Enhanced solubility, permeability, and tabletability of nicorandil by salt and cocrystal formation

Cocrystallization is a rational selection crystal engineering approach for the development of novel solid forms with enhanced physicochemical and mechanical properties. Nicorandil (NCR) is a niacinamide vitamin derivative used to treat angina pectoris. A binary solid form screen of NCR with homologo...

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Published inCrystEngComm Vol. 23; no. 1; pp. 227 - 237
Main Authors Mannava, M. K. Chaitanya, Gunnam, Anilkumar, Lodagekar, Anurag, Shastri, Nalini R, Nangia, Ashwini K, Solomon, K. Anand
Format Journal Article
LanguageEnglish
Published Cambridge Royal Society of Chemistry 07.01.2021
Subjects
Acids
Adducts
Angina pectoris
Carboxylic acids
Chloroform
Cocrystallization
Crystal structure
Crystallization
Crystallography
Dicarboxylic acids
Diffusion rate
Dissolution
Fumaric acid
Homology
Hydrogen bonds
Infrared spectroscopy
Mechanical properties
NMR spectroscopy
Oxalic acid
Phase stability
Physical properties
Single crystals
Solubility
Spectrum analysis
Succinic acid
Thermal analysis
Toluene
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Summary:Cocrystallization is a rational selection crystal engineering approach for the development of novel solid forms with enhanced physicochemical and mechanical properties. Nicorandil (NCR) is a niacinamide vitamin derivative used to treat angina pectoris. A binary solid form screen of NCR with homologous dicarboxylic acids afforded NCR-oxalic acid (NCR-OA, 1 : 1), NCR-fumaric acid (NCR-FA, 1 : 1), NCR-succinic acid (NCR-SA, 1 : 1), and NCR-suberic acid (NCR-SBA, 1 : 0.5). The binary solids were characterized by powder X-ray diffraction, IR and NMR spectroscopy, and DSC. NCR-FA and NCR-SBA were crystallized by slow evaporation from chloroform and toluene solvents, respectively. Single crystal X-ray diffraction confirmed that NCR-FA is a molecular salt, while NCR-SBA is a neutral cocrystal. NCR and the FA anion are connected via the robust carboxylate pyridinium synthon, whereas in the NCR-SBA cocrystal, the components associate via the carboxylic acid pyridine synthon. The phase stability, solubility, dissolution rate, diffusion rate and tabletability studies have demonstrated that the binary solids exhibit improved physical and mechanical properties compared to the NCR drug. Specifically, the NCR-FA salt and NCR-SBA cocrystal have higher solubility, dissolution rate, and hardness at lower pressures, making the formulation suitable for tablet compression. Cocrystallization is a rational selection crystal engineering approach for the development of novel solid forms with enhanced physicochemical and mechanical properties.
Bibliography:Electronic supplementary information (ESI) available: The ORTEP diagram of binary adducts of NCR (Fig. S1), hydrogen bond parameters in NCR salts and a cocrystal (Table S1), NMR of the NCR-SA cocrystal, NCR-OA salts (Fig. S2), to determine ratio of NCR-SA, NCR-OA by PXRD (Fig. S3), thermal analysis by both DSC and TGA for NCR-OA and NCR-SA for chemical stability (Fig. S4). FT-IR spectra of NCR salts and a cocrystal (Fig. S5), and powder XRD of NCR salts and cocrystals at the end of dissolution/phase stability experiment compared with the calculated line pattern from the X-ray crystal structure (Fig. S6). CCDC
For ESI and crystallographic data in CIF or other electronic format see DOI
10.1039/d0ce01316a
2026185
and
2026186
ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 14
ISSN:1466-8033
1466-8033
DOI:10.1039/d0ce01316a