Skip to main content
NCBI home page
AAPS PharmSciTech logoLink to AAPS PharmSciTech
. 2007 Nov 9;8(4):91. doi: 10.1208/pt0804093

Investigation of the solid state properties of amoxicillin trihydrate and the effect of powder pH

Alireza Ghassempour 1, Hasan Rafati 1,✉, Laleh Adlnasab 2, Yosef Bashour 3, Homeira Ebrahimzadeh 2, Mohammad Erfan 4
PMCID: PMC2750679  PMID: 18181553

Abstract

The purpose of this research was to investigate some physicochemical and solid-state properties of amoxicillin trihydrate (AMT) with different powder pH within the pharmacopoeia-specified range. AMT batches prepared using Dane salt method with the pH values from 4.39 to 4.97 were subjected to further characterization studies. Optical and scanning electron microscopy showed that different batches of AMT powders were similar in crystal habit, but the length of the crystals increased as the pH increased. Further solid-state investigations using powder x-ray diffraction (PXRD) demonstrated the same PXRD pattern, but the intensity of the peaks raised by the powder pH, indicated increased crystallinity. Differential scanning calorimetry (DSC) studies further confirmed that as the powder pH increased, the crystallinity and, hence, thermal stability of AMT powders increased. Searching for the possible cause of the variations in the solid state properties, HPLC analysis showed that despite possessing the requirements of the United States Pharmacopoeia (USP) for purity/impurity profile, there was a direct relationship between the increase of the powder pH and the purity of AMT, and also decrease in the impurity I (α-Hydroxyphenylglycine) concentration in AMT powder. Recrystallization studies confirmed that the powder pH could be controlled by adjusting the pH of the crystallization.

Keywords: Amoxicillin trihydrate, impurity profile, degree of crystallinity, DSC, PXRD, HPLC

Full Text

The Full Text of this article is available as a PDF (291.3 KB).

References

  • 1.Zayed MA, Abdallah SM. Synthesis and structure investigation of the antibiotic amoxicillin complexes of d-block elements. Spectrochim Acta A Mol Biomol Spectrosc. 2005;61:2231–2238. doi: 10.1016/j.saa.2004.08.022. [DOI] [PubMed] [Google Scholar]
  • 2.Dousa M, Hosmanova R. Rapid determination of amoxicillin in premixes by HPLC. J Pharm Biomed Anal. 2005;37:373–377. doi: 10.1016/j.jpba.2004.10.010. [DOI] [PubMed] [Google Scholar]
  • 3.Michael IP. The Chemistry of β-Lactams. Glasgow, UK: Chapman & Hall; 1992. [Google Scholar]
  • 4.Youshko MI, Langen LMV, Vroom ED, Rantwijk FV, Sheldon RA, Svedas VK. Penicillin acylase-catalyzed ampicillin synthesis using a pH gradient: a new approach to optimization. Biotechnol Bioeng. 2002;78:589–593. doi: 10.1002/bit.10234. [DOI] [PubMed] [Google Scholar]
  • 5.Giron D, Goldbronn Ch, Mutz M, Pfeffer S, Piechon PH, Schwab PH. Solid state characterizations of pharmaceutical hydrates. J Therm Anal Calorim. 2002;68:453–465. doi: 10.1023/A:1016031517430. [DOI] [Google Scholar]
  • 6.Goncalves LRB, Sousa R, Fernandez-Lafuente R, et al. Enzymatic synthesis of amoxicillin: avoiding limitations of the mechanistic approach for reaction kinetics. Biotechnol Bioeng. 2002;80:622–631. doi: 10.1002/bit.10417. [DOI] [PubMed] [Google Scholar]
  • 7.Dolezalova M, Kunteova B, Jobanek R. Determination of the purity of ampicillin by micellar electrokinetic chromatography and reversed phase liquid chromatography on a monolithic silica column. J Sep Sci. 2004;27:560–568. doi: 10.1002/jssc.200301680. [DOI] [PubMed] [Google Scholar]
  • 8.Kolar P, Shen W, Tsuboi A, Ishikawa T. Solvent selection for pharmaceuticals. Fluid Phase Equilib. 2002;194–197:771–782. doi: 10.1016/S0378-3812(01)00716-6. [DOI] [Google Scholar]
  • 9.Wei DZ, Yang L. Effects of ethylene glycol on the synthesis of ampicillin using immobilized penicillin G acylase. J Chem Technol Biotechnol. 2003;78:431–436. doi: 10.1002/jctb.749. [DOI] [Google Scholar]
  • 10.Tung JC, Gonzales AJ, Sadowsky JD, Leary DJ. On the1H NMR chemical shift assignments for ampicillin. Magn Reson Chem. 2000;38:126–128. doi: 10.1002/(SICI)1097-458X(200002)38:2<126::AID-MRC601>3.0.CO;2-W. [DOI] [Google Scholar]
  • 11.Li Y, Tang Y, Yao HV, Fu J. Determination of ampicillin and amoxycillin by flow injection chemiluminescence method based on their enhancing effects on the luminol-periodate reactin. Luminescence. 2003;18:313–317. doi: 10.1002/bio.741. [DOI] [PubMed] [Google Scholar]
  • 12.Vippagunta SR, Brittain HG, Grant DJW. Crystalline solids. Adv Drug Deliv Rev. 2001;48:3–26. doi: 10.1016/S0169-409X(01)00097-7. [DOI] [PubMed] [Google Scholar]
  • 13.Cetina-Cizmek B, Tudja M, Mestrovic E, Zovko M, Zorc B, Tudja P. Solid-state investigation of piroxicam benzoate. Acta Pharm. 2003;53:165–173. [PubMed] [Google Scholar]
  • 14.Shefter E, Fung H, Mok O. Dehydration of crystalline theophylline monohydrate and ampicillin trihydrate. J Pharm Sci. 1973;62:791–794. doi: 10.1002/jps.2600620518. [DOI] [PubMed] [Google Scholar]
  • 15.Han J, Gupte S, Suryanarayanan R. Applications of pressure differential scanning calorimetry in the study of pharmaceutical hydrates: ampicillin trihydrate. Int J Pharm. 1998;170:63–72. doi: 10.1016/S0378-5173(98)00123-9. [DOI] [PubMed] [Google Scholar]
  • 16.Salari A, Young R. Application of attenuated total reflectance FTIR spectroscopy to the analysis of mixtures of pharmaceutical polymorphs. Int J Pharm. 1998;163:157–166. doi: 10.1016/S0378-5173(97)00378-5. [DOI] [Google Scholar]
  • 17.Brittain H, Bugay D, Boghanovich S, DeVincentis J. Spectral methods for determination of water. Drug Dev Ind Pharm. 1988;14:2029–2048. doi: 10.3109/03639048809152001. [DOI] [Google Scholar]
  • 18.Nojavan S, Ghassempour A, Bashour Y, Khalilian M, Ahmadi SH. Determination of residual solvents and investigation of their effect on ampicillin trihydrate crystal structure. J Pharm Biomed Anal. 2005;36:983–988. doi: 10.1016/j.jpba.2004.08.031. [DOI] [PubMed] [Google Scholar]
  • 19.Henniger PW, Van Der Drift JK, Van Veen GJ, inventors. Gist Brocades, assignee. Process for the preparation of 6-D-alpha-amino-(p-hydroxyphenyl)-acetamido penicillanic acid. EP patent 0001133. March 21, 1979.
  • 20.Han J, Suryanarayanan R. A method for the rapid evaluation of the physical stability of pharmaceutical hydrates. Thermochim Acta. 1999;329:163–170. doi: 10.1016/S0040-6031(99)00054-4. [DOI] [Google Scholar]
  • 21.Boles M, Girven R, Gane A. The structure of amoxycillin trihydrate and a comparison with the structure of ampicillin. Acta Crystallogr. 1978;B34:461–466. [Google Scholar]
  • 22.Van Dooren A, Muller BW. Purity determination of drugs with differential scanning calorimetry (DSC): a critical review. Int J Pharm. 1984;20:217–233. doi: 10.1016/0378-5173(84)90170-4. [DOI] [Google Scholar]
  • 23.Mirmehrabi M, Rohani S, Keshava Murthy KS, Radatus B. Polymorphic behavior and crystal habit of an anti-viral/HIV drug: Stauvidine. Cryst Growth Des. 2006;6:141–149. doi: 10.1021/cg050242g. [DOI] [Google Scholar]
  • 24.Meenan PA, Anderson SR, Klug DA. The influence of impurities and solvents on crystallization. In: Myerson AS, editor. Handbook of Industrial Crystallization. Boston, MA: Butterworth-Heinemann; 2002. pp. 67–97. [Google Scholar]
  • 25.Mukuta T, Lee AY, Kawakami T, Myerson AS. Influence of impurities on the solution-mediated transformation of active pharmaceutical ingredient. Cryst Growth Des. 2005;5:1429–1436. doi: 10.1021/cg049646j. [DOI] [Google Scholar]

Articles from AAPS PharmSciTech are provided here courtesy of American Association of Pharmaceutical Scientists

RESOURCES