New degradation impurities at m/z 327.15 and m/z 311.16 using gradient UHPLC method with UV detection and highly selective QDa mass detection were observed during the ruxolitinib hydrobromide (RUX.HBr) : excipient binary mixture degradation study. High mass resolution LC-MS and nuclear magnetic resonance (NMR) techniques were employed to identify and fully characterize the degradation compounds. The degradation impurities were unambiguously identified as (R)-4-amino-6-(1-(2-cyano-1-cyclopentylethyl)-1H-pyrazol-4-yl)pyrimidine-5-carboxylic acid and (R)-3-(4-(6-amino-5-formylpyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropanenitrile and mechanism of their formation was proposed. It has been confirmed that the degradation products are formed in mixtures of RUX.HBr with some excipients in the presence of oxygen. Based on the forced degradation study, the chemically stable of pharmaceutical formulations were prepared to eliminate the formation of these impurities.
- MeSH
- hmotnostní spektrometrie MeSH
- kontaminace léku MeSH
- kyslík chemie MeSH
- magnetická rezonanční spektroskopie MeSH
- příprava léků MeSH
- pyrazoly analýza MeSH
- referenční standardy MeSH
- roztoky MeSH
- tablety analýza MeSH
- vysokoúčinná kapalinová chromatografie MeSH
- Publikační typ
- časopisecké články MeSH
PURPOSE: Imaging methods were used as tools to provide an understanding of phenomena that occur during dissolution experiments, and ultimately to select the best ratio of two polymers in a matrix in terms of enhancement of the dissolution rate and prevention of crystallization during dissolution. METHODS: Magnetic resonance imaging, ATR-FTIR spectroscopic imaging and Raman mapping have been used to study the release mechanism of a poorly water soluble drug, aprepitant, from multicomponent amorphous solid dispersions. Solid dispersions were prepared based on the combination of two selected polymers - Soluplus, as a solubilizer, and PVP, as a dissolution enhancer. Formulations were prepared in a ratio of Soluplus:PVP 1:10, 1:5, 1:3, and 1:1, in order to obtain favorable properties of the polymer carrier. RESULTS: The crystallization of aprepitant during dissolution has occurred to a varying degree in the polymer ratios 1:10, 1:5, and 1:3, but the increasing presence of Soluplus in the formulation delayed the onset of crystallization. The Soluplus:PVP 1:1 solid dispersion proved to be the best matrix studied, combining the abilities of both polymers in a synergistic manner. CONCLUSIONS: Aprepitant dissolution rate has been significantly enhanced. This study highlights the benefits of combining imaging methods in order to understand the release process.
- MeSH
- chemie farmaceutická metody MeSH
- krystalizace MeSH
- magnetická rezonanční tomografie metody MeSH
- morfoliny chemie MeSH
- nosiče léků chemie MeSH
- polyethylenglykoly chemie MeSH
- polymery chemie MeSH
- polyvinyly chemie MeSH
- pyrrolidiny chemie MeSH
- rozpustnost MeSH
- spektroskopie infračervená s Fourierovou transformací metody MeSH
- uvolňování léčiv MeSH
- voda chemie MeSH
- Publikační typ
- časopisecké články MeSH
PURPOSE: Imaging methods were used as tools to provide an understanding of phenomena that occur during dissolution experiments, and ultimately to select the best ratio of two polymers in a matrix in terms of enhancement of the dissolution rate and prevention of crystallization during dissolution. METHODS: Magnetic resonance imaging, ATR-FTIR spectroscopic imaging and Raman mapping have been used to study the release mechanism of a poorly water soluble drug, aprepitant, from multicomponent amorphous solid dispersions. Solid dispersions were prepared based on the combination of two selected polymers - Soluplus, as a solubilizer, and PVP, as a dissolution enhancer. Formulations were prepared in a ratio of Soluplus:PVP 1:10, 1:5, 1:3, and 1:1, in order to obtain favorable properties of the polymer carrier. RESULTS: The crystallization of aprepitant during dissolution has occurred to a varying degree in the polymer ratios 1:10, 1:5, and 1:3, but the increasing presence of Soluplus in the formulation delayed the onset of crystallization. The Soluplus:PVP 1:1 solid dispersion proved to be the best matrix studied, combining the abilities of both polymers in a synergistic manner. CONCLUSIONS: Aprepitant dissolution rate has been significantly enhanced. This study highlights the benefits of combining imaging methods in order to understand the release process.
- MeSH
- aprepitant MeSH
- chemie farmaceutická metody MeSH
- krystalizace MeSH
- magnetická rezonanční tomografie metody MeSH
- morfoliny chemie MeSH
- nosiče léků chemie MeSH
- polyethylenglykoly chemie MeSH
- polymery chemie MeSH
- polyvinyly chemie MeSH
- pyrrolidiny chemie MeSH
- rozpustnost MeSH
- spektroskopie infračervená s Fourierovou transformací metody MeSH
- uvolňování léčiv MeSH
- voda chemie MeSH
- Publikační typ
- časopisecké články MeSH
The rate of drug release from polymer matrix-based sustained release formulations is often controlled by the thickness of a gel layer that forms upon contact with dissolution medium. The effect of formulation parameters on the kinetics of elementary rate processes that contribute to gel layer formation, such as water ingress, polymer swelling and erosion, is therefore of interest. In the present work, gel layer formation has been investigated by magnetic resonance imaging (MRI), which is a non-destructive method allowing direct visualization of effective water concentration inside the tablet and its surrounding. Using formulations with Levetiracetam as the active ingredient, HPMC as a hydrophilic matrix former and carnauba wax (CW) as a hydrophobic component in the matrix system, the effect of different ratios of these two ingredients on the kinetics of gel formation (MRI) and drug release (USP 4 like dissolution test) has been investigated and interpreted using a mathematical model.
- MeSH
- deriváty hypromelózy chemie MeSH
- hydrofobní a hydrofilní interakce MeSH
- kinetika MeSH
- léky s prodlouženým účinkem chemie MeSH
- magnetická rezonanční tomografie MeSH
- piracetam analogy a deriváty chemie MeSH
- rozpustnost MeSH
- tablety MeSH
- teoretické modely MeSH
- uvolňování léčiv MeSH
- vosky chemie MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
The dissolution mechanism of a poorly aqueous soluble drug from amorphous solid dispersions was investigated using a combination of two imaging methods: attenuated total reflection-Fourier transform infrared (ATR-FTIR) spectroscopic imaging and magnetic resonance imaging (MRI). The rates of elementary processes such as water penetration, polymer swelling, growth and erosion of gel layer, and the diffusion, release and in some cases precipitation of drug were evaluated by image analysis. The results from the imaging methods were compared with drug release profiles obtained by classical dissolution tests. The study was conducted using three polymeric excipients (soluplus, polyvinylpyrrolidone - PVP K30, hydroxypropylmethyl cellulose - HPMC 100M) alone and in combination with a poorly soluble drug, aprepitant. The imaging methods were complementary: ATR-FTIR imaging enabled a qualitative observation of all three components during the dissolution experiments, water, polymer and drug, including identifying structural changes from the amorphous form of drug to the crystalline form. The comparison of quantitative MRI data with drug release profiles enabled the different processes during dissolution to be established and the rate-limiting step to be identified, which - for the drug-polymer combinations investigated in this work - was the drug diffusion through the gel layer rather than water penetration into the tablet.
- MeSH
- časové faktory MeSH
- magnetická rezonanční tomografie * přístrojové vybavení MeSH
- molekulární struktura MeSH
- morfoliny chemie MeSH
- polymery chemie MeSH
- spektroskopie infračervená s Fourierovou transformací přístrojové vybavení MeSH
- uvolňování léčiv MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
