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.

Description

[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 stilt require a final distillation in order to produce a pharmaceutically acceptable form of sevoflurane.[0002]In all of these proces...

AI Technical Summary

Benefits of technology

[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

[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.

Problems solved by technology

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.

It is difficult to separate this decomposition / disproportionation product from sevoflurane by distillation because their boiling points are very similar.

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.

Furthermore, although fluoroethers are excellent anesthetic agents, some fluoroethers have been reported to encounter stability problems.

Hydrofluoric acid is toxic by ingestion and inhalation and is highly corrosive to skin and mucous membranes.

In fact, quantities of Ultane® brand sevoflurane had to be recalled on two occasions due to potentially patient-threatening decomposition caused by exposure to Lewis acids.

The drawbacks of using such agents include the added expense and processing time for their incorporation into the drug product.