Zoltán Aigner

DSC, X-ray and FTIR studies of a gemfibrozil/dimethyl-β-cyclodextrin inclusion complex produced by co-grinding.

The steps of formation of an inclusion complex produced by the co-grinding of gemfibrozil and dimethyl-β-cyclodextrin were investigated by differential scanning calorimetry (DSC), X-ray powder diffractometry (XRPD) and Fourier transform infrared (FTIR) spectroscopy with curve-fitting analysis. The endothermic peak at 59.25°C reflecting the melting of gemfibrozil progressively disappeared from the DSC curves of the products on increase of the duration of co-grinding. The crystallinity of the samples too gradually decreased, and after 35min of co-grinding the product was totally amorphous. Up to this co-grinding time, XRPD and FTIR investigations indicated a linear correlation between the cyclodextrin complexation and the co-grinding time. After co-grinding for 30min, the ratio of complex formation did not increase. These studies demonstrated that co-grinding is a suitable method for the complexation of gemfibrozil with dimethyl-β-cyclodextrin. XRPD analysis revealed the amorphous state of the gemfibrozil-dimethyl-β-cyclodextrin product. FTIR spectroscopy with curve-fitting analysis may be useful as a semiquantitative analytical method for discriminating the molecular and amorphous states of gemfibrozil.

Water-soluble loratadine inclusion complex: analytical control of the preparation by microwave irradiation.

The majority of active pharmaceutical ingredients are poorly soluble in water. The rate-determining step of absorption is the dissolution of these drugs. Inclusion complexation with cyclodextrin derivatives can lead to improved aqueous solubility and bioavailability of pharmacons due to the formation of co-crystals through hydrogen-bonding between the components. Inclusion complexes of loratadine were prepared by a convenient new method involving microwave irradiation and the products were compared with those of a conventional preparation method. Dissolution studies demonstrated that the solubility and rate of dissolution of loratadine increased in both of the methods used. The interactions between the components were investigated by thermal analysis and Fourier Transform Infrared studies. The microwave treatment did not cause any chemical changes in the loratadine molecule.

Polymorph screening of an active material.

Polymorph screening is currently one of the most important tasks for innovators and for generic companies from both pharmaceutical and intellectual property rights aspects. The different polymorphs have different physicochemical properties, such as the crystal polymorph-dependent solubility which influences the bioavailability. A former drug candidate obtained from Sanofi Pharmaceutical Company (Hungary) was investigated to explore its polymorphism, to distinguish the morphologies generated by analytical examinations and to investigate their relative stabilities. An Avantium Crystal 16 automatic laboratory reactor system was used for the polymorph studies and the studies of their dissolution. Eight polymorphs were obtained by crystallization and transformation methods then characterized by XRPD, DSC, and Raman spectroscopy, scanning electron microscopy, and light microscopy. All the morphologies could be stored in solid without any form transformation for a long time (2 years investigated). According to the first relative stability results, Form I, III, IVa, V, VI, VII are unambiguously metastable forms. Form II and IVb have similar thermodynamic stabilities, that were higher than those of the other polymorphs. A special dissolution medium was developed in which the eight polymorphs showed clear differences in the rate of dissolution.

Thermoanalytical studies on complexes of ketoconazole with cyclodextrin derivatives

Inclusion complexation between cyclodextrin derivatives (hydroxypropyl-β-cyclodextrin and methyl-β-cyclodextrin) and a very poorly water-soluble antifungal agent, ketoconazole, was studied. Solid products were prepared by physical mixing, kneading and spray-drying methods in four molecular ratios: 2:1, 1:1, 1:2 and 1:3. The possibility of complex formation between the drug and the cyclodextrins was studied by thermal analysis. Supplementary techniques, such as X-ray diffractometry and Fourier transformation-infrared spectroscopy, were also applied to interpret the results of the thermal study of the products.

Physico-chemical characterization and in vitro/in vivo evaluation of loratadine: dimethyl-β-cyclodextrin inclusion complexes

A tricyclic, piperidine derivative of antihistamines, loratadine, which belongs in class II of the Biopharmaceutical Classification System, was investigated. It is an ionizable drug, whose solubility depends on the gastrointestinal pH, and the bioavailability is therefore very variable. Inclusion complexes were prepared by kneading method, containing loratadine (LOR) and dimethyl-β-cyclodextrin (DIMEB) in two different molar ratios in an attempt to achieve better dissolution and therefore the better bioavailability of loratadine. The formation and physicochemical properties of the inclusion complexes were investigated by means of dissolution tests, pH-dependent solubility studies, electrospray ionization mass spectrometry and diffusion-ordered 1H NMR spectroscopy. The in vivo efficiency of the complexes was examined in rat animal experiments to confirm the better in vitro dissolution. The instrumental examinations proved the presence of total complexes in 1:1 ratio in both compositions. However, the in vitro pH-dependent solubility results, the in vivo blood levels and the greater pharmacological effect prove that excess DIMEB is needed to achieve the pH-independent and complete solubility of LOR, and therefore better and more consistent bioavailability.

Investigation of tenoxicam and γ-cyclodextrin binary and ternary complexes

Tenoxicam is a widely used non-steroidal anti-inflammatory drug (NSAID). Itscomplexation with cyclodextrin was studied in order to improve its aqueoussolubility and to decrease its side-effects. Two- and three-component systems inseveral mole-ratios were prepared by means of two different methods. The drugliberation profile, the in vitro membrane diffusion and the n-octanol/water partitioncoefficient were investigated. The presence of complexes was detected via thermoanalyticaland X-ray diffractometric studies. On the basis of these data, several compositionswere selected for incorporation into topical dosage forms.

Preparation and Investigation of Inclusion Complexes Containing Nifluminic Acid and Cyclodextrins

Nifluminic acid (N) is a frequently used anti-inflammatory drug,but its poor aqueous solubility is a disadvantageous property. Inclusion complexation with cyclodextrinderivatives (CDs) affords a possibility to increase its solubility properties. For thispurpose, different CDs were used, primarily hydroxypropyl-β-CD (HP-β-CD), to prepareproducts by powder mixing or kneading in four molecular ratios. The dissolution and in vitromembrane diffusion of the products were investigated. The wetting angles of pure N andHP-β-CD and of the products, and the n-octanol/water partition coefficients were determined.The interaction, leading to complex formation between the components of the products was examined by thermoanalytical methods.

Improvement of the Physicochemical Properties of Clotrimazole by Cyclodextrin Complexation

Complex formation between CDs and a very poorly water-soluble antifungal agent, clotrimazole (CLT), was studied. Products containing γ-CD were prepared in two molecular ratios by four methods. The rates of dissolution ofthe 1 : 1 drug/CD combinations revealed better dissolution properties than thoseof the 1 : 2 products. Drug/CD interactions in both aqueous solution and the solidstate were studied by phase solubility and thermal analysis. The effects of differentauxiliary materials (polymers, hydroxy acids and surfactants) on the aqueous solubilityof CLT were investigated. The aqueous solubility of CLT was increased significantly bythe addition of the auxiliary materials. Particle size distribution, partition coefficient,surface tension, heat of dissolution and wettability studies were also carried out.

Microstructural analysis of the fast gelling freeze-dried sodium hyaluronate.

Although sodium hyaluronate is a very unstable and heat sensitive molecule, it can remain relatively stable during the freeze-drying process. Aqueous sodium hyaluronate (NaHA) gels were prepared and the obtained samples were freeze-dried. The freeze-dried NaHA samples showed fast gelling ability meanwhile preserved their initial viscoelasticity even after reconstitution. The microstructure of gels obtained from raw substance and freeze-dried NaHA samples was characterized with positron annihilation lifetime spectroscopy and X-ray diffraction patterns while their functionality-related macrostructural properties were tested based on their rheological behavior. The presence of phosphate salts improved the formation of ordered supramolecular structure retaining water in the free volume holes of the polymer chains characterized with decreased ortho-positronium lifetime values. This property may be advantageous in the development of a freeze-dried NaHA injection dosage form.

Reduction of glycine particle size by impinging jet crystallization

The parameters of crystallization processes determine the habit and particle size distribution of the products. A narrow particle size distribution and a small average particle size are crucial for the bioavailability of poorly water-soluble pharmacons. Thus, particle size reduction is often required during crystallization processes. Impinging jet crystallization is a method that results in a product with a reduced particle size due to the homogeneous and high degree of supersaturation at the impingement point. In this work, the applicability of the impinging jet technique as a new approach in crystallization was investigated for the antisolvent crystallization of glycine. A factorial design was applied to choose the relevant crystallization factors. The results were analysed by means of a statistical program. The particle size distribution of the crystallized products was investigated with a laser diffraction particle size analyser. The roundness and morphology were determined with the use of a light microscopic image analysis system and a scanning electron microscope. Polymorphism was characterized by differential scanning calorimetry and powder X-ray diffraction. Headspace gas chromatography was utilized to determine the residual solvent content. Impinging jet crystallization proved to reduce the particle size of glycine. The particle size distribution was appropriate, and the average particle size was an order of magnitude smaller (d(0.5)=8-35 μm) than that achieved with conventional crystallization (d(0.5)=82-680 μm). The polymorphic forms of the products were influenced by the solvent ratio. The quantity of residual solvent in the crystallized products was in compliance with the requirements of the International Conference on Harmonization.