Sealed-heating of salicylic acid (SA) and polyethylene glycol (PEG)/γ-cyclodextrin (CD)-polypseudorotaxane induced a novel complex formation wherein SA was inhabited in the intermolecular spaces formed by the γ-CD/polypseudorotaxane columns. Incorporation of SA into the PEG/γ-CD-polypseudorotaxane structure was clarified by powder X-ray diffraction measurements and 13 C-solid-state NMR spectroscopy. Different water vapor adsorption and desorption behaviors between the novel complex and PEG/ γ-CD-polypseudorotaxane confirmed the incorporation of SA molecules into the intermolecular spaces in the complex.Cyclodextrins (CDs), which are host molecules, are known to include various kinds of guest molecules in their cavities. 1 Inclusion complex formations with active pharmaceutical ingredients (APIs) have been widely studied because inclusion complex formations improve physicochemical properties such as solubility, dissolution rate, bioavailability, and stability of APIs. Guest molecules were reported to be able to exist both in the cavities of CDs and in the intermolecular spaces formed by CDs. 2 Indeed, Harata et al. described that in the evaporated sample of p-nitrophenol/dimethyl-β-CD, p-nitrophenol existed in the interstitial sites of the molecular arrangement of dimethyl-β-CD molecules. 2 In the case of m-nitrophenol or m-bromophenol, the guest molecules were located not only in the cavity of R-CD but also in the intermolecular spaces of R-CD columns. 2 However, there have been few publications that have discussed the existence of guest molecules outside the CD cavities.Recently, a large number of studies on the inclusion complexes of CDs with polymers, named CD-polypseudorotaxanes, have been published. 3,4 CD-polypseudorotaxanes have received a great deal of interest because of their unique structural, electrical, and mechanical properties. Their applications in the pharmaceutical field, however, have been extremely limited because the CD cavities are filled with polymers and no more space in the cavity remains for the inclusion of drugs.Herein we report a novel complex prepared by utilizing the sealed-heating technique, in which both the guest and host molecules are only heated in an enclosed space. 5 In this novel complex, it was found that salicylic acid (SA) molecules were inhabited in the intermolecular spaces formed by polyethylene glycol 2000 (PEG)/γ-CD-polypseudorotaxane columns. A novel inclusion complex was prepared in two steps. In step 1, conventional PEG/γ-CD-polypseudorotaxane was prepared by the coprecipitation method. 3 PEG and γ-CD were suspended in distilled water. The suspension was stirred at 25°C for 2 days and then stored for 1 day at 25°C. The precipitate was filtrated and dried for 1 day at 25°C to obtain PEG/γ-CD-polypseudorotaxane. In step 2, SA and the polypseudorotaxane were sealedheated in order to incorporate SA molecules into the intermolecular spaces of the γ-CD molecules.

Eleven guest drugs with planar structures were incorporated into the intermolecular spaces between polyethylene glycol/γ-cyclodextrin (γ-CD)-polypseudorotaxanes by a sealed-heating method. Drug incorporation changed the crystal packing of γ-CD from hexagonal- to monoclinic-columnar forms, without dependence on the guest species. The incorporation of guest drugs was size dependent and stoichiometric. Guest drugs with one benzene ring and maximum cross sectional areas of ca. 40–55 Å2 exhibited a drug to γ-CD stoichiometry of 2:1. Meanwhile, the stoichiometry was 1:1 for drugs with 2–3 benzene rings and maximum cross sectional areas of ca. 60–75 Å2. More sterically bulky drugs (four and five benzene rings) did form complexes, though the complexation efficiency was insufficient to form stoichiometric complexes, due to steric hindrance. The volume of intermolecular space of the host was estimated to be larger than that of a β-CD cavity and as large as that of a γ-CD cavity. Hydrophobic and van der Waals interactions worked as driving forces for the complexation because polycyclic aromatic hydrocarbons with high log P values formed the complex. The dissolution property of the hydrophobic pharmaceutical drug naproxen was clearly improved by the complexation because naproxen existed in a monomolecular state in the complex.

Co-amorphous technology was recently introduced to stabilize drugs in the amorphous state for drug development. We examined the predictability of the formation of co-amorphous systems and identified two reliable indicators of successful formation: (1) a negative ΔH mix value and (2) small Δlog P between components. Moreover, we found that the stability of co-amorphous systems was improved when (1) ΔH mix was negative and (2) amorphous forms of the constituent compounds were stable. Furthermore, we concluded that co-amorphous systems with small (negatively large) ΔH mix values had lower hygroscopicity. Typically, amorphous solid dispersions exhibit hygroscopicity because polymers exhibit large hygroscopicity. We proved the superiority of co-amorphous technology over amorphous solid dispersion in this respect. Our results provide methods for (1) establishing a screening method and (2) improving hygroscopicity, which may make co-amorphous technology more useful than amorphous solid dispersion technology.

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A crystalline ternary complex was prepared by sealed-heating of naproxen (NPX) with a flurbiprofen (FBP)/g g-cyclodextrin (g g-CD) inclusion complex. The dissolution rates of NPX and FBP in the ternary complex were almost the same, indicating that FBP and NPX from the complex dissolved simultaneously. The ternary CD complex showing a fascinating dissolution property could be a new formulation for combination therapies.Key words cyclodextrin; dissolution; powder X-ray diffraction; sealedheating; inclusion complex Many drug candidates usually show poor water solubility. Various pharmaceutical techniques such as polymorphic control, co-crystal formation, and nanoparticle preparation are available to improve the physicochemical properties of drugs.1-4) Cyclodextrin (CD) inclusion complex formation is also a useful technique for improving the dissolution property and enhancing the bioavailability of drugs.5-7) Co-precipitation, freeze-drying, evaporation, co-grinding, and processing with supercritical CO 2 are used for the preparation of solid CD inclusion complexes. [8][9][10] We have prepared various types of solid CD inclusion complexes by using the sealed-heating method wherein a mixture of guest and CD molecules is simply heated within an enclosed space. [11][12][13] In the sealed-heating method, vaporized guest molecules are assumed to be included in the cavity of CDs through the gas phase. Crystalline inclusion complexes of poorly water-soluble drugs can be obtained through the sealed-heating method without using solvents. Specific inclusion complexes that are difficult to prepare can also be obtained through this method. In our recent study, it was found that the sealed-heating of salicylic acid (SA) with polyethylene glycol (PEG)/g-CDpolypseudorotaxane induced complex formation.14) In this complex, two SA molecules for each g-CD molecule were incorporated into the intermolecular spaces between the columns of g-CD stacks, while double-stranded PEG chains were included in the g-CD cavity. Although a large number of studies have been carried out on the inclusion complexes of CDs, there are only a few reports on the existence of guest molecules outside the CD cavity. [15][16][17][18] New CD complexes with desired properties can be designed if the interstitial spaces outside the CD cavity are utilized for the incorporation of guest drugs. In this study, a ternary g-CD complex containing two active pharmaceutical ingredients (APIs) was prepared by the sealed-heating method. Using this method, guest drugs could be incorporated into the intermolecular spaces between g-CD columns. The dissolution property of the obtained complex was studied in order to assess its potential for pharmaceutical applications.Flurbiprofen (FBP) and naproxen (NPX) are anti-inflammatory drugs with poor water solubility (Fig. 1). In this study, each drug was used as a model guest molecule either for inclusion in the g-CD cavity or incorporation into the intermolecular spaces. The preparation process of the ternary complex consisted of two st...