9 Pharmaceutical Multicomponent Crystals: Structure, Design …
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exploited in pharmaceutical applications to increase the solubility of problematic
APIs. However, from a thermodynamic point of view, the amorphous state of a solid is
unstable and has the tendency to convert to its low-energy and more stable crystalline
form over time [18]. Therefore, the number of successful products available in this
solid form in the market is still limited.
Most marketed APIs, therefore, consist of crystalline solids. In contrast with
amorphous solids, crystalline materials consist of minimal building blocks called
unit cells that contain all the structural features and symmetry elements of the crystal
and are repeated regularly in three-dimensional space [19]. Furthermore, API crystalline molecules are typically amenable to form multiple crystal forms known as
polymorphs [20]. Organic molecules, including APIs, generate polymorphic crystals through two mechanisms. The first mechanism leads to so-called packing polymorphs, in which molecules with relatively rigid conformations can be assembled
into different three-dimensional structures. The second mechanism occurs when a
flexible molecule bends into different conformations to subsequently be packed into
alternative crystal structures [21]. Some polymorphic APIs have mixed mechanisms
and exhibit different packing and conformational polymorphs [22].
API crystalline molecules can also exist as multicomponent crystals by incorporating other molecules into the crystal lattice. “Pseudopolymorph” is the widely
accepted term for crystals with solvent molecules incorporated into their lattice [23–
25]. Hydrates are crystalline solid adducts that contain water molecules and are
known as the largest class of pseudopolymorps [4]. If a crystalline solid accommodates another solvent molecule than water, the solvate terminology is generally used
[26]. If a multicomponent crystal contains two components, both of them solid in
ambient conditions, the multicomponent crystal can further be classified as cocrystal
and salt [27]. Cocrystals are generally defined as crystalline materials comprising two
or more neutral molecules in the same crystal lattice [27]. Contrarily, a salt is formed
if any part of an API gives or receives a proton to or from another molecule [28]. Polymorphic, pseudopolymorphic, cocrystal, and salt states have quickly evolved from
being relative obscure to widely studied crystal forms in the context of pharmaceutical
science and engineering [12, 13].
When APIs form multicomponent crystals, the driving force is typically a molecular synthon, such as a hydrogen bond, π-π interaction, or halogen bond, which
involves supramolecular chemistry [28]. To put this in the pharmaceutical science
context, the study of multicomponent crystal APIs, particularly their physicochemical properties relevant to clinical performance and long-term stability, represents an
important aspect in drug discovery and development. In the past decade, pharmaceutical multicomponent crystals have emerged as promising tools for solid formulation testing during drug discovery and development, as their design can profoundly
influence their physicochemical properties. Pharmaceutical multicomponent crystals
offer massive opportunities for research topics and patent development, as well as
for functional materials applications. The number of research projects and patent
applications in the multicomponent crystal field should, therefore, be unsurprising.
155
exploited in pharmaceutical applications to increase the solubility of problematic
APIs. However, from a thermodynamic point of view, the amorphous state of a solid is
unstable and has the tendency to convert to its low-energy and more stable crystalline
form over time [18]. Therefore, the number of successful products available in this
solid form in the market is still limited.
Most marketed APIs, therefore, consist of crystalline solids. In contrast with
amorphous solids, crystalline materials consist of minimal building blocks called
unit cells that contain all the structural features and symmetry elements of the crystal
and are repeated regularly in three-dimensional space [19]. Furthermore, API crystalline molecules are typically amenable to form multiple crystal forms known as
polymorphs [20]. Organic molecules, including APIs, generate polymorphic crystals through two mechanisms. The first mechanism leads to so-called packing polymorphs, in which molecules with relatively rigid conformations can be assembled
into different three-dimensional structures. The second mechanism occurs when a
flexible molecule bends into different conformations to subsequently be packed into
alternative crystal structures [21]. Some polymorphic APIs have mixed mechanisms
and exhibit different packing and conformational polymorphs [22].
API crystalline molecules can also exist as multicomponent crystals by incorporating other molecules into the crystal lattice. “Pseudopolymorph” is the widely
accepted term for crystals with solvent molecules incorporated into their lattice [23–
25]. Hydrates are crystalline solid adducts that contain water molecules and are
known as the largest class of pseudopolymorps [4]. If a crystalline solid accommodates another solvent molecule than water, the solvate terminology is generally used
[26]. If a multicomponent crystal contains two components, both of them solid in
ambient conditions, the multicomponent crystal can further be classified as cocrystal
and salt [27]. Cocrystals are generally defined as crystalline materials comprising two
or more neutral molecules in the same crystal lattice [27]. Contrarily, a salt is formed
if any part of an API gives or receives a proton to or from another molecule [28]. Polymorphic, pseudopolymorphic, cocrystal, and salt states have quickly evolved from
being relative obscure to widely studied crystal forms in the context of pharmaceutical
science and engineering [12, 13].
When APIs form multicomponent crystals, the driving force is typically a molecular synthon, such as a hydrogen bond, π-π interaction, or halogen bond, which
involves supramolecular chemistry [28]. To put this in the pharmaceutical science
context, the study of multicomponent crystal APIs, particularly their physicochemical properties relevant to clinical performance and long-term stability, represents an
important aspect in drug discovery and development. In the past decade, pharmaceutical multicomponent crystals have emerged as promising tools for solid formulation testing during drug discovery and development, as their design can profoundly
influence their physicochemical properties. Pharmaceutical multicomponent crystals
offer massive opportunities for research topics and patent development, as well as
for functional materials applications. The number of research projects and patent
applications in the multicomponent crystal field should, therefore, be unsurprising.