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 tree 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.

1 . In a process for obtaining commercial quantities of substantially pure fluoromethyl 1,1,1,3,3,3-hexafluoroisopropyl ether (sevoflurane), the process comprising:
 i) providing a crude sevoflurane product;   ii) fractionally distilling the crude sevoflurane product, forming thereby a distillate; and   iii) removing substantially pure sevoflurane from the distillate;   
     the improvement wherein the distillation takes place in equipment having components with surfaces that contact sevoflurane wherein the surfaces contain little or no active metal salts, whereby the substantially pure sevoflurane is stable at room temperature for at least two years. 
   
   
       2 . A process according to  claim 1 , wherein the distillation is conducted without addition of sevoflurane decomposition suppression agents. 
   
   
       3 . A process according to  claim 1 , further comprising storing substantially pure sevoflurane up to two years. 
   
   
       4 . A process according to  claim 3 , wherein the substantially pure sevoflurane product is stored in glass containers. 
   
   
       5 . A process according to  claim 4 , wherein the glass containers are made of Type III glass. 
   
   
       6 . A process according to  claim 3 , wherein sevoflurane decomposition suppression agents are not added to the sevoflurane during storage. 
   
   
       7 . A process according to  claim 1 , wherein the components are selected from the group consisting of reboilers, condensers, fractionating column, transfer lines, and storage vessels. 
   
   
       8 . A process according to  claim 7 , wherein the fractionating column comprises column packing materials, plates, sieve trays, or bubble cap trays. 
   
   
       9 . A process according to  claim 8 , wherein the column packing materials comprise PFA. 
   
   
       10 . A process according to  claim 7 , wherein the components further comprise an agitator. 
   
   
       11 . A process according to  claim 1 , wherein the surface of at least one component is metallic. 
   
   
       12 . A process according to  claim 11 , wherein the surface of at least one component is stainless steel, a nickel-copper alloy, alloy 20, copper, nickel, zirconium, titanium, tantalum, chromium, Hastelloys or a generic equivalent, or combinations thereof. 
   
   
       13 . A process according to  claim 12 , wherein the surface of at least one component is stainless steel type 316. 
   
   
       14 . A process according to  claim 1 , wherein the surface of at least one component is non-metallic. 
   
   
       15 . A process according to  claim 14 , wherein the non-metallic surface is selected from the group consisting of plastic, glass, carbon, ceramic, and combinations thereof. 
   
   
       16 . A process according to  claim 15 , wherein the non-metallic surface is a plastic selected from the group consisting of fluorinated polymers, polyethylene, polypropylene, and combinations thereof. 
   
   
       17 . A process according to  claim 16 , wherein the plastic is a fluorinated polymer selected from the group consisting of poly(tetrafluoroethylene) (PTFE), fluorinated ethylene propylene (FEP), perfluoroalkoxy polytetrafluoroethylene (PEA), ethylene tetrafluoroethylene (ETFE), polyvinylidene fluoride (PVF), ethylene chlorotrifluoroethylene (ECTFE), polyvinylidene difluoride (PVDF), polychlorotrifluoroethylene (PCTFE), and combinations thereof. 
   
   
       18 . A process according to  claim 17 , wherein the surface of at least one component is PEA. 
   
   
       19 . In a process for obtaining commercial quantities of substantially pure fluoromethyl 1,1,1,3,3,3-hexafluoroisopropyl ether (sevoflurane), said process comprising:
 i) reacting a composition comprising hexafluoroisopropanol, formaldehyde or its equivalent, and hydrogen fluoride (HF) to produce a crude sevoflurane product comprising hexafluoroisopropanol;   ii) fractionally distilling the crude sevoflurane product; and   iii) removing the substantially pure sevoflurane;   
     the improvement wherein the act of fractionally distilling in step ii) takes place in equipment having components with surfaces that contact sevoflurane wherein the surfaces contain little or no active metal salts, and the substantially pure sevoflurane is stable at room temperature for at least two years. 
   
   
       10 . A process according to  claim 19 , further comprising reducing the amount of HF in the crude sevoflurane produced in step (i) prior to distillation. 
   
   
       21 . A process according to  claim 19 , wherein the distillation is conducted without addition of sevoflurane decomposition suppression agents. 
   
   
       22 . A process according to  claim 19 , further comprising storing the substantially pure sevoflurane up to two years. 
   
   
       23 . The process according to  claim 22 , wherein the substantially pure sevoflurane product is stored in glass containers. 
   
   
       24 . The process according to  claim 23 , wherein the glass containers are made of Type III glass. 
   
   
       25 . The process according to  claim 23 , wherein sevoflurane decomposition suppression agents are not added to the sevoflurane during storage. 
   
   
       26 . A process according to  claim 19 , wherein the components are selected from the group selected from reboilers, condensers, fractionating column, transfer lines, and storage vessels. 
   
   
       27 . A process according to  claim 14 , wherein the fractionating column comprises column packing materials, plates, sieve trays, or bubble cap trays. 
   
   
       28 . A process according to  claim 27 , wherein the column packing materials comprise PFA. 
   
   
       29 . A process according to  claim 26 , wherein the components further comprise an agitator. 
   
   
       30 . A process according to  claim 19 , wherein the surface of at least one component is metallic. 
   
   
       31 . A process according to  claim 30 , wherein the surface of at least one component is stainless steel, a nickel-copper alloy, alloy 20, copper, nickel, zirconium, titanium, tantalum, chromium, Hastelloys or a generic equivalent, or combinations thereof. 
   
   
       32 . A process according to  claim 31 , wherein the surface of at least one component is stainless steel type 316. 
   
   
       33 . A process according to  claim 19 , wherein the surface of at least one component is non-metallic. 
   
   
       34 . A process according to  claim 33 , wherein the surface is selected from the group consisting of plastic, glass, carbon, ceramic, and combinations thereof. 
   
   
       35 . A process according to  claim 34 , wherein the surface of at least one non-metallic surface is a plastic selected from the group consisting of fluorinated polymers, polyethylene, polypropylene, and combinations thereof. 
   
   
       36 . A process according to  claim 35 , wherein the plastic is a fluorinated polymer selected from the group consisting of 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. 
   
   
       37 . A process according to  claim 36 , wherein the surface of at least one component is PFA. 
   
   
       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° 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° 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° 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° 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° 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° C.