U.S. patent application number 12/833676 was filed with the patent office on 2010-11-04 for distillation method for the purification of sevoflurane and the maintenance of certain equipment that may be used in the distillation process.
This patent application is currently assigned to HALOCARBON PRODUCTS CORPORATION. Invention is credited to Barry Jones, Paul Mazzell, Joel Swinson.
Application Number | 20100280283 12/833676 |
Document ID | / |
Family ID | 41257527 |
Filed Date | 2010-11-04 |
United States Patent
Application |
20100280283 |
Kind Code |
A1 |
Jones; Barry ; et
al. |
November 4, 2010 |
Distillation Method for the Purification of Sevoflurane and the
Maintenance of Certain Equipment that May be Used in the
Distillation Process
Abstract
Processes for preparing commercial quantities of a stable,
pharmaceutically acceptable sevoflurane substantially free of
impurities are claimed. In another embodiment, a process for
removing reactive metal salts from the surface of metallic
equipment used in the distillation of sevoflurane and rendering a
non-inert metallic surface of the metallic equipment inert.
Inventors: |
Jones; Barry; (Augusta,
GA) ; Swinson; Joel; (Augusta, GA) ; Mazzell;
Paul; (Augusta, GA) |
Correspondence
Address: |
HOFFMANN & BARON, LLP
6900 JERICHO TURNPIKE
SYOSSET
NY
11791
US
|
Assignee: |
HALOCARBON PRODUCTS
CORPORATION
North Augusta
SC
|
Family ID: |
41257527 |
Appl. No.: |
12/833676 |
Filed: |
July 9, 2010 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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12113655 |
May 1, 2008 |
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12833676 |
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Current U.S.
Class: |
568/682 |
Current CPC
Class: |
C07C 41/42 20130101;
C07C 41/42 20130101; C07C 43/123 20130101 |
Class at
Publication: |
568/682 |
International
Class: |
C07C 41/42 20060101
C07C041/42 |
Claims
1-37. (canceled)
38. A process for obtaining commercial quantities of substantially
pure sevoflurane comprising: i) providing a crude sevoflurane
product; ii) passivating liquid- and gas-contacting surfaces of
distillation equipment capable of providing commercial quantities
of sevoflurane; iii) distilling the crude sevoflurane product in
the distillation equipment; and iv) recovering substantially pure
sevoflurane.
39. The process according to claim 38, wherein sevoflurane
decomposition suppression agents are not added to the sevoflurane
during the distillation.
40. The process according to claim 38, further composing storing
the substantially pure sevoflurane up to two years.
41. The process according to claim 39, wherein the substantially
pure sevoflurane product is stored in glass containers.
42. The process according to claim 41, wherein the glass containers
are made of Type III glass.
43. The process according to claim 41, wherein sevoflurane
decomposition suppression agents are not added to sevoflurane
during storage.
44. The process according to claim 38, wherein the distillation
equipment is metallic.
45. The process according to claim 44, wherein step ii) comprises:
a) washing the metallic equipment one or more times with water, and
if the pH of the discharged wash is initially less than 6,
continuing washing until the pH of the discharged wash is at least
6; b) contacting the surfaces of the equipment that are to be
treated with an aqueous solution of a passivation agent; c)
removing the aqueous passivation agent; and d) rinsing the
equipment with water, and if the pH of the discharged wash is
initially less than 6, continuing washing until the pH of the
discharged water is at least 6.
46. A process according to claim 38, wherein the passivation agent
is citric acid, nitric acid, and a mixture of nitric acid and
sodium dichromate.
47. A process according to claim 38, wherein the passivation agent
is nitric acid.
48. A process for removing reactive metal salts from the
sevoflurane-contacting surfaces of metallic equipment used in the
distillation of sevoflurane and rendering the surfaces inert, the
process comprising: i) washing the metallic equipment one or more
times with wafer, and if the pH of the discharged wash is initially
less than 6, continuing washing until the pH of the discharged wash
is at least 6; ii) contacting the surfaces of the equipment that
are to be treated with an aqueous solution of a passivation agent;
iii) removing the aqueous passivation agent; and iv) rinsing the
equipment with water, and if the pH of the discharged wash is
initially less than 6, continuing washing until the pH of the
discharged water is at least 6.
49. A process according to claim 48, wherein the concentration of
the passivation agent is a minimum of about 1% by weight of the
aqueous passivation solution.
50. A process according to claim 48, wherein the concentration of
the passivation agent is a minimum of about 10% by weight of the
aqueous passivation solution.
51. A process according to claim 48, wherein the concentration of
the passivation agent is a maximum of about 90% by weight of the
aqueous passivation solution.
52. A process according to claim 48, wherein the concentration of
the passivation agent is a maximum of about 50% by weight of the
aqueous passivation solution.
53. A process according to claim 48, wherein the metallic equipment
is in contact with the aqueous passivation solution for a minimum
total time period of about 0.25 hours.
54. A process according to claim 48, wherein the metallic equipment
is in contact with the aqueous passivation solution for a minimum
total time period of about 0.30 hours.
55. A process according to claim 48, wherein the metallic equipment
is in contact with the aqueous passivation solution for a maximum
total time period of about 48 hours.
56. A process according to claim 48, wherein the metallic equipment
is in contact with the aqueous passivation solution for a maximum
total time period of about 24 hours.
57. A process according to claim 48, wherein the passivation agent
is citric acid, nitric acid, or mixtures of nitric acid and sodium
dichromate.
58. A process according to claim 57, wherein the passivation agent
is nitric acid.
59. A process according to claim 48, wherein the metallic equipment
comprises stainless steel.
60. A process according to claim 48, wherein the contact
temperature when the metallic equipment is in contact with the
aqueous passivation solution is a minimum of about 20.degree.
C.
61. A process according to claim 48, wherein the contact
temperature when the metallic equipment is in contact with the
aqueous passivation solution is a minimum of about 35.degree.
C.
62. A process according to claim 48, wherein the contact
temperature when the metallic equipment is in contact with the
aqueous passivation solution is a minimum of about 50.degree.
C.
63. A process according to claim 48, wherein the contact
temperature when the metallic equipment is in contact with the
aqueous passivation solution is a maximum of about 60.degree.
C.
64. A process according to claim 48, wherein the contact
temperature when the metallic equipment is in contact with the
aqueous passivation solution is a maximum of about 70.degree.
C.
65. A process according to claim 48, wherein the contact
temperature when the metallic equipment Is in contact with the
aqueous passivation solution is a maximum of about 80.degree. C.
Description
BACKGROUND OF THE INVENTION
[0001] Sevoflurane is produced by several known methods. A commonly
used method involves the reaction of formaldehyde (or a
formaldehyde equivalent), hydrogen fluoride (HF), and
hexafluoroisopropanol (HFIP). U.S. Pat. No. 4,250,334 describes a
process in which HFIP is added to a mixture of a stoichiometric
excess of paraformaldehyde and HF plus sufficient sulfuric acid to
sequester most of the water formed in the reaction. WO 97/25303
describes a process for the production of sevoflurane in which
essentially pure bis(fluoromethyl)ether (BFME) is allowed to react
with HFIP and sulfuric acid. U.S. Pat. No. 6,469,219 describes a
process in which HFIP and a formaldehyde equivalent are allowed to
react with excess HF under distillative or extractive conditions in
order to produce sevoflurane. Other synthetic routes generate a
different impurity profile, but still require a final distillation
in order to produce a pharmaceutically acceptable form of
sevoflurane.
[0002] In all of these processes, unreacted HFIP may remain in the
product mixture, as well as BFME, methyl hexafluoroisopropyl ether
(MHFIP), polyethers containing the HFIP and formaldehyde moieties,
and various other undesired species. These impurities must be
removed from the crude sevoflurane product in order to obtain a
pharmaceutically acceptable form of the material.
[0003] Many of these impurities can be removed by distillation, but
it has been disclosed in U.S. Pat. No. 5,684,211 that crude
sevoflurane can decompose or disproportionate under distillative
conditions and that the product could not be adequately purified as
a result of this decomposition/disproportionation. For example,
dehydrofluorination of sevoflurane may occur during distillation,
leading to fluoromethyl 1,1,3,3,3-pentafluoroisopropenyl ether
(also known as Compound A) as a new impurity. It is difficult to
separate this decomposition/disproportionation product from
sevoflurane by distillation because their boiling points are very
similar.
[0004] This type of decomposition can be prevented by the use of a
decomposition suppressive agent in the distillation process.
Suppressive agents known in the art include hydroxides of alkali
metals, hydrogenphosphates of alkali metals, phosphates of alkali
metals, hydrogencarbonates of alkali metals, borates of alkali
metals, sulfites of alkali metals, alkali metal salts of acetic
acid, alkali metal salts of phthalic acid and boric acid. Potential
drawbacks to the use of such agents, however, include added expense
for their use and disposal, as well as the necessity to completely
remove them from the drug product.
[0005] Furthermore, although fluoroethers are excellent anesthetic
agents, some fluoroethers have been reported to encounter stability
problems. More specifically, it has been reported (U.S. Pat. No.
5,990,176 and others) that certain fluoroethers, in the presence of
one or more Lewis acids, degrade into several by-products including
potentially toxic chemicals such as HF and/or HFIP. Hydrofluoric
acid is toxic by ingestion and inhalation and is highly corrosive
to skin and mucous membranes. Therefore, the degradation of
fluoroethers to chemicals such as HF is of great concern to the
medical community. In fact, quantities of Ultane.RTM. brand
sevoflurane had to be recalled on two occasions due to potentially
patient-threatening decomposition caused by exposure to Lewis
acids.
[0006] The Lewis-acid induced decomposition of sevoflurane can be
suppressed by the addition of certain Lewis-acid inhibitors to the
product. Lewis-acid inhibitors include, but are not limited to,
water, butylated hydroxytoluene, methylparaben, propofol, thymol,
and propylparaben. The drawbacks of using such agents include the
added expense and processing time for their incorporation into the
drug product.
[0007] Thus, a distillative method is needed for the efficient
separation of sevoflurane from impurities without further
decomposition/disproportionation that does not require the use of
any type of suppressive agent in order to achieve a substantially
pure product. Also, this method should result in a product that
does not decompose over long periods of time, thus eliminating the
need for the addition of sevoflurane decomposition suppression
agents.
SUMMARY OF THE INVENTION
[0008] The present invention relates to a process for obtaining
commercial quantities of substantially pure fluoromethyl
1,1,1,3,3,3-hexafluoroisopropyl ether (sevoflurane) without
decomposition-causing impurities or decomposition-suppression
agents. The process includes providing a crude sevoflurane product,
fractionally distilling the crude sevoflurane product, forming
thereby a distillate, and removing substantially pure sevoflurane
from the distillate. The distillation takes place in equipment
having common distillation components. The surfaces of the
components that contact sevoflurane contain little or no active
metal salts during the time the surface contacts the sevoflurane.
The resulting substantially pure sevoflurane is stable when stored
at room temperature for at least two years. There is no requirement
for the presence of sevoflurane decomposition suppression agents
during storage, and the substantially pure sevoflurane is
preferably stored in the absence of such suppression agents.
[0009] A commercial quantity of sevoflurane is an amount more than
about 500 liters per year, preferably more than about 1000 liters
per year, and most preferably more than about 2000 liters per
year.
[0010] Substantially pure sevoflurane is sevoflurane which contains
less than 300 ppm of total impurities, and less than 100 ppm of any
individual impurity. In a preferred embodiment, the "substantially
pure sevoflurane" contains less than 100 ppm of total impurities,
and less than 20 ppm of any individual impurity.
[0011] Since the sevoflurane of the present invention is
substantially free of impurities that may lead to decomposition,
there is no need for special containers to store the sevoflurane.
Therefore, the sevoflurane may be stored in common glass for up to
two years and even longer, e.g., three, four, or five years. The
preferred glass is Type III glass.
[0012] In a preferred embodiment, the distillation is conducted in
the absence of sevoflurane decomposition suppression agents. In
another preferred embodiment, sevoflurane decomposition suppression
agents are not added to the substantially pure sevoflurane product
subsequent to distillation, e.g., during storage.
[0013] Some examples of sevoflurane decomposition suppression
agents include hydroxides of alkali metals, hydrogenphosphates of
alkali metals, phosphates of alkali metals, hydrogencarbonates of
alkali metals, borates of alkali metals, sulfites of alkali metals,
alkali metal salts of acetic acid, alkali metal salts of phthalic
acid and boric acid. Some additional examples of sevoflurane
decomposition suppression agents include Lewis-acid inhibitors.
Lewis-acid inhibitors include, but are not limited to, butylated
hydroxytoluene, methylparaben, propofol, thymol, and
propylparaben.
[0014] It should be noted that water is a Lewis-acid inhibitor.
Nevertheless, in this embodiment, water may be present in
substantially pure sevoflurane, usually as a result of previous
processing. In a preferred embodiment, however, water is not added
during the distillation process or during storage, and the
substantially pure sevoflurane product does not use ambient or
remaining water (nor does it serve) as a Lewis acid inhibitor. The
resulting sevoflurane preferably contains less than 100 ppm of
water, and, in a preferred embodiment, contains less than 70 ppm of
water.
[0015] The common distillation components include, for example,
reboilers, condensers, fractionating columns, transfer lines,
and/or storage vessels. The fractionating column preferably
contains one or more materials that aid fractionation. Such
materials include, for example, column packing materials, plates,
sieve trays, or bubble cap trays. In a preferred embodiment, the
column packing materials include PFA. The components may also
include an agitator.
[0016] In one embodiment, the surface of at least one component is
metallic. The metallic surface may be made of any metal that can be
fashioned into distillation equipment and does not easily form
salts. The metallic component should also be stable when in contact
with vapor or liquid phases of a crude sevoflurane product or of
substantially purified sevoflurane. The metallic surfaces include,
for example, stainless steel, a nickel-copper alloy, alloy 20,
copper, nickel, zirconium, titanium, tantalum, chromium, Hastelloys
or generic equivalents, or combinations thereof. For example,
Hastelloy C-276 is sold generically as Alloy C-276, and Hastelloy
C-22 is sold generically as Alloy C-22. In a preferred embodiment,
the metal is stainless steel, and more preferably the stainless
steel is type 316. An example of a nickel-copper alloy is Monel or
its generic equivalents. Monel 400 is the preferred Monel.
[0017] In another embodiment, the surface of at least one component
is non-metallic. The non-metallic surface may be made of any
non-metal that can be fashioned into distillation equipment and is
stable when in contact with vapor or liquid phases of a crude
sevoflurane product or of substantially purified sevoflurane. Some
examples of non-metallic surfaces include plastics, glass, carbon,
ceramic, and combinations thereof. Preferable plastics include
fluorinated polymers, polyethylene, polypropylene, or combinations
thereof. Preferable fluorinated polymers include
poly(tetrafluoroethylene) (PTFE), fluorinated ethylene propylene
(FEP), perfluoroalkoxy polytetrafluoroethylene (PFA), ethylene
tetrafluoroethylene (ETFE), polyvinylidene fluoride (PVF), ethylene
chlorotrifluoroethylene (ECTFE), polyvinylidene difluoride (PVDF),
polychlorotrifluoroethylene (PCTFE), and combinations thereof. In a
preferred embodiment, the surface is PFA.
[0018] Another aspect of the invention relates to a process as
described above, wherein the crude sevoflurane product is provided
by reacting a composition comprising hexafluoroisopropanol,
formaldehyde or its equivalent, and hydrogen fluoride (HF). The
crude sevoflurane product contains hexafluoroisopropanol, and may
contain unreacted starting materials, such as HF.
[0019] In a preferred embodiment, the amount of HF in the crude
sevoflurane is reduced prior to distillation. The amount of HF may
be reduced in accordance with known procedures, such as those
described in U.S. Pat. No. 6,469,219, Examples 4-6.
[0020] Another aspect of the invention relates to a process for
removing reactive metal salts from the surface of metallic
equipment used in the distillation of sevoflurane and rendering a
non-inert surface of the metallic equipment inert (i.e., inerting).
The surface of the metallic equipment is any surface of the
equipment that may come in contact with vapor or liquid phases of a
crude sevoflurane product or of substantially purified sevoflurane
during the distillation.
[0021] Inerting, e.g., passivating, may be accomplished by methods
that are well known in the art. Such methods include, for example,
chemical and electrical treatments. Some examples of chemical
treatments include phosphate treatments, for example Parkerizing,
as well as oxalate and chromium treatments. Some additional
inerting methods include galvanizing and painting. Anodizing is
particularly useful in the case of aluminum.
[0022] The process of the invention includes i) washing the
interior surfaces of the metallic equipment one or more times with
water. If the pH of the discharged wash is initially less than 6,
washing is carried out until the pH of the discharged water is at
least 6. Subsequent steps include ii) contacting interior surfaces
of the equipment with an aqueous solution of a passivation agent;
iii) removing the aqueous passivation solution; and iv) rinsing the
equipment with water until the pH of the discharged water is not
less than 6. The interior surfaces of the equipment may be
contacted with an aqueous solution of a passivation agent by
immersing the surfaces in an aqueous solution of a passivation
agent or by spraying an aqueous solution of a passivation agent
onto the surfaces.
[0023] In this specification, an "interior surface,"
"sevoflurane-contacting surface," or a "liquid- and gas-contacting
surface" is a surface of distillation equipment that contacts crude
or substantially purified sevoflurane in either the gas or liquid
phase during the distillation process.
[0024] A passivation agent is any agent that renders the non-inert
surface of a metal, especially stainless steel, inert. Some
examples of passivation agents include citric acid, nitric acid,
and a mixture of nitric acid and sodium or potassium dichromate. A
commercial example of a citric acid passivation agent is the
CitriSurf product line supplied by Stellar Solutions, 4511 Prime
Parkway, McHenry, Ill. 60050. The preferred passivation agent is
nitric acid. Preferred mole percent ratios of nitric acid and
sodium or potassium dichromate in mixtures of the two include 5:95
to 95:5.
[0025] In one embodiment, the concentration of the passivation
agent is preferably a minimum of about 1% by weight of the aqueous
solution, and more preferably a minimum of about 10% by weight of
the aqueous solution. In another embodiment, the concentration of
the passivation agent is a maximum of about 90% by weight of the
aqueous solution, more preferably a maximum of about 50% by weight
of the aqueous solution.
[0026] The metallic equipment is preferably in contact with the
aqueous passivation solution for a minimum total time period of
about 0.25 hours, and more preferably a minimum total time period
of about 0.5 hour. The metallic equipment is preferably in contact
with the aqueous solution for a maximum total time period of about
48 hours, and more preferably a maximum total time period of about
24 hours.
[0027] The contact temperature when the metallic equipment is in
contact with the aqueous passivation solution is a minimum of about
20.degree. C., more preferably a minimum of about 35.degree. C.,
and more preferably about a minimum of about 50.degree. C. The
contact temperature when the metallic equipment is in contact with
the aqueous passivation solution is a maximum of about 80.degree.
C., preferably a maximum of about 70.degree. C., and more
preferably about a maximum of about 60.degree. C. The preferred
range is about 50.degree. C. to about 60.degree. C.
[0028] In another embodiment, the invention relates to a process
for obtaining commercial quantities of substantially pure
sevoflurane. The process includes i) providing a crude sevoflurane
product; ii) passivating liquid- and gas-contacting surfaces of
distillation equipment capable of providing commercial quantities
of sevoflurane; iii) distilling the crude sevoflurane product in
the distillation equipment; and iv) recovering substantially pure
sevoflurane. The passivating and distilling steps are described
above in further detail.
DETAILED DESCRIPTION
[0029] The present invention provides an improved process for
preparing commercial quantities of stable, pharmaceutically
acceptable sevoflurane substantially free of impurities and without
the use of decomposition suppression agents.
[0030] The phrase "substantially pure sevoflurane," as used herein
is sevoflurane which contains less than 300 ppm of total
impurities, and less than 100 ppm of any individual impurity. In a
preferred embodiment, the term "substantially pure sevoflurane"
means sevoflurane which contains less than 100 ppm of total
impurities, and most preferably less than 20 ppm of any individual
impurity. Total impurities are defined as impurities not including
water.
[0031] The term "stable" as used herein means that the
substantially pure sevoflurane remains substantially pure as herein
defined for at least two years from the time of production at
ambient temperature, or for at least three months at 40.degree. C.
Stability is achieved without the addition of sevoflurane
decomposition suppression agents. Some examples of sevoflurane
decomposition suppression agents include hydroxides of alkali
metals, hydrogenphosphates of alkali metals, phosphates of alkali
metals, hydrogencarbonates of alkali metals, borates of alkali
metals, sulfites of alkali metals, alkali metal salts of acetic
acid, alkali metal salts of phthalic acid and boric acid. Some
additional examples of sevoflurane decomposition suppression agents
include, but are not limited to, Lewis-acid inhibitors. Lewis-acid
inhibitors include, but are not limited to, butylated
hydroxytoluene, methylparaben, propofol, thymol, and propylparaben.
It should be noted that water also is a Lewis-acid inhibitor.
Nevertheless, in this embodiment, water may be present, usually as
a result of previous processing. In a preferred embodiment, water
is not added to any water than may already be present during the
distillation process.
[0032] A commercial quantity of sevoflurane is an amount more than
about 500 liters per year, preferably more than about 1000 liters
per year, and most preferably more than about 2000 liters per
year.
[0033] A crude sevoflurane product comprising unacceptably high
levels of impurities can be purified by distilling the crude
sevoflurane product using process equipment that contains little or
no active metal salts. Such surfaces do not contain enough active
metal salts to cause significant decomposition/disproportionation
of the product. Purified sevoflurane distilled from this type of
equipment is stable, without the addition of sevoflurane
decomposition suppression agents, for at least two years when
stored at ambient temperature and/or for at least three months at
40.degree. C. It should be noted that water may be present as a
result of previous processing, but is not added.
[0034] The crude sevoflurane product can be prepared in any manner.
Preferably the crude sevoflurane product is produced by a process
comprising reacting hexafluoroisopropanol (HFIP), formaldehyde, and
hydrogen fluoride (HF).
[0035] Preferably, the reaction is carried out in a stoichiometric
excess of HF. The reaction temperature is not critical, but the
yields are substantially improved above 50.degree. C. Preferably,
the reaction is conducted under autogenous pressure of 30-40 psig
ensuring temperatures of 45-75.degree. C. The process is described
in U.S. Pat. No. 6,469,219, which is hereby incorporated by
reference.
[0036] In a preferred embodiment, the amount of HF in the crude
sevoflurane is reduced prior to distillation. The amount of HF is
reduced in accordance with known procedures such as those described
in U.S. Pat. No. 6,469,219, Examples 4-6 to obtain a second crude
sevoflurane product.
[0037] The term "formaldehyde" as used herein means not only
formaldehyde per se, but also any equivalent of formaldehyde.
Equivalents of formaldehyde include formaldehyde polymers, such as
trioxane, and paraformaldehyde.
[0038] Fractional distillation is a widely used, well-understood
commercial process. The equipment used in such a process includes,
but is not limited to, reboilers, condensers, fractionating column,
transfer lines, and storage vessels. A fractionating column may
include column packing materials, plates, sieve trays, and bubble
cap trays. The equipment may further comprise agitators, transfer
lines, packing and packing support hardware, nuts and bolts, pipe
fittings and components such as tees, elbows, and valves, and
instrumentation such as that used for measuring differential
pressure, absolute pressure, and temperature.
[0039] The appropriate selection of materials for construction of
surfaces of the equipment depends on well-established factors such
as temperature stability, compatibility with chemical compounds,
cost, etc. In particular, compatibility with sevoflurane and
resistance to acidity/basicity should be considered.
[0040] Appropriate non-metallic materials for construction of
surfaces of the equipment include, but are not limited to, plastics
such as fluorinated polymers and polyolefins; glass; carbon;
ceramics; and combinations thereof. Examples of fluorinated
polymers include, but are not limited to, poly(tetrafluoroethylene)
(PTFE), fluorinated ethylene propylene (FEP), perfluoroalkoxy
polytetrafluoroethylene (PFA), ethylene tetrafluoroethylene (ETFE),
polyvinylidene fluoride (PVF), ethylene chlorotrifluoroethylene
(ECTFE), polyvinylidene difluoride (PVDF),
polychlorotrifluoroethylene (PCTFE). Fluorinated polymers sold by
DuPont under the tradename TEFLON.RTM. and their generic
equivalents are particularly useful in this invention. Examples of
polyolefins include, but are not limited to, polyethylene and
polypropylene.
[0041] Appropriate metals for the construction of equipment
involved in the fractional distillation of sevoflurane include any
metal typically used in making distillation equipment. Metals
appropriate for making the distillation equipment of the invention
do not easily form salts. Examples of appropriate metals include,
but are not limited to, higher grades of stainless steel (such as
316 stainless steel), nickel-copper alloys, alloy 20, copper,
nickel, zirconium, titanium, tantalum, chromium, Hastelloys or
generic equivalents, and combinations of these metals. The
preferred metal is 316 stainless steel. An example of a
nickel-copper alloy is Monel 400, which is sold generically as
Alloy 400. Generic equivalents of Hastelloys are also appropriate
metals. For example, generic equivalents of Hastelloy C-276 and
Hastelloy C-22 include Alloy C-276 and Alloy C-22,
respectively.
[0042] The distillation takes place in equipment having components
with surfaces that contact sevoflurane, and the surfaces contain
little or no active metal salts. The surfaces include all surfaces
that come in contact with vapor or liquid phases of a crude
sevoflurane product or of substantially purified sevoflurane.
[0043] In one embodiment, the equipment can be entirely made of the
non-metallic and metallic materials containing little or no active
metal salts. In another embodiment, only the portion of the
equipment that contacts sevoflurane during distillation may be
coated with the non-metallic and metallic materials containing
little or no active metal salts.
[0044] Surfaces of a component may be made of a non-metallic
material, and the surfaces of another component may be made of a
metallic material, For example, the reboiler may be coated with 316
stainless steel, and the condenser may be made entirely of
glass.
[0045] In a preferred embodiment, a non-metallic material is used
as an inert coating over metallic components. For example, PFA may
be used to coat the packing material used in the column.
[0046] As mentioned above, the surface of the metal components must
contain little or no active metal salts that may react with
sevoflurane to produce impurities. Confirmation that the surfaces
of the equipment contain little or no active metal salts may be
accomplished by various techniques. A preferred method is to add
previously analyzed sevoflurane to the distillation system and
perform a standard distillation. The distillation may, for example,
be conducted using about 300 kg sevoflurane per cubic meter of
equipment volume over a period of 24 hours. The resultant
distillate and residual pot contents are analyzed for impurities.
If there is no increase in the amount of impurities in the
sevoflurane, the distillation system is confirmed to be
sufficiently free of active metal salts, and is ready for use.
[0047] When metallic components are used in the distillation
process equipment, constant care must be maintained in order to
avoid the generation of reactive metal salts which may cause the
decomposition of sevoflurane either during the distillation process
or upon storage for long periods of time. Reactive metal salts are
any salts which contribute to the generation of impurities in
sevoflurane. Common reactive metal salts include halides, nitrates,
and sulfates of the metals used. Examples of reactive metal salts
include iron chloride(s), iron fluoride(s), iron nitrate(s), iron
sulfate(s), copper chloride(s), copper fluoride(s), copper
nitrate(s), copper sulfate(s), nickel chloride(s), nickel
fluoride(s), nickel nitrate(s), and nickel sulfate(s).
[0048] The distillation system must be routinely monitored for
indications of unexpected reactive metal salt formation. Monitoring
techniques include periodic visual inspection of metallic
components for signs of corrosion and regular monitoring of final
product distillate for the presence of elevated quantities of
impurities as described above.
[0049] If unacceptable quantities of reactive metal salts are
detected in the distillation equipment or there is reason to
believe there are salts on the surface of the equipment, the
reactive metal salts must be removed and the surface of the metal
components must be protected before any further processing is
attempted. One potential method for accomplishing this type of
purification, particularly for components made from stainless
steel, is called passivation. This process involves the treatment
of the surfaces of metallic equipment with an aqueous solution of a
passivation agent that removes metal salts while rendering a
non-inert metallic surface of the metallic equipment inert.
Examples of suitable passivation agents include citric acid, nitric
acid, and mixtures of nitric acid and sodium dichromate. The
preferred passivation agent is nitric acid.
[0050] In a typical cleaning/recovery procedure, the equipment
first is washed thoroughly with water, although this step is
optional. If the pH of the discharged wash is initially less than
6, washing should be carried out until the pH of the discharged
water is at least 6. The sevoflurane-contacting surfaces of the
equipment are then placed in contact for a period of time with a
passivation solution. After the passivation solution is removed,
the equipment is rinsed repeatedly with water until all of the
passivation solution and dissolved metal salts have been removed
from the system. After it has been confirmed that all of the
passivation solution has been removed, the equipment is dried by
conventional methods.
[0051] The concentration of the passivation agent in the aqueous
solution is effective at a minimum of about 1% by weight of the
aqueous solution, and more preferably about 10% by weight of the
aqueous solution. The maximum concentration of the passivation
agent in the aqueous solution is about 90% by weight of the aqueous
solution, and more preferably about 50% by weight of the aqueous
solution. The contact time for the treatment of the metallic
components with the aqueous solution will depend on several
factors, including the concentration of the passivation agent and
the amount of metal-salt contamination.
[0052] Sufficient contact time is determined retrospectively by
placing the equipment back into service and monitoring the next
sevoflurane distillate for the presence of unacceptably large
quantities of impurities, as discussed previously. The normal time
for contact of the equipment with the passivation solution is a
minimum of about a quarter of an hour, and more preferably about 30
minutes. The maximum amount of time for contact of the equipment
with the passivation solution is about 48 hours, preferably about
24 hours.
[0053] The contact temperature for the treatment of the metallic
components with the passivation solution will depend upon several
factors including the concentration of the passivation agent, and
the amount of the suspected metal salt contamination. Sufficient
contact temperature is determined retrospectively by placing the
equipment back into service and monitoring the next sevoflurane
distillate for the presence of unacceptably large quantities of
impurities, as discussed previously. The contact temperature when
the metallic equipment is in contact with the aqueous passivation
solution is a minimum of about 20.degree. C., more preferably a
minimum of about 35.degree. C., and more preferably about a minimum
of about 50.degree. C. The contact temperature at when the metallic
equipment is in contact with the aqueous passivation solution is a
maximum of about 80.degree. C., preferably a maximum of about
70.degree. C., and more preferably about a maximum of about
60.degree. C. The preferred range is about 50.degree. C. to about
60.degree. C.
[0054] When metallic equipment used in the distillation of
sevoflurane has been cleaned according to method described above,
the metallic equipment may be reused to make substantially pure
sevoflurane that exhibits stability at room temperature for at
least two years without the addition of sevoflurane decomposition
suppression agents.
[0055] In another embodiment, the invention relates to a process
for obtaining commercial quantities of substantially pure
sevoflurane. The process comprises:
[0056] i) providing a crude sevoflurane product;
[0057] ii) passivating liquid- and gas-contacting surfaces of
distillation equipment capable of providing commercial quantities
of sevoflurane;
[0058] iii) distilling the crude sevoflurane product in the
distillation equipment; and recovering substantially pure
sevoflurane.
[0059] The acts of providing a crude sevoflurane product,
passivating liquid- and gas-contacting surfaces of distillation
equipment capable of providing commercial quantities of
sevoflurane, distilling the crude sevoflurane product in the
distillation equipment, and storing the substantially pure
sevoflurane are as described above. Preferably, sevoflurane
decomposition suppression agents are not added to the sevoflurane
during the distillation. The substantially pure sevoflurane may be
stored up to two years in glass containers, preferably Type III
glass containers, with or without the presence of sevoflurane
decomposition suppression agents.
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