Old Polymorph, New Technique: Assessing Ritonavir Crystallinity Using Low-Frequency Raman Spectroscopy

Abstract

Two decades ago, postmarket discovery of a second crystal form of ritonavir with lower solubility had major implications for drug manufacturers and patients. Since then, ritonavir has been reformulated via the hot−melt−extrusion process in an amorphous form. Here, quantitative low-and midfrequency Raman spectroscopy methods were developed to characterize polymorphs, form I and form II, in commercial ritonavir 100 mg oral tablets as an alternate analysis approach compared to X-ray powder diffraction (XRPD). Crystallization in three lots of ritonavir products obtained from four separate manufacturers was assessed after storage under accelerated conditions at 40 °C and 75% relative humidity (RH). Results were compared with quantitative XRPD methods developed and validated according to ICH Q2 (R1) guidelines. In a four-week open-dish study, form I crystallization occurred in two of the four products and form II crystallization was detected in another ritonavir product. The limits of detection for XRPD, low-frequency Raman (LFR), and mid-frequency Raman (MFR) were determined to be 0.7, 0.8, and 0.5% for form I and 0.6, 0.6, and 1% for form II, respectively. Root-mean-squared-error of predictions were 0.6−1.0 and 0.6−2.5% for LFR-and MFR-based partial least-squares models. Further, ritonavir polymorphs could also be identified and detected directly from ritonavir tablets using transmission LFR. In summary, LFR was applied for the assessment of polymorphism in real-world samples. While providing analytical performance similar to conventional techniques, LFR reduced the single measurement time from 66 min (XRPD) to 10 s (LFR) without the need for tedious sample preparation procedures.

In Operando Analysis of Milk-Based Oral Formulations during Digestion Using Synchrotron Small-Angle X-ray Scattering Coupled to Low-Frequency Raman Spectroscopy

“…Given the demonstrated simplicity of incorporating a LFR setup within a SAXS beamline infrastructure, similar experiments could become part of an analysis framework that could ease the transfer of knowledge to a lab-based (routine analysis) environment, and vice versa. This is particularly important to highlight in relation to the advent of holographic volume Bragg filters necessary for dispersive LFR setups, where custom-built systems can now be substituted with commercial options, allowing for a new user base to utilize the advantages of the technique . This, for example, has resulted in new research directions being explored, including the recent discovery of a potential correlation of LFR domain to lipid mesophase structural information .…”

Tale of Two Polymorphs: Investigating the Structural Differences and Dynamic Relationship between Nirmatrelvir Solid Forms (Paxlovid)

“…In situ VT-Raman spectroscopy makes use of the THz Raman technique, which is a relatively new technology. While it is increasingly being used to distinguish low-frequency phonon vibrations for crystal form characterization owing to its advantage over PXRD, the concept of variable-temperature aspect added into the THz Raman monitoring is not commonly used in pharmaceutical industry to support regulatory filings, let alone simultaneously tracking the functional group and low-frequency vibrations. For this we have built a custom-made technique, where we monitor the functional group and the low-frequency vibrations in parallel to obtain insights into the solid-state transformation of nirmatrelvir while being subjected to thermal cycling at 2 °C/min ramp rate.…”