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.
In
the pharmaceutical industry, poorly water-soluble drugs require
enabling technologies to increase apparent solubility in the biological
environment. Amorphous solid dispersion (ASD) has emerged as an attractive
strategy that has been used to market more than 20 oral pharmaceutical
products. The amorphous form is inherently unstable and exhibits phase
separation and crystallization during shelf life storage. Polymers
stabilize the amorphous drug by antiplasticization, reducing molecular
mobility, reducing chemical potential of drug, and increasing glass
transition temperature in ASD. Here, drug-polymer miscibility is an
important contributor to the physical stability of ASDs. The current
Review discusses the basics of drug-polymer interactions with the
major focus on the methods for the evaluation of solubility and miscibility
of the drug in the polymer. Methods for the evaluation of drug-polymer
solubility and miscibility have been classified as thermal, spectroscopic,
microscopic, solid–liquid equilibrium-based, rheological, and
computational methods. Thermal methods have been commonly used to
determine the solubility of the drug in the polymer, while other methods
provide qualitative information about drug-polymer miscibility. Despite
advancements, the majority of these methods are still inadequate to
provide the value of drug-polymer miscibility at room temperature.
There is still a need for methods that can accurately determine drug-polymer
miscibility at pharmaceutically relevant temperatures.
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