Abstract
The amorphous form of carvedilol phosphate (CVD) was obtained as a result of grinding. The identity of the obtained amorphous form was confirmed by powder X-ray diffraction (PXRD), different scanning calorimetry (DSC), and FT-IR spectroscopy. The process was optimized in order to obtain the appropriate efficiency and time. The crystalline form of CVD was used as the reference standard. Solid dispersions of crystalline and amorphous CVD forms with hydrophilic polymers (hydroxypropyl-β-cyclodextrin, Pluronic® F-127, and Soluplus®) were obtained. Their solubility at pH 1.2 and 6.8 was carried out, as well as their permeation through a model system of biological membranes suitable for the gastrointestinal tract (PAMPA-GIT) was established. The influence of selected polymers on CVD properties was defined for the amorphous form regarding the crystalline form of CVD. As a result of grinding (four milling cycles lasting 15 min with 5 min breaks), amorphous CVD was obtained. Its presence was confirmed by the “halo effect” on the diffraction patterns, the disappearance of the peak at 160.5 °C in the thermograms, and the changes in position/disappearance of many characteristic bands on the FT-IR spectra. As a result of changes in the CVD structure, its lower solubility at pH 1.2 and pH 6.8 was noted. While the amorphous dispersions of CVD, especially with Pluronic® F-127, achieved better solubility than combinations of crystalline forms with excipients. Using the PAMPA-GIT model, amorphous CVD was assessed as high permeable (Papp > 1 × 10−6 cm/s), similarly with its amorphous dispersions with excipients (hydroxypropyl-β-cyclodextrin, Pluronic® F-127, and Soluplus®), although in their cases, the values of apparent constants permeability were decreased.
Highlights
Carvedilol phosphate (CVD) is a phosphate salt derivative of carbazole and propranolol, a non-cardioselective beta-blocker
PcoRnXfDirmweads buysepdowtodceornXfi-rrmaytdhieffcrraycstitoanlli(nPeXfRoDrm), idniftfhereesnttaiartlinscganmnain- g terciaallo. rimetry (DSC), and supported by Fourier-transform infrared spectroscopy (FT-IR) spectroscopy coupled with Density Functional Theory (DFT) calculations
powder X-ray diffraction (PXRD), different scanning calorimetry (DSC), and FT-IR spectroscopy confirmed the identity of the obtained amorphous form and the original crystalline structure of CVD
Summary
Carvedilol phosphate (CVD) is a phosphate salt derivative of carbazole and propranolol, a non-cardioselective beta-blocker. CVD is used in treatment as a racemic mixture; the S (−) enantiomer is a beta-adrenoceptor, and the R (+) enantiomer is both a beta and alpha-1 adrenoceptor blocker [1]. The result of blocking β receptors reduces the stroke and cardiac output capacity, reduces oxygen consumption by the heart muscle, reduces plasma renin activity, and inhibits norepinephrine release. Inhibition of alpha-1 adrenergic receptors determines the relaxation of smooth muscles in the circulatory system and lowers blood pressure. The use of high doses of CVD causes blockage of calcium channels and determines antioxidant activity, blocking the oxidation process of low-density lipoproteins, limiting their access to the coronary circulation. An essential aspect of modifying the therapy is discontinuing beta-blockers gradually before implementing a new treatment [5]
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