Studies on trimethoprim:hydroxypropyl-β-cyclodextrin: aggregate and complex formation
Graphical abstract
Introduction
Trimethoprim (Fig. 1) is a synthetic, broad-spectrum antimicrobial agent which acts as an inhibitor of bacterial dihydrofolate reductase. This drug is mainly used in combination with sulfonamides for prophylaxis and treatment of urinary tract and certain types of pneumonia. Trimethoprim is characterized by a very low aqueous solubility1, 2 fact that complicates the preparation of formulations such as those for the intravenous administration.
A strategy widely used to increase the solubility, stability, and bioavailability of drugs is the complex formation with cyclodextrins (CDs).3, 4, 5 CDs are macrocyclic oligosaccharides with six, seven or eight d-glucose units called α-cyclodextrin, β-cyclodextrin, and γ-cyclodextrin, respectively. Hydroxypropyl-β-cyclodextrin (HP-β-CD) (Fig. 2) is a hydroxyalkylated β-CD derivative that combines relatively high water solubility with low toxicity and satisfactory inclusion ability.6, 7 The cavities of CDs are relatively hydrophobic, while the external faces are hydrophilic. The most important structural feature of CDs is its capacity to form stable inclusion complexes with properly sized drug molecules,8, 9 prevailing this fact in dilute aqueous solutions.10 Moreover, it is known that CD molecules have the tendency to self-assemble to form aggregates which can also participate in the solubilization of poorly soluble drugs. It was observed that the aggregate formation depends on the concentration. Furthermore, the formation of inclusion complexes with lipophilic guests can convert a CD molecule from a simple oligosaccharide into a molecule capable of forming micellar-type aggregates. In addition, poorly soluble guests can participate in the formation of guest-CD co-aggregates where the molecules are kept together through non-inclusion complexes.10, 11
Studies involving the complexation of trimethoprim with natural CDs (α-, β- and γ-) and methylated β-CD have been reported in the literature,12, 13, 14 as well as the formation of a 1:1 complex in presence of HP-β-CD at various pH values, which could improve the aqueous solubility of the drug in trimethoprim/sulfamethoxazole parenteral solutions but could not prevent its precipitation.15 In addition, the chemical stability under oxidation stress of trimethoprim in co-trimoxazole (a 5:1 combination of sulfamethoxazole with trimethoprim) aqueous buffer solutions has been increased using HP-β-CD as a molecular inclusion excipient.16 Moreover, we have previously developed a method for the simultaneous quantification of trimethoprim and sulfamethoxazole in mixtures using HP-β-CD solutions.17 Nevertheless, none of the above mentioned works have characterized the inclusion complex of trimethoprim with HP-β-CD and investigated the possibility of aggregate formation, although there were observed results that may be indicative of non-linear complexation.16
Considering these previous investigations, the present study aimed to investigate the interactions between trimethoprim and HP-β-CD. The characterization has been performed using solubility analysis, nuclear magnetic resonance (1H NMR), infrared spectroscopy (FT-IR), scanning electron microscopy (SEM), differential scanning calorimetry (DSC), and thermogravimetric analysis (TGA). Also, the formation of aggregates was investigated by conductivity measurements.
Section snippets
Chemicals and reagents
All the experiments were performed with analytical grade chemicals and solvents. HP-β-CD, degree of substitution 0.63, was kindly supplied by Ferromet agent of Roquette (France). NMR spectra were taken in deuterium oxide (D2O, deuterium content 99.9%) from Aldrich® USA. A Millipore Milli Q Water Purification System generated the water used in these studies.
Phase solubility studies
The solubility measurements were performed according to the method of Higuchi and Connors.18 An excess of trimethoprim was suspended in
Phase solubility analysis
The effect of HP-β-CD on the solubility of trimethoprim was investigated. The solubility of trimethoprim in water was determined to be 0.4 mg/ml. The solubility profile (Fig. 3) showed an increase in its solubility when the concentration of HP-β-CD increases. The solubility of trimethoprim was of 1.1 mg/ml, 2.1 mg/ml, and 3.2 mg/ml in the presence of 28.6, 71.4, and 142.9 mM HP-β-CD solution, respectively. Therefore, HP-β-CD increased the solubility of trimethoprim by approximately three, five, and
Conclusion
In conclusion, the results reported here revealed that the solubility of trimethoprim was enhanced in presence of HP-β-CD. At low HP-β-CD concentrations, the formation of an inclusion complex produced an increase in the solubility; whereas at concentrations higher than the critical concentration, aggregates capable of solubilizing trimethoprim through the formation of non-inclusion complexes were formed.
Acknowledgments
The financial support from Fondo para la Investigación Científica y Tecnológica (FONCYT) Préstamo BID 1728/OC-AR PICT 1376, the Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET) and the Secretaría de Ciencia y Técnica de la Universidad Nacional de Córdoba (SECyT-UNC), are greatly acknowledged. We also thank the Ferromet S.A. (agent of Roquette in Argentina) for their donation of hydroxypropyl-β-cyclodextrin.
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