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In situ Cross-linking of Polyanionic Polymers to sustain the Drug Release of Acetazolamide Tablets

Shirzad Azarmi^{a, b}, Hadi Valizadeh^{a, b}, Mohammad Barzegar-Jalali^a, and Raimar Löbenberg^b

Department of Pharmaceutics, Faculty of Pharmacy, Tabriz University of Medical Sciences^a, Tabriz (Iran), and Faculty of Pharmacy and Pharmaceutical Sciences, Pharmacy/Dentistry Centre^b, Edmonton (Canada)

The purpose of this study was to develop an extended release tablet using a new in situ cross-linking method. The effect of polyvalent cations on the drug release of acetazolamide (Acz) from tablets made with a fixed amount of either sodium carboxymethylcellulose (NaCMC) or sodium alginate was investigated. Different milliequivalents of the di and tri-valent cations, Ca²⁺and Al³⁺, were added to the tablet formulations. Dissolution tests showed that an incorporation of cations sustained the drug release. This is due to an in situ cross-linking between the polyanionic polymer in the tablet formulation and the added cations. The drug release prolongation depended on the nature of the polymer and the cation con-centration and their valences. Increasing the cation concentration in the formulation decreased the drug release. The drug release within 8 h from NaCMC tablet formulations ranged from 33 to 83 % for Ca²⁺and 44 to 64 % for Al³⁺. A formulation without cations had a drug release of 87 %. A zero order controlled drug release of about 70 to 80 % was observed from formulations containing 150 mg sodium alginate and 2 milliequivalent Ca²⁺or 0.744 milliequivalent Al³⁺. The same altitude of drug release was observed using 500 mg sodium alginate alone. The results show that the in situ cross-linking can be used for controlled drug release using sodium alginate. This method seems to be suitable to manufacture extended release dosage forms using direct compression and can decrease the amount of sodium alginate needed.

Key words Acetazolamide · Dissolution test · Drug release · Extended release · In situ cross-linking · Polyanionic polymers