Isolation, identification, characterization, synthesis and quality control strategy of new process-related impurities in ambrisentan.

Ambrisentan is a highly selective endothelin-A receptor antagonist for the treatment of pulmonary arterial hypertension (PAH). The analysis of the process-related impurities will help not only to optimize the process parameters but also to develop reasonable analytical methods and set the quality standard for a quality control strategy in pharmaceutical manufacturing. During the manufacture of ambrisentan, five unknown impurities were detected in pilot batches ranging from 0.05% to 0.15% by HPLC. All of these impurities were isolated and synthesized successfully and were identified and characterized by LC-MS, HRMS, ESI-MS/MS(Q-Tof), 1D-NMR (1H, 13C, DEPT) and 2D-NMR (COSY, HSQC, HMBC) techniques. The formation mechanisms that yield these impurities are discussed for the first time. Quality control strategies to deal with these impurities are developed to obtain bulk drug of ICH-grade quality.

Modifying sorbents in controlled release formulations to prevent herbicides pollution.

The herbicides chloridazon and metribuzin, identified as groundwater pollutants, were incorporated in alginate-based granules to obtain controlled release properties. In this research the effect of incorporation of sorbents such as bentonite, anthracite and activated carbon in alginate basic formulation were not only studied on encapsulation efficiency but also on the release rate of herbicides which was studied using water release kinetic tests. In addition, sorption studies of herbicides with bentonite, anthracite and activated carbon were made. The kinetic experiments of chloridazon and metribuzin release in water have shown that the release rate is higher in metribuzin systems than in those prepared with chloridazon, which has lower water solubility. Besides, it can be deduced that the use of sorbents reduces the release rate of the chloridazon and metribuzin in comparison to the technical product and to the alginate formulation without sorbents. The highest decrease in release rate corresponds to the formulations prepared with activated carbon as a sorbent. The water uptake, permeability, and time taken for 50% of the active ingredient to be released into water, T(50), were calculated to compare the formulations. On the basis of a parameter of an empirical equation used to fit the herbicide release data, the release of chloridazon and metribuzin from the various formulations into water is controlled by a diffusion mechanism. Sorption capacity of the sorbents for chloridazon and metribuzin, ranging from 0.53mgkg(-1) for the metribuzin sorption on bentonite to 2.03x10(5)mgkg(-1) for the sorption of chloridazon on the activated carbon, was the most important factor modulating the herbicide release.

Synthesis and complete 1H, 13C and 15N NMR assignment of substituted isoxazolo[3,4-d]pyridazin-7(6H)-ones.

The synthesis and complete assignment of all hydrogen, carbon and nitrogen NMR signals of several new isoxazolo[3,4-d]pyridazin-7(6H)-ones is reported. The spectroscopic characterization is extended to previously described analogues.

Comparative effects of 2.5 and 5 mg cilazapril versus placebo on daily blood pressure load.

The antihypertensive efficacy of 2.5 and 5 mg cilazapril and placebo in lowering 24-h ambulatory blood pressure (ABP) and BP load were compared in 42 patients with mild to moderate hypertension. After a 2-week placebo run-in period, patients were randomized double-blind to receive either 2.5 mg cilazapril (n = 14), 5 mg cilazapril (n = 14), or placebo (n = 14) for 4 weeks. There were no significant differences in 24-h and awake ABP or in office BP between 2.5 and 5 mg cilazapril. Moreover, the percentage of patients that had BP control (mean daytime ABP less than 90 mm Hg) was 14% in the placebo group, 64% and 71% with 2.5 and 5 mg cilazapril, respectively. Furthermore, the percentage of BP load was similar with both regimens (29 v 36%). These observations indicate that 2.5 and 5 mg cilazapril have equipotent antihypertensive efficacy.

Efficacy and safety of cilazapril, a new angiotensin-converting enzyme inhibitor.

Cilazapril (CIL), a new angiotensin-converting enzyme inhibitor, was evaluated for 16 weeks in 29 patients with mild to moderate essential hypertension (diastolic pressure 95 mm Hg to 115 mm Hg). Twenty-four patients (83%) normalized their blood pressure (BP) (diastolic pressure less than 90 mm Hg), 11 with low-dose CIL, six with high-dose CIL, one with high-dose CIL plus low-dose thiazide, and six with high-dose CIL and high-dose thiazide. Three withdrew because of side effects (fatigue, bloating, and polyuria). Statistically significant reductions in sitting and standing systolic and diastolic pressures occurred at 8 and 16 weeks on CIL. There was no change in standing or sitting heart rate, white blood cell count, creatinine clearance, urine protein levels. This is the first long-term data on this new converting enzyme inhibitor in human beings.