CONTRACT RESEARCH & TOXICOLOGY solid-form screenings of the API itself along with salts and co-crystals .
Getting reliable information rapidly
At the start of chemical development , no more than a few grams of API are generally available , so miniaturisation is desirable to permit as many experiments to be performed with as little material as possible . High-throughput screening ( HTS ) approaches permit up to 384 crystallisation experiments ( i . e . four microtitre plates ) to be carried out in parallel with subsequent analysis of the solid form by Raman spectroscopy and / or powder X-ray diffraction . In polymorphism screening , a diversity of solvents , crystallisation methods and temperatures is explored . The experimental plan is customised with respect to the properties of the API , particularly its solubility in various organic solvents , so that the screening is carried out in an intelligent manner rather than as a brute force survey of implausible conditions .
A similar approach can be used to screen solvents and methods for crystallising an amorphous API or for changing the crystal habit ( i . e . shape ) into one that is more suitable for downstream processing steps , such as filtration , drying , compaction and formulation . The same highthroughput technology can be used for salt or co-crystal screenings , but in such cases the coformer and the stoichiometry provide two additional variables . It can often be advantageous to deliberately include the amorphous form of the API as a reagent in HTS that uses suspension equilibration as a crystallisation method , because this provides an efficient means of accessing additional solid forms by lowering the energetic barrier to conversion . 3 The leads found in HTS indicate promising crystallisation conditions for the generation of new solid forms . Probable solvates ( i . e . host – guest complexes incorporating solvent molecules ) can often be identified during HTS , due to the consistent association of a particular form with a specific solvent and an early indication of a salt or co-crystal ’ s propensity towards polymorphism can also be ascertained . However , since at most a few milligrams of product are found in each well , it is not possible to fully understand the nature of these solid forms without additional experimental work .
Understanding new forms
Upon completion of HTS , it is necessary to scale up the most interesting leads to at least 20-mg scale to permit further analysis and to assess qualities such as thermal stability , chemical purity , hygroscopicity , aqueous solubility ( and thus bioavailability ), and morphology . In addition , the relationships among the non-solvated forms should be elucidated so as to understand which form is stable at which temperature . Even when the thermodynamically stable form at room temperature has suitable bioavailability , another polymorph might be more stable at slightly higher temperatures ,
Platform for automated high-throughput screening of solid forms
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