Reproducibility related substance

For the analysis of OTC residues and its related substances in food and fisheries products, LC-MS/MS is presently the most modern and promising method due to its high sensitivity, reproducibility, and specificity. 

Fig. 10.25. Separation of tipredane (compound 14) from its five related substances (compounds 11-13, 15, 16) by CEC. Column 250 mm x 50 pm i.d. packed with 3 pm Spherisorb ODS-1 mobile phase, acetonitrile-50 mM Tris buffer, pH 7.8, 80 20 (v/v) applied voltage, 15 kV temperature, 15°C electrokinetic injection, 5 kV/15s. From Euerby et al. [63], Journal of Microcolumn Separations, 1997. Reproduced with permission of John Wiley Sons, Inc.

The above statement has lot of details in reference to what is a SIM The statement starts with method validation (refer to Chapter 9). Next, most methods need to be specific (specificity, resolution of active from related substances, peak purity), reproducible (precision), quantitative (recovery, linearity, LOD, LOQ), and able to monitor a change in chemical, physical, and/or microbiological properties of drug products over time (refer to sections on stability testing and mass balance). 

HPLC provides reliable quantitative precision and accuracy, along with a linear dynamic range (LDR) sufficient to allow for the determination of the API and related substances in the same run using a variety of detectors, and can be performed on fully automated instrumentation. HPLC provides excellent reproducibility and is applicable to a wide array of compound types by judicious choice of HPLC column chemistry. Major modes of HPLC include reversed phase and normal phase for the analysis of small (<2000 Da) organic molecules, ion chromatography for the analysis of ions, size exclusion chromatography for the separation of polymers, and chiral HPLC for the determination of enantiomeric purity. Numerous chemically different columns are available within each broad classification, to further aid method development. 

As it is hoped that the issue of polymorphism is resolved during prenomination and early development, it can remain a concern when the synthesis of the drug is scaled up into a larger reactor or transferred to another production site. It is not unlikely that a metastable form identified in prenomination may not be reproduced in later batch products because of some unrecorded conditions in the early phases of development. Related substances, whether identified or not, can significantly alter the predominance of a specific polymorph. To develop a reliable commercial recrystallization process, the following scheme should be followed in the production of candidate drugs ... 

As illustrated by several examples, experimental design methods proved to be very useful in the development of reproducible and robust CE methods for the analysis of related substances in drugs. This includes the analysis of complex mixtures of substances isolated from natural sources and the simultaneous separation of chiral and achiral impurities as well as compounds with multiple... 

A UV-visible spectroscopic study of 3 and related substances revealed a strong solvatochromic effect, which served as the basis of the establishment of a solvent polarity scale (Buncel and Rajagopal, 1989, 1990,1991). The theoretical study of Rauhut et al. (1993) was based on AMI methodology (Dewar and Storch, 1985,1989) but used a double electrostatic reaction field in a cavity, dependent on both the relative permittivity and the refractive index. Nuclear motions interact with the medium through the relative permittivity, but electronic motions are too fast only the extreme high-frequency part of the dielectric constant is relevant. These authors were able to evaluate solvent-specific dispersion contributions to the solvation energy. The calculations reproduced satisfactorily the experimental solvatochromic results for 3 in 29 different solvents. The method has also been successfully applied to other solvatochromic dyes, including Reichardt s .j,(30) betaine. 

The CA index names must not only be unambiguous, unique, and totally reproducible, but also selected so as to bring the names of structurally related substances into juxtaposition in the alphabetic index. CAS has always recognized that, while a unique name is needed for an index and for substance identification, the use of such invariant name in scientific papers is neither practicable nor desirable. 

During current flow, the concentration of reaction products near the surface of the electrode will increase, and a limiting condition may also arise, but for different reasons, which are related to attainment of the solubility limits by given substances. The material precipitating will screen the electrode surface and interfere with a further increase in current. The value of the limiting current will depend on the nature of the deposit formed and is less reproducible than in the previous case specifically, it may depend on time. 

Thin-layer chromatography does not provide quantitative information of the highest precision and accuracy. Linear relationships between the mass of a substance and the logarithm or square-root of the spot area can sometimes be established under very closely controlled conditions. The optical absorbance of a spot determined by reflectance measurements can be similarly related to mass, or the substances can be scraped from the plate and dissolved in a suitable solvent for a spectrometric determination. The main difficulties with area and density measurements lie in defining the boundaries of spots and controlling chromogenic reactions in a reproducible manner. Relative precision can be as good as 1-2% but is more usually 5-10%. 

Heat capacities at high temperatures, T > 1000 K, are most accurately determined by drop calorimetry [23, 24], Here a sample is heated to a known temperature and is then dropped into a receiving calorimeter, which is usually operated around room temperature. The calorimeter measures the heat evolved in cooling the sample to the calorimeter temperature. The main sources of error relate to temperature measurement and the attainment of equilibrium in the furnace, to evaluation of heat losses during drop, to the measurements of the heat release in the calorimeter, and to the reproducibility of the initial and final states of the sample. This type of calorimeter is in principle unsurpassed for enthalpy increment determinations of substances with negligible intrinsic or extrinsic defect concentrations... 

The test is primarily a screening tool relative to reactivity of substances and reaction mixtures and is highly useful for that purpose. The determined initiation temperature is approximate. The energy calculations based on temperature increase and heat capacities are semi-quantitative because of the quasi-adiabatic mode of the system operation. The method of insulating the test cell results in moderate reproducibility of temperature rise and related pressure rise. Another disadvantage is the relatively small sample quantity with respect to full scale quantities thus, there could be a problem in that the sample may not be truly representative. 

The quantitative relations between pressure and boiling point vary from substance to substance, but among organic compounds the variation is not very great, so that the curves here reproduced can in practice very well be used as a guide. 

Neurotoxicity can be defined as any adverse effect on the structure or function of the nervous system related to exposure to a chemical substance (US-EPA 1998, OECD 2004c). According to the TGD (EC 2003), neurotoxicity can be defined as the induction by a chemical of adverse effects in the central or peripheral nervous system, or in sense organs and a substance is neurotoxic if it induces a reproducible lesion in the nervous system or a reproducible pattern of neural dysfunction. ... 

Singleton and Esau (I) reviewed the methods for phenol analysis of wine. They pointed out that study would be greatly advanced if one could determine the total content of phenolic substances and express it in such a way that analysis of subclasses of phenols could be related to the original total and a balance sheet could be obtained. One could then say, for example, this wine has a total phenolic content of 1200 mg/liter calculated as gallic acid, and of that total, cinnamic acid derivatives account for 200 mg/liter, anthocyanins for 300 mg/liter, other small flavonoids for 200 mg/liter, and condensed tannins complete the total with 500 mg/liter of gallic acid equivalent. To accomplish this, the total phenol analysis not only must meet ordinary criteria of reproducibility and precision, but it also must be based on chemical relationships such that fractions determined separately can be converted to units of the total. Of course when clearcut fractionation can be accomplished by... 

The concept of temperature can be defined operationally that is, in terms of a set of operations or conditions that define the concept. To define a temperature scale operationally we need (1) one particular pure or defined substance (2) a specific property of that substance that changes with a naive sense of degree of hotness (i.e., temperature) (3) an equation relating temperature to the specific property (4) a sufficient number of fixed points (defined as reproducible temperatures) to evaluate the constants in the equation in (3) and (5) the assignment of numerical values to the fixed points. Historically, many different choices have been made with respect to the five conditions listed above, and this, of course, has resulted in many temperature scales. 

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