Mesoscale clusters in multicomponent systems: the effect of solution preparation and pre-treatment on primary nucleation of a carbamazepine-saccharin cocrystal

Abstract

In this work, direct investigation of mesoscale clusters in solution using dynamic light scattering is combined with an indirect method based on the study of primary crystal nucleation and its...

Mesoscale Clusters in the Crystallisation of Organic Molecules

“…Liquid light scattering techniques have been used for gaining understanding of the cluster stability primarily due to its short analysis time. Contrasting results have been obtained where some reports have indicated mesoscale clusters to be stable [18,31] while others have reported them to be metastable [21,29] . In the case of OTBN‐methanol and chloroform solutions, the size of clusters remained stable for several days in the absence of agitation as measured by DLS and NTA [31] .…”

“…for fenoxycarb‐isopropanol (IPA) solutions [29] . They observed a significant decrease in mesoscale cluster concentration (Figure 6C) measured with NTA after incubation at 40 °C compared to freshly dissolved solutions and solutions exposed to near ambient conditions (22 °C) [29] …”

“…Though agitation promoted coalescence of these clusters as hypoth-esised by the authors, [16] a scenario for the growth of these clusters could be argued as the solutions under investigation were supersaturated based on the work involving fenoxycarb. [29] A school of thought exists that distinguishes the mesoscale cluster pathway from the two-step pathway, in that the former involves pre-existing mesoscale clusters in the solution, while the latter involves the "nucleation" of a dense liquid phase during the crystallisation process. [3] As highlighted in the critical properties section (number concentration), with filtration it can be possible to eliminate the population of mesoscale clusters on account of their fragile nature.…”

“…All these studies have demonstrated the existence of mesoscale clusters below the solid–liquid equilibrium, i.e., undersaturated solutions. The existence of clusters in undersaturated solutions has been demonstrated for DL ‐alanine, [18] fenoxycarb, [29–30] salicylic acid, [30] and 2‐cyano‐4′‐methylbiphenyl (OTBN) [31] . Zimbitas et al.…”

“…In the literature, the correlation between increasing solute concentration and cluster size has thus far produced contradictory findings [19,29] . Zong et al.…”