Real-Time In situ XRD Study of Simvastatin Crystallization in Levitated Droplets

Abstract

Simvastatin (SV) is an important active pharmaceutical ingredient (API) for treatment of hyperlipidemias, which is known to exist in different crystalline and amorphous phases. It is, therefore, an interesting model to investigate how the outcome of evaporative crystallization in the contactless environment of an acoustically levitated droplet may be influenced by key experimental conditions, such as temperature, solvent properties (e.g., polarity and hygroscopicity), and dynamics of the evaporation process. Here, we describe a real-time and in situ study of simvastatin evaporative crystallization from droplets of three solvents that differ in volatility, polarity, and protic character (acetone, ethanol, and ethyl acetate). The droplet monitorization relied on synchrotron X-ray diffraction (XRD), Raman spectroscopy, imaging, and thermographic analysis. A pronounced solvent-dependent behavior was observed. In ethanol, a simvastatin amorphous gel-like material was produced, which showed no tendency for crystallization over time; in ethyl acetate, a glassy material was formed, which crystallized on storage over a two-week period to yield simvastatin form I; and in acetone, form I crystallized upon solvent evaporation without any evident presence of a stable amorphous intermediate. The XRD and Raman results further suggested that the persistent amorphous phase obtained from ethanol and the amorphous precrystallization intermediate formed in ethyl acetate were similar. Thermographic analysis indicated that the evaporation process was accompanied by a considerable temperature decrease of the droplet surface, whose magnitude and rate correlated with the solvent volatility (acetone > ethyl acetate > ethanol). The combined thermographic and XRD results also suggested that, as the cooling effect increased, so did the amount of residual water (most likely captured from the atmosphere) remaining in the droplet after the organic solvent was lost. Finally, the interpretation of the water fingerprint in the XRD time profiles was aided by molecular dynamics simulations, which also provided insights into the possible role of H2O as an antisolvent that facilitates simvastatin crystallization.

Evaporative Crystallization of Simvastatin from Different Solutions Using Mid-Frequency Raman Difference Spectra Explanations

“…The small solution volumes and blow-drying are beneficial to obtain high supersaturation, which is beneficial to form amorphous SIM. Different from the amorphous SIM obtained from levitated AC droplets that were not stable and existed only as an intermediate, 33 amorphous SIM obtained here through volatilizing SIM 10 wt% AC solution is a metastable product. The coexistence of amorphous SIM and Form I crystals can be observed in our experiment with a suitable volume of 10 wt % SIM solutions used (Fig.…”

“…The mid-frequency Raman difference spectra analysis results shown above show that the short-range orders of the three SIM solutions studied here are more similar to that of amorphous SIM than Form I, indicating that the three SIM solutions have the trend to form amorphous SIM, and the preparation of amorphous SIM from the three SIM solutions through specific crystallization in levitated droplets has been reported. 33 Herein, amorphous SIM and Form I were prepared separately using 10 wt% SIM solution through a common solvent evaporation method by simply controlling the solvent volatilization rate (Fig. 5).…”

“…Water, as a common antisolvent, has been used to promote the production of crystalline SIM from solutions 33 and is also considered to facilitate the molecular motions needed for an amorphous-to-crystal transition. The effect on the outcome polymorphs of introducing water into SIM AC solutions was researched in this work (Fig.…”

“…29,30 A recent work reported that amorphous SIM could be prepared by evaporative crystallization from levitated droplets of SIM solutions without any additives. 33 Thus, we chose SIM as the model molecule in this work to use the mid-frequency Raman difference spectra method to explain why amorphous SIM can be easily obtained from different SIM solutions.…”

Professor Roger Davey: Master ofAllCrystal Trades

“…More than 20 crystallization scientists trained by Roger have gone on to work in the pharmaceutical industry for at least six different companies. This virtual special issue in Celebration of the Career of Roger Davey contains papers that deal with pharmaceutical materials − or arise from the collaboration between academia and the pharmaceutical industry − or come directly from the pharmaceutical industry. , …”