Abstract
Polymorphism denotes the existence of more than one crystal structure of a substance, and great practical and theoretical interest for the chemical and pharmaceutical industries. In many cases, it is challenging to produce a pure crystal form and establish a sensitive detection method for the identification of crystal form in a mixture of polymorphs. In this study, an accurate and sensitive method based on synchrotron radiation X-ray computed microtomography (SR-μCT) was devised to identify the polymorphs of clopidogrel bisulphate (CLP). After 3D reconstruction, crystal particles were extracted and dozens of structural parameters were calculated. Whilst, the particle shapes of the two crystal forms were all irregular, the surface of CLP II was found to be rougher than CLP I. In order to classify the crystal form based on the quantitative morphological property of particles, Volume Bias Percentage based on Surface Smoothing (VBP) was defined and a new method based on VBP was successfully developed, with a total matching rate of 99.91% for 4544 particles and a lowest detectable limit of 1%. More important for the mixtures in solid pharmaceutical formulations, the interference of excipients can be avoided, a feature cannot achieved by other available analytical methods.
Highlights
Polymorphism is the ability of a solid material to exist in more than one crystal structure, which can potentially be found in many crystalline materials including polymers, minerals, and metals
Its use for quantitative analysis is often marred for samples with complex scattering patterns, since the isolation of the diffraction peaks of the active pharmaceutical ingredients (APIs) and excipients peaks may be difficult and some low intensity peaks may exist in the background because of the effect of residual solvent in the sample, factors which may interfere with the interpretation of results[1]
The powder X-ray diffraction (PXRD) profiles of clopidogrel bisulphate (CLP) I and II are shown in Fig. 1, and these are in good agreement with reported literatures[11,19]
Summary
Polymorphism is the ability of a solid material to exist in more than one crystal structure, which can potentially be found in many crystalline materials including polymers, minerals, and metals. Vibrational spectroscopic methods have been developed for quantitative analysis of Form II of clopidogrel bisulphate in Form I and Form II polymorphic mixtures. Results show that both IR and Raman spectroscopy combined with chemometrics are suitable to quantify low levels of Form II in Form I, down to 2 and 3%, respectively, with less than 1% limit of detection[12]. The microscopic methods based on the image acquisition followed by a suitable image-analysis scheme to extract morphological details may be useful tools to quantify the trace amount of polymorphs by morphology These approaches are especially powerful for the characterization of minor phases in mixtures and, provided that a suitable crystallite can be located, the analysis can be performed on exceptionally small amounts of material. In scanning mode, direct imaging of the crystal lattice can be coupled with spectroscopic analysis to yield chemical information at the unit cell level; in imaging mode, the technique is routinely used for the identification and characterization of defective structures; and in diffraction mode, detailed investigations of both symmetry and crystal structure are possible[13,14]
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