Skip to main content
SpringerLink
Log in

An Automated Approach to Salt Selection for New Unique Trazodone Salts

  • Published:
Pharmaceutical Research Aims and scope Submit manuscript

Abstract

Purpose. The purpose of this study was to establish an automated approach to salt selection and to search for unique trazodone salts for new applications.

Methods. Automated procedures were developed on a Biomek 2000 automation workstation with stacker and plate reader capabilities. Trazodone was dispensed into 96-well plates, and an automated method was set up to form 104 trazodone salts. Salts were observed under a polarized light microscope to determine crystallinity. After stepwise eliminations, the remaining salts were scaled-up and subjected to differential scanning calorimetry (DSC), powder x-ray diffraction (PXRD), hygroscopic, pH-solubility, density, surface area, and particle size analyses.

Results. Oils formed in several cases resulting in preliminary elimination of mesyl and esyl salts and four crystallizing solvents. Crystallinity was observed in 34 of 44 scaled-up trazodone salts. PXRD, DSC, and hygroscopic analyses indicated a number of new salts that were comparable in physicochemical parameters to the marketed HCl salt. Among them, the tosylate salt showed uniqueness for new applications.

Conclusions. Automated procedures can be developed to increase the efficiency of pharmaceutical salt selection. The new tosylate salt gave a unique pH-solubility profile with low solubility over the entire pH range making it a potential candidate for a suspension or prolonged action formulation.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

REFERENCES

  1. R. M. Burch and D. J. Kyle. Mass receptor screening for new drugs. Pharm. Res. 8(2):141-147 (1991).

    Google Scholar 

  2. A. Alanine, M. Nettekoven, E. Roberts, and A. W. Thomas. Lead generation—enhancing the success of drug discovery by investing in the hit to lead process. Comb. Chem. High Throughput Screen. 6(1):51-66 (2003).

    Google Scholar 

  3. C. K. Atterwill and M. G. Wing. In vitro preclinical lead optimization technologies (PLOTs) in pharmaceutical development. Toxicol. Let. 127(1–3):143-151 (2002).

    Google Scholar 

  4. A. Avdeef and B. Testa. Physicochemical profiling in drug research: a brief survey of the state-of-the-art of experimental techniques. Cell. Mol. Life Sci. 59(10):1681-1689 (2002).

    Google Scholar 

  5. P. A. Bell. SNPstream (R) UHT: Ultra-High Throughput SNP Genotyping for Pharmacogenomics and Drug Discovery (vol 32, pg S70, 2001). Biotechniques 34(3):496-496 (2003).

    Google Scholar 

  6. K. H. Bleicher, H. J. Bohm, K. Muller, and A. I. Alanine. Hit and lead generation: beyond high-throughput screening. Nature Reviews Drug Discovery. 2(5):369-378 (2003).

    Google Scholar 

  7. E. H. Kerns. High-throughput physicochemical profiling for drug discovery. J. Pharm. Sci. 90(11):1838-1858 (2001).

    Google Scholar 

  8. L. H. Caporale. Chemical ecology: a view from the pharmaceutical industry. Proc. Natl. Acad. Sci. U. S. A. 92:75-82 (1995).

    Google Scholar 

  9. A.N. Hobden and T.J. Harris. The impact of biotechnology and molecular biology on the pharmaceutical industry. Proc. Royal Soc. Edinburgh. 99B(1–2):37-45 (1992).

    Google Scholar 

  10. Available: http://www.healthyplace.com/medications/trazodone.htm. Healthyplace, Inc. (2002).

  11. Products/Prescription Products. Molipaxin CR tablets. The Pharmaceutical Journal Online. 266(7146):631(2001). www.pharmj.com/Editorial/20010505/products.html#molipaxin.

  12. A. Dobashi. Trazodone hydrochloride. Available: http://www.ps.toyaku.ac.jp/dobashi/database/animation/t_group/trazodone_hydrochloride.html (2003).

  13. N. Sandow. Available: http://www.rxlist.com/cgi/generic/traz_cp.htm (2003). RxList LLC.

  14. M. Haria, A. Fitton, and D. McTavish. Trazodone. a review of its pharmacology, therapeutic use in depression and therapeutic potential in other disorders. Drugs Aging 4(4):331-355 (1994).

    Google Scholar 

  15. R. J. Bastin, M. J. Bowker, and B. J. Slater. Salt selection and optimization procedures for pharmaceutical new chemical entities. Org. Proc. Res. Develop. 4(5):427-435 (2000).

    Google Scholar 

  16. SSCI. drug product studies. amorphous form stabilization. Available: www.ssci-inc.com (2001).

  17. Various. The United States Pharmacopeia (USP 24) and the National Formulary (NF 19), Vol. 24. The United States Pharmacopeial Convention, Inc., Rockville, MD, 2000, pp. 1913-1992.

  18. L. W. Dittert, T. Higuchi, and D. R. Reese. Phase solubility techniques in studying the formation of complex salts of triamterene. J. Pharm. Sci. 53:1325-1328 (1964).

    Google Scholar 

  19. A. T. M. Serajuddin and D. Mufson. pH-Solubility profiles of organic-bases and their hydrochloride salts. Pharmaceut. Res. 2:65-68 (1985).

    Google Scholar 

  20. A. El-Gindy, B. El-Zeany, T. Awad, and M. M. Shabana. Spectrophotometric, spectrofluorimetric, and LC determination of trazodone hydrochloride. J. Pharm. Biomed. Anal. 26:211-217 (2001).

    Google Scholar 

  21. J. Bernstein. Polymorphism in Molecular Crystals. International Union of Crystallography: Monographs on Crystallography, Vol. 14. Oxford University Press, New York, 2002, p. 410.

    Google Scholar 

  22. M. Bowker. A Procedure for salt selection and optimization. In P. H. Stahl and C. G. Wermuth (eds.), Handbook of Pharmaceutical Salts: Properties, Selection and Use, Wiley-VCH, Zurich, 2002, pp. 161-220.

    Google Scholar 

  23. D. Giron and D. J. W. Grant. Evaluation of solid state properties of salts. In P. H. Stahl and C. G. Wermuth (eds.), Handbook of Pharmaceutical Salts: Properties, Selection and Use. Wiley-VCH, Zurich, 2002, pp. 1-80.

    Google Scholar 

  24. A. T. M. Serajuddin and M. Pudipeddi. Salt selection strategies. In P. H. Stahl and C. G. Wermuth (eds.), Handbook of Pharmaceutical Salts: Properties, Selection and Use. Wiley-VCH, Zurich, 2002, pp. 135-160.

    Google Scholar 

  25. P. H. Stahl and C. G. Wermuth. Introduction. In P. H. Stahl and C. G. Wermuth, (eds.), Handbook of Pharmaceutical Salts: Properties, Selection and Use. Wiley-VCH, Zurich, 2002, pp. 1-17.

    Google Scholar 

  26. J. K. Guillory. Generation of polymorphs, hydrates, solvates and amorphous solids. In H. G. Brittain (ed.), Polymorphism in Pharmaceutical Solids. Marcel Dekker, New York, 1999, pp. 183-226.

    Google Scholar 

  27. M. T. Ledwidge and O. I. Corrigan. Effects of surface active characteristics and solid state forms on the pH solubility profiles of drug-salt systems. Int. J. Pharm. 174(1–2):187-200 (1998).

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, University of Georgia, Athens, Georgia, 30602

    Emily C. Ware

  2. Department of Pharmaceutical Sciences, School of Pharmacy, Temple University, Philadelphia, Pennsylvania, 19140

    D. Robert Lu

Authors
  1. Emily C. Ware
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. D. Robert Lu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to D. Robert Lu.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ware, E.C., Lu, D.R. An Automated Approach to Salt Selection for New Unique Trazodone Salts. Pharm Res 21, 177–184 (2004). https://doi.org/10.1023/B:PHAM.0000012167.60180.c3

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/B:PHAM.0000012167.60180.c3

Search

Navigation