Giampiero Bettinetti

Interaction between naproxen and chemically modified β-cyclodextrins in the liquid and solid state

Abstract The complexation between naproxen and some chemically modified β-cyclodextrins (hydroxyethyl β-cyclodextrin with average substitution degree per anhydroglucose unit 0.6, 1.0 and 1.6; hydroxyproyl β-cyclodextrin with average substitution degree per anhydroglucose unit 0.6 and 0.9) was studied using phase-solubility analysis and molecular modelling. The amorphous carriers exhibit similar solubilizing effects and complexing abilities, which are reflected by a comparable increase in drug dissolution rate to about the same extent from equimolar blends with each chemically modified β-cyclodextrin. X-ray diffractometry and differential scanning calorimetry data indicate a role of the degree of substitution of the carrier in the decrease in crystallinity of naproxen in equimolar blends with chemically modified β-cyclodextrins.

Characterization of a diltiazem-lambda carrageenan complex

In the present paper the interaction between lambda carrageenan, a natural sulphated polysaccharide, and diltiazem HCl, a Ca channel blocking agent, was studied. Dialysis equilibria were performed to quantify the binding capacity of lambda carrageenan for diltiazem. The relevance of the interaction to hydrophilic matrix systems was confirmed: a relationship was found between the binding capacity and the release profiles of matrix tablets containing a fixed amount of drug and different percentages of lambda carrageenan. Dialysis equilibria in buffered media showed that the interaction is quite insensitive to the pH of the medium (in the range 1.8-6.8), while it is reduced by increasing ionic strength; this behaviour is in line with the importance of ionic bonds in diltiazem-carrageenan interaction. On the basis of the calculated binding capacity, the complex was prepared, dried and milled. A preliminary characterization of the diltiazem-carrageenan complex in the solid state was effected by means of X-ray and DSC analysis. The amount of drug going into solution from the complex was not significantly affected by the pH of the medium (in the range 1.8-6.8), while it was increased by increasing ionic strength.

Thermal behaviour and dissolution properties of naproxen in combinations with chemically modified ß-Cyclodextrins

AbstractBinary systems of naproxen with statistically-alkylated s-cyclodextrins (methyl, hydroxyethyl and hydroxypropyl derivatives) were investigated for both solid phase characterization (differential scanning calorimetry, X-ray powder diffraction) and dissolution properties (dispersed amount and rotating disc methods). Kneading, coevaporation and colyophilization of the 1:1 (mol/mol) naproxen/methyl s-cyclodextrin combination, as well as colyophilization of analogous combinations of naproxen with hydroxyethyl and hydroxypropyl s-cyclodextrin, led to amorphous products with higher dissolution rates than the corresponding physical mixtures. A conversion of crystalline to amorphous naproxen was also observed by heating the physical mixtures at about 393 K. The amorphous statistically-alkylated s-cyclodextrins, in particular methyl s-cyclodextrin, can be employed as amorphizing agents for crystalline naproxen.

Structure and solid-state chemistry of anhydrous and hydrated crystal forms of the trimethoprim-sulfamethoxypyridazine 1:1 molecular complex

The crystal structure of the equimolar trimethoprim (TMP) and sulfamethoxypyridazine (SMPD) complex in the anhydrous form (TMP. SMPD) and that of the species with 1.5 molecules of water of crystallization (TMP.SMPD.W) are reported in this article. X-ray powder diffraction patterns (both computer generated and experimental) and thermal analytical data from differential scanning calorimetry (DSC) and thermogravimetry useful for the characterization of TMP.SMPD and TMP.SMPD.W are provided. The stability of TMP.SMPD.W, which retains its crystallographic order under 0% relative humidity (RH) conditions at room temperature (22 degrees C) and 20 mmHg, is accounted for in terms of crystal structure and hydrogen bonding. Transformation of TMP.SMPD to the hydrate complex by exposure to approximately 100% RH, suspension in water, and wet granulation, and dehydration of TMP.SMPD.W by thermal treatment and by desiccation with methanol were investigated and tentatively interpreted in terms of crystal properties. Interactions in the physical mixture of TMP and SMPD by grinding, compression, heating, and contact with water were also studied. Water-mediated formation of TMP.SMPD.W by wetting and metastable eutectic melting-mediated formation of TMP.SMPD by heating was demonstrated. Mechanical activation by milling makes the physical mixture prone to solid-state transformation into dimorphic anhydrous cocrystals by supply of thermal energy during a DSC scan.

Dissolution properties of naproxen in combinations with polyvinylpyrrolidone

AbstractThe effect of the molecular weight of polyvinylpyrrolidone on the solubility and dissolution properties of naproxen using solid dispersions (coevaporates and colyophilized products) and physical mixtures was investigated. Factors such as method of drug incorporation with the polymer and polymer mass fraction influence the dissolution rate of naproxen from both powders and constant surface area discs. The best results were obtained with the colyophilized products at the drug-to-polymer 7:3 weight ratio, in the rank order (most effective to least) K15>K30>lK90 (dispersed amount) and K30>K90>K15 (rotating disc). The physical state of naproxen, i.e. amorphous or crystalline, in solid combinations with polyvinylpyrrolidone was checked by means of X-ray powder diffraction. Drug-polymer interactions in the liquid state were revealed with solubility experiments. Drug-polymer interactions in solid state were demonstrated by combining the X-ray diffraction data with the results of thermal analysis (DSC, TGA...

Interaction of naproxen with noncrystalline acetyl β- and acetyl γ-cyclodextrins in the solid and liquid state

Abstract Randomly acetylated, amorphous β-cyclodextrin (AcβCd) and γ-cyclodextrin (AcγCd), having an average substitution degree per anhydroglucose unit, respectively, of 1.1 and 0.95 (∼7.7 acetyl residues per macrocycle), were investigated for their interactions in the solid and liquid state with naproxen (NAP). Differential scanning calorimetry (DSC), supported by X-ray powder diffractometry (XRD), of NAP–AcβCd and NAP–AcγCd blends revealed an apparent decrease in drug crystallinity which was related to a heating-induced solid-state interaction between the drug and each carrier. A solubility of ∼0.40 NAP mass fraction in amorphous AcβCd and amorphous AcγCd at room temperature was determined. Phase-solubility analysis at 25, 37, and 45°C accounted for A L -type inclusion complexation of NAP with AcβCd ( K 1:1,25°C =4.5(4)×10 3 l mol −1 ) and AcγCd ( K 1:1,25°C =0.80(7)×10 3 l mol −1 ) and revealed a solubilizing efficiency of AcβCd toward NAP ∼4 times that of AcγCd. Equimolar drug–carrier combinations prepared from the respective blends by grinding, kneading, coevaporation and freeze-drying were characterized by DSC and XRD and tested for dissolution rate of NAP using the dispersed amount and continuous flow through methods. The best performance in terms of dissolution rate enhancement (∼23 times and ∼10 times the dissolution efficiency of pure drug in the dispersed amount and continuous flow through tests, respectively) was displayed by the NAP–AcβCd colyophilized product.

Thermal behaviour and physicochemical properties of naproxen in mixtures with polyvinylpyrrolidone

The thermal behaviour (DSC, TGA) of naproxen (NAP) and various grades of polyvinylpyrrolidone (PVP; Mr ≈ 10000, 25000, 40000 and 360000), and their mixtures was investigated. A profound modification of the NAP melting peak, observed in the DSC curves of simply blended systems (physical mixtures) with PVP, was attributed to a solid-state interaction. This interaction proved to be influenced by the composition of the mixture, the PVP average molecular weight and the type of manipulation of the sample (grinding, compaction, heating). The high dispersion of NAP within the PVP matrix probably gives rise to the formation of crystalline drug microaggregates (molecular clusters) responsible for the thermal behaviour. The chemical and physical stability (dissolution rate, crystallinity) of NAP was not significantly affected in the mixtures with PVP.

The influence of water content on the binding capacity of β-cyclodextrin

Abstract The binding capacities of ⨿-cyclodextrin samples containing different amounts of water have been investigated. Crushing strength of tablets obtained with a single-punch tableting machine was used as a measure of the cohesive properties of powders. The results clearly indicate a determinant role of adsorbed water on powder compactability. The effect of aging is also stressed and discussed.

Interaction of naproxen with alpha-cyclodextrin and its noncyclic analog maltohexaose.

AbstractPurpose. To study the effect of mechanical grinding on crystallinity changes of naproxen (NAP) in mixtures with α-cyclodextrin (αCd), amorphous αCd, and maltohexaose (M6); and the possible formation of a pseudo-inclusion complex between NAP and M6 in aqueous solution. Methods. NAP-additive physical mixtures at 0.30,0.18, and 0.10 mass fraction of drug were tested, after increasing grinding times, by differential scanning calorimetry (DSC) and X-ray powder diffractometry (XRD). Interaction in aqueous solution was examined by phase-solubility and fluorescence analyses supported by molecular modelling. Results. In the mixtures with each additive the fusion enthalpy per unit mass of NAP decreased and the half width at half maximum of selected X-ray diffraction peaks of NAP increased with the progress of grinding time following the loss of crystallinity of the samples. The mechanical treatment apparently did not affect the chemical integrity of the drug. Particularly active in the equimolar mixture was the best amorphizing agent, M6. Solution studies and molecular modelling confirmed M6 may have the feature of a supermolecule for NAP, which forms a 1:1 pseudo-inclusion complex that was as stable as the true inclusion complex with αCd. Conclusions. The intrinsically amorphous linear analog of αCd might be a potential amorphism-inducing agent and solubilizer for scarcely water soluble drugs.

Solid-state microcalorimetry on drug-cyclodextrin binary systems

Differential scanning calorimetry DSC has been applied to the analysis of drugcyclodextrin binary systems in order to gain experimental evidence of the interaction and determine the stoichiometry of the inclusion compound. Two model systems, paracetamolbetacyclodextrin and vinburnineg-ammacyclodextrin were tested through the comparison of thermal behaviors of interacted and non-interacted mixtures containing excess drug. DSC allowed a confirmation of both interaction and stoichiometry of the inclusion compounds.ZusammenfassungMittels DSC wurde eine Analyse binärer Medikament-Cyclodextrin Systeme durchgeführt, um eine experimentelle Bestätigung der Wechselwirkung zu erhalten und die Stöchiometrie der Einschlußverbindung zu ermitteln. Über den Vergleich des thermischen Verhaltens von in Wechselwirkung stehenden und nicht in Wechselwirkung stehenden Gemischen mit einem Überschußgehalt an Medikament wurden zwei Modellsysteme getestet: Paracetamol-Betacyclodextrin und Vinburnin-Gammacyclodextrin. DSC erlaubt es, sowohl die Wechselwirkung als auch die Stöchiometrie der Einschlußverbindung zu bestätigen.