Preparation and Characterization of Solid Complexes of Naphtoquinone and Hydroxypropyl-b-Cyclodextrin

Abstract

The formation of an inclusion compound between a naphthoquinone derivative (I) and HP-ß-CD was studied in solid state by X-ray diffractometry, DSC, and IR.

Introduction

The formation of inclusion complexes with cyclodextrins constitutes a widely used strategy to in-crease the aqueous solubility and to decrease the countereffects of many drugs. Isoxazolylnaphthoqui-nones belong to a family of compounds with bacterial and tripanocidal activity [1,2], as well as with very low solubility in water. In previous studies in our laboratory, we demonstrated that their hydro-philic capacity increases markedly through complexation with hydroxypropyl-ß-cyclodextrin (HP-ß-CD) in aqueous solution [3].

In this study we investigate the formation of complexes between 2-hydroxy-N-(3,4-dimethyl-5-isoxazolyl)-1,4-naphthoquinone-4-imine (I) and HP-ß-CD in solid state. Thermoanalytic techniques, X-ray diffraction and IR spectroscopy were performed [4].

Experimental

1. Materials

The synthesis and identification procedures for I have been described previously. HP-β-CD (MW = 1326 - 1400; degree of molar substitution, 7.0) was a gift from CERESTAR USA Inc. (Hammond, IN). All other materials and solvents were of analytical reagent grade.

2. Methods

2.1 Preparation of inclusion complexes

Formation of solid complexes: aqueous solutions were prepared between I and HP-ß-CD in con-centrations of 1:0,5; 1:1 and 1:2, respectively. The solutions were then placed in a thermostat bath at 25°C for 72 hours and subsequently filtered by using nylon membranes 0.45 μm pores. The solid com-plexes were obtained after water removal. The freeze drying technique (LABCONCO, Freeze Dry System) was used to prepare inclusion complexes of I and cyclodextrin in solid state. Physical mix-tures were prepared in parallel by mixing the powders employing the same molar ratios of I and HP-ß-CD.

2.2 Characterization of inclusion complexes

2.2.1 Fourier Transformed Infra Red ( FTIR) Spectral Studies 

The spectra of I, physical mixtures and inclusion complexes were recorded in a KBr pellet using a NICOLET FT / IR 5-SXC Spectrophotometer.

2.2.2 Differential Scanning Calorimetry ( DSC) Studies 

The samples were subjected to DSC studies using a Shimadzu DSC-50 model. In , Sn, Pb and Zn were used as reference materials. The samples were scanned at the rate of 6°C / min.

2.2.3 Powder X-ray diffraction (XRD) Studies

The XRD patterns were recorded using a Philips X-ray generator (PW 1010), using Cu-K_α radia-tion.

Results and Discussion

Differential Scanning Calorimetry ( DSC) Studies

The appearance of two endothermal peaks corresponding to the melting of compound I and to the dehydration of HP-β-CD is clearly observed in the thermogram corresponding to the physical mixture. It can also be observed the disappearance of the melting point at 223,6°C corresponding to compound I in the thermogram of the inclusion complex 1:1.

Powder X-ray diffraction (XRD) Studies

The XR model corresponding to the physical mixture resulted from the simple overlapping of the diffractograms of compound I in its crystalline form and of the amorphous diffractogram of HP-β-CD. The diffractograms corresponding to the inclusion complexes were free of interference due to the amorphous state of the product obtained after the liophilic process.

Fourier Transformed Infra Red ( FTIR) Spectral Studies

No significant variations were observed in the absorption spectra corresponding to the physical mixtures which resulted from the overlapping of the simple spectra (compound I and HP-β-CD). On the other hand, a shift and attenuation in the absorption band corresponding to the carbonyl of com-pound I were observed when the complex is formed by liophilization.

Conclusions

The FTIR, DSC and XRD studies for the complexes showed significant evidence of complexation 1:1 when the complexes are prepared by the freeze drying technique. The results demonstrate the ca-pacity of HP-β-CD to interact with compound I.

When the complex was prepared by mixing the powders, it was evident in all cases that there was no true inclusion taking into account a simple physical mixture of both compound I and HP-β-CD.