Mechanistic Insight into Caffeine–Oxalic Cocrystal Dissociation in Formulations: Role of Excipients

Abstract

Caffeine-oxalic acid cocrystal, widely reported to be stable under high humidity, dissociated in the presence of numerous pharmaceutical excipients. In cocrystal-excipient binary systems, the water mediated dissociation reaction occurred under pharmaceutically relevant storage conditions. Powder X-ray diffractometry was used to identify the dissociated products obtained as a consequence of coformer-excipient interaction. The proposed cocrystal dissociation mechanism involved water sorption, dissolution of cocrystal and excipient in the sorbed water, proton transfer from oxalic acid to the excipient, and formation of metal salts and caffeine hydrate. In compressed tablets with magnesium stearate, the cocrystal dissociation was readily discerned from the appearance of peaks attributable to caffeine hydrate and stearic acid. Neutral excipients provide an avenue to circumvent the risk of water mediated cocrystal dissociation.

Sweet graphene: exfoliation of graphite and preparation of glucose-graphene cocrystals through mechanochemical treatments

“…LAG samples had lower thermal stability, as can be observed from the second and third weight losses ( Table 5). This behaviour has also been observed for other cocrystals, 75 but this is the first cocrystal sample involving carbon nanostructures and its behaviour is mostly underexplored. Finally, after the weight loss at 600°C for all neat and LAG samples only around 10-20% of the material remained.…”

Stability of co‐crystals of caffeine with gallic acid in presence of coformers

“…p‐XRD analysis of CG co‐crystal, COX co‐crystal, and caffeine‐gallic acid‐oxalic acid solid phase is shown in Figure . The peaks at 2θ values of 9.26, 14.05, 25.78, 34.33, and 38.35 are present in the CG co‐crystal and caffeine‐gallic acid‐oxalic acid XRD spectra whereas the COX co‐crystal does not have the peaks at the same 2θ values (Duggirala, Vyas, Krzyzaniak, Arora, & Suryanarayanan, ). On comparing the XRD spectra of three solid phases, it can be inferred that oxalic acid cannot replace gallic acid from the CG co‐crystal at 300 K. Interpretation of the FTIR spectra also gives the same conclusion.…”

Influence of Excipients on Cocrystal Stability and Formation

“…PVP is highly hygroscopic 43 and the sticky and rubber-like nature of the ctz-aca/PVP sample suggests significant water uptake which may promote the decomposition of the cocrystal as reported in the literature for theophylline-glutaric acid, theophylline-isonicotinamide and caffeine-urea. [21][22][23][24] In the IR spectrum of milled nia/PVP strong shifts of the (N-H) bands are observed compared to crystalline nia which may explain why the ctz-nia cocrystal does not form in the presence of PVP. However,  for the C=O stretching vibration of nia in the IR spectrum of the free coformer and ctz-nia is 21 cm -1 suggesting also strong interactions in the cocrystal and once formed, the ctz-nia cocrystal is stable towards grinding with PVP.…”