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.
Beschreibung
vor 20 Jahren
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.
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.
Weitere Episoden
Kommentare (0)