Cocrystal construction between the ethyl ester with parent drug of diclofenac: structural, stability, and anti-inflammatory study

Abstract

This study aimed to collect the crystallographic data of ethyl diclofenac and discover a cocrystal from this ester with its parent, diclofenac acid, and to investigate their physicochemical properties and anti-inflammation activity. Firstly, ethyl diclofenac single crystal was isolated and continued by the cocrystal screening and isolation. Solid characterization was conducted by thermal analysis, infrared spectroscopy, powder x-ray diffractometry, followed by structural determination using a single crystal x-ray diffractometer. The stability of the cocrystal toward heating and high humidity, followed by the anti-inflammatory activity, was also studied. Ethyl diclofenac and the cocrystal were successfully isolated and subsequently subjected to lattice system determination. Interestingly, the new cocrystal can be generated directly by Fischer equilibrium reaction during esterification of diclofenac acid. Structurally, ethyl diclofenac reveals a P21/c monoclinic and the cocrystal between this ester with its parent drug is a P-1 triclinic system. A hydrophobic interaction-C-Cl-, which is rarely found in a cocrystal, involved in the molecular interaction between ethyl diclofenac and the parent drug, besides the hydrogen bonds. The newly isolated cocrystal has a melting point AE103-104 C, which is higher than that of ethyl diclofenac (AE67.5 C) but lower than that of diclofenac acid (AE173 C). Hence, this cocrystal is stable towards accelerated stability testing by heating in a microwave, as well as storing in high relative humidity. Moreover, the antiinflammation test also showed promising activity improvement.

Salt Cocrystal of Diclofenac Sodium-L-Proline: Structural, Pseudopolymorphism, and Pharmaceutics Performance Study

“…Based on dissolution profiles on pH 1.2 medium ( Figure 17 a), the maximum drug release from all samples (ND, NDPM, and NDPT) was achieved after 15 min dissolution, but in a very low concentration. This result was in line with the information from references [ 26 , 49 , 58 ]. Due to the acidity of ND (pKa: 4, at 25 °C), it showed that in the gastric medium, each sample was not completely separated because hydrogen ions inhibited diclofenac dissociation.…”

“…However, NDPM was superior in increasing the percentage of drug release. Based on the Henderson–Hasselbach’s equation at a pH below the pKa of ND, the percentage of non-ionized substance will be greater than at a pH above the pKa so that the percentage of substances absorbed into the solute tends to increase [ 55 , 57 , 58 ].…”

Fragmentation and transferability in Hirshfeld atom refinement

“…APPENDIX A References to experimental data used in this work Sorted alphabetically by CSD refcodes: ACUCIN (Nikonova et al, 2018), ADOWUO (Hermann et al, 2017), AHUKIZ (Weber et al, 2015), AMEPOS (Janicki & Starynowicz, 2010), ARAQUH (Hemgesberg et al, 2016), BECFAT (Veronelli et al, 2017), CAMVES (Dittrich et al, 2002), DAYCEO (Uppal et al, 2017), DNEDAM01 (Gruhne et al, 2021), DUBWAB (Nugrahani et al, 2019), DUCMAQ (Grabowsky et al, 2009), EDAWIP (Evans & Gilardi, 2001), EGUFIY (Malassis et al, 2019), GLYALB08 (Capelli et al, 2014), IYAQOP02 (Marshall et al, 2016), KOVPIX (Thanzeel et al, 2019), LETHIE (Chen et al, 2018), LOKPOT (Ballmann et al, 2019), LOSLEL (Johnas et al, 2009), MANMUJ08 (Jorgensen et al, 2014), MOSCOP (Clegg, 2019), MOVPIZ (Lapointe et al, 2019), MUHBOI (Butschke et al, 2015), OXACDH46 (Kamin ´ski et al, 2014), PCYPOL04 (Mohanraj et al, 2018), PPHCHN11…”

Challenges and Progress in Nonsteroidal Anti-Inflammatory Drugs Co-Crystal Development

“…Thus, the ED and DFA co-crystal were chemically stable. Moreover, anti-inflammatory activity was studied using five groups of mice, which showed that the co-crystals between ED and DFA increased anti-inflammatory activity more than the single components [ 50 ].…”