Improvement in solubility and dissolution rate of 1,2‐dithiole‐3‐thiones upon complexation with β‐cyclodextrin and its hydroxypropyl and sulfobutyl ether‐7 derivatives

Inclusion complexes between β‐cyclodextrin derivatives and 1,2‐dithione‐3‐thiones were studied in aqueous solution and in the solid state. Phase solubility study was used to evaluate the complexation in solution, at 37 °C, of three cyclodextrins, i.e., β‐cyclodextrin (βCD), hydroxypropyl‐β‐cyclodext...

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Published in:Journal of pharmaceutical sciences 1999-09, Vol.88 (9), p.889-895
Main Authors: Dollo, Gilles, Corre, Pascal Le, Chollet, Marylene, Chevanne, François, Bertault, Marcel, Burgot, Jean‐Louis, Verge, Roger Le
Format: Article
Language:English
Subjects:
2-Hydroxypropyl-beta-cyclodextrin
beta-Cyclodextrins
Biological and medical sciences
Calorimetry, Differential Scanning
Chromatography, High Pressure Liquid
Cyclodextrins - chemistry
General pharmacology
Hydrogen-Ion Concentration
Kinetics
Medical sciences
Microscopy, Electron, Scanning
Particle Size
Pharmaceutical technology. Pharmaceutical industry
Pharmacology. Drug treatments
Physicochemical properties. Structure-activity relationships
Solubility
Spectrophotometry, Ultraviolet
Thiones - chemistry
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Summary:Inclusion complexes between β‐cyclodextrin derivatives and 1,2‐dithione‐3‐thiones were studied in aqueous solution and in the solid state. Phase solubility study was used to evaluate the complexation in solution, at 37 °C, of three cyclodextrins, i.e., β‐cyclodextrin (βCD), hydroxypropyl‐β‐cyclodextrin (HPβCD), sulfobutyl ether‐7‐β‐cyclodextrin (SBE7βCD), and four 1,2‐dithiole‐3‐thiones, i.e., the parent compound dithiolethione (DTT), dimethyldithiolethione (DMDTT), 5‐phenyldithiolethione (5PDTT), and anetholetrithione (ATT). Stability constants of the DTT complexes with HPβCD and SBE7βCD were also determined spectrophotometrically using a nonlinear least‐squares methodology. Differential scanning calorimetry (DSC) and scanning electronic microscopy (SEM) were used to characterize spray‐dried complexes formed between 5PDTT and SBE7βCD, ATT and SBE7βCD. Dissolution studies using the USP paddle method were carried out in water at 37 °C for both ATT and 5PDTT binary systems with HPβCD and SBE7βCD. Solubility enhancements were much greater with the more lipophilic ATT and 5PDTT compared to DTT and DMDTT, whatever the cyclodextrin used, in the rank order SBE7βCD > HPβCD ≫ βCD. Stability constants obtained (between 120 and 12800 mol−1) were also the highest for the more lipophilic drugs and in the same rank order SBE7βCD > HPβCD ≫ βCD. Results obtained by UV spectrophotometry were in good agreement with those obtained by phase‐solubility study. DSC thermograms of spray‐dried complexes of ATT and 5PDTT with HPβCD and SBE7βCD lacked the endothermal peak of pure drug peak which was found for the physical mixtures (107 °C and 125 °C for ATT and 5PDTT, respectively). Finally, dissolution profiles of spray‐dried inclusion complexes studied displayed a faster dissolution rate compared to physical mixtures and pure drugs. The present study showed that complexation of 1,2‐dithiole‐3‐thiones with β‐cyclodextrin derivatives resulted in an increase in solubility, allowing intravenous formulation for bioavailability and metabolism studies and an increase in the dissolution rate of the drugs, which shoud be of interest for oral absorption of these lipophilic compounds.
ISSN:0022-3549
1520-6017
DOI:10.1021/js990067o