Untersuchungen zur schnellen Freigabe von HI-6 Dichlorid und HI-6 Dimethansulfonat aus verschiedenen Autoinjektorsystemen. Neue Aspekte des Stabilitätsverhaltens dieser Salze und ihrer ungepufferten, konzentrierten Lösungen.

HI-6 Dichloride or HI-6 Dimethanesulfonate are potent acetylcholinesterase reactivators especially in cases of life-threatening poisoning by sarin, VX or cyclosarin. About 1.0 mmol of such a bispyridinium salt concomitantly given with 2 mg atropine is sufficient for first aid. Because of its instability in water, combinations of dry HI-6 powder with atropinesulfate solutions are available in autoinjectors. Since the salt is to be dissolved within seconds i.e. by shaking, the dimethanesulfonate salt proved to be superior even at 5°C in simulations with injector devices. The above doses were delivered within 10 seconds at 5°C, handling inclusive, using devices manufactured by ASTRA. The observed surmountable pressure of 1.4 bar is anticipated to allow a complete dose to be injected even in contracted muscles. Prototypes of Meridian Medical Technologies injectors were designed to be easier to handle. They were tested in a newly developed fast fraction-collector. At 5°C they delivered 1.2 mmol dimethanesulfonate against 1.2 bar in only 5 seconds. Forcing the atropine solution through a dry HI-6 powder-bed during the injection dissolved the salt very efficiently. However, this lead to highly viscous solutions with osmotic pressure peaks of up to 3000 mOsmol. Consequently, the ejected atropine dose was lowered to only 1.2 mg. Possible improvements to both devices are discussed by means of the Noyes-Whitney equation. Insufficient moisture barriers in the injector can lead to unwanted highly concentrated HI-6 solutions at the crystals’ surfaces. As a result of yet unknown pH-lowering reactions in unbuffered solutions of 350-400 mM, the so called „HI-6 acid“ is formed in surprisingly high amounts. This known hydrolysis product of HI-6 is deaminated in the isonicotinic part of the molecule. It could be isolated at a purity level of up to 94 mol% from degraded HI-6 solutions and be characterised. Reactivation tests on human erythrocytes that were fully inhibited by VX, sarin or cyclosarin didn’t show any HI-6 disturbance nor remarkable reactivation potency of the acid. But this findings don’t still explain a reported dramatic loss in efficacy to 1/6 when treating sarin-poisoned mice with an HI-6 quality which contained an unknown impurity. Certain polymorphic forms of HI-6 Dimethanesulfonate exhibit a high crystal water content which is released as moisture during some weeks storage, even at 5°C. Therefore a properly guided manufacturing process is necessary to prevent a consecutive degradation of the salt.

Level thesis:degree_level

thesis.doctoral

Grantor dc:publisher

Ludwig-Maximilians-Universität

Year

2004

Author dc:creator

• Hartwich, Wilhelm

Repository record source_url

https://edoc.ub.uni-muenchen.de/2091/

OAI identifier oai:identifier

oai:edoc.ub.uni-muenchen.de:2091