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Strategies for the Analysis of Pharmaceutical Cocrystals Using HPLC with Charged Aerosol Detection

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Abstract

Several active pharmaceutical ingredients are currently being developed as pharmaceutical cocrystals as these systems often have superior properties compared to traditional pharmaceutical forms. Pharmaceutical cocrystal formers typically used are polar, small molecule acids or bases which often lack a UV chromophore. Their polar nature results in almost no reversed phase retention and their detection typically cannot be done with UV. Here we discuss approaches for the analysis of pharmaceutical cocrystals using HPLC columns designed for polar retention, ion pairing chromatography (IPC), and hydrophilic interaction chromatography (HILIC) using model cocrystal formers. Corona charged aerosol detection (CAD) was used to monitor the cocrystal formers. l-alanine was used as a model basic cocrystal former, and succinic acid and glutaric acid were used as model acidic cocrystal formers. The acidic cocrystal formers were adequately retained on a C18 column. Heptafluorobutyric acid was used as the ion-pairing reagent for l-alanine as it was unretained without the ion-pairing reagent. HILIC, a newer approach for polar compound retention, was also investigated. Using the HILIC mode, all three model cocrystal formers were retained adequately. Of all the approaches studied for the analysis of the cocrystal formers, HILIC appears to be the best choice as the same column can be used for both acidic and basic cocrystal formers. With IPC, the ion-pairing reagent permanently alters the column chemistry and dedicated columns are required for each ion-pairing reagent used. CAD detection provided a linear response in the 80–100% test concentration range for the analytes studied here.

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References

  1. Vishweshwar P, McMahon JA, Bis JA, Zaworotko MJ (2006) Pharmaceutical co-crystals. J Pharm Sci 95:499–516

    Article  CAS  Google Scholar 

  2. Blagden N, de Matas M, Gavan PT, York P (2007) Crystal engineering of active pharmaceutical ingredients to improve solubility and dissolution rates. Adv Drug Deliv Rev 59:617–630

    Article  CAS  Google Scholar 

  3. Shan N, Zaworotko MJ (2008) The role of cocrystals in pharmaceutical science. Drug Discov Today 95:440–446

    Article  Google Scholar 

  4. Schultheiss N, Newman A (2009) Pharmaceutical cocrystals and their physicochemical properties. Cryst Growth Des 9:2950–2967

    Article  CAS  Google Scholar 

  5. Good DJ, Naír R-H (2009) Solubility advantage of pharmaceutical cocrystals. Cryst Growth Des 9:2252–2264

    Article  CAS  Google Scholar 

  6. Haleblian JK (1975) Characterization of habits and crystalline modification of solids and their pharmaceutical applications. J Pharm Sci 64:1269–1288

    Article  CAS  Google Scholar 

  7. Remenar JF, Morissette SL, Peterson ML, Moulton B, MacPhee JM, Guzman HR, Almarsson O (2003) Crystal engineering of novel cocrystals of a triazole drug with 1,4-dicarboxylic acids. J Am Chem Soc 125:8456–8457

    Article  CAS  Google Scholar 

  8. McNamara DP, Childs SL, Giordano J, Iarriccio A, Cassidy J, Shet MS, Mannion R, O’Donnell E, Park A (2006) Use of a glutaric acid cocrystal to improve oral bioavailability of a low solubility API. Pharm Res 23:1888–1897

    Article  CAS  Google Scholar 

  9. Babu NJ, Reddy LS, Nangia A (2007) Amide N-oxide heterosynthon and amide dimer homosynthon in cocrystals of carboxamide drugs and pyridine N-oxides. Mol Pharma 4:417–434

    Article  CAS  Google Scholar 

  10. Childs SL, Hardcastle KI (2007) Cocrystals of piroxicam with carboxylic acids. Cryst Growth Des 7:1291–1304

    Article  CAS  Google Scholar 

  11. Chen AM, Ellison ME, Peresypkin A, Wenslow RM, Variankaval N, Savarin CG, Natishan TK, Mathre DJ, Dormer PG, Euler DH, Ball RG, Ye Z, Wang Y, Santos I (2007) Development of a pharmaceutical cocrystal of a monophosphate salt with phosphoric acid. Chem Commun 4:419–421

    Article  Google Scholar 

  12. Basavoju S, Bostrom D, Velaga SP (2008) Indomethacin-saccharin cocrystal: design, synthesis and preliminary pharmaceutical characterization. Pharm Res 25:530–541

    Article  CAS  Google Scholar 

  13. Storm T, Reemtsma T, Jekel M (1999) Use of volatile amines as ion-pairing agents for the high-performance liquid chromatographic-tandem mass spectrometric determination of aromatic sulfonates in industrial wastewater. J Chromatogr A 854:175–185

    Article  CAS  Google Scholar 

  14. Schmidt TC, Buetehorn U, Steinbach K (2004) HPLC-MS investigations of acidic contaminants in ammunition wastes using volatile ion-pairing reagents (VIP-LC-MS). Anal Bioanal Chem 378:926–931

    Article  CAS  Google Scholar 

  15. Shibue M, Mant CT, Hodges RS (2005) Effect of anionic ion-pairing reagent concentration (1–60 mM) on reversed-phase liquid chromatography elution behaviour of peptides. J Chromatogr A 1080:58–67

    Google Scholar 

  16. Gao S, Bhoopathy S, Zhang Z, Wright DS, Jenkins R, Karnes HT (2006) Evaluation of volatile ion-pair reagents for the liquid chromatography-mass spectrometry analysis of polar compounds and its application to the determination of methadone in human plasma. J Pharm Biomed Anal 40:679–688

    Article  CAS  Google Scholar 

  17. Hakkinen MR, Keinanen TA, Vepsalainen J, Khomutov AR, Alhonen L, Janne J, Auriola S (2007) Analysis of underivatized polyamines by reversed phase liquid chromatography with electrospray tandem mass spectrometry. J Pharm Biomed Anal 45:625–634

    Article  Google Scholar 

  18. LoBrutto R, Jones A, Kazakevich YV (2001) Effect of counter-anion concentration on retention in high-performance liquid chromatography of protonated basic analytes. J Chromatogr A 913:189–196

    Article  CAS  Google Scholar 

  19. Yang X, Dai J, Carr PW (2003) Effect of amine counterion type on the retention of basic compounds on octadecyl silane bonded silica-based and polybutadiene-coated zirconia phases. Anal Chem 75:3153–3160

    Article  CAS  Google Scholar 

  20. Kazakevich YV, LoBrutto R, Vivilecchia R (2005) Reversed-phase high-performance liquid chromatography behavior of chaotropic counteranions. J Chromatogr A 1064:9–18

    Article  CAS  Google Scholar 

  21. Dai J, Mendonsa SD, Bowser MT, Lucy CA, Carr PW (2005) Effect of anionic additive type on ion pair formation constants of basic pharmaceuticals. J Chromatogr A 1069:225–234

    Article  CAS  Google Scholar 

  22. Flieger J (2006) The effect of chaotropic mobile phase additives on the separation of selected alkaloids in reversed-phase high-performance liquid chromatography. J Chromatogr A 1113:37–44

    Article  CAS  Google Scholar 

  23. Flieger J, Swieboda R (2008) Application of chaotropic effect in reversed-phase liquid chromatography of structurally related phenothiazine and thioxanthene derivatives. J Chromatogr A 1192:218–224

    Article  CAS  Google Scholar 

  24. Alpert AJ (1990) Hydrophilic-interaction chromatography for the separation of peptides, nucleic acids and other polar compounds. J Chromatogr A 499:177–196

    Article  CAS  Google Scholar 

  25. Churms SC (1990) Recent developments in the chromatographic analysis of carbohydrates. J Chromatogr A 500:555–583

    Article  CAS  Google Scholar 

  26. Wang X, Li W, Rasmussen HT (2005) Orthogonal method development using hydrophilic interaction chromatography and reversed-phase high-performance liquid chromatography for the determination of pharmaceuticals and impurities. J Chromatogr A 1083:58–62

    Article  CAS  Google Scholar 

  27. Olsen BA (2001) Hydrophilic interaction chromatography using amino and silica columns for the determination of polar pharmaceuticals and impurities. J Chromatogr A 913:113–122

    Article  CAS  Google Scholar 

  28. Guo Y, Gaiki S (2005) Retention behavior of small polar compounds on polar stationary phases in hydrophilic interaction chromatography. J Chromatogr A 1074:71–80

    Article  CAS  Google Scholar 

  29. Guo Y, Huang A (2003) A HILIC method for the analysis of tromethamine as the counter ion in an investigational pharmaceutical salt. J Pharm Biomed Anal 31:1191–1201

    Article  CAS  Google Scholar 

  30. Strege MA (1998) Hydrophilic interaction chromatography-electrospray mass spectrometry analysis of polar compounds for natural product drug discovery. Anal Chem 70:2439–2445

    Article  CAS  Google Scholar 

  31. Tolstikov VV, Fiehn O (2002) Analysis of highly polar compounds of plant origin: combination of hydrophilic interaction chromatography and electrospray ion trap mass spectrometry. Anal Biochem 301:298–307

    Article  CAS  Google Scholar 

  32. Almarsson O, Zaworotko MJ (2004) Crystal engineering of the composition of pharmaceutical phases. Do pharmaceutical co-crystals represent a new path to improve medicines? Chem Commun 1889–1896

  33. Boersema PJ, Mohammed S, Heck AJR (2008) Hydrophilic interaction liquid chromatography (HILIC) in proteomics. Anal Bioanal Chem 391:151–159

    Article  CAS  Google Scholar 

  34. Crafts C, Bailey B, Plante M, Acworth I (2009) Evaluation of methods for the simultaneous analysis of cations and anions using HPLC with charged aerosol detection and a zwitterionic stationary phase. J Chromatogr Sci 47:534–539

    CAS  Google Scholar 

  35. Gamache PH, McCarthy RS, Freeto SM, Asa DJ, Woodcock MJ, Laws K, Cole RO (2005) HPLC analysis of non-volatile analytes using charged aerosol detection. LC-GC Europe 18(6):345–354

    CAS  Google Scholar 

  36. Forsatz B, Snow NH (2007) HPLC with charged aerosol detection for pharmaceutical cleaning validation. LC-GC North America 25(9):960–968

    CAS  Google Scholar 

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  1. Analytical Development, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Rd, Ridgefield, CT, 06877, USA

    Susan Jacob & Shaun D. Mendonsa

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  1. Susan Jacob
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  2. Shaun D. Mendonsa
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Correspondence to Shaun D. Mendonsa.

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Jacob, S., Mendonsa, S.D. Strategies for the Analysis of Pharmaceutical Cocrystals Using HPLC with Charged Aerosol Detection. Chromatographia 75, 321–328 (2012). https://doi.org/10.1007/s10337-012-2201-0

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  • DOI: https://doi.org/10.1007/s10337-012-2201-0

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