Abstract
Drugs with low water solubility are predisposed to low and variable oral bioavailability and, therefore, to variability in clinical response. Despite significant efforts to “design in” acceptable developability properties (including aqueous solubility) during lead optimization, approximately 40% of currently marketed compounds and most current drug development candidates remain poorly water-soluble. The fact that so many drug candidates of this type are advanced into development and clinical assessment is testament to an increasingly sophisticated understanding of the approaches that can be taken to promote apparent solubility in the gastrointestinal tract and to support drug exposure after oral administration. Here we provide a detailed commentary on the major challenges to the progression of a poorly water-soluble lead or development candidate and review the approaches and strategies that can be taken to facilitate compound progression. In particular, we address the fundamental principles that underpin the use of strategies, including pH adjustment and salt-form selection, polymorphs, cocrystals, cosolvents, surfactants, cyclodextrins, particle size reduction, amorphous solid dispersions, and lipid-based formulations. In each case, the theoretical basis for utility is described along with a detailed review of recent advances in the field. The article provides an integrated and contemporary discussion of current approaches to solubility and dissolution enhancement but has been deliberately structured as a series of stand-alone sections to allow also directed access to a specific technology (e.g., solid dispersions, lipid-based formulations, or salt forms) where required.
Footnotes
ABBREVIATIONS:
- ABT-229; 8,9-anhydro-40-deoxy-39-N-desmethyl-39-N-ethylerythromycin B-6,9-hemiaceta; AMG 517
- N-(4-[6-(4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-benzothiazol-2-yl)-acetamide
- AUC
- area under the curve
- BCRP
- breast cancer–resistant protein
- BCS
- Biopharmaceutical Classification System
- CD
- cyclodextrin
- CMC
- critical micelle concentration
- CNT
- classical nucleation theory
- CRA13
- naphthalen-1-yl(4-(pentyloxy)naphthalen-1-yl)methanone
- DG
- diglyceride
- DMA
- dimethylacetamide
- DMSO
- dimethyl sulfoxide
- DSC
- differential scanning calorimetry
- FA
- fatty acid
- FABP
- fatty acid-binding protein
- FaSSGF
- fasted-state simulated gastric fluid
- FaSSIF
- fasted-state simulated intestinal fluid
- FATP
- fatty acid transport protein
- FeSSIF
- fed-state simulated intestinal fluid
- FTIR
- Fourier transform infrared spectroscopy
- GI
- gastrointestinal
- HDL
- high-density lipoprotein
- HPC
- hydroxypropyl cellulose
- HLB
- hydrophilic-lipophilic balance
- HPMC
- hydroxypropyl methylcellulose
- HPH
- high-pressure homogenization
- HPMCAS
- hydroxypropyl methylcellulose acetate succinate
- K-832
- 2-benzyl-5-(4-chlorophenyl)-6-[4-(methylthio)phenyl]-2H-pyridazin-3-one
- L-883555
- N-cyclopropyl-1-{3-[6-(1-hydroxy-1-methylethyl)-1-oxidopyridin-3-yl]phenyl}-1,4-dihydro-[1,8]naphthyridin-4-one 3-carboxamide
- LBF
- lipid-based formulations
- LC
- long chain
- LCQ789
- 5-(4-chlorophenyl)-1-phenyl-6-(4-(pyrazin-2-yl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one
- LDL
- low-density lipoprotein
- LFCS
- Lipid Formulation Classification System
- LPC
- lysophosphatidylcholine
- MC
- medium chain
- mdr or MDR
- multi-drug resistant
- MG
- monoglyceride
- MRP
- multiresistance protein
- NMR
- nuclear magnetic resonance
- NSC-639829
- N-[4-(5-bromo-2-pyrimidyloxy)-3-methylphenyl]-(dimemethylamino)-benzoylphenylurea
- OZ209
- cis-adamantane-2-spiro-3′-8′-(aminomethyl)-1′,2′,4′-trioxaspiro[4.5]decane mesylate
- PEG
- polyethylene glycol
- PG-300995
- 2-(2-thiophenyl)-4-azabenzoimidazole
- P-gp
- P-glycoprotein
- PL
- phospholipid
- PPI
- polymer precipitation inhibitor
- PVP
- polyvinylpyrrolidone
- RPR200765
- {t-2-[4-(4-fluoro-phenyl)-5-pyridin-4-yl-1H-imidazol-2-yl]-5-methyl-[1,3]dioxan-r-5-yl}-morpholin-4-yl-methanone;
- SCF
- super critical fluids
- SEDDS
- self-emulsifying drug-delivery systems
- SD
- solid dispersion
- SGF
- simulated gastric fluid
- SLN
- solid lipid nanoparticle
- TG
- triglyceride
- TPGS
- d-α-tocopheryl polyethylene glycol succinate
- TRL
- triglyceride-rich lipoprotein
- UWL
- unstirred water layer
- XRPD
- X-ray powder diffraction
- Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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In this issue
Jump to section
- Article
- Abstract
- I. Introduction
- II. In Vitro Complexities of Working with Poorly Water-Soluble Drugs
- III. In Vivo Assessment of Poorly Water-Soluble Compounds
- IV. Buffers and Salt Formation
- V. Optimization of Crystal Habit: Polymorphism and Cocrystal Formation
- VI. Cosolvents
- G. Summary
- VII. Surfactants
- VIII. Cyclodextrins
- IX. Particle Size Reduction Strategies
- X. Solid Dispersions
- XI. Lipid-Based Formulations
- XII. Emerging Strategies for Improving the Aqueous Solubility of Poorly Water-Soluble Drugs
- XIII. Conclusions
- Acknowledgments
- Authorship Contributions
- Footnotes
- References
- Figures & Data
- Info & Metrics
- eLetters