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Radiation effects on hydroxypropyl methylcellulose phthalate in aqueous system
Available online at www.sciencedirect.com
NIM B Beam Interactions with Materials & Atoms
Nuclear Instruments and Methods in Physics Research B 265 (2007) 394–398 www.elsevier.com/locate/nimb
Radiation effects on hydroxypropyl methylcellulose phthalate in aqueous system Ling Xu a, Zhiying Yue a, Min Wang a, Maolin Zhai a,*, Fumio Yoshii b, Noriaki Seko b, Jing Peng a, Genshuan Wei a, Jiuqiang Li a a
b
Beijing National Laboratory for Molecular Sciences (BNLMS), Department of Applied Chemistry, College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, PR China Environment and Industrial Materials Research Division, Quantum Beam Science Directorate, Japan Atomic Energy Agency, 1233 Watanuki, Takasaki 370-1292, Japan Available online 8 September 2007
Abstract A water-insoluble cellulose derivative, hydroxypropyl methylcellulose phthalate (HPMCP) hydrogels, was converted to Na type to form hydrogel in paste-like status by radiation crosslinking. Mechanism for radiation crosslinking of cellulose-derivatives in paste-like status was discussed. Crosslinkers, i.e. methyl N,N-bis-acrylamide (MBA) or ethyleneglycol dimethacrylate (EGDMA) has been used to decrease gelation dose (Dg) of synthesis HPMCP hydrogels and improve its mechanical properties. HPMCP-MBA hydrogels were found to be more rigid and HPMCP-EGDMA hydrogels were more flexible. Swelling degree of HPMCP hydrogel in many kinds of salt solutions followed Hofmeister series, which is ubiquitous in polyelectrolyte hydrogel. Specific reswelling was observed in concentrated KF solution, implying a very strong F binding ability of benzyl group. The comprehensive results obtained in this study will be utilized on the design of HPMCP-based controlled release system. 2007 Elsevier B.V. All rights reserved. PACS: 61.80.Ed; 61.82.Pv Keywords: Hydroxypropyl methylcellulose phthalate; Hydrogel; Radiation crosslinking; Gel strength; Ion-specific swelling; F binding
1. Introduction Natural polymers and their derivatives were regarded as radiation-degraded polymers for a long time. However, since the successful crosslinking of CMC in so call ‘‘paste-like status’’ [1], quite a few natural polymers, which including derivatives of cellulose, chitosan, starch etc. were found to be capable of crosslinking via irradiation [2–5]. Furthermore, novel properties were imparted into synthetic polymer hydrogels by incorporation of natural polymer derivatives [6–8]. Hydroxypropyl methylcellulose phthalate (HPMCP) is water-insoluble cellulose ether with phthalate substitution *
Corresponding author. Tel./fax: +86 10 62753794. E-mail address: [email protected] (M.L. Zhai).
0168-583X/$ - see front matter 2007 Elsevier B.V. All rights reserved. doi:10.1016/j.nimb.2007.09.012
and has been widely used in the pharmaceutical industry due to its resistance to hydrolysis [9]. It was reported that HPMCP can form hydrogel by radiation crosslinking in Na2CO3 solution, while HPMCP organo gel can be synthesized by radiation method after dissolution in organic solvent such as methanol, chloroform, acetone etc. The gels prepared from aqueous solution behaved as polyelectrolyte gels, while those gels prepared from organic solvents were hydrophobic [10,11]. Problems remained unsolved were the comparatively high gelation dose and the mechanism of radiation crosslinking. As HPMCP is a material widely used in pharmaceutical field, ion-specific effects might have profound influence on the drug-delivery behavior of HPMCP. Ion-specific phenomenon is ubiquitous in polymer aqueous systems and a classical Hofmeister series is used to sequence the
L. Xu et al. / Nucl. Instr. and Meth. in Phys. Res. B 265 (2007) 394–398
salting-in or salting-out ability of protein and many polymers in various salt solutions. A typical order for anions is SCN < I < ClO 4 < NO3 < Br < ClO3 < Cl < 2 + + BrO3 < F < SO4 and for cations is K < Na Li+ Ca2+ [12]. The swelling of many polymer gels in salt solutions followed similar sequence and is decided by the stability or destability of the ions to the hydrogen-bond hydration involved in the systems. Hydrogels swell if it follows stabilization mechanism and deswell if destabilization occurs [13,14]. In other words, the ion-specific swelling of hydrogel reflects the interactions involved in the aqueous systems of polymer and should have correlation with the embedment and control release behavior of drug-delivery system. In this study, radiation effects of HPMCP in aqueous solution were investigated to discuss the mechanism for gel formation; crosslinkers were used to reduce the Dg and improve the gel strength of HPMCP; and the ion-specific swelling of the hydrogel was investigated to evaluate the interactions between HPMCP and various ions in aqueous solution. The comprehensive results obtained in this study were expected to be valuable guidance on the design of HPMCP-based controlled release system. 2. Experimental 2.1. Materials HPMCP-55. with phthalyl content of 33% was ACROS organic reagent. MBA obtained from Beijing Chemical Co. Ltd and EGDMA obtained from Aldrich were used as crosslinkers. Other chemicals used were analytical reagent. 2.2. Preparation of HPMCP hydrogel HPMCP (20 wt%) was dissolved in 5% Na2CO3 and kept overnight. The solutions were filled into glass tubes and mixed by a centrifugal mixer with speed of 2000 r/ min for 10 min to make a homogeneous solution. Capillary with inner diameter of 0.9 mm was set into the solution to prepare capillary-type hydrogel for swelling experiment. Thus prepared samples were irradiated by c-ray at a dose rate of 50 Gy min1 using 60Co source of Peking University.
395
25 C and the effect of irradiation on HPMCP was characterized by the change of intrinsic viscosity of HPMCP solution before and after irradiation. 2.5. Gel fraction The sol part was extracted by immersing the hydrogel in 5% Na2CO3 for 2 days. The Na2CO3 adsorbed to the hydrogel was washed with deionized water thoroughly. The gel fraction was defined as the fraction of hydrogel which cannot be extracted by Na2CO3 solution. 2.6. Mechanical properties of HPMCP hydrogel Rod-type hydrogels with diameter of 1.1 cm after 80 kGy irradiation were cut to a length of 1 cm. The compression ratio of different samples was evaluated by determining the relative change in height of the hydrogel cylinders under 100 g/cm2 pressure and calculated as following: CR ¼ ðh=h0 Þ 100%;
ð1Þ
where h and h0 were referred as the height of the hydrogels after and before compression, respectively. The hydrogel samples were further pressed by higher pressure until gel collapse and the gel strength of the hydrogel was defined as the pressure applied at gel collapse point. The results of each sample were obtained from the average of three measurements. 2.7. Swelling degree Capillary-type hydrogel samples were prepared for ionspecific swelling investigation using the method described in our previous study [13]. The diameters of the hydrogels were measured by a microscope (20·) and the swelling degree was defined as Swelling degree ¼ d=d 0 ;
ð2Þ
where d and d0 represented diameters of the hydrogels after and before swelling in salt solutions, respectively. 3. Results and discussion 3.1. Conversion of HPMCP to Na type
2.3. SEMEDX Na profile of HPMCP hydrogel was measured using scanning electron microscopy with energy dispersive analysis of X-rays (SEMEDX) (JEOL JXA-superprobe 773). The hydrogels were dried in vacuum, cut and coated by Ag prior to the measurement. 2.4. Intrinsic viscosity Intrinsic viscosity of HPMCP solution was measured in a Ubbelhode viscometer in 0.1 M NaCl aqueous solution at
In our previous work, concentration of Na2CO3 was found to have significant influence on the synthesis of HPMCP hydrogel and HPMCP failed to form hydrogel in NaOH solution. Na2CO3 was essential for HPMCP dissolution but unfavorable for its radiation crosslinking [10]. To clarify the mechanism of these phenomena, we analyzed the distribution of Na and the Na/C weight ratio in the HPMCP hydrogel synthesized in the optimal condition by SEMEDX (spectra not show). EDX elemental mapping revealed that Na distribute homogeneously in hydrogel cross-section, further calculation based on the Na/C weight
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ratio proved that phthalate group of HPMCP was converted to Na type during dissolution procedure and the conversion was nearly complete (96.4%). The decrement of gel fraction with increasing Na2CO3 concentration suggests that excessive salt has negative impact on hydrogel formation. Furthermore, the nearly complete conversion in optimal synthesis condition suggests that HPMCP hydrogel can only form from Na salt of HPMCP which is soluble in water. The advantage to choose Na2CO3 solution as solvent was that no side product will be introduced into the system at the neutralized point. Although NaOH can dissolve HPMCP easier than Na2CO3, H2O will be produced during the dissolution and change the concentration of the solution. Furthermore, the presence of excessive NaOH will serve as strong free radical scavenger so that HPMCP failed to crosslink in NaOH solution. Another finding in our previous work is that HPMCP prepared from aqueous solution behaved as typical hydrophilic polyelectrolyte gels, while those prepared from organic solvent solutions showed strong hydrophobicity [10–11]. The hydrophobicity of HPMCP organo gels can be ascribed to the hydrophobic nature of HPMCP, while the hydrophilicity of HPMCP hydrogel can be ascribed to the ionization of phthalate group. 3.2. Radiation effects on HPMCP solution before gel formation Although many kinds of natural polymer derivatives were found to be capable of crosslinking in paste-like status, the mechanism for gel formation was far from clear. It was reported that CMC, CM-chitosan etc. was degraded by irradiation in solid status and diluted solution [1,15,16]. However, it is necessary to clear that before the formation of visible hydrogel, the paste-like solution undergoes radiation crosslinking or degradation mechanism. Fig. 1 shows the change of intrinsic viscosity of HPMCP solutions with two different concentrations by irradiation. It was found 1.8
3.3. Effects of crosslinker on the radiation crosslinking To decrease the Dg and improve the gel strength, the effects of two crosslinkers, MBA and EGDMA, on the synthesis of HPMCP hydrogels were investigated. The gel fractions of HPMCP hydrogel as a function of absorbed dose with the presence of MBA or EGDMA were illustrated in Fig. 2 and the data for those without crosslinker were also shown for comparison. Dg was calculated from Rosiak-Charlesby equation using Gelsol 95 software [10]. The mechanical properties and gel fractions of the hydrogels irradiated by 80 kGy were listed in Table 1. It was found that after the addition of crosslinker, the gel fractions in the level stage were slightly lower than that of the control. Especially, in the presence of 1% MBA, the gel fractions of the hydrogels after 100 kGy irradiation was 54% which was much lower than that of control (77%). Some white aggregations formed inside the hydrogel might lead to the lower gel fraction. However, Dg of HPMCP was decreased with addition of crosslinker, especially when compare with 0.5% MBA system and the control, Dg decreased from 50.9 kGy to 32.4 kGy. Furthermore, the gel fractions of the hydrogels prepared in low dose range (40–80 kGy) was significantly increased and the mechanical properties were significantly improved. The HPMCP hydrogel without crosslinker after 80 kGy irradiation was too soft to measure the compression ratio and gel strength. Compared with MBA and 100
HPMCP 10% HPMCP 20%
1.6
1.2 1.0
Controll MBA 0.5% MBA 1% EGDMA 0.5% EGDMA1%
80
Gel fraction [%]
1.4 [n]/[n]0
that no matter visible gel was formed or not, a clear tendency of crosslinking for 20% HPMCP. On the other hand, gel formation did not occur in 10% HPMCP and decreasing of viscosity started from a low absorbed dose. Viscosity of 20% HPMCP increased very rapidly after the absorbed dose reached its Dg. For 10% HPMCP, the decrement of viscosity was less significant in low and high dose range compared with those between 25 kGy and 40 kGy.
60
40
20
0.8 0
0.6
0
20
40
60
80
100
Absorbed dose [kGy] Fig. 1. Effect of HPMCP concentrations on the relative viscosities of HPMCP solutions after irradiation.
0
20
40
60 80 100 120 Absorbed dose [kGy]
140
160
Fig. 2. Effect of crosslinkers (MBA and EGDMA) on the gel fractions of HPMCP hydrogels.
L. Xu et al. / Nucl. Instr. and Meth. in Phys. Res. B 265 (2007) 394–398 Table 1 Effect of crosslinkers on the gelation dose, mechanical properties and gel fraction of the hydrogels
Control 0.5% MBA 1% MBA 0.5% EGDMA 1%EGDMA
*
Dg (kGy)
Compression ratio (%)
Gel strength (g/cm2)
Gel Fraction (%)
50.9 32.4 40.3 51.5 45.2
Immeasurable 49.6 45.6 57.3 57.6
Immeasurable 300 240 575 450
43.0 66.3 48.8 64.1 68.0
Hydrogel samples for compression ratio, gel strength and gel fraction measurement were prepared by 80 kGy irradiation.
EGDMA systems, it was found that both of the compression ratios and gel strength for MBA system were lower than that of EGDMA system, which means that HPMCP-MBA hydrogels were more rigid and HPMCPEGDMA hydrogels were more flexible. The significantly decreasing of Dg as well as improving gel strength implied that the presence of appropriate amount of MBA, accelerates the radiation crosslinking of HPMCP. Note that although the gel fractions of 1% MBA system were decreased, its rigidity was highest in the investigated series, which implied that the aggregation of HPMCP and MBA served as anti-compression enhancer in the hydrogel. Similar effect of particle filler on the improvement of anti-compression ability of hydrogel was observed in CMC/activate carbon hybrid hydrogel [17]. On the other hand, the addition of EGDMA only slightly decreased the Dg, but significantly improved the gel strength, i.e. flexibility of HPMCP hydrogel. The different impact of MBA and EGDMA on the mechanical properties of HPMCP hydrogel might be caused by their different molecular lengths. In other word, crosslinker with shorter molecular length (MBA) leads to higher gel rigidity; while crosslinker with longer molecular length leads to higher flexibility of the hydrogel. 3.4. Ion-specific swelling of HPMCP hydrogel The swelling degrees of HPMCP hydrogel prepared by irradiation to 80 kGy were measured in salt solution with different cation species (K+, Li+, Na+, Ca2+) and anion species (F, Cl, Br, SCN, NO 3 ), the counterion for cations was Cl and that for anions was K+. It was found that the swelling degrees in most of the ion species followed the sequence of Hofmeister series except that a specific reswelling was observed in concentrated KF solution. To condense the content of this paper, only data of anions’ were illustrated in Fig. 3. Generally polyelectrolyte hydrogels deswelled in aqueous solution of inorganic salts. Some exceptions occurred in solutions containing certain amount of salting-in ions that the gel reswelling was observed [18]. A typical Hofmeister series for anions is SCN < I < ClO 4 < NO3 < Br < ClO3 < Cl < BrO3 < F < 2 SO4 . The sequence of swelling degree in various ion species was generally in accordance with the Hofmeister series if specific interactions were not involved in the systems. The anions in the left side of Cl were called as saltingout ions or water-structure-makers; and the anions in the
1.2 1.0 0.8 d/d0
*
397
0.6 KBr KCl KSCN KNO3
0.4 0.2
KF 0.0 0
0.1
1
10
[anion] [mol/L]
Fig. 3. Effect of anion species on the swelling degrees of HPMCP hydrogel in salt solutions.
right side of Cl were called as salting in ions or waterstructure-breakers. The deswelling of the hydrogels can be interpreted by the dehydration of hydrogels due to the osmostic pressure inside and outside the hydrogel. The deswelling was more significant in ion species with stronger hydration ability, i.e. ions in the right side of Hofmeister series. A reswelling in concentrated KF was never reported but was observed in our recent studies on several aromatic hydrogels such as poly (sodium styrene sulfonate) hydrogel [18]. This phenomenon can be ascribed to the specific F binding ability of benzyl ring and the mechanism is under investigation. It is reasonable to foretell that the embedment and control release behavior of simple drugs in HPMCP hydrogels should have similar ion-specific effects and correlation with Hofmeister series. 4. Conclusions 1. HPMCP should be converted to Na type to synthesize the hydrogel by radiation crosslinking. 2. HPMCP in high concentration solution (paste-like) underwent mainly radiation crosslinking mechanism starting from even very low doses and vice versa for low concentration solution (low viscous). 3. Addition of crosslinkers such as MBA or EGDMA improved the mechanical properties of HPMCP hydro-
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gel and accelerated the radiation crosslinking especially in low dose range. HPMCP-MBA hydrogels were more rigid and HPMCP-EGDMA ones were more flexible. The different impact of MBA and EGDMA on the mechanical properties of HPMCP hydrogel might be caused by their different molecular lengths. 4. Ion-specific swelling of HPMCP hydrogel was in accordance with normal polyelectrolyte hydrogel except for F, which probably implying a specific F binding ability of benzyl ring. References [1] B. Fei, R.A. Wach, H. Mitomo, F. Yoshii, T. Kume, J. Appl. Polym. Sci. 78 (2000) 278. [2] R.A. Wach, H. Mitomo, F. Yoshii, T. Kume, Macromol. Mater. Eng. 287 (2002) 285. [3] N. Pekel, F. Yoshii, T. Kume, O. Guven, Carbohyd. Polym. 55 (2004) 139. [4] L. Zhao, H. Mitomo, N. Nagasawa, F. Yoshii, T. Kume, Carbohyd. Polym. 51 (2003) 169. [5] M.L. Zhai, F. Yoshii, T. Kume, Carbohyd. Polym. 52 (2003) 311.
[6] L. Zhao, H. Mitomo, M.L. Zhai, F. Yoshii, N. Nagasawa, T. Kume, Carbohyd. Polym. 53 (2003) 439. [7] M.L. Zhai, F. Yoshii, T. Kume, K. Hashim, Carbohyd. Polym. 50 (2002) 295. [8] L. Zhao, L. Xu, H. Mitomo, F. Yoshii, Carbohyd. Polym. 64 (2006) 473. [9] G. Weib, A. Knoch, A. Laicher, F. Stanislaus, R. Daniels, Int. J. Pharm. 124 (1995) 87. [10] L. Xu, N. Nagasawa, F. Yoshii, T. Kume, J. Appl. Polym. Sci. 89 (2003) 2123. [11] L. Xu, N. Nagasawa, F. Yoshii, T. Kume, J. Appl. Polym. Sci. 92 (2004) 3002. [12] F. Hofmeister, Arch. Exp. Pathol. Pharmakol. 24 (1888) 247. [13] L. Xu, E. Yokoyama, H. Watando, R. Okuda-Fukui, S. Kawauchi, M. Satoh, Langmuir 20 (2004) 7064. [14] H. Muta, M. Miwa, M. Satoh, Polymer 42 (2001) 6313. [15] L. Huang, M.L. Zhai, J. Peng, J.Q. Li, G.S. Wei, Carbohyd. Polym. 67 (2007) 305. [16] L. Huang, J. Peng, M.L. Zhai, J.Q. Li, G.S. Wei, Radiat. Phys. Chem. 76 (2007) 1679. [17] J.Y. Qiu, L. Xu, J. Peng, M.L. Zhai, L. Zhao, J.Q. Li, G.S. Wei, Carbohyd. Polym. 70 (2007) 236. [18] L. Xu, X. Li, M.L. Zhai, L. Huang, J. Peng, J.Q. Li, G.S. Wei, J. Phys. Chem. B 111 (2007) 3391.
NIM B Beam Interactions with Materials & Atoms
Nuclear Instruments and Methods in Physics Research B 265 (2007) 394–398 www.elsevier.com/locate/nimb
Radiation effects on hydroxypropyl methylcellulose phthalate in aqueous system Ling Xu a, Zhiying Yue a, Min Wang a, Maolin Zhai a,*, Fumio Yoshii b, Noriaki Seko b, Jing Peng a, Genshuan Wei a, Jiuqiang Li a a
b
Beijing National Laboratory for Molecular Sciences (BNLMS), Department of Applied Chemistry, College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, PR China Environment and Industrial Materials Research Division, Quantum Beam Science Directorate, Japan Atomic Energy Agency, 1233 Watanuki, Takasaki 370-1292, Japan Available online 8 September 2007
Abstract A water-insoluble cellulose derivative, hydroxypropyl methylcellulose phthalate (HPMCP) hydrogels, was converted to Na type to form hydrogel in paste-like status by radiation crosslinking. Mechanism for radiation crosslinking of cellulose-derivatives in paste-like status was discussed. Crosslinkers, i.e. methyl N,N-bis-acrylamide (MBA) or ethyleneglycol dimethacrylate (EGDMA) has been used to decrease gelation dose (Dg) of synthesis HPMCP hydrogels and improve its mechanical properties. HPMCP-MBA hydrogels were found to be more rigid and HPMCP-EGDMA hydrogels were more flexible. Swelling degree of HPMCP hydrogel in many kinds of salt solutions followed Hofmeister series, which is ubiquitous in polyelectrolyte hydrogel. Specific reswelling was observed in concentrated KF solution, implying a very strong F binding ability of benzyl group. The comprehensive results obtained in this study will be utilized on the design of HPMCP-based controlled release system. 2007 Elsevier B.V. All rights reserved. PACS: 61.80.Ed; 61.82.Pv Keywords: Hydroxypropyl methylcellulose phthalate; Hydrogel; Radiation crosslinking; Gel strength; Ion-specific swelling; F binding
1. Introduction Natural polymers and their derivatives were regarded as radiation-degraded polymers for a long time. However, since the successful crosslinking of CMC in so call ‘‘paste-like status’’ [1], quite a few natural polymers, which including derivatives of cellulose, chitosan, starch etc. were found to be capable of crosslinking via irradiation [2–5]. Furthermore, novel properties were imparted into synthetic polymer hydrogels by incorporation of natural polymer derivatives [6–8]. Hydroxypropyl methylcellulose phthalate (HPMCP) is water-insoluble cellulose ether with phthalate substitution *
Corresponding author. Tel./fax: +86 10 62753794. E-mail address: [email protected] (M.L. Zhai).
0168-583X/$ - see front matter 2007 Elsevier B.V. All rights reserved. doi:10.1016/j.nimb.2007.09.012
and has been widely used in the pharmaceutical industry due to its resistance to hydrolysis [9]. It was reported that HPMCP can form hydrogel by radiation crosslinking in Na2CO3 solution, while HPMCP organo gel can be synthesized by radiation method after dissolution in organic solvent such as methanol, chloroform, acetone etc. The gels prepared from aqueous solution behaved as polyelectrolyte gels, while those gels prepared from organic solvents were hydrophobic [10,11]. Problems remained unsolved were the comparatively high gelation dose and the mechanism of radiation crosslinking. As HPMCP is a material widely used in pharmaceutical field, ion-specific effects might have profound influence on the drug-delivery behavior of HPMCP. Ion-specific phenomenon is ubiquitous in polymer aqueous systems and a classical Hofmeister series is used to sequence the
L. Xu et al. / Nucl. Instr. and Meth. in Phys. Res. B 265 (2007) 394–398
salting-in or salting-out ability of protein and many polymers in various salt solutions. A typical order for anions is SCN < I < ClO 4 < NO3 < Br < ClO3 < Cl < 2 + + BrO3 < F < SO4 and for cations is K < Na Li+ Ca2+ [12]. The swelling of many polymer gels in salt solutions followed similar sequence and is decided by the stability or destability of the ions to the hydrogen-bond hydration involved in the systems. Hydrogels swell if it follows stabilization mechanism and deswell if destabilization occurs [13,14]. In other words, the ion-specific swelling of hydrogel reflects the interactions involved in the aqueous systems of polymer and should have correlation with the embedment and control release behavior of drug-delivery system. In this study, radiation effects of HPMCP in aqueous solution were investigated to discuss the mechanism for gel formation; crosslinkers were used to reduce the Dg and improve the gel strength of HPMCP; and the ion-specific swelling of the hydrogel was investigated to evaluate the interactions between HPMCP and various ions in aqueous solution. The comprehensive results obtained in this study were expected to be valuable guidance on the design of HPMCP-based controlled release system. 2. Experimental 2.1. Materials HPMCP-55. with phthalyl content of 33% was ACROS organic reagent. MBA obtained from Beijing Chemical Co. Ltd and EGDMA obtained from Aldrich were used as crosslinkers. Other chemicals used were analytical reagent. 2.2. Preparation of HPMCP hydrogel HPMCP (20 wt%) was dissolved in 5% Na2CO3 and kept overnight. The solutions were filled into glass tubes and mixed by a centrifugal mixer with speed of 2000 r/ min for 10 min to make a homogeneous solution. Capillary with inner diameter of 0.9 mm was set into the solution to prepare capillary-type hydrogel for swelling experiment. Thus prepared samples were irradiated by c-ray at a dose rate of 50 Gy min1 using 60Co source of Peking University.
395
25 C and the effect of irradiation on HPMCP was characterized by the change of intrinsic viscosity of HPMCP solution before and after irradiation. 2.5. Gel fraction The sol part was extracted by immersing the hydrogel in 5% Na2CO3 for 2 days. The Na2CO3 adsorbed to the hydrogel was washed with deionized water thoroughly. The gel fraction was defined as the fraction of hydrogel which cannot be extracted by Na2CO3 solution. 2.6. Mechanical properties of HPMCP hydrogel Rod-type hydrogels with diameter of 1.1 cm after 80 kGy irradiation were cut to a length of 1 cm. The compression ratio of different samples was evaluated by determining the relative change in height of the hydrogel cylinders under 100 g/cm2 pressure and calculated as following: CR ¼ ðh=h0 Þ 100%;
ð1Þ
where h and h0 were referred as the height of the hydrogels after and before compression, respectively. The hydrogel samples were further pressed by higher pressure until gel collapse and the gel strength of the hydrogel was defined as the pressure applied at gel collapse point. The results of each sample were obtained from the average of three measurements. 2.7. Swelling degree Capillary-type hydrogel samples were prepared for ionspecific swelling investigation using the method described in our previous study [13]. The diameters of the hydrogels were measured by a microscope (20·) and the swelling degree was defined as Swelling degree ¼ d=d 0 ;
ð2Þ
where d and d0 represented diameters of the hydrogels after and before swelling in salt solutions, respectively. 3. Results and discussion 3.1. Conversion of HPMCP to Na type
2.3. SEMEDX Na profile of HPMCP hydrogel was measured using scanning electron microscopy with energy dispersive analysis of X-rays (SEMEDX) (JEOL JXA-superprobe 773). The hydrogels were dried in vacuum, cut and coated by Ag prior to the measurement. 2.4. Intrinsic viscosity Intrinsic viscosity of HPMCP solution was measured in a Ubbelhode viscometer in 0.1 M NaCl aqueous solution at
In our previous work, concentration of Na2CO3 was found to have significant influence on the synthesis of HPMCP hydrogel and HPMCP failed to form hydrogel in NaOH solution. Na2CO3 was essential for HPMCP dissolution but unfavorable for its radiation crosslinking [10]. To clarify the mechanism of these phenomena, we analyzed the distribution of Na and the Na/C weight ratio in the HPMCP hydrogel synthesized in the optimal condition by SEMEDX (spectra not show). EDX elemental mapping revealed that Na distribute homogeneously in hydrogel cross-section, further calculation based on the Na/C weight
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ratio proved that phthalate group of HPMCP was converted to Na type during dissolution procedure and the conversion was nearly complete (96.4%). The decrement of gel fraction with increasing Na2CO3 concentration suggests that excessive salt has negative impact on hydrogel formation. Furthermore, the nearly complete conversion in optimal synthesis condition suggests that HPMCP hydrogel can only form from Na salt of HPMCP which is soluble in water. The advantage to choose Na2CO3 solution as solvent was that no side product will be introduced into the system at the neutralized point. Although NaOH can dissolve HPMCP easier than Na2CO3, H2O will be produced during the dissolution and change the concentration of the solution. Furthermore, the presence of excessive NaOH will serve as strong free radical scavenger so that HPMCP failed to crosslink in NaOH solution. Another finding in our previous work is that HPMCP prepared from aqueous solution behaved as typical hydrophilic polyelectrolyte gels, while those prepared from organic solvent solutions showed strong hydrophobicity [10–11]. The hydrophobicity of HPMCP organo gels can be ascribed to the hydrophobic nature of HPMCP, while the hydrophilicity of HPMCP hydrogel can be ascribed to the ionization of phthalate group. 3.2. Radiation effects on HPMCP solution before gel formation Although many kinds of natural polymer derivatives were found to be capable of crosslinking in paste-like status, the mechanism for gel formation was far from clear. It was reported that CMC, CM-chitosan etc. was degraded by irradiation in solid status and diluted solution [1,15,16]. However, it is necessary to clear that before the formation of visible hydrogel, the paste-like solution undergoes radiation crosslinking or degradation mechanism. Fig. 1 shows the change of intrinsic viscosity of HPMCP solutions with two different concentrations by irradiation. It was found 1.8
3.3. Effects of crosslinker on the radiation crosslinking To decrease the Dg and improve the gel strength, the effects of two crosslinkers, MBA and EGDMA, on the synthesis of HPMCP hydrogels were investigated. The gel fractions of HPMCP hydrogel as a function of absorbed dose with the presence of MBA or EGDMA were illustrated in Fig. 2 and the data for those without crosslinker were also shown for comparison. Dg was calculated from Rosiak-Charlesby equation using Gelsol 95 software [10]. The mechanical properties and gel fractions of the hydrogels irradiated by 80 kGy were listed in Table 1. It was found that after the addition of crosslinker, the gel fractions in the level stage were slightly lower than that of the control. Especially, in the presence of 1% MBA, the gel fractions of the hydrogels after 100 kGy irradiation was 54% which was much lower than that of control (77%). Some white aggregations formed inside the hydrogel might lead to the lower gel fraction. However, Dg of HPMCP was decreased with addition of crosslinker, especially when compare with 0.5% MBA system and the control, Dg decreased from 50.9 kGy to 32.4 kGy. Furthermore, the gel fractions of the hydrogels prepared in low dose range (40–80 kGy) was significantly increased and the mechanical properties were significantly improved. The HPMCP hydrogel without crosslinker after 80 kGy irradiation was too soft to measure the compression ratio and gel strength. Compared with MBA and 100
HPMCP 10% HPMCP 20%
1.6
1.2 1.0
Controll MBA 0.5% MBA 1% EGDMA 0.5% EGDMA1%
80
Gel fraction [%]
1.4 [n]/[n]0
that no matter visible gel was formed or not, a clear tendency of crosslinking for 20% HPMCP. On the other hand, gel formation did not occur in 10% HPMCP and decreasing of viscosity started from a low absorbed dose. Viscosity of 20% HPMCP increased very rapidly after the absorbed dose reached its Dg. For 10% HPMCP, the decrement of viscosity was less significant in low and high dose range compared with those between 25 kGy and 40 kGy.
60
40
20
0.8 0
0.6
0
20
40
60
80
100
Absorbed dose [kGy] Fig. 1. Effect of HPMCP concentrations on the relative viscosities of HPMCP solutions after irradiation.
0
20
40
60 80 100 120 Absorbed dose [kGy]
140
160
Fig. 2. Effect of crosslinkers (MBA and EGDMA) on the gel fractions of HPMCP hydrogels.
L. Xu et al. / Nucl. Instr. and Meth. in Phys. Res. B 265 (2007) 394–398 Table 1 Effect of crosslinkers on the gelation dose, mechanical properties and gel fraction of the hydrogels
Control 0.5% MBA 1% MBA 0.5% EGDMA 1%EGDMA
*
Dg (kGy)
Compression ratio (%)
Gel strength (g/cm2)
Gel Fraction (%)
50.9 32.4 40.3 51.5 45.2
Immeasurable 49.6 45.6 57.3 57.6
Immeasurable 300 240 575 450
43.0 66.3 48.8 64.1 68.0
Hydrogel samples for compression ratio, gel strength and gel fraction measurement were prepared by 80 kGy irradiation.
EGDMA systems, it was found that both of the compression ratios and gel strength for MBA system were lower than that of EGDMA system, which means that HPMCP-MBA hydrogels were more rigid and HPMCPEGDMA hydrogels were more flexible. The significantly decreasing of Dg as well as improving gel strength implied that the presence of appropriate amount of MBA, accelerates the radiation crosslinking of HPMCP. Note that although the gel fractions of 1% MBA system were decreased, its rigidity was highest in the investigated series, which implied that the aggregation of HPMCP and MBA served as anti-compression enhancer in the hydrogel. Similar effect of particle filler on the improvement of anti-compression ability of hydrogel was observed in CMC/activate carbon hybrid hydrogel [17]. On the other hand, the addition of EGDMA only slightly decreased the Dg, but significantly improved the gel strength, i.e. flexibility of HPMCP hydrogel. The different impact of MBA and EGDMA on the mechanical properties of HPMCP hydrogel might be caused by their different molecular lengths. In other word, crosslinker with shorter molecular length (MBA) leads to higher gel rigidity; while crosslinker with longer molecular length leads to higher flexibility of the hydrogel. 3.4. Ion-specific swelling of HPMCP hydrogel The swelling degrees of HPMCP hydrogel prepared by irradiation to 80 kGy were measured in salt solution with different cation species (K+, Li+, Na+, Ca2+) and anion species (F, Cl, Br, SCN, NO 3 ), the counterion for cations was Cl and that for anions was K+. It was found that the swelling degrees in most of the ion species followed the sequence of Hofmeister series except that a specific reswelling was observed in concentrated KF solution. To condense the content of this paper, only data of anions’ were illustrated in Fig. 3. Generally polyelectrolyte hydrogels deswelled in aqueous solution of inorganic salts. Some exceptions occurred in solutions containing certain amount of salting-in ions that the gel reswelling was observed [18]. A typical Hofmeister series for anions is SCN < I < ClO 4 < NO3 < Br < ClO3 < Cl < BrO3 < F < 2 SO4 . The sequence of swelling degree in various ion species was generally in accordance with the Hofmeister series if specific interactions were not involved in the systems. The anions in the left side of Cl were called as saltingout ions or water-structure-makers; and the anions in the
1.2 1.0 0.8 d/d0
*
397
0.6 KBr KCl KSCN KNO3
0.4 0.2
KF 0.0 0
0.1
1
10
[anion] [mol/L]
Fig. 3. Effect of anion species on the swelling degrees of HPMCP hydrogel in salt solutions.
right side of Cl were called as salting in ions or waterstructure-breakers. The deswelling of the hydrogels can be interpreted by the dehydration of hydrogels due to the osmostic pressure inside and outside the hydrogel. The deswelling was more significant in ion species with stronger hydration ability, i.e. ions in the right side of Hofmeister series. A reswelling in concentrated KF was never reported but was observed in our recent studies on several aromatic hydrogels such as poly (sodium styrene sulfonate) hydrogel [18]. This phenomenon can be ascribed to the specific F binding ability of benzyl ring and the mechanism is under investigation. It is reasonable to foretell that the embedment and control release behavior of simple drugs in HPMCP hydrogels should have similar ion-specific effects and correlation with Hofmeister series. 4. Conclusions 1. HPMCP should be converted to Na type to synthesize the hydrogel by radiation crosslinking. 2. HPMCP in high concentration solution (paste-like) underwent mainly radiation crosslinking mechanism starting from even very low doses and vice versa for low concentration solution (low viscous). 3. Addition of crosslinkers such as MBA or EGDMA improved the mechanical properties of HPMCP hydro-
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gel and accelerated the radiation crosslinking especially in low dose range. HPMCP-MBA hydrogels were more rigid and HPMCP-EGDMA ones were more flexible. The different impact of MBA and EGDMA on the mechanical properties of HPMCP hydrogel might be caused by their different molecular lengths. 4. Ion-specific swelling of HPMCP hydrogel was in accordance with normal polyelectrolyte hydrogel except for F, which probably implying a specific F binding ability of benzyl ring. References [1] B. Fei, R.A. Wach, H. Mitomo, F. Yoshii, T. Kume, J. Appl. Polym. Sci. 78 (2000) 278. [2] R.A. Wach, H. Mitomo, F. Yoshii, T. Kume, Macromol. Mater. Eng. 287 (2002) 285. [3] N. Pekel, F. Yoshii, T. Kume, O. Guven, Carbohyd. Polym. 55 (2004) 139. [4] L. Zhao, H. Mitomo, N. Nagasawa, F. Yoshii, T. Kume, Carbohyd. Polym. 51 (2003) 169. [5] M.L. Zhai, F. Yoshii, T. Kume, Carbohyd. Polym. 52 (2003) 311.
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