Development of eco-friendly spectrophotometric methods for analysis of metformin hydrochloride and linagliptin in presence of metformin toxic impurity in their pure and dosage forms: Validation, practicality and greenness studies.

Metformin is considered as type 2 diabetes first line treatment according to American Diabetes Association and European Association. But, in some cases, di- or tri - therapy should be prescribed for glycemic management, prevention of the maximum dose side effects and induced effectiveness. Co-administration of Linagliptin with metformin has many benefits on diabetic patients such as decrease the possibility of hypoglycemia. For the first time, novel and reliable techniques were developed and verified for the concurrent quantification of metformin hydrochloride and linagliptin, while accounting for the existence of metformin toxic impurity 1-cyanoguanidine in their pure and dosage forms. Method (A) utilizes the zero-order spectrophotometric approach to quantitatively determine the concentration of linagliptin. The measurements are performed at a wavelength of 295 nm. The double divisor derivative ratio spectrophotometric method is used in Method (B) to measure the amounts of metformin and cyanoguanidine at 252 nm and 219 nm wavelengths, respectively. The spectrophotometric method (C) for determining metformin and cyanoguanidine at 252 nm and 223 nm, respectively, is based on the single divisor derivative ratio-zero crossing technique. The obtained findings were subjected to statistical comparison with the reported method, revealing no statistically significant differences. The Green Analytical Procedure Index (GAPI) and Analytical GREEnness Metric approach (AGREE) determined that these approaches had a high degree of environmental friendliness. Additionally, the proposed strategy was deemed to be practical according to the Blue Applicability Grade Index (BAGI) assessment tool.

Development and validation of an eco-friendly HPLC-UV method for determination of atorvastatin and vitamin D3 in pure form and pharmaceutical formulation.

Statin-associated muscle symptoms are considered as obvious adverse effects of prolonged statin therapy such as myopathy, myalgia, and rhabdomyolysis. These side effects are associated with vitamin D3 deficiency and can be adjusted by amendment of serum vitamin D3 level. Green chemistry aims to decrease the harmful effects of analytical procedures. Here we have developed a green and eco-friendly HPLC method for the determination of atorvastatin calcium and vitamin D3. The two drugs were separated in less than 10 min on Symmetry column C18 (100 × 4.6 mm, 3.5 µm) using a mixture consisting of 0.1% ortho-phosphoric acid (OPA) (pH = 2.16) and ethanol as the mobile phase in gradient manner. We have used Green Analytical Procedure Index (GAPI) tools and the Analytical GREEnness Metric Approach (AGREE) for assessment of the greenness of our proposed method. The method proved linearity over concentration ranges of (5-40) and (1-8) µg/ml with low limit of detection of 0.475 and 0.041 µg/ml for atorvastatin calcium and vitamin D3 respectively. The method was successfully validated in accordance with ICH instructions and utilized for determination of the drugs of interest either in pure form or in their pharmaceuticals.

Cost-effective, green HPLC determination of losartan, valsartan and their nitrosodiethylamine impurity: application to pharmaceutical dosage forms.

Angiotensin-converting enzyme inhibitors are one of the most widely used anti-hypertensive drugs which are used to reduce hypertension. In 2018, the United States Food and Drug Administration together with the European Medicine Agency declared the presence of carcinogenic nitrosamine impurities such as nitrosodiethylamine (NDEA) in some of the products, including valsartan (VLS) and losartan (LOS), and drugs' recall procedures were started. Thus, they should be controlled to be below the acceptable cancer risk level to ensure safety of the pharmaceutical products. Therefore, sensitive and reliable analytical methods were required for detection and quantitation of NDEA in bulk and finished drug products. Green analytical chemistry has received great interest to minimize the amount of organic solvents consumed without loss in chromatographic performance. A green and sensitive HPLC method was developed for the determination of NDEA in LOS and VLS using mobile phase of 0.02 M ammonium acetate adjusted to pH 7.2 and ethanol in gradient manner. Limits of detection and limits of quantification for NDEA were estimated to be 0.2 and 0.5 µg ml-1, respectively. The standardized limits of NDEA impurity in drug substances were set as 0.56 ppm, which indicates the feasibility of its determination by the proposed conventional method without need for expensive instrumentations (e.g. MS/MS detectors) that are not found in most pharmaceutical quality control laboratories.

Laryngopharyngeal reflux with sore throat: an ultrastructural study of oropharyngeal epithelium.

OBJECTIVES: We performed an electron microscopic ultrastructural study of oropharyngeal epithelium in patients with laryngopharyngeal reflux (LPR) and sore throat to evaluate whether dilatation of intercellular spaces could be traced at this level. METHODS: The study included 20 patients with LPR and sore throat and 5 control subjects. The patients were subjected to upper gastrointestinal tract endoscopy and flexible pharyngolaryngoscopy. Oropharyngeal biopsy specimens were taken from the patients and controls for ultrastructural study by transmission electron microscopy. RESULTS: The entire group of patients with LPR showed dilatation of intercellular spaces essentially at the squamous basal and suprabasal levels in their oropharyngeal biopsy specimens, whereas none of the control subjects showed such a morphological marker. CONCLUSIONS: Dilatation of intercellular spaces as a morphological marker can be traced in patients with LPR and sore throat at the level of the oropharynx. This contributes to a better understanding of the pathophysiology of LPR. If this finding is confirmed in a large series, it will represent a cost-effective, relatively noninvasive method for diagnosis of LPR.