Effects of various parameters on solution-mediated phase transformation of calcium d-gluconate: an approach to obtain pure metastable monohydrate

The high risk of solution-mediated phase transformation (SMPT) from the metastable monohydrate to stable Form I makes it difficult to produce pure metastable monohydrate of calcium d-gluconate. In this work, we explored the effect of various operating parameters on the SMPT of calcium d-gluconate in water and proposed an effective approach to obtain the desired monohydrate. First, the two forms of calcium d-gluconate were characterized and compared using powder X-ray diffraction (PXRD), thermal analysis, and Raman spectroscopy. The lower solubility of Form I in water illustrates its higher thermodynamic stability than monohydrate when the temperature is higher than 292 K. Afterward, the SMPT of calcium d-gluconate from monohydrate to Form I was investigated in water using in situ Raman spectroscopy combined with scanning electron microscopy and PXRD. Results showed that the nucleation and growth of Form I was the rate-limiting step in the SMPT from monohydrate to Form I. The phase transformation from monohydrate to Form I was delayed to produce pure monohydrate by decreasing temperature and agitation rate, reducing the amount of solid loading, and increasing the particle size of solid loading. Furthermore, the transformation kinetics were studied by the JMA model to explore how temperature influences the SMPT process. This study enriches the study of the calcium d-gluconate SMPT mechanism, and also provides guidance for obtaining high-quality injection-grade calcium gluconate monohydrate.