ISSN 0012-5016, Doklady Physical Chemistry, 2011, Vol. 437, Part 2, pp. 78–81. © Pleiades Publishing, Ltd., 2011. Original Russian Text © A.G. Ogienko, E.V. Boldyreva, A.Yu. Manakov, V.V. Boldyrev, M.A. Mikhailenko, A.S. Yunoshev, A.A. Ogienko, A.I. Ancharov, A.F. Achkasov, A.V. Ildyakov, A.A. Burdin, N.A. Tumanov, A. S. Stoporev, and N. V. Kutaev, 2011, published in Doklady Akademii Nauk, 2011, Vol. 437, No. 6, pp. 785–788. 78 Paracetamol (N-(p-hydroxyphenyl)acetamide) is a widely used non-narcotic analgesic having also anti- inflammatory and antipyretic action. Several crystal- line polymorphs of paracetamol are known. One of these (monoclinic form I) is thermodynamically stable and is readily prepared but cannot be compressed to tablets without excipients (fillers). Another poly- morph (orthorhombic form II) can be readily com- pressed to tablets without excipients [1, 2] and is better soluble but its formation as a pure phase is not repro- ducible, and, what is worse, it is metastable and is spontaneously converted to the monoclinic form on storage [1]. The idea of obtaining compressible forms of paracetamol that would be stable on storage attracts considerable attention of the scientific community and pharmaceutical companies. For solving this prob- lem, it has been proposed to use, instead of pure paracetamol, its mixtures with polyvinylpyrrolidone [3], carbohydrates [4], chitosan and sodium alginate [5] or mixed crystals based on oxalic acid, naphthalene and other compounds [6] or the inclusion compounds with hydroxypropyl-β-cyclodextrin [7]. An attempt to prepare pure monoclinic paraceta- mol suitable for direct compression has been under- taken [8]. To this end, paracetamol was recrystallized from a solution or suspension in 1,4- dioxane to give a paracetamol solvate with dioxane (1 : 1/2) and then the solvating dioxane was removed. This gave highly porous paracetamol particles. It was noted [8] that a considerable disadvantage of this method for the prep- aration of paracetamol for tablet manufacture is the high thermal stability of the solvate and also rather low product yield in the case where saturated solutions are used (~21 g of paracetamol from 1000 mL of a solution saturated at 50°С). Meanwhile, the use of higher tem- perature (80–90°С) with the same solvent increased the product yield (200–300 g per 1000 mL of the solu- tion). However, at higher temperature, paracetamol may be partly oxidized. In the case of a suspension, the yield was even higher (at 50°С, this was ~164 g from 1000 mL of a suspension containing 200 g of paraceta- mol). Although the authors demonstrated some improvement of the compressibility and dissolution rate of the paracetamol samples they obtained as com- pared with the starting reagent, the subsequent testing was carried out with the standard excipients used to prepare paracetamol tablets. Instrumental methods for the preparation of fine powders of pharmaceutical products based on spray or freeze drying have been reported [9]. The use of high cooling rates to give amorphous phases followed by the removal of solvents by sublimation makes it possible to avoid enlargement of the formed crystallites due to the absence of contact with the liquid phase. By the beginning of our studies, it was known that a considerable increase in the paracetamol solubility is attained when a binary mixture comprising a volatile liquid (dioxane, ethanol, acetone) and water is used as the solvent [10]. One more reason for using systems with dioxane and acetone is the formation of clathrate hydrates with cubic structure II at low temperatures (CS II, the volatile liquid to water ratio is 1 : 17) [11]. Hence, only solid phases coexist over broad concen- tration and temperature ranges. A favorable condition PHYSICAL CHEMISTRY A New Method for Obtaining Fine Powders of Paracetamol for Compression without Excipients A. G. Ogienko a, b , E. V. Boldyreva a, c , A. Yu. Manakov a, b , Academician V. V. Boldyrev a, c , M. A. Mikhailenko a, c , A. S. Yunoshev a, d , A. A. Ogienko a, e , A. I. Ancharov a, c , A. F. Achkasov a , A. V. Ildyakov b , A. A. Burdin b , N. A. Tumanov a , A. S. Stoporev a, b , and N. V. Kutaev a, b Received December 3, 2010 DOI: 10.1134/S0012501611040063 a Molecular Design and Environmentally Safe Technologies Science and Educational Center, Novosibirsk State University, ul. Pirogova 2, Novosibirsk, 630090 Russia b Nikolaev Institute of Inorganic Chemistry, Siberian Branch, Russian Academy of Sciences, pr. Akademika Lavrent’eva 3, Novosibirsk, 630090 Russia c Institute of Solid State Chemistry and Mechanochemistry, Siberian Branch, Russian Academy of Sciences, ul. Kutateladze 18, Novosibirsk, 630128 Russia d Lavrent’ev Institute of Hydrodynamics, Siberian Branch, Russian Academy of Sciences, pr. Akademika Lavrent’eva 15, Novosibirsk, 630090 Russia e Institute of Cytology and Genetics, Siberian Division, Russian Academy of Sciences, pr. Akademika Lavrent’eva 10, Novosibirsk, 630090 Russia