AbstractIn this work two well known oral hypoglycemic drugs that are administered in combination for patients with type‐II diabetes were simultaneously determined. Several spectrophotometric methods were developed and validated for the determination of metformin hydrochloride (MET), pioglitazone hydrochloride (PIO) and pioglitazone acid degradate (PIO Deg). Derivative, ratio derivative, isosbestic and chemometric‐assisted spectrophotometric methods were developed. The first derivative (D1) method was used for the determination of MET in the range of 5–30 µg.mL−1 and PIO in the range of 10–90 µg.mL−1 by measuring the peak amplitude at 247 nm and 280 nm, respectively. The concentration of PIO was calculated directly at 268 nm. The first derivative of ratio spectra (DD1) method used the peak amplitudes at 238 nm and 248.6 nm for the determination of MET in the range of 5–30 µg.mL−1.In the isosbestic point method (ISO), the total mixture concentration was calculated by measuring the absorbance at 254.6 nm. Classical least squares (CLS), principal component regression (PCR) and partial least squares (PLS‐2) were used for the quantitative determination of MET, PIO and PIO Deg. The methods developed have the advantage of simultaneous determination of the cited components without any pre‐treatment. Resolution and quantitative determination of PIO degradate with a minimum concentration of 3 µg.mL−1 in drug samples was done. The proposed methods were successfully used to determine each drug and the acid degradate in a laboratory‐prepared mixture and pharmaceutical preparations. The results were statistically compared using one‐way analysis of variance (ANOVA). The methods developed were satisfactorily applied to the analysis of the two drugs in pharmaceutical formulations. Copyright © 2009 John Wiley & Sons, Ltd.