Active pharmaceutical structure elucidation

The discovery of novel, small molecules through screening secondary microbial metabolites is still an important and fruitful activity in pharmaceutical and biotech industries. However, the isolation and structure elucidation of lead compounds is often a tedious and time-consuming process especially when the compounds being sought may only be present in infinitesimal quantities. When one considers, for example, that microorganism extracts have thousands of constituents, the difficulties in separating out one particular component can be appreciated. 

FIGURE 7 Representative data set for the characterization and structure elucidation of low-level related substances in an active pharmaceutical ingredient (API). Top panel—Mass chromatogram (ESI) representing the 1200 mass spectra (one per second) acquired throughout the HPLC separation. Mass spectra are acquired to determine nominal and/or exact molecular masses183 for all observed analyte ions. Subsequent CID experiments yield fragmentation (product-ion MS/MS) spectra that contain structural information about the ions of interest. Second panel—CID product-ion spectrum of related substance A (m/z 132 for [M+H]+). Third panel—CID product-ion spectrum of related substance B (m/z 156 for [M + H]+). Bottom panel—CID product-ion spectrum of the API, peak C (m/z 315 for [M + H]+). 

The characterization (identification or structure elucidation) of chemical compounds at trace levels in complex matrices is a crucial activity during many stages of the pharmaceutical development process. Complete and unequivocal determination of chemical structure is the product of a comprehensive and coordinated process that involves a variety of instrumental techniques and information from various sources (e.g., synthetic scheme, storage conditions, nature, and composition of excipients, published scientific literature, personal experience, etc.). The source, purity, and... 

Dr. Mukund Chorghade then introduces readers to the field of process chemistry the quest for the elucidation of novel, cost-effective, and scalable routes for production of active pharmaceutical ingredients. The medicinal chemistry routes used in the past have often involved the use of cryogenic reactions, unstable intermediates, and hazardous or expensive reagents. A case smdy of the development of a process for an antiepileptic drug is presented readers will also see how problems in the isolation, structure elucidation, and synthesis of metabolites were circumvented. Described is an interesting application of the technology of metalloporphyrins assisted metabolite prediction, estimation, quantitation and synthesis. 

Structure determination from PXRD data has been regarded as an invaluable tool to elucidate the structures of active pharmaceutical ingredient (API) co-crystals [41]. Trask et al. described the mechanochemical synthesis of several caffeine co-crystal... 

Hence, a multiplicity-edited H-C HSQC and a H—N HMBC were UIC transformed into a C—N correlation, referred to as C-N HSQC-HMBC [42]. This otherwise inaccessible —spectrum of a few milligrammes of strychnine was constructed after a total recording time of less than 4 h for both component spectra. The spectral representation was predicted to be of interest for the structure elucidation of pharmaceutical actives, agrochemicals and alkaloids due to their elevated nitrogen content. 

There is a growing interest in the pharmaceutical properties of compounds derived from lichens. However, relatively few lichen substances have been screened in detail for biological activity and therapeutic potential, due principally to difficulties in obtaining them in quantities and purities sufficient for structural elucidation and pharmacological testing. Additionally, precise lichen determinatirHi is essential and requires taxonomic expertise (Boustie and Grube 2005). 

The technique is highly suitable for quality assessment of the active pharmaceutical ingredients (APIs) or excipients. Quantitative NMR is useful in drug analysis to determine the level of impurities and to elucidate their structure, as well as to evaluate the content of residual solvents. It enables determination the isomeric composition, i.e., the ratio of diastereomers and the ee by means of chiral additives. It also allows for the measurement of molar ratios of (proton-ated) basic drugs and (deprotonated) organic acids in respective salts. 

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