797 ISSN 0036-0244, Russian Journal of Physical Chemistry A, 2015, Vol. 89, No. 5, pp. 797–801. © Pleiades Publishing, Ltd., 2015. Original Russian Text © A.V. Anshakova, Yu.V. Yermolenko, V.Yu. Konyukhov, V.I. Polshakov, O.O. Maksimenko, S.E. Gelperina, 2015, published in Zhurnal Fizicheskoi Khimii, 2015, Vol. 89, No. 5, pp. 791–795. Intermolecular Interactions in Rifabutin—2-Hydroxypropyl-β- cyclodextrin—Water Solutions A. V. Anshakova a,b , Yu. V. Yermolenko a,b , V. Yu. Konyukhov b , V. I. Polshakov c , O. O. Maksimenko a , and S. E. Gelperina a a Nanosystem LTD, Moscow, Russia b Mendeleev University of Chemical Technology of Russia, Moscow, Russia c Faculty of Fundamental Medicine, Moscow State University, Moscow, Russia e-mail: anshakova_a@mail.ru Received May 25, 2014 Abstract—The possibility of a intermolecular complex rifabutin (RB)–2-hydroxypropyl-β-cyclodextrin (HP-β-CD) formed as a result of the interaction of the piperidine fragment of the RB molecule and the hydrophobic cavity of the HP-β-CD molecule was found. The stability constant of the intermolecular com- plex was determined. Keywords: rifabutin, 2-hydroxypropyl-β-cyclodextrin, complexation, molecular modeling, quantum-chemi- cal calculation, phase solubility diagram, apparent complex stability constant. DOI: 10.1134/S0036024415050052 INTRODUCTION Rifabutin (RB) is widely used as an antituberculo- sis antibiotic in modern pharmacology. However, its low solubility in water (~0.2 mg/cm 3 [1, 2]) and, as a consequence, low bioavailability (with only ~20% of the administered drug entering the blood flow [3]) necessitate the use of high doses (300–500 mg daily). This causes side effects (mainly, in the gastrointestinal tract (GIT)) [4]. One method to increase the solubility of poorly soluble substances in pharmaceutics is their use with water-soluble complexes. The most suitable sub- stances for this purpose are compounds from the group of cyclodextrins (CDs)—cyclic oligomers of glucose having a hydrophobic inner cavity and a hydrophilic surface and known due to their ability to form “guest–host” inclusion complexes. Due to their hosting ability, CDs can substantially improve the use- ful properties of the complexed substances, namely, they can increase their solubility in water (tenfold and even thousandfold); lower the volatility of readily evaporating organic liquids; increase their stability against the action of oxygen, light, heating; reduce the irritating action, etc. [5–12]. The most widely used compound is modified hydroxypropyl-β-cyclodextrin (HP-β-CD), primarily due to its low toxicity (the median lethal dose LD 50 is >2243 mg/kg for oral administration in rats) and high solubility in water (500 mg/cm 3 ) [5]. As shown by previous studies, the formation of a complex of RB with HP-β-CD allows one to increase the concentration of the drug in the aqueous phase and raise its efficiency with respect to the experimental tuberculosis infection [13]. The goal of this study was to evaluate the stability of intermolecular interaction in the rifabutin–hydroxy- propyl-β-cyclodextrin system and investigate the geometry of the resulting structures. EXPERIMENTAL Rifabutin (Luohe Nanjiecun Pharmaceutical Group, China (98.5%) was used in the experiments. Hydroxypropyl-β-cyclodextrin HP-β-CD (M w ~ 1.460 kDa; molar substitution 0.8), poloxamer 188 (Pluronic® F-68), and mannitol were purchased from Sigma-Aldrich (Germany). Aqueous suspensions containing 2.6 mM of RB and different quantities of HP-β-CD (molar ratios RB: HP-β-CD = 1 : 0, 1 : 1, 1 : 4, and 1 : 6) were mixed at room temperature for 7 days. The absorption spec- tra of RB solutions were recorded in the range 200– 700 nm (Helios Zeta spectrophotometer, Thermo Sci- entific, Great Britain). To determine the medium acidity level that is opti- mum for the formation of an intermolecular complex, suspensions of RB with HP-β-CD (molar ratio RB: HP-β-CD = 1 : 10) were stirred for 3 h at 45°С in solu- tions: 10 –3 N HCl (рН 3) and phosphate (рН 4, 6, 7) and tetraborate (рН 8, 9) buffers. The total molar con- centration of the buffer solutions and the solutions of individual substances was 0.05 М; a NaCl solution was added if necessary. PHYSICAL CHEMISTRY OF SOLUTIONS