Repeatability related substances

To investigate the effect of both factors (i.e., sample preparation and detector sensitivity), solutions of different concentrations near the ICH reporting limits are prepared by spiking known amounts of related substances into excipients. Each solution is prepared according to the procedure and analyzed repeatedly to determine the S/N ratio. The average S/N ratio from all analyses at each concentration level is used to calculate the QL or DL. The following equation can be used to estimate the QL at each concentration level. Since different concentration levels give different QLs, typically the worst-case QL will be reported as the QL of the method. 

Repeatability of a method can be determined by multiple replicate preparations of the same sample. This can be done either by multiple sample preparations (n = 6) in the same experiment or by preparing three replicates at three different concentrations. In general, one should evaluate results of individual related substances, total related substances, and the consistency of related substance profiles in all experiments. The percent RSD and confidence level of these results are reported to illustrate the method repeatability. 

Consideration of reasonable mechanisms for producing formic acid from an aldose led to the hypothesis that the sugar forms an addition product with the hydroperoxide anion, comparable with an aldehyde sulfite or the addition product of aldoses with chlorous acid (52). The intermediate product (12) could decompose by a free-radical or an ionic mechanism. In the absence of a free-radical catalyst, the ionic mechanism of Scheme VIII seems probable. By either mechanism the products are formic acid and the next lower sugar. The lower sugar then repeats the process, with the result that the aldose is degraded stepwise to formic acid. Addition of the hydroperoxide anion to the carbonyl carbon is in accord with its strong nucleophilic character (53) and with certain reaction mechanisms suggested in the literature (54) for related substances. 

It has been found that closely related substances with almost similar physical and chemical properties which cannot be separated from one another by ordinary means, are adsorbed to different extents on the surface of adsorbents. This facilitates their separation and purification. If a solution containing different solutes is poured down a column filled with a finely divided adsorbent, the solute most readily absorbed is retained on the top layer along with smaller amounts of the other constituent while the less readily adsorbed constituents are held on lower portions of the column. A partial separation of the constituents of the mixture is thus easily achieved. A fuller separation is possible by repeating and modifying the process. 

Following the establishment of specificity, the method(s) should be validated to allow for use in release and stability testing. Such validation is typically less stringent than for final methods (sec Chapter 12), but should demonstrate specificity, linearity, range, accuracy, and analysis repeatability for the API. For related substances, specificity should be demonstrated and the limit of detection (LOD) and limit of quantitation (LOQ) should be established for the API to serve as surrogate values for the LOD and LOQ of impurities for which authentic substances are not available. To achieve a sufficient LOD and simultaneously keep the API in the linear dynamic range of the detector, it may be necessary to use different sample concentrations for the analyses of the API and related substances. It is additionally beneficial to repeat the separation on new columns from different batches to ascertain that the separation obtained can be maintained column to column. 

TLC with multiple development often allows separation of complex mixtures or closely related substances not resolvable with a single development. The plate is repeatedly developed in the same... 

The addition of riboflavin to the system repeatedly caused a small but significant synthesis of cyanocobalamin. More efficient shunting of the synthesis toward cyanocobalamin took place when parts of the riboflavin molecule and related substances were added, e.g. l-amino-3,4-di-methyl-6-D-ribitylaminobenzene l,2-dimethyl-4,5-diaminobenzene and 5,6-dimethylbenzimidazole. These findings seem consistent with the view of Woolley (1951) that the metabolic paths of the two vitamins are closely interconnected. The activity of riboflavin itself in promoting the synthesis of cyanocobalamin need not of course imply that the vitamin is actually broken down to provide a precursor of cyanocobalamin nucleotide. It could equally well be that a common precursor of riboflavin and cyanocobalamin nucleotide is normally available in limiting amounts and is used preferentially in the synthesis of riboflavin. The provision of preformed riboflavin might then spare this precursor for the synthesis of cyanocobalamin. 

Once the extensive validation experiments are complete, minor changes to the method description may be required. Typically, these involve adding validation data (RRFs for the related substances, LOQs, etc.) but may also include slight changes to the system suitability requirements due to data from multiple laboratories. There should not be any fundamental changes that would alter the principles of the methodology or necessitate revalidation unless a portion of the validation failed, suggesting minor method adjustment and repeat of the required validation experiments. 

Abscisic acid is a terpenoid (Fig. 171). Abscisic acid is the name recently proposed. In addition, the older names dormin and abscisin II are still in use. Dormin refers to the fact that abscisic acid brings about the dormancy of buds and abscisin to the fact that abscisic acid can promote the shedding of leaves and fruit. Abscisic acid seems to be ubiquitous in the plant kingdom. Chemically closely related substances exhibiting, to some extent, a similar effect have also been detected repeatedly. 

Tolerance is characterized by reduced responsiveness to the initial effects of a drug after repeated exposure or reduced responsiveness to a related compound (i.e., cross-tolerance). Animal studies have not provided conclusive evidence of tolerance to the effects of the centrally active compounds in toluene or trichloroethane (Moser and Balster 1981 Moser et al. 1985). Observations in humans, on the other hand, have documented pronounced tolerance among subjects who chronically inhale substances with high concentrations of toluene (Glaser and Massengale 1962 Press and Done 1967) and butane (Evans and Raistrick 1987). Kono et al. (2001) showed that tolerance to the reinforcing effects of solvents is comparable to that conditioned by nicotine but less intense than that reported with alcohol or methamphetamine use. 

Substance abuse A maladaptive pattern of substance use characterized by repeated adverse consequences related to the repeated use of the substance. 

In this chapter, we will focus primarily on treatments for the substance use disorders. However, because detoxification during a substance-induced withdrawal is often the first step in treating a substance use disorder, we will discuss withdrawal states to some extent. The substance use disorders include both substance abuse and the more serious substance dependence. Substance abuse consists of a pattern of misuse that causes recurring problems in at least one aspect of life. This can be a failure to fulfill responsibilities at home or work, reckless use of the substance such as drunken driving, repeated substance-related arrests, and ongoing substance use despite resulting problems in family relationships. See Table 6.1 for the diagnostic criteria for substance abuse. 

In aU other situations, nonguideline studies cannot stand alone for a hazard assessment of a substance and thus cannot serve as the sole basis for an assessment of repeated dose toxicity, i.e., cannot be used to identify a substance as being of no concern in relation to repeated dose toxicity. 

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