Jellylike phase (JLP) is usually harmful to the process of crystallization. The special state of cefotaxime sodium (CTX) jellylike phase and its spontaneous transition to crystals is investigated in this paper. The crystals transformed from JLPs containing different solvents have distinct habits and forms. The solvent used in JLP formation and crystallization was very important. The results show that the polarity and hydrogen bonding ability of the solvent plays a decisive role in the JLP formation and its crystallization. Combined with Fourier transform infrared spectra, in situ Raman spectroscopy monitoring experiment indicates that the orientational hydrogen bonding between the solvent and CTX molecule facilitates the construction of the CTX crystal structure. JLP crystallization offers a new way for novel polymorph development and crystal habit modification, especially for drugs that are difficult to crystallize from solution.

In this paper, gelation phenomenon during the crystallization process of cefotaxime sodium (CTX) is systematically studied. First, the gelation process is monitored using a nanoparticle size analyzer; the gel and xerogel are studied by different characterization tools to speculate the gelation mechanism. It is found that the gelation is driven by the crystallization of CTX and the nanoparticles act as gelators before they can be seen by the naked eye. Moreover, the solid-solution interfacial tension used to predict the rate of crystal growth is calculated using the induction periods and solvents are classified using the Hansen solubility parameters method, according to whether it can be gelated by CTX. It is shown that the strong polar interaction between solvent molecules and the carboxyl, amine, or acyl groups exposed on the CTX crystal surface is the key factor for gelation.

Aimed at exploring the influence of acetic acid on crystallization thermodynamics of cefotaxime sodium (CTX), the solubility of CTX in ethanol + water mixtures under acetic acid conditions at various temperatures are measured by a gravimetrical method. Different from the solubility curve when acetic acid is absent, the solubility curves of CTX under acetic acid conditions have a maximum value. The maximum solubility drifts as temperature varies, which is related to the dielectric constants of solvent mixtures. A combination of the Jouyban–Acree model and Apelblat equation is used to correlate the solubility data, and the correlation precision is improved when compared with that of the Jouyban–Acree model. By using the Wilson model, the activity coefficients of CTX and the mixing Gibbs free energies, enthalpies, and entropies of CTX solution are also predicted. The data presented in this study explain why the crystallization of CTX in ethanol + water mixtures is difficult and are helpful for guiding the industrial reaction and crystallization process of CTX.