Scanning electron microscopy has been used to characterize solid-state changes on the surfaces of dosage forms after dissolution [10] and [17]. X-ray powder diffraction has been used to depth profile phase changes on samples undergoing dissolution related solid-state changes [17]. However, both SEM and XRPD are unsuitable for in situ analysis of dissolution due to sample preparation

requirements. Spontaneous Raman spectroscopy has been shown to be suitable for in situ analysis of solid-state transformations during dissolution [9] and [10]. Spontaneous Raman spectroscopy has the advantage that it can generate full IPI-145 cell line vibrational spectra in a relatively short period of time. Coupled with a flow through cell and UV flow through absorption spectroscopy, it has been used in situ to monitor various solid-state conversions and their effects on dissolution, including transformation from TPa to TPm, and the crystallization of amorphous IMC and CBZ. However, spontaneous Raman spectroscopy gives no spatial information, meaning that it is not capable of identifying where solid-state conversions are occurring during dissolution and techniques developed to map Raman intensity are slow Abiraterone solubility dmso (minutes to hours), precluding in

situ analysis during dissolution testing. Instead, we use coherent anti-Stokes Raman scattering (CARS) microscopy as a tool for in situ analysis during dissolution. A summary of CARS microscopy is provided in [18]. Briefly, CARS microscopy is capable of rapid spectrally- and spatially-resolved imaging

allowing the visualization of different solid-state forms of drugs based on their Raman vibrational spectra. A narrowband CARS setup typically utilizes two synchronized pulsed lasers, one of which is tuneable in wavelength. The two laser beams are Vasopressin Receptor temporally and spatially overlapped before being focused on the sample. If the frequency difference between the two laser beams matches a Raman active vibrational mode, an anti-Stokes (blueshifted with respect to input beams) signal is produced. Raman vibrational modes are specific for compounds or groups of compounds providing chemically specific images. As the CARS signal is produced only within the focal volume of the lasers, the process is inherently confocal, allowing resolution down to the diffraction limit in three dimensions. CARS is a third order non-linear optical technique that probes the same molecular vibrational frequencies as spontaneous Raman techniques. This means that CARS spectra are comparable to but not the same as Raman spectra. Coherent Raman techniques such as CARS have about 100 times faster imaging speed when compared to spontaneous Raman mapping techniques [19]. Spontaneous Raman techniques collect information over a wide spectral range, while narrowband coherent Raman techniques collect information from only a single Raman shift.