7 A modified method for ibuprofen / β-cyclodextrin (IBU/β-CD) complex formation, 8 based on ball milling (BM) under controlled conditions was developed and its efficiency 9 with respect to the drug encapsulation yield was compared with the well-known kneading 10 and solid dispersion synthetic approaches. Quantitative evaluation of the efficiency of 11 drug-cyclodextrin interaction applying various methods and experimental conditions as 12 well as characterization of the inclusion complexes were carried out by x-ray diffraction 13 (XRD), differential scanning calorimetry (DSC), thermogravimetry (TG), scanning 14 electron microscopy (SEM), infrared (IR) and nuclear-magnetic resonance ( 1 HNMR) 15 spectroscopy. It was found that the yield of the formed IBU / β-CD complex varies in a 16 large range, depending on the techniques applied. The degree of complexation between 17 IBU and β-CD using the proposed optimized BM method is very high and close to the 18 complete inclusion complex formation achieved by a modified solid dispersion method. 19Furthermore, using DSC, TG and 1 HNMR we proved that the ibuprofen molecules enter 20 the β-CD hydrophobic cavities replacing completely the water molecules present naturally 21 inside, which we determined to be 7. 22 23 24

Cyclodextrins (CDs) are native host systems with inherent ability to form inclusion complexes with various molecular entities, mostly hydrophobic substances. Host cyclodextrins are accommodative to water molecules as well and contain water in the native state. For β-cyclodextrin (β-CD), there is no consensus regarding the number of bound water molecules and the location of their coordination. A number of intriguing questions remain: (1) Which localities of the host’s macrocycle are the strongest attractors for the guest water molecules? (2) What are the stabilizing factors for the water clusters in the interior of β-CD and what type of interactions between water molecules and cavity walls or between the water molecules themselves are dominating the energetics of the β-CD hydration? (3) What is the maximum number of water molecules inside the cavity of β-CD? (4) How do the thermodynamic characteristics of β-CD hydration compare with those of its smaller α-cyclodextrin (α-CD) counterpart? In this study, we address these questions by employing a combination of experimental (DSC/TG) and theoretical (DFT) approaches.

Cyclodextrins (CDs) are among the most widely used native host systems with ability to form inclusion complexes with various molecular objects. This ability is so strong that the "hydrophobic" CD cavity never remains empty, even in the guest-free state it is filled with water molecules. However, no consensus has been reached concerning both the total number of hydrating water molecules and their preferred binding location in the CDs. Several outstanding questions regarding the CD hydration still wait to be answered: (1) Which spots of the CD cavity ("hot spots") have the highest affinity for the guest water molecules? (2) How stable are water clusters inside the cavity? (3) Which mode of water binding, sequential or bulk, is thermodynamically more favored? (4) What is the upper limit of the number of water molecules bound inside the host cavity? (5) What factors do control the CD hydration process? Here, using αCD as a typical representative of the cyclodextrin family, we endeavor to answer these questions by combining experimental measurements (differential scanning calorimetry and thermogravimetry) with theoretical (DFT) calculations. Enthalpies of the αCD hydrate formation are evaluated and the role of different factors, such as the number and mode of binding (sequential vs bulk) of water molecules, type of hydrogen bonds established (water-water vs water-αCD), and the dielectric properties of the medium, on the complexation process is assessed. The results obtained shed light on the intimate mechanism of water binding to αCD and disclose the key factors governing the process.

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"Cyclodextrin-gas" clathrates were obtained by crystallization from water solution of α-, β-, and γ-cyclodextrins (CDs) under pressure of the gas to be entrapped into the CD molecules. When the pressure is released, these clathrates are stable at ambient conditions and dissociate at elevated temperature, which makes them interesting for various applications as foam boosters in food and other industries. It was found that under these conditions α-CD forms clathrates with all of the gases used in this study (N2, N2O, CO2, Ar), whereas β- and γ-CDs can form clathrates only with N2. The concentration of the cyclodextrin and the temperature and pressure of the gas were varied for achieving higher clathrate yield and larger amount of embedded gas. Highest values of about 2 wt % were found for α-CD-N2O, as it releases in the temperature range of 40-60 °C.