4.4.2. Raman Spectroscopy (RS)

RS is a versatile analytical technique that can be used in drug and formulation development, process control, as well as post-sale analyses [88]. Multivariate data analysis techniques are valuable for opening spectra to interpretation, allowing quantification of compounds, and simplification of large spectral data sets. In the pharmaceutical industry, multivariate techniques, such as partial least squares (PLS) analysis has permitted compounds or properties of compounds to be quantified. API quantification and the ability to determine interactions between API and excipients are examples of this [88].

RS can be used as a tool to identify the phases and phase transitions of various NCM, determine which regions of a nanomaterial are amorphous or crystalline [113–115], whether there are any defects present in the nanomaterial, determine the size (diameter, lateral

dimensions, etc.) of various types of nanomaterials [116,117], whether the nanomaterial is homogenous or whether a dispersion of nanoparticles is uniform in size, determine the shape of nanomaterials (rod, spherical, etc.), and differentiate between different allotropes of the same material [118].

Spironolactone NC were synthesized with different stabilizers including poloxamers 407 and 188, hydroxypropyl methylcellulose (HPMC), and sodium deoxycholate. Preformulation and post-formulation experiments using RS to compare the drug nanosuspensions and raw materials were used. Peak shifts were not observed in spironolactone NC stabilised with poloxamer 188, HPMC, and sodium deoxycholate. However, the Raman spectra revealed API peak disappearance with poloxamer 407 stabilized NC, indicating that interactions between drug and stabiliser had occurred in that case [119].

A novel bottom-up process to fabricate fenofibrate NCM termed as "controlled crystallization during freeze-drying" (CCDF) was used to synthesize NC. The size of the NC in this process was influenced by various factors including the freezing rate. To determine the stage at which solute crystallisation occurred, RS monitoring was used. The in-line Raman measurements showed that the first two steps, the freezing step, and the crystallization step are critical steps that determined the final size of the fenofibrate crystals [120].
