Partial characterization of different mixtures of solids by measuring the optical nonlinear response

We report on the theoretical basis and first experimental results of a new method based on optical nonlinearity, for characterising crystallinity and polymorphism of pharmaceuticals in the solid state. Once the theoretical basis of optical nonlinearity of crystalline structures is established, a new and rapid method based on this physical theory can be developed to quantitatively determine polymorphism or crystallinity. An apparatus was set up to measure the second harmonic response of powdered samples when irradiated with a pulsed laser source. The response of quartz-glass, enalapril maleate forms I-II and enalapril maleate form II-PVP mixtures were measured and modeled. It was found that the quartz-glass system showed high sensitivity to the presence of quartz and was well predicted by our theoretical model. The response of enalapril maleate polymorph mixtures was also sensitive to changes in the polymorph ratio. The theoretical predictions of the polymorph mixtures agreed quantitatively with the experimental results. The response of enalapril maleate form II-PVP mixtures agreed quantitatively with the physical model and showed extremely low noise and high sensitivity, giving very promising limits of detection (LOD) and quantification (LOQ) of 0.12 and 0.41%, respectively. This rapid, novel technique has potential for industrial monitoring of pharmaceutical manufacturing processes.