Solid-State Techniques for Improving Solubility

Part of the AAPS Advances in the Pharmaceutical Sciences Series book series (AAPS, volume 3)


Poor aqueous solubility of a drug substance can often be attributed to strong intermolecular forces within its crystal lattice which, in turn, prevent molecules from escaping in solution. Through the use of solid-state chemistry, it is possible to modify the crystal structure in such a way that mitigates intermolecular forces, thus improving aqueous solubility and increasing rates of dissolution. Solid-state techniques utilized for solubility enhancement include the formation of salts, polymorphic or amorphous forms, and co-crystals. Each technique has specific advantages and, in some cases, disadvantages that may prevent its successful use. The purpose of this chapter is to describe each of the methods, allowing the reader to gain an understanding of solid-state modifications available for solubility enhancement.


Aqueous Solubility Drug Substance Polymorphic Form Amorphous Form Solubility Enhancement 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. Aguiar AJ, Zelmer JE (1969) Dissolution behavior of polymorphs of chloramphenicol palmitate and mefenamic acid. J Pharm Sci 58:983–987PubMedCrossRefGoogle Scholar
  2. Aguiar AJ, Krc J, Kinkel AW, Samyn JC (1967) Effect of polymorphism on the absorption of chloramphenicol from chloramphenicol palmitate. J Pharm Sci 56:847–853PubMedCrossRefGoogle Scholar
  3. Allesø M, van den Berg F, Cornett C, Jørgensen FS, Halling Sørensen B, de Diego HL, Hovgaard L, Aaltonen J, Rantanen J (2008) Solvent diversity in polymorph screening. J Pharm Sci 97:2145–2159PubMedCrossRefGoogle Scholar
  4. Alvarez AJ, Singh A, Myerson AS (2009) Polymorph screening: comparing a semi-automated approach with a high throughput method. Cryst Growth Des 9:4181–4188CrossRefGoogle Scholar
  5. Bastin RJ, Bowker MJ, Slater BJ (2000) Salt selection and optimisation procedures for pharmaceutical new chemical entities. Org Process Res Dev 4:427–435CrossRefGoogle Scholar
  6. Bauer J, Spanton S, Henry R, Quick J, Dziki W, Porter W, Morris J (2001) Ritonavir: an extraordinary example of conformational polymorphism. Pharm Res 18:859–866PubMedCrossRefGoogle Scholar
  7. Bechtloff B, Nordhoff S, Ulrich J (2001) Pseudopolymorphs in industrial use. Cryst Res Tech 36:1315–1328CrossRefGoogle Scholar
  8. Berge SM, Bighley LD, Monkhouse DC (1977) Pharmaceutical salts. J Pharm Sci 66:1–19PubMedCrossRefGoogle Scholar
  9. Bis JA, Vishweshwar P, Weyna D, Zaworotko MJ (2007) Hierarchy of supramolecular synthons: ersistent hydroxyl pyridine hydrogen bonds in cocrystals that contain a cyano acceptor. Mol Pharm 4:401–416PubMedCrossRefGoogle Scholar
  10. Black SN, Collier EA, Davey RJ, Roberts RJ (2007) Structure, solubility, screening, and synthesis of molecular salts. J Pharm Sci 96:1053–1068PubMedCrossRefGoogle Scholar
  11. Blagden N, Md M, Gavan PT, York P (2007) Crystal engineering of active pharmaceutical ingredients to improve solubility and dissolution rates. Adv Drug Deliv Rev 59:617–630PubMedCrossRefGoogle Scholar
  12. Bowker MJ, Stahl PH (2008) Preparation of water soluble compounds through salt formation. In: Wermuth CG (ed) The practice of medicinal chemistry. Academic, New York, p 749Google Scholar
  13. Byrn SR, Pfeiffer RR, Stowell JG (1999a) Drugs as molecular solids. Solid-state chemistry of drugs. SSCI, West Lafayette, pp 143–241Google Scholar
  14. Byrn SR, Pfeiffer RR, Stowell JG (1999b) Polymorphs. Solid-state chemistry of drugs. SSCI, West Lafayette, pp 143–241Google Scholar
  15. Chemburkar SR, Bauer J, Deming K, Spiwek H, Patel K, Morris J, Henry R, Spanton S, Dziki W, Porter W, Quick J, Bauer P, Donaubauer J, Narayanan BA, Soldani M, Riley D, McFarland K (2000) Dealing with the impact of ritonavir polymorphs on the late stages of bulk drug process development. Org Process Res Dev 4:413–417CrossRefGoogle Scholar
  16. Corrigan OI (2006) Salt forms: pharmaceutical aspects. In: Swarbrick J (ed) Encyclopedia of pharmaceutical technology. Informa Healthcare, New York, pp 3177–3187Google Scholar
  17. Dannenfelser R-M, He H, Joshi Y, Bateman S, Serajuddin ATM (2004) Development of clinical dosage forms for a poorly water soluble drug I: application of polyethylene glycol–polysorbate 80 solid dispersion carrier system. J Pharm Sci 93:1165–1175PubMedCrossRefGoogle Scholar
  18. Elder DP, Delaney E, Teasdale A, Eyley S, Reif VD, Jacq K, Facchine KL, Oestrich RS, Sandra P, David F (2010) The utility of sulfonate salts in drug development. J Pharm Sci 99:2948–2961PubMedGoogle Scholar
  19. Engel GL, Farid NA, Faul MM, Richardson LA, Winneroski LL (2000) Salt form selection and characterization of LY333531 mesylate monohydrate. Int J Pharm 198:239–247PubMedCrossRefGoogle Scholar
  20. Etter MC, Adsmond DA (1990) The use of cocrystallization as a method of studying hydrogen bond preferences of 2-aminopyrimidine. Journal of the Chemical Society, Chemical Communications, pp 589–591Google Scholar
  21. Etter MC, Reutzel SM, Choo CG (1993) Self-organization of adenine and thymine in the solid state. J Am Chem Soc 115:4411–4412CrossRefGoogle Scholar
  22. Fleischman SG, Kuduva SS, McMahon JA, Moulton B, Bailey Walsh RD, Rodríguez-Hornedo N, Zaworotko MJ (2003) Crystal engineering of the composition of pharmaceutical phases: ­multiple-component crystalline solids involving carbamazepine. Cryst Growth Des 3:909–919CrossRefGoogle Scholar
  23. Gardner CR, Almarsson O, Chen H, Morissette S, Peterson M, Zhang Z, Wang S, Lemmo A, Gonzalez-Zugasti J, Monagle J, Marchionna J, Ellis S, McNulty C, Johnson A, Levinson D, Cima M (2004) Application of high throughput technologies to drug substance and drug product development. Comput Chem Eng 28:943–953CrossRefGoogle Scholar
  24. Good DJ, Rodríguez-Hornedo Nr (2009) Solubility advantage of pharmaceutical cocrystals. Cryst Growth Des 9:2252–2264CrossRefGoogle Scholar
  25. Gould PL (1986) Salt selection for basic drugs. Int J Pharm 33:201–217CrossRefGoogle Scholar
  26. Grant DJW, Higuchi T (1990) Solubility, intermolecular forces, and thermodynamics. In: Saunders WH (ed) Solubility behavior of organic compounds, vol XXI. Wiley-Interscience, New York, pp 12–88Google Scholar
  27. Gross TD, Schaab K, Ouellette M, Zook S, Reddy JP, Shurtleff A, Sacaan AI, Alebic-Kolbah T, Bozigian H (2007) An approach to early-phase salt selection: Application to NBI-75043. Org Process Res Dev 11:365–377CrossRefGoogle Scholar
  28. Gupta P, Chawla G, Bansal AK (2004) Physical stability and solubility advantage from amorphous celecoxib: the role of thermodynamic quantities and molecular mobility. Mol Pharm 1:406–413PubMedCrossRefGoogle Scholar
  29. Haleblian J, McCrone W (1969) Pharmaceutical applications of polymorphism. J Pharm Sci 58:911–929PubMedCrossRefGoogle Scholar
  30. Hancock BC (2002) Disordered drug delivery: destiny, dynamics and the Deborah number. J Pharm Pharmacol 54:737–746PubMedCrossRefGoogle Scholar
  31. Hancock BC, Parks M (2000) What is the true solubility advantage of the different forms? Pharm Res 17:397–404PubMedCrossRefGoogle Scholar
  32. Hancock BC, Zografi G (1997) Characteristics and significance of the amorphous state in pharmaceutical systems. J Pharm Sci 86:1–12PubMedCrossRefGoogle Scholar
  33. Hancock BC, Shamblin SL, Zografi G (1995) Molecular mobility of amorphous pharmaceutical solids below their glass transition temperatures. Pharm Res 12:799–806PubMedCrossRefGoogle Scholar
  34. Hickey MB, Peterson ML, Scoppettuolo LA, Morrisette SL, Vetter A, Guzmán H, Remenar JF, Zhang Z, Tawa MD, Haley S, Zaworotko MJ, Almarsson Ö (2007) Performance comparison of a co-crystal of carbamazepine with marketed product. Eur J Pharm Biopharm 67:112–119PubMedCrossRefGoogle Scholar
  35. Huang L-F, Tong W-Q (2004) Impact of solid state properties on developability assessment of drug candidates. Adv Drug Deliv Rev 56:321–334PubMedCrossRefGoogle Scholar
  36. Jain N, Yalkowsky SH (2001) Estimation of the aqueous solubility I: Application to organic nonelectrolytes. J Pharm Sci 90:234–252PubMedCrossRefGoogle Scholar
  37. Jain N, Yang G, Machatha SG, Yalkowsky SH (2006) Estimation of the aqueous solubility of weak electrolytes. Int J Pharm 319:169–171PubMedCrossRefGoogle Scholar
  38. Kim J-S, Kim M-S, Park HJ, Jin S-J, Lee S, Hwang S-J (2008) Physicochemical properties and oral bioavailability of amorphous atorvastatin hemi-calcium using spray-drying and SAS process. Int J Pharm 359:211–219PubMedCrossRefGoogle Scholar
  39. Kobayashi Y, Ito S, Itai S, Yamamoto K (2000) Physicochemical properties and bioavailability of carbamazepine polymorphs and dihydrate. Int J Pharm 193:137–146PubMedCrossRefGoogle Scholar
  40. Kumar L, Amin A, Bansal AK (2007) An overview of automated systems relevant in pharmaceutical salt screening. Drug Discov Today 12:1046–1053PubMedCrossRefGoogle Scholar
  41. Kuroda R, Imai Y, Tajima N (2002) Generation of a co-crystal phase with novel coloristic properties via solid state grinding procedures. Chem Commun 2848–2849Google Scholar
  42. Lang M, Kampf JW, Matzger AJ (2002) Form IV of carbamazepine. J Pharm Sci 91:1186–1190PubMedCrossRefGoogle Scholar
  43. Lee S, Hoff C (2002) Large-scale aspects of salt formation: processing of intermediates and final products. In: Stahl PH, Wermuth CG (eds) Pharmaceutical salts: properties, selection, and use. Wiley-VCH, New York, pp 191–220Google Scholar
  44. Leuner C, Dressman J (2000) Improving drug solubility for oral delivery using solid dispersions. Eur J Pharm Biopharm 50:47–60PubMedCrossRefGoogle Scholar
  45. Li S, Wong S, Sethia S, Almoazen H, Joshi YM, Serajuddin ATM (2005) Investigation of solubility and dissolution of a free base and two different salt forms as a function of pH. Pharm Res 22:628–635PubMedCrossRefGoogle Scholar
  46. Lipinski CA (2002) Poor aqueous solubility: industry wide problem in drug discovery. Am Pharmaceut Rev 5:82–85Google Scholar
  47. Lipinski CA, Lombardo F, Dominy BW, Feeney PJ (2001) Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Deliv Rev 46:3–26PubMedCrossRefGoogle Scholar
  48. Loftsson T, Brewster ME (1996) Pharmaceutical applications of cyclodextrins. 1. Drug solubilization and stabilization. J Pharm Sci 85:1017–1025PubMedCrossRefGoogle Scholar
  49. Mao C, Pinal R, Morris KR (2005) A quantitative model to evaluate solubility relationship of polymorphs from their thermal properties. Pharm Res 22:1149–1157PubMedCrossRefGoogle Scholar
  50. McNamara D, Childs S, Giordano J, Iarriccio A, Cassidy J, Shet M, 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 23:1888–1897PubMedCrossRefGoogle Scholar
  51. Medina C, Daurio D, Nagapudi K, Alvarez-Nunez F (2010) Manufacture of pharmaceutical co-crystals using twin screw extrusion: a solvent-less and scalable process. J Pharm Sci 99:1693–1696PubMedGoogle Scholar
  52. Miller DA, DiNunzio JC, Yang W, McGinity JW, Williams RO III (2008) Targeted intestinal delivery of supersaturated itraconazole for improved oral absorption. Pharm Res 25:1450–1459PubMedCrossRefGoogle Scholar
  53. Morissette SL, Soukasene S, Levinson D, Cima MJ, Almarsson Ö (2003) Elucidation of crystal form diversity of the HIV protease inhibitor ritonavir by high-throughput crystallization. Proc Natl Acad Sci USA 100:2180PubMedCrossRefGoogle Scholar
  54. Morissette SL, Almarsson Ö, Peterson ML, Remenar JF, Read MJ, Lemmo AV, Ellis S, Cima MJ, Gardner CR (2004) High-throughput crystallization: polymorphs, salts, co-crystals and solvates of pharmaceutical solids. Adv Drug Deliv Rev 56:275–300PubMedCrossRefGoogle Scholar
  55. Morris KR, Fakes MG, Thakur AB, Newman AW, Singh AK, Venit JJ, Spagnuolo CJ, Serajuddin A (1994) An integrated approach to the selection of optimal salt form for a new drug candidate. Int J Pharm 105:209–217CrossRefGoogle Scholar
  56. O’Connor KM, Corrigan OI (2001) Preparation and characterisation of a range of diclofenac salts. Int J Pharm 226:163–179PubMedCrossRefGoogle Scholar
  57. Parks GS, Huffman HM, Cattoir FR (1928) Studies on glass II: the transition between the glassy and liquid states in the case of glucose. J Phys Chem 32:1366–1379CrossRefGoogle Scholar
  58. Parks GS, Snyder LJ, Cattoir FR (1934) Studies on glass XI. Some thermodynamic relations of glassy and alpha-crystalline glucose. J Phys Chem 2:595–598CrossRefGoogle Scholar
  59. Paulekuhn GS, Dressman JB, Saal C (2007) Trends in active pharmaceutical ingredient salt selection based on analysis of the orange book database. J Med Chem 50:6665–6672PubMedCrossRefGoogle Scholar
  60. Peterson ML, Morissette SL, McNulty C, Goldsweig A, Shaw P, LeQuesne M, Monagle J, Encina N, Marchionna J, Johnson A, Gonzalez-Zugasti J, Lemmo AV, Ellis SJ, Cima MJ, Almarsson Ö (2002) Iterative high-throughput polymorphism studies on acetaminophen and an experimentally derived structure for form III. J Am Chem Soc 124:10958–10959PubMedCrossRefGoogle Scholar
  61. Porter WW III, Elie SC, Matzger AJ (2008) Polymorphism in carbamazepine cocrystals. Crys Growth Des 8:14–16CrossRefGoogle Scholar
  62. Pudipeddi M, Serajuddin ATM (2005) Trends in solubility of polymorphs. J Pharm Sci 94:929–939PubMedCrossRefGoogle Scholar
  63. Remenar JF, Morissette SL, Peterson ML, Moulton B, MacPhee JM, Guzmán HR, Almarsson Ö (2003) Crystal engineering of novel cocrystals of a triazole drug with 1,4-dicarboxylic acids. J Am Chem Soc 125:8456–8457PubMedCrossRefGoogle Scholar
  64. Rodríguez-Spong B, Price CP, Jayasankar A, Matzger AJ, Rodríguez-Hornedo N (2004) General principles of pharmaceutical solid polymorphism: a supramolecular perspective. Adv Drug Deliv Rev 56:241–274PubMedCrossRefGoogle Scholar
  65. Schultheiss N, Newman A (2009) Pharmaceutical cocrystals and their physicochemical properties. Crys Growth Des 9:2950–2967CrossRefGoogle Scholar
  66. Serajuddin ATM (2007) Salt formation to improve drug solubility. Adv Drug Deliv Rev 59:603–616PubMedCrossRefGoogle Scholar
  67. Shalaev E, Zografi G (2002) The concept of “structure” in amorphous solids from the perspective of the pharmaceutical sciences. Amorphous Food and Pharmaceutical Systems 281:11–30CrossRefGoogle Scholar
  68. Shan N, Zaworotko MJ (2008) The role of cocrystals in pharmaceutical science. Drug Discov Today 13:440–446PubMedCrossRefGoogle Scholar
  69. Shattock TR, Arora KK, Vishweshwar P, Zaworotko MJ (2008) Hierarchy of supramolecular synthons: persistent carboxylic acid-pyridine hydrogen bonds in cocrystals that also contain a hydroxyl moiety. Cryst Growth Des 8:4533–4545CrossRefGoogle Scholar
  70. Singhal D, Curatolo W (2004) Drug polymorphism and dosage form design- a practical perspective. Adv Drug Deliv Rev 56:335–347PubMedCrossRefGoogle Scholar
  71. Tong WQT, Whitesell G (1998) In situ salt screening-a useful technique for discovery support and preformulation studies. Pharm Dev Technol 3:215–223PubMedCrossRefGoogle Scholar
  72. Torchilin V (2007) Micellar nanocarriers: pharmaceutical perspectives. Pharm Res 24:1–16PubMedCrossRefGoogle Scholar
  73. Trask AV, Motherwell WDS, Jones W (2004) Solvent-drop grinding: green polymorph control of cocrystallisation. Chem Commun 7:890–891CrossRefGoogle Scholar
  74. Trask AV, Motherwell WDS, Jones W (2005a) Pharmaceutical cocrystallization: engineering a remedy for caffeine hydration. Cryst Growth Des 5:1013–1021CrossRefGoogle Scholar
  75. Trask AV, van de Streek J, Motherwell WDS, Jones W (2005b) Achieving polymorphic and stoichiometric diversity in cocrystal formation: importance of solid-state grinding, powder x-ray structure determination, and seeding. Cryst Growth Des 5:2233–2241CrossRefGoogle Scholar
  76. Ware E, Lu DR (2004) An automated approach to salt selection for new unique trazodone salts. Pharm Res 21:177–184PubMedCrossRefGoogle Scholar
  77. Wells JI (1988) Pharmaceutical preformulation: the physicochemical properties of drug substances. Ellis Horwood, ChichesterGoogle Scholar
  78. Xiang T-X, Anderson BD (2004) A molecular dynamics simulation of reactant mobility in an amorphous formulation of a peptide in poly(vinylpyrrolidone). J Pharm Sci 93:855–876PubMedCrossRefGoogle Scholar
  79. Yu L (1995) Inferring thermodynamic stability relationship of polymorphs from melting data. J Pharm Sci 84:966–974PubMedCrossRefGoogle Scholar
  80. Yu L (2001) Amorphous pharmaceutical solids: preparation, characterization and stabilization. Adv Drug Deliv Rev 48:27–42PubMedCrossRefGoogle Scholar
  81. Yu L, Reutzel SM, Stephenson GA (1998) Physical characterization of polymorphic drugs: an integrated characterization strategy. Pharmaceut Sci Tech Today 1:118–127CrossRefGoogle Scholar
  82. Zhang GGZ, Henry RF, Borchardt TB, Lou X (2007) Efficient co-crystal screening using solution-mediated phase transformation. J Pharm Sci 96:990–995PubMedCrossRefGoogle Scholar

Copyright information

© American Association of Pharmaceutical Scientists 2012

Authors and Affiliations

  1. 1.Division of Pharmaceutics, College of PharmacyThe University of Texas at AustinAustinUSA

Personalised recommendations