Pharmaceutical analysis beyond compendial requirements

Abstract

Recent ICH recommendations on test procedures and acceptance criteria for new drug substances of synthetic chemical origin and new drug products produced from them (Q6A) sets the frame for registration of new chemical entities. These requirements are automatically applied by all pharmaceutical companies to products in late developmental phases. Furthermore, and justifiably so, they do not provide any guideline for setting specifications other than those for residual solvents and residues of heavy metal catalysts. During development of new chemical entities, ICH requirements represent a minimum beyond which additional testing has to be carried out in order to accumulate a body of scientific data which may ultimately permit simplified testing. This information is furthermore needed for drafting of registration files. This presentation will provide information on salt and polymorph selection, as well as morphology of particles. The need for more sophisticated techniques for assay of trace impurities by LC/MS will be illustrated with examples of alkylating agents. Complementary information from techniques such as CE, orthogonal to HPLC, is often needed to ensure absence of additional impurities. Finally, beyond compendial characterisation of hydroxypropylmethylcellulose, a commonly used excipient, by size exclusion chromatography with triple detection will be described.

Pharmaceutical impurities and degradation products: Uses and applications of NMR techniques

“…An 800 MHz NMR spectrometer equipped with a 1 H{ 13 C/ 15 N} Triple Resonance 13 C Enhanced Salt Tolerant Cold Probe was employed, where 2D experiments could be run overnight with 10 mg samples. 1 H-1 H, direct 1 H-13 C, long-range 1 H- 13 C scalar and dipolar spin-spin connectivities were established from a combination of 1D ( 1 H, 13 C) and 2D (gHSQCAD, zTOCSY, gHMBCAD, NOESY and ROESY) NMR experiments. A DBPPSTE DOSY diffusion experiment was also performed.…”

“…NMR was employed as an orthogonal technique to HPLC for quantitative analysis of potential impurities of alanine. Organic acids such as malic, fumaric, aspartic and glutamic, were assessed by 1 H NMR spectroscopy with 400 and 600 MHz spectrometers using 128 and 16 scans, respectively [35,98]. In addition, L-Isoleucine and L-leucine present as impurities in L-valine are responsible for some of the process impurities found in lopinavir [100].…”

“…As a result, the current enoxaparin USP monograph contains a 13 C NMR spectroscopy test and the heparin sodium monograph includes a 1 H NMR identification test [103]. 1 H NMR spectroscopy is very sensitive to minor structural variations, allowing easy identification of the repeating pattern of the disaccharide units of heparin. Therefore, not surprisingly NMR spectroscopy proved to be a powerful tool for quali-and quantitative analysis of compounds related to the extraction and purification processes of heparin, including dermatan sulfate, chondroitin sulfate A, galactosamine and 3-O-acetylated uronic acid derived impurities [104][105][106][107].…”

“…Quality control methods are regulated in the pharmacopeias and other documents, which are continuously revised in order to keep updated drugs, excipients, and also their methods for analysis. Furthermore, internationally agreed recommendations, such as those issued by the International Conference on Harmonization (ICH) are steadily moving pharmaceutical analysis beyond compendial requirements, with the advantage of the most modern analytical technologies [1]. Pharmaceutical impurities are the unwanted chemicals that remain with the API, develop during formulation, or upon degradation of both API and drug products.…”

“…NMR spectroscopy as an analytical tool: Advantages and disadvantages NMR spectroscopy, an information rich analytical tool, is capable to deliver the most complete molecular structural information, including atomic connectivity, spatial geometry, conformation, and stereochemistry. 1 H is the most simple and sensitive, and therefore most frequently detected nucleus. Many more isotopes of elements in the periodic table ( 11 B, 13 C, 15 N, 17 O, 19 F, 31 P, etc.)…”