PHASE SOLUBILITY STUDIES OF THE INCLUSION COMPLEXES OF REPAGLINIDE WITH β-CYCLODEXTRIN AND β-CYCLODEXTRIN DERIVATIVES

Abstract

The present study is intended to evaluate the possibilities to improve repaglinide - an oral antidiabetic drug - solubility in water, based on inclusion complexes formation with β-cyclodextrin (β-CD), hydroxypropyl β-cyclodextrin (HP-β-CD) and randomly methylated β-cyclodextrin (RAMEB), respectively, and also to estimate their composition and apparent stability constants, K st , from the phase-solubility diagrams. We have noticed that the phase solubility diagram for the repaglinide ‐ HP-β-CD inclusion complex is A type, while those of repaglinide - β-CD and RAMEB are B type. Taking into account the lipophilicity of the zwitterionic structure of repaglinide, all determinations were performed in buffered phosphate solutions (pH 6). The phase-solubility diagrams indicate an enhancement of the repaglinide solubility in the presence of β-CD, as well as its derivatives, HP-β-CD and RAMEB in different extents, related to the type of cyclodextrin. Rezumat Studiul prezentat are ca scop evaluarea posibilitaţilor de crestere a solubilitaţii in apa a repaglinidei (antidiabetic oral) prin intermediul formarii unor complecsi de incluziune cu β-ciclodextrina (β-CD), hidroxipropil β-ciclodextrina (HP-β-CD) si β-ciclodextrina metilata aleator (RAMEB) si, de asemenea, determinarea, din diagramele de fazasolubilitate, a rapoartelor de combinare si a constantelor aparente de stabilitate, K st . Diagrama de faza-solubilitate in cazul complexului de incluziune repaglinida ‐ HP-β-CD este de tip A, in timp in cazul complecsilor repaglinidei cu β-CD si RAMEB, diagramele de faza-solubilitate sunt de tipul B. Ţinând cont de lipofilia structurii amfionice a repaglinidei, toate determinarile au fost realizate in soluţii tampon fosfat (pH=6). Diagramele de faza ‐ solubilitate indica o crestere a solubilitaţii repaglinidei in prezenţa βciclodextrinei, precum si a derivaţilor acesteia, HP-β-CD si RAMEB, in proporţii care variaza in funcţie de tipul ciclodextrinei.