Chitosan/pectin polyelectrolyte complexes: selection of suitable preparative conditions for colon-specific delivery of vancomycin.

The influence of polyelectrolyte complexes composed of chitosan and pectin on the release behaviour of vancomycin has been investigated. Polyelectrolyte complexes between chitosan and pectin were prepared in various pH regions and at different molar ratios by mixing solutions of pectin and chitosan with the same ionic strength. The precipitates were collected by spray-drying and tablets were obtained with the different complexes and vancomycin. FT-IR spectra and TGA thermograms were analysed to study the degree of interactive strength between polyions. In vitro swelling, mucoadhesion and release tests were performed in order to investigate the chitosan/pectin complex ability in the delivery of vancomycin in the gastro-intestinal tract. The results confirmed the formation of polyelectrolyte complexes between pectin and chitosan at pH values in the vicinity of the pKa interval of the two polymers. Chitosan/pectin complexes showed a pH-sensitive swelling ability and drug release behaviour suggesting their possible use for colon-specific localization of vancomycin. Among the different complexes, chitosan/pectin complex prepared in molar ratio of 1:9 showed the highest mucoadhesive properties and a pH-dependent swelling sensitivity suitable for colon-delivery. Moreover, the particular composition of these complexes improved vancomycin availability at alkaline pH on the bases of an enzyme-dependent degradation as confirmed from release studies performed in presence of beta-glucosidase.

Assessment of solid-state interactions of naproxen with amorphous cyclodextrin derivatives by DSC.

A microcalorimetric method based on differential scanning calorimetry (DSC) of drug-additive binary systems to assess kneading-induced interactions was applied to naproxen (NAP) in combinations with amorphous hydroxypropyl beta-cyclodextrin (HPbetaCd), beta-cyclodextrin sulfobutyl ether, sodium salt ((SBE)(7m)-betaCd), acetyl beta-cyclodextrin (AcbetaCd) and acetyl gamma-cyclodextrin (AcgammaCd). Modifications of thermal parameters of NAP in DSC curves of physical mixtures indicate heating-induced interactions which resulted in a broadening of the NAP melting endotherm in the combinations with HPbetaCd, AcbetaCd and AcgammaCd. The effect of kneading on the interaction was particularly pronounced for the NAP-HPbetaCd and NAP-(SBE)(7m)-betaCd systems, which show a similar drug-to-carrier interaction ratio (1:2 by weight) as that of the other systems. Drug-to-carrier ratios, calculated considering the amount of NAP which recrystallizes from the melted mixtures equivalent to NAP not bound to the carrier, show a distinctly lower affinity in solid-state of the drug for the anionically charged (SBE)(7m)-betaCd with respect to other neutral carriers. The similar affinity of NAP for AcbetaCd and AcgammaCd demonstrates that the geometry of the cavity, which is a determinant factor for the inclusion complexation in liquid state, does not influence the interaction process in solid-state.

Investigation of the effects of grinding and co-grinding on physicochemical properties of glisentide.

The purpose of the present study was to investigate the possibility of improving the dissolution properties of glisentide, a poorly water-soluble antidiabetic drug, by grinding in a high energy micromill, alone or in mixture with polyvinylpyrrolidone (PVP). Conventional and modulated differential scanning calorimetry (DSC, MDSC), thermogravimetry (TGA), X-ray powder diffraction (XRD), Fourier transform infrared spectroscopy (FT-IR), hot-stage FT-IR thermomicroscopy and scanning electron microscopy (SEM) were used to characterize the drug solid state, whereas its dissolution rates were determined according to the dispersed amount method. The techniques utilized enabled exclusion of polymorphism phenomena as a consequence of mechanical treatment, and revealed a progressive drug amorphization during grinding. In particular, MDSC allowed a clear determination of the glass transition temperature of the amorphous drug, enabling separation of glass transition from enthalpic relaxation. The amorphous state of the ground drug was the main responsible factor for the obtained 100% dissolution efficiency increase in comparison with the untreated drug. Further significant increases in dissolution properties, directly related to the polymer content in the mixture, were obtained by co-grinding with PVP, whose presence clearly favored drug amorphization, allowing a strong reduction of time and frequency of grinding necessary for obtaining complete drug amorphization.

The influence of polyvinylpyrrolidone on naproxen complexation with hydroxypropyl-beta-cyclodextrin.

The combined effect of hydroxypropyl-beta-cyclodextrin (HPbetaCD) and polyvinylpyrrolidone (PVP) on the solubility of naproxen (NAP) was studied. Phase-solubility analysis at different temperatures was used to investigate interactions in aqueous solution between NAP and the carriers, either alone or in combination. Equimolar NAP-HPbetaCD solid systems, in the presence or the absence of 15% (w/w) PVP, were prepared by cogrinding, kneading, coevaporation or freeze-drying, and characterized by differential scanning calorimetry, X-ray powder diffraction analysis, infrared spectroscopy and dissolution rates. The combined use of PVP and HPbetaCD resulted in a synergistic increasing effect of the aqueous solubility of NAP (120 times that of the pure drug). The phenomenon was interpreted in terms of the strongest complexation capacity of HPbetaCD towards NAP, which was reflected by an about 65% increase in the apparent stability constant of the NAP-HPbetaCD complex in the presence of only 0.1% (w/v) PVP. Variations in thermodynamic parameters accounted for a PVP role in the formation of a NAP-HPbetaCD-PVP ternary complex. The positive effect of PVP also reflected on NAP dissolution rates from solid preparations, because all ternary systems, with the exception of physical mixtures, dissolved faster than the corresponding NAP-HPbetaCD binary systems. The results of solid state studies accounted for the occurrence of mechanically- and/or thermally-induced stronger interactions in ternary than in binary systems, that in some cases led to a complete loss of NAP crystallinity.

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.

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.

Physical characterization of picotamide monohydrate and anhydrous picotamide.

Picotamide is an antiplatelet agent given by mouth as monohydrate (PICOW) (Plactidil) in thrombo-embolic disorders. This study deals with physical characterization of PICOW recrystallized from various solvents and the respective dehydration products using X-ray powder diffractometry (XRD), infrared spectroscopy (IR), and thermal analytical techniques (differential scanning calorimetry, DSC; thermogravimetric analysis, TGA; simultaneous TGA/DSC; hot stage microscopy, HSM). Monophasic and biphasic DSC and TGA profiles of water loss were recorded under open conditions for PICOW samples which showed the same monoclinic crystal structure. Biphasic profiles became monophasic for gently ground samples which were, however, structurally identical to the intact samples. Morphological factors, the various degree of "perfection" of the PICOW crystal lattice, and/or cluster aggregation of PICOW crystals were assumed to be responsible for the differing dehydration patterns. Polymorphism in anhydrous picotamide, i.e., nucleation of crystal forms A, mp 135.5 +/- 0.4 degrees C, and B, mp 152.9 +/- 0.3 degrees C after dehydration of PICOW, was detected by DSC and HSM. The dehydration product of PICOW under isothermal conditions (115 degrees C, 20 mmHg), PICOA, was mainly composed of the lower melting polymorph A (fusion enthalpy 74.4 +/- 2.2 J g(-1)), which gradually reverted to the starting hydrate by storing in an ambient atmosphere. Dissolution tests of PICOW and PICOA in water at 37 degrees C as both powders and compressed disks reflected to some extent the higher solubility of the metastable form (by 24% at 37 degrees C) in terms of both higher dissolution efficiency and percent of active ingredient dissolved (by 28%) and intrinsic dissolution rate (by 32%).

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

PURPOSE: To study the effect of mechanical grinding on crystallinity changes of naproxen (NAP) in mixtures with alpha-cyclodextrin (alphaCd), amorphous alphaCd, 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 alphaCd. CONCLUSIONS: The intrinsically amorphous linear analog of aCd might be a potential amorphism-inducing agent and solubilizer for scarcely water soluble drugs.

A physiochemical approach to the investigation of the stability of trimethoprim-sulfamethoxazole (co-trimoxazole) mixtures for injectables.

The stability of the trimethoprim/sulfamethoxazole (1:5, w/w) combination suitable for administration by injection was investigated to determine the nature of solid phases that can separate after dilution with infusion fluids. Phase-solubility analysis was performed on the binary system in water and in buffered aqueous media (pH 7 and 9), thus allowing a comprehensive picture of solid-solution compositions. Commercial samples of this combination were tested for solid phases separating after dilution with various infusion fluids. The interaction between trimethoprim and sulfamethoxazole, forming a 1:1 molecular compound with low solubility in water, is mainly responsible for the physicochemical properties of mixtures of these drugs in solution. Other solid phases (i.e., trimethoprim monohydrate and sulfamethoxazole emihydrate) can separate on long-term standing of solutions, depending on the value of the pH of the medium and the fluid used for dilution.

Improvement of clonazepam release from a Carbopol hydrogel.

The performance of Tween 80, Tween 60, oleic acid, oleyl alcohol and Azone as enhancers of clonazepam permeation from a Carbopol hydrogel through a cellulose nitrate membrane was investigated. The effect of incorporating methyl beta-cyclodextrin (DS 1.8) in combination with clonazepam as a solid phase into some vehicles was also tested. In vitro release studies were carried out with a Sartorius apparatus and the following parameters were evaluated: drug solubility in the vehicle; partition coefficient of the drug between lauryl alcohol (the solvent which impregnates the membrane) and the vehicle; steady state flux; permeability constant; diffusion coefficient; lag time. The release kinetics followed a nearly zero-order pattern, although the diffusion-controlled mechanism might also have been operative. Maximum drug release (2.5 times that of the gel base) was achieved for the formulation containing clonazepam and methyl beta-cyclodextrin in a 1:1 (mol/mol) ratio as a solid phase, in a vehicle composed of water, propylene glycol, Tween 80 and Azone at a mass fraction of 43%, 50%, 2% and 5%, respectively.

Carbon-13 nuclear magnetic resonance study of naproxen interaction with cyclodextrins in solution.

Changes in naproxen (NAP) 13C-chemical shifts were measured as a function of the concentration of alpha-, beta-, and gamma-cyclodextrin (alpha Cd, beta Cd, and gamma Cd, respectively) in aqueous solution in order to obtain details on the mechanism, geometry, and stoichiometry of the respective interactions. The probable structures of the inclusion compounds of NAP with natural cyclodextrins were constructed using a molecular graphics program. The higher stability of the beta Cd:NAP 1:1 (mol/mol) complex in comparison with alpha Cd:NAP 2:1 (mol/mol) and gamma Cd:NAP 1:1 or 1:2 (mol/mol) complexes was accounted for in terms of a deeper, more complete, and better fitting inclusion of the drug into the cavity of beta Cd. The inclusion behavior of NAP with some statistically substituted beta Cd derivatives [hydroxyethyl-beta Cd (HE beta Cd), hydroxypropyl-beta Cd (HP beta Cd), and methyl-beta Cd (M beta Cd)] was also investigated through 13C-NMR, UV, circular dichroism spectroscopy, and phase-solubility analysis. The stoichiometry of host:guest interactions was the same as with beta Cd, as were thermodynamics and basic complexation mechanisms. The binding between the host and guest molecules is thought to be mainly due to van der Waals, dipole-dipole, and hydrophobic interactions. The inclusion ability of the parent beta Cd was enhanced by the introduction of methyl, hydroxyethyl, and hydroxypropyl groups. The M beta Cd formed the most stable inclusion complex (apparent formation constant K(1:1) = 6892 L.mol-1 at 298 K); it was about three times more stable than those with HP beta Cd or HE beta Cd and four times more stable than that with beta Cd.(ABSTRACT TRUNCATED AT 250 WORDS)

[Morphological and structural aspects of solid drug forms]. / Aspetti morfologici e strutturali dei composti farmaceutici solidi.

As a follow-up to a previous article, where the characteristics of the solid state and the X-ray properties and pharmaceutical applications were described ("X-rays, diffractometry in the analysis of drugs and pharmaceutical forms", Boll. Chim. Farm. 128, 149; 1989), the Author has more specifically considered the so-called "variants" of a drug's solid state, which can be employed in the dosage forms (polymorph, solvate, crystalline habitus, amorphous). In addition, mention is made of drugs' isomorphism and the difference between a polymorphic solvate and the polymorphism of a solvate is clearly stressed.

Sobrerol enantiomers and racemates: solid-state spectroscopy, thermal behavior, and phase diagrams.

The characterization of the solid state of sobrerol enantiomers and racemates has been accomplished by a number of techniques on solid phase such as thermal analysis (DSC) and spectroscopy (IR, 13C NMR, and X-ray diffraction both on powders and on single crystal). Experimental and theoretical binary phase diagrams of cis- and trans-sobrerol enantiomers and their mixtures have been drawn and are discussed. Thermal analysis allowed, moreover, the detection of cis racemate polymorphism. Finally, the quantitative analysis of the cis racemate as an impurity of the trans racemate by means of microcalorimetric determinations is reported.

Preformulation studies on suppositories by thermal methods.

The application of differential scanning calorimetry (DSC) is described for investigating the interaction between trimethoprim and sulfamethoxypyridazine in suppository formulations containing fat bases (Suppocire, Novata, Witepsol). The thermal behavior of suppositories at various storage times is deeply influenced by the fat base and by interaction between active ingredients. Liquefaction time and dropping temperature were also evaluated for comparison and control purposes.

Formulation factors influencing the release of clonazepam from a carbopol hydrogel.

A study of formulation factors influencing the release of clonazepam from a Carbopol hydrogel through a cellulose nitrate membrane impregnated with lauryl alcohol was performed using two diffusion cell assemblies. The formulation variables were the cosolvent effects of propylene glycol and polyethylene glycol of different molecular weights in aqueous solutions of various composition. The gel formulation phenomenologically behaves as a zero-order release system, although the diffusion controlled mechanism may also be operative. The results showed that both methods were practically equivalent in terms of drug release profile and total drug released allowing the best formulation to be found.

[X-ray diffractometry in the analysis of drugs and pharmaceutical forms]. / La diffrattometria dei raggi X nell'analisi dei farmaci e delle forme farmaceutiche.

As a consequence of the importance of solid drug substance characterization, analytical tools such as X-ray diffractometry (powder and single crystal methods) are usually employed in the pharmaceutical field. The diagnostic power of X-ray powder diffraction in identifying crystalline compounds, even in multicomponent mixtures, and in showing the non-crystalline ones, has brought about the usual characterization through the X-ray powder diffraction pattern of polymorphic, pseudopolymorphic, and amorphous drugs and of some drug-carrier systems such as solid dispersions, glass dispersions, solid surface dispersions, physical mixtures, eutectics, solid solutions, addition and inclusion compounds, etc. Moreover this technique is also used in the qualitative and quantitative analysis both of drug mixtures and dosage forms, and also in the study of relationships between crystal habit and technological characteristics of pharmaceutical formulations. Single crystal methods are employed for calculating the unit cell lenghts and angles, for indexing powder diffraction patterns, and for demonstrating the crystal and molecular structure of the drug. After a picture of the solid state properties and the X-ray characteristics, as well as of the interaction between X-rays and solid matter, the main pharmaceutical applications of X-ray diffraction are described.