Chemometric approach to the development of HPLC/UV and HPLC/MS methods for determination and stability testing of torasemide and its impurities

Torasemid je diuretik Henleove petlje sa sličnim dejstvom kao furosemid. Koristi se u stanjima edema udruženim sa srčanom bolešću, uključujući i plućni edem, kao i u slučajevima oboljenja bubrega i jetre. Takoñe se koristi u tretmanu hipertenzije, samostalno ili u kombinaciji sa drugim antihipertenzivima. Torasemid ostvaruje dejstvo u uzlaznom, debljem kraku Henleove petlje inhibirajući tubularnu reapsorpciju natrijuma (Na+) i hlora (Cl-) ograničavanjem natrijum/hlorid/kalijum prenosnog sistema. U kontroli kvaliteta farmaceutskih proizvoda testovi identifikacije i odreñivanja sadržaja aktivne supstance i nečistoća su veoma važni sa ciljem da se obezbedi visok kvalitet proizvoda, bez promena u hemijskim, farmakološkim ili toksikološkim karakteristikama. Prema ICH smernicama, sve nečistoće prisutne u farmaceutskom doziranom obliku u količini većoj od 0.1% moraju se ispitati. Za istovremeno odreñivanje torasemida i njegovih nečistoća razvijene su nove, osetljive i pouzdane HPLC/UV i HPLC/MS metode. Kompletno hromatografsko ponašanje ispitivanih supstanci i pronalaženje optimalnih hromatografskih uslova ostvareno je uz upotrebu eksperimentalnog dizajna. Frakcioni faktorski dizajn je korišćen za izbor varijabli koji značajno utiču na hromatografsko razdvajanje. Puni faktorski dizajn je korišćen za optimizaciju tih varijabli kako bi se postiglo zadovoljavajuće razdvajanje izmeñu ispitivanih supstanci u najkraćem mogućem vremenu trajanja analize. Nakon toga, obe metode su uspešno validirane u skladu sa ICH smernicama i primenjene za ispitivanje farmaceutskog doziranog oblika, torasemid tableta. Kako u literaturi postoji nedostatak informacija o degradacionom mehanizmu torasemida, to su aktivna farmaceutska supstanca torasemid i farmaceutski dozirani oblik (torasemid tablete) podvrgnuti studijama forsirane degradacije sa ciljem da se identifikuju potencijalni degradacioni proizvodi i ustanovi mogući degradacioni put i sveukupna stabilnost torasemida. Studija je sprovedena u skladu sa ICH smernicama, a uzorci su izlagani uslovima hidrolize (kisele, bazne i neutralne), oksidacije, fotolize i termalne degradacije. Za karakterizaciju nastalih degradacionih proizvoda primenjene su HPLC/UV i HPLC/MSn tehnike. Kvadrupolni i jonski trap maseni analizatori su korišćeni da se ustanovi način fragmentacije degradacionih proizvoda...Torasemide is a loop diuretic with actions similar to those of furosemide. Torasemide is used for edema associated with heart failure, including pulmonary edema, and with renal and hepatic disorders. It is also used in the treatment of hypertension, either alone or with other antihypertensives. It acts in the ascending limb of the loop of Henle by inhibiting tubular reapsorption of sodium and chloride and interacting with the sodium/chloride/potassium co-transport system. In the quality control of pharmaceutical products identification and quantification of the active ingredient and its impurities is very important in order to achieve a high quality of the product, without change in chemical, pharmacological and toxicological properties. According to ICH guidelines, determination of impurities present in pharmaceutical dosage forms above 0.1% is necessary. A new, sensitive and reliable HPLC/UV and HPLC/MS methods for simultaneous determination of torasemide and its impurities were developed. The complete chromatographic behavior and optimal chromatographic conditions were evaluated with the assistance of experimental design. The fractional factorial design was used for selection of variables which significantly influence the chromatographic separation of the investigated substances. Full factorial design was used for optimization of these variables in order to achieve satisfactory resolution between all investigated substances with the shortest possible analysis time. Afterwards, both analytical methods were successfully validated in accordance with ICH guidelines and the applicability of the proposed methods on the torasemide tablet dosage form has been demonstrated. As the degradation mechanism of torasemide has been lacking in the literature, torasemide active pharmaceutical ingredient and torasemide tablets drug product were subjected to forced degradation studies in order to identify the potential degradation products and establish the possible degradation pathways and intrinsic stability of the drug. The study was performed according to ICH guidelines and samples were exposed to hydrolysis (acid, base and neutral), oxidation, photolysis and thermal degradatio

Etching of Uncompensated Convex Corners with Sides along <n10> and <100> in 25 wt% TMAH at 80 °C

This paper presents etching of convex corners with sides along and crystallographic directions in a 25 wt% tetramethylammonium hydroxide (TMAH) water solution at 80 °C. We analyzed parallelograms as the mask patterns for anisotropic wet etching of Si (100). The sides of the parallelograms were designed along and crystallographic directions (1 and crystallographic directions were smaller than 45°. All the crystallographic planes that appeared during etching in the experiment were determined. We found that the obtained types of 3D silicon shape sustain when n > 2. The convex corners were not distorted during etching. Therefore, no convex corner compensation is necessary. We fabricated three matrices of parallelograms with sides along crystallographic directions and as examples for possible applications. Additionally, the etching of matrices was simulated by the level set method. We obtained a good agreement between experiments and simulations

Etch rates of Si crystallographic planes in a 25 wt % TMAH water solution

Nagrizane su silicijumske strukture koje su na početku nagrizanja definisane kvadratnim ostrvima od termičkog silicijum dioksida. Stranice kvadrata su projektovane u različitim kristalografskim pravcima. Određene su kristalografske ravni koje se pojavljuju tokom nagrizanja ovih struktura u vodenom rastvoru TMAH koncentracije 25 tež. % na temperaturi od 80 0 C. Merenjem odgovarajućih parametara nagrizanih kristalografskih ravni sa vremenom odredili smo brzine nagrizanja uočenih kristalografskih ravni.We etched Si structures that had been defined at the beginning of etching by square islands of thermal SiO2. The sides of the squares were designed with orientations along various crystallographic directions. All the planes that appeared during etching of these Si structures in a 25 wt % TMAH water solution at a temperature of 80 deg C were determined. By measuring the time dependence of the appropriate parameters of the etched Si crystallographic planes we indirectly calculated their etch rates

Reinforcement of the pressure sensor diaphragm by etching in 25%tmah water solution

Primenom maskless tehnike, koja se bazira na vlažnom hemijskom nagrizanju u vodenom rastvoru TMAH koncentracije 25 tež. %. na temperaturi od 80 0 C, na Si pločice uspešno su napravljene dijafragme sa ojačanjem. Ojačanje je projektovano za ravne kvadratne dijafragme debljine 30 μm i površine 2040 μm x 2040 μm, čiji je nominalni opseg rada 1 bar. Vrednost pritiska na kojoj neojačana dijafragma puca je 12 bar. Eksperimentalno je pokazano da je ojačanje povećalo pritisak na kojem puca dijafragma 1.8 puta za dijafragmu sa ojačanjem širine 90 μm, odnosno 2.5 puta za dijafragmu sa ojačanjem širine 40 μm. Ovo poboljšanje pokazuje da je u okviru samog senzora moguće MEMS tehnologijama povećati vrednost pritiska na kojem dolazi do pucanja dijafragme i njenog nepopravljivog oštećenja.Reinforcements of a pressure sensor diaphragm have been designed and fabricated on the Si wafers by maskless wet etching technique. Maskless wet etching technique has been performed in the 25% TMAH water solution at the temperature of 800. Reinforcements are designed for the 30 μm thick and flat square diaphragm. Area of the diaphragm is 2040 μm x 2040 μm. Operation pressure range of the flat diagrapham is 1 bar. Measured burst pressure of the flat diaphragm is 12 bar. For the samples of the diaphragm with the 90 μm wide reinforcement measured burst pressures are 1.8 times higher than for the flat one. For the samples of the diaphragm with the 40 μm wide reinforcement measured burst pressures are 2.5 times higher than for the flat one. Higher measured burst pressures of the diaphragms with reinforcements show that the improvement is possible on the sensor level by using maskless wet etching technique

SOI piezoresistive low pressure sensor for high temperature environments

Silicon-On-Insulator (SOI) wafers utilizing a novel maskless wet etching technique. The prototype has a structured square diaphragm with a concentric boss. The SOI pressure sensors have piezoresistors dielectrically isolated from each other and from the substrate by silicon dioxide. A high temperature transducer prototype has been made utilizing the fabricated sensor. A high temperature method for pressure measurements has been formed. The transducer prototype performance was measured at temperatures up to 300 0С. These SOI pressure sensors are intended for extreme environmental conditions and high operating temperatures that are often needed in military-grade applications and where it is necessary to perform sensitive low pressure measurements. Some examples include aerospace applications like aircraft engines, wind tunnels, various missiles, etc

A comparison of different convex corner compensation strucutures applicable in anisotropic wet chemical etching of {100} oriented silicon

This paper presents fabrication of microcantilevers on {100} oriented Si substrate by bulk micromachining. Two types of CCC (Convex Corner Compensation) structures, namely ⟨100⟩ oriented simple beam and structure using symmetric rectangular blocks oriented in the ⟨110⟩ direction at the apex of the square peg have been analyzed. Etching solution has been KOH water solution (80 wt. %) at etching temperature of 80 o C. Detailed construction and etching behavior of both structures have been given and explained

Experimental study of PDMS membranes fabricated either by spin coating or transfer bonding to a silicon chip with etched cavity

Nowadays, with no doubt, PDMS, poly(dimethylsiloxane) elastomer is material of choice for microfluidic fabrication because of its unique chemical, optical and mechanical properties. Unfortunately, it is not photo-definable (i.e. not a photoresist) and fabrication of PDMS MEM (micro-electro-mechanical) devices is typically done using soft lithography. Some steps of the process are difficult to perform without manually handling PDMS layers. Next problem to be considered in patterning PDMS membranes is bond strength between membrane and silicon substrate. To investigate this, we fabricated PDMS membranes on silicon either by spin coating Si wafer or transferring previously fabricated PDMS membrane to Si chip with bonding layer on it. PDMS network samples for this research were synthesized with the same composition, which are Sylgard 184 (Dow Corning, USA) silicone elastomer base and silicone elastomer curing agent, volume ratio 10:1. Fabrication of test structures is based on bulk micromachining on ⟨100⟩ oriented Si wafers to fabricate square cavities on which PDMS membranes were realized by one of mentioned procedures. Mechanical testing of PDMS membranes, elastic properties and adhesion strength of membranes with different thicknesses were investigated applying pressurized bulge testing. Pressure was applied to the PDMS membrane via nitrogen gas and the resulting load-deflection curves were monitoring

Etched Parallelogram Patterns with Sides Along <100> and <n10> Directions in 25 wt % TMAH

In this paper, we present and analyze etching of parallelogram patterns in the masking layer on a (100) silicon in 25 wt % TMAH water solution at the temperature of 80 0C. Sides of parallelogram islands in the masking layer are designed along and crystallographic directions. A 3D simulation of the profile evolution from these patterns during etching of silicon using the level set method is also presented. We determined all crystallographic planes that appear during etching in the experiment and obtained simulated etching profiles of these 3D structures. A good agreement between dominant crystallographic planes through experiments and simulations is obtained

Stress Degradation Studies on Zolpidem Tartrate Using LC-DAD and LC-MS Methods

The present study was designed to characterize the possible degradation products of zolpidem tartrate under various stress conditions according to International Conference on Harmonization (ICH) guidelines Q1A(R2). After exposure to light, heat, hydrolysis, and oxidation, the drug significantly degraded under photolytic and acid/base hydrolytic conditions. Degradation resulted in the formation of four key degradants. Degradation products were resolved from each other and the drug by employing an isocratic elution method on Luna C-18 column with mobile phase consisting of methanol-10 mM ammonium acetate (68.4: 31.6, v/v), wherein pH was adjusted to 5.4 with glacial acetic acid. To characterize the degradation products, a method was extended to LC-MS and a mass fragmentation pattern was established using single quad-rupole. The degradants were identified as zolpacid, oxozolpidem, zolpaldehyde, and zolpyridine. Finally, the most possible degradation mechanism of zolpidem tartrate in different environments was proposed