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.

Strategies to Address Low Drug Solubility in Discovery and Development

Supersaturating Drug Delivery Systems: The Answer to Solubility-Limited Oral Bioavailability?

Manufacturing of solid dispersions of poorly water soluble drugs by spray drying: formulation and process considerations.

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Fundamental aspects of solid dispersion technology for poorly soluble drugs.

Evaluation of amorphous solid dispersion properties using thermal analysis techniques.

Spray-dried dispersions (SDDs) of low-solubility drugs have been prepared using the polymer hydroxypropyl methylcellulose acetate succinate (HPMCAS). For a variety of drug structures, these SDDs provide supersaturation in in vitro dissolution determinations and large bioavailability increases in vivo. In bile-salt/lecithin in vitro solutions, these SDDs provide amorphous drug/polymer colloids and an increased concentration of free drug and drug in micelles relative to crystalline or amorphous drug. As dry powders, the SDDs are a single amorphous phase in which the drug remains amorphous and dispersed and does not crystallize over storage times relevant for practical drug products. A melting temperature (Tm)/glass-transition temperature (Tg) (K/K) versus log P map for 139 compounds formulated as SDDs provides a perspective on an appropriate formulation strategy for low-solubility drugs with various physical properties.

http://pubs.acs.org/doi/pdf/10.1021/mp8000793

Hydroxypropyl methylcellulose acetate succinate-based spray-dried dispersions: an overview.

Disclosed are polymers of hydroxypropyl methyl cellulose acetate succinate (HPMCAS) and hydroxypropyl methyl cellulose acetate (HPMCA) with unique degrees of substitution of hydroxypropoxy, methoxy, acetyl, and succinoyl groups. When used in making compositions comprising a low-solubility drug and such polymers, the polymers provide enhanced aqueous concentrations and/or improved physical stability.

Pharmaceutical compositions with enhanced performance

A pharmaceutical composition comprises a solid amorphous dispersion comprising a low-solubility drug and a concentration-enhancing polymer and a lipophilic microphase-forming material. Alternatively, a solid amorphous dispersion comprising a low-solubility drug and a concentration-enhancing polymer is co-administered with a lipophilic microphase-forming material to an in vivo use environment.

Pharmaceutical Compositions of Amorphous Dispersions of Drugs and Lipophilic Microphase-Forming Materials

Pharmaceutical compositions comprise a low-solubility drug adsorbed onto a high surface area substrate to form an adsorbate. The compositions in some embodiments include a concentration-enhancing polymer.

Pharmaceutical compositions of adsorbates of amorphous drug

Solutions containing polymer/drug assemblies of a low-solubility drug and polymer are disclosed. In addition, solid aggregated polymer/drug assemblies are disclosed comprising a low-solubility drug and polymer.

Daniel Tod Smithey

Papers

Hydroxypropyl methylcellulose acetate succinate-based spray-dried dispersions: an overview.

Pharmaceutical compositions with enhanced performance

Pharmaceutical Compositions of Amorphous Dispersions of Drugs and Lipophilic Microphase-Forming Materials

Pharmaceutical compositions of adsorbates of amorphous drug

Pharmaceutical compositions containing polymer and drug assemblies