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Tactics in Contemporary Drug Design pp 69–106Cite as

Improving Solubility via Structural Modification

Part of the Topics in Medicinal Chemistry book series (TMC,volume 9)

Abstract

The examples and discussion presented in this review are intended to serve as resource for medicinal chemists engaged in the task of optimizing drug physical properties. A discussion of the factors governing aqueous solubility is presented followed by specific examples drawn from the recent literature. According to the general solubility equation (GSE), the factors involved in the solubility of a compound are represented by logP and melting point. Improved solubility can be accomplished by reducing logP or melting point by increasing polarity or disrupting intermolecular interactions in the solid state. Tactics for increasing polarity include introducing a solubilizing appendage onto the drug or modifying the template or attached substituents. The melting point of a compound can be lowered by disrupting specific intermolecular interactions or changing the topology or shape of the molecule.

Keywords

  • Crystal lattice stability
  • Enthalpy of solvation
  • Entropy of solvation
  • Fluorine
  • General solubility equation
  • Hydrogen bonding
  • Hydrophobicity
  • Matched molecular pairs
  • Melting point
  • Molecular planarity
  • Molecular symmetry
  • Packing efficiency
  • Solubilizing appendage
  • Solvation
  • X-Ray crystallography

An erratum to this chapter can be found at http://dx.doi.org/10.1007/7355_2014_71

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Notes

  1. 1.

    ΔH m, melting (fusion) enthalpy; ΔS m, melting (fusion) entropy.

  2. 2.

    Z, number of molecules per unit cell; V mol, molecular volume (Å3); V cell, unit cell volume (Å3).

Abbreviations

C k :

The Kitaigorodski packing coefficient

CSD:

Cambridge Structural Database

DGAT1:

Diacylglycerol O-acyltransferase 1

GSE:

General solubility equation

ICAM 1:

Intercellular adhesion molecule 1

MMP:

Matched molecular pair

mp:

Melting point

PDE:

Phosphodiesterase

PEG:

Polyethylene glycol

S1P1:

Sphingosine 1-phosphate receptor subtype 1

sol:

Solubility

SPT:

Scaled particle theory

T m :

Melting temperature

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  1. Department of Medicinal Chemistry, Bristol Myers-Squibb, 5 Research Pkwy, Wallingford, CT, 06492, USA

    Michael A. Walker

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    Nicholas A. Meanwell

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Walker, M.A. (2013). Improving Solubility via Structural Modification. In: Meanwell, N. (eds) Tactics in Contemporary Drug Design. Topics in Medicinal Chemistry, vol 9. Springer, Berlin, Heidelberg. https://doi.org/10.1007/7355_2013_32

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