WO2020229823A1 - Procédé de purification - Google Patents

Procédé de purification Download PDF

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Publication number
WO2020229823A1
WO2020229823A1 PCT/GB2020/051169 GB2020051169W WO2020229823A1 WO 2020229823 A1 WO2020229823 A1 WO 2020229823A1 GB 2020051169 W GB2020051169 W GB 2020051169W WO 2020229823 A1 WO2020229823 A1 WO 2020229823A1
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WO
WIPO (PCT)
Prior art keywords
difluoroethane
contaminated
methyl chloride
molecular sieve
weight
Prior art date
Application number
PCT/GB2020/051169
Other languages
English (en)
Inventor
Stuart Corr
Steve Flaherty
Original Assignee
Mexichem Fluor S.A. De C.V.
Mexichem Uk Limited
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Filing date
Publication date
Application filed by Mexichem Fluor S.A. De C.V., Mexichem Uk Limited filed Critical Mexichem Fluor S.A. De C.V.
Publication of WO2020229823A1 publication Critical patent/WO2020229823A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C17/00—Preparation of halogenated hydrocarbons
    • C07C17/38—Separation; Purification; Stabilisation; Use of additives
    • C07C17/389—Separation; Purification; Stabilisation; Use of additives by adsorption on solids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C17/00—Preparation of halogenated hydrocarbons
    • C07C17/38—Separation; Purification; Stabilisation; Use of additives
    • C07C17/383—Separation; Purification; Stabilisation; Use of additives by distillation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C21/00—Acyclic unsaturated compounds containing halogen atoms
    • C07C21/02—Acyclic unsaturated compounds containing halogen atoms containing carbon-to-carbon double bonds
    • C07C21/18—Acyclic unsaturated compounds containing halogen atoms containing carbon-to-carbon double bonds containing fluorine

Definitions

  • the present invention relates to a process for the preparation of pharmaceutical grade 1 ,1- difluoroethane (H FA- 152a) that is suitable for use in medication delivery devices such as metered dose inhalers where the propellant is used to deliver a drug from the device for subsequent inhalation by the patient.
  • the present invention is concerned with a finishing process for drying and purifying what is already quite a pure 1 ,1-difluoroethane material, but which does not meet the exacting standards required for medical applications.
  • propellants to deliver drugs from devices for subsequent inhalation into the lungs of a patient is a common method for delivering drugs for treating respiratory disorders, such as asthma, chronic obstructive pulmonary disease and pneumonia.
  • One particularly common and effective device is a metered dose inhaler (MDI) in which the drug is contained in a pressurised aerosol cannister together with the propellant and optionally further components, such as polar co-solvents to assist with the dissolution of the drug in the propellant, surfactants to assist with the suspension of the drug in the propellant, valve lubricants and preservatives.
  • MDI metered dose inhaler
  • MDIs are well known to those skilled in the art and are described in many standard textbooks, as well as in the patent literature. They are designed to deliver, on demand, a discrete and accurate amount of a drug to the respiratory tract of a patient using a liquefied propellant in which the drug is dissolved, suspended or dispersed. They all comprise a pressurised container that holds the drug formulation, a nozzle and a valve assembly that is capable of dispensing a controlled quantity of the drug through the nozzle when the MDI is activated.
  • the nozzle and valve assembly are typically located in a housing that is equipped with a mouth piece and a receptacle with a coupling for receiving the pressurised container holding the drug and propellant.
  • H FA- 152a is an environmentally acceptable material that is a potential replacement for chlorofluorocarbon (CFG) and hydrofluorocarbon (HFC) materials that have been used traditionally as propellants in medical devices such as metered dose inhalers.
  • H FA- 152a is a potential low GWP replacement for 1 ,1 ,1 ,2-tetrafluoroethane (H FA- 134a) and 1 ,1 ,1 ,2,3,3,3-heptafluoropropane (HFA-227ea) which have become the predominant propellants in metered dose inhalers owing to their low ozone depletion potentials compared to CFCs, but which are now considered to have unacceptably high global warming potentials
  • a fluorination catalyst such as an aluminium-based fluorination catalyst or a tin-based fluorination catalyst.
  • H FA- 152a may also be contaminated with unacceptable levels of water.
  • H FA- 1523 is hygroscopic and many of the drugs that will be combined with H FA- 152a in metered dose inhalers exhibit unacceptably poor stability in the presence of water. Thus, it is important that any water that contaminates the H FA- 152a is removed to acceptably low levels.
  • the present invention provides a process for purifying 1 ,1- difluoroethane (H FA- 152a) contaminated with methyl chloride which comprises contacting the contaminated 1 ,1-difluoroethane with a molecular sieve other than a carbon molecular sieve.
  • the present invention provides a process for treating 1 ,1-difluoroethane (H FA- 152a) contaminated with methyl chloride so as to remove at least a proportion and preferably substantially all of the methyl chloride from the 1 ,1-difluoroethane, said process comprising contacting the contaminated 1 ,1-difluoroethane with a molecular sieve other than a carbon molecular sieve.
  • the methyl chloride is sequestered and entrapped by the molecular sieve and is thus separated from the H FA- 152a that it contaminates.
  • the process may be termed a polishing process.
  • the contacting step of the above described processes may be conducted in either the liquid or the vapour phase, but the liquid phase is preferred as it is more economical to run.
  • the molecular sieve may be dried before use. Alternatively, it may be used in the form it is obtained from the manufacturer.
  • the preferred moisture level is less than about 1.5 % by weight.
  • the molecular sieve may also be treated to remove any materials that might be adsorbed on or within the molecular sieve, e.g. within its pores, prior to being used in the processes of the present invention.
  • the treatment step comprises heating the molecular sieve to a maximum temperature of at least 150°C, e.g. of at least 200°C, preferably at least 250°C, more preferably at least 300°C, and particularly at least 350°C, e.g. at least 400°C.
  • the molecular sieve treatment step comprises heating the molecular sieve to the chosen maximum temperature at a rate of 1 °C/min to 100°C/min.
  • the molecular sieve treatment step comprises heating the molecular sieve to the chosen maximum temperature at a rate of 10°C/min to 60°C/min.
  • the molecular sieve treatment step comprises heating the molecular sieve to the chosen maximum temperature at a rate of 15°C/min to 40°C/min, e.g. around 20°C/min.
  • the molecular sieve treatment step is sufficiently long in duration to ensure that any adsorbed materials present on or in the molecular sieve prior to use are removed.
  • the treatment step may include maintaining the molecular sieve at or around the chosen maximum temperature for between 1 second and 1 hour.
  • the molecular sieve treatment step comprises exposing the molecular sieve to one or more inert gases, e.g. N2 or one or more noble gases.
  • the exposure is performed before, during or after the or a heat treatment step.
  • the exposure is performed during at least part of the heat treatment step.
  • the purified 1 , 1-difluoroethane may be recovered and then used in the manufacture of pharmaceutical formulations comprising the 1 , 1-difluoroethane as a propellant and one or more drugs.
  • the 1 , 1-difluoroethane will be transported to a facility having a filling line for charging containers for MDIs with both the 1 , 1-difluoroethane and the drug(s).
  • the 1 ,1- difluoroethane that is produced may be subjected to one or more additional purification processes, e.g. to remove vinyl fluoride, and/or a drying step to remove water.
  • additional purification processes e.g. to remove vinyl fluoride, and/or a drying step to remove water.
  • the preferred molecular sieves for use in the processes of the first and second aspects of the present invention are zeolitic materials.
  • Zeolites are a known group of natural and synthetic microporous minerals consisting of hydrated aluminosilicates of alkali and alkaline earth metals, such as sodium, potassium, calcium, magnesium and barium. They are characterized by three-dimensional structures of silica and alumina with cavities that can accommodate the alkali and alkaline earth metals in cationic form as well as other molecules. Zeolites can be readily dehydrated and rehydrated.
  • the molecular sieve adsorbent has a mean pore size, or diameter if the pores are spherical, of around 0.5 ⁇ to around 20 ⁇ , e.g. around 1 ⁇ to around 10 ⁇ , and more preferably around 2 ⁇ to around 10 ⁇ .
  • the pores may be spherical or elliptical or even irregularly shaped. In the case of elliptical or irregularly shaped pores, the pore size refers to the size across their smallest/largest dimension.
  • the preferred zeolitic molecular sieves for use in the polishing processes of the present invention are those that have small pores of substantially uniform size.
  • the most preferred zeolite molecular sieve is molecular sieve 4A. Mixtures of different zeolitic molecular sieves may be used if desired.
  • zeolite molecular sieve examples include MS514 (4 ⁇ ) available from Grace.
  • the methyl chloride that contaminates commercially available H FA- 152a is typically present in amounts of between about 10 and about 200 ppm by weight, e.g. between about 10 and about 100 ppm by weight, based on the total weight of the H FA- 152a.
  • the amount of methyl chloride contaminating the H FA- 1523 should be reduced to levels of 5 ppm or less by weight, e.g. to levels of 1 ppm or less by weight, based on the total weight of the H FA- 152a.
  • the methyl chloride is removed entirely or at least to a level around or below the limit of detection by gas chromatography.
  • the conditions which are applied when contacting the contaminated H FA- 152a with the molecular sieve can vary widely.
  • the process may be operated at ambient temperatures or below or above ambient temperatures.
  • the process is operated at a temperature in the range of from about 250K to about 380 K, preferably in the range of from about 270K to about 320 K and particularly in the range of from about 285K to about 310K.
  • Atmospheric, sub-atmospheric and super-atmospheric pressures may be used in the process.
  • the process is operated at a pressure in the range of from about 0.1 MPa to about 4 MPa, preferably in the range of from about 0.2 MPa to about 1.5 MPa and particularly in the range of from about 0.4 MPa to about 0.7 MPa.
  • the process is conducted in the liquid phase, it is preferably conducted at its autogenous pressure, i.e. the pressure that the liquid itself exerts, or higher if desired.
  • the process is conducted in the vapour phase, it is preferably conducted at a pressure of from 0.1 MPa to the saturation pressure. For a given temperature, the saturation pressure of a pure component is that pressure at which vaporisation of the liquid takes place.
  • the process can be conducted as a batch process or as a continuous process. Batch processes are preferred.
  • the molecular sieve may be contained in a static bed through which the contaminated H FA- 152a is conveyed.
  • the molecular sieve may be packed in a column through which the contaminated H FA-152a is conveyed under pressure, e.g. by means of a pump.
  • the molecular sieve may be mechanically agitated, e.g. using an impeller, or subjected to a forced flow of gas to provide a fluidized bed through which the contaminated H FA- 152a is passed.
  • the contaminated H FA- 152a may be passed through the static or fluidized molecular sieve bed multiple times if required to reduce the levels of methyl chloride to acceptably low levels. Multiple passes may, in particular, be required when the adsorbent bed has aged.
  • the molecular sieve and the contaminated H FA- 152a may be conveyed counter-currently through a suitable purification chamber with an inlet for the contaminated H FA-152a at one end and an inlet for the molecular sieve at the other.
  • Other techniques for contacting the molecular sieve with the contaminated H FA- 152a will be apparent to those skilled in the art.
  • the precise nature of the molecular sieve bed is not critical providing the contact between the molecular sieve and the contaminated H FA- 152a is sufficient to reduce the amount of methyl chloride contaminating the H FA- 152a to acceptably low levels.
  • the total contact time will depend on the amount of molecular sieve in the bed and on its age, by which we mean the length of time that has passed since the molecular sieve was first used in the polishing process.
  • the contact time between the contaminated H FA- 152a and the molecular sieve is between about 0.1 and about 10,000 seconds, preferably between about 1 and about 10,000 seconds and more particularly between about 100 and about 10,000 seconds. The skilled person will readily be able to determine a suitable contact time.
  • the effectiveness of the molecular sieve used in the process will deteriorate with time.
  • the time that it takes for the molecular sieve to deteriorate depends on a number of factors, such as the ratio of the amount of molecular sieve to the amount of contaminated H FA- 152a being treated as well as the level of methyl chloride contaminating the H FA- 152a.
  • the processes of the present invention may further comprise the step of regenerating the molecular sieve after it has been contacted with the contaminated H FA- 152a.
  • the molecular sieve may be regenerated by contacting it with a heated nitrogen stream or by heating it whilst nitrogen is passed over it.
  • the molecular sieve polishing process of the present invention can result in the dehydrofluorination of a small proportion of the H FA- 152a to yield vinyl fluoride which needs to be removed following the polishing process if the H FA- 152a is to be used in medical applications.
  • This problem can arise, in particular, when the molecular sieve is a zeolite.
  • H FA- 152a contaminated with methyl chloride is first subjected to a polishing process in which it is contacted with a molecular sieve to remove at least a proportion and preferably substantially all of the methyl chloride followed by a distillation process that is designed to remove any vinyl fluoride that happens to contaminate the H FA- 152a following the molecular sieve polishing process to acceptably low levels.
  • a polishing process in which it is contacted with a molecular sieve to remove at least a proportion and preferably substantially all of the methyl chloride followed by a distillation process that is designed to remove any vinyl fluoride that happens to contaminate the H FA- 152a following the molecular sieve polishing process to acceptably low levels.
  • the vinyl fluoride that contaminates the H FA- 152a may include material that contaminated the H FA- 1523 that was fed originally to the molecular sieve polishing process as well as material that was generated as a result of the molecular sieve polishing process.
  • the distillation process may include one or more distillation steps. Where multiple distillation steps are employed, they will be conducted in separate distillation/fractionation columns. Preferably, the distillation process uses just a single distillation step conducted in a single distillation column.
  • the vinyl fluoride contaminating the H FA- 152a that is fed to the distillation process is typically present in amounts of between about 5 and about 50 ppm by weight, e.g. between about 10 and about 20 ppm by weight, based on the total weight of the H FA- 152a.
  • the amount of vinyl fluoride contaminating the H FA- 152a should be reduced to levels of 5 ppm or less by weight, e.g. to levels of 1 ppm or less by weight, based on the total weight of the H FA- 152a.
  • the vinyl fluoride is removed entirely or at least to a level around or below the limit of detection by gas chromatography.
  • a process for purifying 1 ,1-difluoroethane (H FA- 152a) contaminated with methyl chloride and vinyl fluoride which comprises:
  • step (b) subjecting the purified 1 ,1-difluoroethane produced in step (a) to a distillation process to remove vinyl fluoride.
  • any vinyl fluoride contaminating the H FA- 1523 that is subjected to the process of the third aspect of the present invention may only be present as a result of the molecular sieve contacting step (a).
  • vinyl fluoride may also contaminate the H FA- 152a that is fed to the molecular sieve contacting step (a) as well as being generated as a result of the contacting step.
  • the purified H FA- 152a produced in step (a) may be recovered before it is fed to distillation step (b). However, it is convenient to feed the purified H FA- 152a produced in step (a) directly to distillation step (b).
  • the purified 1 ,1-difluoroethane may be recovered from step (b) and then used in the manufacture of pharmaceutical formulations comprising the 1 ,1-difluoroethane as a propellant and one or more drugs.
  • the 1 ,1-difluoroethane will be transported to a facility having a filling line for charging containers for MDIs with both the 1 ,1-difluoroethane and the drug(s).
  • the 1 ,1-difluoroethane that is produced following distillation step (b) may be subjected to a drying step to remove water.
  • Step (a) of the process of the third aspect of the present invention is conducted so that at least a proportion and preferably substantially all of the methyl chloride is removed. If the H FA- 152a is to be used in medical applications, then contacting step (a) should be conducted so that the amount of methyl chloride contaminating the H FA- 152a following completion of step (a) is 5 ppm or less by weight, e.g. 1 ppm or less by weight, based on the total weight of the H FA- 1523. Preferably, the methyl chloride is removed entirely or at least to a level around or below the limit of detection by gas chromatography.
  • step (a) of the process of the third aspect of the present invention could use a carbon molecular sieve in contacting step (a), zeolitic molecular sieves are preferred.
  • the typical and preferred conditions and the preferred zeolites for step (a) of the process of the third aspect of the present invention are as described above for the processes of the first and second aspects of the present invention.
  • Step (b) of the process of the third aspect of the present invention is conducted so that at least a proportion and preferably substantially all of the vinyl fluoride is removed. If the H FA- 152a is to be used in medical applications, then distillation step (b) should be conducted so that the amount of vinyl fluoride contaminating the H FA- 152a following completion of step (b) is 5 ppm or less by weight, e.g. 1 ppm or less by weight, based on the total weight of the H FA- 152a. Preferably, the vinyl fluoride is removed entirely or at least to a level around or below the limit of detection by gas chromatography.
  • the H FA- 152a that is produced following the molecular sieve polishing process of step (a) and the distillation process of step (b) contains 5 ppm by weight or less, e.g. 1 ppm by weight or less, of methyl chloride based on the total weight of the H FA- 152a and 5 ppm by weight or less, e.g. 1 ppm by weight or less, of vinyl fluoride based on the total weight of the H FA- 152a.
  • the H FA- 152a that is produced following the molecular sieve polishing process of step (a) and the distillation process of step (b) is free or essentially free of both methyl chloride and vinyl fluoride.
  • distillation conditions for the removal of vinyl fluoride in distillation step (b) are not critical. Typically, the distillation may be conducted at a pressure in the range of from about 50 kPa to about 2300 kPa, preferably in the range of from about 200 kPa to about 2000 kPa, and more preferably in the range of from about 500 to about 1500 kPa.
  • the present invention provides a process for purifying 1 ,1-difluoroethane (H FA- 152a) contaminated with vinyl fluoride recovered from a process in which the 1 ,1- difluoroethane was contacted with a molecular sieve to remove at least a proportion and preferably substantially all of any methyl chloride that contaminated the 1 ,1-difluoroethane, said process comprising subjecting the vinyl fluoride contaminated 1 ,1-difluoroethane to a distillation process to remove the vinyl fluoride and then recovering purified H FA- 152a.
  • H FA- 152a 1 ,1-difluoroethane
  • the process of the fourth aspect of the present invention is conducted so that at least a proportion and preferably substantially all of the vinyl fluoride is removed. If the H FA- 152a is to be used in medical applications, then the distillation process should be conducted so that the amount of vinyl fluoride contaminating the H FA- 152a recovered from the distillation process is 5 ppm or less by weight, e.g. 1 ppm or less by weight, based on the total weight of the H FA- 152a. Preferably, the vinyl fluoride is removed entirely or at least to a level around or below the limit of detection by gas chromatography.
  • the purified 1 ,1-difluoroethane produced in the process of the fourth aspect of the present invention may be recovered and then used in the manufacture of pharmaceutical formulations comprising the 1 ,1-difluoroethane as a propellant and one or more drugs.
  • the 1 ,1- difluoroethane will be transported to a facility having a filling line for charging containers for MDIs with both the 1 ,1-difluoroethane and the drug(s).
  • the 1 ,1-difluoroethane that is produced in the process of the fourth aspect of the present may be subjected to a drying step to remove water.
  • H FA- 152a product that is recovered from the processes of any of the first, second, third and fourth aspects of the present invention may often contain water in unacceptable quantities.
  • H FA- 152a is hygroscopic and many of the drugs that will be combined with H FA- 152a in metered dose inhalers exhibit unacceptably poor stability in the presence of water. Thus, it is important that any water that contaminates the H FA- 152a is removed to acceptably low levels.
  • Zeolites could, in principle, be used to remove water. However, as discussed above at least some zeolites can result in dehydrofluorination of a small proportion of the H FA- 152a to yield vinyl fluoride which is undesirable and as the drying step is usually conducted last, the preferred drying agents are those materials that are able to remove water without causing any decomposition of the HFA-152a. We have found that silica gels are especially useful for the drying step although other materials such as concentrated sulphuric acid may also be useful.
  • a process for purifying 1 ,1-difluoroethane (H FA- 152a) contaminated with methyl chloride and water which comprises:
  • step (a) contacting the contaminated 1 ,1-difluoroethane with a molecular sieve to remove methyl chloride; (b) subjecting the purified 1 ,1-difluoroethane produced in step (a) to a drying step to remove water; and
  • step (c) recovering dry and purified 1 ,1-difluoroethane from step (b).
  • a process for purifying 1 ,1- difluoroethane (H FA- 152a) contaminated with methyl chloride, vinyl fluoride and water which comprises:
  • step (b) subjecting the purified 1 ,1-difluoroethane produced in step (a) to a distillation process to remove vinyl fluoride;
  • step (c) subjecting the purified 1 ,1-difluoroethane produced in step (b) to a drying step to remove water;
  • step (d) recovering dry and purified 1 ,1-difluoroethane from step (c).
  • any vinyl fluoride contaminating the H FA- 1523 that is subjected to the process of the sixth aspect of the present invention may only be present as a result of the molecular sieve contacting step (a).
  • vinyl fluoride may also contaminate the H FA- 152a that is fed to the molecular sieve contacting step (a) as well as being generated as a result of the contacting step.
  • the purified H FA- 1523 produced in step (a) may be recovered before it is fed to drying step (b). However, it is convenient to feed the purified H FA- 152a produced in step (a) directly to drying step (b).
  • the purified H FA- 152a produced in step (a) may be recovered before it is fed to distillation step (b). However, it is convenient to feed the purified H FA-152a produced in step (a) directly to distillation step (b).
  • the purified H FA- 152a produced in step (b) may be recovered before it is fed to drying step (c). However, it is convenient to feed the purified H FA- 152a produced in step (b) directly to drying step (c).
  • Step (a) of the process of the fifth and sixth aspects of the present invention is conducted so that at least a proportion and preferably substantially all of the methyl chloride is removed. If the H FA- 152a is to be used in medical applications, then contacting step (a) should be conducted so that the amount of methyl chloride contaminating the H FA- 152a following completion of step (a) is 5 ppm or less by weight, e.g. 1 ppm or less by weight, based on the total weight of the H FA- 152a. Preferably, the methyl chloride is removed entirely or at least to a level around or below the limit of detection by gas chromatography.
  • zeolitic molecular sieves are preferred.
  • the typical and preferred conditions and the preferred zeolites for step (a) of the process of the fifth and sixth aspects of the present invention are as described above for the processes of the first and second aspects of the present invention.
  • Step (b) of the process of the sixth aspect of the present invention is conducted so that at least a proportion and preferably substantially all of the vinyl fluoride is removed. If the H FA- 152a is to be used in medical applications, then distillation step (b) should be conducted so that the amount of vinyl fluoride contaminating the H FA- 152a following completion of step (b) is 5 ppm or less by weight, e.g. 1 ppm or less by weight, based on the total weight of the H FA- 152a. Preferably, the vinyl fluoride is removed entirely or at least to a level around or below the limit of detection by gas chromatography.
  • Drying step (b) of the process of the fifth aspect of the present invention and drying step (c) of the process of the sixth aspect of the present invention are conducted so that at least a proportion and preferably substantially all of the water is removed. If the H FA- 152a is to be used in medical applications, then the drying steps should be conducted so that the amount of water contaminating the H FA- 152a following completion of the drying step is 500 ppm or less by weight, preferably 100 ppm or less by weight, more preferably 50 ppm or less by weight, particularly 10 ppm or less by weight and especially 5 ppm or less by weight based on the total weight of the H FA- 152a.
  • the conditions which are applied when contacting the‘wet’ H FA- 152a with the drying agent can vary widely.
  • the drying step may be operated at ambient temperatures or below or above ambient temperatures.
  • the drying step is operated at a temperature in the range of from about 250K to about 380K, preferably in the range of from about 270K to about 320 K and particularly in the range of from about 285K to about 310K.
  • Atmospheric, sub-atmospheric and super-atmospheric pressures may be used in the process.
  • the drying step is operated at a pressure in the range of from about 1 bar to about 40 bar, preferably in the range of from about 2 bar to about 15 bar and particularly in the range of from about 4 bar to about 7 bar.
  • the drying step can be conducted as a batch process or as a continuous process. Continuous processes are preferred.
  • the drying agent may be contained in a static bed through which the ‘wet’ H FA- 152a is conveyed.
  • the drying agent may be packed in a column through which the contaminated H FA- 152a is conveyed under pressure, e.g. by means of a pump.
  • the drying agent may be mechanically agitated, e.g. using an impeller, or subjected to a forced flow of gas to provide a fluidized bed through which the‘wet’ H FA- 152a is passed.
  • drying agent and the ‘wet’ H FA- 152a may be conveyed counter-currently through a suitable drying chamber with an inlet for the H FA- 152a at one end and an inlet for the drying agent at the other.
  • suitable drying chamber with an inlet for the H FA- 152a at one end and an inlet for the drying agent at the other.
  • the contact between the drying agent and the‘wet’ H FA- 152a should be sufficient to reduce the amount of water contaminating the H FA- 152a to acceptably low levels.
  • the present invention provides a process for treating 1 ,1-difluoroethane (H FA- 152a) contaminated with methyl chloride and water so as to remove at least a proportion and preferably substantially all of the methyl chloride and water from the 1 ,1-difluoroethane, said process comprising contacting the contaminated 1 ,1-difluoroethane with a molecular sieve to remove methyl chloride and with a drying agent to remove water and recovering dry, purified 1 ,1-difluoroethane.
  • H FA- 152a 1 ,1-difluoroethane
  • the process of the seventh aspect of the present invention is conducted so that at least a proportion and preferably substantially all of the methyl chloride and the water are removed. If the H FA- 152a is to be used in medical applications, then the process of the seventh aspect of the present invention should be conducted so as to reduce the amount of methyl chloride contaminating the H FA- 152a to 5 ppm or less by weight, e.g. 1 ppm or less by weight, based on the total weight of the HFA-152a. Preferably, the methyl chloride is removed entirely or at least to a level around or below the limit of detection by gas chromatography.
  • the process of the seventh aspect of the present invention should be conducted so as to reduce the amount of water contaminating the H FA- 152a to 500 ppm or less by weight, preferably 100 ppm or less by weight, more preferably 50 ppm or less by weight, particularly 10 ppm or less by weight and especially 5 ppm or less by weight based on the total weight of the H FA- 152a.
  • process of the seventh aspect of the present invention could use a carbon molecular sieve to remove the methyl chloride, zeolitic molecular sieves are preferred.
  • the typical and preferred conditions and the preferred zeolites for the molecular sieve contacting step of the process of the seventh aspect of the present invention are as described above for the processes of the first and second aspects of the present invention.
  • the present invention provides a process for treating 1 ,1-difluoroethane (H FA- 152a) contaminated with methyl chloride, vinyl fluoride and water so as to remove at least a proportion and preferably substantially all of the methyl chloride, vinyl fluoride and water from the 1 ,1-difluoroethane, said process comprising contacting the contaminated 1 ,1- difluoroethane with a molecular sieve to remove methyl chloride, subjecting the contaminated 1 ,1-difluoroethane to a distillation step to remove vinyl fluoride and contacting the contaminated 1 ,1-difluoroethane with a drying agent to remove water and recovering dry, purified 1 ,1-difluoroethane.
  • H FA- 152a 1 ,1-difluoroethane
  • the process of the eighth aspect of the present invention is conducted so that at least a proportion and preferably substantially all of the methyl chloride, vinyl fluoride and the water are removed. If the H FA- 152a is to be used in medical applications, then the process of the eighth aspect of the present invention should be conducted so as to reduce the amount of each of methyl chloride and vinyl fluoride contaminating the H FA- 152a to 5 ppm or less by weight, e.g. 1 ppm or less by weight, based on the total weight of the HFA-152a. Preferably, the methyl chloride and vinyl fluoride are removed entirely or at least to a level around or below the limit of detection by gas chromatography.
  • the process of the eighth aspect of the present invention should be conducted so as to reduce the amount of water contaminating the H FA- 152a to 500 ppm or less by weight, preferably 100 ppm or less by weight, more preferably 50 ppm or less by weight, particularly 10 ppm or less by weight and especially 5 ppm or less by weight based on the total weight of the H FA- 152a.
  • the process of the eighth aspect of the present invention could use a carbon molecular sieve to remove the methyl chloride, zeolitic molecular sieves are preferred.
  • the typical and preferred conditions and the preferred zeolites for the molecular sieve contacting step of the process of the eighth aspect of the present invention are as described above for the processes of the first and second aspects of the present invention.
  • the H FA- 152a that is produced in accordance with the processes of the fifth and seventh aspects of the present invention contains 5 ppm by weight or less, e.g. 1 ppm by weight or less, of methyl chloride based on the total weight of the H FA- 1523 and 500 ppm or less by weight, preferably 100 ppm or less by weight, more preferably 50 ppm or less by weight, particularly 10 ppm or less by weight and especially 5 ppm or less by weight of water based on the total weight of the HFA-152a.
  • the H FA- 152a that is produced in accordance with the processes of the fifth and seventh aspects of the present invention is free or essentially free of both methyl chloride and water.
  • the H FA- 152a that is produced in accordance with the processes of the sixth and eighth aspects of the present invention contains 5 ppm by weight or less, e.g. 1 ppm by weight or less, of each of methyl chloride and vinyl fluoride based on the total weight of the H FA- 152a and 500 ppm or less by weight, preferably 100 ppm or less by weight, more preferably 50 ppm or less by weight, particularly 10 ppm or less by weight and especially 5 ppm or less by weight of water based on the total weight of the HFA-152a.
  • the H FA- 152a that is produced in accordance with the processes of the sixth and eighth aspects of the present invention is free or essentially free of methyl chloride, vinyl fluoride and water.
  • the present invention provides a pharmaceutical composition containing one or more pharmaceutically active substances and/or compositions and a propellant component comprising H FA-152a prepared by a process as defined in any one of the first to eighth aspects of the present invention.
  • the present invention provides a medication delivery device and especially a metered dose inhaler having a container holding one or more pharmaceutically active substances and/or compositions and a propellant component comprising H FA- 152a prepared by a process as defined in any one of the first to eighth aspects of the present invention.
  • the propellant component consists essentially of and more preferably consists entirely of H FA- 1523.
  • a 10kg cylinder of Chemours 1 ,1-difluoroethane (152a) was prepared.
  • the preparation involved pre-treatment of the (as supplied) industrial grade Chemours 152a to remove oils and / or other 'heavy' materials, which can potentially block pores or 'coat' the active surface of the adsorbent.
  • the pre-treatment consists of vapourising the industrial grade 152a and condensing it into clean 10Kg cylinders for use in the Examples.
  • the molecular sieve was activated by pre-drying in an oven at a temperature of 300°C under a purge of nitrogen for 24 hours.
  • the whitey cylinder was swirled gently and then placed into a stability cabinet.
  • Pairs of samples were removed from the cabinet on different days and analysed to represent composition on that particular day during the seven day period.
  • the molecular sieves used was MS514 (4A) - available from Grace. All organic analysis was performed by gas chromatography on Agilent equipment and moisture content was by a Metrohm moisture meter.
  • the level of vinyl fluoride rises and continues to rise at a constant rate.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

L'invention concerne un procédé de purification de 1,1-difluoroéthane (H FA- 152a) contaminé par du chlorure de méthyle. Le procédé comprend la mise en contact du 1,1-difluoroéthane contaminé avec une zéolite. L'invention concerne également un procédé de purification du 1,1-difluoroéthane (HFA -152a) contaminé par du chlorure de méthyle et du fluorure de vinyle. Le procédé comprend : la mise en contact du 1,1-difluoroéthane contaminé avec une zéolite pour éliminer le chlorure de méthyle et la soumission du 1,1-difluoroéthane à un procédé de distillation pour éliminer le fluorure de vinyle. Le 1,1-difluoroéthane purifié peut également être soumis à une étape de séchage pour éliminer l'eau, le 1,1-difluoroéthane étant mis en contact avec un agent de séchage.
PCT/GB2020/051169 2019-05-14 2020-05-13 Procédé de purification WO2020229823A1 (fr)

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GB1906778.4A GB2583934A (en) 2019-05-14 2019-05-14 Purification process

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998019982A1 (fr) * 1996-11-01 1998-05-14 E.I. Du Pont De Nemours And Company Procede de purification de 1,1-difluoroethane
WO2004005226A1 (fr) * 2002-07-02 2004-01-15 Showa Denko K. K. Procede de purification de pentafluoroethane, procede de production de pentafluoroethane, et utilisation de ce pentafluoroethane
US20050133360A1 (en) * 2003-12-23 2005-06-23 Honeywell International Inc. Process for the purification of pharmaceutical grade HFC-134a and polymer grade HCFC-22
WO2014174281A1 (fr) * 2013-04-23 2014-10-30 Mexichem Amanco Holding S.A. De C.V. Procédé de purification de compositions (hydro)halogénocarbonées
WO2017122222A1 (fr) * 2016-01-14 2017-07-20 Srf Limited Procédé pour la préparation d'oléfine contenant du fluor

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998019982A1 (fr) * 1996-11-01 1998-05-14 E.I. Du Pont De Nemours And Company Procede de purification de 1,1-difluoroethane
WO2004005226A1 (fr) * 2002-07-02 2004-01-15 Showa Denko K. K. Procede de purification de pentafluoroethane, procede de production de pentafluoroethane, et utilisation de ce pentafluoroethane
US20050133360A1 (en) * 2003-12-23 2005-06-23 Honeywell International Inc. Process for the purification of pharmaceutical grade HFC-134a and polymer grade HCFC-22
WO2014174281A1 (fr) * 2013-04-23 2014-10-30 Mexichem Amanco Holding S.A. De C.V. Procédé de purification de compositions (hydro)halogénocarbonées
WO2017122222A1 (fr) * 2016-01-14 2017-07-20 Srf Limited Procédé pour la préparation d'oléfine contenant du fluor

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