4.1.4 Controlling Solid Form
Solid form control is the ability to select an appropriate morphology, structural
polymorph and physical properties for a particular formulation of a particular
compound and is one of the major challenges in pharmaceutical development.
Many approaches, including informatics tools, are used in an attempt to reduce the
risk of issues being found further along the development pipeline.
An example of one current direction is the use of multi-component systems
(co-crystals, solvates and hydrates) which are an increasingly important consideration in the formulation of active pharmaceutical ingredients [211] and are now
becoming available on the market. The void calculation functionality and visualisation of solvate and hydrate pockets or channels in Mercury led to the development of
the Hydrate and Solvate Analysers to understand the behaviour of these molecules in
crystal lattices. A study of molecular complementarity [212] used the CSD to
describe pairs of molecules that form co-crystals with each other in terms of their
calculated molecular properties. This has applications in the rational design of
co-crystals and the modification of solid form’s physical properties.
4.1.5 Crystallographic Data Driving Other Forms of Structure Solution
and Refinement
The experimental approach and large volumes of rich data that we have discussed
herein are founded in single-crystal X-ray diffraction analysis. While structure
solution from this technique has some problematic examples, it is largely well
understood, follows a well-trodden process, is universally accepted and has a ‘data
currency’. These factors are far from established in other techniques that probe the
solid state. For example, solid-state structure determination from powder diffraction,
pair distribution function, NMR crystallography and electron diffraction data are
inherently challenging. All of these techniques draw from and leverage data and
knowledge derived from acquisition of many single-crystal structures – from providing a starting point for refinement to imposing geometrical restraints/constraints
derived from many observations.
Ab initio structure solution from powder diffraction data has been relatively
widely possible for about 15 years and provides a good example of how acquired
data can be used to influence and inform the process. The other solid-state structure
determination approaches also use crystal structure data in much the same way – to
facilitate matching calculated and observed data. There are a number of structure
solution packages for analysing molecular structures from X-ray powder diffraction
data, e.g. EXPO [213], GEST [214], GSAS-II [215] and TOPAS [216], including
one provided by the CCDC [217], DASH [218, 219], which we use as an example
here. DASH is a graphical user interface-driven program for solving crystal structures from measured powder diffraction data. It uses a simulated annealing approach
to search for the global minimum in the agreement between observed and calculated
124
S. J. Coles et al.
Solid form control is the ability to select an appropriate morphology, structural
polymorph and physical properties for a particular formulation of a particular
compound and is one of the major challenges in pharmaceutical development.
Many approaches, including informatics tools, are used in an attempt to reduce the
risk of issues being found further along the development pipeline.
An example of one current direction is the use of multi-component systems
(co-crystals, solvates and hydrates) which are an increasingly important consideration in the formulation of active pharmaceutical ingredients [211] and are now
becoming available on the market. The void calculation functionality and visualisation of solvate and hydrate pockets or channels in Mercury led to the development of
the Hydrate and Solvate Analysers to understand the behaviour of these molecules in
crystal lattices. A study of molecular complementarity [212] used the CSD to
describe pairs of molecules that form co-crystals with each other in terms of their
calculated molecular properties. This has applications in the rational design of
co-crystals and the modification of solid form’s physical properties.
4.1.5 Crystallographic Data Driving Other Forms of Structure Solution
and Refinement
The experimental approach and large volumes of rich data that we have discussed
herein are founded in single-crystal X-ray diffraction analysis. While structure
solution from this technique has some problematic examples, it is largely well
understood, follows a well-trodden process, is universally accepted and has a ‘data
currency’. These factors are far from established in other techniques that probe the
solid state. For example, solid-state structure determination from powder diffraction,
pair distribution function, NMR crystallography and electron diffraction data are
inherently challenging. All of these techniques draw from and leverage data and
knowledge derived from acquisition of many single-crystal structures – from providing a starting point for refinement to imposing geometrical restraints/constraints
derived from many observations.
Ab initio structure solution from powder diffraction data has been relatively
widely possible for about 15 years and provides a good example of how acquired
data can be used to influence and inform the process. The other solid-state structure
determination approaches also use crystal structure data in much the same way – to
facilitate matching calculated and observed data. There are a number of structure
solution packages for analysing molecular structures from X-ray powder diffraction
data, e.g. EXPO [213], GEST [214], GSAS-II [215] and TOPAS [216], including
one provided by the CCDC [217], DASH [218, 219], which we use as an example
here. DASH is a graphical user interface-driven program for solving crystal structures from measured powder diffraction data. It uses a simulated annealing approach
to search for the global minimum in the agreement between observed and calculated
124
S. J. Coles et al.