Emerging role of primary heterogeneous nucleation in pharmaceutical crystallization

Abstract

Crystallization is an important and difficult to control unit operation in the pharmaceutical industry. Crystallization can control molecular (i.e., polymorphism) and particulate (i.e., particle size and crystal habit) properties of active pharmaceutical ingredient (API). Moreover, these molecular and particulate properties govern the manufacturability, stability, and biopharmaceutical performance of the API and drug product. Nucleation is a key step and primary heterogeneous nucleation is a common mode of nucleation during crystallization. Hence, it is important to understand the parameters affecting primary heterogeneous nucleation, to achieve desirable properties in crystalline APIs. Primary heterogeneous crystallization has usually been linked to the surface characteristics like topography and functionality of the heteronucleant. The review outlines recent findings in the primary heterogeneous crystallization with specific emphasis on its pharmaceutical applications including regulatory considerations. Molecular‐level mechanisms governing heteronucleation and subsequent outcome in terms of molecular as well as particulate‐level properties of API have also been discussed. Moreover, general guidance for the selection of heteronucleant has also been included. Heterogeneous crystallization is a promising tool for efficient crystallization of API having properties for optimal pharmaceutical performance.

Combining Surface Templating and Confinement for Controlling Pharmaceutical Crystallization

“…These are transitional states that are lower in energy than a supersaturated solution but are not the most thermodynamically stable form. Metastable polymorphs have higher solubilities than the thermodynamically favored state but face the same stability issue as amorphous forms [ 28 , 34 ]. Chloramphenicol palmitate (CAP) is an example of this phenomenon.…”

“…Seeding also does not completely eliminate the formation of undesired polymorphs from the supersaturated bulk solution [ 69 , 76 ]. This has resulted in the need for new crystallization approaches involving heterogeneous crystallization onto surfaces that are not identical to the APIs, but where the desired polymorph is more favorable than the most stable form [ 28 , 67 , 77 , 78 ].…”

“…Additionally, having a lower area available for crystallization leads to higher supersaturation, which can be used to induce formation of desired nuclei. This is particularly important for crystallizing metastable polymorphs, as metastable phases form more readily at high supersaturations [ 28 , 84 , 85 ].…”

“…Additionally, while some reviews have presented the current state of studies relating to heterogeneous crystallization from surfaces [ 27 , 28 ] and crystallization within nanopores [ 29 , 30 , 31 ], this review focuses on studies using a combination of these methods to tailor the drug form. We first introduce polymorphism in Section 2 , then discuss heterogeneous crystallization and crystallization under confinement in Section 3 and Section 4 to provide a strong context for Section 5 , which reviews the state of the art on combined approaches to controlling crystallization.…”

Selective Crystallization of d-Mannitol Polymorphs Using Surfactant Self-Assembly

“… 24 Heterogeneous nucleation, in general, is driven by the characteristics of the templates, including topography, surface functionality, and lattice matching between the crystal and substrate’s lattices, favoring directional growth of the crystal. 1 , 19 The main advantage is that the templates can be tailored to produce the desired polymorphs. Solid heteronucleants, such as self-assembled monolayers (SAMs), on surfaces were reported to enhance nucleation, control polymorphs, and probe nucleation mechanisms.…”