Spectroscopic and X-Ray Diffraction Study of Structural Disorder in Cryomilled and Amorphous Griseofulvin

Abstract

Structural disorder induced by cryogenic milling and by heating to the amorphous phase in the active pharmaceutical ingredient Griseofulvin has been studied using Raman spectroscopy, X-ray powder diffraction (XRPD), and fluorescence spectroscopy. A broad, exciting-frequency-independent scattering background in the Raman spectra and changes in intensities and splitting of some of the Raman lines due to lattice and molecular modes have been observed. In the cryomilled samples this strong background is deconvoluted into two components: one due to lattice disorder induced by cryomilling and the other due to Mie scattering from nanosized crystallites. A single-component background scattering attributed to lattice disorder is seen in the Raman spectrum of the amorphous sample. Fluorescence measurements showed an intrinsic fluorescence signal in as-received Griseofulvin that does not correspond to the inelastic background in the Raman spectra and, moreover, decreases in intensity upon cryomilling, thus excluding an assignment of the Raman background intensity to impurity- or molecular-defect-induced fluorescence. Wide-angle XRPD measurements on cryomilled Griseofulvin shows a broad two-component background consistent with the background-scattering component in the Raman data associated with lattice disorder, but at longer correlation lengths. Persistence of this disorder to even longer lengths is evident in small-angle synchrotron XRPD data on micronized Griseofulvin taken as a function of temperature from the crystalline to the amorphous phase.

Spray-Dried Amorphous Solid Dispersions of Griseofulvin in HPC/Soluplus/SDS: Elucidating the Multifaceted Impact of SDS as a Minor Component

“…Figure 4 illustrates the Raman spectra of as-received GF, the spray-dried formulation with a 1:3 GF:polymer ratio, and the corresponding PMs. The spectra of as-received GF and PMs of GF agree well with the Fourier transform Raman data of Feng et al [64] and Raman data ofŻarów et al [65] for crystalline GF. In the Raman lines of the GF crystals, the spectral range from 1550 to 1800 cm −1 corresponds to the C=O stretching vibrational frequencies and displays a characteristic triplet of lines.…”

Use of low-frequency Raman spectroscopy and chemometrics for the quantification of crystallinity in amorphous griseofulvin tablets

“…A study of structural disorder in cryo-milled amorphous drug reported the Raman spectra of micronized crystalline and various amorphous forms [33]. The changes described in this paper on going from amorphous to crystalline material are similar to those observed in this study (noting that the different excitation Fig.…”

“…There are three reported crystalline polymorphic forms of griseofulvin: the stable form I and the metastable forms II and III [32]. The amorphous form of griseofulvin can be prepared either by quench cooling or cryomilling [33,34]. The crystallization of amorphous forms of griseofulvin has previously been characterized using XRPD, DSC and isothermal microcalorimetry [35][36][37].…”

Complementary Near‐Infrared and Raman Chemical Imaging of Pharmaceutical Thin Films

“…Figure 5 shows the Raman spectra of HPMC, griseofulvin, and clusters of griseofulvin found within the film. The boxed region indicates the spectral region with the strong 1620 cm −1 griseofulvin band 25. The griseofulvin cluster spectrum was obtained directly from Film 3 regions wherein the 1620 cm −1 band had a high intensity.…”

“…Higher spatial resolution is therefore obtained by micro‐Raman mapping, and this method could also eventually detect the presence of inhomogeneity, impurities, and/or API polymorphs in the films 12,26. The spectra obtained were compared with those from a prior study wherein the structural disorder induced by cryogenic milling and by heating to the amorphous phase of the API were studied using Raman spectroscopy, X‐ray powder diffraction, and fluorescence spectroscopy 25. For griseofulvin films, Raman mapping analysis did not show a solid phase transition such as amorphization upon film formation, as determined by the enhanced intensity of a characteristic Raman line for crystalline griseofulvin at 830 cm −1 reported by Zarow et al25…”