Solubility is an important factor for achieving the desired plasma level of drug for pharmacological response. About 40% of drugs are not soluble in water in practice and therefore are slowly absorbed, which results in insufficient and uneven bioavailability and GI toxicity. Rubusoside (Ru) is a sweetener component in herbal tea and was discovered to enhance the solubility of a number of pharmaceutically and medicinally important compounds, including anticancer compounds. In this study, thirty-one hydrolyzing enzymes were screened for the conversion of stevioside (Ste) to Ru. Recombinant lactase from Thermos thermophiles which was expressed in Escherichia colt converted stevioside to rubusoside as a main product. Immobilized lactase was prepared and used for the production of rubusoside; twelve reaction cycles were repeated with 95.4% of Ste hydrolysis and 49 g L-1 of Ru was produced. The optimum rubusoside synthesis yield was 86% at 200 g L-1, 1200U lactase. The purified 10% rubusoside solution showed increased water solubility of liquiritin from 0.98 mg mL(-1) to 4.70 +/- 0.12 mg mL(-1) and 0 mg mL(-1) to 3.42 +/- 0.11 mg mL(-1) in the case of teniposide. (C) 2014 Elsevier Inc. All rights reserved.