Solubility and Crystal Size of Sirolimus in Different Organic Solvents Pankaj J. Gandhi and Z. V. P. Murthy* Department of Chemical Engineering, S. V. National Institute of Technology, Surat 395007, Gujarat, India The solubility of sirolimus drug in different organic solvents, viz., acetone, chloroform, methanol, ethanol, and dichloromethane, has been measured for the temperature range of (295 to 345) K by a gravimetric method. The relation between solubility and crystal size formation has also been studied. It was found that the higher the solubility of material, the larger the crystal size and vice versa. The stability of crystals has been measured, and it was found that smaller crystals have a moderate level of stability when compared with that of larger crystals. From the observations of the present study, it may be suggested that for cardiovascular applications of sirolimus drug one can use ethanol and methanol as a solvent for deriving crystals of less than 400 nm size. Introduction Nowadays, nanosize particles are used by many industries, such as cosmetics, dyes, electronics, pharmaceuiticals, etc. 1 Nanosize particles have also gained importance in the field of drug delivery. 2 An increasing number of newly developed drugs are poorly soluble in water, and poor solubility results in low bioavailability and/or erratic absorption of the drugs. 2 Sirolimus (an immunosuppressant drug) is a triene marcolide antibiotic isolated from Streptomyces hygroscopicus and is known to have poor solubility in water. 3,4 Due to the physical properties of sirolimus, such as water insolubility and log P (i.e., log of octanol-water partition coefficient), which is a measure of a drug’s lipophilicity, of greater than 5, it is a challenging task to formulate it into either an intravenous or oral dosage form. 5 The solubility of sirolimus 6 is 2.6 μg · mL -1 , which is far below the target solution concentration of 1 mg · mL -1 . It is difficult to enhance the solubility of sirolimus by the generation of a salt form because of the lack of an ionizable group of sirolimus in the pH range 6 of 1 to 10. Over the past ten years, the number of poorly soluble drugs has steadily increased. Estimates state that (40 to 60) % of the drugs in the pipelines have solubility problems. 7,8 Poor solubility in water correlates with poor bioavailability. If there is no way to improve drug solubility, then it will not be able to be absorbed from the gastrointestinal tract into the bloodstream and reach the site of action. 9 Tong 10 has pointed out that solubility is one of the most important physicochemical properties studied during pharmaceutical preformulation, hence accurate solubility data are essential to ensure the robustness of the finished product. Park et al. 11 studied the estradiol solubility in phosphate buffer saline and crystal habits in different organic solvents and found that estradiol crystal habits prepared from ethanol and methanol had larger crystal size. Crystallizing solvents having various polarities are preferred since molecules in such solutions tend to form different types of hydrogen-bonded aggregates. 12 Some solvents favor crystal- lization of a particular form because they selectively adsorb to specific faces of the crystal, and some of the commonly used solvents are water, methanol, ethanol, propanol, iso-propanol, acetone, acetonitrile, ethyl acetate, hexane, etc. 13 Also, crystal habit in organic solvent plays an important role in affecting the crystal product physicochemical properties, such as solubility, dissolution rate, compressibility, and bulk density that have an effect on the product biological activity and production cost. 11 As sirolimus is used in local drug delivery on medical devices, such as drug eluting stents and balloons, it is important to understand the solubility and crystal habit of it for its biological activity. 14-16 On the basis of the available literature, it can be said that drug crystals of less that 400 nm are suitable for arterial penetration and tissue uptake for cardiovascular applications. 17-19 Therefore, the study of the solubility of a drug and its crystal habit is necessary from pharmaceutical industry requirements. The solubility of sirolimus in organic solvents directly affects the size of crystal formation, yield, and cost of production. Hence, it is necessary to know the solubility of sirolimus in different organic solvents. In the present work, an attempt has been made to study the solubility of sirolimus in different organic solvents, viz., acetone, chloroform, methanol, ethanol, and dichloromethane from (295 to 345) K at atmospheric pressure using the gravimetric method. 20 The crystal size (L) of the drug in respective organic solvent has been derived under sonication in a setup similar to our previous work, 21 and we tried to establish a relationship between the solubility of the drug in organic solvent and the size of crystal formation in antisolvent media. Materials and Methods Materials. Sirolimus ((3S,6R,7E,9R,10R,12R,14S,15E,17E, 19E,21S,23S,26R,27R,34aS)-9,10,12,13,14,21,22,23,24,25,26, 27,32,33,34,34a-hexadecahydro-9,27-dihydroxy-3-[(1R)-2- [(1S,3R,4R)-4-hydroxy-3-methoxycyclohexyl]-1-methylethyl]- 10,21-dimethoxy-6,8,12,14,20,26-hexamethyl-23,27-epoxy-3H- pyrido [2,1-c] [1,4]-oxaazacyclohentriacontine-1,5,11,28,29- (4H,6H,31H)-pentone), C 51 H 79 NO 13 , molecular weight 914.175, CAS RN 53123-88-9) was provided by Gayatri Medico Distributors, Bharuch, India, with a purity of 98 %. All organic solvents (HPLC grade) used as solubilizing agents, for dissolving the sirolimus, were supplied by Himedia Lab, Mumbai, India. For sonication experiments, biodegradable Tomadol 23-6.5 was used as a surfactant (provided by Air Products Asia Inc., Singapore), and Millipore water was used as water base (antisolvent media for crystal fall-out). All the chemicals and drug were used as supplied without further purification. * Corresponding author. E-mail: zvpm2000@yahoo.com, zvpm@ ched.svnit.ac.in. Tel.: +91 261 2201648, 2201642. Fax: +91 261 2227334. J. Chem. Eng. Data 2010, 55, 5050–5054 5050 10.1021/je100626x  2010 American Chemical Society Published on Web 08/20/2010