Enrico Redenti

Drug/cyclodextrin/hydroxy acid multicomponent systems. Properties and pharmaceutical applications.

The objective of this mini-review is to summarize the findings concerning the properties and the pharmaceutical applications of multicomponent complexes made of a sparingly water-soluble amino-type drug, a cyclodextrin, and a hydroxy carboxylic acid. Simultaneous complexation and salt formation with these acids significantly increase the solubilizing power, allowing us to reduce the amount of cyclodextrin necessary for making the targeted formulation. In many cases, the aqueous solubility of the hydrophobic drug can be enhanced by several orders of magnitude, while that of CD can be enhanced more than 10-fold. The mechanism through which these complexes elicit their synergetic effects on the drug solubility is also discussed. Finally, some general observations are made concerning the structural requirements of the drug necessary for exploiting the aforementioned effect.

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.

Interaction of Hydroxy Acids with β-Cyclodextrin

The solubility of β-cyclodextrin (β-CD) was studied in aqueous solutions of various organic acids. The hydroxy acids, especially citric and tartaric acid were found to increase the solubility of β-CD, while some other carboxylic acids reduced it. From solubility data the apparent complex association constants were calculated.

The terfenadine/β-cyclodextrin inclusion complex

Terfenatine (TFN) is a very hydrophobic antiallergic drug. It exists in three polymorphic and two solvated forms and is practically insoluble in water. These properties make a pharmaceutical formulation with acceptable biopharmaceutical characteristics difficult to prepare. Inclusion complexation with β-cyclodextrin (βCD) may eliminate such problems. The properties of the TFN/βCD system have been studied in liquid, gaseous and solid phases by1H and13C NMR spectroscopy, powder X-ray diffractometry, differential scanning calorimetry and fast atom bombardment mass spectrometry. The solubility phase diagram was also recorded. In solution and in the gaseous phase the 1∶1 complex prevails, whereas a 1∶2 TFN/βCD complex has been isolated by precipitation from homogeneous solution.

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

Complexation of Manidipine with Cyclodextrins and their Derivatives

Manidipine (MDP,(±)-2-[-(diphenylmethyl)-1-piperazinyl]ethylmethyl-1,4-dihydro-2,6-dimethyl-4(m-nitrophenyl)-3,5-pyridinedicarboxylate methyl-ester) is a poorlysoluble (<1 μg/mL) long acting antihypertensive drug. Salt formingwith citric or tartaric acid results in a 400 to 600 fold solubilityenhancement, respectively, which can be further increased by an order ofmagnitude with cyclodextrins. Dimethyl-βCD alone results in a more than8000 fold solubility enhancement. Besides the strongly enhanced solubility1HNMR spectroscopy also proves the inclusion-type interactionbetween Manidipine and cyclodextrins. From the attained 5-8 mg/mL solubilityof the drug in water an improved bioavailability and pharmacokinetics isexpected.

The Molecular Structure and Crystal Organization Of Rac -terfenadine/β-cyclodextrin/tartaric Acid Multicomponent Inclusion Complex

The crystalline ternary inclusion complex terfenadine/ g -cyclodextrin/tartaric acid (TFN/ g CD/TA, 2:4:1) has been prepared from a aqueous solution (terfenadine, TFN, rac - f -[4-(1,1-dimethylethyl)phenyl]-4-(hydroxy-diphenylmethyl)-1-piperidine-butanol). The solubility of the multicomponent system in water is remarkably different from that of the single components. The crystal structure shows that the TFN guest adopts an extended conformation and that the diphenyl end of the molecule is docked in the cavity formed by the association of two independent g CD molecules through hydrogen bonds connecting their wide rims. The structure of the dimer is deformed with respect to uncomplexed g CDs, due to the shape of the guest. The two aromatic rings interact differently with the macrocycles forming the dimer, one being included perpendicular in the central cavity of one g CD, the other laying parallel to the interface between the two rims. The t-Bu- end of the guest is included in the cavity of a g CD belonging to a different dimer, entering from the side of the narrow rim. The central part of the guest is surrounded by water molecules and tartaric acid, which creates a hydrophilic microenvironment in the interstices among dimers. The enhanced solubility of the multicomponent system could be related to the hydrogen bonds between the tartaric acid and the oxygens belonging to the wide rims. The overall structural arrangement of the g CD units is driven by the shape of the TFN guest which needs a hydrophobic environment at both ends. The lipophilic interactions between TFN and g CD cavities are responsible for the relevant perturbation in the regularity of the packing of the hosts.

Preparation and Characterization of Piroxicam Alkali-Salt γ-Cyclodextrin Complexes

Piroxicam sodium-, potassium- and ammonium salts form complexes with yCD by precipitation from even highly alkaline solution, giving stoichiometric compounds in crystalline state with good yield.