Skip to main content
SpringerLink
Log in

Discovery Formulations: Approaches and Practices in Early Preclinical Development

  • Chapter
  • First Online:
Discovering and Developing Molecules with Optimal Drug-Like Properties

Part of the book series: AAPS Advances in the Pharmaceutical Sciences Series ((AAPS,volume 15))

Abstract

Reduced portfolio attrition and faster development of high quality drugs that address unmet medical needs is an established imperative within the pharmaceutical industry. Given the complexity of modern drug discovery, this goal can only be achieved through well-designed pharmacology, pharmacokinetic, and toxicology studies resulting in the identification of exceptional development candidates. Pivotal to the success of these studies is the use of appropriate formulations designed to deliver the compound to the desired site via the desired route, in a consistent and acceptable manner. It is also essential that the formulations are developed with a clear understanding of the goals of the studies, future application of the formulations, and/or the data from the studies. However, the development of an appropriate discovery formulation can be challenging due to a myriad of factors that include suboptimal biopharmaceutical properties, dose, compound purity, compound availability, and aggressive timelines. This chapter will cover formulations used in the discovery setting from conventional vehicles to solubilizing systems and alternate delivery approaches. The application of the appropriate formulation approach to meet the study goals and efficient development timelines will also be discussed.

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

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 169.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 219.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Similar content being viewed by others

References

  • Akimoto M, Nagahata N et al (2000) Gastric pH profiles of beagle dogs and their use as an alternative to human testing. Eur J Pharm Biopharm 49(2):99–102

    Article  PubMed  CAS  Google Scholar 

  • Anderson GD, Saneto RP (2012) Current oral and non-oral routes of antiepileptic drug delivery. Adv Drug Deliv Rev 64(10):911–918

    Article  PubMed  CAS  Google Scholar 

  • Balazs O (2011) Preclinical formulation in early drug research. In: Tihanyi K, Vastag M (eds) Solubility, delivery and ADME problems of drugs and drug candidates. Budapest, Bentham, p 22

    Google Scholar 

  • Bernabei R, Rossini PM et al (2012) Compliance and caregiver satisfaction in Alzheimer’s disease: results from the AXEPT study. Dement Geriatr Cogn Dis Extra 2(1):418–432

    Article  PubMed  PubMed Central  Google Scholar 

  • Bhattachar SN, Perkins EJ et al (2011) Effect of gastric pH on the pharmacokinetics of a BCS class II compound in dogs: utilization of an artificial stomach and duodenum dissolution model and GastroPlus, simulations to predict absorption. J Pharm Sci 100(11):4756–4765

    Article  PubMed  CAS  Google Scholar 

  • Bikiaris DN (2011) Solid dispersions, part I: recent evolutions and future opportunities in manufacturing methods for dissolution rate enhancement of poorly water-soluble drugs. Expert Opin Drug Deliv 8(11):1501–1519

    Article  PubMed  CAS  Google Scholar 

  • Bittner BG, Bravo RC, Walter I, Huwyler J (2005) Impact of oral administration of the surface-active excipient Solutol HS 15 on the pharmacokinetics of intravenously administered colchicine. Lett Drug Des Discov 2(3):3

    Article  Google Scholar 

  • Blagg J, Allerton CM et al (2007) Design and synthesis of a functionally selective D3 agonist and its in vivo delivery via the intranasal route. Bioorg Med Chem Lett 17(24):6691–6696

    Article  PubMed  CAS  Google Scholar 

  • Bravo González RC, Huwyler J, Boess F, Walter I, Bittner B (2004) In vitro investigation on the impact of the surface-active excipients Cremophor EL, Tween 80 and Solutol HS 15 on the metabolism of midazolam. Biopharm Drug Dispos 25(1):13

    Article  CAS  Google Scholar 

  • Brewster M, Claire M, Noppe M, Lampo A, Loftsson T (2007) The use of solubilizing excipients and approaches to generate toxicology vehicles for contemporary drug pipelines. In: Augustijns P, Brewster M (eds) Solvent systems and their selection in pharamceutics and biopharmaceutics. Springer, New York, pp 221–256

    Chapter  Google Scholar 

  • Buckley LA, Dorato MA (2009) High dose selection in general toxicity studies for drug development: a pharmaceutical industry perspective. Regul Toxicol Pharmacol 54(3):301–307

    Article  PubMed  CAS  Google Scholar 

  • Buggins TR, Dickinson PA et al (2007) The effects of pharmaceutical excipients on drug disposition. Adv Drug Deliv Rev 59(15):1482–1503

    Article  PubMed  CAS  Google Scholar 

  • Carino SR, Sperry DC et al (2006) Relative bioavailability estimation of carbamazepine crystal forms using an artificial stomach-duodenum model. J Pharm Sci 95(1):116–125

    Article  PubMed  CAS  Google Scholar 

  • Carrier RL, Miller LA et al (2007) The utility of cyclodextrins for enhancing oral bioavailability. J Control Release 123(2):78–99

    Article  PubMed  CAS  Google Scholar 

  • Chapman CD, Frey WH 2nd et al (2013) Intranasal treatment of central nervous system dysfunction in humans. Pharm Res 30(10):2475–2484

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Charman SA, Perry CS et al (2006) Alteration of the intravenous pharmacokinetics of a synthetic ozonide antimalarial in the presence of a modified cyclodextrin. J Pharm Sci 95(2):256–267

    Article  PubMed  CAS  Google Scholar 

  • Chaubal MV (2004) Application of drug delivery technologies in lead candidate selection and optimization. Drug Discov Today 9(14):603–609

    Article  PubMed  CAS  Google Scholar 

  • Chen XQ, Gudmundsson OS et al (2012) Application of lipid-based formulations in drug discovery. J Med Chem 55(18):7945–7956

    Article  PubMed  CAS  Google Scholar 

  • Chien JY, Ho RJ (2011) Drug delivery trends in clinical trials and translational medicine: evaluation of pharmacokinetic properties in special populations. J Pharm Sci 100(1):53–58

    Article  PubMed  CAS  Google Scholar 

  • Chiou WL, Barve A (1998) Linear correlation of the fraction of oral dose absorbed of 64 drugs between humans and rats. Pharm Res 15(11):1792–1795

    Article  PubMed  CAS  Google Scholar 

  • Dafallah AA, al-Mustafa Z (1996) Investigation of the anti-inflammatory activity of Acacia nilotica and Hibiscus sabdariffa. Am J Chin Med 24(3–4):263–269

    Article  PubMed  CAS  Google Scholar 

  • Dietrich E, Gums JG (2012) Intranasal fentanyl spray: a novel dosage form for the treatment of breakthrough cancer pain. Ann Pharmacother 46(10):1382–1391

    Article  PubMed  Google Scholar 

  • Dimitrov NV, Meyer-Leece C et al (1996) Plasma alpha-tocopherol concentrations after supplementation with water- and fat-soluble vitamin E. Am J Clin Nutr 64(3):329–335

    PubMed  CAS  Google Scholar 

  • Dorato MA, Buckley LA (2007) Toxicology testing in drug discovery and development. Curr Protoc Toxicol Chapter 19: Unit 19 11

    Google Scholar 

  • Dudley RE, Constantinides P (2011) Oral testosterone ester formulations and methods of treating testosterone deficiency comprising same. WIPO, Clarus Therapeutics, Inc

    Google Scholar 

  • Fancher RM, Zhang H et al (2011) Development of a canine model to enable the preclinical assessment of pH-dependent absorption of test compounds. J Pharm Sci 100(7):2979–2988

    Article  PubMed  CAS  Google Scholar 

  • Ferguson SA, Boctor SY (2009) Use of food wafers for multiple daily oral treatments in young rats. J Am Assoc Lab Anim Sci 48(3):292–295

    PubMed  CAS  PubMed Central  Google Scholar 

  • Foster KA, Sun H et al (2013) Utility of gastric-retained alginate gels to modulate pharmacokinetic profiles in rats. J Pharm Sci 102(8):2440–2449

    Article  PubMed  CAS  Google Scholar 

  • Friesen DT, Shanker R et al (2008) Hydroxypropyl methylcellulose acetate succinate-based spray-dried dispersions: an overview. Mol Pharm 5(6):1003–1019

    Article  PubMed  CAS  Google Scholar 

  • Gad SC, Cassidy CD et al (2006) Nonclinical vehicle use in studies by multiple routes in multiple species. Int J Toxicol 25(6):499–521

    Article  PubMed  CAS  Google Scholar 

  • Gao P, Guyton ME et al (2004) Enhanced oral bioavailability of a poorly water soluble drug PNU-91325 by supersaturatable formulations. Drug Dev Ind Pharm 30(2):221–229

    Article  PubMed  CAS  Google Scholar 

  • Gao Y, Carr RA et al (2010) A pH-dilution method for estimation of biorelevant drug solubility along the gastrointestinal tract: application to physiologically based pharmacokinetic modeling. Mol Pharm 7(5):1516–1526

    Article  PubMed  CAS  Google Scholar 

  • Gartner K, Buttner D et al (1980) Stress response of rats to handling and experimental procedures. Lab Anim 14(3):267–274

    Article  PubMed  CAS  Google Scholar 

  • Gayrard V, Lacroix MZ et al (2013) High bioavailability of bisphenol A from sublingual exposure. Environ Health Perspect 121(8):951–956

    PubMed  CAS  PubMed Central  Google Scholar 

  • Gleeson MP, Hersey A et al (2011) Probing the links between in vitro potency, ADMET and physicochemical parameters. Nat Rev Drug Discov 10(3):197–208

    Article  PubMed  CAS  Google Scholar 

  • Goswami T, Kokate A et al (2013) In silico model of drug permeability across sublingual mucosa. Arch Oral Biol 58(5):545–551

    Article  PubMed  CAS  Google Scholar 

  • Gullapalli R, Wong A et al (2012) Development of ALZET(R) osmotic pump compatible solvent compositions to solubilize poorly soluble compounds for preclinical studies. Drug Deliv 19(5):239–246

    Article  PubMed  CAS  Google Scholar 

  • Hageman MJ (2006) Solubility, solubilization and dissolution in drug delivery during lead optimization. In: Borchardt RT, Kerns EH, Hageman MJ, Thakker DR, Stevens JL (eds) Optimizing the drug-like properties of leads in drug discovery, vol VI, Biotechnology: pharmaceutical aspects. Springer, New York, pp 99–103

    Chapter  Google Scholar 

  • He K, Qian M et al (2008) N-in-1 dosing pharmacokinetics in drug discovery: experience, theoretical and practical considerations. J Pharm Sci 97(7):2568–2580

    Article  PubMed  CAS  Google Scholar 

  • Higgins J, Cartwright ME et al (2012) Progressing preclinical drug candidates: strategies on preclinical safety studies and the quest for adequate exposure. Drug Discov Today 17(15–16):828–836

    Article  PubMed  CAS  Google Scholar 

  • Hopkins AL, Groom CR (2002) The druggable genome. Nat Rev Drug Discov 1:727–730

    Article  PubMed  CAS  Google Scholar 

  • Jacquemin E, Hermeziu B et al (2009) Bioavailability of oral vitamin E formulations in adult volunteers and children with chronic cholestasis or cystic fibrosis. J Clin Pharm Ther 34(5):515–522

    Article  PubMed  CAS  Google Scholar 

  • Kesisoglou F, Mitra A (2012) Crystalline nanosuspensions as potential toxicology and clinical oral formulations for BCS II/IV compounds. AAPS J 14(4):677–687

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Kesisoglou F, Panmai S et al (2007) Nanosizing—oral formulation development and biopharmaceutical evaluation. Adv Drug Deliv Rev 59(7):631–644

    Article  PubMed  CAS  Google Scholar 

  • Kumar R, Knick VB et al (2007) Pharmacokinetic-pharmacodynamic correlation from mouse to human with pazopanib, a multikinase angiogenesis inhibitor with potent antitumor and antiangiogenic activity. Mol Cancer Ther 6(7):2012–2021

    Article  PubMed  CAS  Google Scholar 

  • Kurkov SV, Loftsson T (2013) Cyclodextrins. Int J Pharm 453(1):167–180

    Article  PubMed  CAS  Google Scholar 

  • Kurkov SV, Madden DE et al (2012) The effect of parenterally administered cyclodextrins on the pharmacokinetics of coadministered drugs. J Pharm Sci 101(12):4402–4408

    Article  PubMed  CAS  Google Scholar 

  • Kwong E, Higgins J et al (2011) Strategies for bringing drug delivery tools into discovery. Int J Pharm 412(1–2):1–7

    Article  PubMed  CAS  Google Scholar 

  • Lam JK, Xu Y et al (2013) Oral transmucosal drug delivery for pediatric use. Adv Drug Deliv Rev 73C:50–62

    Google Scholar 

  • Larger PJ, Breda M et al (2005) Ion-suppression effects in liquid chromatography-tandem mass spectrometry due to a formulation agent, a case study in drug discovery bioanalysis. J Pharm Biomed Anal 39(1–2):206–216

    Article  PubMed  CAS  Google Scholar 

  • Lee YC, Zocharski PD et al (2003) An intravenous formulation decision tree for discovery compound formulation development. Int J Pharm 253(1–2):111–119

    Article  PubMed  CAS  Google Scholar 

  • Lee PH, Conradi R et al (2010) Development of an in silico model for human skin permeation based on a Franz cell skin permeability assay. Bioorg Med Chem Lett 20(1):69–73

    Article  PubMed  CAS  Google Scholar 

  • Lehman PA, Raney SG (2012) In vitro percutaneous absorption of ketoprofen and testosterone: comparison of pluronic lecithin organogel vs. pentravan cream. Int J Pharm Compd 16(3):248–252

    PubMed  CAS  Google Scholar 

  • Li P, Zhao L (2007) Developing early formulations: practice and perspective. Int J Pharm 341(1–2):1–19

    Article  PubMed  CAS  Google Scholar 

  • Li S, Pollock-Dove C et al (2012) Enhanced bioavailability of a poorly water-soluble weakly basic compound using a combination approach of solubilization agents and precipitation inhibitors: a case study. Mol Pharm 9(5):1100–1108

    PubMed  CAS  Google Scholar 

  • Loftsson T, Brewster ME (2010) Pharmaceutical applications of cyclodextrins: basic science and product development. J Pharm Pharmacol 62(11):1607–1621

    Article  PubMed  CAS  Google Scholar 

  • Loftsson T, Brewster ME (2011) Pharmaceutical applications of cyclodextrins: effects on drug permeation through biological membranes. J Pharm Pharmacol 63(9):1119–1135

    Article  PubMed  CAS  Google Scholar 

  • Long G, Works J (2013). Innovation in the biopharmaceutical pipeline: a multidimensional view. www.pharma.org

  • Lorenz W, Reimann HJ et al (1977) Histamine release in dogs by Cremophor E1 and its derivatives: oxethylated oleic acid is the most effective constituent. Agents Actions 7(1):63–67

    Article  PubMed  CAS  Google Scholar 

  • Lorenz W, Schmal A et al (1982) Histamine release and hypotensive reactions in dogs by solubilizing agents and fatty acids: analysis of various components in cremophor El and development of a compound with reduced toxicity. Agents Actions 12(1–2):64–80

    Article  PubMed  CAS  Google Scholar 

  • Lui CY, Amidon GL et al (1986) Comparison of gastrointestinal pH in dogs and humans: implications on the use of the beagle dog as a model for oral absorption in humans. J Pharm Sci 75(3):271–274

    Article  PubMed  CAS  Google Scholar 

  • Lukas G, Brindle SD et al (1971) The route of absorption of intraperitoneally administered compounds. J Pharmacol Exp Ther 178(3):562–564

    PubMed  CAS  Google Scholar 

  • Luke DR, Tomaszewski K et al (2010) Review of the basic and clinical pharmacology of sulfobutylether-beta-cyclodextrin (SBECD). J Pharm Sci 99(8):3291–3301

    Article  PubMed  CAS  Google Scholar 

  • M3(R2) Guidance on nonclinical safety studies for the conduct of human clinical trials and marketing authorization for pharmaceuticals. I. C. o. Harmonization

    Google Scholar 

  • Maas J, Kamm W et al (2007) An integrated early formulation strategy—from hit evaluation to preclinical candidate profiling. Eur J Pharm Biopharm 66(1):1–10

    Article  PubMed  Google Scholar 

  • Mactier RA, Khanna R et al (1987) Role of peritoneal cavity lymphatic absorption in peritoneal dialysis. Kidney Int 32(2):165–172

    Article  PubMed  CAS  Google Scholar 

  • Mathias NR, Hussain MA (2010) Non-invasive systemic drug delivery: developability considerations for alternate routes of administration. J Pharm Sci 99(1):1–20

    Article  PubMed  CAS  Google Scholar 

  • Merisko-Liversidge EM, Liversidge GG (2008) Drug nanoparticles: formulating poorly water-soluble compounds. Toxicol Pathol 36(1):43–48

    Article  PubMed  CAS  Google Scholar 

  • Miller JM, Dahan A (2012) Predicting the solubility-permeability interplay when using cyclodextrins in solubility-enabling formulations: model validation. Int J Pharm 430(1–2):388–391

    Article  PubMed  CAS  Google Scholar 

  • Morphy R (2010) Selectively nonselective kinase inhibition: striking the right balance. J Med Chem 53(4):1413–1437

    Article  PubMed  CAS  Google Scholar 

  • Mu J, Woods J et al (2006) Chronic inhibition of dipeptidyl peptidase-4 with a sitagliptin analog preserves pancreatic beta-cell mass and function in a rodent model of type 2 diabetes. Diabetes 55(6):1695–1704

    Article  PubMed  CAS  Google Scholar 

  • Mu J, Petrov A et al (2009) Inhibition of DPP-4 with sitagliptin improves glycemic control and restores islet cell mass and function in a rodent model of type 2 diabetes. Eur J Pharmacol 623(1–3):148–154

    Article  PubMed  CAS  Google Scholar 

  • Muramatsu RS, Litzinger MH et al (2010) Alternative formulations, delivery methods, and administration options for psychotropic medications in elderly patients with behavioral and psychological symptoms of dementia. Am J Geriatr Pharmacother 8(2):98–114

    Article  PubMed  CAS  Google Scholar 

  • Musther H, Olivares-Morales A et al (2013) Animal versus human oral drug bioavailability: do they correlate? Eur J Pharm Sci 57:280–291

    Article  PubMed  CAS  Google Scholar 

  • Nagapudi KJ, Jona J (2008) Amorphous active pharmaceutical ingredients in preclinical studies: preparation, characterization, and formulation. Curr Bioactive Compd 4(4):213–224

    Article  CAS  Google Scholar 

  • Nagilla R, Nord M et al (2011) Cassette dosing for pharmacokinetic screening in drug discovery: comparison of clearance, volume of distribution, half-life, mean residence time, and oral bioavailability obtained by cassette and discrete dosing in rats. J Pharm Sci 100(9):3862–3874

    Article  PubMed  CAS  Google Scholar 

  • Neely BJ, Madihally SV et al (2009) Nonlinear quantitative structure-property relationship modeling of skin permeation coefficient. J Pharm Sci 98(11):4069–4084

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Neervannan S (2006) Preclinical formulations for discovery and toxicology: physicochemical challenges. Expert Opin Drug Metab Toxicol 2(5):715–731

    Article  PubMed  CAS  Google Scholar 

  • Oh DM, Curl RL et al (1993) Estimating the fraction dose absorbed from suspensions of poorly soluble compounds in humans: a mathematical model. Pharm Res 10(2):264–270

    Article  PubMed  CAS  Google Scholar 

  • Pammolli F, Magazzini L et al (2011) The productivity crisis in pharmaceutical R&D. Nat Rev Drug Discov 10(6):428–438

    Article  PubMed  CAS  Google Scholar 

  • Paudel KS, Milewski M et al (2010) Challenges and opportunities in dermal/transdermal delivery. Ther Deliv 1(1):109–131

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Pfeil E, Dobs AS (2008) Current and future testosterone delivery systems for treatment of the hypogonadal male. Expert Opin Drug Deliv 5(4):471–481

    Article  PubMed  CAS  Google Scholar 

  • Pole DL (2008) Physical and biological considerations for the use of nonaqueous solvents in oral bioavailability enhancement. J Pharm Sci 97(3):1071–1088

    Article  PubMed  CAS  Google Scholar 

  • Porter CJ, Pouton CW et al (2008) Enhancing intestinal drug solubilisation using lipid-based delivery systems. Adv Drug Deliv Rev 60(6):673–691

    Article  PubMed  CAS  Google Scholar 

  • Pouton CW, Porter CJ (2008) Formulation of lipid-based delivery systems for oral administration: materials, methods and strategies. Adv Drug Deliv Rev 60(6):625–637

    Article  PubMed  CAS  Google Scholar 

  • Qian F, Huang J et al (2010) Drug-polymer solubility and miscibility: stability consideration and practical challenges in amorphous solid dispersion development. J Pharm Sci 99(7):2941–2947

    PubMed  CAS  Google Scholar 

  • Rabinow BE (2004) Nanosuspensions in drug delivery. Nat Rev Drug Discov 3(9):785–796

    Article  PubMed  CAS  Google Scholar 

  • Rao VM, Stella VJ (2003) When can cyclodextrins be considered for solubilization purposes? J Pharm Sci 92(5):927–932

    Article  PubMed  CAS  Google Scholar 

  • Reed KW, Yalkowsky SH (1985) Lysis of human red blood cells in the presence of various cosolvents. J Parenter Sci Technol 39(2):64–69

    PubMed  CAS  Google Scholar 

  • Roth BL, Sheffler DJ et al (2004) Magic shotguns versus magic bullets: selectively non-selective drugs for mood disorders and schizophrenia. Nat Rev Drug Discov 3(4):353–359

    Article  PubMed  CAS  Google Scholar 

  • Saxena V, Panicucci R et al (2009) Developability assessment in pharmaceutical industry: an integrated group approach for selecting developable candidates. J Pharm Sci 98(6):1962–1979

    Article  PubMed  CAS  Google Scholar 

  • Scannell JW, Blanckley A et al (2012) Diagnosing the decline in pharmaceutical R&D efficiency. Nat Rev Drug Discov 11(3):191–200

    Article  PubMed  CAS  Google Scholar 

  • Shah AK, Agnihotri SA (2011) Recent advances and novel strategies in pre-clinical formulation development: an overview. J Control Release 156(3):281–296

    Article  PubMed  CAS  Google Scholar 

  • Sheth AR (2011) In vitro screening methods to assess the potential of in vivo precipitation of injectable formulations upon intravenous administration. PDA J Pharm Sci Technol 65(1):71–80

    PubMed  CAS  Google Scholar 

  • Shiotani K, Uehata K et al (1995) Differential effects of sulfate and sulfobutyl ether of beta-cyclodextrin on erythrocyte membranes in vitro. Pharm Res 12(1):78–84

    Article  PubMed  CAS  Google Scholar 

  • Six K, Verreck G et al (2004) Increased physical stability and improved dissolution properties of itraconazole, a class II drug, by solid dispersions that combine fast- and slow-dissolving polymers. J Pharm Sci 93(1):124–131

    Article  PubMed  CAS  Google Scholar 

  • Stella VJ, He Q (2008) Cyclodextrins. Toxicol Pathol 36(1):30–42

    Article  PubMed  CAS  Google Scholar 

  • Stella VJ, Rao VM et al (1999) Mechanisms of drug release from cyclodextrin complexes. Adv Drug Deliv Rev 36(1):3–16

    Article  PubMed  CAS  Google Scholar 

  • Strickley RG (2008) Formulation in drug discovery (chapter 24). Annu Rep Med Chem 43:419–451

    Article  CAS  Google Scholar 

  • Sutton SC, Engle K et al (1993) Intranasal delivery of the bisphosphonate alendronate in the rat and dog. Pharm Res 10(6):924–926

    Article  PubMed  CAS  Google Scholar 

  • ten Tije AJ, Verweij J et al (2003) Pharmacological effects of formulation vehicles: implications for cancer chemotherapy. Clin Pharmacokinet 42(7):665–685

    Article  PubMed  Google Scholar 

  • Tong WQ, Whitesell G (1998) In situ salt screening—a useful technique for discovery support and preformulation studies. Pharm Dev Technol 3(2):215–223

    Article  PubMed  CAS  Google Scholar 

  • Traber MG, Kayden HJ et al (1986) Absorption of water-miscible forms of vitamin E in a patient with cholestasis and in thoracic duct-cannulated rats. Am J Clin Nutr 44(6):914–923

    PubMed  CAS  Google Scholar 

  • Turner PV, Brabb T et al (2011) Administration of substances to laboratory animals: routes of administration and factors to consider. J Am Assoc Lab Anim Sci 50(5):600–613

    PubMed  CAS  PubMed Central  Google Scholar 

  • Van Eerdenbrugh B, Van den Mooter G et al (2008) Top-down production of drug nanocrystals: nanosuspension stabilization, miniaturization and transformation into solid products. Int J Pharm 364(1):64–75

    Article  PubMed  CAS  Google Scholar 

  • Vandecruys R, Peeters J et al (2007) Use of a screening method to determine excipients which optimize the extent and stability of supersaturated drug solutions and application of this system to solid formulation design. Int J Pharm 342(1–2):168–175

    Article  PubMed  CAS  Google Scholar 

  • Vasconcelos T, Sarmento B, Costa P (2007) Solid dispersions as strategy to improve oral bioavailability of poor water soluble drugs. Drug Discov Today 12(23–24):8

    Google Scholar 

  • Venkatesh S, Lipper RA (2000) Role of the development scientist in compound lead selection and optimization. J Pharm Sci 89(2):145–154

    Article  PubMed  CAS  Google Scholar 

  • Verreck G, Six K et al (2003) Characterization of solid dispersions of itraconazole and hydroxypropylmethylcellulose prepared by melt extrusion—part I. Int J Pharm 251(1–2):165–174

    Article  PubMed  CAS  Google Scholar 

  • Vitic Nexus. Lhasa Limited, Leeds, UK. http://www.lhasalimited.org/products/vitic-nexus.html

  • Vo CL, Park C et al (2013) Current trends and future perspectives of solid dispersions containing poorly water-soluble drugs. Eur J Pharm Biopharm 85(3):799–813

    Article  PubMed  CAS  Google Scholar 

  • Warren DB, Benameur H et al (2010) Using polymeric precipitation inhibitors to improve the absorption of poorly water-soluble drugs: a mechanistic basis for utility. J Drug Target 18(10):704–731

    Article  PubMed  CAS  Google Scholar 

  • Waters C (2013) The development of the rotigotine transdermal patch: a historical perspective. Neurol Clin 31(3 Suppl):S37–S50

    Article  PubMed  Google Scholar 

  • Watkinson AC (2013) A commentary on transdermal drug delivery systems in clinical trials. J Pharm Sci 102(9):3082–3088

    Article  PubMed  CAS  Google Scholar 

  • Weiss RB, Donehower RC et al (1990) Hypersensitivity reactions from taxol. J Clin Oncol 8(7):1263–1268

    PubMed  CAS  Google Scholar 

  • Williams HD, Trevaskis NL et al (2013) Strategies to address low drug solubility in discovery and development. Pharmacol Rev 65(1):315–499

    Article  PubMed  CAS  Google Scholar 

  • Willmann S, Schmitt W et al (2004) A physiological model for the estimation of the fraction dose absorbed in humans. J Med Chem 47(16):4022–4031

    Article  PubMed  CAS  Google Scholar 

  • Woodburn K, Kessel D (1994) The alteration of plasma lipoproteins by cremophor EL. J Photochem Photobiol B 22(3):197–201

    Article  PubMed  CAS  Google Scholar 

  • Wright BA, Waters CH (2013) Continuous dopaminergic delivery to minimize motor complications in Parkinson's disease. Expert Rev Neurother 13(6):719–729

    Article  PubMed  CAS  Google Scholar 

  • Xu S, Dai WG (2013) Drug precipitation inhibitors in supersaturable formulations. Int J Pharm 453(1):36–43

    Article  PubMed  CAS  Google Scholar 

  • Yalkowsky SH (1999) Solubility and solubilization in aqueous media. American Chemical Society, New York

    Google Scholar 

  • Yamada I, Haga K (1990) Measurement of gastric pH during digestion of a solid meal in dogs. Chem Pharm Bull (Tokyo) 38(6):1755–1756

    Article  CAS  Google Scholar 

  • Yin AY, Htun M et al (2012) Reexamination of pharmacokinetics of oral testosterone undecanoate in hypogonadal men with a new self-emulsifying formulation. J Androl 33(2):190–201

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Zhang H, Zhang J et al (2002) Oral mucosal drug delivery: clinical pharmacokinetics and therapeutic applications. Clin Pharmacokinet 41(9):661–680

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Small Molecule Design and Development, Eli Lilly and Company, 893 S Delaware St, Indianapolis, IN, 46285, USA

    Shobha N. Bhattachar, David M. Bender, Stephanie A. Sweetana & James A. Wesley

Authors
  1. Shobha N. Bhattachar
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. David M. Bender
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Stephanie A. Sweetana
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. James A. Wesley
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to James A. Wesley .

Editor information

Editors and Affiliations

  1. Pharmaceutical Sciences & Clinical Supply, Merck & Co, Inc., West Point, Pennsylvania, USA

    Allen C Templeton

  2. Department of Industrial and Physical Pharmacy, Purdue University, West Lafayette, Indiana, USA

    Stephen R. Byrn

  3. Discovery Pharmaceutics, Bristol-Myers Squibb, Wallingford, Connecticut, USA

    Roy J Haskell

  4. Department of Medicinal Chemistry, University of Kansas School of Pharmacy, Lawrence, Kansas, USA

    Thomas E. Prisinzano

Rights and permissions

Reprints and permissions

Copyright information

© 2015 American Association of Pharmaceutical Scientists

About this chapter

Cite this chapter

Bhattachar, S.N., Bender, D.M., Sweetana, S.A., Wesley, J.A. (2015). Discovery Formulations: Approaches and Practices in Early Preclinical Development. In: Templeton, A., Byrn, S., Haskell, R., Prisinzano, T. (eds) Discovering and Developing Molecules with Optimal Drug-Like Properties. AAPS Advances in the Pharmaceutical Sciences Series, vol 15. Springer, New York, NY. https://doi.org/10.1007/978-1-4939-1399-2_2

Download citation

Publish with us

Policies and ethics

Search

Navigation