Theophylline Molecular Imprinted Composite Membranes Prepared

Article pubs.acs.org/IECR

Theophylline Molecular Imprinted Composite Membranes Prepared on a Ceramic Hollow Fiber Substrate Yi-Ting Ye, Xiao-Hua Ma, Zhen-Liang Xu,* and Ying Zhang State Key Laboratory of Chemical Engineering, Membrane Science and Engineering R&D Lab, Chemical Engineering Research Center, East China University of Science and Technology, 130 Meilong Road, Shanghai 200237, China S Supporting Information *

ABSTRACT: Theophylline (THO) molecular imprinted composite membranes (MIM) were successfully prepared by thermalinitiated free radical polymerization on the surface of α-Al2O3 ceramic microporous hollow fiber substrate membranes. Molecular imprinted polymerization layer was synthesized by taking theophylline as the template molecule, methacrylic acid (MAA) as the functional monomer, ethylene glycol dimethacrylate (EDMA) as the cross-linker, and 2,2′-azobisisobutyronitrile (AIBN) as the free-radical initiator. After polymerization and the elution of the imprinted molecule, the Rmax (the maximum pore size) upon the membrane surface decreased from 2.8 to 1.9 μm. The imprinted layer upon the ceramic membranes was investigated by scanning electron microscopy (SEM), atomic force microscope (AFM) and Fourier transform infrared spectroscopy (FTIR). SEM micrographs showed a 1 μm thick composite membrane, and AFM showed different surface roughness. Moreover, the selectivity separation factor of theophylline (THO) to theobromine (TB) was determined as 2.63 in a mixed feed solution, thus suggesting that the imprinting process allowed for preferential permeance and affinity selectivity to THO.

1. INTRODUCTION

Scheme 1. Theophylline and Theobromine

Membrane separation shows lots of promising properties, such as better feasibility to scale up, easy and low energy continuous operation under mild conditions and the resulting low cost of operation, and so on.1 Therefore, it is fundamental to a great number of modern applications, ranging from gas cleaning and separation, drinking water production, and pharmaceutical production to the separations needed for the manufacture of chemicals, electronics, and many other products.2 However, it can not be achieved by membranes alone to separate one single targeted substance from a mixed solution that contains many substances with similar molecular weights.3−5 So many efforts have been made to prepare membranes that have specific selectivity toward some certain molecules, and molecular imprinted technology (MIT) is thought to be the most applicable method for molecular recognition. Molecular imprinted technology has been widely applied in research areas such as sensors,6 chromatographic separation,7 solid phase extraction,8,9 and drug separation10,11 since the introduction of the noncovalent method by Vlatakis and the covalent method by Wulff and Sarhan.12,13 The specific recognition sites in the imprinted polymer are created by grinding, sieving, and template extraction, though they will also be destroyed during the grinding step.14 To address this problem, molecular imprinted composite membranes (MIM) can ensure the integrity of molecular recognition sites and also combine the advantages of membrane separation with MIT. Therefore, it is significant to separate substances with similar molecular structures by MIM. Theophylline (THO) and theobromine (TB) are alkaloids from tea leaves and coffee beans. They have several similar physical properties depending upon their molecular structures, which are shown in Scheme 1. © 2013 American Chemical Society

However, their pharmacological effects have big differences. Theophylline is mainly used to treat asthmatic symptoms, as well as apnea in premature infants, whereas theobromine has effects on diuresis, cardiac excitation, vasodilatation, and so on. Unfortunately, alkaloids with similar configurations cannot be separated easily by traditional separation methods. They have lots of drawbacks such as long extraction time, high energy consumption, and complex operations. Therefore, the separation of theophylline and theobromine by MIM is becoming more and more attractive. Although different methods such as molecular imprinted polymer solid phase extraction,15 capillary electro-chromatography,16 molecular imprinted membrane prepared by phase inversion technique,17−19 and free radical polymerization method20 have been developed to separate theophylline and its isomeride using the molecular imprinted mechanism. Nevertheless, the way to prepare the molecular imprinted composite membranes by immobilizing a layer of polymer matrix on the ceramic hollow fiber substrate using thermal initiated free radical polymerization method has not been explored. Besides, the ceramic hollow fiber composite membranes have the ability of solvent resistance, which can Received: Revised: Accepted: Published: 346

July 29, 2013 November 18, 2013 December 5, 2013 December 5, 2013 dx.doi.org/10.1021/ie4024534 | Ind. Eng. Chem. Res. 2014, 53, 346−354

Industrial & Engineering Chemistry Research

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Figure 1. Preparation process of α-Al2O3 ceramic hollow fiber substrate membranes.

Figure 2. Reaction mechanism of MIM.

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dx.doi.org/10.1021/ie4024534 | Ind. Eng. Chem. Res. 2014, 53, 346−354


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avoid membrane swelling21−24 and improve the use ratio of MIM. Considering the solvent resistance and the regeneration of MIM, we focused on developing the molecular imprinted composite membranes using ceramic hollow fiber substrate as the support for separation of theophylline and theobromine. In our work, alkaloid (i.e., theophylline) was used as a template because it contains several carbonyl groups and amino groups that can form hydrogen bonds with the alkaline groups in methacrylic acid. Preorganized solution was synthesized by taking theophylline as the template molecule, methacrylic acid (MAA) as the functional monomer, ethylene glycol dimethacrylate (EDMA) as the cross-linker, and 2,2′-azobisisobutyronitrile (AIBN) as the free radical initiator. The MIM were prepared by coating a templated THO polymerization layer on α-Al2O3 substrate and subsequently followed by template removal, thus forming the molecular imprinted recognition sites. The selectivity property of MIM was investigated by both single molecule and multimolecule filtration experiments. After that, the regeneration experiments of MIM were also conducted to verify their solvent resistance ability. The membranes were characterized by FTIR, SEM, and AFM. The permeation and selective mechanism of the composite membranes were studied by high performance liquid chromatography (HPLC).

substrate membranes were immersed into the solution for 3 min and followed by reacting in a vacuum oven at 60 °C for 24 h to initiate the polymerization. After that, the imprinted membranes were first washed using acetic acid/methanol (1/9, v/v) in an ultrasonic bath for 4 h, then washed with pure methanol to remove the residues, and finally dried at 60 °C for 8 h. The synthesis reaction mechanism including the interaction between THO and MAA was evident by Figure 2. 2.3. Characterization of Theophylline Molecular Imprinted Ceramic Hollow Fiber Membranes. 2.3.1. Morphological Structures. The morphological structures of MIM were examined using a scanning electron microscope (SEM, S3400N, Hitachi). Both the surface and cross section of the samples were sputtered by gold before tested. Surface roughness analysis of the membranes was measured using AFM (Veeco, Nanoscope IIIa Multimode AFM). The airdried membrane sample was fixed on a specimen holder and 5 μm × 5 μm areas were scanned by tapping mode in air. In the AFM analysis, Rms is defined as the mean of the root for deviation from the standard surface to the indicated surface. 2.3.2. Membrane Porosity Measurement and Rmax. Membranes dried under a vacuum until they were a constant weight and were immersed in pure water for 48 h were weighed. The membrane porosity ε (%) was usually determined by gravimetric method and tested based on the weight of water contained in the membrane pores. It could be calculated using eq 1 m wet − mdry Δm × 100% = × 100% ε= VρH O (π /4)(D2 − d 2)lρH O 2

2. EXPERIMENTAL SECTION 2.1. Materials and Instruments. α-Al2O3 ceramic hollow fiber substrate membranes were prepared in the lab, with the outside diameter of 1.90 mm, wall thickness of 0.50 mm, and porosity of 40−50%. Theophylline (≥99.0%, HPLC grade) and theobromine (≥99.0%, HPLC grade) were purchased from Sigma-Aldrich Company, U. S. A. Ethylene glycol dimethacrylate (EDMA) (98.0%) and methacrylic acid (MAA) (99.0%) were purchased from Acros Organics Company, U. S. A. Other reagents with AR grade for this work were purchased from Shanghai Sinopharm Chemical Reagent Co. LTD (China), and the free radical initiator 2,2′-azobisisobutyronitrile (AIBN) was recrystallized in pure ethanol before use. The 1H NMR spectroscopy of MIP and NIP was carried out on an AVANCE III 500 MHz Superconducting Nucleus Magnetic Resonance Spectrometer (Bruker, Switzerland). The concentrations of THO and TB in the permeate solution were analyzed by HPLC (Waters Co. Ltd., U. S. A.) using Symmetry C18 column (4.6 mm × 150 mm) at 275 nm. The injection volume was 20.0 μL, elution rate was 1.0 mL/min, and the mobile phase was composed of acetonitrile/water = 1/9. The selectivity performance of the membrane was evaluated by an experimental device built in lab. 2.2. Preparation of Theophylline Molecular Imprinted Ceramic Hollow Fiber Membranes. 2.2.1. Preparation of α-Al2O3 Ceramic Hollow Fiber Substrate Membranes. The fabricated process of α-Al2O3 ceramic hollow fiber substrate membranes has been investigated by L. F. Han25 from our research team, which is shown in Figure 1. The substrate membranes after sintering should be washed in ultrasonic bath for 4 h in order to eliminate the unreacted α-Al2O3 particles. 2.2.2. Preparation of Theophylline Molecular Imprinted Ceramic Hollow Fiber Membranes. In the preparation experiment, the template molecule theophylline and functional monomer MAA were dissolved in chloroform and mixed under ultrasonic for 30 min, then the cross-linker EDMA and initiator AIBN were added in and mixed for 30 min to form the preorganized solution. Subsequently, the ceramic hollow fiber

2

(1)

where mwet is the weight of wet membrane (g), ρ is the water density (1.0 g/cm3), mdry is the weight of dry sample (g), D is the outer diameter (m), d is the inner diameter (m), and l is the effective length of the sample (m). A wet membrane immersed in pure water for 48 h to become fully wetted was used to test its bubble point. Rmax was calculated following eq 2 R max =

2σ P

(2)

where σ is surface tension of pure water, which is 72.75 × 10−3 N m−1, and P is the bubble point of membrane (MPa). To ensure the results were credible, each sample was tested three times, and the average value was taken. 2.3.3. Membrane Chemical Structures. Samples were mixed with KBr and pressed into disks to analyze with the Fourier transform infrared spectroscopy. 2.4. Membrane Specific Binding Experiments. A methanol solution containing 1.0 mmol/L of THO and 1.0 mmol/L of TB was prepared. Specific binding experiments were carried out in the presence of certain amount of MIM into 5.0 mL of a 1.0 mmol/L methanol solution. The solution was placed at ambient temperature for 24 h to reach adsorption equilibrium. Then, the surplus concentration in the solution was analyzed using HPLC, and the binding capacity of each substance was calculated as follows

Q=

(C0 − Ce)V m

(3)

where C0 and Ce represent the molar concentrations of substances measured at an initial and balanced binding time (24 348



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reached up to 60.9 μmol/g with the amount of EDMA increasing to 20.0 mmol. Besides, Figure 4c and d display that the binding capacity reached a maximum when the chloroform volume was 20.0 mL with a coating of 3 min. In addition, we can see from Table 1 that the binding capacity was highest up to 64.5 μmol/g when the MIM were polymerized twice. Considering the synergy effect from Figure 4, the maximum binding capacity was obtained when the polymerization conditions were optimized as 0.05 mol/L THO, 0.2 mol/L MAA, 1.0 mol/L EDMA, and 0.02 mol/L AIBN (in 20.0 mL chloroform) reacting at 60 °C for 24 h with coating for 3 min and polymerization twice, which was used for the preparation of following investigated MIM. From the results in Figure 5, we can have a qualitative analysis with the support membrane and MIM. It is easy to find that the porosity of MIM was conformably lower than the support membrane. It could be explained as the existence of an imprinted layer upon substrate membranes, indicating that the surface of MIM became denser. Moreover, the Rmax upon the membrane surface decreased from 2.8 ± 0.2 μm to 1.9 ± 0.1 μm according to bubble point tests. What’s more, in order to make sure whether the imprinted molecule was successfully synthesized into the copolymer, the MIP and NIP were prepared according to the above optimization conditions of preorganized solution. From the 1 H NMR spectrum in Figure 6, we can see that the peak appearances of the chemical shift at 1−2 ppm are assigned to CCH3, 3−4 ppm are assigned to OCH2, 4−5 ppm are assigned to OCCH, and 5−6 ppm are assigned to CC in the copolymer. We can find that there’s a CC peak in the spectrum result of MIP rather than NIP, which exists in the theophylline molecule, indicating that the template molecule was successfully synthesized into the polymer matrix. 3.2. Structures and Properties of MIM. As mentioned in above, the THO molecule with carbonyl groups and amino groups can react with MAA via hydrogen bonds. MIPs were combined upon membrane by H-bonds interaction between the carbonyl group of EDMA and the hydroxyl group upon the ceramic membrane, which was justified by the transformation of the free carbonyl adsorption band in 1730 cm−1 of MIPs into bond carbonyl adsorption band in 1715 cm−1 of MIM27 in Figure 7b. In the spectrum of MIM before washing from Figure 7a, we can clearly observe the appearance of the broad adsorption band of hydrogen bonds between THO and MAA at about 3500 cm−1, the CN stretching vibration at about 2400 cm−1, the characteristic band of CC at 1400 cm−1, and typical bands of NH in the theophylline molecule at about 3100 and 1500 cm−1, which disappeared in MIM after washing except the CO at 1715 cm−1. All these characteristic bands cannot be found in the support membrane, and these results indicated that theophylline was first incorporated into the polymer layer in MIM, and then the theophylline imprinted recognition sites were created after theophylline was successfully washed out by ultrasonic washing. Definitely, we’ve made it clear that the membrane chemical structures were changed after coating a layer of polymer matrix upon the substrate membrane. At the same time, we can observe the morphological structures of membranes from the SEM images given in Figure 8. It can be seen from the crosssectional images that a 1 μm thick molecular imprinted layer was successfully coated upon the membrane surface without changing the structure of supporting layer. The top surface of MIM was denser than the substrate membrane, which is shown

h) (mmol/L), V is the volume of feed solution (5.0 mL), and W is the weight of membrane (g). To ensure the results, each sample was tested for three to five times and the average result was taken. 2.5. Membrane selectivity experiments. Single molecule solution filtration and multimolecule solution filtration were conducted to investigate the specific recognition property of MIM. Solution concentration was both 0.5 mmol/L, and the filtration process was cross-flow filtration; that is, methanol flowed inside the membranes to extract the imprinted molecules that permeated from the feed via imprinted sites under concentration gradients (Figure 3), which was called facilitated permeation.26

Figure 3. Selective permeance of the template molecule.

The operation temperature was 25 °C and the pressure was standard atmospheric pressure. The concentrations of THO and TB in the permeate solution were analyzed by HPLC. The membrane selectivity factor of THO to TB (αH) was estimated as follows: αH =

C THOe/C TBe C THO,0/C TB,0

(4)

where CTHOe and CTBe are the concentrations of THO and TB in the permeate solution (mmol/L) and where CTHO,0 and CTB,0 are the concentrations of THO and TB in the feed solution (mmol/L).

3. RESULTS AND DISCUSSION 3.1. Optimization of Polymerization Conditions. To investigate the effect of polymerization conditions on MIM binding capacity and to obtain the optimum polymerization conditions, different MAA and EDMA mole ratios, volumes of CHCl3, coating times, and polymerization times were investigated to synthesis the MIM. The binding capacity and membrane porosity were measured accordingly. It can be seen from Figure 4a that the binding capacity (Q) increased to a maximum with the amount of MAA increasing to 4.0 mmol, whereas Q decreased with keeping MAA mole ratio increasing. We can also find from Figure 4b that the binding capacity 349



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Figure 4. Binding capacity of different polymerization conditions. (a) Theophylline/MAA mole ratio (theophylline:EDMA:AIBN = 1.0:20.0:0.4, CHCl3: 20.0 mL), (b) theophylline/EDMA mole ratio (theophylline:MAA:AIBN = 1.0:4.0:0.4, CHCl3: 20.0 mL), (c) volume of CHCl3 (theophylline:MAA:EDMA:AIBN = 1.0:4.0:20.0:0.4), and (d) coating time (theophylline:MAA:EDMA:AIBN = 1.0:4.0:20.0:0.4, CHCl3: 20.0 mL).

in Figure 8A and B. In addition, the surface images of different polymerization times were also presented, and it is easy to find that the surface of MIM polymerized three times (Figure 8G) was the densest, illustrating that the volume of polymer matrix upon the membrane increased with the increasing polymerization times. Figure 9 shows the AFM images of surface morphologies of support membrane and MIM, which covered an area of 5 μm × 5 μm. The Rms of support membrane and

Table 1. Effect of Polymerization Times on Binding Capacity polymerization times

Mmem (g)

CTHO (mmol/L)

Q (μmol/g)

once twice triple

0.0424 ± 0.0016 0.0400 ± 0.0008 0.0484 ± 0.0016

0.512 ± 0.006 0.484 ± 0.017 0.503 ± 0.009

57.7 ± 0.9 64.5 ± 0.3 51.3 ± 1.6

Figure 5. Membrane porosity of different polymerization conditions. (a) Theophylline/MAA mole ratio (theophylline:EDMA:AIBN = 1.0:20.0:0.4, CHCl3: 20.0 mL), and (b) theophylline/EDMA mole ratio (theophylline:MAA:AIBN = 1.0:4.0:0.4, CHCl3: 20.0 mL). 350



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Figure 6. 1H NMR spectra of MIP and NIP: (a) MIP and (b) NIP.

Figure 7. FTIR spectra of (a) the support membrane and MIM before and after washing and (b) THO, MIP, and MIM after washing.

Figure 8. SEM images of the substrate membrane (A, C) and MIM (B, D, E, F, G) A and B are the surfaces of the membranes, C and D are the cross sections of the membranes, and E,F, and G are the surfaces of increasing polymerization times.

However, the THO binding performance of MIM was higher than TB, which illustrated the specific selectivity of imprinted sites toward THO and also laid a theoretical foundation for further filtration experiments. 3.3. Permeability and Separation Properties of Membranes. To investigate the different separation properties and confirm the recognition properties of the imprinted sites, the support membranes and MIM were assembled in modules and followed a cross-flow filtration process. Figure 11 showed

MIM were 124.0 and 153.2 nm, respectively, also indicating the existence of a dense separation layer. Both the membrane chemical structures and morphological structures have effects on the properties of the membranes. The selectivity separation property mainly depends upon the molecular imprinted recognition sites. Figure 10 displayed the selective binding capacity of support membrane and MIM. We can find that the support membrane showed no specific binding property with a similar binding amount toward THO and TB. 351



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Figure 9. AFM images of surface morphologies of (a) support membrane and (b) MIM.

Figure 12. Change of THO concentration on the permeation side.

Figure 10. Binding capacity of support membrane and MIM.

Table 2. Different Binding Capacity and Separation Factor of Membranes membrane

QTHO (μmol/g)

αH

sup-mem MIM NIM

15.4 ± 1.2 64.5 ± 0.3 18.1 ± 2.0

1.08 2.63 1.02

Figure 11. Change of THO and TB concentrations on the permeation side.

the THO and TB concentrations on the permeation side of support membrane and MIM. The concentrations of THO for both membranes increased with time and reached steady at about 140 min. Besides, the steady concentrations of THO and TB filtrated by MIM were 0.143 mmol/L and 0.072 mmol/L, achieving a separation factor of 1.98, which was higher than the support membrane separation factor of 1.08. This separation phenomenon also verified the preferential filtration for the template molecule attributing to the imprinted recognition cavities and channels. Nevertheless, we can find that the selectivity factor decreased from 2.63 to 1.98 with the

Figure 13. Effect of elution time on the THO concentration.

increasing filtration time. It could be explained in two reasons. On one hand, the imprinted molecules combined on the recognition sites were not totally desorbed, leading to a decreasing binding capacity of next time. On the other hand, 352



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increasing use times as well as the longer filtration time. The stable separation factor of MIM decreased with the increasing regeneration times. It showed a similar selectivity separation factor with the support membrane after using three times and filtrating for 3 h. This maybe because the regeneration of MIM decreased the amount of imprinted recognition sites. Some THO molecules were adsorbed in the cavities and could not be washed out. However, although the MIM had been used three times, the selectivity factor did not decrease obviously if just filtrated for 1 h, which demonstrated that there’s no swelling phenomenon existing in the MIM and also could be used as a reference for further scale-up research.

Table 3. Effect of MIM Used Times on Separation Property (αH) filtration time (h) times used

1

2

3

1 2 3 support membrane

2.63 2.60 2.58 1.26

2.02 1.41 1.20 1.08

1.98 1.36 1.09 1.08

the pore size on the surface of MIM was not small enough, resulting in the existence of permeance. Figure 12 showed the different THO separation performances of both membranes. The THO production of 0.128 mmol/L using MIM was 1.52 times higher than the support membrane of 0.084 mmol/L. This was attributed to the molecular imprinted recognition mechanism resulting in the specific adsorption of THO molecule. Table 2 exhibited different binding capacity and separation factor of membranes, including NIM (nonimprinted molecular membranes) and MIM. We can find that the NIM showed no selectivity effects on the separation of THO and TB. Also, its THO binding capacity was similar to the support membrane, which were both less than the binding capacity of MIM. All these results demonstrated that MIM showed specific binding property and selectivity separation effects toward THO. 3.4. Regeneration of MIM. Based on the above research, we can find that theophylline molecular imprinted ceramic hollow fiber composite membranes were successfully prepared. MIM showed high selectivity properties to separate THO and TB. However, membrane regeneration was definitely thought to be an important issue when industrial applications are considered. In this part of the work, MIM were taken to investigate their regeneration properties by filtrating to separate THO and TB in the mixed feed solution. MIM were still assembled and filtrated with acetic acid/methanol (1/9, v/v) at 25 °C for 5 h to remove the THO molecules combined in the cavities, then they were washed with methanol to remove the residues for 2 h, and finally they were dried in ambient temperature for further use. The filtration washing time can be confirmed from Figure 13; the THO concentration in the eluent increased with the washing time until 3.5 h, suggesting the THO was removed from the membrane matrix. From the results listed in Table 3 and Figure 14, we can find that the selectivity separation factor decreased with the

4. CONCLUSIONS Theophylline molecular imprinted membranes were successfully prepared by the method of thermal-initiated free radical polymerization. SEM, AFM, and FTIR results confirmed that the THO imprinted layer was successfully coated upon the surface of the ceramic hollow fiber substrate by taking THO as a template molecule, MAA as functional monomer, and EDMA as cross-linker. The optimum polymerization condition for the preparation of MIM was confirmed as 0.05 mol/L THO, 0.2 mol/L MAA, 1.0 mol/L EDMA, and 0.02 mol/L AIBN (in 20.0 mL chloroform) reacting at 60 °C for 24 h in a vacuum oven. The membranes were polymerized twice, with coating 3 min each time. The MIM showed high separation selectivity and molecular recognition property by reaching a selectivity factor of 2.63 for the separation of THO and TB. After using them three times, there’s no swelling phenomenon existing in the MIM. The selectivity factor did not decrease obviously if just filtrated for 1 h, which verified the solvent resistance of MIM and also can be used as a reference for further scale-up researches.

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ASSOCIATED CONTENT

S Supporting Information *

The chemical, binding, and separation properties of the imprinted layer. This information is available free of charge via the Internet at http://pubs.acs.org/.

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AUTHOR INFORMATION

Corresponding Author

*Z.-L. Xu. E-mail: [email protected]. Tel.: 86-2164253061. Fax: 86-21-64252989.

Figure 14. Effect of regeneration times on permeation property: (a) regeneration once and (b) regeneration twice. 353



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Notes

(13) Wulff, G.; Sarhan, A. Use of polymers with enzyme-analogous structures for the resolution of racemates. Angew. Chem., Int. Ed. 1972, 11, 341. (14) Piscopo, L.; Prandi, C.; Coppa, M. Uniformly sized molecularly imprinted polymers (MIPs) for 17 beta-estradiol. Macromol. Chem. Phys. 2002, 203, 1532. (15) Mullett, W. M.; Lai, E. P. C. Determination of Theophylline in Serum by Molecularly Imprinted Solid-Phase Extraction with Pulsed Elution. Anal. Chem. 1998, 70, 3636. (16) Lai, E. P. C.; Zlotorzynska, E. D. Separation of theophylline, caffeine and related drugs by normal-phase capillary electrochromatography. Electrophoresis 1999, 20, 2366. (17) Wang, H. Y.; Kobayashi, T.; Fujii, N. Molecular imprint membranes prepared by the phase inversion precipitation technique. Langmuir 1996, 12, 4850. (18) Wang, H. Y.; Kobayashi, T.; Fukaya, T.; Fujii, N. Molecular imprint membranes prepared by the phase inversion precipitation technique. 2. Influence of coagulation temperature in the phase inversion process on the encoding in polymeric membranes. Langmuir 1997, 13, 5396. (19) García Del Blanco, S.; Donato, L.; Drioli, E. Development of molecularly imprinted membranes for selective recognition of primary amines in organic medium. Sep. Purif. Technol. 2012, 87, 40. (20) Wang, J. Y.; Liu, F.; Xu, Z. L.; Li, K. Theophylline molecular imprint composite membranes prepared from poly(vinylidene fluoride) (PVDF) substrate. Chem. Eng. Sci. 2010, 65, 3322. (21) Agoudjil, N.; Benmouhoub, N.; Larbot, A. Synthesis and characterization of inorganic membranes and applications. Desalination 2005, 184, 65. (22) Choi, H.; Stathatos, E.; Dionysiou, D. D. Sol-gel preparation of mesoporous photocatalytic TiO2 films and TiO2/Al2O3 composite membranes for environmental applications. Appl. Catal., B 2006, 63, 60. (23) Su, Y.; Hu, L.; Liu, M. S. The characterostics, manufacture and application of inorganic membrane. Chem. World 2001, 11, 604. (24) Tian, Y. L.; Liu, G. Z.; Yuan, D. D.; L, R. Q. Contrastive analysis on materials characteristics and processing performance of inorganic membrane and polymeric membrane. Ind. Water Treat. 2011, 31, 15. (25) Han, L. F.; Xu, Z. L.; Cao, Y.; Wei, Y. M.; Xu, H. T. Preparation, characterization and permeation property of Al2O3, Al2O3-SiO2 and Al2O3-Kaolin hollow fiber membranes. J. Membr. Sci. 2011, 372, 154. (26) Ulbricht, M. Membrane separation using molecularly imprinted polymers. J. Chromatogr. B: Anal. Technol. Biomed. Life Sci. 2004, 804, 113. (27) Chen, Y. Z.; Zhang, J. L.; Jia, M. Y.; Yu, J.; Guo, Z. X. Adsorption of Poly(methyl methacrtlate) on Nano-alumina and Bound Carbonyls. Gaodeng Xuexiao Huaxue Xuebao 2010, 31, 2093.

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The authors are thankful for the financial support from the National Natural Science Foundation of China (20076009, 21176067, and 21276075).

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ABBREVIATIONS THO = theophylline TB = theobromine MAA = methacrylic acid EDMA = ethylene glycol dimethacrylate AIBN = 2,2′-azobisisobutyronitrile CHCl3 = chloroform MIP = molecular imprinted polymer NIP = nonimprinted polymer MIM = molecular imprinted membranes NIM = nonimprinted molecular membranes Sup-mem = support membrane NMR = nuclear magnetic resonance SEM = scanning electron microscopy AFM = atomic force microscope FTIR = Fourier transform infrared spectroscopy HPLC = high-performance liquid chromatography MIT = molecular imprinted technology

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REFERENCES

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Theophylline Molecular Imprinted Composite Membranes Prepared

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