Amoxicillin trihydrate

The XRD powder patterns of the anhydrate and trihydrate phases of ampicil-lin are shown in Fig. 5. The nonequivalence in the crystal structures is immediately evident from a comparison of the powder patterns. It is also known that amoxicillin trihydrate is isomorphous with ampicillin trihydrate [39], and a comparison of the corresponding powder patterns demonstrates the equivalence of the structures. 

Fig. 5 X-ray powder patterns of (A) ampicillin anhydrate, (B) ampicillin trihydrate, and (C) amoxicillin trihydrate.

Penicillins have several properties that are characteristic of /i-lactam antibiotics. They are obtained in relatively pure form as off-white, tan, or yellow freeze-dried or spray-dried solids that are usually amorphous. Alternatively they are sometimes obtained as crystalline solids, often as hydrates. Penicillins do not usually have sharp melting points, but decompose upon heating to elevated temperatures. Most natural members have a free carboxyl group and commercial preparations are generally either supplied as salts, most frequently as sodium salts, or in zwitterionic form as hydrates, e.g.. amoxicillin trihydrate. The acid strength of the carboxyl group in aqueous solution varies from pAT = 2.73 for oxacillin to p= 3.06 for carbenicillin. 

Dr. David Johnson (1975-1982). Of all my senior managers, Dave Johnson was the one who knew most about organic chemistry and synthesis. He was a hard-driving chemist with a nose for practical solutions to process development problems. Being a student of Professor John Sheehan, his knowledge of (3-lactam chemistry was extensive. Indeed he was called on to represent Bristol-Myers in its many patent battles with Beecham in which Bristol-Myers staked out its own patent position covering ampicillin and amoxicillin trihydrates.8... 

Calculate the lowest solubility of amoxicillin trihydrate. pKal and pKa2 are 2.67 and 7.11, respectively. The saturated concentration of the drug at pH 2 is 0.073 M. 

In another method, Pandey and Rathanand [35] used a combination of acetonitrile and water to analyze ezetimibe as a single compound. In contrast, Sistla et al. [36] reported that combination of water and acetonitrile produced peak tailing and poor resolution of ezetimibe with amoxicillin trihydrate as the internal standard. To overcome this, an ion pair reagent was added to the system, successfully reducing the peak tailing and increasing resolution between ezetimibe and amoxicillin trihydrate. 

The excipients ethylcellulose and pectin " show the possibilities for complex interactions of the type intermolecular H-bonds. The latter result in increased therapeutic activity of the amoxicillin trihydrate (granules) and nystatin (plaque). The nature and complex character of these interactions have been investigated by means of IR spectroscopy and X-ray diffraction. " ... 

Gasheva, L.M. Kalinkova, G. Minkov, E. Krestev, V. IR spectroscopic investigations of amoxicillin trihydrate included in the technological models sirup granules in ethylcellulose. J. Mol. Struct. 1984, 115, 323-326. 

Fig. 10 Release profiles of hard gelatin capsule containing amoxicillin trihydrate (A) soft gelatin capsules containing cephalexin (B) soft gelatin capsules containing nimesulide (C) and sugar-coated tablets containing trifluoperazine (D) upon storage at 40°C/75% RH in the presence of light.

The drug concentration in a parenteral suspension can influence the plasma concentration profile. When different concentrations of amoxicillin (100 and 200mg/ml) in aqueous suspensions of amoxicillin trihydrate were administered intramuscularly at the same site and same dose level (lOmg/kg) to horses, the preparation of lower concentration (10%) provided relatively better absorption and a more consistent plasma concentration profile. Intramuscular injection of amoxicillin trihydrate (15% in a mixed oil base) in the neck (10 cm behind the ear) of pigs produced two peaks, 1.7 and 0.8pg/ml at 1.3 and 6.6 h, respectively, rather than a single peak in the plasma concentration profile and an eight-fold longer mean residence time of the antibiotic than a preparation of the same... 

Fig. 6 Effect of species and weight on the bioavailability of amoxicillin after i.m. injection of amoxicillin trihydrate aqueous suspension (lOOmg/ml) at the same dose (7mg/kg) in the various species except cats (10-12mg/kg).

Age and body weight (45, 55, and 62, kg) of calves was shown to influence the systemic availability of amoxicillin administered intramuscularly as amoxicillin trihydrate (10% aqueous suspension). When the same preparation was administered intramuscularly to different animal species, the trend was for smaller animals (piglets, dogs, cats) to show an early high peak concentration followed by a rapid decline, whereas larger animals (calves, horses) show a lower and relatively constant plasma concentration of amoxicillin over at least an 8-h period (Fig. 6). ... 

Parenteral preparations with antimicrobial activity, which depends on the causative pathogenic microorganism, and pharmacokinetic properties that meet most of these criteria include procaine penicillin G (aqueous suspension), amoxicillin trihydrate-clavulanate potassium combination (aqueous suspension), and enro-floxacin (solution). Enrofloxacin is not approved for use... 

An antibiotic dry syrup formulation is shown in Table 143 as an application of micronized crospovidone of low bulk density. The formulation has been developed in the laboratory for two different drugs, so that it can be regarded as a typical guide formulation. It contains citric acid, to adjust the pH to 4.9, to optimize the chemical stability of the drug, ampicillin trihydrate or amoxicillin trihydrate. 

Formulation (sales product) Ampicillin trihydrate or amoxicillin trihydrate 5.0 g... 

Amoxicillin trihydrate is a white or almost white crystalline powder. Amoxicillin sodium salt is a white or almost white powder, sometimes with a pinkish tinge. As normally produced it is amorphous and hygroscopic. Freshly prepared aqueous solutions may show a transient pink colouration [2], Both compounds may have the slightly sulphurous odour that is typical of many penicillins. 

Comparison of the crystal structure of amoxicillin trihydrate with that of ampicillin anhydrate showed [14] that the p-OH group would reduce the benzene ring overlap which contributes to the stability of the anhydrate crystal form. This is consistent with the failure of amoxicillin to crystallise under the conditions used to prepare ampicillin anhydrate [14]. However, a hygroscopic crystalline anhydrate of amoxicillin has been obtained [16], by solid state removal of methanol from a crystalline monomethanolate, but little information is available about this form. 

The powder dififractogram of amoxicillin trihydrate obtained with copper Ka radiation is shown in Figure 1. Diffraction lines with a relative intensity greater than 10% are listed below, with their d spacings and relative intensities. 

Differential Scanning Calorimetry (DSC) and Thermogravimetric Analysis (TGA) of amoxicillin trihydrate showed loss of the water of crystallisation from about 50 to 150 °C followed by decomposition of the amoxicillin from about 160°C upwards [18], DSC and TGA of amoxicillin sodium salt in an oxygen atmosphere showed loss of water at about 100°C and thermal decomposition in multiple events from about 200 to 500°C [19]. The techniques are of little practical value for these compounds. 

IR spectra of amoxicillin trihydrate and amoxicillin sodium salt in a potassium bromide disc are shown in Figures 2 and 3 respectively. The frequencies and assignments of significant bands are listed below. 

The 100 MHz C-13 spectrum of amoxicillin trihydrate in D20 at pD 8 is shown in Figure 5. The lower trace is the full proton decoupled spectrum and the upper trace is the DEPT 135 spectrum in which signals from the quaternary carbons are suppressed. Chemical shifts relative to external dioxan at 67.4 ppm and assignments are ... 

The assignments are based on 2D COSY and COLOC experiments, as well as the chemical shifts and results of the DEPT spectrum. All the assignments, except C7 and C9 which are interchanged, are consistent with published values for amoxicillin trihydrate dissolved in dimethyl sulphoxide [23], although there are some chemical shift differences due to solvent effects. 

Solid state C-13 NMR spectra of amoxicillin trihydrate and other penicillins have been used to compare thiazolidine ring conformations in the solution and solid states [24], The results indicated rapid interconversion between the S out of plane and the C3 out of plane conformations in solution, with an equilibrium ratio of 74 to 26 for solutions of amoxicillin sodium salt. 

Figure 6. Positive Ion Mass Spectrum of Amoxicillin Trihydrate...

Amoxicillin trihydrate did not give a useful mass spectrum by the conventional electron impact ionisation technique, even with a specialised in beam procedure which gave spectra from several other penicillins [26], Laser desorption [27] and desorption chemical ionisation [28] both gave pseudomolecular ions and the latter technique also gave significant fragmentation. 

Kinetic studies of the degradation of amoxicillin trihydrate and sodium salt in sealed containers at 37, 50, 80, 90, 100 and 110°C have been reported... 

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