(A slight theory intensive dive into curcumin nucleation)
The influence of impurities on the induction time during the nucleation of curcumin (CUR), demethoxycurcumin (DMC) and bisdemethoxycurcumin (BDMC), altogether known as curcuminoids were determined experimentally and the collected nucleation data is examined statistically [1].
(Molecular structures of CUR, DMC, and BDMC (Source))
By classical nucleation theory (CNT), the induction time (time to form a stable/critical nucleus before growth) data and nucleation rates are used to estimate the solid−liquid interfacial energy, pre-exponential factor, and time of growth to visibility. The impurities influence the solubility of CUR and this has been accounted for in the estimation of the driving force. Molecular modeling tools have been employed in order to interpret the experimental nucleation results and to understand the observed effects of the impurities on the nucleation of CUR.
The use of various distribution functions to examine induction time data has previously been examined using the cumulative exponential-based probability distribution function (LDF):
From the nucleation rate (J) data, the solid−liquid interfacial energy (γSL) and pre-exponential factor (A) can be determined within the classical nucleation theory, according to
if the nucleus is assumed to be spherical, where NA is the Avogadro number, R is the gas constant, T is temperature, υ is the molecular volume (4.4E−28 m3 ) of CUR in the cluster, and S is the supersaturation ratio (C/C*). The second term on the right-hand side, is the nucleation work (ΔGcrit/RT), and includes the free energy barrier that needs to be exceeded for a cluster to turn into a nucleus. The pre-exponential factor is taken here as the total number of clusters which form per unit volume and time. The fraction of these clusters which progress to viable nuclei is determined by the exponential factor.
(Induction time distributions: (a) for CUR in pure solutions at different supersaturation ratios (b) for CUR at S = 3.16 in the presence of different concentrations of DMC (mmol·dm−3) and (c) for CUR at S = 3.16 in the presence of different concentrations of BDMC (mmol·dm−3 ). Fitted according to the probability distribution function (Source))
In a homogeneous supersaturated solution, molecules of solute cluster eventually turn into crystals that are thermodynamically stable in the solution. The clustering tends to be thermodynamically unfavorable until the clusters reach sufficient size or structural order. Thus, clusters are prone to reconstructions due to alternate assembling and dissembling of molecules resulting from their random collisions with molecules of solute and solvent.
The solid−liquid interfacial energy for the pure CUR system is lower than the corresponding value for the impure systems (with one exception). The interfacial energy tends to be lower for the DMC systems compared to the BDMC systems, but there is no clear trend with respect to the impurity concentration.
(Critical free energy versus supersaturation for the pure and impure CUR system (Source))
Experimental induction time data obtained reveal that both DMC and BDMC impurities clearly prolong the nucleation of CUR, especially at low supersaturation of CUR (S = 3.16). However, no clear trend was observed when different concentrations (0.10 mmol·dm−3 , 0.30 mmol·dm−3 , and 0.60 mmol·dm−3 ) of impurities were added to the crystallizing CUR solution, and no obvious trend was noticed between the impurities themselves.

(Curcumin nuclei formed from impure solutions, SEM (Source))
Statistical analysis was performed on the collected nucleation data according to the classical nucleation theory reveal that the structurally related impurities primarily decrease the pre-exponential factor for CUR crystallization, while the increase in interfacial energy is comparatively small.
In addition, the impurities are found to increase the time of growth to visibility. Both the DFT and metadynamics computations accordingly indicated that the binary interactions of CUR−DMC and CUR−BDMC are stronger than the respective binding between two CUR molecules. A certain energy barrier has to be overcome in order to remove the impurity molecules from their structures; this could explain why nucleation of CUR is more difficult in presence of the structurally related impurities DMC and BDMC [2].
References:
Karthikeyan, A., Senthil, N. & Min, T. Nanocurcumin: A Promising Candidate for Therapeutic Applications. Frontiers in Pharmacology vol. 11 Preprint at https://doi.org/10.3389/fphar.2020.00487 (2020).
Claire Heffernan, Marko Ukrainczyk, Jacek Zeglinski, Influence of Structurally Related Impurities on the Crystal Nucleation of Curcumin Cryst. Growth Des. 2018, 18, 4715−4723 http://dx.doi.org/10.1021/acs.cgd.8b00692
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