Mupirocin is an antibacterial agent produced as pseudomonic acid A by fermentation of Pseudomonas fluorescens. It is active against susceptible strains of Staphylococcus aureus and Streptococcus pyogenes, and is typically utilized as a topical solution. Mupirocin has the molecular formula C26H44O9 (molecular weight=500.63) and the chemical name (E)-(2S,3R,4R,5S)-5-[(2S,3S,4S,5S)-2,3-Epoxy-5-hydroxy-4-methylhexyl]tetra-hydro-3,4-dihydroxy-(beta)-methyl-2H-pyran-2-crotonic acid, ester with 9-hydroxynonanoic acid. The chemical structure of mupirocin is shown below:

The calcium salt of pseudomonic acid A, mupirocin calcium or calcium pseudomonate, provides higher thermal stability, especially in crystalline state (U.S. Pat. No. 5,191,093). This stability is particularly favorable in formulations that involve higher temperatures.
Several methods for purifying mupirocin and derivatives thereof are known in the art. For example, U.S. Pat. No. 5,191,093 describes a process for preparing crystalline calcium pseudomonate or a hydrate thereof which process comprises reacting pseudomonate ions with calcium ions in solution in an aqueous solvent, recovering a crystalline calcium pseudomonate hydrate from the solution and therafter optionally removing water of crystallization. The method provides a simple means of converting mupirocin acid to the calcium salt. However, the purification effect of the operation is limited and a pure starting material is required to obtain a product that is acceptable for pharmaceutical use. U.S. Pat. No. 3,977,943 relates to purification from culture broth by chromatography on Amberlite XAD-2 polystyrene resin and elution using a series of low molecular weight acids. German patent 2227739 and U.S. Pat. No. 4,289,703 relate to a purification process using sodium barium and methyl isobutyl ketone (MIBK). Belgian Pat. No. 870,855 relates to a process involving extraction of mupirocin from fermentation broth using MIBK and sodium hydrogen carbonate and crystallization from a MIBK-n-heptane mixture. U.S. Pat. No. 4,222,942 relates to a process involving extraction in a polar water immiscible organic solvent, and dilution in a non-polar solvent to effect crystallization. U.S. Pat. No. 6,254,921 relates to a process of extraction using a chlorinated aliphatic hydrocarbon or isobutyl acetate and evaporation of organic solvent.
Like U.S. Pat. No. 5,191,093, WO03/065975 A2 provides a process for preparing mupirocin calcium from mupirocin in a two phase system by using an organic carboxylate and isolating solid mupirocin calcium from the aqueous phase, or by first precipitating amorphous mupirocin calcium from a C1-C4 alcohol, and then convert the amorphous product to the crystalline form.
Several methods for purification of Mupirocin Acid are known in the art, e.g. U.S. Pat. No. 4,222,942 (as noted above), these methods generally relates to partitioning of mupirocin in acidified/alkaline aqueous solution and polar water immiscible organic solvents such as methyl isobutyl ketone (MIBK) and isobutyl acetatate, followed by crystallization from an organic solvent such as MIBK. According to U.S. Pat. No. 4,289,703 A, soluble barium salts are added to the fermentation broth, then the microorganism cells with the insoluble inactive agents are separated by centrifugation and finally the antibiotics are extracted by MIBK. The antibiotics are then removed from the methyl isobutyl ketone extract by alkaline water and the resulting alkaline aqueous extract is cleaned by re-extraction with MIBK. The crude product obtained is subjected to chromatography and an ester derivative is prepared from the pseudomonic acid antibiotic complex and purified with preparative thin layer chromatography. The acid form of the pure antibiotic is obtained by hydrolysis.
These methods involve high volumes of hazardous agents, and there still remains a need for a novel method for the manufacture of mupirocin calcium, which combines purification and conversion of the mupirocin to the calcium salt. Such a novel process would lead to a shorter production process, and as such be commercially and environmentally more attractive.
There is a need in the art for more efficient processes for producing purified preparations of mupirocin derivatives, such as mupirocin calcium. Such processes and products produced thereby are provided herein, as discussed below.
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