Moxalactam disodium

As an example, the API moxalactam disodium undergoes decarboxylation at the benzylic site to form decarboxylated moxalactam in the solid state (Fig. 18) (34). 

Additional examples of thioether hydrolysis in solution include the API moxalactam disodium to form thiotetrazole (111). Thioethers are susceptible to oxidation to sulfoxides and sulfones (Fig. 72). 

Moxalactam disodium is a drug entity which was discovered at Shionogi and Company, Limited, Osaka, Japan, and codeveloped with Eli Lilly and Company. The drug is marketed under the trade names of MOXAM and LAMOXAM . The chemical entity is the disodium salt of (6R,7R)-7-[[carboxy(4-hydroxy-phenyl)-acetyl]amino]-7-methoxy-3-[[l-methyl-lH-tetrazole-5-yl)thio]-methyl]-8-oxo-5-oxa-l-azabi cyclo[4.2.0]oct-2-ene-2-carboxyli c acid. 

As seen in the structure, moxalactam disodium has three asymmetric centers. Two centers in the ring system, C6 and C7, are stereospecifically defined during the biosynthesis of the penicillin used to produce the compound. A third asymmetric center exists adjacent to the amide carbon on the side chain of the antibiotic. The configuration of this center is free to equilibrate and thus a pair of diasterioisomers is possible for moxalactam disodium. The rate of interconversion between the isomers increases with increasing acidity, with the maximum rate occurring at a pH of about 2.5. For solutions with pH lower than 2.5, the rate of interconversion is decreased only slightly from the maximum rate. 

Moxalactam disodium is a white to slightly cream-colored amorphous powder. 

The infrared spectrum of moxalactam disodium in a potassium bromide pellet is presented in Figure 1. The assignments for the spectral peaks are given in Table 1. 

Figure 2 shows the proton magnetic resonance spectrum for moxalactam disodium. The spectrum was recorded on a 60 MHz instrument. An interpretation of the spectrum is presented in Table 2. The spectrum is complex, for the configuration at site a undergoes rapid equilibrium and the proton at a is exchanged with deuterium. At high resolution such as at 360 MHz every resonance is split except for that of HQ. 

Figure 3. The Carbon-13 Nuclear Magnetic Resonance Spectrum for Moxalactam Disodium in D20 Plus Dioxane...

Moxalactam disodium can yield a mass spectrum when run in the field desorption mode. The major ions for moxalactam disodium are at m/z of 116 and 130. These are attributed to... 

Figure 4 shows the ultraviolet spectrum for moxalactam disodium. The major chromophore contributing to the ultraviolet absorbance spectrum is the 3-oxacephem nucleus. This entity leads to peaks at 271 nm (e=12,100) which is assigned to a tt+it transition and at 229 nm (e=18,000) which is a n- -iT transition. 

Figure 4. The Ultraviolet Spectrum of Moxalactam Disodium in Water...

In section 1.2. moxalactam disodium is described as consisting of a pair of diasterioisomers which can interconvert in solution. The observed value for optical rotation is therefore a function of the isomer distribution in solution at the time of measurement. No experimental data are available for the rotation of the pure isomers. 

The thermogram for moxalactam disodium shows an exotherm at about 170°C. This exotherm indicates the decomposition of the substance. 

The thermogram for moxalactam disodium shows a weight loss throughout the curve beginning at about 30°C. A major loss in mass occurs near 170°C which corresponds to the exotherm in the DTA curve for moxalactam disodium. Moxalactam disodium is thermally labile and undergoes increased decomposition with increasing temperature. 

The following dissociation constants have been determined for moxalactam disodium ... 

The solubility properties of moxalactam disodium are described in Table 4. 

The infrared spectrum of a sample in a potassium bromide pellet may be used as an identity test. In such cases, the infrared spectrum of the sample should compare favorably with the moxalactam disodium reference spectrum over the range of 2.5 to 16 microns. 

The NMR spectrum may be used as a means of identification for moxalactam disodium. In such cases, the NMR spectrum of the moxalactam sample dissolved in deuterium oxide should have chemical shifts and integrations over the range of 0 to 10 ppm which compare favorably to those of the moxalactam disodium reference spectrum. 

Amorphous disodium moxalactam and crystalline diammonium moxalactam salts have been used as standard materials in the control of moxalactam products. Special handling is required for all moxalactam standards used in quantitative testing of moxalactam. Amorphous moxalactam disodium is somewhat unstable and must be stored in a dry state. The dry material is hydroscopic and therefore difficult to weigh. The diammonium salt of moxalactam is a stable crystalline substance however, it exists almost completely in the R configuration. For most assay procedures the required R to S ratio is about one therefore, the material must be treated to equilibrate the ratio of the isomers. 

Moxalactam disodium reference standards are equilibrated under controlled humidity conditions to raise the moisture content to a level where the material can be handled by ordinary means. This is accomplished by spreading a thin layer of material in a wide mouth weighing bottle which is placed in a 42% relative humidity chamber for about 16 hours before use. The 42% relative humidity chamber is prepared by storing a saturated aqueous solution of potassium carbonate in a desiccator or closed chamber held at room temperature. After a 16 hour equilibration period, the water content of the standard is determined by Karl Fischer titration. The activity of the standard is then corrected for the water content of the equilibrated reference material. Experience indicates that the water content of a properly equilibrated reference material should be in the range of 10 to 12%. 

HPLC is the technique of choice for determining the purity of moxalactam disodium in raw materials, formulated products, and in body fluids. Moxalactam is determined in a system containing 0.05 to 0.1 M ammonium acetate with about 6 percent methanol present. An ES Industries Chromegabond C18 column or other alternative column with similar retention characteristics is used to determine the purity of the moxalactam sample. The substance may be monitored at 254 nm or, when available, a variable wavelength detector can be operated at 271 nm for assay. The sample is dissolved in water or in 0.1 M ammonium acetate solution. Under conditions of this method, the assay should be completed within 4 hours of sample dissolution. 

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