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Online powder X-ray diffraction, employing a flow-through cell [Hammond et al. Cryst. Growth Des. 2004, 4, 943] and a previously developed chemometric method [Chen et al. Anal. Chem. 2005, 77, 6563], was applied for quantitative analysis of the polymorphic phase transformation from the metastable R-form to the stable β-form of L-glutamic acid (LGA). The process of interconversion was monitored in aqueous slurries, using a jacketed 400 mL magnetically stirred reactor as a function of temperature. Calibration studies revealed that the current detection limits are ca. 0.8 and 0.2 wt%, respectively, for Rand β-forms of LGA as determined for slurries of LGA in methanol and good signal detection can be accomplished using a data acquisition time of 10 s albeit with increased noise levels. Compositions of slurries, in terms of the amounts of the individual solid phases present, were calculated from the areas of individual, discriminating peaks associated with the phases. Analysis of the diffraction peaks arising from the (111) reflection, 2θ ) 18°for the R-form and (102) reflection, 2θ ) 31°for the β-form, was used to obtain the rates of phase interconversion. Phenomenologically, the rate law observed for dissolution of the R-form was -D R ) k dR and the rate law observed for growth of the β-form was D β ) k gβ C β where C β is the concentration of the β-form expressed in weight percent. At 45 °C, the values of the rate constants k dR and k gβ were 18 × 10 -4 wt% s -1 and 3 × 10 -4 s -1 , respectively. Activation energies calculated, using the Arrhenius relationship, were found to be 43.9 kJ/mol with k dR0 calculated to be 25.9 × 10 3 wt% s -1 for the dissolution of R-form and 47.0 kJ/mol with k gβ0 calculated to be 16.2 × 10 3 s -1 for the growth of the β-form. The activation energy calculated from a different, characteristic peak of the β-form at 2θ ) 21°, corresponding to the reflection from (101) planes, was 32.1 kJ/mol suggesting that there might be some texture effects manifested in the flow field of the crystalline slurry. The overall quantitative accuracy of this method together with potential for improvement is also discussed. † This paper was originally intended for publication as part of the special issue on Facets of

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X-ray diffraction is one of the most widely applied methodologies for the in situ analysis of kinetic processes involving crystalline solids. However, due to its relatively high detection limit, it has only limited application in the context of crystallizations from liquids. Methods that can improve the detection limit of X-ray diffraction are therefore highly desirable. Signal processing approaches such as Savitzky-Golay, maximum likelihood, stochastic resonance, and wavelet transforms have been used previously to preprocess X-ray diffraction data. Since all these methods only utilize the frequency information contained in the single X-ray diffraction profile being processed to discriminate between the signals and the noise, they may not successfully identify very weak but important peaks especially when these weak signals are masked by severe noise. Smoothed principal component analysis (SPCA), which takes advantage of both the frequency information and the common variation within a set of profiles, is proposed as a methodology for the preprocessing of the X-ray diffraction data. Two X-ray diffraction data sets are used to demonstrate the effectiveness of the proposed approach. The first was obtained from mannitol-methanol suspensions, and the second data set was generated from slurries of L-glutamic acid (GA) in methanol. The results showed that SPCA can significantly improve the signal-to-noise ratio and hence lower the detection limits (approximately 0.389% g/mL for mannitol-methanol suspensions and 0.4 wt % for beta-form GA in GA-methanol slurries comprising mixtures of both alpha- and beta-forms of GA) thereby providing an important contribution to crystallization process performance monitoring.