Cocrystal and Salt Forms of Furosemide: Solubility and Diffusion Variations

Multicomponent solid forms of the BCS class IV drug furosemide (FSM) were obtained upon liquid assisted grinding with coformers anthranilamide (ANT), 4-toluamide (TOL), 2-picolinamide (PCM), piperazine (PPZ), 2,3,5,6-tetramethylpyrazine (TMPZ), pyrazine (PYZ), 2-picolinic acid (PIC), isoniazid (INZ), and theophylline (THP), and identified with powder X-ray diffraction. Solid forms FSM–TMPZ (2:1), FSM–ANT (1:1), FSM–PPZ (1:1), and FSM–TOL ethanol solvate (1:1:1) were further characterized with single crystal X-ray diffraction and differential scanning calorimetry; a sesquihydrate structure for FSM–PCM (1:1:1.5) was additionally confirmed with thermogravimetric analysis. The thermodynamically stable form I of FSM contains O–H···O acid···acid and N–H···O sulfonamide dimer synthons and chains. These synthons are modified in the cocrystals/salts sometimes leading to changes in physicochemical properties. The FSM–PPZ (1:1) salt converted to a thermodynamically more stable form FSM–PPZ (2:1) within 1 h. The apparent solubility of FSM–PPZ (1:1) salt is ∼3 times higher than the equilibrium solubility of the thermodynamically stable FSM–PPZ (2:1) salt. The solubilities of FSM–TMPZ and FSM–ANT are comparable to FSM, and this could be linked to coformer solubility. The metastable FSM–PCM sesquihydrate exhibited unusually high FSM concentration in solution as a function of time and as monitored in a slurry experiment. This prolonged presence of FSM in solution is rationalized by a synthon-extended-spring-and-parachute model. Our rationale starts with Nangia’s explanation of the apparently high solubility of pharmaceutical cocrystals based on the simple spring-and-parachute model of Guzman et al. and later detailed by Brouwers et al. We go on to suggest that certain heteromolecular aggregates might well persist in soluble amorphous forms leading to a higher persistence of the drug in solution. Cocrystals/salts with higher solubility show higher values of initial diffusion/flux. A few bases when used as coformers render stable salt/cocrystals that resulted in low solubility/diffusion. In the new solid forms of FSM studied here, solubility and flux are seen to go hand in hand—an observation of import in drug absorption.