In vitro dissolution-permeation evaluation of an electrospun cyclodextrin-based formulation of aripiprazole using µFlux™.

Since it is a well-known fact that among the newly discovered active pharmaceutical ingredients the number of poorly water soluble candidates is continually increasing, dissolution enhancement of poorly water soluble drugs has become one of the central challenges of pharmaceutical studies. So far the preclinical studies have been mainly focused on formulation methods to enhance the dissolution of active compounds, in many cases disregarding the fact that the formulation matrix not only affects dissolution but also has an effect on the transport through biological membranes, changing permeation of the drug molecules. The aim of this study was to test an electrospun cyclodextrin-based formulation of aripiprazole with the novel µFlux apparatus, which monitors permeation together with dissolution, and by this means better in vitro-in vivo correlation is achieved. It was evinced that a cyclodextrin-based electrospun formulation of aripiprazole has the potential to ensure fast drug delivery through the oral mucosa owing to the ultrafast dissolution of the drug from the formulation and the enhanced flux across membranes as shown by the result of the novel in vitro dissolution and permeation test.

NMR assignments and the acid-base characterization of the pomegranate ellagitannin punicalagin in the acidic pH-range.

In exploring the capability of nuclear magnetic resonance (NMR) spectroscopy for pomegranate juice analysis, the eight aromatic singlet resonances of α- and ß-punicalagin were clearly identified in the (1)H NMR spectra of juice samples. The four downfield resonances were found to be sensitive to small pH changes around pH 3.50 where the NMR spectra of the juice samples were recorded. To understand this unusual behavior, the (1)H and (13)C resonance assignments of the punicalagin anomers were determined in aqueous solution and pH titrations with UV and (1)H NMR detection carried out to characterize the acid-base properties of punicalagin over the pH range 2-8. Simultaneous fitting of all of the pH-sensitive (1)H NMR signals produced similar but significantly different pKa values for the first two deprotonation equilibria of the gallagic acid moiety of the punicalagin α- (pKa1 = 4.57 ± 0.02, pKa2 = 5.63 ± 0.03) and ß- (pKa1 = 4.36 ± 0.01, pKa2 = 5.47 ± 0.02) anomers. Equivalent pKa values, (α : 6.64 ± 0.01, ß : 6.63± 0.01) were measured for the third deprotonation step involving the ellagic acid group, in good agreement with a prior literature report. The punicalagin anomer equilibrium readjusts in parallel with the proton dissociation steps as the pH is raised such that ß-punicalagin becomes the most abundant anomer at neutral pH. The unusual upfield shifts observed for the glucose H3 and H5 resonances with increasing pH along with the shift in the α/ß anomer equilibrium are likely the consequence of a conformational rearrangement.

Solution-state NMR spectroscopy of famotidine revisited: spectral assignment, protonation sites, and their structural consequences.

Multinuclear one (1D-) and two-dimensional (2D) nuclear magnetic resonance (NMR) spectroscopic investigations of famotidine, the most potent and widely used histamine H(2)-receptor antagonist, were carried out in dimethyl sulfoxide-d(6) (DMSO-d(6)) and water. Previous NMR assignments were either incomplete or full assignment was based only on 1D spectra and quantum-chemical calculations. Our work revealed several literature misassignments of the (1)H, (13)C, and (15)N NMR signals and clarified the acid-base properties of the compound at the site-specific level. The erroneous assignment of Baranska et al. (J. Mol. Struct. 2001, 563) probably originates from an incorrect hypothesis about the major conformation of famotidine in DMSO-d(6). A folded conformation similar to that observed in the solid-state was also assumed in solution, stabilized by an intramolecular hydrogen bond involving one of the sulphonamide NH(2) protons and the thiazole nitrogen. Our detailed 1D and 2D NMR experiments enabled complete ab initio (1)H, (13)C, and (15)N assignments and disproved the existence of the sulphonamide NH hydrogen bond in the major conformer. Rather, the molecule is predominantly present in an extended conformation in DMSO-d(6). The aqueous acid-base properties of famotidine were studied by 1D (1)H- and 2D (1)H/(13)C heteronuclear multiple-bond correlation (HMBC) NMR-pH titrations. The experiments identified its basic centers including a new protonation step at highly acidic conditions, which was also confirmed by titrations and quantum-chemical calculations on a model compound, 2-[4-(sulfanylmethyl)-1,3-thiazol-2-yl]guanidine. Famotidine is now proved to have four protonation steps in the following basicity order: the sulfonamidate anion protonates at pH = 11.3, followed by the protonation of the guanidine group at pH = 6.8, whereas, in strong acidic solutions, two overlapping protonation processes occur involving the amidine and thiazole moieties.

[Solid-state NMR spectroscopy and its pharmaceutical use]. / Sziárdfázisú NMR spektroszkópia es gyógyszerészeti alkalmazása.

Liquid-state NMR spectroscopy has become an essential analytical tool in almost all fields of chemical research. However, the scope of NMR spectroscopy is not confined to the analysis of fluids. The progress in the investigation of solid samples is remarkably fast and solid-state NMR has developed to a high performance method. The majority of drug substances and products manufactured in the pharmaceutical industry are formulated in solid state, their analysis gains the increasing potential of solid-state NMR spectroscopy. The aim of this work is to survey the basics of solid-state NMR and to highlight some pharmaceutical applications focusing on polymorphism.

Triprotic acid-base microequilibria and pharmacokinetic sequelae of cetirizine.

(1)H NMR-pH titrations of cetirizine, the widely used antihistamine and four related compounds were carried out and the related 11 macroscopic protonation constants were determined. The interactivity parameter between the two piperazine amine groups was obtained from two symmetric piperazine derivatives. Combining these two types of datasets, all the 12 microconstants and derived tautomeric constants of cetirizine were calculated. Upon this basis, the conflicting literature data of cetirizine microspeciation were clarified, and the pharmacokinetic absorption-distribution properties could be interpreted. The pH-dependent distribution of the microspecies is provided.