A series of novel 4-Benzyl-1,3-thiazole derivatives was synthesized by applying analogue-based drug design approach and they were screened for anti-inflammatory activity. Darbufelone (CI 1004) a dual COX/LOX inhibitor, served as a lead molecule for designing a molecular scaffold. The derivatives with the 1,3 thiazole molecular scaffold bearing a side chain at position-2 resembling that of Romazarit (Ro-31-3948) were synthesized. The substitution at the second position of thiazole scaffold consisted of either carbalkoxy amino or aryl amino side chain. The introduction of an NH linker at the second position was the bioisoteric approach to impart the metabolic stability to the carbalkoxy side chains in designed molecules so as to avoid the likelihood of generating toxic moieties, like in Romazarit, which was withdrawn due to its toxicity profile. An important outcome of this study is the optimization of the substitution at the second position of the thiazole scaffold in eliciting better biological activity. The biological activity exhibited by the two designed series were in the order of carbalkoxy amino series . phenyl amino series. Molecule RS31 had emerged to be best compound in the whole series, having the side chain -NH-(CvO)O-R which resemble to Romazerit with 1,3 thiazole scaffold and substituted phenyl carbonyl group at fifth position derived from the retro-analysis of Darbufelone. This novel three-point pharmacophore, which is necessarily evolved from a lead-based drug design strategy, has opened up new avenues in designing of molecules acting on more than one rate-limiting step along the inflammatory cascade.

Stability can be defined as the capacity of a drug substance or drug product to sustain its identity, strength, quality, and purity throughout the retest or expiration period (1). Stability testing of an active substance or finished product provides evidence of the quality of a drug substance or drug product to remain acceptable up to the stated period under storage conditions stated on the label. The International Conference on Harmonization (ICH) guidelines Q1A (R2) require the use of a validated stability-indicating assay method (SIAM) for stability testing of a drug substance or product (2). It also empha- A simple, sensitive and precise RP-HPLC-DAD method was developed and validated for the determination of olmesartan medoxomil (AT-II receptor blocker) in the presence of its degradation products. Olmesartan medoxomil and all the degradation products were resolved on a C 18 column with the mobile phase composed of methanol, acetonitrile and water (60:15:25, V/V/V, pH 3.5 by orthophosphoric acid) at 260 nm using a photodiode array detector. The method was linear over the concentration range of 1-18 mg mL -1 and precise with RSD < 1 % in intra-and inter-day study. Excellent recoveries of 99.3 ± 0.9 to 100.8 ± 1.2 % proved the accuracy of the method. Developed method was specific, as indicated by chromatographic resolution > 2.0 for each peak and sensitive with LOD 0.03 mg mL -1 and LOQ 0.1 mg mL -1 . The method was used to study the drug degradation behavior under forced conditions. Four degradation products (DP-I, II, III, IV) were formed during the degradation study in 0.1 mol L -1 HCl whereas only DP-I, II and III were formed in water, 0.01 mol L -1 NaOH and 3 % H 2 O 2 . No significant thermal or photolytic degradation was observed in solid drug. The method was applied successfully for the assay of olmesartan medoxomil in the tablet dosage form.

Hypertension is emerging as one of the most significant health complications in recent years (1). There has been a marked increase in the use of combinations of antihypertensive drugs as well with complementary mechanisms of action, with the aim of reducing blood pressure levels more rapidly and improving treatment compliance. The A simple RP-HPLC method for the quantification of valsartan (VAL), amlodipine (AML) and hydrochlorothiazide (HCT) in human plasma was developed and validated. VAL, AML and HCT were resolved using a Gemini C 18 column and mobile phase gradient starting from 20 % acetonitrile and 80 % 10 mmol L -1 ammonium formate (V/V, pH 3.5 ± 0.2, by formic acid) to 70 % acetonitrile and 30 % 10 mmol L -1 ammonium formate, over 20 minutes, with a flow rate of 1 mL min -1 . The samples were purified by protein precipitation and extraction. Telmisartan was used as internal standard. The method was validated according to USFDA and EMEA guidelines with good reproducibility and linear responses R = 0.9985 (VAL), 0.9964 (AML), and 0.9971 (HCT). RSDs of intra-and inter-day precision ranged 2.2-8.1 and 4.6-11.7 %, respectively, for all three drugs. Mean extraction recoveries of three QCs for the triple drug combination were 76.5 (VAL), 72.0 (AML) and 73.0 (HCT) % for human plasma. Although the LC-MS/MS method is more sensitive than HPLC, HPLC is still suitable for preliminary pharmacokinetic study. The experiments performed demostrated that simultaneous determination of all components of the triple drug combination in human plasma can be done by this method. Proposed method can be also used for guidance to the LC-MS/MS method.

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Carotid intima-media thickness is used as a surrogate marker for cardiovascular complications in diabetes mellitus. The combination of atorvastatin and pioglitazone was found to be effective in reducing the thickness of the carotid intima-media layer. The method of RP-HPLC coupled with a diode array detector (DAD) was developed for the pharmacokinetic interaction study of atorvastatin with pioglitazone and cholestyramine, respectively, in Wistar rats. Atorvastatin (ATR) and pioglitazone (PIO) were resolved on a C18 column with a mobile phase composed of 48% methanol, 19% acetonitrile, and 33% 10 mM ammonium formate (v/v/v; pH 3.5±0.3, by formic acid) and a 260 nm detection wavelength on the diode array detector. The method was validated according to international standards with good reproducibility and linear response; mean (r) 0.9987 and 0.9972 to ATR and PIO, respectively. The coefficients of variation of intra- and interassay precision ranged between 4.95–8.12 and 7.29–9.67, respectively. Pharmacokinetic parameters were determined in rats following an oral administration of atorvastatin in the presence and absence of pioglitazone and also with cholestyramine. Compared with the control given atorvastatin alone, the Cmax and AUC of atorvastatin were merely unchanged in rats with the co-administration of pioglitazone, while they decreased by nearly 21 and 15%, respectively, with the concurrent use of cholestyramine. There were no significant changes in Tmax and the plasma half-life (T1/2) of atorvastatin in both cases. The performed experiment demonstrated that the presented method was suitable for the estimation and pharmacokinetic interaction study of atorvastatin with pioglitazone and cholestyramine in Wistar rat plasma.