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A modified method for ibuprofen/β-cyclodextrin (IBU/β-CD) complex formation, based on ball milling (BM) under controlled conditions was developed and its efficiency with respect to the drug encapsulation yield was compared with the well-known kneading and solid dispersion synthetic approaches. Quantitative evaluation of the efficiency of drug-cyclodextrin interaction applying various methods and experimental conditions as well as characterization of the inclusion complexes were carried out by X-ray diffraction (XRD), differential scanning calorimetry (DSC), thermogravimetry (TG), scanning electron microscopy (SEM), infrared (IR) and nuclear-magnetic resonance (1HNMR) spectroscopy. It was found that the yield of the formed IBU/β-CD complex varies in a large range, depending on the techniques applied. The degree of complexation between IBU and β-CD using the proposed optimized BM method is very high and close to the complete inclusion complex formation achieved by a modified solid dispersion method. Furthermore, using DSC, TG and 1HNMR we proved that the ibuprofen molecules enter the β-CD hydrophobic cavities replacing completely the water molecules present naturally inside, which we determined to be 7.

The influence of the water structure promoters, mannitol and sucrose, on the indomethacin/β-cyclodextrin inclusion process at different pH values was evaluated using the phase solubility method and circular dichroism spectroscopy. The effect of mannitol and sucrose on the total solubilizing activity of β-cyclodextrin as well as on the stabilization of the complex was moderate, and depended strongly on the pH value of the medium. The most pronounced effect on the association constant of the indomethacin inclusion compound was observed in KCl/HCl buffer of pH 1.6, because mannitol and sucrose, in the absence of β-cyclodextrin, approximately double the indomethacin solubility so that the constant value decreases. On the other hand, a very strong complex formation between indomethacin and β-cyclodextrin was observed in acid medium (KCl/HCl buffer, pH = 1.6), a fact not much discussed in the literature. The apparent association constant of the inclusion compound formed in the absence of mannitol or sucrose was found to be of the same order of magnitude as for the complex formed at pH 6.8. Changes in the optical activity of the indomethacin/β-cyclodextrin inclusion complex were registered in the presence of sucrose, which interacts more strongly than mannitol with water molecules, and could probably adhere to the surface of the inclusion complex, thus changing its configuration and environment.

The phase state and solubility of indomethacin in adsorbates onto hydroxyethylcellulose have been studied. The characterization of the adsorbates and their relevant physical mixtures was made by the use of DSC, X-ray diffractometry, FT-IR spectrometry, and solubility analysis. The drug-to-polymer ratio determines either a partial crystallization of the metastable alpha-form onto hydroxyethylcellulose surface or complete inhibition of indomethacin crystallization. Significantly improved drug aqueous solubility was achieved. A stable immobilization of indomethacin molecules onto hydroxyethylcellulose due to drug/polymer interactions can be assumed. The changed indomethacin phase state in the adsorbates remains stable for one-year storage at ambient conditions. These results could be of practical importance.