Quantifying Solid-State Mixtures of Crystalline Indomethacin by Raman Spectroscopy Comparison with Thermal Analysis

This paper investigates Raman spectroscopy as a quick and reliable method to quantify the alpha (α) and gamma (γ) polymorphic forms of indomethacin compared to differential scanning calorimetry (DSC). Binary mixtures with different ratios of α and γ indomethacin were prepared and analyzed by Raman and DSC. The Raman method was found to be more reliable and superior compared to DSC. The partial conversion of the alpha to gamma polymorphic form during the DSC measurement was the major limitation for the use of full DSC as a quantitative method and resulted in difference between the calculated and measured enthalpy of both polymorphic forms. 1. Introduction Polymorphism is a commonly encountered phenomenon in pharmaceutical formulations and final products. Scientists’ interest in understanding pharmaceutically relevant aspects of polymorphism have increased over the years, in particular the drugs’ different metastable polymorphic forms, the polymorphic forms dissolution rate, and their thermodynamic properties, as well as the in vivo drug kinetics [1–3]. The appearance or disappearance of a defined drug polymorphic form during manufacturing or storage is a major concern in drug process development [4–7]. Thus rapid and reliable quantification of polymorphic forms of active drug ingredients (API) is essential during drug manufacturing [8–10]. DSC monitors the heat changes associated with physical transformations; this includes transformation from (i) amorphous to crystalline form, (ii) crystalline drug to a different polymorph form, and (iii) crystalline drug to an amorphous solid-state mixture. Thus, DSC is routinely used to characterize amorphous systems, polymorphic changes studies, and in the quantification of the amorphous and crystalline contents in solid mixture [11–13]. The quantity of one polymorphic form can be estimated by either heat of crystallization or heat of fusion [14, 15]. A major limitation in using DSC as a quantitative tool is the relative thermodynamic stability of the polymorphic forms. The interconversion of the polymorphic forms during the thermograms collection is the chief obstacle in the extensive use of DSC as a quantitative tool. Experimental modifications and validation may be required to overcome this potential problem. IR has widely been used in quantitative and qualitative analysis of drugs in solid-state mixtures and blends. Although near infrared (IR) has been a dominating technique for the past decades, there is a significant increase in using Raman spectroscopy in solid- and liquid-state quantitative analysis [16].