Chapter One - Azithromycin

https://doi.org/10.1016/B978-0-12-800173-8.00001-5Get rights and content

Abstract

Azithromycin is an azalide, a subclass of macrolide antibiotics. It is derived from erythromycin, with a methyl-substituted nitrogen atom incorporated into the lactone ring, thus making the lactone ring 15-membered. It prevents bacteria from growing by interfering with their protein synthesis. It binds to the 50S subunit of the bacterial ribosome and thus inhibits translation of mRNA. Azithromycin is used to treat or prevent certain bacterial infections, most often those causing middle ear infections, strep throat, pneumonia, typhoid, bronchitis, and sinusitis. In recent years, it has been used primarily to prevent bacterial infections in infants and those with weaker immune systems. It is also effective against certain sexually transmitted infections, such as nongonococcal urethritis, chlamydia, and cervicitis. Recent studies have indicated it also to be effective against late-onset asthma, but these findings are controversial and not widely accepted.

The present study gives a comprehensive profile of azithromycin, including detailed physico-chemical properties, nomenclature, formulae, methods of preparation, and methods of analysis (including compendial, electrochemical, spectroscopic, and chromatographic methods of analysis). Developed validated stability-indicating (HPLC and biodiffusion assay methods under accelerated acidic, alkaline, and oxidative conditions, in addition to effect of different types of light, temperature, and pH. Detailed clinical applications also presented (mechanism of action, ADME profile, clinical uses and doses, side effects, and drug interactions). Each of the above stages includes appropriate figures and tables. More than 80 references were given as a proof of the above-mentioned studies.

Section snippets

Background

A team of researchers at the Croatian pharmaceutical company Pliva, led by Dr. Slobodan Đokić, discovered azithromycin in 1980. It was patented in 1981. Pfizer launched azithromycin under Pliva's license in other markets under the brand name Zithromax in 1991. After several years, the U.S. Food and Drug Administration approved AzaSite, an ophthalmic formulation of azithromycin, for the treatment of eye infections [1].

Systematic chemical names [2–5]

  • (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-(2,6-dideoxy-3-C-3-O-dimethyl-α-l-ribo-hexopyranosyloxy)-2-ethyl-3,4,10-trihydroxy-3,5,6,8,10,12,14-heptamethyl-11-(3,4,6-tride-oxy-3-dimethylamino-β-d-xylo-hexopyranosyloxy)-1-oxa-6-aza-cyclopentadecan-15-one dehydrate.

  • (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-3,5,6,8,10,12,14-heptamethyl-15-oxo-11-{[3,4,6-trideoxy-3-(dimethylamino)-β-d-xylo-]oxy}-1-oxa-6-azacyclopentadec-13-yl 2,6-dideoxy-3-C-methyl-3-O-methyl-α-l

Methods of Preparation of Azithromycin

Azithromycin (5) was prepared from erythromycin A [9], [10] by treating the erythromycin (1) in methanol with hydroxylamine hydrochloride and a base at reflux temperature for 10 h to form oxime (2). The oxime was isolated, purified, and subjected to Beckmann's rearrangement to obtain the intermediary (6,9-iminoether) (3) (Scheme 1.1) in aqueous acetone in the presence of p-toluenesulfonyl chloride and base for 2 h at 5 °C (and 2 h more at room temperature). The iminoether was reduced to the

Specific optical rotation [5,21]

[α]20 45° to − 49° (anhydrous substance) (C = 1 in anhydrous ethanol R)

[α]20 37° (C = 1 in CHCl3)

Ionization constant [22]

pKa = 7.34

Solubility characteristics [21]

Azthiromycin is practically insoluble in water and freely soluble in anhydrous ethanol and methylene chloride.

Partition coefficient

The octanol/water partition coefficient (Kow) of azithromycin was 0.65 at 20 °C and pH 7 [23]. Adsorption isotherm studies indicated that the thermodynamic data revealed that the adsorption of azithromycin on the surface of zinc was endothermic, spontaneous, and consistent with the

IR spectrum of Azithromycin

The IR spectra of the drug were obtained in the solid state using 90 g/l solutions in methylene chloride [21], [34]

HPLC drug chromatogram

The principal peak in the HPLC drug chromatogram obtained with test solution was similar in retention time and size to the principal peak in the chromatogram obtained with reference solution [21], [34].

Impurity Analysis [47]

The specified impurities (A, B, C, D, E, F, G, H, I, K, J, L, M, N, O, and P) of azithromycin were determined using liquid.

  • (A) R1 = OH, R2 = R6 = H, R3 = R4 = R5 = CH3: 6-demethylazithromycin,

  • (B)

Stability

El-Gindy et al. [75] developed a validated stability-indicating HPLC method for the analysis of azithromycin (AZ) and its related compounds in raw materials and capsules. The stability of AZ was studied under accelerated acidic, alkaline, and oxidative conditions. The major peak detected from the degradation of AZ in alkaline and acidic conditions was decladinosylazithromycine, while azithromycin N-oxide was detected from the oxidative degradation. Long-term stability studies for capsule and

An overview

Azithromycin is the member of macrolide antibiotics. It is semisynthetic derivatives of erythromycin. Azithromycin differs from erythromycin by the addition of a methyl-substituted nitrogen atom into the lactone ring. This structural modification improved acid stability and tissue penetration and broaden the spectrum of activity. Macrolides generally cover a wide range of Gram-positive and Gram-negative bacterial species including intracellular pathogens such as Chlamydia and Legionella. They

References (90)

  • M. Avramov Ivić et al.

    Studies on electrochemical oxidation of azithromycin and Hemomycin® at gold electrode in neutral electrolyte

    Electrochim. Acta

    (2006)
  • S. Ashour et al.

    Novel spectrophotometric method for determination of some macrolide antibiotics in pharmaceutical formulations using 1,2-naphthoquinone-4-sulphonate

    Spectrochim. Acta A Mol. Biomol. Spectrosc.

    (2012)
  • P.Y. Khashaba

    Spectrofluorimetric analysis of certain macrolide antibiotics in bulk and pharmaceutical formulations

    J. Pharm. Biomed. Anal.

    (2002)
  • A.P. Kumar et al.

    Azithromycin as a new chiral selector in capillary electrophoresis

    J. Chromatogr. A

    (2011)
  • L. Miguel et al.

    LC determination of impurities in azithromycin tablets

    J. Pharm. Biomed. Anal.

    (2003)
  • P. Zubata et al.

    A new HPLC method for azithromycin quantitation

    J. Pharm. Biomed. Anal.

    (2002)
  • Z.Y. Yang et al.

    Determination of azithromycin by ion-pair HPLC with UV detection

    J. Pharm. Biomed. Anal.

    (2009)
  • K. Hurt et al.

    Cystic fibrosis

    Medicine

    (2012)
  • Z. Banić Tomišić

    The story of azithromycin

    Kemija u Industriji

    (2011)
  • Martindale the Complete Drug Reference, 36th, the Pharmaceutical Press,...
  • ...
  • ...
  • The Merck Index, 12th, 1996, Merck & CO., Inc., USA....
  • ...
  • ...
  • Z.J. Li, A.V. Trask, Crystal forms of azithromycin, 2005, U.S. Patent No....
  • S. Turchetta, P. Massardo, P. Casellato, Process for preparing high purity azithromycin, 2003, U.S. Patent Application...
  • S.P. Singh, S.M.J. Mukarram, M. Purohit, A.R. Khan, Process for preparation of anhydrous azithromycin, 2008, U.S....
  • M. Bayod-Jasanada et al.

    Synthesis of 9-deoxo-9a-aza-9a-homoerythromycin A 11,12-hydrogen borate and azithromycin 11,12-hydrogen borate. A new procedure to obtain azithromycin dihydrate

    J. Org. Chem.

    (1997)
  • S. Djokić et al.

    Erythromycin series. Part 11. Ring expansion of erythromycin A oxime by the Beckmann rearrangement

    J. Chem. Soc. Perkin Trans.

    (1986)
  • J.A. De La Torre Garcia, F.F. Andrade, J.M.F.L. Ochoa, Single-step process for preparing 7,...
  • S.H. Pine et al.

    Formic acid-formaldehyde methylation of amines

    J. Org. Chem.

    (1971)
  • J.S. Davies et al.

    The chemistry of erythromycin. Reactions of erythromycin A imine and its 6-methyl ether with aldehydes and hydrazines

    J. Chem. Soc. Perkin Trans.

    (1990)
  • Y. Ni et al.

    Recent progress on industrial fermentative production of acetone–butanol–ethanol by Clostridium acetobutylicum in China

    Appl. Microbiol. Biotechnol.

    (2009)
  • H.A. Kirst

    Recent Progress in the Chemical Synthesis of Antibiotics

    (1990)
  • S. Mutak

    Azalides from azithromycin to new azalide derivatives

    J. Antibiotics

    (2007)
  • S. Rengaraju, Process for the preparation of non-hygroscopic azithromycin dihydrate, 2002, U.S. Patent Application...
  • European Pharmacopoeia. ed. t. edition. vol. 16. 2005....
  • Material Safety Data Sheet, 2012....
  • S. Odoemelam et al.

    Inhibition of the corrosion of zinc in H2SO4 by 9-deoxy-9a-aza-9a-methyl-9a-homoerythromycin A (azithromycin)

    Portugaliae Electrochim. Acta

    (2009)
  • A.K. Tiwary et al.

    Influence of crystal habit on trimethoprim suspension formulation

    Pharm. Res.

    (1999)
  • Z.H. Zhang et al.

    A simple and efficient procedure for deprotection of tetrahydropyranyl ethers catalysed by expansive graphite 

    J. Chem. Res. Synopses

    (1998)
  • Z.J. Li, A.V. Trask, Crystal forms of azithromycin, 2006, Google...
  • D.J.M. Allen, K.M. Nepveux, Azithromycin dihydrate, in European Patent, 1992, EP...
  • S. Timoumi et al.

    Stability and thermophysical properties of azithromycin dihydrate

    Arab. J. Chem.

    (2010)
  • Cited by (90)

    • Suspension electrospinning of azithromycin loaded nanofibers

      2023, Journal of Drug Delivery Science and Technology
    View all citing articles on Scopus
    View full text