Enhancing solubility by disrupting crystal packing

Drug candidates can be classified, according to the BCS system, into four groups on the basis of their permeability and aqueous solubility.  Molecules with lower solubility tend to be more difficult to develop and are subject to closer scrutiny by regulatory bodies (e.g. FDA).  Whilst formulation can address solubility deficits to an extent, designing clinical candidates with sufficient intrinsic solubility is generally preferred.  The most widespread approach to improving solubility within a compound class relies on the introduction of hydrophilic groups in order to lower the  log P (which generally correlates with aqueous solubility).  However, this strategy is not always appropriate or possible and an alternative approach involves devising structural modifications which, by disrupting planarity and/or symmetry, lower crystal packing energies and reduce the energy barrier to dissolution in water.

The latter approach is the subject of a J.Med.Chem. perspective by authors from the University of Tokyo.  The paper describes some of their own work in the area and also reviews relevant examples from the literature.  The various examples are grouped according to the specific structural modification:

  • Removal of aromaticity
  • Increased dihedral angle/disruption of molecular symmetry  (see example below)
  • Introduction of substituents into benzylic position
  • Twisting of fused rings

The examples presented in this paper clearly demonstrate the utility of this approach and the importance of considering these types of molecular modifications alongside the more classical introduction of polar, solubilizing groups.

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6 Responses to Enhancing solubility by disrupting crystal packing

  1. milkshake says:

    One modification that is particularly helpful with poorly soluble kinase inhibitors is covering up acidic hydrogens, especially NH, and reducing the number of hydrogen bond acceptors, such as carbonyls and heteroaromatic nitrogens. In cases when one cannot replace NH with NMe (O, CH2 etc) for potency reasons, adding a small substituent to close vicinity may also help to disrupt the hydrogen bonding that is often responsible for kinase “brick dust” compounds.

    Another common reason why polyaromatic compounds form strong crystalline structure is pi-stacking. Charge transfer complex is most stable when electron deficient ring can stack with electron rich aromatic partner, for example trinitrobenzene with naphthalene. So if you have a poorly soluble molecule with two distant aryl parts, one aryl has strongly-electron donating substituents and the other one is electron deficient, it is possible that that the molecules like to form strong chain-like intermolecular pi-stacking arrangements in crystal structures based on charge-transfer, and this will (similarly to intermolecular bonds) stabilize the crystal structure and thus lower the solubility. To make this interaction weaker, it is worth in such case to try to adjust the electron density in one part of the molecule, for example by a isosteric modifications of the substituents (swapping methyl and methoxy for chloro or cyano) in order to reduce the difference in electron density between the two parts of the molecule.

  2. mcb says:

    Thanks for the great comment milkshake.

  3. Needle Finder says:

    Milkshake: Very useful comments .
    One of the series that I worked on failed to progress because of very poor solubility. All the attempts including creation of spiro centers did not help. The main reason for this is the scaffold has HB Acceptor–HB donor–HB acceptor arrangement which is important for activity. Modifications of the scaffold distant from this motif were not helpful. Small molecule x-ray showed that the molecule exist as a dimer in the crystal lattice. We also tried different forumations including nanosuspension technology, but nothing worked. Finally, we abondoned the chemical series. So in my opinion, getting an early undestrstanding of crystal packing is very importnat.

  4. Anonymous says:

    sir have u any molecule example who’s ADMET properties is enchanced by structure modification.if yes then please send me the name of that compound or molecule if u can


  5. Pingback: Improving Solubility using X-ray crystal structure data | MedChemBuzz

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