Crystallization of Monohydrate Citric Acid. 1. In Situ Monitoring through the Joint Use of Raman Spectroscopy and Image Analysis

Abstract

Seeded batch crystallizations of monohydrate citric acid were performed under isothermal conditions (15 °C). Continuous monitoring of the overall solid concentration during the crystallization process was developed using in situ Raman spectroscopy. Quantitative estimation of the crystal size distribution (CSD) was made possible thanks to in situ image acquisition: off-line CSD measurements were further computed from the recorded pictures. The growth rate of monohydrate citric acid was estimated from solid concentration. Through in situ particle size visualization and quantitative analysis of the pictures, activated surface secondary nucleation was also shown to significantly impact the final CSD. It is underlined that, in addition to continuous Raman in situ spectroscopic concentration measurements, image acquisition yields highly valuable data on the dispersed phase. Advantages and drawbacks of the technique for the monitoring of solution crystallization are discussed.

Factors affecting crystallization of hydrates

“…We have also observed the crystallization of the thermodynamically stable monohydrate of nitrofurantoin from water–acetone mixtures at temperatures below the transition point [43] . The direct nucleation of the thermodynamically stable hydrates below their transition point in aqueous solutions has been reported for other systems, such as the monohydrate citric acid [47] and hemipenta hydrate risedronate monosodium [48] . It has to be mentioned here that for the more complicated hydrate polymorphs, for which the hydrate itself can exist as more than one polymorph, the most stable hydrate polymorph does not necessarily have to be the first one to crystallize out.…”

Using Raman spectroscopy in tablet moisture surface analysis: Tablet surface markers

“…Raman spectroscopy has been used for (i) chemical fingerprinting of solids, (ii) determination of hydration [3,4] and (iii) analysis of crystallinity and crystal polymorphism [5]. Quantitative analysis using Raman Spectroscopy has increased over the past few years [6][7][8][9]. Moreover the use of Raman spectroscopy in tablets and powders mapping has increased as demonstrated by several industrial applications [10][11][12][13].…”

A population balance model of the solution‐mediated phase transition of citric acid

“…As far as complex multiphase systems are concerned, several articles have reported on the use of ex situ Raman spectroscopy for monitoring purposes. It should be noticed that in situ application are more seldom, as outlined in the sequel 11–22. These papers describe calibration procedures enabling the in situ measurement of the polymorphic or “pseudo‐polymorphic” composition of particles in suspension, and present in‐line data on the time variations of the solid phase composition during phase transition experiments.…”

“…During the present study, the transition of citric acid from the anhydrous to the monohydrate state was selected as a model system. The solid composition and the overall solid concentration were measured using Raman spectroscopy,21 while the time variation of the CSD of citric acid particles was assessed through in situ image acquisition 22. Following these experiments, a dynamic Population Balance Equation (PBE) model was designed and reported23 to describe the isothermal seeded crystallization of pure monohydrate Citric Acid (mCA is the stable form at 15°C).…”

“…Bearing the aforementioned literature data in mind, the aim of the present paper is twofold: A synthesis of our previously published results about the crystallization of citric acid monohydrate21–23 is made to extend the application of these results to the modeling of the whole SMPT of citric acid. New experiments are presented later, during which seeded anhydrous to monohydrate phase transition of citric acid were monitored using Raman spectroscopy and image analysis. During the development of an overall PBE model describing the SMPT of citric acid, original results were obtained about the secondary nucleation of the stable phase.…”