into the contour maps by the Originprogram ver. 8.0. In the contour maps, red colors are definedas positive intensities, while blue colors as negative ones.
Perturbation correlation moving window (PCMW)
Fourier transform infrared spectroscopy spectraused for 2D correlation analysis were also used to perform PCMW analysis. Primarydata processing was carried out with the method Moritaprovided and further correlation calculation was performedusing the same software 2D Shige ver. 1.3 (©ShigeakiMorita,Kwansei-Gakuin University, Japan, 2004–2005). Similarly, the final contour maps were plotted by the Origin programver. 8.0, with the red colors defined as positive intensities and blue colors as negative ones. An appropriate window size (2m + 1 = 11) was chosen to generate PCMW spectra with good quality.
Results and discussion
Tentative band assignments according to 2Dcos during the heating process and phase transition temperatures of certain functional groups in HPC determined by Boltzmann Fitting
νas (CH in C1′H3) strong hydrationa
νas (CH in C1′H3) weak hydration
νas (CH in C3′H2)a
ν (CH in C2′H)
ν (CH in C1−6H)
νas (CH in C1′H3) strong hydrationb
νas (CH in C3′H2)b
2ν (OH in water) weak hydrogen bond with HPC
2ν (OH in water) strong hydrogen bond with HPC
2ν (OH in HPC) weak hydrogen bond with watera
2ν (OH in HPC) strong hydrogen bond with water
2ν (OH in HPC) self-assembled
2ν (OH in HPC) weak hydrogen bond with waterb
In this work, MIR and NIR spectroscopy were combined to better illustrate the spectroscopic vibrations of the hydroxypropyl groups and cellulose backbones of HPC, together with the solvent molecules, during the two phase transition processes. In MIR analysis, D2O rather than H2O, was used here as the solvent to eliminate the overlap of the O–H stretching vibrations (υ(OH)) of water at about 2,900–3,300 cm−1 with the C–H stretching vibrations (υ(CH)) of HPC at about 2,800–3,000 cm−1 (Sun et al. 2008). In NIR analysis, H2O was directly used as the solvent, and the υ(OH) first overtones of both H2O and HPC could be obtained simultaneously.
Analysis of the first transition: coil-to-globule transition
The C–H region
As has been mentioned above, 2Dcos can not only enhance spectral resolution, but also discern the specific order taking place under external perturbations. The 2D-IR correlation spectra are charaterized by two independent wavenumber axes (υ1,υ2) and a correlation intensity axis. Two types of spectra, 2D synchronous and asynchronous spectra are obtained in general. The 2D synchronous spectra are symmetric with respect to the diagonal line in the correlation map. Some peaks appearing along the diagonal are called the autopeaks, and the symbols of them are always positive, as autopeaks represent the degree of autocorrelation of perturbation-induced molecular vibrations. Where the autopeak appears, the peak at this wavenumber would change greatly under environmental perturbation. Off-diagonal peaks, named cross-peaks (Φ(ν1, ν2)), can be positive or negative. Positive cross-peaks demonstrate the intensity variations of the two peaks are taking place in the same direction (both increase or both decrease) under the environmental perturbation; while the negative cross-peaks help to infer that the intensities of the two peaks change in opposite directions under perturbation. The 2D asynchronous spectra are asymmetric with respect to the diagonal line in the correlation map. Unlike synchronous spectra, only off-diagonal cross-peaks would appear in asynchronous spectra, and these cross-peaks can be either positive or negative. The intensity of the asynchronous spectrum (ψ(ν1, ν2)) represents sequential or successive changes of spectral intensities observed at ν1 and ν2. With the cross-peaks both in synchronous and asynchronous maps, we can get the specific order of the spectral intensity changes taking place while the sample is subjected to an environmental perturbation. According to Noda’s rule (Noda 1993, 2000; Noda et al. 1999), if the cross-peaks (ν1, ν2, and assume ν1 > ν2) in synchronous and asynchronous spectra have the same sign, the change at ν1 occurs prior to that of ν2, and vice versa. If the intensity of the cross-peak in synchronous spectrum is zero, ν1 has no relationship with ν2. If the intensity of the cross-peak in asynchronous spectrum is zero, ν1 and ν2 change simultaneously.
2D asynchronous spectra can significantly enhance the spectral resolution. In Fig. 5b, two new bands, 2,922 and 2,904 cm−1 have been identified. The symbols of the cross-peaks at (2,990, 2,922) cm−1 and (2,945, 2,922) cm−1 are positive in the synchronous and negative in the asynchronous spectra. This infers that when heated, the intensity of the 2,922 cm−1 band varies prior to those of the 2,990 and 2,945 cm−1 bands. The symbols of the cross-peak at (2,965, 2,922) cm−1 are negative in the synchronous and positive in the asynchronous spectra, which also infers that the 2,922 cm−1 band varies prior to the 2,965 cm−1 band. However, the symbols of the cross-peaks at (2,990, 2,904) cm−1 and (2,945, 2,904) cm−1 are all negative in the synchronous and asynchronous specra, indicating that 2,990 and 2,945 cm−1 change before 2,904 cm−1. The cross-peaks at (2,965, 2,904) cm−1 are both positive in the synchronous and asynchronous spectra, also indicating that 2,965 cm−1 changes before 2,904 cm−1. The cross-peaks in the 2D spectra finally help to conclude the changing sequence of the five bands observed in the spectra as 2,922 > 2,990, 2,945 > 2,965 > 2,904 cm−1. (The symbol “>” means change prior to, and the detailed determination process is in supporting information).
The stretching vibration of methyne groups (C1−6H) in the cellulose backbone lies at 2,904 cm−1 (Maeda 2001). However, due to the hydrogen bond acceptor effect of hydroxyl groups, the stretching vibration of methyne groups (C2′H) will shift to higher wavenumber at 2,922 cm−1 (Gruenloh et al. 1999).The 2,990 cm−1 band with the highest wavenumber is attributed to the asymmetric stretching vibration of methyl groups (C1′H3) interacting with a greater number of D2O molecules (Maeda et al. 2000; Sun et al. 2007). The 2,945 cm−1 band belongs to the asymmetric stretching vibration of methylene groups (C3′H2) (Maeda et al. 2000; Sun et al. 2007). During the heating process, the methyl groups (2,990 cm−1) go through dehydration, and the band moves to lower wavenumber as shown in the 1D spectrum (Tamai et al. 1996).The band of the vibration of methyl groups without hydration interaction with water exists at 2,965 cm−1 (Sun et al. 2007). Detailed band assignments concerning all the bands appearing in 2Dcos in this paper are listed in Table 1.
The O–H region
Analysis of the second transition: sol–gel transition
Apart from the coil-to-globule transition, concentrated HPC solution will go through another sol–gel transition at higher temperature, and its microdynamic mechanism is eagerly studied.
The C–H region
After the coil-to-globule transition process, most HPC chains or segments precipitate, leaving behind a dilute solution of coil-like HPC chains or segments, which are designated as “active molecules” (Carotenuto and Grizzuti 2006). The 2,985 and 2,938 cm−1 bands belong to the methyl (C1H3) and methylene (C3′H2) groups of the “active molecules”. There is a red shift in the two bands of the “active molecules” compared with those of the HPC molecules before the coil-to-globule transition (2,990 cm−1 for C1′H3 and 2,945 cm−1 for C3′H2 respectively). It is the less hydration of the “active molecules” at higher temperature that causes the red shift. During the sol–gel transition, the methyl groups of the remaining “active molecules” (2,985 cm−1) dehydrate first, and then the methylene groups of the HPC molecules (2,938 cm−1) experience the process of dehydration. Because of the dilution of “active molecules”, HPC backbones (2,904 cm−1) have to move in order to shorten the distances of structure units far apart, thus allowing the hydrophobic interactions of dehydrated methyl groups (2,965 cm−1).
The O–H region
The remaining coil-like HPC “active molecules” after the coil-to-globule transition result in the dilution of the solution where the O–H groups of HPC “active molecules” at low wavenumber 6,470 cm−1 may form strong hydrogen bonds with water molecules (Sun and Wu 2011). However, with the advent of the sol–gel transition, the strong hydrogen bonds turn to weak ones. The appearance of high wavenumber 6,800 cm−1 band indicates that the combination of HPC O–H groups with water molecules becomes weak—a dehydration process (Sun and Wu 2011). After the dehydration process, O–H groups of HPC “active molecules” may self-assemble to form a network, and the 6,890 cm−1 band is attributed to self-assembled O–H groups (Sun and Wu 2011).
The coil-to-globule and sol–gel transition phenomena of concentrated HPC aqueous solution are observed during heating and their microdynamic mechanisms are well studied using FTIR spectroscopy in combination with 2Dcos and PCMW. Two regions involving C–H-related fundamental stretching vibrations and O–H-related overtones are focused on to trace nearly all the group motions of HPC molecules as well as the solvent molecules upon heating. In the first transition process, water dissociate with the O–H groups of HPC, and the dehydrated O–H groups of HPC initiate the motion of the methyne groups (C2′H). And then the methyl (C1′H3) and methylene (C3′H2) groups dehydrate simultaneously, followed by the hydrophobic interactions of the dehydrated methyl groups (C1′H3). The diffusion and aggregation of the adjacent inter or intramolecular structural units of HPC backbone result in the shrinkage of the coil. In the second transition process, the HPC “active molecules” play the most important role. The O–H groups of HPC “active molecules” dehydrate and self-assemble to form a network. And then the methyl (C1′H3) and methylene groups (C3′H2) of HPC “active molecules” dehydrate. The self-assembly of O–H groups and the hydrophobic interactions of C–H groups after the aggregating of the main chain lead to the crosslinking of the system. The dominating effect in each phase transition process is clearly revealed. However, it is worth noting that the two phase transitions are not clear-cut because of the overlap in the transition temperatures of certain functional groups.
This work was financially supported by National Science Foundation of China (NSFC) (No. 20934002, 51073043) and the National Basic Research Program of China (No.2009CB930000).