The solid-state form of an active pharmaceutical ingredient (API) in an oral dosage form plays an important role in determining the dissolution rate of the API. As the solid-state form can change during dissolution, there is a need to monitor the oral dosage form during dissolution testing. Coherent anti-Stokes Raman scattering (CARS) microscopy provides rapid, spectrally selective imaging to monitor the oral dosage form during dissolution. In this study, in situ CARS microscopy was combined with inline UV absorption spectroscopy to monitor the solid-state change in oral dosage forms containing theophylline anhydrate undergoing dissolution and to correlate the solid-state change with a change in dissolution rate. The results from in situ CARS microscopy showed that theophylline anhydrate converted to theophylline monohydrate during dissolution resulting in a reduction in the dissolution rate. The addition of methyl cellulose to the dissolution medium was found to delay the theophylline monohydrate growth and changed the morphology of the monohydrate. The net effect was an increased dissolution rate for theophylline anhydrate. Our results show that in situ CARS microscopy combined with inline UV absorption spectroscopy is capable of monitoring oral dosage forms undergoing dissolution and correlating changes in solid-state form with changes in dissolution rate.

Drug particles can be produced in the proper aerodynamic particle size distribution (PSD) for inhalation by techniques such as micronisation or spray drying (1–5 µm). However, mixing with coarse carrier particles may change the PSD by agglomeration. Furthermore, the spatial distribution of the drug particles on the carrier particles in adhesive mixtures is highly relevant to the dispersion performance of inhalation powders. Coherent anti‐Stokes Raman scattering (CARS) microscopy is capable of chemically selective imaging, allowing the distribution of drug particles on the surface of carrier particles to be visualised. We used CARS microscopy to image the drug distribution for budesonide and salmeterol on the surface of lactose carrier particles. Image analysis was performed to determine the drug PSD that was then compared with the PSD obtained from laser diffraction. Additionally, comparative CARS and scanning electron microscopy (SEM) images were recorded to allow a direct comparison of the images obtained from CARS microscopy and from SEM. CARS microscopy revealed the drug to be in clusters on the surface of the carrier particles, while the image analysis identified 68% of the particles to have a median area of 0.4 µm2. Image analysis resulted in measurement of larger particles than laser diffraction, which may be caused by agglomeration during mixing. The combined chemical and morphological information from comparative CARS and SEM analysis resulted in unambiguous identification of the spatial drug distribution over the carrier surface. Our results indicate that CARS microscopy is a useful tool to study adhesive mixtures for inhalation. Copyright © 2014 John Wiley & Sons, Ltd.

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Implications: Extreme caution should be applied when examining data about subgroups within the 'Asian' category.