Skip to main content
SpringerLink
Log in

Solubilizing Excipients in Oral and Injectable Formulations

  • Published:
Pharmaceutical Research Aims and scope Submit manuscript

Abstract

A review of commercially available oral and injectable solution formulations reveals that the solubilizing excipients include water-soluble organic solvents (polyethylene glycol 300, polyethylene glycol 400, ethanol, propylene glycol, glycerin, N-methyl-2-pyrrolidone, dimethylacetamide, and dimethylsulfoxide), non-ionic surfactants (Cremophor EL, Cremophor RH 40, Cremophor RH 60, d-α-tocopherol polyethylene glycol 1000 succinate, polysorbate 20, polysorbate 80, Solutol HS 15, sorbitan monooleate, poloxamer 407, Labrafil M-1944CS, Labrafil M-2125CS, Labrasol, Gellucire 44/14, Softigen 767, and mono- and di-fatty acid esters of PEG 300, 400, or 1750), water-insoluble lipids (castor oil, corn oil, cottonseed oil, olive oil, peanut oil, peppermint oil, safflower oil, sesame oil, soybean oil, hydrogenated vegetable oils, hydrogenated soybean oil, and medium-chain triglycerides of coconut oil and palm seed oil), organic liquids/semi-solids (beeswax, d-α-tocopherol, oleic acid, medium-chain mono- and diglycerides), various cyclodextrins (α-cyclodextrin, β-cyclodextrin, hydroxypropyl-β-cyclodextrin, and sulfobutylether-β-cyclodextrin), and phospholipids (hydrogenated soy phosphatidylcholine, distearoylphosphatidylglycerol, l-α-dimyristoylphosphatidylcholine, l-α-dimyristoylphosphatidylglycerol). The chemical techniques to solubilize water-insoluble drugs for oral and injection administration include pH adjustment, cosolvents, complexation, microemulsions, self-emulsifying drug delivery systems, micelles, liposomes, and emulsions.

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. Liu (ed.). Water-Insoluble Drug Formulation, Interpharm Press, Denver, Colorado, 2000.

    Google Scholar 

  2. Physician's Desk Reference, 57rd ed., Medical Economics Company, Inc., Montvale, NJ, 2003.

  3. Web sites: www.rxlist.com, www.fda.gov/cder, www.croda.com/pharma/index.htm, www.sasol.com, www.gattefosse.com/pharma/pharma.htm, www.basf.de/pharma.com, www.cydexinc.com, www.atrixlabs.com, www.accessdata.fda.gov/scripts/cder/iig/index.cfm.

  4. A. L. Trissel. Handbook on Injectable Drugs, 11th ed., American Society of Health-System Pharmacists, Inc., Bethesda, MD, 2001.

    Google Scholar 

  5. Y-C. J. Wang and R. R. Kowal. Review of excipients and pH's for parenteral products used in the United States. J. Parent. Sci. Technol. 34:452-462 (1980).

    Google Scholar 

  6. S. Sweetana and M. J. Akers. Solubility principles and practices for parenteral dosage form development. J. Parent. Sci. Technol. 50:330-342 (1996).

    Google Scholar 

  7. M. F. Powell, T. Nguyen, and L. Baloian. Compendium of excipients for parenteral formulations. J. Parent. Sci. Technol. 52:238-311 (1998).

    Google Scholar 

  8. R. G. Strickley. Parenteral formulations of small molecule therapeutics marketed in the United States (1999)—Part I. J. Parent. Sci. Technol. 53:324-349 (1999).

    Google Scholar 

  9. R. G. Strickley. Parenteral formulations of small molecule therapeutics marketed in the United States (1999)—Part II. J. Parent. Sci. Technol. 54:69-96 (2000).

    Google Scholar 

  10. R. G. Strickley. Parenteral formulations of small molecule therapeutics marketed in the United States (1999)—Part II. J. Parent. Sci. Technol. 54:152-169 (2000).

    Google Scholar 

  11. S. Yoshioka and V. Stella. Stability of Drugs and Dosage Forms, Kluwer Academic/Plenum Publishers, New York, 2000.

    Google Scholar 

  12. J. S Trivedi and M. L. Wells. Solubilization using cosolvent approach. In R. Liu (ed.), Water-Insoluble Drug Formulation, Interpharm Press, Denver, Colorado, 2000, pp. 141-168.

    Google Scholar 

  13. R. A. Rajexski and V. J. Stella. Pharmaceutical applications of cyclodextrins. II. In vivo drug delivery. J. Pharm. Sci. 85:1142-1169 (1996).

    Google Scholar 

  14. R. G. Strickley and B. D. Anderson. Solubilization and stabilization of an anti-HIV thiocarbamate, NSC 629243, for parenteral delivery using extemporaneous emulsions. Pharm. Res. 10:1076-1082 (1993).

    Google Scholar 

  15. S. E. Tabibi and S. L. Gupta. Soft gelatin capsules development. In R. Liu (ed.), Water-Insoluble Drug Formulation, Interpharm Press, Denver, Colorado, 2000, pp. 609-633.

    Google Scholar 

  16. Shionogi Qualicaps, Inc. Web site: http://www.qualicaps.com/shionogi/Capsules/Products.html.

  17. E. T. Cole, R. A. Scott, A. L. Connor, I. R. Widding, H-U Petereit, C. Schminke, T. Beckert, and C. Cade. Enteric coated HPMC capsules designed to achieve intestinal targeting. Int. J. Pharm. 231:83-95 (2002).

    Google Scholar 

  18. CTP Plasro Web site: www.p.lasro.com.

  19. R. Pidgeon. PVOH developments offer new possibilities. Packaging Magazine June 26:3(2003).

    Google Scholar 

  20. Arkopharma Laboratories Pharmaceutiques Web site: www.arkopharma.com/english/IndexProduits.html.

  21. Physician's Desk Reference, 54th ed., Medical Economics Company, Inc., Montvale, NJ, 2000.

  22. D. Law, S. L. Krill, E. A. Schmitt, J. J. Fort, Y. Qiu, W. Wang, and R. R. Porter. Physicochemical considerations in the preparation of amorphous ritonavir-poly(ethylene glycol) 8000 solid dispersions. J. Pharm. Sci. 90:1015-1025 (2001).

    Google Scholar 

  23. S. Budavari (ed.). The Merck Index, 13th ed., Merck Research Laboratories Division of Merck & Co., Inc., Whitehouse Station, NJ, 2001.

    Google Scholar 

  24. J. Alsenz, H. Steffen, and R. Alex. Active apical secretory efflux of the HIV protease inhibitors saquinavir and ritonavir in caco-2 cell monolayers. Pharm. Res. 15:423-428 (1998).

    Google Scholar 

  25. V. Stella, J. Haslam, N. Yata, H. Okada, and S. Lindebaum. Enhancement of bioavailability of a hydrophobic amine antimalarial by formulation with oleic acid in a soft gelatin capsule. J. Pharm. Sci. 67:1375-1377 (1978).

    Google Scholar 

  26. R. C. Rowe, P. J. Sheskey, and P. J. Weller. Handbook of Pharmaceutical Excipients, Fourth Edition, Pharmaceutical Press, London, United Kingdom, and the American Pharmaceutical Association, Washington, DC, 2003.

    Google Scholar 

  27. Product literature, Gattefosse Corp., 372 Kinderkamack Road, Westwood, NJ 07675.

  28. N. H. Shah, M. T. Carvajal, C. I. Patel, M. H. Infeld, and A. W. Malick. Self-emulsifying drug delivery systems (SEDDS) with polyglycolyzed glycerides for improving in vitro dissolution and oral absorption of lipophilic drugs. Int. J. Pharm. 106:15-23 (1994).

    Google Scholar 

  29. Physician's Desk Reference, 51st ed., Medical Economics Company, Inc., Montvale, NJ, 1997.

  30. T. M. Abu. Serajuddin. Solid dispersion of poorly water-soluble drugs: early promises, subsequent problems, and recent breakthroughs. J. Pharm. Sci. 88:1058-1066 (1999).

    Google Scholar 

  31. Pharmacy Today. An Official Publication of the American Pharmaceutical Association 5:10(1999).

  32. J. D. Cawley and M. H. Stern. Water-Soluble Tocopherol Derivatives, U.S. Patent No. 2,680,749 (1954).

  33. S. H-W. Wu and W. K. Hopkins. Characteristics of D-α-tocopheryl PEG 1000 succinate for applications as an absorption enhancer in drug delivery systems. Pharm. Tech. 23:44-58 (1999).

    Google Scholar 

  34. L. Yu, A. Bridgers, J. Polli, A. Vickers, S. Long, A. Roy, R. Winnike, and M. Coffin. Vitamin-E-TPGS increases absorption flux of an HIV protease inhibitor by enhancing its solubility and permeability. Pharm. Res. 16:1812-1817 (1999).

    Google Scholar 

  35. S. Tenjarla. Microemulsions: an overview and pharmaceutical applications. Crit. Rev. Ther. Drug Carrier Syst. 16:461-521 (1999).

    Google Scholar 

  36. T. Loftsson and M. E. Brewster. Pharmaceutical applications of cyclodextrins. I. Drug solubilization and stabilization. J. Pharm. Sci. 85:1017-1024 (1996).

    Google Scholar 

  37. T. Irie and K. Uekama. Pharmaceutical applications of cyclodextrins. III. Toxicology issues and safety evaluation. J. Pharm. Sci. 86:147-162 (1997).

    Google Scholar 

  38. G. Mosher and D. Thompson. Complexation and cyclodextrins. In J. Swarbrick and J. C. Boylan (eds.), Encyclopedia of Pharmaceutical Technology, 2000, Vol. 19, Suppl. 2, pp. 49-88.

  39. D. Thompson. Cyclodextrins-enabling excipients: their present and future use in pharmaceuticals. Crit. Rev. Ther. Drug Carrier Syst. 14:1-104 (1997).

    Google Scholar 

  40. W-Q. Tong. Applications of complexation in the formulation of insoluble compounds. In R. Liu (ed.), Water-Insoluble Drug Formulation, Interpharm Press, Denver, Colorado, 2000, pp. 111-140.

    Google Scholar 

  41. M. J. Akers. Excipient-drug interactions in parenteral formulations. J. Pharm. Sci. 91:2283-2306 (2002).

    Google Scholar 

  42. J. Napaporn, M. Thomas, K. A. Svetic, Z. Shahrokh, and G. A. Brazeau. Assessment of the myotoxicity of pharmaceutical buffers using an in vitro muscle model: Effect of pH, capacity, tonicity, and buffer type. Pharm. Dev. Tech. 5:123-130 (2000).

    Google Scholar 

  43. Y-C. Lee, P. D. Zocharski, and B. Samas. An intravenous formulation decision tree for discovery compound formulation development. Intl. J. Pharm 253:111-119 (2003).

    Google Scholar 

  44. G. A. Brazeau, B. Cooper, K. A. Svetic, C. L. Smith, and P. Gupta. Current perspectives on pain upon injection of drugs. J. Pharm. Sci. 87:667-677 (1998).

    Google Scholar 

  45. K. W. Reed and S. H. Yalkowsky. Lysis of human red blood cells in the presence of various cosolvents. J. Parent. Sci. Technol. 38:64-69 (1985).

    Google Scholar 

  46. K. W. Reed and S. H. Yalkowsky. Lysis of human red blood cells. II. The effect of differing NaCl concentrations. J. Parent. Sci. Technol. 40:88-95 (1986).

    Google Scholar 

  47. J. F. Krzyaniak, D. M. Raymond, and S. H. Yalkowsky. Lysis of human red blood cells 1: effect of contact time on water induced hemolysis. J. Pharm. Sci. Tech. 50:223-226 (1996).

    Google Scholar 

  48. J. F. Krzyaniak, D. M. Raymond, and S. H. Yalkowsky. Lysis of human red blood cells 2: effect of contact time on cosolvent induced hemolysis. Int. J. Pharm. 152:193-200 (1997).

    Google Scholar 

  49. R. C-C. Fu, D. M. Lidgate, J. L. Whatley, and T. McCullough. The biocompatibility of parenteral vehicles-in vitro/in vivo screening comparison and the effect of excipients on hemolysis. J. Parent. Sci. Technol. 41:164-168 (1987).

    Google Scholar 

  50. P. Montaguti, E. Melloni, and E. Cavalletti. Acute intravenous toxicity of dimethyl sulfoxide, polyethylene glycol 400, dimethylformamide, absolute ethanol, and benzyl alcohol in inbred mouse strains. Arzneim.-Forsch/Drug Res. 44:566-570 (1994).

    Google Scholar 

  51. G. A. Brazeau and H-L. Fung. Physicochemical properties of binary organic cosolvent-water mixtures and their relationships to muscle damage following intramuscular injection. J. Parent. Sci. Technol. 43:144-149 (1989).

    Google Scholar 

  52. G. A. Brazeau and H-L. Fung. Use of an in vitro model for the assessment of muscle damage from intramuscular injections: in vitro-in vivo correlation and predictability with mixed cosolvent systems. Pharm. Res. 6:766-771 (1989).

    Google Scholar 

  53. G. A. Brazeau and H-L. Fung. Effect of organic solvent-induced skeletal muscle damage on the bioavailability of intramuscular 14C diazepam. J. Pharm. Sci. 79:773-777 (1990).

    Google Scholar 

  54. M. Radwan. In vivo screening model for excipients and vehicles used in subcutaneous injections. Drug Dev. Ind. Pharm. 20:2753-2762 (1994).

    Google Scholar 

  55. R. Dunn. Controlled drug delivery using in-situ gelled biodegradable polymer solutions. American Association of Pharmaceutical Scientists National Meeting, Denver, CO (2001).

    Google Scholar 

  56. R. Dunn. Application of the ATRIGEL implant drug delivery technology for patient-friendly, cost-effective product development. Drug Delivery Tech 3:38-44 (2003).

    Google Scholar 

  57. BASF Corporation Web site: www.basf.de/pharma and www.pharma-solutions.basf.com/pdf/pharma/excipients/ME151e_Solutol_HS15.pdf.

  58. Personal communication, Brendan O'Leary, BASF Corporation. (2003).

  59. R. G. Strickley, L. Liu, and P. Lapresca. Preclinical parenteral and oral formulations of water insoluble molecules. ISSX Meeting, Nashville, TN (USA) Abstract # 291 (1999).

  60. R. Liu and N. Sadrzadeh. Micellization and drug solubility enhancement. In R. Liu (ed.), Water-Insoluble Drug Formulation, Interpharm Press, Denver, Colorado, 2000, pp. 213-277.

    Google Scholar 

  61. P. K. Gupta and J. B. Cannon. Emulsions and microemulsions for drug solubilization and delivery. In R. Liu (ed.), Water-Insoluble Drug Formulation, Interpharm Press, Denver, Colorado, 2000, pp. 169-211.

    Google Scholar 

  62. D. Thompson and D.M.V. Chaubai, Cyclodextrins (CDS)—excipients by definition, drug delivery systems by function (part I: injectable applications), Drug Deliv. 2:34-38 (2002).

    Google Scholar 

  63. Y. Kim, D. A. Oksanen, W. Massrfski, J. F. Blake, E. M. Duffy, and B. Chrunyx. Inclusion complexation of ziprasidone mesylate with β-cyclodextrin sulfobutylether. J. Pharm. Sci. 87:1560-1567 (1998).

    Google Scholar 

  64. Captisol Wins in Regulatory Hurdle, Cyclopedia Quarterly 4(1), (2001), CyDex, Inc.

  65. Personal communication, Gerold L Mosher, Ph.D.and Karl W. Strohmeier, CyDex, Inc. (2001).

  66. A. Y. Tinwalla, B. L. Hoesterey, T-X. Xiang, K. Lim, and B. D. Anderson. Solubilization of thiazolobenzimidazole using a combination of pH adjustment and complexation with 2-hydroxypropyl-β-cyclodextrin. Pharm. Res. 10:1136-1143 (1993).

    Google Scholar 

  67. T-X. Xiang and B. D. Anderson. Stable supersaturated aqueous solutions of silatecan 7-t-butyldimethylsilyl-10-hydroxy-camptothecin via chemical conversion in the presence of a chemically modified β-cyclodextrin. Pharm. Res. 19:1215-1222 (2002).

    Google Scholar 

  68. S.P. Apte and S.O. Ugwu. A review and classification of emerging excipients in parenteral medications. Pharm. Tech. 27:3:46-60 (2003).

    Google Scholar 

  69. L. A. Felton and J. W. McGinity. Enteric film coating of soft gelatin capsules. Drug Deliv. Tech. 3:46-51 (2003).

    Google Scholar 

  70. J. S. Woo, C. H. Lee, C. K. Shim, and S-J Hwang. Enhanced oral bioavailability of paclitaxel by coadministration of the P-glycoprotein inhibitor KR-30031. Pharm. Res. 20:24-30 (2003).

    Google Scholar 

  71. F. Mottu, A. Laurent, D. A. Rüfenacht, and E. Doelker. Organic solvents for pharmaceutical parenterals and embolic liquids: a review of toxicity data. J. Parent. Sci. Tech. 54:456-469 (2000).

    Google Scholar 

  72. Gattefossé Corporation Web site: www.gattefosse.com/pharma/products/transcup.

  73. M-L Chen. Lipid based oral dosage forms—regulatory perspective. Am. Pharm. Rev. 5:30-35 (2002).

    Google Scholar 

  74. D. J. Hauss. Lipid-based systems for oral drug delivery: enhancing the bioavailability of poorly water-soluble drugs. Am. Pharm. Rev. 5:22-36 (2002).

    Google Scholar 

  75. W. C. Charman. Lipids, lipophilic drugs, and oral drug delivery—some emerging concepts. J. Pharm. Sci. 89:967-978 (2000).

    Google Scholar 

  76. R. Holm. C. J. H. Porter, A. Müllertz, H. G. Kristensen, and W. M. Charman. Structured triglyceride vehicles for oral delivery of halofantrine: examination of intestinal lymphatic transport and bioavailability in conscious rats. Pharm. Res. 19:1354-1361 (2002).

    Google Scholar 

  77. R. C. B. Gonzalez, J. Huwyler, I. Walter, R. Mountfield, and B. Bittner. Improved oral bioavailability of cyclosporin A in male Wistar rats comparison of a Solutol HS 15 containing self-dispersing formulation and a microsuspension. Intl. J. Pharm 245:143-151 (2002).

    Google Scholar 

  78. Y. V. R. Prasad, S. P. Puthli, S. Eaimtrakarn, M. Ishida, Y. Yoshikawa, N. Shibata, and K. Takada. Enhanced intestinal absorption of vancomycin with Labrasol and D-α-tocopherol PEG 1000 succinate in rats. Intl. J. Pharm. 250:181-190 (2003).

    Google Scholar 

  79. Southern Biosystems, Inc., Web site: www.southernbiosystems.com.

  80. Durect Corporation Web site: www.durect.com.

  81. A. V. Kabanov, E. V. Batrakova, and D. W. Miller. Pluronic blocks as modulators of drug efflux transporter activity in the blood-brain barrier. Adv. Drug. Del. Rev. 55:151-164 (2003).

    Google Scholar 

  82. E. D. Hugger, K. L. Audus, and R. T. Borchardt. Effects of polyethylene glycol on efflux transporters activity in Caco-2 cell monolayers. J. Pharm. Sci. 91:1980-1990 (2002).

    Google Scholar 

  83. E. D. Hugger, B. Novak, P. S. Burton, K. L. Audus, and R. T. Borchardt. A comparison of commonly used polyethoxylated pharmaceutical excipients on their ability to inhibit P-glycoprotein activity in vitro. J. Pharm. Sci. 91:1991-2002 (2002).

    Google Scholar 

  84. R. T. Borchardt, R. M. Freidinger, T. K. Sawyer, and P. L. Smith (eds.). Integration of Pharmaceutical Discovery and Development, Case Histories, Plenum Press, New York, 1998.

    Google Scholar 

  85. S. Venkatesh and R. A. Lipper. Role of the development scientist in compound lead selection and optimization. J. Pharm. Sci. 89:145-154 (2000).

    Google Scholar 

  86. E.F. “Gene” Fiese. General pharmaceutics—the new physical pharmacy. J. Pharm. Sci. 92:1331-1342 (2003).

    Google Scholar 

  87. W. Curatolo. Physical chemical properties of oral drug candidates in the discovery and exploratory development settings. Pharm. Sci. Tech. Today 1:387-393 (1998).

    Google Scholar 

  88. P. J. Sinko. Drug selection in early development: screening for acceptable pharmacokinetic properties using combined in vitro and computational approaches. Curr. Opin. Drug Disc. Dev. 2:42-48 (1999).

    Google Scholar 

  89. C. A. Lipinski, F. Lombardo, B. W. Dominy, and P. J. Feeney. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv. Drug Del. Rev. 23:3-25 (1997).

    Google Scholar 

  90. P. H. Stahl and C. G. Wermuth (eds.). Handbook of Pharmaceutical Salts: Properties, Selection and Use, VHCA, Verlag Helvetica Chimica Acta, Zürich, and Wiley-VCH, Weinheim, 2002.

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Formulation & Process Development, Gilead Sciences Inc., Foster City, California, 94404

    Robert G. Strickley

Authors
  1. Robert G. Strickley
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Robert G. Strickley.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Strickley, R.G. Solubilizing Excipients in Oral and Injectable Formulations. Pharm Res 21, 201–230 (2004). https://doi.org/10.1023/B:PHAM.0000016235.32639.23

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/B:PHAM.0000016235.32639.23

Search

Navigation