Margherita Zanol

A study on the differentiation between amorphous piroxicam:β-cyclodextrin complex and a mixture of the two amorphous components

Amorphous piroxicam was prepared by the melt spinning method to prove that freeze-dried amorphous piroxicam:β-cyclodextrin is a true inclusion compound and not a dispersed mixture of the two amorphous components. Differential scanning calorimetry (DSC) and near-infrared Fourier transform Raman spectroscopy (NIR FT-Raman) established the success of the encapsulation. Thermal analysis can also be used to evaluate the inclusion complex purity with regard to crystalline and/or amorphous free piroxicam content.

Raman and solid state13C-NMR investigation of the structure of the 1 : 1 amorphous piroxicam : ?-cyclodextrin inclusion compound

The results of a Raman and solid state 13C-NMR spectroscopic investigation aimed at studying the conformation of piroxicam (P) and its interaction with beta-cyclodextrin (betaCD) in 1 : 1 amorphous PbetaCD inclusion compound are reported. The 1700-1200 cm(-1) FT-Raman and the 13C CP/MAS NMR spectra of 1 : 1 PbetaCD inclusion compound are discussed and assigned in comparison with those of the three main modifications of piroxicam (alpha, beta, and monohydrate). The FT-Raman and 13C-NMR results show that in 1 : 1 PbetaCD inclusion compound piroxicam mainly assumes the zwitterionic structure typical of monohydrate, even if the presence of a different structure, that is, beta form, is not excluded. Piroxicam monohydrate, differently from alpha and beta forms, is characterized by a zwitterionic structure with an internal proton transfer and an increased charge delocalization, as shown by our spectroscopic results. The charge delocalization characteristic of this zwitterionic structure gives rise to the interaction with betaCD via electrostatic and hydrogen bonds. The possibility of a host-guest interaction between piroxicam and betaCD is not excluded; the guest molecule can be accommodated in betaCD cavity by interaction via hydrophobic bonds.

Study of β-cyclodextrin-ketoconazole-tartaric acid multicomponent non-covalent association by positive and negative ionspray mass spectrometry

In continuation of studies of multicomponent non-covalent associations (MCAs) of cyclodextrin (CD) inclusion or host–guest (H–G) complexes of hydrophobic or barely water-soluble drugs with suitable counter ions, which can dramatically increase the hydrosolubility of the guest drug, was the β-CD–KC–tartaric acid (TA) MCA, where KC=ketoconazole, an antifungal drug, investigated by ionspray (IS) mass spectrometry (MS) and MS/MS in both the positive and negative ion modes. In the positive IS mode a protonated 1:1:1 β-CD–KC–TA gaseous species is obtained, which dissociates by the loss of TA upon collisional activation (CA), thus reproducing the same behaviour as observed previously for a β-CD–terfenadine–TA MCA. Unprecedented results were obtained in the negative ion mode. In particular, deprotonated 1:1:1 β-CD–KC–TA MCA was detected, which upon CA yielded mainly deprotonated 1:1 β-CD–TA and tartrate anion. Hence, while a relatively strong interaction binding β-CD to TA within the MCA parent anion emerges, the fair abundance of tartrate anion could suggest the formation of its neutral complementary fragment, 1:1 β-CD–KC, a possibly H–G complex not observed as a negatively charged MS/MS fragmentation product. The role of the KC–TA ionic bonding of the neutral MCA appears very pertinent to the study by positive and negative ISMS of the non-covalent interactions within the gaseous protonated or deprotonated ternary complex thereof.

Letter: Support for the proposed observation by ionspray mass spectrometry of piroxicam/β-cyclodextrin and terfenadine/β cyclodextrin non-covalent inclusion complexes

Dear Sir In recent years increasing effort has been directed to the investigation of guest–host non-covalent inclusion complexes by mass spectrometry. Almost all of the so-called “soft” mass spectrometric methods have been exploited in order to generate and characterise intact charged species in the gas phase of such weak supramolecular associations. We are presently concerned l–3 with the study of the non-covalent inclusion complexes of guest-drug molecules in the hydrophobic cavity of host-cyclic oligosaccharides such as cyclodextrins (CDs). These complexes are of current interest to the pharmaceutical industry, as they are able to improve the solubility, stability and bioavailability of the guest-drug. 4

Studies on the metabolism of cadralazine in rat

SummaryThe metabolism of cadralazine I was studied after oral administration to rat. Besides consistent amount of unchanged drug, three metabolites were separated in urine by TLC and GC and their structures elucidated by mass spectrometry in comparison with synthetie samples. A specific and sensitive method was developed to detect the decarbethoxylated metabolite III at nanogram levels.

Quantitative determination of propildazine in rat plasma by gas-liquid chromatography

A gas-liquid chromatographic method for the evaluation of the new anti-hypertensive drug propildazine (ISF 2123) in rat plasma is described. The procedure involves separation of the drug from plasma by cation-exchange chromatography, subsequent acylation of the dried eluate with heptafluorobutyric anhydride and quantitation with electron-capture detection. Propildazine can be determined in concentrations down to ca. 0.4 microgram/ml.

Letter: Structural identification of 1-(4-hydroxy-3-methoxymethyl-phenyl)-2-(t-butylamino)-ethanol, a new impurity in the manufacture of Salbutamol

Dear Sir Impurities (related substances) in raw materials can arise from a number of sources. These include the more obvious types such as synthetic starting materials, reagents and intermediates. In addition, there are the less predictable synthetic by-products and degradation products. The identification of the majority of them undoubtedly helps to speed up the granting of a product license, such information being a mandatory component of the submission. Salbutamol [1-(4-hydroxy-3-hydroxymethyl-phenyl)2-(t-butylamino)ethanol, Figure 1] is a β-adrenergic amine used for the treatment of asthma, which has long been available to the medical profession. Therefore, its synthetic and degradative impurities have been characterised by earlier workers. 1–7

Raman spectra of piroxicam: a polymorphic drug

Piroxicam (P, 4-hydroxy-2-methyl-NK2-pyridyl)-2H1, 2-benzothiazine-3-arboxaimde-1, 1 -dioxide) represents an example of a polymorphic drug, since it can exist in two stable polymorphic forms (α and β) and in one pseudopolymorph (monohydrate) [1]. It is a non-steroidal anti-inflammatory drug poorly soluble in water; therefore, in order to improve its absorption, achieve a rapid onset of analgesic activity and increase its gastric tolerability, the compound was complexed with β-cyclodextrin (βCD) [2].

Structural characterization and solution rotational isomerism of delapril hydrochloride, a dipeptide angiotensin-converting enzyme inhibitor

Abstract The solid state structure of delapil hydrochloride was determined by single-crystal X-ray diffraction analysis (monoclinic, P21, a=16.098(5), b=10.712(3), c=7.856(2) A , β=97.85(2)° . The comparison between delapril and other ACE inhibitors of the same family is discussed with regard to the geometry of the phenomenological active site of the enzyme. In the solid state the amide bond conformation resulted in being trans, whereas, in solution, NMR spectra indicate that the molecule exists as a mixture of rotational isomers trans and cis (approximately 70:30). The free energy of activation for the hindered rotation about the amide bond was determined by line-shape analysis. The attempt to isolate possible conformational polymorphs failed, indicating that the trans conformation is favored when molecules pack together in the crystal.