U.S. patent application number 14/054194 was filed with the patent office on 2015-04-16 for point of use generation of amyl nitrite.
The applicant listed for this patent is Southwest Research Institute. Invention is credited to Darrel W. JOHNSTON, Joseph A. McDONOUGH, Paul M. THOMPSON.
Application Number | 20150105475 14/054194 |
Document ID | / |
Family ID | 52683277 |
Filed Date | 2015-04-16 |
United States Patent
Application |
20150105475 |
Kind Code |
A1 |
McDONOUGH; Joseph A. ; et
al. |
April 16, 2015 |
POINT OF USE GENERATION OF AMYL NITRITE
Abstract
The present disclosure relates to devices and methods for the
preparation of amyl nitrite formulations at a point of use location
from relatively shelf-stable reagents employing acidic cationic
exchange resins.
Inventors: |
McDONOUGH; Joseph A.;
(Helotes, TX) ; JOHNSTON; Darrel W.; (Boerne,
TX) ; THOMPSON; Paul M.; (San Antonio, TX) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Southwest Research Institute |
San Antonio |
TX |
US |
|
|
Family ID: |
52683277 |
Appl. No.: |
14/054194 |
Filed: |
October 15, 2013 |
Current U.S.
Class: |
514/740 ;
558/488; 604/191 |
Current CPC
Class: |
C07C 203/00 20130101;
C07C 201/04 20130101; C07C 201/04 20130101 |
Class at
Publication: |
514/740 ;
558/488; 604/191 |
International
Class: |
C07C 201/04 20060101
C07C201/04; A61M 5/19 20060101 A61M005/19 |
Goverment Interests
GOVERNMENT FUNDING
[0001] This invention was made with United States Government
support under Contract No. HHSO100201100038C awarded by the
Department of Health and Human Services, Assistant Secretary for
Preparedness and Readiness, Office of Acquisitions Management,
Contracts and Grants. The Government has certain rights in this
invention.
Claims
1. A method for preparing amyl nitrites of the formula
C.sub.5H.sub.11ONO comprising: forming a mixture of amyl alcohol of
the formula C.sub.5H.sub.11OH with a nitrite of the formula
MNO.sub.2 in an aqueous medium wherein M represents a metal cation
selected from an alkali metal or alkali earth metal; exposing said
mixture to an acidic cationic exchange resin and forming amyl
nitrite.
2. The method of claim 1 wherein said acidic cationic exchange
resin comprises a sulfonic acid resin comprising a polymer formed
from polymerization of the mixture of styrene monomer and
divinylbenzene and having the structure: ##STR00006##
3. The method of claim 1 wherein said amyl alcohol comprises
3-methyl butyl alcohol.
4. The method of claim 3 wherein said amyl nitrite comprises
3-methyl butyl nitrite.
5. The method of claim 1 wherein said nitrite of the formula
MNO.sub.2 comprises NaNO.sub.2.
6. The method of claim 1 wherein said amyl nitrite is exposed to a
base to neutralize nitrous acid (HNO.sub.2).
7. A method for the administration of amyl nitrite comprising:
supplying a first sealed compartment which contains amyl alcohol
(C.sub.5H.sub.11OH), a second sealed compartment which contains
nitrite of the formula MNO.sub.2 in an aqueous medium wherein M
represents a metal cation selected from an alkali metal or alkali
earth metal; and a third sealed compartment which contains an
acidic cationic exchange resin; wherein said first and second
sealed compartments are opened and said amyl alcohol and said
nitrite are introduced into said third sealed compartment and said
amyl alcohol is converted to amyl nitrite (C.sub.5H.sub.11ONO).
8. The method of claim 7 wherein said acidic cationic exchange
resin comprises a sulfonic acid resin comprising a polymer formed
from polymerization of the mixture of styrene monomer and
divinylbenzene and having the structure: ##STR00007##
9. The method of claim 7 wherein said amyl alcohol comprises
3-methyl butyl alcohol.
10. The method of claim 9 wherein said amyl nitrite comprises
3-methyl butyl nitrite.
11. The method of claim 7 wherein said nitrite of the formula
MNO.sub.2 comprises NaNO.sub.2.
12. The method of claim 7 wherein said device comprises a
syringe.
13. The method of claim 7 wherein said sealed compartments comprise
ampoules.
14. The method of claim 7 wherein said method is employed for
treatment of cyanide poisoning.
15. The method of claim 7 wherein said method is employed for
treatment of H.sub.2S poisoning.
16. A device for the delivery of amyl nitrite comprising: a. a
first sealed compartment containing which contains amyl alcohol
(C.sub.5H.sub.11OH) b. a second sealed compartment which contains
nitrite of the formula MNO.sub.2 in an aqueous medium wherein M
represents a metal cation selected from an alkali metal or alkali
earth metal; and c. a third sealed compartment which contains an
acidic cationic exchange resin.
17. The device of claim 14 wherein said device comprises a
syringe.
18. The device of claim 14 wherein said amyl alcohol comprises
3-methyl butyl alcohol.
19. The device of claim 14 wherein said nitrite of the formula
MNO.sub.2 comprises NaNO.sub.2.
Description
FIELD OF THE INVENTION
[0002] This disclosure relates to the preparation of amyl nitrite
formulations at point of use from relatively shelf stable reagents,
employing acidic cationic exchange resins. The amyl nitrite so
produced may be used as an antidote for cyanide and/or hydrogen
sulfide poisoning as well as high blood pressure.
BACKGROUND
[0003] Amyl nitrite (C.sub.5H.sub.11ONO) is a known vasodilator and
expands blood vessel to lower blood pressure. It is therefore
employed to treat heart disease and angina. In addition, amyl
nitrite is used as an antidote for cyanide poisoning where it acts
as an oxidant to induce the formation of methemoglobin which in
turn can attenuate cyanide as cyanomethemoglobin. The alkyl group
is generally unreactive and the chemical and biological properties
are primarily due to the nitrite (ONO) group.
[0004] U.S. Pat. No. 3,106,511 relates to medicament compositions
containing amyl nitrite and to their preparation and use. U.S. Pat.
No. 4,309,303 relates to a method of stabilizing liquid alkyl
nitrites by adding ethyl hydroxyethyl cellulose, calcium silicate
and mixtures thereof and mixing to produce solid state compositions
and to stabilize compositions thereof. U.S. Patent Publication No.
2003/0149292 relates to the continuous synthesis of alkyl nitrites
by reacting an alcohol with an inorganic nitrite in an acidic
medium.
[0005] However, amyl nitrite's utility as a field antidote
treatment remains limited by its drug product stability
characteristics (presently 2 year storage at 2-8.degree. C. and
limited storage at 25.degree. C.). It is also known that amyl
nitrite is unstable unless protected for oxygen and light. Thus,
even with stabilization it cannot be left unprotected for
relatively long periods of time.
[0006] In addition, amyl nitrite is administered by nasal
inhalation, which makes it difficult to determine dose level and
the amount of amyl nitrite that is delivered (as measured by blood
methemoglobin concentration) is relatively low. Additionally, due
to unknown dose delivery, there has been no dose to efficacy or
dose to safety relationship established.
[0007] It is also useful to note that amyl nitrite is a relatively
low viscosity and volatile fluid with a boiling point of
97-99.degree. C. As noted, it is typically employed in drug form by
inhalation of vapors of the liquid. Accordingly, the relative high
volatility will separately reduce the efficacy of a dose through
evaporation away from the target zone or uncontrolled release.
SUMMARY
[0008] A method for preparing amyl nitrites of the formula
C.sub.5H.sub.11ONO comprising forming a mixture of amyl alcohol of
the formula C.sub.5H.sub.11OH with a nitrite of the formula
MNO.sub.2 in an aqueous medium wherein M represents a metal cation
selected from an alkali metal or alkali earth metal. The mixture
may then be exposed to an acidic cationic exchange resin which
results in the formation of amyl nitrite.
[0009] In addition, the present disclosure relates to a method for
the administration of amyl nitrite wherein one supplies a first
sealed compartment which contains amyl alcohol (C.sub.5H.sub.11OH),
a second sealed compartment which contains nitrite of the formula
MNO.sub.2 in an aqueous medium wherein M represents a metal cation
selected from an alkali metal or alkali earth metal; and a third
sealed compartment which contains an acidic cationic exchange
resin. The first and second sealed compartments are opened and the
amyl alcohol and the nitrite are introduced into the third sealed
compartment and the amyl alcohol is converted to amyl nitrite
(C.sub.5H.sub.11ONO). The method may be employed for the treatment
of cyanide poisoning and/or H.sub.2S poisoning in a human or
animal.
[0010] Finally, the present disclosure relates to a device for
delivery of amyl nitrite. The device comprises a first sealed
compartment which contains amyl alcohol (C.sub.5H.sub.11OH), a
second sealed compartment which contains nitrite of the formula
MNO.sub.2 in an aqueous medium wherein M represents a metal cation
selected from an alkali metal or alkali earth metal, and a third
sealed compartment which contains an acidic cationic exchange
resin.
[0011] As discussed more fully herein, the above device and
associated methods offer a procedure to now produce amyl nitrite
from stable reagents at the time of desired administration of amyl
nitrite to a selected patient. Accordingly, a shelf-stable point of
use protocol is now disclosed and provided for therapeutic amyl
nitrite administration.
FIGURES
[0012] The above mentioned and other features of this disclosure,
and the manner of attaining them, will become more apparent and
better understood by reference to the following description of
embodiments described herein taken in conjunction with the
accompanying drawings, wherein:
[0013] FIG. 1 illustrates a schematic diagram for a point of use
generation of amyl nitrite employing an acidic cationic exchange
resin.
[0014] FIG. 2 illustrates a syringe for providing point of use
generation of amyl nitrite employing an acidic cationic exchange
resin.
DETAILED DESCRIPTION
[0015] It may be appreciated that the present disclosure is not
limited in its application to the details of construction and
arrangement of components set forth in the following description or
illustrated in the drawings. The invention(s) herein may be capable
of other embodiments and of being practiced or being carried out in
various ways. Also, it may be appreciated that the phraseology and
terminology used herein is for the purpose of description and
should not be regarded as limiting as such may be understood by one
of skill in the art.
[0016] As noted, the present disclosure provides for the
preparation of amyl nitrite when needed for use and such that it is
conveniently available for a point-of-use application. Amyl nitrite
is a chemical compound with the formula C.sub.5H.sub.11ONO. A
variety of isomers are known which all feature the amyl group
attached to the nitrite functional group. One common form of amyl
nitrite includes isoamyl nitrite of the formula
(CH.sub.3).sub.2CHCH.sub.2CH.sub.2ONO. This is otherwise known as
3-methylbutyl nitrite.
[0017] Preparation of amyl nitrite involves the reaction of amyl
alcohol (any alcohol with the formula C.sub.5H.sub.11OH) with
nitrous acid where the nitrous acid is formed in situ via the
reaction of sulfuric acid with sodium nitrite:
##STR00001##
[0018] It has now been found that an acidic cation exchange resin
may now be employed which resin replaces the sulfuric acid as a
component for amyl nitrite formation. Accordingly, one now has the
ability to package the reagents (amyl alcohol, alkali metal
nitrite, water, cation exchange resin) to provide a shelf-stable
system that synthesizes amyl nitrite as needed at a desired
location. The alkali metal nitrite that may be employed or
MNO.sub.2 includes that situation where M is any alkali metal
cation (e.g. lithium, sodium or potassium) or alkaline-earth metal
cation (e.g. magnesium, calcium). For example, M may preferably
include Na.sup.+, Li.sup.+, or Ca.sup.+.
[0019] An acidic cation exchange resin herein may be understood as
an insoluble organic polymer resin having negatively charged
radicals attached to it that can attract and hold H.sup.+ in
surrounding solution. The H.sup.+ is then subsequently exchanged
with M.sup.+ (e.g. Na.sup.+) during the point-of-use preparation of
the amyl nitrate. In such context, the acidic cation exchange resin
replaces the use of sulfuric acid in the reaction noted above,
where H.sup.+[Polymer Resin] represents an acidic cation exchange
resin:
##STR00002##
[0020] One preferred acidic cationic exchange resin includes a
sulfonic acid resin that contains a backbone chain of polymer
prepared from polymerization of a mixture of styrene monomer and
divinylbenzene which is then treated with sulfuric acid to provide
the acidic cationic exchange resin of the following general
structure (where the crosslinks due to the presence of polymerized
divinylbenzene are not shown for clarity):
##STR00003##
[0021] Accordingly, in preferred embodiment, the preparation of
amyl nitrite herein may proceed as follows:
##STR00004##
[0022] One particularly preferred acidic cationic exchange resin is
available from Dow Chemical Company and amounts to a DOWEX.TM. 50W
resin that as noted above, contains polystyrene and poly(vinyl
benzene) wherein the level of divinylbenzene may vary between 2% to
8%. In addition, the mesh size may vary from 50-400 and the water
retention may vary from 50-82%. The total exchange capacity may
also vary from 0.6-1.7 meq/mL. The resins also indicate a density
in the range of 46-50 lbs/ft.sup.3.
[0023] As alluded to above, the amyl nitrite prepared herein using
an acidic cationic exchange resin may include n-alkyl amyl nitrite
(CH.sub.3(CH.sub.2).sub.4ONO) as well as 2-methylbutyl nitrite
(CH.sub.3CH.sub.2CH(CH.sub.3)CH.sub.2ONO) and/or 3-methylbutyl
nitrite ((CH.sub.3).sub.2CHCH.sub.2CH.sub.2ONO). Such nitrite
compounds may all be conveniently prepared for point of use
application herein from their corresponding alcohols. For example,
2-methylbutyl nitrite may be prepared from 2-methylbutyl alcohol
and 3-methylbutyl nitrite may be prepared from 3-methylbutyl
alcohol. In addition, one may produce a mixture of the
2-methylbutyl nitrite and 3-methyl-butyl nitrite, wherein the
3-methylbutyl nitrite is present at a level of 90% by weight or
greater, and in particular, at a level of 91%, 92%, 93%, 94%, 95%,
96%, 97%, 98% and 99% by weight. More preferably, a mixture of
2-methylbutyl nitrite and 3-methyl butyl nitrite may be produced,
wherein the level of 3-methyl butyl nitrite is at a level of 98% by
weight or greater.
[0024] It is worth noting that upon combination of the amyl
alcohol, metal nitrite/water and exposure to the acidic cationic
exchange resin, amyl nitrite is produced and the remaining
components after mixing and reacting include water, the alkali
metal form of the acidic cationic exchange resin and any remaining
amyl alcohol. These are relatively innocuous and therefore have no
adverse influence on the point of use generation of amyl nitrite
for therapeutic purposes.
[0025] FIG. 1 now illustrates one convenient method herein of
producing amyl nitrite for a point of use application. As shown,
one may now, in a field deployable apparatus, with stability for a
period of 1-3 years, isolate amyl nitrite, sodium nitrite and water
and the acidic cationic exchange resin. Such may be conveniently
achieved by placement of the selected amyl alcohol and mixture of
sodium nitrite and water in break-seal ampoules which can be broken
by the user to allow for the indicated flow of reagents into the
acidic cationic exchange resin compartment. Reference to break-seal
ampoules may be generally understood as any sort of sealed
containment compartment which contains and preserves the identified
reagent. Such sealed compartments may have a volume of 0.1-1000 ml.
The produced amyl nitrite can then be delivered to the user that
would preferably make the amyl nitrite available for inhalation.
This could be achieved by placement of cloth at the amyl nitrite
output location which would then provide amyl nitrite vapors.
[0026] It is contemplated herein that the device indicated in FIG.
1 may, as shown, optionally include the ability to treat the amyl
nitrite output with a base (e.g. a metal carbonate
(MCO.sub.3.sup.2-) or metal bicarbonate (MHCO.sub.3.sup.-)). This
in turn will assist in neutralizing any nitrous acid (HNO.sub.2)
formation.
[0027] With attention next directed to FIG. 2, the point of use
delivery of amyl nitrite herein may also be conveniently provided
via a syringe 20. A syringe may be broadly understood herein as a
device that includes a plunger that fits within a containment
sections (e.g. a tube) allowing the syringe to expel a liquid (amyl
nitrite) through an opening (orifice). Specifically, the syringe
may contain compartment 22 which contains amyl alcohol, compartment
24 which contains sodium nitrite and water, and compartment 26
which contains the acidic cationic exchange resin. Upon compression
of the syringe the compartments 22 and 24 can release and introduce
the amyl alcohol in mixture with the sodium nitrite and water to
the acidic cationic exchange resin, which will then convert the
amyl alcohol and deliver a required amount of amyl nitrite.
Compartments 22, 24 and 26 may all be sealed and therefore provide
an indefinite shelf life for the syringe device for a selected
field application. Compartment 22, 24, and 26 may each be of a size
suitable to accommodate 1-500 ml of reagent. Accordingly, the
syringe herein may have a capacity of 3 ml to 1500 ml of reagent as
may be necessary for the delivery of amyl nitrite compound.
[0028] It is also contemplated herein that the acidic cationic
exchange resin noted above may be conveniently replaced with a
Lewis Acid reagent. Reference to a Lewis Acid is reference to an
acid compound which is an electron pair acceptor. An example of a
Lewis Acid contemplated for use herein is BF.sub.3.
##STR00005##
Working Examples
Acidic Cationic Exchange Resin Catalyzed Synthesis of 3-Methyl
Butyl Nitrite
[0029] On a coarse Buchner frit was conditioned 300 mL DOWEX
50WX4-50 acidic cationic exchange resin by rinsing with 100 ml DI
water, 200 ml methanol and 1000 ml D water. The proton form of the
resin was assured by rinsing with 250 ml 10% v/v H2SO4 in DI water
followed by 2000 ml DI water. Rinse same pH to paper as DI
water.
[0030] A 2 L three-neck round bottom flask was flushed with N.sub.2
and outfitted with a magnetic stirrer and internal temperature
monitoring equipment and an addition funnel modified for subsurface
addition. The flask was charged with the conditioned acidic
cationic exchange resin (300 ml, 330 meq), 200 ml DI water and
3-methyl butanol (22 g, 250 mmol). A solution of sodium nitrite was
prepared (21 g, 304 mmol) by dissolving the salt up to 150 ml with
DI water. The sodium nitrite solution was added to the modified
addition funnel. The reactor was cooled to a temperature of about
-1.degree. C. to 1.degree. C. The reaction was carried out under a
N.sub.2 blanket. The reactor was allowed to warm to 20.degree. C.
under N.sub.2 with stirring for 2 hours. Upon opening of the
reactor a red brown gas was observed. The inhomogeneous mixture of
resin, aqueous and organic components was filtered through a coarse
Buchner frit to remove resin facilitating transfer with a minimum
of DI water. The aqueous phase was saturated with 25 g of sodium
chloride and the phases were separated. The organic phase was
washed with 25 ml of 4% potassium carbonate in water. An organic
yellow product was dried with about 400 mg of anhydrous potassium
carbonate. The final product was 3-methyl butyl nitrite (9.3 g,
79.2 mmol) produced in 32% yield. Proton NMR confirmed the 3-methyl
butyl nitrite formation with 2% 3-methyl butanol remaining. .sup.1H
NMR (400 MHz, CdCl.sub.3, .delta.) 4.75 (m, 2H, --CH.sub.2--ONO)
2.75 (m 2H, --CH.sub.2--CH.sub.2--ONO), 2.63 (m, 1H,
--CH(CH.sub.3).sub.2), 0.93 (d, 6H, --CH(CH.sub.3)).
[0031] Acidic Cationic Resin Synthesis of 3-Methyl Butyl Nitrite at
Room Temperature
[0032] On a coarse Buchner frit was conditioned 30 ml of DOWEX
50WX-50 acidic cationic exchange resin by rinsing with 300 ml DI
water, 50 ml methanol and 300 ml DI water. The proton form of the
resin was assured by rinsing with 30 ml 10% v/v H.sub.2SO.sub.4 in
DI water then 500 ml DI water. Rinse same pH to paper as DI
water.
[0033] A round bottom flask was charged with resin, 3-methyl
butanol (AA)(2.0 g, 23 mmol) and 20 ml DI water. Open to the
atmosphere and without stirring, at room temperature, was added
sodium nitrite (2 g, 29 mmol). Some warming and bubbling was
observed. The flask was allowed to stand open to air for 20
minutes. The resin was removed by filtration on a coarse Buchner
frit. Phases then separated. Retained 1.1 g crude organic product
shown to be 76.9% 3-methyl butyl nitrite with AA starting material.
42.3% crude yield or 32.5% yield of 3-methyl butyl nitrite adjusted
for purity. .sup.1H NMR (400 MHz, CdCl.sub.3, .delta.) 4.75 (m, 2H,
--CH.sub.2--ONO), 2.75 (m, 2H, --CH.sub.2--CH.sub.2--ONO), 2.63 (m,
1H, --CH(CH.sub.3).sub.2), 0.93 (d, 6H, --CHCH.sub.3).
[0034] As may now be appreciated, the present disclosure provides a
convenient method to produce amyl nitrite from stable reagents at
time of administration which minimizes stability issues involved
with direct delivery of amyl nitrite protocols. Amyl nitrite is now
produced by the reaction of amyl alcohol with metal nitrite in
water catalyzed by an acidic cationic exchange resin. The resin
acts in place of aqueous acid as a non-irritating component. The
delivery methods and devices of the present disclosure are suitable
for use in a variety of field conditions, including but not limited
to relatively high temperatures (30.degree. C.-45.degree. C.) such
as what may be encountered in a desert environment and for periods
extending up to 1-3 years. That is, the reagents (amyl alcohol and
metal nitrite) and the acidic cationic exchange resin are preserved
in sealed condition and remain active and suitable for mixing and
reacting with the acidic cationic exchange resin to provide a point
of use antidote for cyanide and/or hydrogen sulfide poisoning as
well as high blood pressure.
* * * * *