Recrystallized HI-6 dimethylsulfate
Inventors
Blumberg, Shawn T. • MIGUEL, Paul W.
Assignees
Southwest Research Institute SwRI
Publication Number
US-11986779-B2
Publication Date
2024-05-21
Expiration Date
2040-11-10
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Abstract
The present invention is directed at the synthesis and characterization of recrystallized HI-6 dimethylsulfate (DMS). The method can comprise dissolving HI-6 DMS in an alkyl-based glycol and adding an antisolvent to recrystallize HI-6 DMS or dissolving HI-6 DMS in methanol and adding dimethoxy ethane or dimethyl formamide as the antisolvent to recrystallize HI-6 DMS. The recrystallized HI-6 DMS indicates a resistance to moisture absorption and/or a DSC melting point onset (MP Onset) at least at or above 160.0° C.
Core Innovation
The invention is focused on a method for synthesizing and characterizing recrystallized HI-6 dimethylsulfate (DMS), particularly targeting the preparation of its solvates and hydrates. The described methods include dissolving HI-6 DMS in alkyl-based glycols such as ethylene glycol or 1,2-propane diol, followed by the addition of antisolvents like tert-butanol to induce precipitation and recrystallization. Alternative methods involve dissolving HI-6 DMS in methanol and then adding dimethoxy ethane or dimethyl formamide as antisolvents to achieve recrystallization.
The background identifies the need for improved forms of bis-pyridinium oxime antidotes, especially HI-6 DMS, used as OPNA reactivators, in response to challenges such as instability in aqueous environments, difficulties in developing stable injectable formulations, and the tendency of existing solids to absorb moisture. The invention addresses these problems by providing a form of HI-6 DMS that demonstrates resistance to water absorption and greater thermal stability, as indicated by a DSC melting point onset of at least 160.0°C.
Experimental data confirms that the process results in recrystallized HI-6 DMS which does not absorb water over a seven-day period at ambient temperature and humidity, particularly when specific solvent and antisolvent ratios are used. Characterization through DSC, X-ray powder diffraction, and NMR analyses further support the formation of stable solvates and hydrates with controlled water content and improved performance traits.
Claims Coverage
There is one independent claim, which defines the primary inventive feature for producing a solvate and hydrate of HI-6 DMS.
Method for making a solvate and hydrate of HI-6 DMS with resistance to water absorption
The main inventive feature includes: - Dissolving (1-(2-(hydroxyiminomethyl)pyridinium)-3-(4-carbamoylpyridinium)-2-oxapropane) dimethanesulfonate in an alkyl-based glycol (either ethylene glycol or 1,2-propane diol). - Adding an antisolvent comprising tert-butanol to induce precipitation and form a solvate and hydrate of the compound. - The resultant solvate and hydrate does not absorb water over a seven-day period when kept at ambient temperature and humidity conditions.
The independent claim centers on a method for producing a moisture-resistant solvate and hydrate form of HI-6 DMS using specific solvent and antisolvent systems.
Stated Advantages
The recrystallized HI-6 DMS demonstrates resistance to water absorption, enhancing shelf life stability.
The process yields HI-6 DMS with relatively low levels of hygroscopicity, making it suitable for injectable formulations.
The invention produces a solid form that is relatively stable at high temperatures for prolonged periods.
The recrystallized HI-6 DMS shows improved thermal properties with a DSC melting point onset at or above 160.0°C.
Documented Applications
Use as an OPNA (organophosphorus nerve agent) reactivator in injectable formulations, including autoinjectors.
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