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Drugs as materials: valuing physical form in drug discovery

Nature Reviews Drug Discovery volume 3, pages 926–934 (2004)Cite this article

Key Points

  • The principles of materials science have been applied in many areas of chemistry, but have not found general application in the discovery and development of active pharmaceuticals ingredients (APIs). There is now a growing understanding of the importance of solid-state and physico-chemical properties of APIs in influencing their acceptability as marketable drugs.

  • Until now, medicinal chemists have not had at their disposal the means to explore and evaluate physico-chemical properties of drug candidates in a time frame consistent with the turnaround of other assays for potency, selectivity and metabolism that are used in structure–activity calculations.

  • The development of high-throughput experimentation (HTE) platforms to rapidly create and characterize solid-state forms and formulations of APIs using very small amounts of compound opens up opportunities for co-optimizing not only potency and selectivity but physical properties during the lead optimization process.

  • These HTE techniques can provide valuable information to the scientists responsible for formulation design and scale up of chemical and pharmaceutical processes.

  • In addition, the information accumulated on crystal forms provides added intellectual property to protect the active moiety.

Abstract

Traditionally, potency and selectivity (and to some extent metabolism) have been the key parameters to consider in the process of discovering new drug candidates. Recently, heads of research and CEOs have been learning a new reality: drugs can move around the body and act at the molecular level, but the chemical and material properties of their physical form need to be identified and optimized for in vivo performance, reliable manufacture and the protection of intellectual property. This review discusses the challenge of pharmaceutical materials discovery, and suggests strategies for addressing the characterization and evaluation of physico-chemical and material properties in the drug discovery and development process.

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Figure 1: Schematic representation of different types of physical form of active pharmaceutical ingredients.
Figure 2: Process formulation.
Figure 3: Influence of high-throughput experimentation technology on improving the lead optimization process by co-optimizing multiple dimensions, including physical and material properties.
Figure 4: Interplay between compound solubility and the evaluation of biological activity, absorption, distribution, metabolism, excretion and toxicity parameters.
Figure 5: Decision tree for incorporating physico-chemical data into the drug discovery process.

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Acknowledgements

The authors acknowledge helpful discussions with the scientists at TransForm Pharmaceuticals and several large pharmaceutical companies.

Author information

Authors and Affiliations

  1. TransForm Pharmaceuticals Inc., 29 Hartwell Avenue, Lexington, 02421, Massachusetts, USA

    Colin R. Gardner & Örn Almarsson

  2. Harvard Medical School, Room 301 LHRRB, 240 Longwood Avenue, Boston, 02115, Massachusetts, USA

    Christopher T. Walsh

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  3. Örn Almarsson
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Corresponding author

Correspondence to Colin R. Gardner.

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Competing interests

C.R.G. and O.A. are emloyees of TransForm Pharmaceuticals, Inc.

C.T.W. is on the Board of Directors of TransForm Pharmaceuticals, Inc.

All three authors hold stock options in TransForm Pharmaceuticals, Inc.

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FURTHER INFORMATION

Avantium

Avantium Solid-State Chemistry

Symyx Technologies

TransForm Pharmaceuticals

Glossary

STRUCTURE–ACTIVITY RELATIONSHIPS

Correlations that are constructed between the features of chemical structure in a set of candidate compounds and parameters of biological activity, such as potency, selectivity and toxicity.

POLYMORPH

A compound of a defined chemical composition that exists in more than one molecular arrangement and/or conformation in the solid state.

ACHLORHYDRIA

Condition of relative absence of hydrochloric acid (HCl) from gastric juice (common in dogs due to pulsatile secretion of HCl in their stomachs, as well as in humans as a result of disease or age) that can have a dramatic effect on oral absorption of weak base compounds.

HIT

A compound, form or formulation satisfying an initial set of criteria (for example, minimum potency and solubility), but requiring elaboration or validation through further detailed analysis of performance or additional iterations.

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Gardner, C., Walsh, C. & Almarsson, Ö. Drugs as materials: valuing physical form in drug discovery. Nat Rev Drug Discov 3, 926–934 (2004). https://doi.org/10.1038/nrd1550

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