Prodrugs pp 1083-1110 | Cite as

Formulation Challenges of Prodrugs

  • Robert G. Strickley
  • Reza Oliyai
Part of the Biotechnology: Pharmaceutical Aspects book series (PHARMASP, volume V)


This chapter aims to review and highlight some examples of challenges and limitations of formulating prodrugs for clinical and commercial development. The reader should note that the existing literature on the formulation and pharmaceutical development of prodrugs is somewhat limited as pharmaceutical companies tend to not publish pharmaceutical development data. While the prodrug strategy has been used to overcome various drug delivery issues, it tends to present various formulation challenges. These challenges arise from various physicochemical properties of the prodrug as compared to the parent drug such as:
  • Lack of chemical stability, often the drug-promoiety linker

  • Potential for the formation of degradation by-products that are reactive intermediates resulting in secondary degradation pathways

  • Aqueous solubility

  • Aqueous solubility of degradation products

  • Disruption of solid state crystallinity

  • •|Polymorphism


Benzyl Alcohol Adefovir Dipivoxil Ester Prodrug Testosterone Enanthate Testosterone Undecanoate 
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.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Ansel HC, Allen LV, Jr., and Popovich NG. Pharmaceutical Dosage Forms and Drug Delivery Systems. New York, NY, Lippincott Williams & WilkinsGoogle Scholar
  2. Arimilli M, Kim C, and Bischofberger N. Synthesis, In Vitro Biological Evaluation and Oral Bioavailability of 9-[2-(Phosphonomethoxy)propyl]adenine (PMPA) Prodrugs. Antivir Chem Chemother 1997; 8:557–564Google Scholar
  3. Badawy SI, Williams RC, and Gilbert DL. Chemical Stability of an Ester Prodrug of a Glycoprotein IIb/IIIa Receptor Antagonist in Solid Dosage Forms. J Pharm Sci 1999; 88:428–433PubMedCrossRefGoogle Scholar
  4. Badawy SI, Williams RC, and Gilbert DL. Effect of Different Acids on Solid-state Stability of an Ester Prodrug of a IIb/IIIa Glycoprotein Receptor Antagonist. Pharm Dev Technol 1999; 4:325–331PubMedCrossRefGoogle Scholar
  5. Constantinides PP, Tustian A, and Kessler DR. Tocol Emulsions for Drug Solubilization and Parenteral Delivery. Adv Drug Deliv Rev 2004; 56:1243–1255PubMedCrossRefGoogle Scholar
  6. Digenis GA, Gold TB, and Shah VP. Cross-linking of Gelatin Capsules and its Relevance to their In Vitro-In Vivo Performance. J Pharm Sci 1994; 83:915–921PubMedCrossRefGoogle Scholar
  7. Ennis RD, Pritchard R, Nakamura C, Coulon M, Yang T, and Lee W. Glass Delamination in Small Volume Parenterals. PDA Spring Conference 1997Google Scholar
  8. Gu L, and Strickley RG. Diketopiperazine Formation, Hydrolysis, and Epimerization of the New Dipeptide Angiotensin-converting Enzyme Inhibitor RS-10085. Pharm Res 1987; 4:392–397PubMedCrossRefGoogle Scholar
  9. Gu L, and Strickley RG, A Profound Solvent Effect on the Diketopiperazine Formation of the New Dipeptide Angiotensin-converting Enzyme Inhibitor, Moexipril. Int J Pharm 1990; 60:99–107CrossRefGoogle Scholar
  10. Gu L, Strickley RG, Chi L-H, and Chowhan ZT. Drug-excipient Incompatibility Studies of the Dipeptide Angiotensin-converting Enzyme Inhibitor, Moexipril Hydrochloride: Dry Powder vs Wet Granulation. Pharm Res 1990; 7:379–383PubMedCrossRefGoogle Scholar
  11. Lee JW, Lu JY, Low PS, and Fuchs PL. Synthesis and Evaluation of Taxol-Folic Acid Conjugates as Targeted Antineoplastics. Bioorg Med Chem 2002; 10:2397–2414PubMedCrossRefGoogle Scholar
  12. Lundberg BB, Risovic V, Ramaswamy M, and Wasan KM. A Lipophilic Paclitaxel Derivative Incorporated in a Lipid Emulsion for Parenteral Administration. J Control Release 2003; 86:93–100PubMedCrossRefGoogle Scholar
  13. Narisawa S, and Stella VJ. Increased Shelf-life of Fosphenytoin: Solubilization of a Degradant, Phenytoin, through Complexation with (SBE)7m-beta-CD. J Pharm Sci 1998; 87:926–930PubMedCrossRefGoogle Scholar
  14. Rose WC, Clark JL, Lee FYF, and Casazza AM. Preclinical Antitumor Activity of Water-soluble Paclitaxel Derivatives. Cancer Chemother Pharmacol 1997; 39:486–492PubMedCrossRefGoogle Scholar
  15. Safadi M, Oliyai R, and Stella VJ. Phosphoryloxymethyl Darbamates and Darbonates—novel Water-soluble Prodrugs for Amines and Hindered Alcohols. Pharm Res 1993; 10:1350–1355PubMedCrossRefGoogle Scholar
  16. Shaw J-P, Sueoka CM, Oliyai R, Lee WA, Arimilli MN, Kim CU, and Cundy KC. Metabolism and Pharmacokinetics of Novel Oral Prodrugs of 9-[(R)-2-(Phosphonomethoxy)propyl]-adenine (PMPA) in Dogs. Pharm Res 1997; 14:1824–1829PubMedCrossRefGoogle Scholar
  17. Stevens PJ, Sekido M, and Lee RJ. A Folate Receptor-targeted Lipid Nanoparticle Formulation for a Lipophilic Paclitaxel Prodrug. Pharm Res 2004; 21:2153–2157PubMedCrossRefGoogle Scholar
  18. Strickley RG. Parenteral Formulations of Small Molecules Therapeutics Marketed in the United States (1999)—Part I. PDA J Pharm Sci Technol 1999; 53:324–Google Scholar
  19. Strickley RG. Solubilizing Excipients in Oral and Injectable Formulations. Pharm Res 2004; 21:201–230PubMedCrossRefGoogle Scholar
  20. Strickley RG, Visor GC, Lin L-H, and Gu L. An Unexpected pH Effect on the Stability of Moexipril Lyophilized Powder. Pharm Res 1989; 6:971–975PubMedCrossRefGoogle Scholar
  21. Versluis AJ, Rump ET, Rensen PCN, Van Berkel TJC, and Bijsterbosch MK. Synthesis of a Lipophilic Daunorubicin Derivative and its Incorporation into Lipidic Carriers Developed for LDL Receptor-mediated Tumor Therapy. Pharm Res 1998; 15:531–537PubMedCrossRefGoogle Scholar
  22. Wrasidlo W, Gaedicke G, Guy RK, Renaud J, Pitsinos E, Nicolaou KC, Reisfeld RA, and Lode HN. A Novel 2′-(N-methylpyridinium acetate) Prodrug of Paclitaxel Induces Superior Antitumor Responses in Preclinical Cancer Models. Bioconjug Chem 2002; 13:1093–1099PubMedCrossRefGoogle Scholar
  23. Xiang T-X, and Anderson BD. Stable Supersaturated Aqueous Solutions of Silatecan 7-T-Butyldimethylsilyl-10-hydroxycamptothecin via Chemical Conversion in the Presence of a Chemically Modified beta-Cyclodextrin. Pharm Res 2002; 19:1215–1222PubMedCrossRefGoogle Scholar
  24. Yuan L-C, Dahl TC, and Oliyai R. Effect of Carbonate Salts on the Kinetics of Acid-catalyzed Dimerization of Adefovir Dipivoxil. Pharm Res 2000; 17:1098–1103PubMedCrossRefGoogle Scholar
  25. Yuan L-C, Dahl TC, and Oliyai R. Degradation Kinetics of Oxycarbonyloxymethyl Prodrugs of Phosphonates in Solution. Pharm Res 2001; 18:234–237PubMedCrossRefGoogle Scholar

Copyright information

© American Association of Pharmaceutical Scientists 2007

Authors and Affiliations

  • Robert G. Strickley
  • Reza Oliyai

There are no affiliations available

Personalised recommendations