Influence of the preparation method on the physical–chemical properties of ketoprofen–cyclodextrin–phosphatidylcholine ternary systems

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Abstract

The aim of this work was to assess the effectiveness and actual advantages of the microwave (MW) technology for preparing ternary complexes of ketoprofen (Keto) with β-cyclodextrin (β-Cd) or methylated-β-cyclodextrin (Meβ-Cd) and phosphatidylcholine (EPC3) with respect to conventional preparation methods, such as co-grinding and sealed-heating. The products obtained with the different techniques were characterized by differential scanning calorimetry (DSC), X-ray powder diffractometry, FT-IR spectroscopy and dissolution studies. For each method, the influence of different experimental conditions on the physical–chemical properties of the final products has been also investigated. DSC analysis was used to monitor physical stability of ternary complexes during 2 years storage under ambient conditions. MW irradiation resulted to be a rapid and very convenient preparation technique. In fact, it was more effective than the considered conventional methods, enabling obtainment in shorter times of products with better performance. In particular, the Keto–Meβ-Cd–EPC3 product prepared by MW treatment at 750 W for 10 min allowed achievement of about 80% of drug dissolution after 60 min, in comparison with the 50% and 63% values obtained for the corresponding products prepared by 30-min co-grinding or 60-min sealed-heating. Moreover, such ternary products were more effective in improving drug dissolution than the corresponding Keto–Meβ-Cd systems. Furthermore, the MW treatment at such irradiation energy enabled obtainment of totally dehydrated samples, which maintained unchanged solid-state characteristics and showed no susceptibility to ambient humidity after 2 years storage at ambient temperature. Therefore, MW-treated Keto–Meβ-Cd–EPC3 systems can be successfully used for formulation of tablets with enhanced drug dissolution behaviour.

Introduction

Ketoprofen is a potent non-steroidal anti-inflammatory drug belonging to Class II of Biopharmaceutics Classification System (BCS), whose poor water-solubility can cause formulation problems and limit its therapeutic applications and bioavailability. Cyclodextrin complexation has been successfully employed in improving the solubility and dissolution properties of ketoprofen [1] and a clear influence of the complex preparation methods on the drug dissolution behaviour has been demonstrated [2]. Moreover, previous studies pointed out that the presence of suitable auxiliary substances such as phospholipids had a synergistic effect in improving the cyclodextrin solubilizing power towards ketoprofen [3]. On the other hand, it has been demonstrated that the improved drug dissolution rate obtained by cyclodextrin complexation gives rise to a corresponding enhancement of its bioavailability [4].

Microwave (MW) technology has recently received an increasing interest in the pharmaceutical field even though its applications are still rather limited [5], [6]. It has been shown that the polarizing aspect of MW heating gives rise to enhanced mass transport, and it can be exploited as an effective tool for generating drug solid dispersions at molecular or nano-scale level in a suitable stabilizing medium [7]. In particular, MW irradiation has been recently experimented as a new method for preparing interaction products of drugs with different kinds of cyclodextrins [8], [9], [10], [11], [12], [13]. We recently used a new MW-based method for the preparation of ternary interaction products of ketoprofen with cyclodextrins and phospholipids which showed improved dissolution performance with respect to the corresponding binary drug–cyclodextrin or drug–phospholipid systems [3].

Therefore, in the present work, it seemed of interest to continue our studies and to investigate more in depth the actual effectiveness and advantages of such a new technology. With this aim we prepared selected ketoprofen:cyclodextrin:phosphatidylcholine ternary complexes by MW irradiation [3] and we characterized and compared their physical–chemical properties with those of the corresponding products obtained by conventional preparation methods, such as co-grinding and sealed-heating. For each considered technique, the influence of different experimental conditions was also evaluated, in order to individuate the most suitable ones for improving drug–carrier interactions and enhancing ketoprofen dissolution performances. The solid-state characterization of the ternary systems obtained by the different preparation methods was mainly performed by DSC analysis, supported by X-ray powder diffractometry and FT-IR spectroscopy, whereas their dissolution behaviour was assessed according to the dispersed amount method [1]. DSC analysis was also used to monitor the effect of ageing on the physical stability of selected ternary complexes. In fact, since the amorphous forms are in general thermodynamically unstable and more reactive than their crystalline forms, it is important to evaluate their stability and the influence of ageing conditions on drug recrystallization [14]. Moreover, the adsorption of environmental humidity may substantially affect the physicochemical, mechanical, and biological properties of the drug [15].

Section snippets

Materials

Ketoprofen (Keto) was a gift from Menarini (Firenze, Italy). Egg phosphatidylcholine (EPC3) was kindly supplied from Lipoid GmbH (Germany), β-cyclodextrin (β-Cd) from Roquette (France) and methyl-β-cyclodextrin (Meβ-Cd) with an average substitution degree per anhydroglucose unit DS 1.8 from Wacker-Chemie GmbH, Germany. All other chemicals and solvents used in this study were of analytical reagent grade.

Preparation of ternary solid systems

Four different methods were employed to prepare ternary systems of Keto with each

Results and discussion

The DSC curves of individual components and the respective drug–carriers ternary systems prepared by MW irradiation, co-grinding and sealed-heating techniques at different treatment times are shown in Fig. 1. The thermal curve of Keto was characterized by a flat profile followed by a sharp endothermic peak at 96.5 °C (ΔHfus = 102.2 J/g) indicative of its crystalline anhydrous state. β-Cd showed an intense, broad endothermal band, in the 80–140 °C range, associated with water loss (14.5% as mass

Conclusions

It has been shown that the physical–chemical properties of Keto–Cd–EPC3 ternary systems are clearly influenced by both the type of preparation technique and experimental conditions, as well by the type of Cd (β-Cd or Meβ-Cd) present in the product. In particular, the amorphous Cd-derivative exhibited a better performance than the corresponding native one from the point of view of both amorphizing and solubilizing efficacy towards the drug. On the other hand, among the preparation methods

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