Supramolecular modification of active pharmaceutical ingredients (APIs) and new chemical entities (NCEs) to enhance their physicochemical properties and improve their delivery can be achieved via crystal engineering methods, which involve the generation of alternative, multiple solid forms of a given bioactive compound, including polymorphs, amorphs, solvates, co-crystals and inclusion complexes. Shortcomings such as poor tabletability, hygroscopic tendency, poor aqueous solubility and variable bioavailability have been successfully addressed via this approach in recent years, leading to more systematic and rapid optimisation of solid-form selection for eventual formulation. In our laboratory, strong emphasis is placed on X-ray diffraction and complementary methods for analysing newly generated phases. Powder X-ray diffraction allows rapid identification of novel crystalline and non-crystalline bulk phases, while the ability to characterize them at the molecular level using single crystal X-ray diffraction ensures their accurate description, including, for example, the distinction between co-crystals and salts, which is critical for patenting new entities. For solvated solid forms and some inclusion complex phases, thermogravimetric analysis yields stoichiometric information while differential scanning calorimetric techniques enable the identification and quantitative characterization of polymorphic transitions, the resulting data being essential for the construction of an energy-temperature diagram that displays the thermodynamic interrelationships amongst the various phases of a single bioactive compound. In this presentation comprehensive screening for new solid forms of several APIs and NCEs will be described with reference to the use of inexpensive mechanochemical techniques for producing a variety of crystalline and non-crystalline phases, the comprehensive physicochemical characterization of such new phases using X-ray diffraction, thermoanalytical and spectroscopic methods, and assessment of their dissolution properties.
Audience Take away:
• Utility of mechanochemical methods in crystal engineering to produce small quantities of new solid phases of APIs and NCEs for comprehensive physicochemical characterization will be illustrated
• Advantages of X-ray diffraction and complementary methods for unequivocal characterization of new solid phases will be demonstrated
• The merits of applying crystal engineering at an early stage in the lifetime of an NCE, resulting in improvement of its pharmaceutically relevant properties and thus promoting its rapid development, will be highlighted