Pharmaceutical Cocrystals of Nicorandil with Enhanced Chemical Stability and Sustained Release

Abstract

Nicorandil (NCD) is a chemically unstable drug and sensitive to humidity, heat, and mechanical stress in manufacturing processes. In this work, the cocrystals of NCD with organic acids were designed and synthesized to enhance the stability of NCD. Cocrystals of NCD with 1-hydroxy-2-naphthoic acid, salicylic acid, 3-hydroxybenzoic acid, and 2,5-dihydroxybenzoic acid were obtained. Hydrothermal stability study showed that cocrystals performed with remarkable stability advantages compared with pure NCD. On the basis of mechanism research, the stability improvements of NCD molecules can be attributed to the realignments of NCD molecules in cocrystals. After the formation of cocrystals, the novel packing styles of NCD break the selfcatalyzed decomposition process in pure NCD structure. Moreover, intrinsic dissolution rate characterizations showed that the formation of cocrystals could also optimize the dissolution behavior of NCD to realize the objective of sustained release.

Pharmaceutical cocrystals: A review of preparations, physicochemical properties and applications

“…It is critical to develop an effective strategy to eliminate or minimize drug degradants. Recently, pharmaceutical cocrystals have emerged as a prospective approach to overcome the chemical instability of APIs in the solid state 100 , 101 . Table 1 shows the list of cocrystals with enhanced photostability.…”

“…Nicorandil (NCD) is an effective drug for cardiovascular disorders, suffering from low chemical stability under high humidity, heat and mechanical stress ( Fig. 13 A) 101 . In the crystal packing of NCD, the distance between lone pair electrons on pyridines (N1) and C8 of the nearby NCD molecule is 3.367 Å ( Fig.…”

“…Guo et al. 101 developed a series of nicorandil cocrystals with 1-hydroxy-2-naphthoic acid (1-HNA), salicylic acid (SA), 3-hydroxybenzoic acid (3-HBA), and 2,5-dihydroxybenzoic acid (2,5-DHBA). All cocrystals exhibited superior hydrothermal stability in comparison with that of NCD alone ( Fig.…”

“…In the recent years, cocrystallization has been demonstrated as an alternative approach to sustain the drug release 165 , 166 , 167 , 168 , 169 , 170 . For example, the half-life of nicorandil (NCD) was prolonged by cocrystallizing with poorly soluble organic acids, such as 1-hydroxy-2-naphthoic acid (1-HNA) and salicylic acid (SA) 101 . The NCD‒1-HNA cocrystal displayed a reduction in the dissolution rate by approximately 22.7, 21.6 and 7.4 times in pH 2.0, 4.6, and 6.8 buffer, respectively, compared with pure NCD.…”

Formulation, Optimization, in Vitro and in Vivo Investigation of Ketoprofen - Fumaric Acid Co-crystal for the Solubility Enhancement of Ketoprofen

“…Numerous strategies to improve bioavailability of drugs with poor/low solubility include drug micronization in to amorphous form [1], complexation with hydrophilic carrier [2][3][4], solid dispersion [5,6], micellar solubilization [7], nanoparticle technology [8][9][10][11], self-emulsifying drug delivery systems [12][13][14], salt formation [15], liposomes [16], nanostructured lipid carriers (NLC) [17,18], prodrug [19] and formation of co-crystal [20][21][22][23][24][25] etc. However, there are disadvantages associated with these techniques like agglomeration, instability during storage, requirement of advanced/or sophisticated instruments, tacky product etc.…”