Red-Excitation Dispersive Raman Spectroscopy is a Suitable Technique for Solid-State Analysis of Respirable Pharmaceutical Powders

Abstract

Dispersive Raman spectroscopy with excitation by a red diode laser is suitable for quantitative crystallinity measurements in powders for pulmonary drug delivery. In spray-dried mixtures of salmon calcitonin and mannitol, all three crystalline polymorphs of mannitol and amorphous mannitol were unambiguously identified and their mass fractions were measured with a limit of quantification of about 5%. The instrument design offered high sensitivity and adequate background suppression, resulting in a low limit of detection in the range of 0.01% to 1%. This spectroscopy method has significant advantages over established techniques regarding specificity, sensitivity, and sample requirements.

Characterization of Mannitol Polymorphic Forms in Lyophilized Protein Formulations Using a Multivariate Curve Resolution (MCR)-Based Raman Spectroscopic Method

“…There are five known polymorphic forms of mannitol reported in the literature, which include three anhydrous crystal forms [α-, β-, and δ-mannitol forms (3)], one hemihydrate form (4), and the amorphous form (5). At ambient conditions, β-mannitol was identified as the thermodynamically most stable form, while α-and δ-mannitol show significant kinetic stability (3).…”

“…However, the preparation of mixtures of all five mannitol forms is far more challenging due to the potential for phase transitions during mixing. Some efforts to establish analytical methods not based on reference mixture standards for the determination of mannitol crystallinity have been reported (5,23). Vehring reported the quantitation of amorphous mannitol and the three anhydrous crystal forms of α-, β-, and δ-mannitol from spray-dried mixtures of salmon calcitonin and mannitol.…”

“…XRPD was used to check the purity of the resulting mannitol forms by comparison with the literature data (3,4,25). Due to the instability of amorphous mannitol under ambient conditions, amorphous mannitol was confirmed by comparing its Raman spectrum with the Raman spectrum of a concentrated mannitol solution (5).…”

Raman characterization and chemical imaging of biocolloidal self-assemblies, drug delivery systems, and pulmonary inhalation aerosols: A review

“…It has been reported that red-excitation dispersive Raman spectroscopy can be applied to quantify polymorphism and amorphous content in a multicomponent dry powder formulation consisting of spray-dried mixtures of salmon calcitonin and mannitol 142 and in the study of the physical stability of these dry powder inhalation systems. 143 This technique of combining red diode laser excitation with dispersive Raman spectroscopy provides enhanced signal-to-noise ratio, higher sensitivity, and less sample heating compared with FT or dispersive Raman spectroscopy.…”

“…143 This technique of combining red diode laser excitation with dispersive Raman spectroscopy provides enhanced signal-to-noise ratio, higher sensitivity, and less sample heating compared with FT or dispersive Raman spectroscopy. 142 Combining a sensitive Raman system with visible excitation provides an enhanced signal-to-noise ratio, and the fluorescence background caused by visible excitation is not a limitation (as it is for biological applications) for pharmaceutical materials (excipients, biopolymers, proteins) owing to their high purity. These dry powder aerosols were analyzed by a diode laser operating at a wavelength of 669.85 nm, at a power of 250 mW, and with a spectral bandwidth of 1 cm .…”