Erythromycin stability

A complication here, however, is noted with those drugs that exhibit a limited chemical stability in either acidic or alkaline fluids. Since the rate and extent of degradation is directly dependent on the concentration of drug in solution, an attempt is often made to retard dissolution in the fluid where degradation is seen. There are preparations of various salts or esters of drugs (e.g., erythromycin) that do not dissolve in gastric fluid and thus are not degraded there but which dissolve in intestinal fluid prior to absorption. A wide variety of chemical derivatives are used for such purposes. 

Erythromycin is unstable in acidic or alkaline solutions and shows its maximum stability between pH 6.0 and 9.525. Its aqueous, alcoholic solution buffered at pH 7.0 - 8.0 is stable for about one week under refrigeration. 

He found the order of stability for several drugs in sugar syrup and honey were as follows sulfa drugs > streptomycin > tetracycline > chlortetracycline > erythromycin > oxytetracycline. 

The PKS TE from erythromycin biosynthesis and the NRPS TE from surfactin biosynthesis are remarkably similar in three-dimensional topology (Figure 7.3) [42, 43]. It is expected that the application of enzyme-directed evolution will be able to further broaden the synthehc applications of TEs by increasing their activity and stability [44]. 

Erythromycins are macrolide antibiotics produced by bacterial fermentation. Fluoiination of erythromycin has been studied as a strategy to insure better stability in acidic medium and/or to achieve better bioavailability. An erythromycin, fluorinated at C-8, flurithromycin, was launched several years ago. Its preparation involves an electrophilic fluorination, with CF3OF [119] or with an N-F reagent A/-fluorobenzenesulfonimide (NFSI) [120], of the 8,9-anhydroerythromy-cin-6,9-hemiacetal or of the erythronolide A (Fig. 44). 

Erythromycins are macrolide antibiotics produced by bacterial fermentation. Fluori-nation of erythromycin has been studied to ensure abetter stability in acidic medium and/or a better bioavailability. 

Other Fluorinated Antibiotic Drugs Flurithromydn is an erythromycin fluorinated atC-9. It was launched some years ago (Figure 8.21). Its preparation involves electrophilic fluorination of 8,9-anhydroerythromycin-6,9-hemiacetal or of erythronolide A with CFsOF, or with a N— F reagent (NFSI) (cf. Chapter 4). The advantage of the fluorine substitution is a better stability in acidic medium and an increased bioavailability. Two erythromycins fluorinated at C-14 are in clinical development HMR-3562 and HMR-3787). 

Clarithromycin is derived from erythromycin by addition of a methyl group and has improved acid stability and oral absorption compared with erythromycin. Its mechanism of action is the same as that of erythromycin. Clarithromycin and erythromycin are virtually identical with respect to antibacterial activity except that clarithromycin is more active against Mycobacterium avium complex (see Chapter 47). Clarithromycin also has activity against M leprae and Toxoplasma gondii. Erythromycin-resistant streptococci and staphylococci are also resistant to clarithromycin. 

Modification of Chemical Structure of Drug The use of a Hammett linear free-energy relationship to investigate the effects of substituents on the rates of aromatic side-chain reactions such as hydrolysis of esters has been alluded to earlier vis-a-vis attainment of optimum stability [9,10]. Degradation of erythromycin under acidic pH conditions is inhibited by substituting a methoxy group for the C-6 hydroxyl as found for the acid stability of clathromycin, which is 340 times greater than that of erythromycin [70]. 

Nakagawa, Y., Itai, S., Yoshida, T., and Nagai,T. (1992), Physicochemical properties and stability in the acidic solution of a new macrolide antibiotic, clarithromycin, In comparison with erythromycin, Chem. Pharm. Bull., 40,725-728. 

Topical corticosteroids are used in cases of exacerbation and should be applied sparingly to the affected area. Hydrocortisone 1% twice a day or dexamethasone 0.1% applied to the periorbital area helps to relieve symptoms during these periods. Secondary infection manifested as blepharitis or keratoconjimctivitis should be treated with topical ophthalmic antibiotic ointments such as bacitracin or erythromycin.Topical antihistamines, NSAIDs, or mast cell stabilizers can be used to control itching, and topical steroids are sometimes required to treat severe keratoconjunctivitis associated with the atopic response. Because of side effects, steroids are not indicated for longterm use. 

Several complex antibiotics are prepared by whole-cell fermentations. Examples are the pencillin antibiotics in which the side chain can be removed and replaced with a synthetic one to enhance activity or stability. Other examples include the macrolide antiobiotics, such as avermectin (56) and erythromycin (57), in which the organism uses an enzyme cassette to build up the seco-chain before cyclization. 

The pH-stability profile is a plot of reaction rate constant for drug degradation versus pH and may help to predict if some of the drug will decompose in the GI tract. The stability of erythromycin is pH-dependent. In acidic medium, erythromycin decomposition occurs rapidly, whereas at neutral or alkaline pH the drug is relatively stable. Consequently, erythromycin tablets are enteric coated to protect against acid degradation in the stomach. In addition, less soluble erythromycin salts that are more stable in the stomach have been prepared. 

El-Shattaway HH, Klldslg DO, Peck GE. Erythromycin direct compression excipients preformulation stability screening using differential scanning calorimetry. Drug Dev Ind Pharm 1982 8(6) 937-947. 

Additionally, sodium bicarbonate is used in solutions as a buffering agent for erythromycin, lidocaine, local anesthetic solutions, and total parenteral nutrition (TPN) solutions. In some parenteral formulations, e.g., niacin, sodium bicarbonate is used to produce a sodium salt of the active ingredient that has enhanced solubility. Sodium bicarbonate has also been used as a freeze-drying stabilizer and in toothpastes. 

Allwood MC. The influence of buffering on the stability of erythromycin injection in small-volume Infusions. Int ] Pharm 1992 80 (SuppL) R7-R9. 

Among the many antibiotics isolated from the actinomycetes isthe group of chemically related compounds called the mac-mlides. In I9S0, picromycin, the first of this group to be identified as a macrolide compound, was first reported. In 1952. erythromycin and carbomycin were reported us new antibiotics, and they were followed in subsequent years by other macrolides. Currently, more than 40 such compounds ate known, and new ones are likely to appear in the future. Of all of these, only two, erythromycin and oleandomycin, have been available consistently for medical use in the United States. In recent years, interest has shifted away from novel macrolides isolated from soil samples (e.g.,. spiramycin, josamycin, and rosamicin), all of which thus far have proved to be clinically inferior to erythromycin and semisynthetic derivatives of erythromycin (e.g., clarithromycin and azithromycin), which have superior pharmacokinetic properties due to their enhanced acid stability and improved distribution properties. 

Capillary approaches have been shown to be useful for many chiral separations as well as achiral separations. For chiral separations, separation buffer additives containing chirogenic centers (tecoplainin, erythromycin, vancomycin, or cyclodextrans) have facilitated the resolution of enantiomers [26,30,31]. Chiral capillary separations could readily be combined with mass spectrometry because the volume of effluent moving from the separation capillary to the ion source is small and makeup solvent is commonly added by means of an union to stabilize the ion beam. Chiral capillary separations provide an attractive alternative to analytical-scale normal-phase separations when using atmospheric pressure ion-ization mass spectrometry. 

Insoluble salts may be prepared using high molecular weight counterions to reduce the solubility of the drug for formulation of a suspension, to improve chemical stability, provide improvements in solid-state stability, reduce acid lability and permit formulation of tasteless or controlled release products. Erythromycin stearate, which is poorly soluble in acidic media (an enteric salt), is less prone to decomposition in gastric fluids than the more acid-soluble free base. 

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