Intermediates, impurity profile

Figure 4.8. Comparison of impurity profiles for the same chemical intermediate from two different suppliers. The impurity peak-areas for each chromatogram were tallied in 0.02 area-% bins for each vendor, the data was normalized by dividing by the number of chromatograms. Vendor A s material has many more peaks in the 0.05-0.2% range, which drives the total impurity level to =5.2% (vs. 1.9 for Vendor B) for <0.2% the number of excess peaks above 0.2% does not appear as dramatic, but greatly adds to the total impurity level = 13.3 v.v. = 2.3% ...

Figure 4.18. Peak-size correlation in an HPLC-chromatogram. The impurity profile of a chemical intermediate shown in the middle contains peaks that betray the presence of at least two reaction pathways. The strength of the correlation between peak areas is schematically indicated by the thickness of the horizontal lines below the chromatogram. The top panel gives the mean and standard deviation of some peak areas (n = 21) the two groups of peaks immediately before and after the main peak were integrated as peak groups.

A piperidene-based intermediate was found to crystallize as either an anhydrate or a hydrate, but the impurity profile of the crystallized solids differed substantially [26], Considerations of molecular packing led to the deduction that there was more void volume in the anhydrate crystal structure than in that of the hydrate form, thereby facilitating more clathration in the anhydrate than in the hydrate phase. This phenomenon was led to a decision to crystallize the hydrate form, since lower levels of the undesired impurity could be occluded and greater compound purity could be achieved in the crystallization step. 

FIGURE 7 (a) Impurity profile of Intermediate produced by the new process. Peaks after 8 min were impurities that were not previously observed when the Intermediate was produced via the old process, (b) Chromatogram of the drug substance made from intermediate of poor quality. Peak at 22 min retention time is the drug substance Impurity at 36 min retention time was a new impurity and failed specifications. 

FIGURE 8 Impurity profile using a new method. Intermediate peaks are at 10 min while those in the range of 23-30 min are the trimer peaks which were not separated using the previous method. Peaks prior to 10 min are the solvent front and other known impurities. 

The development of an impurity profile for a dosage form follows many of the same principles as in the drug substances however, instead of identifying all precursors and intermediates, the analyst will identify and place all of the components of the dosage form (excipients, preservatives, and others) and their affiliated impurity profiles within a master profile. Here again additional method development may be needed to... 

In cases where a general QL is required, as in pharmaceutical analysis, it is essential to define a realistic QL (or DL) for the analytical procedure, independently from the equipment used, because this limit has important consequences (e.g., for the consistent reporting of impurities or for method transfer). They may be derived by taking QL (or DL) from various instruments into account ( intermediate QL, during the development process) or can be defined taking the requirements of the control test (specification limits imposed by toxicology or by a qualified impurity profile) into consideration. For example, a QL which... 

Characterization starts once the synthetic route has been selected, although there will be opportunities to modify the route if the changes do not impact the final solid state or impurity profile of the final active pharmaceutical ingredient. The primary objective is to understand, through experimentation, the chemical and physical chemical processes involved in the transformation of raw materials to intermediates and products. The primary outcome is a process definition that includes the order of manufacturing steps, process parameter control methodology, process parameter limits, raw material specification, and diagnostic metrics. 

Metrics for purity may simply be a statement of the purity or the impurity profile of the final product for any given process. However, if one is interested in purity from a perspective of greening syntheses, we might be more interested in how many times we isolate intermediates and or how many times we recrystallize the final substance to achieve the desired purity. Another point worthy of consideration is the idea that quality is defined as delivering the exact requirements needed in the eyes of the customer, and it is therefore possible for higher purity to go beyond the customer s needs. Additional purification steps will, in almost every case, add to the mass and energy intensity of a product without necessarily adding value to the customer. 

Finally, the process design will require crystalline intermediates and the use of telescoped reaction sequences that are robust enough to provide clean intermediates with defined impurity profiles. This is an essential for commercial viability. 

One critical factor that the team needed to be cognizant of was the impurity profile of penultimate intermediate emd API (advance pharmaceutical intermediate) that would be derived from a new synthesis. A significant number of clinical trials had already been conducted with kilograms of material that had already been synthesized. A new batch of API that contained an elevated level of an impurity or that contained a new impurity could not immediately be used for clinical trials without a time consuming qualification process. Hence, the task at hand was the discovery and development of a more efficient synthesis with the caveat that no new impurities could be present in the final bulk drug. 

Three synthetic priorities were set for this route 1) development of an efficient and economical way to access lactam lactol 69 2) optimization of the acetalization, effecting a crystallization-induced resolution, and isolation the diastereomerically pure desired acetal 71 3) investigation of the aryl Grignard addition and demonstration of the envisioned debenzylation/reduction step. In addition, a significant chore of ensuring that secondary amine 5 was sufficiently pure was of paramount importance. Assiduous analysis of secondary amine 5 impurity profiles was necessary to assure that this penultimate intermediate, as well as the final drug substance that would result from this process, was identical (or better) compared with previous batches. The final step in the synthesis. 

Appropriate tests should be conducted on reprocessed batches to ensure that reprocessing does not adversely affect the quality or purity of the API or intermediate. These tests should include, as appropriate, purity, physical attributes, and impurity profiles, in all cases, the significance of the nonconformance and its impact on the critical quality attributes of the API or intermediate should determine how much analytical data is sufficient to justify the reprocessing. 

GC is used widely for analysis in the pharmaceutical industry, and applications for assays and impurity profiles for raw materials, intermediates and APIs are commonplace. GC is often chosen as the method of analysis when compounds have poor or widely different UV chromophores. A common case is when the... 

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