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  • Review Article
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Crystal structures of drugs: advances in determination, prediction and engineering

Nature Reviews Drug Discovery volume 3, pages 42–57 (2004)Cite this article

Key Points

  • The crystalline form of a drug affects properties such as its solubility, stability, dissolution rate, bioavailability and tabletability, and so understanding the crystalline state is crucial for many of the activities of the pharmaceutical industry.

  • This article first discusses the fundamental concepts of the crystalline state, focusing on those relevant to the properties of pharmaceutical crystals.

  • Methods for determination of the crystal structure of pharmaceutical crystals are then described. In particular, recent advances in the use of computational approaches in crystal structure solution and prediction are highlighted.

  • Finally, the potential of crystal engineering to design novel pharmaceutical compounds with desired physical and mechanical properties is reviewed.

Abstract

Most marketed pharmaceuticals consist of molecular crystals. The arrangement of the molecules in a crystal determines its physical properties and, in certain cases, its chemical properties, and so greatly influences the processing and formulation of solid pharmaceuticals, as well as key drug properties such as dissolution rate and stability. A thorough understanding of the relationships between physical structures and the properties of pharmaceutical solids is therefore important in selecting the most suitable form of an active pharmaceutical ingredient for development into a drug product. In this article, we review the different crystal forms of pharmaceuticals, the challenges that they present and recent advances in crystal structure determination. We then discuss computational approaches for predicting crystal properties. Finally, we review the analysis of crystal structures in furthering crystal engineering to design novel pharmaceutical compounds with desired physical and mechanical properties.

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Figure 1: Influence of crystal structure on properties of polymorphs.
Figure 2: Fundamentals of crystal structure.
Figure 3: Types of racemate.
Figure 4: Application of the Monte Carlo method in crystal structure solution.
Figure 5: Application of the genetic algorithm (GA) method in crystal structure solution.
Figure 6: Application of the maximum entropy (ME) method to crystal structure solution.
Figure 7: Crystal engineering.

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Acknowledgements

We thank A. Sheth for kindly reviewing the manuscript and for his valuable suggestions.

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Authors and Affiliations

  1. Department of Pharmaceutics, College of Pharmacy, University of Minnesota, Weaver-Densford Hall, 308 Harvard Street SE, Minneapolis, 55455-0343, Minnesota, USA

    Sharmistha Datta & David J. W. Grant

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  1. Sharmistha Datta
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Correspondence to David J. W. Grant.

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FURTHER INFORMATION

Cambridge Crystallographic Data Centre

International Union of Crystallography

Glossary

PHASE TRANFORMATION

The transformation of a solid from one physical form to another. Phase transformation can involve the transformation of a single component into one or more components, and can result from changes in physical conditions, as in pharmaceutical processing. Examples of phase transformation include polymorphic transitions, crystallization of amorphous solids, and solid-state solvation and desolvation.

MOLECULAR ADDUCT

A crystal is termed a molecular adduct when its lattice consists of more than one chemical component.

SOLVATE

A solid phase that contains solvent molecules, in addition to molecules of the major component, in the crystal lattice.

HYDRATE

A solid phase that contains water molecules, in addition to molecules of the major component, in the crystal lattice.

HYDROGEN BOND

An attractive interaction between two electronegative atoms through a hydrogen bridge. The hydrogen bond is partly electrostatic and partly covalent in nature, with limited orbital overlap between the participating atoms. Of the two electronegative atoms, one is the proton donor and the other is a proton acceptor. When present within the same molecule, a hydrogen bond is termed intramolecular. When present between two molecules, a hydrogen bond is termed intermolecular.

SLIP SYSTEM

The term slip refers to the translational motion of lattice planes relative to each other. Such planes are termed slip planes. A family of slip planes, together with the slip direction, is termed a slip system.

ENANTIOTROPE

The members of a pair of polymorphs are termed enantiotropes when their mutual transition temperature is less than the melting point of either polymorph. Each enantiotrope has its own temperature range of stability.

MONOTROPE

The members of a pair of polymorphs are termed monotropes when they have no mutual transition temperature. One monotrope is always more stable than the other polymorph under all conditions in which the solid state can exist.

ISOLATED SITE HYDRATE

In an isolated site hydrate, the water molecules in the crystal lattice of the hydrate are isolated from direct contact with other water molecules by intervening molecules of the major component.

ION-ASSOCIATED HYDRATE

In an ion-associated hydrate, the water molecules in the crystal lattice of the hydrate are coordinated to certain ions (often metal ions).

CHANNEL HYDRATE

In a channel hydrate, the water molecules present in the crystal lattice of the hydrate lie next to other water molecules of adjoining unit cells, forming channels through the crystals along a direction in the lattice.

EXPANDED CHANNEL HYDRATE

An expanded channel hydrate can take up water into the channels when exposed to relatively high humidity and can release water from the channels when exposed to relatively low humidity. The crystal lattice can expand or contract as hydration or dehydration proceeds, changing the dimensions of the unit cell.

PLANAR HYDRATE

A planar hydrate is a channel hydrate in which water molecules are localized in a plane, corresponding to two-dimensional order.

SOLID SOLUTION

A solid solution can be substitutional or interstitial. A substitutional solid solution is a homogeneous crystalline phase in which some of the constituent molecules are substituted by foreign molecules that possess sufficient similarity that the lattice dimensions are changed only slightly. In an interstitial solid solution, the foreign molecules are inserted into interstitial positions, such that the lattice dimensions are changed only slightly.

IMPROPER ROTATION ELEMENT

A 360°/n rotation about an n-fold axis of improper rotation, followed by a reflection through a mirror plane perpendicular to the rotation axis.

SYNCHROTRON

An electron accelerator that uses synchronized magnetic fields. When the high-speed electrons are directed to collide with an appropriate target, high-energy X-ray radiation or ultraviolet radiation is produced.

MELT

When a solid is heated beyond its melting temperature, it fuses (melts) to produce a liquid that can be termed a melt.

EPITAXIAL GROWTH

The growth of one crystal on the surface of another crystal (the substrate), on which the growth of the deposited crystal is oriented by the lattice structure of the substrate.

CAPILLARY CRYSTALLIZATION

A specific crystallization technique in which the crystals nucleate and grow inside a capillary as a result of slow solvent evaporation.

SYSTEMATIC ABSENCES

The systematic absence of specific groups of reflections in a diffraction pattern of a crystal indicates the presence of certain symmetry elements and enables the crystallographic space group of the crystal lattice to be defined.

PATTERSON METHOD

The Patterson method employs the relatively large electron diffraction resulting from the presence of heavy atoms (atomic number >17) to determine the crystal structures of inorganic and organic compounds.

ISOMORPHOUS REPLACEMENT METHOD

In the isomorphous replacement method, a heavy atom is introduced into the crystal lattice without disrupting the original crystal structure. The new crystal obtained is known as the derivative crystal. The aim of isomorphous replacement is to obtain the structure of the original crystal by constructing a map (that is, a Patterson map) of the difference in electron density between the diffraction pattern of the derivative crystal and that of the heavy atom. This method is used to determine the crystal structures of proteins.

TAUTOMERISM

An equilibrium, usually under ambient conditions, of two isomers of a compound.

SPORANOX BEAD

An amorphous capsule that is used to achieve the required oral bioavailability of extremely water-insoluble drugs, such as itraconazole.

YOUNG'S MODULUS

A measure of a material's elasticity, which is defined as the force per unit cross-section of the material divided by the fractional increase in length that results from the stretching of a standard specimen of the material.

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Datta, S., Grant, D. Crystal structures of drugs: advances in determination, prediction and engineering. Nat Rev Drug Discov 3, 42–57 (2004). https://doi.org/10.1038/nrd1280

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