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1521-0081/65/1/315499$25.00
http://dx.doi.org/10.1124/pr.112.005660PHARMACOLOGICAL REVIEWS
Pharmacol Rev 65:315499, January 2013Copyright 2013 by The American
Society for Pharmacology and Experimental Therapeutics
ASSOCIATE EDITOR: ARTHUR CHRISTOPOULOS
Strategies to Address Low Drug Solubilityin Discovery and
Development
Hywel D. Williams, Natalie L. Trevaskis, Susan A. Charman, Ravi
M. Shanker, William N. Charman,Colin W. Pouton, and Christopher J.
H. Porter
Drug Delivery, Disposition and Dynamics (H.D.W., N.L.T., W.N.C.,
C.J.H.P.), Centre for Drug Candidate Optimisation (S.A.C.),and Drug
Discovery Biology (C.W.P.), Monash Institute of Pharmaceutical
Sciences, Monash University, Parkville,
Victoria, Australia; and Pfizer Global Research and Development,
Groton Laboratories, Groton, Connecticut (R.M.S.)
Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . 319I. Introduction . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . 319
A. What Is Low Drug Solubility? . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . 320B. Determinants of Aqueous Solubility . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . 323
1. Ideal Versus Nonideal Solubility . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . 323C. Hydrophobic or Lipophilic Drug Candidates? . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . 324D. Solubility of Electrolytes, Weak Electrolytes, and
Nonelectrolytes . . . . . . . . . . . . . . . . . . . . . . . 324E.
Solubility and Dissolution Rate. . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . 325F. Summary . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . 326
II. In Vitro Complexities of Working with Poorly Water-Soluble
Drugs . . . . . . . . . . . . . . . . . . . . . . . . . 326A. Drug
Precipitation, Adsorption, Binding, and Complexation in In Vitro
Assays . . . . . . . . . . 326B. Changes to Thermodynamic Activity
Resulting from Complexation, Binding,
or Solubilization . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . 327III. In Vivo Assessment of Poorly
Water-Soluble Compounds. . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . 328
A. Parenteral Administration . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . 3291. Complexities with Parenteral Administration
of Poorly Water-Soluble Drugs. . . . . . . . . 3292. Parenteral
Formulation Approaches for Poorly Water-Soluble Drugs . . . . . . .
. . . . . . . . . . 329
B. Oral Administration . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . 3311. Formulations to Support Drug
Discovery . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . 3312. Use of Enabling Formulations to
Promote Oral Absorption . . . . . . . . . . . . . . . . . . . . . .
. . . . 3333. Preclinical Toxicology Formulations . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . 3334. Development of Clinical Formulations for Poorly
Water-Soluble Drugs . . . . . . . . . . . . . . . 334
IV. Buffers and Salt Formation . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . 334A. Solution Behavior of Weak
Electrolytes and Their Salts. . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . 335
1. Ionic Equilibria . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . 3352. pH Solubility Relationships for
Weak Electrolytes and Salts of Weak Electrolytes . . . . 3353.
Factors Affecting Salt Formation at pHmax . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3374.
Determinants of Salt Solubility . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. 338
a. pHmax . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . 338b. Choice of Counterion to Maximize
Salt Solubility. . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . 338c. The Effect of Common Ions on Salt Solubility .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. 341d. Effect of Organic Solvents on Salt Solubility . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 342
B. pH adjustment Strategies for Addressing Low Drug Solubility .
. . . . . . . . . . . . . . . . . . . . . . . . . 3421. Buffered
Systems Used in Parenteral Formulations . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . 3422. Impact of
Cosolubilizers and Electrolytes on pH-Mediated Solubilization . . .
. . . . . . . . . . 343
a. pH Adjustment and Cosolvents . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
343b. pH Adjustment and Strong Electrolytes . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 344c.
pH Adjustment and Surfactants . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 344
Address correspondence to: Christopher J. H. Porter, Drug
Delivery, Disposition and Dynamics, Monash Institute of
PharmaceuticalSciences, Monash University, 381 Royal Parade,
Parkville, VIC, 3052, Australia. E-mail:
[email protected]
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d. pH Adjustment and Cyclodextrins . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3443. Effects of Dilution on Drug Solubilization by pH Adjustment .
. . . . . . . . . . . . . . . . . . . . . . . 345
a. Methods for Assessing Precipitation Potential for Buffered
Parenteral Formulations . 3464. Buffer Systems in Nonparenteral
Formulations. . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . 346
C. The Use of Salts to Address Low Aqueous Solubility in
Parenteral Formulations . . . . . . . . 347D. The Use of Salt Forms
to Address Low Aqueous Solubility in Oral Formulations . . . . . .
. . 347
1. The Use of Pharmaceutical Salts to Enhance Dissolution . . .
. . . . . . . . . . . . . . . . . . . . . . . . . 347a. Effect of
Self-Buffering on Salt Dissolution . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . 348b. Effect of pH
Changes on Drug Supersaturation and Precipitation. . . . . . . . .
. . . . . . . . 349c. Potential for Salt Conversion to Un-Ionized
Drug/Hydrates/Other Salt Forms In Situ 350d. Effect of Common Ions
on Dissolution in the Gastrointestinal Tract . . . . . . . . . . .
. . . 352
2. Physical Properties of Pharmaceutical Salts . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3533. Potential Toxicity of Pharmaceutical Counterions. . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 353
E. Feasibility of Salt Formation and Salt Selection Strategies.
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3541.
Salt Formation Feasibility . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . 3542. Salt-Screening Strategies . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . 355
F. Summary . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . 356V. Optimization of Crystal
Habit: Polymorphism and Cocrystal Formation . . . . . . . . . . . .
. . . . . . . . . 357
A. Polymorphs . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . 3581. Crystal Packing,
Polymorphism, and Phase Transformations . . . . . . . . . . . . . .
. . . . . . . . . . 3582. Effect of Polymorphism on Drug
Solubility, Dissolution Rate, and Oral Absorption . . . 359
B. Cocrystals . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . 3601. Cocrystals as a Mechanism
of Enhanced Drug Solubility and Dissolution . . . . . . . . . . . .
3602. Solubility Assessment of Cocrystals . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . 3623. Solubility Advantages of Cocrystals . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . 3634. Design and Preparation of Cocrystals . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . 3655. Recent Examples of Pharmaceutical Cocrystals for
Improving Solubility
and Bioavailability. . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . 366C. Summary . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . 367
VI. Cosolvents . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . 367A. Rationale for the
Use of Cosolvents for the Solubilization of Poorly Water-Soluble
Drugs 367B. Commonly Used Organic Cosolvents in Parenteral Drug
Delivery . . . . . . . . . . . . . . . . . . . . . . . 368C.
Solubilization by Cosolvents. . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . 369
1. Cosolvent Effects on Solubility Parameters . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3692. Predicting Solubility in Cosolvent Systems: The Log-Linear
Solubility Model. . . . . . . . . 370
D. Impact of Solubilizers and Electrolytes on Cosolvent-Mediated
Drug Solubilization . . . . . . 3721. Cosolvents and pH Adjustment
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . 3722. Cosolvents and
Surfactants . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3723.
Cosolvents and Cyclodextrins . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . 3724. Cosolvents and Strong Electrolytes. . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . 373
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 cancerresistant protein;
BCS, Biopharma-ceutical 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,
hydroxypropylmethylcellulose 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 for-mulations; 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; mdror 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-39-89-(aminomethyl)-19,29,49-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-a-tocopheryl
polyethylene glycol succinate;TRL, triglyceride-rich lipoprotein;
UWL, unstirred water layer; XRPD, X-ray powder diffraction.
316 Williams et al.
-
E. Effects of Dilution on Drug Solubilization by Cosolvents . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 374F.
Potential Pharmacological Properties of Cosolvents . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 374
1. In Vitro Assessment of Cosolvent Toxicity . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3742. Lytic Effects of Commonly Used Cosolvents . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
375
G. Summary . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . 375VII. Surfactants . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . 375
A. Rationale for the Use of Surfactants to Enhance the
Solubilization of PoorlyWater-Soluble Drugs . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . 375
B. Commonly Used Nonionic Surfactants in Drug Delivery. . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . 377C.
Solubilization by Surfactants . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . 378
1. Micelle Formation and Drug Solubilization . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3782. Quantification of Micellar Solubilization. . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. 3793. Effect of Surfactant Type and Structure on Drug
Solubilization . . . . . . . . . . . . . . . . . . . . . . 3804.
Effect of Temperature on Drug Solubilization. . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . 380
D. Impact of Cosolubilizers and Electrolytes on
Surfactant-Mediated Drug Solubilization . . . 3811. Surfactants and
Cosolvents . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3812.
Surfactants and pH Adjustment. . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3813. Surfactant Mixtures . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . 3824. Surfactants and Cyclodextrins . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . 3835. Surfactants and Strong and Weak
Electrolytes . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . 383
E. Effects of Dilution on Drug Solubilization by Surfactants . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 383F.
Potential Pharmacological Properties of Nonionic Surfactants . . .
. . . . . . . . . . . . . . . . . . . . . . . . 384
1. Toxicity . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . 3842. Pharmacokinetic Effects . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . 386
G. Summary . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . 387VIII. Cyclodextrins . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . 387
A. Rationale for the Use of Cyclodextrins in the Solubilization
of Poorly Water-Soluble Drugs. . 387B. Drug-Cyclodextrin Inclusion
Complexes . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . 389
1. Binding Equilibria between a Drug and Cyclodextrin . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . 3892.
Measurements of Drug-Cyclodextrin Binding Constants . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . 3903. Secondary
Equilibria: Micelles and Cyclodextrin Aggregate Formation . . . . .
. . . . . . . . . . 392
C. Drug Factors Affecting Complexation by Cyclodextrins. . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3931.
Size . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . 3932. Polarity and Charge . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . 3933. Presence of
Counterions . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
395
D. Impact of Cosolubilizers and Excipients on
Cyclodextrin-Mediated Drug Solubilization . . 3951. Cyclodextrins
and Water-Soluble Polymers . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . 3952. Cyclodextrins and
Cosolvents . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . 3963.
Cyclodextrins and Surfactants . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. 396
E. In Vivo Utility of Drug-Cyclodextrin Complexes in Parenteral
Formulations. . . . . . . . . . . . . 3961. Effect of Cyclodextrins
on Drug Pharmacokinetics after Intravenous Administration . 3962.
Effects of Dilution on Drug Solubilization by Cyclodextrins . . . .
. . . . . . . . . . . . . . . . . . . . . . 3973. Potential
Toxicological Properties of Parenterally Administered
Cyclodextrins. . . . . . . . 397
F. In Vivo Utility of Drug-Cyclodextrin Complexes in Oral
(Nonparenteral) Formulations . . 3981. Effect of Cyclodextrins on
Oral Drug Bioavailability . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . 3982. Oral Administration of Physical
Mixtures Versus Isolated
Drug-Cyclodextrin Complexes . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . 3993. Using Cyclodextrins to Stabilize Amorphous Drug . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3994.
Cyclodextrin Complexation as a Limitation to Oral Bioavailability .
. . . . . . . . . . . . . . . . . . 4005. Potential Toxicological
Properties of Orally Administered Cyclodextrins. . . . . . . . . .
. . . . 4016. Effect of Cyclodextrins on Membrane Transport and
Drug Metabolism . . . . . . . . . . . . . . . 402
G. Manufacture of Cyclodextrin Formulations . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. 4021. Parenteral Formulations . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . 4022. Solid Drug-Cyclodextrin Complexes . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . 402
H. Summary . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . 402IX. Particle Size Reduction
Strategies. . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 403
A. Particle Size Effects on Dissolution, Solubility, and In Vivo
Performance . . . . . . . . . . . . . . . . 404
Strategies for Low Drug Solubility 317
-
1. Effect of Particle Size on Dissolution Rate . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4042. Effect of Particle Size on Saturated Solubility . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4053. Effect of Particle Size and Shape on the Diffusional Layer
Thickness . . . . . . . . . . . . . . . . 405
B. Common Methods to Reduce Particle Size . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. 4061. Top-Down Particle Size Reduction . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . 406
a. Pearl Milling . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . 406b. High-Pressure Homogenization . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . 407
2. Bottom-up Nanoparticle Assembly . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
408a. Controlled Crystallization Via Solvent Shift . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 409b.
Precipitation after Solvent Evaporation . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . 410
C. Oral and Parental Delivery of Formulations Containing
Nanosized Drug Particles. . . . . . . 4111. Oral Delivery . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4112. Nanosuspensions for Parenteral Delivery of Poorly
Water-Soluble Drugs . . . . . . . . . . . . . 411
D. Summary . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . 415X. Solid Dispersions . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. 416
A. Classification of Solid Dispersions . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . 4171. Nontraditional Solid Dispersions . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . 419
B. Mechanisms by which Solid Dispersions Enhance Dissolution
Rate andOral Bioavailability . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . 4191. Reduced Particle Size and
Enhanced Drug Wetting and Solubilization . . . . . . . . . . . . .
. . 4192. Administration of Drug in the Amorphous Form. . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4213.
Maintenance of Supersaturation after Drug Dissolution . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . 421
a. The Impact of Dissolution Rate and Supersaturation Ratio
onPrecipitation Inhibition . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . 423
b. Mechanisms by which Polymers Maintain Supersaturation in
Solution . . . . . . . . . . . 423c. Screening for Potential
Polymer Precipitation Inhibitors. . . . . . . . . . . . . . . . . .
. . . . . . . . 425
C. Recent Examples of Bioavailability Enhancement Using Solid
Dispersions . . . . . . . . . . . . . . 426D. Role of the Carrier
and the Drug-Carrier Ratio in Dictating Drug Release Kinetics
from Solid Dispersions . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . 427E. Common Methods to Manufacture Solid
Dispersions . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . 429
1. Melting/Fusion . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . 4292. Solvent Evaporation . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . 4293. Solvent Evaporation
Using Supercritical Fluids . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . 4304. Electrospinning and
Microwave Irradiation. . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . 431
F. Physical Stability of Amorphous Solid Dispersions . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4311. Structural Changes at the Glass Transition Temperature. . . .
. . . . . . . . . . . . . . . . . . . . . . . . 4312. Glass-Forming
Potential . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4323.
Polymer Effects on the Glass Transition Temperature . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . 4334. Moisture
Effects on Glass Transition Temperature . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . 434
G. Factors Affecting Drug Crystallization from Solid
Dispersions. . . . . . . . . . . . . . . . . . . . . . . . . . .
4341. Drug-Polymer Intermolecular Association . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4352. Inhibition of Crystal Nucleation. . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . 4353. Molecular Mobility, Strength, and Fragility . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . 4364. Limitations to the Use of Thermal Analysis to Estimate
Molecular Mobility. . . . . . . . . . 4395. Drug-Polymer
Miscibility and Relationship to Drug Loading . . . . . . . . . . .
. . . . . . . . . . . . . . 439
H. Summary . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . 444XI. Lipid-Based Formulations.
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
445
A. Mechanisms of Bioavailability Enhancement by Lipid-Based
Formulations . . . . . . . . . . . . . . 4461. Stimulation of
Intestinal Lipid Absorption and Transport Pathways . . . . . . . .
. . . . . . . . . 4462. Enhanced Drug Dissolution and
Solubilization in the Intestinal Lumen . . . . . . . . . . . . . .
4503. Enhanced Intestinal Permeability and Inhibition of Intestinal
Efflux and
First-Pass Metabolism . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . 452a. Correlation of In Vitro Effects of Lipid-Based
Formulation Excipients on
Permeability with Changes to In Vivo Exposure?. . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . 4574. Promotion of
Lymphatic Drug Transport . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . 459
B. Design and Formulation of Lipid-Based Formulations. . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4611.
Lipid-Based Fomulations for Parenteral Administration . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . 461
318 Williams et al.
-
2. Lipid-Based Formulations for Oral Administration . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . 4633. The
Lipid Formulation Classification System. . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . 4644. Selection
of Lipid-Based Formulation Excipients . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . 465
a. Solvent Capacity . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . 466b. Mutual Miscibility. . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . 466c. Toxicity/Irritancy . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . 466d. Purity and
Chemical Complexity. . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . 467e. Capsule
Compatibility . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
467f. Polymers . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . 468
C. Assessment of Lipid-Based Formulations . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . 4681. In Vitro Dispersion Testing . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . 4682. In Vitro Digestion Models. . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . 4683. In Vivo Studies . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . 470
D. Summary . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . 471XII. Emerging Strategies for
Improving the Aqueous Solubility of Poorly Water-Soluble Drugs . .
. 472
A. Drug Adsorption to Microporous Adsorbents . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
472B. Solid Lipid Nanoparticles . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . 473
XIII. Conclusions. . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . 474Acknowledgments. . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . 475References . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . 476
AbstractDrugs with low water solubility are pre-disposed to low
and variable oral bioavailability and,therefore, to variability in
clinical response. Despitesignificant efforts to design in
acceptable developabil-ity properties (including aqueous
solubility) during leadoptimization, approximately 40% of currently
marketedcompounds and most current drug development candi-dates
remain poorly water-soluble. The fact that somanydrug candidates of
this type are advanced into develop-ment and clinical assessment is
testament to an increas-ingly sophisticated understanding of the
approachesthat can be taken to promote apparent solubility in
thegastrointestinal tract and to support drug exposure afteroral
administration. Here we provide a detailed com-mentary on the major
challenges to the progression ofa poorly water-soluble lead or
development candidate
and review the approaches and strategies that can betaken to
facilitate compound progression. In particular,we address the
fundamental principles that underpin theuse of strategies,
including pH adjustment and salt-formselection, polymorphs,
cocrystals, cosolvents, surfac-tants, cyclodextrins, particle size
reduction, amorphoussolid dispersions, and lipid-based
formulations. In eachcase, the theoretical basis for utility is
described alongwith a detailed review of recent advances in the
field.The article provides an integrated and contemporarydiscussion
of current approaches to solubility anddissolution enhancement but
has been deliberatelystructured as a series of stand-alone sections
to allowalso directed access to a specific technology (e.g.,
soliddispersions, lipid-based formulations, or salt forms)where
required.
I. Introduction
High hydrophobicity and intrinsically low water solu-bility are
increasingly common characteristics of hits,leads, development
candidates, and ultimately marketeddrugs. Many hypotheses have been
put forward as towhy these trends have emerged, and the true
explana-tion is clearly multifaceted. The application of
combi-natorial chemistries to generate large chemical librariesand
the common application of high-throughput screen-ing modalities,
often in nonaqueous media (or mixed-solvent media), have probably
played a role. The desirefor increased potency, coupled with the
realization thatreceptor binding is mediated, at least in part,
byhydrophobic interactions, further magnifies the likelihoodthat
drug candidates will have limited aqueous solubility.Finally, the
quest to explore unprecedented drug targets,some of which are
associated with intracellular signalingpathways, lipid processing
architecture, or highly lipo-philic endogenous ligands, only
amplifies the requirement
for highly lipophilic, poorly water-soluble drug candidatesto
access and interact with the target.
These drivers ultimately bias the identification ofpoorly
water-soluble hits during early drug screens.Poor water solubility
is a significant risk factor in loworal absorption because drug
molecules must, in mostcases, be in solution to be absorbed, and
oral bioavail-ability is usually a required characteristic in a
targetproduct profile of an orally administered medicine. Assuch,
medicinal chemistry strategies during lead opti-mization typically
seek to modify physicochemical pro-perties (including solubility)
such that drug leads havemore developable characteristics. Many
decision gates,or idealized character panels, are used to identify
andreject drug candidates with inappropriate
developabilityproperties and, subsequently, to synthetically
modifystructures to improve physicochemical characteristics.Perhaps
the best known of these is Chris Lipinskis ruleof 5 (Lipinski et
al., 1997), but there are many others.
Strategies for Low Drug Solubility 319
-
In all cases, however, at least moderate water solubilityis
usually a focus.Nonetheless, even with contemporary medicinal
chemistry programs and increasingly sophisticatedlead
optimization strategies, it is apparent that forsome targets,
reducing lipophilicity and increasingwater solubility will result
in an unacceptable reductionin potency. In spite of attempts to
circumvent solubilityproblems, approximately 40% of currently
marketeddrugs (Fig. 1) and up to 75% of compounds currentlyunder
development have been suggested to be poorlywater-soluble (Di et
al., 2009, 2011). Furthermore, theproblems of low water solubility
do not seem to bediminishing and may well be increasing (Takagi et
al.,2006). Low water solubility therefore continues to bea
challenge to successful drug development.This review seeks to
provide an overview of the
strategies that may be taken to address the problemsof low
solubility during drug discovery and develop-ment and includes a
comprehensive review of formu-lation approaches to support the
clinical developmentof oral and parenteral drug products for poorly
water-soluble drugs. In addition, even when lead optimiza-tion is
successful in increasing aqueous solubility, earlypreclinical
studies are still required with less thanoptimal leads to provide
the data sets to allow informedprogression or rejection; therefore,
we also address thestrategies that might be used when dealing with
thecomplexities of low solubility during the discoveryphase. In the
former case, at least for oral drug products,the market typically
dictates the need for traditionalsolid dosage forms (e.g.,
capsules, tablets). In the latter,where studies are usually
conducted in small animals(rodents), liquid formulations are often
used to alloworal dosing, and therefore a slightly different
ap-proach must be taken.
This review is structured to provide an initial andrelatively
brief introduction to the determinants of lowwater solubility to
provide the theoretical basis forthe approaches that might be taken
to address solu-bility challenges. We subsequently present
summarysections that outline potential strategies for
addressingsolubility issues, first in vitro and second in vivo,
withthe latter section addressing both parenteral and
oraladministration. Subsequently, we provide a compre-hensive
review of the technologies that can be used topromote solubility or
dissolution. These latter sectionsare necessarily dense and are
intentionally separatedfrom the higher-level strategy summaries
provided inthe introduction. The technology overviews providea
reference source for the summaries that precede them.A schematic
representation of each of these formulationapproaches is provided
in Fig. 2 and is intended tohighlight the variety of proven
strategies available tothose working with poorly water-soluble
drugs.
A. What Is Low Drug Solubility?
Although low water solubility of drug candidatespresents varied
and significant challenges throughoutdrug discovery and
development, the greatest concernis generally the risk of reduced
and variable absorp-tion after oral administration. The value at
whichlimited solubility begins to impact absorption isdifficult to
state definitively since it is dependent ona number of other system
variables, including drugpermeation, dose, and the environment
presentwithin the gastrointestinal (GI) tract. To understandthese
variables, and therefore, the factors that impactthe required
solubility for a drug candidate, it isinstructive first to
appreciate the drivers of flux across anabsorptive membrane since
these in turn will determinewhether the drug dose can be absorbed
over the timescaleavailable.
Assuming appropriate chemical and metabolic sta-bility and an
absence of transporter or carrier-mediatedprocesses, flux (F)
across an absorptive membrane is theproduct of the concentration
gradient and the perme-ability across the membrane and is described
as follows:
F5D K A
hCm 2C0 1
where Cm is the drug concentration immediatelyadjacent to the
membrane, C0 is the drug concentrationon the abluminal side of the
membrane, K is the par-tition coefficient between the aqueous
solution overlay-ing the membrane and the membrane itself, h is
thewidth of the diffusion layer, D is the diffusion coefficientof
the drug in the membrane, and A is the surface area.Assuming that
the drug concentration on the abluminalside of the absorptive
membrane is low relative to theconcentration at the absorptive site
(i.e., Cm .. C0), eq.1 can be simplified to the following:
Fig. 1. A comparison of the distribution of solubilities for the
top 200 oraldrug products in the United States (US), Great Britain
(GB), Spain, andJapan and from the World Health Organization (WHO)
Essential DrugList. Very soluble drugs: over 1000 mg/ml; freely
soluble drugs: 1001000mg/ml; soluble drugs: 33100 mg/ml; sparingly
soluble drugs: 1033 mg/ml;slightly soluble drugs: 110 mg/ml; very
slightly soluble drugs: 0.11 mg/ml;practically insoluble drugs:
,0.1 mg/ml. Adapted from Takagi et al. (2006).
320 Williams et al.
-
F5D K A
hCm 2
The values for D, K, and h are typically fixed fora particular
system and are used to define thepermeability coefficient (P)
where
P5D Kh
3
In the absence of supersaturation, the maximumconcentration that
can be attained at the surface of anabsorptive membrane is
equivalent to the equilibriumsolubility (Cs) of the drug, and
therefore the maximumflux (per unit area) (F) is the product of
solubility andpermeability:
F95P Cs 4Appreciation of this relationship illustrates that
knowledge of the solubility alone is insufficient toanticipate
whether solubility will limit flux (or absorp-tion) since flux is
also a function of permeability. Tosome extent, therefore, low
solubility can be offset byhigh permeability; similarly, if
permeability is low, therequirements for solubility to generate
appropriateflux increase.A well recognized approach applied in
early drug
discovery for estimating the required solubility andpermeability
needed to achieve good oral absorption isthe concept of a maximum
absorbable dose (MAD),
originally derived by Johnson and Swindell (1996) andfurther
applied by Curatolo (1998) and Lipinski (2000):
MAD 5 Cs kabs SIWV SITT 5
where Cs is the solubility (mg/ml) at pH 6.5 (represent-ing the
pH of the small intestine); kabs is the rateconstant (h21) for
intestinal absorption (which isrelated to the permeability); SIWV
is the smallintestinal water volume (in milliliters), which
istypically assumed to be ;250 ml (the volume of fluidassumed to be
present in the fasted GI tract aftera glass of water has been drunk
when takingmedication orally); and SITT is the small
intestinaltransit time (min) of ;270 min (4.5 h). Rearrangingthis
relationship provides an expression for thenecessary or target
solubility for a given dose and kabs(or permeability) and provides
an initial indication asto whether solubility is likely to limit
oral absorption.This concept is shown graphically in Fig. 3, the
datafrom which are taken from a seminal review thatshows the
theoretical required solubility to providegood oral absorption for
drugs with projected dosesranging from 0.1 to 10 mg/kg and
permeabilitiesranging from low to high. At one end of the
spectrum,highly potent drugs for which the dose is low and
themembrane permeability is high have relatively lowsolubility
requirements to achieve good oral absorp-tion. At the other
extreme, low-potency drugs for whichthe dose is high and the
permeability is low need
Fig. 2. Schematic diagram illustrating the common strategies
currently used (and discussed in this review) to address low drug
solubility in drugdiscovery and development.
Strategies for Low Drug Solubility 321
-
considerably higher solubility for good oral absorption(by
several orders of magnitude in this example). Asa broad initial
estimation, and assuming moderatepotency (1.0 mg/kg) and moderate
permeability (kabs 51.0 h21), this approach indicates that where
aqueoussolubilities are ,50 mg/ml, problems associated withlow
water solubility might be anticipated. It is clear,however, that
the required solubility to support drugabsorption must be evaluated
in light of both thepotency (or dose) and the permeability
characteristics.It is also clear that at stages during the
developmentpathway, in particular during preclinical
toxicitytesting, exposure at doses considerably in excess ofthe
predicted clinical dose will be required, magnifyingthe need for
solubility support.A further application of the
solubility-permeability
relationship to oral drug absorption is the Biophar-maceutics
Classification System (BCS) (Fig. 4),originally developed by Amidon
et al. (1995), withsubsequent variations by others (Wu and Benet,
2005;Butler and Dressman, 2010; Chen et al., 2011). Theprinciples
of the BCS are well described elsewhere(Amidon et al., 1995; Yu et
al., 2002; Dahan et al., 2009),but in brief, the BCS allows
classification of drugmolecules as a function of their solubility
and
permeability properties. Originally proposed to providea
scientific basis for biowaivers based on a correlation ofin vitro
drug dissolution and in vivo drug absorption,this classification
system has found much broaderapplicability across many areas of
drug discovery anddevelopment. According to the BCS, class I
moleculesare those having both high solubility and high
perme-ability (and therefore likely few problems with
oralabsorption); class II compounds are those that have
lowsolubility and high permeability (where solubility is theprimary
limitation to absorption); class III compoundshave high solubility
but low permeability (whereabsorption is limited by membrane
permeation andnot solubility); and class IV compounds are those
inwhich both poor solubility and poor permeability limitdrug
absorption. The focus of the current review istherefore BCS class
II compounds, which often exhibitsolubility-limited absorption.
Class IV compounds arealso relevant, although they have additional
prob-lems associated with low permeability.
Drug dose is also an important factor in the BCSbecause highly
soluble drugs are defined as those inwhich the highest dose will
dissolve in 250 ml overthe pH range of the GI tract (i.e., pH
16.8). Severalexamples of dose, solubility, and volume
requirements(taken from Amidon et al., 1995) are shown in Table
1.As with the MAD, these calculations are not designed tobe
definitive but rather illustrate that low-dose com-pounds, such as
digoxin, can have good absorption andbioavailability, even when GI
solubility is low, whereasthe absorption of high-dose compounds,
such as griseo-fulvin, is more often low, variable, and highly
formula-tion dependent as a result of their solubility
limitations.
A complication of the BCS definition of highsolubility is that
the highest strength dose must besoluble in 250 ml of water at all
pH values that mightbe encountered in the GI tract. Therefore,
drugs maybe classified as class II even though they have
goodsolubility at one end of this pH range. For example,many weak
acids have low solubility at pH 1 and arestrictly classified as BCS
class II compounds but arequite soluble at intestinal pH (pH 67)
and in manycases do not exhibit solubility-limited absorption.
Assuch, a BCS class II designation does not alwaysdictate that
solubility will be a limitation to absorption;rather, compounds in
this BCS class are more likely tobe solubility limited than are
those in class I. Indeed,
Fig. 3. The relationship between the projected dose and the
requiredaqueous solubility for low, medium, and high permeability
compounds.Permeability is indicated by the magnitude of the
absorption rateconstant (kabs), where low permeability, kabs 5 0.1;
medium 5 1.0, high 510 h21. From this analysis, moderately
permeable compounds (kabs 51.0 h21), with projected potencies of
1.0 mg/kg, require aqueoussolubilities of ;52 mg/ml. Adapted from
Lipinski (2000).
TABLE 1Examples of dose, solubility, and volume requirements for
a range of poorly water-soluble drugs
Drug Dose Solubility Volume Required forComplete Solubilization
Absorption
mg mg/ml ml
Piroxicam 20 0.007 2857 Low, variableDigoxin 0.5 0.024 21
GoodGriseofulvin 500 0.015 33,333 Low, variableChlorthiazide 500
0.78 636 Reasonable
From Amidon et al. (1995).
322 Williams et al.
-
a more practical description of BCS class II may bedrugs that do
not have high solubility rather thanthose that have low solubility
since the classificationsystem specifically identifies compounds
that fall intoclass I and all those with solubilities below this
fallinherently into class II (or class IV if permeability isalso
low) (Fig. 4).The preceding discussion serves to illustrate
further
that low solubility is a somewhat arbitrary conceptwhen
assessing the likelihood that solubility will limitdrug absorption
and that additional knowledge of thelikely dose and membrane
permeability is inevitablyrequired to put a solubility value into
an appropriatecontext.
B. Determinants of Aqueous Solubility
A detailed description of the thermodynamic deter-minants of
drug solubility in aqueous media is beyondthe scope of the current
discussion; for more informa-tion, the interested reader is
directed to the followingreferences: Grant and Higuchi (1990),
Yalkowsky (1999),and Murdande et al. (2010a). An overview of the
broadphysicochemical drivers of drug solubility is war-ranted,
however, since these drivers underpin theapproaches that can be
taken to enhance solubility.Simplistically, the potential for a
drug (solute) to passinto solution in an aqueous fluid (solvent) is
dictated bythree separate events, as shown in Fig. 5. First,
solutemolecules must be abstracted from the solid state,a process
that involves breaking solute-solute bonds.The strength of
solute-solute attractive forces in dif-ferent solids varies
significantly and is typically higherfor electrolytes than for
nonelectrolytes (since ionicattractive forces in the solid state
are stronger thannonionic forces), for crystalline solids compared
withamorphous materials, and for planar nonelectrolytes(which pack
more effectively in the solid state)
compared with nonplanar molecules. The melting pointprovides a
reasonable indication of the strength of in-termolecular
solute-solute interactions in the solidmaterial. Second, a void
must be created in the solventthat is sufficient to accommodate the
abstracted solutemolecule. Since intermolecular forces in the
liquidstate are much lower than those in the solid state, theenergy
required to create a void in the solvent is lowand is usually
ignored when assessing energy changesduring dissolution. Finally,
the solute molecule isinserted into the solvent void. For molecules
with someaffinity for a polar solvent such as water, this process
isenergetically favorable and therefore drives drug solu-bility.
This last concept is the rationale behind the oftenquoted maxim
like dissolves like. This is largely true,but it captures only half
the story since it ignores theimpact of changes to solid-state
properties on solubility.Since the energy transitions associated
with changesto solvent structure are small, it is apparent that
thereare two primary determinants of drug solubility: 1) theenergy
required to overcome the strength of intermo-lecular forces in the
solute solid state and 2) the energygenerated on the interaction of
solute and solventmolecules in solution (solvation)
For an analogous structural series, solubility istherefore
generally lower for molecules that havehigher melting points
(stronger attractive forces) andlower affinity for water (poor
solvation).
1. Ideal Versus Nonideal Solubility. Solubilitytheory defines an
idealized condition or an ideal solu-tion, where the intermolecular
forces between soluteand solvent are equivalent to those between
solute andsolute and those between solvent and solvent. Underthese
circumstances, the mixing of solute and solventmolecules in the
liquid state results in no net energy
Fig. 4. Diagrammatic representation of the BCS, which classifies
drugsaccording to their permeability and solubility properties.
Compounds aredefined as high solubility when the quantity of drug
that is present inthe highest strength immediate release dose form
is soluble in 250 ml ofwater across the likely range of
gastrointestinal pH (1.27.5). Highlypermeable compounds are defined
as those that are .90% absorbedor where permeability as assessed by
in vitro or in vivo methods isequivalent to or higher than that of
a reference compound that is 90%absorbed. Adapted from Amidon et
al. (1995).
Fig. 5. Three essential steps are required for a solute drug
molecule to bedisplaced from a solid particle and to enter
solution. Step 1: A singlesolute molecule is removed from the
crystal lattice; energy is required inthis step to overcome
solute-solute interactions in the solid state. Step 2:A void is
created within the solvent to accommodate the solute
molecule.Although this step also requires energy, it is likely to
be considerablylower than the energy required in step 1. Step 3:
The solute moleculeinserts into the solvent, forming solute-solvent
interactions. Simplisti-cally, if the energy released from the
solute-solvent interactions (i.e., step3) is greater than the
energy required for steps 1 and 2, solubility isfavored.
Strategies for Low Drug Solubility 323
-
change. Where this is the case, solubility is dependenton the
strength of the solute crystal lattice and may bedefined by
logX52DHf
2:303R
Tm 2TTmT
6
where X is the ideal mole fraction solubility of solute,DHf is
the enthalpy of fusion of solute, Tm is solutemelting point, T is
the absolute temperature, and R isthe gas constant.In reality,
ideal solutions are highly unusual, and
solution conditions close to ideality exist pharmaceu-tically
only in solutions of highly lipophilic drugs innonaqueous (lipidic)
solutions. In contrast, in aqueoussolution, the differences between
solute-solute inter-actions and solute-solvent interactions are
highly sig-nificant, leading to nonideal solution behavior andmuch
lower solubility than would otherwise be pre-dicted. In this case,
the difference between ideal andnonideal behavior is captured by a
correction factortermed the activity coefficient (g), where
logX52DHf
2:303R
Tm 2TTmT
2 log g 7
In turn, the activity coefficient is a function of themolar
volume of the solvent (Vs), the volume fraction ofthe solute (w1),
and the difference in the solubilityparameters for the solvent (d1)
and solute (d2):
log g 5Vsw21
2:303RTd1 2 d22 8
The solubility parameters provide a measure of thecohesive
forces in either solute or solvent, and from eq. 8,it is evident
that smaller differences between thesolubility parameters of the
solvent and solute give riseto lower activity coefficients and,
therefore, an increasein solubility toward ideality (i.e., d1 5 d2)
(Rubino, 2002).The solubility equation (eq. 7) captures the
determi-
nants of solubility as dictated by changes to the solid-state
properties of a drug (and usually manifest bychanges to melting
point) and the activity coefficient(reflecting differences between
the solubility parame-ters), and it reiterates the importance of
solute-soluteinteractions in the solid state and the need to
minimizedifferences between solute and solvent properties
tomaximize solvation (i.e., like dissolves like). Theseprinciples
underpin all the approaches to solubilityenhancement that are
subsequently described in thisreview, as each of these approaches
either change solid-state properties or change the nature of the
interactionbetween drug (solute) and solvent molecules.
C. Hydrophobic or Lipophilic Drug Candidates?
An understanding of the primary drivers of drugsolubility allows
an important distinction to be made
between poorly water-soluble drugs that are limited
bysolid-state properties (e.g., the strength of the
crystallattice), those that are limited by solvation (i.e.,
solute-solvent interactions in solution), and those that arelimited
by both. In practice, most compounds fall intotwo categories since
almost all poorly water-solublecompounds have limited affinity for
water (i.e., they arehydrophobic) and are therefore
solvation-hydrationlimited. Where compounds are hydrophobic and
alsoshow strong intermolecular forces in the solid state,they are
typically poorly soluble in both aqueous andnonaqueous solvents. In
contrast, hydrophobic mole-cules, in which solubility is not
limited by solid-stateproperties, often show varying degrees of
solubility innonaqueous solvents such as lipids (since the
molecularproperties that reduce hydration in aqueous media
oftenpromote solvation in nonaqueous media). The lattercompounds
are therefore both hydrophobic and lipo-philic, with the former
simply being hydrophobic. Thedifference between these two types of
molecules can beillustrated using the analogies of brick dust for
hydro-phobic molecules with poor solubility in all solvents
andgrease balls for compounds that are hydrophobic andlipophilic
and show reasonable solubility in lipids (Stellaand Nti-Addae,
2007). This distinction is importantsince the formulation options
available for eitherhydrophobic or lipophilic compounds differ
considerably.Simplistically, the increased lipid solubility of
lipophilicdrug candidates allows access to liquid surfactants
andlipid-based delivery technologies that can be filled intosoft
gelatin capsules (or sealed hard gelatin capsules),whereas the lack
of solubility for hydrophobic moleculesin almost all vehicles
precludes formulation in anythingother than modified solid dosage
forms.
D. Solubility of Electrolytes, Weak Electrolytes,and
Nonelectrolytes
The solvation properties of drug molecules, andtherefore a
significant part of the driving force for drugsolubility in aqueous
media, are highly dependent on theextent of ionization. The
presence of a charged functionalgroup provides an opportunity for
favorable ion-dipoleinteractions with polar solvents such as water,
whichdirectly enhance hydration and water solubility.
Strongelectrolytes (such as NaCl) that completely dissociate
inwater are generally highly water soluble. This is notalways the
case, however, as solubility remains a com-posite function of the
energy required to break thecrystal lattice versus the energy
liberated on hydrationof the ions formed. In some extreme cases,
for example,an inorganic salt such as AgCl, the crystal lattice
energyis sufficiently high that aqueous solubility remains low.As a
strong electrolyte, therefore, dissociation of AgClmolecules in
solution is complete, but as a poorly water-soluble strong
electrolyte, solubility is limited.
In reality, most drugs are organic materials that areeither
nonelectrolytes (which do not dissociate to form
324 Williams et al.
-
ionic species in water) or weak electrolytes thatdissociate only
partially in water such that both un-ionized solute and the
dissociated ions are present insolution.The solubility of weak
electrolytes is highly de-
pendent on the degree of ionization (dissociation) sincethe
affinity of the ionized species for water is markedlyhigher than
that of the un-ionized species. The degreeof dissociation is in
turn dependent on the pKa of theweak electrolyte and the pH of the
solution into whichit is dissolving. Simplistically, at pH values
above thepKa of a weak acid and below the pKa of a weak
base,solubility increases significantly as a result of ioniza-tion.
For weak acids and bases with a single ionizablegroup, solubility
increases by a factor of 10 for every pHunit away from the pKa
(although this trend does notcontinue indefinitely and solubility
is ultimatelylimited by the solubility product of the salts that
areformed in situ with available counterion; see SectionIV).
Nonetheless, optimization of solution pH is aneffective means by
which solubility can be enhancedand is commonly used to enhance the
solubilityproperties of solution formulations for weak
electro-lytes. For solid dosage forms, the principles of
pH-dependent solubility may be manipulated by theisolation of a
drug (or drug candidate) as an appropri-ate salt form. The use of
pH and salt selection toenhance solubility and the dissolution rate
is describedin more detail in Section IV. For
nonelectrolytes,solubility behavior is not complicated by the
effects ofionization and remains a function of hydration and
thestrength of the crystal lattice.
E. Solubility and Dissolution Rate
The solubility of a drug in aqueous solution isa fundamentally
important property that affects notonly the potential for drug
absorption after oraladministration and the ability to administer
the drugparenterally but also the ease of manipulation andtesting
in the laboratory and during manufacture.However, drug solubility
is an equilibrium measureand the rate at which solid drug or drug
in a formula-tion passes into solution (i.e., the dissolution rate)
isalso critically important when the time available fordissolution
is limited. This rate is particularly relevantafter oral
administration since intestinal transit timeis finite and the rate
of drug dissolution must sig-nificantly exceed the rate of transit
for absorption to bemaximized. For example, the absorption of a
drug withreasonable solubility may still be poor if the rate
ofdissolution is low since the solubility limit may neverbe reached
during the intestinal transit time. Simi-larly, even where the rate
of dissolution is relativelyrapid, if the equilibrium solubility is
low, the quantityof drug available in solution for absorption is
unlikelyto support rates of flux across the intestine that
aresufficient to absorb the entire drug dose in the time
available. For different drugs, and under
differentcircumstances, either solubility or dissolution rate
(orboth) may be the limiting feature.
The process of drug dissolution from the solid state
issummarized in Fig. 6. An unstirred water layer ispresent on the
surface of every dissolving solid andprovides the barrier to drug
equilibration with the wellstirred bulk solution. The dissolution
rate is thereforedefined by the rate at which drug diffuses across
theunstirred water layer, and the equations that describedrug
dissolution (i.e., the Noyes Whitney Equation, eq.9) are analogous
to simple diffusion equations. The rateof transfer across the
unstirred layer is a function of theconcentration gradient across
the unstirred layer, thewidth of the diffusion layer (h), the
surface area ofcontact of the solid with the dissolution fluid (A),
andthe diffusion rate of the drug in water (D). Theconcentration
gradient in turn is a function of themaximum drug concentration at
the surface of thedissolving solid (drug solubility Cs) and the
concentra-tion in the well-stirred bulk (C) (Noyes and
Whitney,1897):
dcxdt
5D Ah
Cs 2C 9
If we assume sink conditions where the concentra-tion of drug in
bulk solution (C) is low relative to theconcentration on the
surface of the dissolving solid (Cs),then this relationship
collapses to
dcxdt
5D Ah
Cs 10
Fig. 6. Graphic depicting the process of drug dissolution from a
soliddrug particle. An unstirred water layer of width (h) is
present on thesurface of the dissolving solid. A concentration
gradient is establishedacross the unstirred water layer that drives
dissolution and results fromthe difference in drug concentration
between that on the surface of thedissolving solid (usually assumed
to be the equilibrium solubility of thedrug, Cs) and the
concentration in the well stirred bulk (C).
Strategies for Low Drug Solubility 325
-
For most small molecules, the diffusion rate constantin water
(D) is relatively high and manipulation ofdrug structure does not
typically affect D to the extentthat it has a significant impact on
dissolution rate.Similarly, whereas the width of the diffusion
layer canbe altered by agitation or stirring in vitro, this
aspectcannot be easily manipulated in vivo.The major determinants
of in vivo drug dissolution
rate are therefore solubility and surface area. Sincesolubility
is a function of the strength of the crystallattice and the
affinity of the solute (drug) for theaqueous environment, three
major strategies can bedefined to increase the solubility or
dissolution rate(realizing that the dependence of dissolution
onsolubility dictates that increases in solubility inher-ently
increase the dissolution rate):
Reducing intermolecular forces in the solid state(increases
solubility and dissolution rate)
Increasing the strength of solute-solvent interac-tions in
solution (increases solubility and dissolu-tion rate)
Increasing the surface area available for dissolu-tion
(increases dissolution rate, potential to mod-erately increase
solubility at very small particlesizes (,1 mm)
F. Summary
Low aqueous solubility and reduced dissolutionrates are a common
property of many new drugcandidates, and these properties create a
number ofchallenges during drug discovery and development.An
understanding of the determinants of solubilityand dissolution
provides a framework from whichapproaches to enhance solubilization
may be devel-oped. In subsequent sections of this review, we
firstaddress the complexities of working with poorlywater-soluble
drugs in vitro and subsequently sum-marize the approaches that can
be taken to assist inthe development of both parenteral and oral
formula-tions. The main body of the review follows andprovides a
detailed account of the technologicalapproaches that can be taken
to support the de-velopment of effective formulations for poorly
water-soluble drugs. Comment is made as to the manydifferent
approaches that might be taken during leadoptimization and
preclinical development and alsothose strategies that are also
appropriate for exten-sion into clinical development and ultimately
to themarket. To constrain the scope of this review,
syntheticmedicinal chemistry approaches to solubility manipula-tion
are not addressed and the discussion is limited toapproaches that
do not result in the generation ofa fundamentally new chemical
entity. For more in-formation on approaches to solubility
manipulation viastructural modification, the interested reader is
directedto the following reviews: Fleisher et al. (1996), Stella
and
Nti-Addae (2007), Di et al. (2009), Keseru and Makara(2009), and
Ishikawa and Hashimoto (2011).
II. In Vitro Complexities of Working with PoorlyWater-Soluble
Drugs
Despite the drive to identify drug-like leads withacceptable
physicochemical properties, lead series areoften plagued by poor
aqueous solubility. The basis forthis trend was discussed earlier
in this introduction,but regardless of the source, working with
inherentlypoorly water-soluble compounds creates a number
ofchallenges throughout drug discovery, beginning withprimary
activity screens and progressing through tosecondary in vitro
assays and in vivo assessment.
In many in vitro assays, there is little scope for im-proving
solubility given the poor tolerability of many invitro biologic
test systems for solubilizing components.In this instance, the
focus must be on understandingthe consequences of simple solution
preparation andmanipulation (e.g., dilution), appreciating the
poten-tially confounding effects of compound precipitation onassay
results, and grasping the impact of commonlyused buffer components
in dictating free compoundconcentrations in solution. The sections
that followhighlight some of the common problems associated withthe
in vitro testing of poorly water-soluble compoundsand, where
available, approaches that can be taken toovercome, or at least
minimize, these issues.
A. Drug Precipitation, Adsorption, Binding, andComplexation in
In Vitro Assays
Beyond the realms of chemical synthesis, most invitro
evaluations of compound performance are con-ducted using
aqueous-based biologic buffers and re-lated media. The range of in
vitro testing protocols is,of course, broad but might include
binding or displace-ment assays, enzyme inhibition studies,
activity screen-ing in cell culture, traditional organ-bath
pharmacology,assessment of uptake and transport in cell
culturesystems, or excised tissues and metabolic stabilitystudies
using microsomes or hepatocytes. In all cases,an accurate knowledge
of the concentration of drug insolution is required as it is
critical to the determinationof the experimental endpoint. For
example, most invitro assays of drug activity are based on a
concentra-tion-response relationship, with the endpoint beingsome
measure of the inhibitory or effective concentra-tion (e.g., IC50
or EC50). In other assays, changes to drugconcentrations in
solution during the assay are used asan indicator of cellular
uptake or transport, metabolism,or binding, all of which rely on a
known concentration ofcompound in solution.
In most drug discovery settings, moderate- to high-throughput
assay formats (i.e., 96-, 384-, or 1536-wellplates) are used, and
compounds are introduced intoaqueous biologic media via dilution of
concentrated
326 Williams et al.
-
stock solutions prepared in water miscible organicsolvents, the
most common being dimethyl sulfoxide(DMSO). DMSO is an excellent
solvent for many poorlysoluble compounds, including those with
diversechemical structures, and allows for the preparation ofhighly
concentrated stock solutions for subsequentdilution for most
compounds. However, compoundprecipitation after dilution of
concentrated cosolventsolutions is common (see Section VI) and can
lead tovariable responses depending on how the dilution isconducted
and the composition of the final assaymedia. This in turn can lead
to a high degree ofvariability and inconsistent results between
assayswhere these variables may be different. Differentbiologic
assays also vary in their tolerance to the finalDMSO (or other
cosolvent) concentrations, making itdifficult to standardize
experimental conditions anddilution procedures across different
assay formats.For many in vitro assays (with the exception of
high-
throughput assays specifically designed to assesssolubility), it
may be difficult, if not impossible, todetect the presence of
finely precipitated material ondilution into aqueous media, and
measuring the finalconcentration of drug may be impractical.
Workingwith compounds with inherently low aqueous
solubilitiesgenerally limits the available range of drug
concentra-tions that can be used to define
concentration-dependentprocesses. Under these circumstances,
complete bindingor inhibition profiles may be difficult to define
since thesolubility limit is reached before saturation of
bindingsites or approach to maximal inhibition.Furthermore, the
physicochemical properties that
predispose compounds to low aqueous solubility canalso lead to
an association of drug molecule withhydrophobic environments and
surfaces. In fact, thisphenomenon is often a driving force for
biologic potencysince partitioning into and across cell membranes
andinteraction with cellular and molecular targets
arethermodynamically favored compared with residencewithin an
aqueous solution. However, these character-istics also lead to an
inherent propensity for non-specific adsorption to surfaces such as
tubes, pipettetips, filters, syringes, multiwell plates and
cellularsupports. Under these circumstances, a decrease indrug
concentration in solution may be reflective ofnonspecific
adsorption rather than binding, uptake, ortransport, artificially
reducing the concentration ofdrug in solution and leading to an
erroneous endpointdetermination if concentrations are assumed on
thebasis of only the dilution factor. Clearly, there areadvantages
to obtaining measured concentrations toprovide confidence in the
experimental results whenpractical and also to provide an assurance
of massbalance, which is a critical control measurement in anymass
transport experiment.The adsorption of drug to filter membranes
requires
special mention since separation of free drug from
bound, complexed, or precipitated drug is a commonprocedure
during the conduct of many in vitro assays.Assessment of the
potential for adsorption duringfiltration is an important
validation step but isparticularly critical for poorly
water-soluble drugs.Where significant adsorption is evident, and
unavoid-able, then it may be necessary to avoid the process
offiltration. Equilibrium dialysis may provide an alter-native
under such circumstances, but the potential foradsorption to the
dialysis membrane is also high. Afinal approach is to use
ultracentrifugation to separatelarger drug complexes from free drug
in solution, butthese measurements are time consuming,
requirespecialized equipment and a significant density differ-ence
between species, and ultimately still carry the riskof drug
adsorption to centrifuge tubes or plates.
Several different approaches can be taken to over-come issues of
adsorption. The first is the choice of tube,filter, culture flask,
multiwell plate, filter or pipette tip,as many manufacturers supply
materials with modifiedsurface properties to reduce nonspecific
adsorption. Itis important to appreciate the consequences of
usingdifferent surfaces as those specifically designed to,
forexample, promote cell adhesion by making them morehydrophobic,
will also increase the likelihood of non-specific drug adsorption.
In contrast, more hydrophilicsurfaces will generally reduce
adsorption by reducingthe thermodynamic favorability of drug
leaving thelargely aqueous solution environment. Another ap-proach
involves pre-exposing potential adsorptionsites to drug solution
with a view to saturating adsorptionbefore conduct of the
experiment. Finally, alteration ofthe solution properties can
reduce adsorption by in-creasing drug affinity for the bulk
solution and reducingthe effective partition coefficient between
solution anddrug adsorption sites. Most commonly, this is
achievedvia the inclusion of small quantities of a
cosolvent(depending on the sensitivity of the particular assay)
orby manipulating solution pH to increase
solute-solventinteractions in solution. The use of pH and
cosolvents toenhance solubility is described in more detail
inSections IV and VI, respectively.
Adsorption may also be reduced via the addition ofa complexation
or solubilization agent such as a sur-factant (see Section VII),
cyclodextrin (see SectionVIII), or protein. Although these
approaches are oftenhighly effective, they introduce a further
complexity,namely, changes to the chemical potential or
thermo-dynamic activity of free (unbound) drug in solution
asdiscussed in the following section.
B. Changes to Thermodynamic Activity Resultingfrom Complexation,
Binding, or Solubilization
The effective concentration of a species in solution ismost
accurately defined by its thermodynamic activity(a), which is
related to the concentration (C) and theactivity coefficient
(g):
Strategies for Low Drug Solubility 327
-
a 5 g C 11A detailed evaluation of thermodynamic activity
and
chemical potential is beyond the scope of this review,but in
simple terms, the effective concentration orthermodynamic activity
can be considered as the con-centration of drug in solution that is
unconstrained byinteraction with any other molecular species and
istherefore available to exert its effect, regardless ofwhether the
effect is to bind to a receptor or to diffuseacross a membrane. In
concentrated solutions, forexample, the close molecular proximity
of drug moleculesto each other may promote solute-solute
interactions(i.e., enhance intramolecular association), thereby
re-ducing thermodynamic activity. Under these circum-stances, the
activity coefficient is less than unity, andthe effective
concentration or activity is less than themeasured concentration.
In typical dilute solutions, thedegree of dilution is expected to
reduce solute-soluteintermolecular interactions in solution such
that eachmolecule effectively acts independently, and underthese
circumstances, the activity coefficient is unityand activity is
equal to concentration. This allows thedefinition of equilibrium
constants, for example, indilute solution using drug concentration
instead of thethermodynamically correct use of activities.The
relevance of this discussion to the in vitro
testing of poorly water-soluble drugs is that manystrategies
that promote drug solubility in aqueoussolution and assay media can
change the thermody-namic activity of the drug in solution. This is
mostreadily illustrated by considering the impact of theaddition of
a surfactant to an aqueous solution of drug.Surfactants are
amphiphilic molecules, and in aqueoussolutions, they can exist as
either monomers or asmicellar structures. As surfactant
concentrations areincreased above the critical micelle
concentration(CMC), the concentration of monomeric
surfactantremains constant while the concentration of
surfactantpresent as micelles in solution increases.
Surfactantmicelles typically enhance drug solubility by providinga
hydrophobic environment in the micellar core tosolubilize poorly
water-soluble drugs as they havea greater affinity for this
hydrophobic environment thanfor the surrounding aqueous environment
(see SectionVII). However, under this circumstance, the
thermody-namic activity of the drug is much lower than the
totalconcentration as the activity coefficient of the drug islower
than unity. In the case of drug solubilized ina surfactant micelle,
drug can be considered as existingin equilibrium between
solubilized drug within themicelle and free drug in an
intermicellar phase or bulksolution phase. Here, solubilized drug
is highly con-strained by the surrounding micellar structure, and
theeffective concentration (i.e., the thermodynamic activity)is
more accurately represented by the free (nonmicellar)concentration
of drug.
In addition to the use of surfactants, other commoncircumstances
where the thermodynamic activity ofa compound might be reduced
include the introductionof a complexation agent, such as a
cyclodextrin, or theaddition of plasma or serum proteins to
cell-basedassay media. For the latter situation, the so-calledserum
shift phenomenon is widely recognized where invitro activity
changes in response to changing concen-trations of serum present in
the media. For a morecomprehensive review of the effect of protein
bindingon the pharmacological activity of drugs and the
com-plexities of interpreting static (in vitro) versus dynamic(in
vivo) situations, the reader is referred to theexcellent review by
Smith et al. (2010). In each ofthese cases, the total concentration
of drug is signifi-cantly higher than the effective or free
concentration,and the situation is further confounded by the
difficultyin accurately quantifying free drug concentrations.
Incontrast, solubility enhancement through pH manipula-tion or
cosolvency will typically have limited impact onthermodynamic
activity of drug in solution.
III. In Vivo Assessment of PoorlyWater-Soluble Compounds
In vivo assessment of new drug candidates beginswith early in
vivo efficacy studies in animal models andcontinues through
pharmacokinetic and dose-limitingtoxicology studies in various
preclinical species andultimately into human clinical trials.
Preclinicalpharmacokinetic studies are heavily used to supporthuman
dose and pharmacokinetic predictions and,along with results from
toxicology studies, are used toselect a safe starting dose in
humans. For in vivoevaluations in animals, there are multiple
approachesthat can be used to facilitate i.v. administration and
toimprove exposure after oral dosing by the use ofenabling
formulations. However, there is always a riskthat early
incorporation of an enabling formulationapproach may shift the
focus away from structuraloptimization. Even in circumstances where
lead opti-mization strategies are successful in identifying
drugcandidates with improved solubility properties, it islikely
that at some stage during drug discovery therewill be the need to
assess less soluble early leads forintrinsic activity and proof of
concept efficacy to justifycompound or series progression.
A complication of poor aqueous solubility in the invivo
assessment of compounds throughout drug dis-covery and development
is that compound supply isfrequently limited (particularly in early
discovery), andmaterial that is available most likely will not have
thefinal, or optimal, solid-state properties. As compoundsprogress
through discovery and into development, thesolid-state properties
will almost certainly change;crystal forms will become better
defined, particle sizereduction may be introduced, and salt forms
will likely
328 Williams et al.
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become available for compounds with ionizable func-tional
groups. The timing at which these changes occurduring development
will impact early preclinical data,and this needs to be appreciated
and factored intostudy design and data interpretation.
A. Parenteral Administration
1. Complexities with Parenteral Administration ofPoorly
Water-Soluble Drugs. In comparison with thelarge number of drugs
intended for oral administration,parenteral formulations constitute
a more limited pro-portion of marketed products. However, the
generationof useful parenteral formulations remains a key
compo-nent of drug discovery and drug development for almostall
drug molecules (regardless of the intended route ofclinical
administration) since data obtained after i.v.administration is
necessary to generate fundamentalpharmacokinetic parameters (volume
of distribution,clearance, half-life, absolute bioavailability) to
supportcompound optimization and progression, and such dataare also
useful to support early stage pharmacodynamicassessment of drugs
intended for acute administration.Low aqueous solubility
significantly complicates the
development of i.v. formulations since, in almost allcases,
simple solution formulations are required. Thefollowing section
describes several different approachesthat can be used as i.v.
solution formulations, dependingon the physicochemical properties
of the drug and theintended use (e.g., animal or humans). Depending
onthe formulation strategy adopted, increases in solubilityof
several orders of magnitude are possible. The risksassociated with
i.v. administration of poorly water-soluble drugs include, first,
the potential for drugprecipitation on administration and, second,
the poten-tial for formulation components to cause pain,
phlebitis,inflammation, hemolysis, or unacceptable
toxicology.Precipitation is more likely for formulations where
pHadjustment or cosolvents form the basis for drug solu-bilization
since both are likely to be altered significantlyon dilution (see
Sections IV and VI). In contrast, sur-factant solubilization,
complexation, and i.v. emulsionsare far less sensitive to dilution
(see Sections VII, VIII,and XI). Where dilution-mediated
precipitation ispossible, slow administration into large veins,
wherethe blood flow is higher (and therefore the supply ofplasma
proteins and lipoproteins to provide in vivobinding is higher) is
preferred, and this can also reducethe possibility of pain on
injection, hemolysis, andphlebitis since the irritant component is
maximallydiluted. For studies in rats and dogs, this can
beaccomplished by implanting a dosing cannula into thejugular vein
(or another large vein) with administrationover a period of 5 to 10
min for rats and up to 30 min orlonger in dogs. In contrast,
administration into smallveins in the extremities (where blood flow
is muchslower), such as the tail vein in rodent models, and
rapidbolus injection, should be avoided with poorly water-
soluble drugs, if possible, because of the potential
forprecipitation. Addition of small quantities of
surfactants(,0.5%) or polymers may assist in preventing
pre-cipitation at the injection site.
Drug administration via other parenteral routes,including s.c.,
i.m., and i.p. administration, is onoccasion warranted,
particularly in proof-of-conceptbiology studies where there is
evidence of poor oralexposure resulting from solubility
limitations. Withnon-i.v. parenteral routes, the potential for the
routeand the formulation vehicle to have an effect (eitherdesirable
or undesirable) on the absorption profile isgreater, and depot
effects are often seen. For theseadministration routes, solution
formulations are stillpreferred since the volume of fluid at the
injection siteis low, and, therefore, dissolution of suspension
for-mulations may be limited. The lack of formulationdilution at
the injection site dictates that the range ofexcipients and
conditions to promote drug solubiliza-tion is even more limited
than it is after i.v. admini-stration. Ideally, non-i.v. parenteral
formulationsshould be as close as possible to physiologic pH,
andconcentrations of cosolvents should be minimized.
2. Parenteral Formulation Approaches for PoorlyWater-Soluble
Drugs. The most common approachesfor the development of parenteral
formulations forpoorly water-soluble drugs are summarized in
thefollowing discussion, and strategies for rapid identifi-cation
of the most appropriate approach are discussed.The acceptable
limits for each of these will depend onmany factors including the
species (animal or human),dose volume, rate of administration
(e.g., infusion orbolus), parenteral route (i.v., i.m., s.c.,
i.p.), and durationof treatment (Gad et al., 2006; Li and Zhao,
2007). Asummary of parenteral formulation approaches is givenin
Table 2, and these are briefly described as follows.
pH adjustment (see Section IV) is a powerfulmechanism by which
the solubility of weak acids andweak bases may be enhanced, but the
approach islimited by the pKa of the compound and the acceptablepH
range of the formulation. In this regard, acidicsolutions are
generally more readily tolerated than arebasic solutions, and
working pH ranges of 29 (Li andZhao, 2007) or 49 (Lee et al., 2003)
have beensuggested. The pH of parenteral solutions can
bemanipulated via the addition of small quantities ofstrong acids
or bases, such as HCl or NaOH but is moreusefully achieved via the
use of a buffer, generally withas low a buffer concentration as
possible while stillmaintaining the desired pH. Common buffer
systemsused in parenteral formulations include phosphate
andbicarbonate at neutral or slightly basic pH and citrate,lactate,
tartrate, acetate, and maleate for more acidicsolutions (Flynn,
1980; Kipp, 2007).
Cosolvents (see Section VI) are also commonly usedto promote
solubility in parenteral formulations, andethanol, propylene glycol
(PG), low-molecular-weight
Strategies for Low Drug Solubility 329
-
polyethylene glycol (PEG 300 or 400), dimethylaceta-mide (DMA),
and DMSO have been used. Combina-tions of cosolvents provide
benefits since cosolvency isadditive, whereas toxicity is often
dependent on theparticular solvent.In many cases, judicious
manipulation of solution pH
in combination with cosolvents is sufficient to
providesolubilization and is typically viewed as the
first-lineapproach. For example, in a review of 317
discoverycompounds, Lee et al., (2003) reported that .90%
ofcompounds could be formulated using pH and cosol-vents and that
.60% of these could be formulatedusing cosolvent levels of less
than 50% v/v.However, where pH adjustment and cosolvents fail
to provide the required solubility, alternative approachesmust
be used. Second-tier approaches include the use ofcyclodextrins,
surfactants, and lipid emulsions and,ultimately, more complex
formulations such as lip-osomes, microemulsions, or
nanosuspensions. Formore complex systems, however, the potential
effect,either positive or negative, on systemic clearance
anddistribution (and also absorption for non-i.v. paren-teral
formulations) should be carefully considered.Surfactants (see
Section VII) can also be used to
enhance drug solubility via micellar solubilization.Surfactants
are generally limited to those that arenonionic because of their
more favorable safety profileand may include polysorbates (e.g.,
Tween 80), Cremo-phors (including Cremophor EL and RH40),
SolutolHS-15 (BASF Corporation, Washington, DC), vitamin E
TPGS, and poloxamers (Pluronics, including PluronicF68; BASF
Corporation). Whereas surfactants providefor relatively robust
solubilization, a complexity is thegrowing realization that many
surfactants can affecttransport processes, such as cellular efflux,
and mayalso result in significant adverse effects,
includinghypersensitivity reactions (Gelderblom et al., 2001;
tenTije et al., 2003). Cremophor EL, in particular, seems topromote
an immune reaction in some species (mostnotably dogs) when
administered parenterally. Surfactantsbring additional complexities
to data interpretation and,where possible, might usefully be
avoided in favor of pHchanges, cosolvents, or the use of
cyclodextrins.
Complexation agents (see Section VIII), such ascyclodextrins,
provide a mechanism for enhancingsolubility for many drugs and have
been increasinglyused as modified cyclodextrins, such as
hydroxypropyl-b-cyclodextrin (HP-b-CD) and
sulfobutylether-b-cyclo-dextrin (SBE-b-CD), have become more cost
effective.HP-b-CD and SBE-b-CD have higher aqueous