International Journal of Pharmaceutics 244 (2002) 99 – 104 Solubilization and preformulation of carbendazim Nina Ni *, Tapan Sanghvi, Samuel H. Yalkowsky College of Pharmacy, The Uniersity of Arizona, Tucson, AZ 85721, USA Received 19 December 2001; received in revised form 5 June 2002; accepted 6 June 2002 Abstract The solubilization of carbendazim by pH in combination with cosolvents, surfactants or complexants was investigated. At pH 7 the total drug solubility is 6.11 0.45 g/ml which increases by 1–7 fold with cosolvent, surfactant or complexant. However, at pH 2 the solubility increases by 250 times. Cosolvents have a negligible effect (50% increase) on the total drug solubility at pH 2 because of the high polarity of the cationic drug. Also pH combined with nonionic surfactants does not improve solubility, as relatively less polar micelles are not able to accommodate the cationic drug. Interestingly, the total drug solubility increases by combining pH 2 with complex- ants, as they can form a complex with the isolated aromatic ring of both the unionized and the ionized drug. The proposed oral formulation of 1 mg/ml carbendazim at pH 2 does not precipitate in the presence of Seven Up or water. But it does precipitate with pH 7 buffer when diluted 1:10 but not 1:100 or 1:250. © 2002 Elsevier Science B.V. All rights reserved. Keywords: Solubility; Carbendazim; Buffer; Surfactant and Complexant www.elsevier.com/locate/ijpharm 1. Introduction Carbendazim (methyl-2-benzimidazolecarba- mate) is a well known anti-fungal agent that may have significant anti-cancer activity. Unfortu- nately its projected oral dose up to 100 mg per day is far greater than its water solubility of 6.11 g/ml. Furthermore, because of its high melting point its dissolution rate is very low. Therefore, it must be solubilized before it can be adequately tested in the clinic. According to Yalkowsky (1999), buffers, cosol- vents, surfactants, and complexants are the most commonly used excipients to improve the solubil- ity of a nonpolar drug in aqueous media. These can be used either alone or in combination (Mar- tin, 1993; Li et al., 1998, 1999a,b). It is well known that ionized species are more soluble than their unionized counterparts in aqueous solution. Li and Yalkowsky (Li et al., 1998, 1999a,b) have reported that the ionization of a drug not only increases the solubility of the ionized species in water, but also can increase its solubilization by cosolvents, micelles, or complexants. Carben- dazim has a calculated octanol-water partition coefficient of 1.71 by using CLOGP ® 4.0 software (Bio Byte Corp., Claremont, CA). Its amphoteric * Corresponding author. Tel.: +1-520-626-4308; fax: +1- 520-626-4063 E-mail address: na@pharmacy.arizona.edu (N. Ni). 0378-5173/02/$ - see front matter © 2002 Elsevier Science B.V. All rights reserved. PII: S0378-5173(02)00318-6