Tools for the Quality Control of Pharmaceutical Heparin

Abstract

Heparin is a vital pharmaceutical anticoagulant drug and remains one of the few naturally sourced pharmaceutical agents used clinically. Heparin possesses a structural order with up to four levels of complexity. These levels are subject to change based on the animal or even tissue sources that they are extracted from, while higher levels are believed to be entirely dynamic and a product of their surrounding environments, including bound proteins and associated cations. In 2008, heparin sources were subject to a major contamination with a deadly compound—an over-sulphated chondroitin sulphate polysaccharide—that resulted in excess of 100 deaths within North America alone. In consideration of this, an arsenal of methods to screen for heparin contamination have been applied, based primarily on the detection of over-sulphated chondroitin sulphate. The targeted nature of these screening methods, for this specific contaminant, may leave contamination by other entities poorly protected against, but novel approaches, including library-based chemometric analysis in concert with a variety of spectroscopic methods, could be of great importance in combating future, potential threats.

Heparin‐Derived Theranostic Nanoprobes Overcome the Blood–Brain Barrier and Target Glioma in Murine Model

“…[ 29 ] To achieve this, we first grafted disulfide hydrazide groups and dopamine moiety to the unfractionated heparin (UHP) by conjugating 3,3’‐dithiobis(propanoic hydrazide) or DTPH (8% with respect to the carboxylate groups) and dopamine units (13% with respect to the carboxylate groups) following carbodiimide coupling chemistry as estimated by UV–vis spectroscopy. The NMR analysis of HP and its derivatives are complex [ 42 ] as HP polymer is composed of N ‐acetyl glucosamine and glucuronic acid as the repeat units with dispersed iduronic acid in its backbone, thus making the assignment of reference signal difficult. In addition, the complex sulfation pattern in the HP further complicates the NMR analysis.…”

Pharmacology of Heparin and Related Drugs: An Update

“…Since the episode of contamination of pharmaceutical heparin with OSCS in 2007-2008 that led to serious adverse events associated with the clinical use of certain heparin preparations, including fatalities (Chess et al, 2012), development of new methods for the assessment of heparin continues (Devlin et al, 2019). It has now been established that the contaminant OSCS was added at an early stage of heparin manufacture, so methods applicable to the efficient screening of crude heparin samples rather than API and final product are particularly useful (Mauri et al, 2017b;Mendes et al, 2019) in ensuring such contamination does not occur in the future.…”

Heparin-derived theranostic nanoprobes overcome the blood brain barrier and target glioma in murine model

“…[29] To achieve this, we first grafted disulfide hydrazide groups and dopamine moiety to the unfractionated heparin (UHP) by conjugating 3,3'-dithiobis(propanoic hydrazide) or DTPH (8% with respect to the carboxylate groups) and dopamine units (13% with respect to the carboxylate groups ) following carbodiimide coupling chemistry as estimated by UV-Vis spectroscopy. The NMR analysis of HP and its derivatives are complex [37] as HP polymer is composed of N-acetyl glucosamine and glucuronic acid as the repeat units with dispersed iduronic acid in its backbone, thus making the assignment of reference signal difficult. In addition, the complex sulfation pattern in the HP further complicates the NMR analysis.…”