Strategies to Address Low Drug Solubility in Discovery and Development (2024)

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

• dx.doi.org/10.1124/pr.111.005660.

• 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 hom*ogenization

  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