How can we improve the physical stability of co-amorphous system containing flutamide and bicalutamide? The case of ternary amorphous solid dispersions

The article describes the preparation and characterization of binary mixtures of two antiandrogens used in prostate cancer treatment, i.e. flutamide (FL) and bicalutamide (BIC), as well as their ternary mixtures with either poly(methyl methacrylate-co-ethyl acrylate) (MMA/EA) or polyvinylpyrrolidone...

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Bibliographic Details
Published in:European journal of pharmaceutical sciences 2019-08, Vol.136, p.104947, Article 104947
Main Authors: Pacult, Justyna, Rams-Baron, Marzena, Chmiel, Krzysztof, Jurkiewicz, Karolina, Antosik, Agata, Szafraniec, Joanna, Kurek, Mateusz, Jachowicz, Renata, Paluch, Marian
Format: Article
Language:English
Subjects:
Acrylates - chemistry
Anilides - chemistry
Bicalutamide
Co-amorphous
Crystallization - methods
Drug Delivery Systems - methods
Drug Stability
Excipients - chemistry
Flutamide
Flutamide - chemistry
Glass transition
Methylmethacrylate - chemistry
Molecular dynamics
Nitriles - chemistry
Physical stability
Polymers - chemistry
Povidone - chemistry
Solubility - drug effects
Tosyl Compounds - chemistry
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Summary:The article describes the preparation and characterization of binary mixtures of two antiandrogens used in prostate cancer treatment, i.e. flutamide (FL) and bicalutamide (BIC), as well as their ternary mixtures with either poly(methyl methacrylate-co-ethyl acrylate) (MMA/EA) or polyvinylpyrrolidone (PVP). The samples were converted into amorphous form to improve their water solubility and dissolution rate. Broadband dielectric spectroscopy and differential scanning calorimetry revealed that FL-BIC (65%) (w/w) does not tend to crystallize from the supercooled liquid state. We made the assumption that the drug-to-drug weight ratio should be maintained as in the case of monotherapy so we decided to investigate the system containing FL and BIC in 15:1 (w/w) ratio with 30% additive of polymers as stabilizers. Our research has shown that only in the case of the FL-BIC-PVP mixture the crystallization has been completely inhibited, both in glassy and supercooled liquid state, which was confirmed by X-ray diffraction studies. In addition, we performed solubility and dissolution rate tests, which showed a significant improvement in solubility of ternary system as compared to its crystalline counterpart. Enhanced physical stability and water solubility of the amorphous ternary system makes it promising for further studies. [Display omitted]
ISSN:0928-0987
1879-0720
DOI:10.1016/j.ejps.2019.06.001