Transmission Low-Frequency Raman Spectroscopy for Quantification of Crystalline Polymorphs in Pharmaceutical Tablets

Abstract

The purpose of this study was to quantify polymorphs of active pharmaceutical ingredients in pharmaceutical tablets using a novel transmission low-frequency Raman spectroscopy method. We developed a novel transmission geometry for low-frequency Raman spectroscopy and compared quantitative ability in transmission mode versus backscattering mode using chemometrics. We prepared two series of tablets, (1) containing different weight-based contents of carbamazepine form III and (2) including different ratios of carbamazepine polymorphs (forms I/III). From the relationship between the contents of carbamazepine form III and partial least-squares (PLS) predictions in the tablets, correlation coefficients in transmission mode (R 2 = 0.98) were found to be higher than in backscattering mode (R 2 = 0.97). The root-mean-square error of cross-validation (RMSECV) of the transmission mode was 3.9 compared to 4.9 for the backscattering mode. The tablets containing a mixture of carbamazepine (I/III) polymorphs were measured by transmission low-frequency Raman spectroscopy, and it was found that the spectral shape changed according to the ratio of polymorphs: the relationship between the actual content and the prediction showed high correlation. These findings indicate that transmission low-frequency Raman spectroscopy possesses the potential to complement existing analytical methods for the quantification of polymorphs.

Application of Transmission Raman Spectroscopy in Combination with Partial Least-Squares (PLS) for the Fast Quantification of Paracetamol

“…In pharmaceutical manufacturing and finished product testing, determining the content of drugs using high-performance liquid chromatography (HPLC) testing is not only time-consuming but also destructive. In recent years, transmission Raman spectroscopy (TRS) has been widely used in the quantification of API and excipients in drugs [ 1 , 2 , 3 ] and the quantification of polymorphs in pharmaceutical formulations [ 4 , 5 ]. It is a fast and practical technique and also has the ability to obtain highly chemical-specific information and quantitative volumetric data from thick and highly turbid samples [ 6 , 7 , 8 ].…”

A New Frontier for Nondestructive Spatial Analysis of Pharmaceutical Solid Dosage Forms: Spatially Offset Low-Frequency Raman Spectroscopy

“…This phenomena enables nondestructive subsurface data collection from different objects, including pharmaceutical mixtures, drug containers, and solid dosage forms such as tablets and capsules. ,, Additionally, with advances in instrumentation and narrow wavelength band filters, low-frequency Raman spectroscopy (LFRS), sometimes also called THz Raman spectroscopy, has recently experienced a surge in popularity as it probes low-energy vibrational modes (<300 cm –1 ) related to long-range order (i.e., crystallinity) and thus provides a unique information on solid-state/structural properties . It has also been incorporated into various instrumental setups allowing, for example, the analysis of solid dosage forms via transmission measurements among other variations . This study aimed to combine both aforementioned Raman subtechniques into spatially offset low-frequency Raman spectroscopy (SOLFRS) and highlight its capabilities through the analysis of several pharmaceutical model systems.…”

Recent advances in nano-photonic techniques for pharmaceutical drug monitoring with emphasis on Raman spectroscopy

“…for drug sensing [33][34][35][36][37][38][39] in forensics [28,29,31,40] and in the pharmaceutical industry [32]. For example, transmission Raman-based methods enable at-line or on-line analysis of bulk content of tablets [41][42][43] or active pharmaceutical ingredients (APIs) of other solid dosage forms [44]. This technique reached a high level of applicability [44]: cost-savings have been demonstrated in real-world use [45], and considerations for regulatory submission are being discussed [46] for pharmaceutical applications.…”