Solvent impurities, routes

However, where a starting materia has been prepared by a method liable to leave impurities not controlled by the monograph, these impurities and their maximum tolerance limits must be declared and a suitable test procedure described. For example, changing a route of synthesis might lead to different solvent impurities, catalysts or related substances. NMR techniques are, of course, particularly useful for identifying new organic impurities if they can be isolated in sufficient quantities. 

Illicit cocaine is extracted from coca leaf in three stages. This is usually done in three different laboratories that can be hundreds of miles apart, by a solvent-extraction route. In the final step at a crystal lab , the cocaine molecules are dissolved in an organic solvent such as ether (ethoxyethane) and insoluble impurities are filtered off. To this filtrate is added a mixture of concentrated HCl and propanone, then cocaine hydrochloride crystallizes out. Other solvents like butanone are also used. 

The first step on transfer of the sythesis is to evaluate the discovery route, looking particularly at overall yield and purity, as well as parameters such as cost of production (cost of starting materials, solvents, labor and overhead, and disposal of waste stream), ease of removal of impurities or catalyst from products, and the degree of hazard associated with solvents, reactants, intermediates, and products. The route used in discovery is... 

Meanwhile attempts to find an air oxidation route directly from p-xylene to terephthalic acid (TA) continued to founder on the relatively high resistance to oxidation of the /Moluic acid which was first formed. This hurdle was overcome by the discovery of bromide-controlled air oxidation in 1955 by the Mid-Century Corporation [42, 43] and ICI, with the same patent application date. The Mid-Century process was bought and developed by Standard Oil of Indiana (Amoco), with some input from ICI. The process adopted used acetic acid as solvent, oxygen as oxidant, a temperature of about 200 °C, and a combination of cobalt, manganese and bromide ions as catalyst. Amoco also incorporated a purification of the TA by recrystallisation, with simultaneous catalytic hydrogenation of impurities, from water at about 250 °C [44], This process allowed development of a route to polyester from purified terephthalic acid (PTA) by direct esterification, which has since become more widely used than the process using DMT. 

Regarding production of bulk drug substances, specifications for contaminants should be established for all solvents used in the process. A comparison should be performed between the manufacturer s Certificate of Analysis and the submitted specifications, and any discrepancies should be justified. A full description for the route of synthesis should be given, as this is important for the testing and control of impurities and process solvent residues. The FDA expects that, at the time of submission, it will be determined if the drug substance exists in a multiple solid state form (racemic mixture stereoisomer) and whether this affects the dissolution and bioavailability of the drug product. 

Testing for solvent content in intermediates may need to be performed if a critical amount of residual solvent(s) remaining in the intermediate can alter the next step of the process. Knowledge of the solvent content in regulatory starting materials may help the development chemist to understand the synthetic route and predict potential process-related impurities. Knowing the solvents used in a process allows the development chemist to look for possible compound-solvent interactions which can lead to the formation of impurities. 

Examination of the synthetic route used in production allows for the prediction of potential residual synthetic impurities present in the drug substance. The API structure allows for the postulation of degradation pathways via hydrolytic, oxidative, catalytic, and other mechanisms. Both of these evaluations serve to facilitate the interpretation of (subsequent) identification tests. An examination of the physicochemical properties also allows for the rational establishment of method screening experiments by precluding certain conditions. For example, the use of normal-phase HPLC will be eliminated if the API is a salt or shows limited solubility in nonpolar organic solvents. Similarly, if the API (or suspected related substances) has no significant chromophore above 250 nm, the use of tetrahydrofuran (THE) and other solvents as mobile-phase components is severely limited. For compounds with an ionizable group, variation of pH will have considerable influence on elution behavior and can be exploited to optimize the selectivity of a reversed-phase separation. 

Acute Toxicity. There is a clear requirement for single-dose studies by relevant routes of exposure to determine lethal toxicity (LD50 or timed LC50), and sublethal injuring potential with dose-response relationships, including a no observable adverse effect level (NOAEL). In addition to testing the pure material, it is advisable to study the technical material to include any impurities that may be in the material used for munitions, and also determine the influence of variants on acute toxicity for example, solvents, additives, and the effect of pyrotechnic decomposition products. 

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