Comprehensive exploration of riboflavin solid forms and preparation mechanism of stable forms

Abstract

Riboflavin is a water-soluble vitamin regarded as an essential nutrient participating in biological oxidation in vivo. The strong hygroscopicity and crystalline phase impurity of riboflavin in the solid state are obstacles to its industrial production and storage. Riboflavin is polymorphic and is usually produced and marketed in crystalline form. However, the phase transformation among riboflavin polymorphs and preparation mechanism of stable crystal form have not been clarified, hindering the production optimization and storage management of products. In this work, the relationship of phase transformation among the riboflavin polymorphs was elucidated, and their thermal stability as well as hygroscopicity were evaluated. Anhydrate I is the most stable form with the best thermal stability and lowest hygroscopicity could not be prepared in antisolvent crystallization process, where monohydrate is the most frequent form. Consequently, a solution-mediated phase transformation (SMPT) process was proposed to prepare anhydrate I from monohydrate. In-situ Raman, UV–VIS spectrum and Powder X-ray Diffraction were utilized to monitoring the SMPT process. It was found that the nucleation and growth of anhydrate I was the rate-determining step. Elevated temperatures, reduced solid loads and addition of seeds can accelerate the conversion procedure. This work provides guiding significance for the product development and quality control of Riboflavin.