Abstract
The role of the developability (aka preformulation) scientist at the discovery development interface has been extensively discussed in the literature. In response to shifting trends in discovery and the continued push to shorten timelines and reduce costs, the engagement of the developability scientist on discovery teams has steadily moved upstream over the past two decades. In this new and continually changing role, the developability scientist has the opportunity to influence the selection of chemistry scaffolds entering the lead optimization phase and subsequently the selection of developable compounds for clinical testing. In its current state, developability assessment of clinical candidates is an assessment of the physicochemical and biopharmaceutical properties of the compound, carried out with due consideration to the patient in question, the clinical testing plan, and the commercial landscape. This chapter describes the dynamic and integrated nature of this assessment, along with a description of the in silico, in vitro, and in vivo tools used, and illustrative case studies. Key areas of focus include:
-
(a)
Solid form design and selection.
-
(b)
Characterization of the physicochemical properties associated with the solid form, such as solubility, stability, and dissolution properties.
-
(c)
Absorption modeling, including the definition of clinical product performance criteria and the need (if any) for absorption enhancement.
-
(d)
Assessment of absorption enhancement potential using technology platforms that lend themselves to commercial development (including in vivo evaluation where relevant).
-
(e)
The assembly of a comprehensive data package that includes an assessment of potential risks to clinical and commercial development.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Saxena V, et al. Developability assessment in pharmaceutical industry: an integrated group approach for selecting developable candidates. J Pharm Sci. 2009;98(6):1962–79.
Steele G. Pharmaceutical Preformulation and Formulation: a practical guide from candidate drug selection to commercial dosage form. New York: Informa Healthcare; 2009.
Venkatesh S, Lipper RA. Role of the development scientist in compound lead selection and optimization. J Pharm Sci. 2000;89(2):145–54.
Lipinski CA. Drug-like properties and the causes of poor solubility and poor permeability. J Pharmacol Toxicol Methods. 2000;44(1):235–49.
Lipinski CA, et al. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Deliv Rev. 2001;46(1-3):3–26.
Woodward RB. The total synthesis of strychnine. Experientia. 1955;(Suppl 2):213–28.
Martin DB, Nguyen LQ, Vanderwal CD. Syntheses of strychnine, norfluorocurarine, dehydrodesacetylretuline, and valparicine enabled by intramolecular cycloadditions of Zincke aldehydes. J Org Chem. 2012;77(1):17–46.
Suresh P, Basu PK. Improving pharmaceutical product development and manufacturing: impact on cost of drug development and cost of goods sold of pharmaceuticals. J Pharm Innov. 2008;3(3)
Bertz SH. The first general index of molecular complexity. J Am Chem Soc. 1981;103(12):3.
Bottcher T. An additive definition of molecular complexity. J Chem Inf Model. 2016;56(3):462–70.
Barone R, Chanon M. A new and simple approach to chemical complexity. Application to the synthesis of natural products. J Chem Inf Comput Sci. 2001;41(2):269–72.
Kjell DP, et al. Complexity-based metric for process mass intensity in the pharmaceutical industry. Org Process Res Dev. 2013;17(2):5.
Gaisford S, Saunders M. Essentials of pharmaceutical preformulation. Hoboken, NJ: Wiley-Blackwell; 2012.
Allen RI, et al. Multiwavelength spectrophotometric determination of acid dissociation constants of ionizable drugs. J Pharm Biomed Anal. 1998;17(4-5):699–712.
Zhou C, et al. Rapid pKa estimation using vacuum-assisted multiplexed capillary electrophoresis (VAMCE) with ultraviolet detection. J Pharm Sci. 2005;94(3):576–89.
Takacs-Novak K, Avdeef A. Interlaboratory study of log P determination by shake-flask and potentiometric methods. J Pharm Biomed Anal. 1996;14(11):1405–13.
Lombardo F, et al. ElogPoct: a tool for lipophilicity determination in drug discovery. J Med Chem. 2000;43(15):2922–8.
Lombardo F, et al. ElogD(oct): a tool for lipophilicity determination in drug discovery. 2. Basic and neutral compounds. J Med Chem. 2001;44(15):2490–7.
Hill AP, Young RJ. Getting physical in drug discovery: a contemporary perspective on solubility and hydrophobicity. Drug Discov Today. 2010;15(15–16):648–55.
Friesen DT, et al. Hydroxypropyl methylcellulose acetate succinate-based spray-dried dispersions: an overview. Mol Pharm. 2008;5(6):1003–19.
Giron D. Applications of thermal analysis in the pharmaceutical industry. J Pharm Biomed Anal. 1986;4(6):755–70.
Avdeef A. Solubility of sparingly-soluble ionizable drugs. Adv Drug Deliv Rev. 2007;59(7):568–90.
Elder D, Holm R. Aqueous solubility: simple predictive methods (in silico, in vitro and bio-relevant approaches). Int J Pharm. 2013;453(1):3–11.
Morrison JS, Nophsker MJ, Haskell RJ. A combination turbidity and supernatant microplate assay to rank-order the supersaturation limits of early drug candidates. J Pharm Sci. 2014;103(10):3022–32.
Andersson T, Broo A, Evertsson E. Prediction of drug candidates' sensitivity toward autoxidation: computational estimation of C-H dissociation energies of carbon-centered radicals. J Pharm Sci. 2014;103(7):1949–55.
Lienard P, et al. Predicting drug substances autoxidation. Pharm Res. 2015;32(1):300–10.
Kieffer J, et al. In silico assessment of drug substances chemical stability. J Mol Struct (THEOCHEM). 2010;954(1-3):75–9.
Brittain, HG, Polymorphism in Pharmaceutical Solids. Informa Healthcare. 2009.
Huang LF, Tong WQ. Impact of solid state properties on developability assessment of drug candidates. Adv Drug Deliv Rev. 2004;56(3):321–34.
Brittain HG, et al. Physical characterization of pharmaceutical solids. Pharm Res. 1991;8(8):963–73.
Yu LX, et al. Scientific considerations of pharmaceutical solid polymorphism in abbreviated new drug applications. Pharm Res. 2003;20(4):531–6.
Bauer J, et al. Ritonavir: an extraordinary example of conformational polymorphism. Pharm Res. 2001;18(6):859–66.
Hentzschel CM, Sakmann A, Leopold CS. Suitability of various excipients as carrier and coating materials for liquisolid compacts. Drug Dev Ind Pharm. 2011;37(10):1200–7.
Van Speybroeck M, et al. Ordered mesoporous silica material SBA-15: a broad-spectrum formulation platform for poorly soluble drugs. J Pharm Sci. 2009;98(8):2648–58.
Johnson KC, Swindell AC. Guidance in the setting of drug particle size specifications to minimize variability in absorption. Pharm Res. 1996;13(12):1795–8.
Serajuddin AT. Salt formation to improve drug solubility. Adv Drug Deliv Rev. 2007;59(7):603–16.
Elder DP, Holm R, Diego HL. Use of pharmaceutical salts and cocrystals to address the issue of poor solubility. Int J Pharm. 2013;453(1):88–100.
Li S, et al. Investigation of solubility and dissolution of a free base and two different salt forms as a function of pH. Pharm Res. 2005;22(4):628–35.
Zannou EA, et al. Stabilization of the maleate salt of a basic drug by adjustment of microenvironmental pH in solid dosage form. Int J Pharm. 2007;337(1-2):210–8.
Hsieh YL, et al. Salt stability - the effect of phmax on salt to free base conversion. Pharm Res. 2015;32(9):3110–8.
Stephenson GA, Aburub A, Woods TA. Physical stability of salts of weak bases in the solid-state. J Pharm Sci. 2011;100(5):1607–17.
Rohrs BR, et al. Tablet dissolution affected by a moisture mediated solid-state interaction between drug and disintegrant. Pharm Res. 1999;16(12):1850–6.
Cosmetic Ingredient Review Expert Panel. Final report on the safety assessment of maleic acid. Int J Toxicol. 2007;26(Suppl 2):125–30.
Bhatt PM, et al. Saccharin as a salt former. Enhanced solubilities of saccharinates of active pharmaceutical ingredients. Chem Commun. 2005;8:1073–5.
Bak A, et al. The co-crystal approach to improve the exposure of a water-insoluble compound: AMG 517 sorbic acid co-crystal characterization and pharmacokinetics. J Pharm Sci. 2008;97(9):3942–56.
Williams HD, et al. Strategies to address low drug solubility in discovery and development. Pharmacol Rev. 2013;65(1):315–499.
Brittain HG. Cocrystal systems of pharmaceutical interest: 2009. Profiles Drug Subst Excip Relat Methodol. 2011;36:361–81.
FDA. Guidance for industry: regulatory classification of pharmaceutical co-crystals. In: FDA, editor. 2011.
Brouwers J, Brewster ME, Augustijns P. Supersaturating drug delivery systems: the answer to solubility-limited oral bioavailability? J Pharm Sci. 2009;98(8):2549–72.
Bevernage J, et al. Evaluation of gastrointestinal drug supersaturation and precipitation: strategies and issues. Int J Pharm. 2013;453(1):25–35.
Brewster ME, et al. Comparative interaction of 2-hydroxypropyl-beta-cyclodextrin and sulfobutylether-beta-cyclodextrin with itraconazole: phase-solubility behavior and stabilization of supersaturated drug solutions. Eur J Pharm Sci. 2008;34(2-3):94–103.
Vasconcelos T, Sarmento B, Costa P. Solid dispersions as strategy to improve oral bioavailability of poor water soluble drugs. Drug Discov Today. 2007;12(23-24):1068–75.
Leuner C, Dressman J. Improving drug solubility for oral delivery using solid dispersions. Eur J Pharm Biopharm. 2000;50(1):47–60.
Engers D, et al. A solid-state approach to enable early development compounds: selection and animal bioavailability studies of an itraconazole amorphous solid dispersion. J Pharm Sci. 2010;99(9):3901–22.
Dinunzio JC, et al. Fusion production of solid dispersions containing a heat-sensitive active ingredient by hot melt extrusion and Kinetisol dispersing. Eur J Pharm Biopharm. 2010;74(2):340–51.
Gupta J, et al. Prediction of solubility parameters and miscibility of pharmaceutical compounds by molecular dynamics simulations. J Phys Chem B. 2011;115(9):2014–23.
Baird JA, Taylor LS. Evaluation of amorphous solid dispersion properties using thermal analysis techniques. Adv Drug Deliv Rev. 2012;64(5):396–421.
Newman A, Knipp G, Zografi G. Assessing the performance of amorphous solid dispersions. J Pharm Sci. 2012;101(4):1355–77.
Kostewicz ES, et al. Forecasting the oral absorption behavior of poorly soluble weak bases using solubility and dissolution studies in biorelevant media. Pharm Res. 2002;19(3):345–9.
Hancock BC, Parks M. What is the true solubility advantage for amorphous pharmaceuticals? Pharm Res. 2000;17(4):397–404.
Bard B, Martel S, Carrupt PA. High throughput UV method for the estimation of thermodynamic solubility and the determination of the solubility in biorelevant media. Eur J Pharm Sci. 2008;33(3):230–40.
Jantratid E, et al. Dissolution media simulating conditions in the proximal human gastrointestinal tract: an update. Pharm Res. 2008;25(7):1663–76.
Markopoulos C, et al. In-vitro simulation of luminal conditions for evaluation of performance of oral drug products: choosing the appropriate test media. Eur J Pharm Biopharm. 2015;93:173–82.
Bevernage J, et al. Drug supersaturation in simulated and human intestinal fluids representing different nutritional states. J Pharm Sci. 2010;99(11):4525–34.
Kalantzi L, et al. Characterization of the human upper gastrointestinal contents under conditions simulating bioavailability/bioequivalence studies. Pharm Res. 2006;23(1):165–76.
Curatolo W. Physical chemical properties of oral drug candidates in the discovery and exploratory development settings. Pharmaceut Sci Technol Today. 1998;1(9)
Reppas C, et al. Biorelevant in vitro performance testing of orally administered dosage forms-workshop report. Pharm Res. 2014;31(7):1867–76.
Kostewicz ES, et al. In vitro models for the prediction of in vivo performance of oral dosage forms. Eur J Pharm Sci. 2014;57:342–66.
Mathias NR, et al. Assessing the risk of pH-dependent absorption for new molecular entities: a novel in vitro dissolution test, physicochemical analysis, and risk assessment strategy. Mol Pharm. 2013;10(11):4063–73.
Carino SR, Sperry DC, Hawley M. Relative bioavailability of three different solid forms of PNU-141659 as determined with the artificial stomach-duodenum model. J Pharm Sci. 2010;99(9):3923–30.
Gao Y, et al. A pH-dilution method for estimation of biorelevant drug solubility along the gastrointestinal tract: application to physiologically based pharmacokinetic modeling. Mol Pharm. 2010;7(5):1516–26.
Takeuchi S, et al. Evaluation of a three compartment in vitro gastrointestinal simulator dissolution apparatus to predict in vivo dissolution. J Pharm Sci. 2014;103(11):3416–22.
Sjogren E, et al. In vivo methods for drug absorption - comparative physiologies, model selection, correlations with in vitro methods (IVIVC), and applications for formulation/API/excipient characterization including food effects. Eur J Pharm Sci. 2014;57:99–151.
Agoram B, Woltosz WS, Bolger MB. Predicting the impact of physiological and biochemical processes on oral drug bioavailability. Adv Drug Deliv Rev. 2001;50(Suppl 1):S41–67.
Rohrs BR. Biopharmaceutics modeling and the role of dose and formulation on oral exposure. In: Optimizing the “drug-like” properties of leads in drug discovery. New York: Springer; 2006. p. 151–66.
Mithani SD, et al. Estimation of the increase in solubility of drugs as a function of bile salt concentration. Pharm Res. 1996;13(1):163–7.
Sugano K. A simulation of oral absorption using classical nucleation theory. Int J Pharm. 2009;378(1-2):142–5.
Kesisoglou F, Xia B, Agrawal NGB. Comparison of deconvolution-based and absorption modeling IVIVC for extended release formulations of a BCS III drug development candidate. AAPS J. 2015;17(6):1492–500.
González-García I, et al. In vitro–in vivo correlations: general concepts, methodologies and regulatory applications. Drug Dev Ind Pharm. 2015;41(12):1935–47.
Carlert S, et al. In vivo dog intestinal precipitation of mebendazole: a basic BCS class II drug. Mol Pharm. 2012;9(10):2903–11.
Bhattachar SN, Bender DM, Sweetana SA, Wesley JA. Discovery formulations: approaches and practices in early preclinical development. In: Discovering and developing molecules with optimal drug-like properties. New York: Springer; 2015.
FDA and Rapamune. http://www.fda.gov/ohrms/dockets/ac/02/briefing/3832b1_03_FDA-RapamuneLabel.htm.
Davies H, et al. Mutations of the BRAF gene in human cancer. Nature. 2002;417(6892):949–54.
Niculescu-Duvaz I, et al. Novel inhibitors of B-RAF based on a disubstituted pyrazine scaffold. Generation of a nanomolar lead. J Med Chem. 2006;49(1):407–16.
Bollag G, et al. Vemurafenib: the first drug approved for BRAF-mutant cancer. Nat Rev Drug Discov. 2012;11(11):873–86.
Ravnan MC, Matalka MS. Vemurafenib in patients with BRAF V600E mutation-positive advanced melanoma. Clin Ther. 2012;34(7):1474–86.
Grippo JF, et al. A phase I, randomized, open-label study of the multiple-dose pharmacokinetics of vemurafenib in patients with BRAF V600E mutation-positive metastatic melanoma. Cancer Chemother Pharmacol. 2014;73(1):103–11.
Flaherty KT, Yasothan U, Kirkpatrick P. Vemurafenib. Nat Rev Drug Discov. 2011;10(11):811–2.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2017 American Association of Pharmaceutical Scientists
About this chapter
Cite this chapter
Bhattachar, S.N., Tan, J.S., Bender, D.M. (2017). Developability Assessment of Clinical Candidates. In: Bhattachar, S., Morrison, J., Mudra, D., Bender, D. (eds) Translating Molecules into Medicines. AAPS Advances in the Pharmaceutical Sciences Series, vol 25. Springer, Cham. https://doi.org/10.1007/978-3-319-50042-3_7
Download citation
DOI: https://doi.org/10.1007/978-3-319-50042-3_7
Published:
Publisher Name: Springer, Cham
Print ISBN: 978-3-319-50040-9
Online ISBN: 978-3-319-50042-3
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)