In-line monitoring of solid-state properties in crystallization processes is of great significance in controlling the quality of crystalline active pharmaceutical ingredients. In this work, the solvent-mediated phase transformation of anhydrous to dihydrated carbamazepine in ethanol-water mixtures was studied using an in-line Raman immersion probe. The solute concentration profile was measured by off-line sampling. The transformation experiments were conducted with different operation parameters in terms of solvent composition and temperature. The transformation rate depends on both solvent composition and temperature. The mechanism of the transition was interpreted with the two-step polymorphic form transformation mechanism. It was observed that the crystallization of the stable form was the rate-controlling step. The influence of the operation parameters on the transformation rate can be interpreted as the effects of solvent and supersaturation on the crystallization kinetics. Another interpretation is proposed by correlating the deviation of the water activity from the equilibrium value to the rate of phase transformation. It was observed that the correlation of the water activity deviation and the phase transformation rate was independent of solvent composition and temperature.

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Additives are one of the most influential factors that can affect the polymorphism and solvation state and the morphology of the crystals during crystallization. In this work, the effects of five different additives, sodium lauryl sulfate (SLS), polyethylene glycol 6000 (PEG), hydroxypropyl methylcellulose (HPMC), polyvinylpyrrolidone (PVP), d-mannitol, on the phase transition from anhydrous (CBZA) to dihydrate (CBZH) carbamazepine in an ethanol−water mixture containing 61 mol % ethanol were studied. A Raman in-line probe was used to obtain the real time transformation rate during the transformation. The mechanism of the additive effects on the phase transition was studied by investigating the influence of the additives on the solubility of CBZA and CBZH and on the cooling crystallization of CBZH. It was observed that HPMC exhibited a strong inhibiting effect on the phase transformation at both 15 and 10 °C. Furthermore, it was found that HPMC selectively increased the solubility of CBZH but had no effect on the CBZA solubility. As a consequence, the solubility difference of CBZA and CBZH decreased dramatically. This resulted in a reduced supersaturation level during the phase transformation. SLS showed a slight promotion effect on the nucleation and crystal growth of CBZH by decreasing the metastable zone width and increasing the size of the final CBZH crystals. The additives had an insignificant effect on the viscosity of the solvent.

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