Pendent chain linked delivery systems: II. Facile hydrolysis through molecular imprinting effects

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Abstract

In an earlier communication we reported the synthesis of hydrogels containing an imidazole group and the polymer conjugate which formed a charge transfer complex. The catalytic activity of imidazole enhanced the rate of release of p-nitrophenol. To further extend this approach to polymer conjugates which cannot form such complexes, we now show how the functional groups in such cases can be brought in proximity by metal-ion coordination and molecular imprinting techniques. The hydrolysis of the inactive esters from these hydrogels takes place under facile conditions and is pH responsive.

Introduction

Pendent chain linked polymers have been extensively investigated as drug delivery systems. The key step in this case is the hydrolysis of the polymer-active ingredient linkage. Shah et al. 1, 2studied the release of substituted benzoic acids chemically linked to 2-hydroxyethyl methacrylate in the alkaline medium. It was shown that the electron donating groups such as p-methoxy or p-amino groups suppressed the rate of hydrolysis considerably as compared to that for the unsubstituted acid. On the other hand, the incorporation of a strongly electron withdrawing group such as p-nitro group, resulted in a significant enhancement in the rate of hydrolysis. The release studies were carried out in highly alkaline medium (0.01 N NaOH, pH = 11) and therefore these systems did not have any practical applications. In order to bring about the release of the active ingredient at pH 7–8, the rate of hydrolysis of the polymer active ingredient linkage has to be considerably enhanced.

In the earlier communication, we reported the synthesis of hydrogels containing pendent chain linked active ingredient and a nucleophilic catalyst brought in vicinity by charge transfer complexation. The release of p-nitrophenol was considerably enhanced due to the hydrolysis of the ester linkage by the neighboring imidazole group [3]. These systems comprised activated esters and could only be designed for those polymer-active ingredient conjugates which formed such a charge transfer complex.

For situations wherein such charge transfer complexes are not formed, we have sought to bring the catalytic and substrate groups together by metal-ion coordination and molecular imprinting methods. Thus, the release rates of polymer conjugates which cannot otherwise be brought in proximity of the catalytic group can also be enhanced.

Section snippets

Materials

p-Amino benzoic acid, p-nitro benzoic acid, p-nitroaniline, p-nitrophenol, β-alanine, nicotinic acid, l-histidine, ethylene glycol, diethylene glycol, isobutyric acid and CoCl2·6H2O, were obtained from local suppliers. 2-Hydroxyethyl methacrylate (HEMA), N-vinyl imidazole (NVIm), methacrylic acid (MAA) and azobisisobutyronitrile (AIBN) were obtained from Aldrich Chemical Co.

Synthesis of esters of 2-hydroxy ethyl methacrylate, PAP and PNP

2-Methacryloyl ethyl p-amino benzoate (PAP) and 2-methacryloyl ethyl p-nitro benzoate (PNP) were synthesized and

Results and discussion

In order to achieve catalytic hydrolysis of the polymer-active ingredient conjugate which could be an ester or an amide, the conjugate has to be brought in proximity of the nucleophilic catalyst. In our earlier communication we showed that the two could be brought together by charge transfer interactions [3]. Due to the anchimeric effect of the catalyst the rate of hydrolysis of the conjugate was considerably enhanced. We also demonstrated that by manipulating the structure of the polymer,

Concluding remarks

This paper reports the synthesis of pendent chain linked delivery systems based on two types of aliphatic esters. The catalytic hydrolysis of PAP is brought about by the imidazole group located on the same chain. On the other hand, PNP occupies the cavity created by the print molecule. This leads to imidazole catalyzed hydrolysis, which could be further enhanced by the presence of the carboxyl group in its vicinity. The hydrolysis of an amide is also demonstrated. The results indicate that it

Acknowledgements

R.N. Karmalkar would like to acknowledge the financial support received from the University Grants Commission, New Delhi.

References (11)

  • S.S. Shah, M.G. Kulkarni and R.A. Mashelkar, A mechanistic interpretation of the zero order release from pendent chain...
  • S.S. Shah, M.G. Kulkarni and R.A. Mashelkar, Release kinetics of pendent substituted bioactive molecules from swellable...
  • R.N. Karmalkar, M.G. Kulkarni and R.A. Mashelkar, Pendent chain linked delivery systems: I. Facile hydrolysis through...
  • Y. Okuda, M. Yoshihara and T. Maeshima, Stereoselective differentiation in heterogeneous methanolysis of amino acid...
  • L. Pinchuk and E.C. Eckstein, Effects of low levels of methacrylic acid on the swelling behaviour of poly...
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