Search

Abstract The direct quantification of Active Pharmaceutical Ingredients in solid formulations is a challenging open issue. A consolidated analytical technique based on X-ray Powder Diffraction is available, being the definitive test for the identification of polymorphs and crystal phases. However, its application for quantitative analysis is hindered by matrix effects: refinement methods (e.g. Rietveld method) require a complete knowledge of samples' composition, while univariate calibration methods require the matrix effect to be studied and severely suffer from the co-presence of crystalline and amorphous phases in the sample. Multivariate analysis is the only way to bypass problems affecting refinements procedures and univariate calibration. In particular, the multivariate standard addition method (SAM) is promising; however, it is straightforward only when the analytical blank (matrix devoid of analyte) is available: in that case SAM is applied by simply extrapolating the SAM model to the matrix experimental signal. In this work, the quantitative analysis of polymorphic forms of Active Pharmaceutical Ingredients based on X-ray Powder Diffraction is performed for the first time by a method based on multivariate standard addition method combined with net analyte signal procedure; it allows for reliable quantification of polymorphs of active principles in solid formulations, which are rapidly analyzed without any sample pre-treatment. Two test cases are presented: quantification of two polymorphs of piracetam in binary mixtures (forms II and III), and quantification of paracetamol (form I) in Tachifludec®. Graphical abstract Unlabelled Image [ABSTRACT FROM AUTHOR]

The additions of 3-aryl-2-propenyllithium and -zinc reagents to N,N′-di[1(S)-phenylethyl]ethanediimine in THF occurred by α and γ-addition, affording 4,5-diamino-1,7-dienes with linear and branched allylic substituents, respectively. 3-Phenoxy- and 3-alkoxy-2-propenyllithiums reacted with lack of regioselectivity, whereas the corresponding zinc reagents exclusively followed the γ-addition pathway. The (S)-configuration of the auxiliaries induced the preferential attack to the Re face of the azomethine groups. In the γ-addition route, four new stereocentres were formed and the simple (syn/anti) diastereoselectivity was dependent on the alkene geometry in the allylmetal reagents. C2-symmetric compounds with syn–syn–syn or anti–syn–anti relative stereochemistry were prevalently obtained. In contrast, when 3-ethoxy-2-propenylzinc chloride was prepared by transmetallation of the corresponding titanium reagent, a C1-symmetric compound (anti–syn–syn) was mainly formed. [Copyright &y& Elsevier]

The crystal structures of the monohydrate and anhydrous forms of ambazone were determined by single-crystal X-ray diffraction (SC-XRD). Ambazone monohydrate is characterized by an infinite three-dimensional network involving the water molecules, whereas anhydrous ambazone forms a two-dimensional network via hydrogen bonds. The reversible transformation between the monohydrate and anhydrous forms of ambazone was evidenced by thermal analysis, temperature-dependent X-ray powder diffraction and accelerated stability at elevated temperature, and relative humidity (RH). Additionally, a novel ambazone acetate salt solvate form was obtained and its nature was elucidated by SC-XRD. Powder dissolution measurements revealed a substantial solubility and dissolution rate improvement of acetate salt solvated form in water and physiological media compared with ambazone forms. Also, the acetate salt solvate displayed good thermal and solution stability but it transformed to the monohydrate on storage at elevated temperature and RH. Our study shows that despite the requirement for controlled storage conditions, the acetate salt solvated form could be an alternative to ambazone when solubility and bioavailability improvement is critical for the clinical efficacy of the drug product. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 103:3594-3601, 2014 [ABSTRACT FROM AUTHOR]

The water soluble dicarboxylic cationic acid [(η5-C5H4COOH)2CoIII]+ (1) as its Cl− salt has been treated thermally to produce the neutral zwitterion [(η5-C5H4COOH)(η5-C5H4COO)CoIII] (2). 2 reacts with HBr in water solution to yield the bromide salt of the dicarboxylic acid [(η5-C5H4–COOH)2CoIII]Br, 1Br. Preparation of the iodide [(η5-C5H4–COOH)2CoIII]I, 1I, has been achieved by direct oxidation of [(η5-C5H4Me)2CoIII]OH with KMnO4 immediately followed by reaction with HI. The crystal structures of 1Br and 1I have been determined by single crystal X-ray diffraction. The hydrogen bonding interactions between the acid cations and between the acid cation and the halide ions have been investigated. [Copyright &y& Elsevier]

Direct derivation (DD) is a novel Powder X-ray diffraction quantification method based on intensity–composition equation, which can determine the weight fraction of individual phases in a mixture of components by chemical formulas. The DD method was applied to determine crystallinity degree of binary mixtures containing amorphous hydroxypropyl methylcellulose and crystalline monohydrate α-lactose in weight percentage ≤ 15% w/w. Three different scenarios were considered: a) the unit cell parameters of the crystalline phases are available b) the unit cell parameters are unknown but the patterns of pure crystalline and amorphous references are available and c) only the mixtures' patterns are available. Relative errors in scenarios a and b were comparable and reasonable (<20%), while in c, the crystalline degree was clearly underestimated evidencing the importance of determining the maximum number of crystalline reflections This can be easily achieved when the unit cell parameters and/or the patterns of pure references are available. To simulate the quantification of high potent API, the method was evaluated considering the scenario b, in samples covered by Kapton® film as containment system. In this case, an accurate quantification was achieved by subtracting the film signal from the observed pattern. Image, graphical abstract [ABSTRACT FROM AUTHOR]