Cocrystal and Salt Forms of Furosemide: Solubility and Diffusion Variations

Banik, Manas and Gopi, Shanmukha Prasad and Ganguly, Somnath and Desiraju, Gautam R (2016) Cocrystal and Salt Forms of Furosemide: Solubility and Diffusion Variations. In: CRYSTAL GROWTH & DESIGN, 16 (9). pp. 5418-5428.

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Abstract

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), 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 Xray 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 center dot center dot center dot O acid.. acid and N-H center dot center dot center dot 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 similar to 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-andparachute 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.

Item Type:	Journal Article
Publication:	CRYSTAL GROWTH & DESIGN
Additional Information:	Copy right for this article belongs to the AMER CHEMICAL SOC, 1155 16TH ST, NW, WASHINGTON, DC 20036 USA
Department/Centre:	Division of Chemical Sciences > Solid State & Structural Chemistry Unit
Date Deposited:	28 Oct 2016 07:18
Last Modified:	28 Oct 2016 07:18
URI:	http://eprints.iisc.ac.in/id/eprint/55152

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