Studies on the Vitrified and Cryomilled Bosentan.

Aldona Minecka,Rafał Łunio,Daniel Żakowiecki,Barbara Hachuła,Krzysztof Chmiel,Karolina Jurkiewicz,Marian Paluch,Kajetan Koperwas,Bartłomiej Milanowski,Kamil Kamiński,Ewa Kamińska,Kinga Hyla

doi:10.1021/acs.molpharmaceut.1c00613

Abstract

In this paper, several experimental techniques [X-ray diffraction, differential scanning calorimetry (DSC), thermogravimetry, Fourier transform infrared spectroscopy, and broad-band dielectric spectroscopy] have been applied to characterize the structural and thermal properties, H-bonding pattern, and molecular dynamics of amorphous bosentan (BOS) obtained by vitrification and cryomilling of the monohydrate crystalline form of this drug. Samples prepared by these two methods were found to be similar with regard to their internal structure, H-bonding scheme, and structural (α) dynamics in the supercooled liquid state. However, based on the analysis of α-relaxation times (dielectric measurements) predicted for temperatures below the glass-transition temperature (Tg), as well as DSC thermograms, it was concluded that the cryoground sample is more aged (and probably more physically stable) compared to the vitrified one. Interestingly, such differences in physical properties turned out to be reflected in the lower intrinsic dissolution rate of BOS obtained by cryomilling (in the first 15 min of dissolution test) in comparison to the vitrified drug. Furthermore, we showed that cryogrinding of the crystalline BOS monohydrate leads to the formation of a nearly anhydrous amorphous sample. This finding, different from that reported by Megarry et al. [Carbohydr. Res.2011, 346, 1061−106421492830] for trehalose (TRE), was revealed on the basis of infrared and thermal measurements. Finally, two various hypotheses explaining water removal upon cryomilling have been discussed in the manuscript.

Highlights

Over the years, the pharmaceutical industry developed a number of approaches that led to the increase of the solubility, dissolution rate, and bioavailability of poorly watersoluble drugs from solid dosage forms
Amorphous BOS obtained by two methods, vitrification and cryomilling, was thoroughly characterized
X-ray diffraction and infrared spectroscopy examinations showed that both disordered samples are very similar in terms of the local structure and H-bonding scheme

Summary

■ INTRODUCTION

The pharmaceutical industry developed a number of approaches that led to the increase of the solubility, dissolution rate, and bioavailability of poorly watersoluble drugs from solid dosage forms. We found out that regardless of the chosen method of amorphization (vitrification or cryogrinding), the samples are nearly identical in terms of the local structure and H-bonding scheme They differ significantly with respect to their dynamical properties below the Tg, as well as in dissolution rates with respect to the crystalline form of API. The IDRs were calculated from each curve’s slope for periods of 0−120 min for crystalline BOS, and 0−15 and 60− 120 min for vitrified and cryomilled BOS, respectively

■ RESULTS AND DISCUSSION

■ CONCLUSIONS

■ ACKNOWLEDGMENTS

■ REFERENCES