The unprecedented polymorphism of the non-steroidal anti-inflammatory drug (NSAID) flufenamic acid (FFA) is described here. Nine polymorphs were accessed through the use of polymer-induced heteronucleation (PIHn) and solid-solid transformation at low temperature. Structural elucidation of six of these forms, in addition to the two previously known forms, makes FFA indisputably octamorphic. Although the structure of at least one other form of FFA remains elusive, the occurrence of most of these polymorphs under one crystallization condition through PIHn illustrates that a fine interplay exists among the kinetic factors that lead to phase selection in this NSAID.
The non-steroidal anti-inflammatory drug (NSAID) tolfenamic acid (TA), previously thought to be dimorphic, is demonstrated to have at least five polymorphs. The new forms were uncovered through the emerging screening technique of polymer-induced heteronucleation (PIHn). The presence of conformational changes among forms, whole molecule disorder, space group diversity, and varying number of molecules in the asymmetric unit occurring within a very narrow free energy window (∼0.3 kcal/mol) make the solid-state chemistry of this molecule uniquely complex among pharmaceuticals. These aspects make it a particularly suitable benchmark compound for crystal structure prediction methods.
The solubility of 5-fluorouracil (5-FU), a widely used chemotherapeutic agent to treat solid tumors, which include colorectal, head and neck, breast, and lung cancer, was determined at temperatures ranging from 278.15 to 333.15 K in 11 pure solvents and binary water + ethanol solvent mixtures using the polythermal method. It was demonstrated that the solubility of 5-FU increases with increasing temperature in the pure solvents and at constant solvent composition in the solvent mixtures. Moreover, the solubility of 5-FU in the solvent mixtures exceeds its solubility in pure water and ethanol. The experimental solubility data of 5-FU in the pure solvents and solvent mixtures were correlated using the modified Apelblat and λh model equations. The predicted solubility data obtained agree with the experimental data based on the calculated relative deviation (RD) and the average relative deviation (ARD%) values. The selected solvents are categorized as either Class 2 or 3 (less toxic and lower risk to human health) solvents, and hence the correlated and experimentally derived solubility data of 5-FU presented provide a pathway to develop and engineer enhanced pharmaceutical processes and products based on this compound.
of ACM into hydrogels by equilibrium partitioning is quantified and found to be inversely proportional to ALG concentration. For hydrophobic model APIs, loading via equilibrium partitioning is inefficient; hence we suggest emulsion-laden hydrogels where emulsion droplets are encapsulated inside the hydrogel matrix. The incorporation of emulsion droplets inside hydrogels enables the high loading of the hydrophobic API leveraging the high solubility of the hydrophobic API in the dispersed emulsion droplets. By carefully choosing the emulsification method and the dispersed phase, we demonstrate significant loading (up to ~80% w/w) and crystallization of the stable form of FEN. Our results provide new insights for designing biocompatible nucleation-active materials capable of carrying industrially significant amounts of water-soluble and insoluble APIs in the crystalline form and serving as designer final drug formulation.
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