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%).

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.

Evaluation of transcutol as a clonazepam transdermal permeation enhancer from hydrophilic gel formulations.

The influence of diethyleneglycol monoethyl ether (transcutol), alone or in combination with propylene glycol, on clonazepam permeation through an artificial membrane and excised rabbit ear skin from Carbopol hydrogels was investigated. Drug kinetic permeation parameters were determined for both series of experiments and compared. Rheological characteristics, drug solubility and membrane/vehicle partition coefficient for each gel formulation were also determined, and their role in the formulation performance was investigated. Both series of experiments showed an increase of drug permeation as a function of transcutol content in the formulation. The combination of transcutol and propylene glycol resulted in a synergistic enhancement of clonazepam flux. A different trend was found in experiments with gels containing mixtures of the two enhancers, where an increase (in the case of artificial membrane) or a decrease (in the case of rabbit ear skin) of drug permeation was found by increasing the transcutol/propylene glycol ratio in the mixture. Such a result is explained on the basis of the particular mechanism of action demonstrated for transcutol which associates the increase of drug solubility to the potent effect of a depot in the skin.

Influence of the preparation method on the physicochemical properties of binary systems of econazole with cyclodextrins.

Equimolar combinations of econazole, a very poorly water soluble antifungal agent, with beta-cyclodextrin and statistically substituted methyl-beta-cyclodextrin were investigated for both solid state characterization (differential scanning calorimetry, hot-stage microscopy, infrared spectroscopy, scanning electron microscopy) and dissolution properties (dispersed amount method). The influence of the preparation method (physical mixing, ball-milling, kneading, sealed-heating) on the physicochemical properties of the products was evaluated. Kneading and sealed-heating techniques led to amorphous products in the case of systems with methyl-beta-cyclodextrin, whereas crystalline drug was still clearly detectable in all products with beta-cyclodextrin. Independently of the preparation technique, all combinations with methyl-beta-cyclodextrin yielded better performance than the corresponding ones with beta-cyclodextrin. However, the influence of the preparation method was clearly more marked for products with methyl-beta-cyclodextrin and made to be possible to better display the different performance of the examined carriers. In fact, the sealed-heated with the beta-derivative showed an increase of drug dissolution efficiency of 130% with respect to the corresponding physical mixture, in comparison to the 70% increase obtained from that with beta-cyclodextrin. Moreover, whereas the difference in dissolution efficiency values between coground products was only about 8% in favor of the beta-derivative, it reached 80 and 90% between sealed-heated and kneaded products, respectively.

Influence of the preparation method on the physicochemical properties of ketoprofen-cyclodextrin binary systems.

Binary systems of ketoprofen with native crystalline beta-cyclodextrin and amorphous statistically substituted methyl-beta-cyclodextrin were investigated for both solid phase characterization (Differential Scanning Calorimetry, powder X-ray diffraction, Infrared Spectroscopy, Scanning Electron Microscopy) and dissolution properties (dispersed amount and rotating disc methods). Grinding, kneading, sealed-heating and colyophilization of equimolar combinations of ketoprofen with methyl-beta-cyclodextrin, as well as colyophilization of analogous combinations with beta-cyclodextrin, led to amorphous products. Crystalline drug, instead, was still clearly detectable in coground, kneaded and sealed-heated products with beta-cyclodextrin. Both the preparation method, and even more the nature of the carrier, played an important role in the performance of the system. Colyophilized and sealed-heated products showed the best dissolution properties. However, independently of the preparation technique, all combinations with methyl-beta-cyclodextrin yield better performances than the corresponding ones with the beta-cyclodextrin. Moreover, intrinsic dissolution rate of ketoprofen from simple physical mixture with the beta-cyclodextrin derivative was even five-fold higher than that from the best product with the parent beta-cyclodextrin.

1H-NMR and molecular modelling techniques for the investigation of the inclusion complex of econazole with alpha-cyclodextrin in the presence of malic acid.

Carrying on a study where the combination of alpha-cyclodextrin and malic acid was found to be the most effective in improving the solubility of econazole, an antifungal drug very poorly water soluble, in the present work 1H-NMR and nuclear overhauser effect (NOE) experiments and molecular modelling studies were performed to gain insight into the interactions in solution between such three components and the structure of the supposed multicomponent complex. Findings demonstrated that two different complexes can be simultaneously present in solution involving, respectively, the inclusion of econazole monochloro-phenyl group within the host cavity from the primary hydroxyl side of the cyclodextrin cavity, or that of the other phenyl group through the opposite side of the cavity. It was shown that also malic acid is strictly involved in the molecular assembly of the complex, particularly through interactions with primary hydroxyl groups of the cyclodextrin molecule. Molecular modelling studies allowed to elaborate possible geometric models of the multicomponent complex and to select the more energetically favourable conformations which complied better with experimental data. Results suggested the possible formation in solution of stable oligomeric aggregates constituted by the repeated concatenation of the three components.

Characterization of physicochemical properties of naproxen systems with amorphous beta-cyclodextrin-epichlorohydrin polymers.

Ground mixtures of naproxen with amorphous beta-cyclodextrin-epichlorohydrin soluble (betaCd-EPS) or insoluble cross-linked (betaCd-EPI) polymers were investigated for both solid phase characterization (Differential Scanning Calorimetry, powder X-ray Diffractometry) and dissolution properties (dispersed amount method). The effect of different grinding conditions and of drug-to-carrier ratio was also evaluated. Co-grinding induced a decrease in drug crystallinity to an extent which depended on the grinding time, and was most pronounced for the cross-linked insoluble polymer, particularly in combinations at the lowest drug content. Both cyclodextrin polymers were more effective in improving the naproxen dissolution properties, not only than the parent betaCd but also than hydroxyalkyl-derivatives, and their performance was almost comparable to that of methyl-derivatives, previously found as the best carriers for naproxen. Dissolution efficiencies of naproxen from physical mixtures with betaCd-EPS, thanks to the high water solubility of this Cd-derivative, were up to three times higher than those from the corresponding products with betaCd-EPI. However this difference in their performance became much less evident in co-ground products and tended to progressively diminish with increasing the polymer content in the mixture, according to the better amorphizing power shown by betaCd-EPI during the co-grinding process. The 10/90 (w/w) drug-carrier co-ground products exhibited the best dissolution properties, giving dissolution efficiencies about 30 times higher than that of naproxen alone.

Compatibility study between ibuproxam and pharmaceutical excipients using differential scanning calorimetry, hot-stage microscopy and scanning electron microscopy.

Differential scanning calorimetry (DSC) was used as a screening technique for assessing the compatibility of ibuproxam with some currently employed pharmaceutical excipients. The influence of processing effects (simple blending, cogrinding or kneading) on drug stability was also evaluated. On the basis of DSC results, ibuproxam was found to be compatible with corn starch, avicel and sodium carboxymethylcellulose. Some drug-excipient interaction was observed with polyethyleneglycol 4000, palmitic acid, stearic acid, Ca and Mg stearate. Actual solid-phase interactions of the drug with polyvinylpolypyrrolidone and polyvinylpirrolidone K30 were induced by mechanical treatments. Hot-stage microscopy (HSM) and scanning electron microscopy (SEM) were of help in interpreting the DSC results and excluding in all cases relevant pharmaceutical incompatibilities.

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.

Effect of water-soluble polymers on naproxen complexation with natural and chemically modified beta-cyclodextrins.

The combined effect of cyclodextrins (CDs) (beta-, methyl-beta-, hydroxypropyl-beta-cyclodextrins) and water-soluble polymers (sodium carboxymethylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone K30, polyethylene glycol 6000) on naproxen solubility improvement was studied. Phase solubility analysis at 25 degrees C was used to investigate the interaction of the drug with each cyclodextrin (or polymer, alone or in the presence of the different water-soluble polymers (or cyclodextrins). The combined use of polymer and cyclodextrin was always clearly more effective in enhancing the aqueous solubility of naproxen in comparison with the corresponding drug-polymer or drug-cyclodextrin binary systems, and the solubilization enhancement was not simply additive, but synergistic. Water-soluble polymers increased the complexation efficacy of cyclodextrins toward naproxen (as shown by the increased stability constants of the complexes), which resulted in enhanced drug solubility. No previous sonication or heating treatments of the drug-cyclodextrin-polymer suspensions was necessary to obtain this favorable effect. The best results were obtained in ternary systems with beta-cyclodextrin, which had a solubilizing effect toward naproxen in the presence of 0.25% w/v of the different hydrophilic polymers examined that was improved from 25% to about 80%, depending on the type of polymer.

Effects of grinding with microcrystalline cellulose and cyclodextrins on the ketoprofen physicochemical properties.

Ground mixtures of ketoprofen (KETO) with native crystalline beta-cyclodextrin, amorphous statistically substituted methyl-beta-cyclodextrin, and microcrystalline cellulose were investigated for both solid phase characterization (differential scanning calorimetry (DSC) powder X-ray diffractometry, and infrared (IR) spectrometry) and dissolution properties (dispersed amount and rotating disk methods) to evaluate the role of the carrier on the performance of the final product. The effects of different grinding conditions, partial sample dehydration, and 1 year storage at room temperature were also investigated. The results pointed out the importance of the carrier nature on the efficiency of the cogrinding process. Both cyclodextrins were much more effective than was microcrystalline cellulose, even though no true inclusion complex formation occurred by mechanochemical activation. The best results were obtained from ground mixtures with methyl-beta-cyclodextrin, which showed the best amorphizing and solubilizing power toward the drug and permitted an increase of approximately 100 times its intrinsic dissolution rate constant, in comparison with the approximate 10 times increase obtained from ground mixtures with beta-cyclodextrin.

Thermal analysis as a screening technique in preformulation studies of picotamide solid dosage forms.

The potential compatibilities of several commonly used pharmaceutical excipients with picotamide were evaluated using differential scanning calorimetry (DSC). The effects of aging and of mechanical treatment (blending, grinding, or kneading) of samples were also evaluated. Hot-stage microscopy (HSM) and scanning electron microscopy (SEM) were used as complementary techniques to implement and assist in interpretation of the DSC results. DSC analysis evidenced a noticeable modification of drug thermal features in the mixtures with palmitic acid, stearic acid, stearyl alcohol, polyethylene glycol (PEG) 20,000, and sorbitol, but HSM analysis showed that the DSC behavior was mainly because of the drug dissolution in the melted excipient, which allowed the presence of important solid-solid interactions to be excluded. Compatibility with Mg stearate was also found, even if sample manipulation induced the partial conversion of Mg stearate in a pseudo-polymorphic modification. Mechanical stress displayed an increased hygroscopicity of mixtures with glucose and lactose, as well as some solid-solid interactions with lactose and mannitol.

Optimisation and validation of a capillary electrophoresis method for the simultaneous determination of diazepam and otilonium bromide.

A simultaneous assay of diazepam and otilonium bromide in coated tablets by capillary zone electrophoresis (CZE) was developed. The influence of various parameters (voltage, temperature, buffer concentration and pH, ethanol percentage) on analysis time and on the theoretical plates of the two peaks was investigated by means of experimental design. A response surface study was carried out by means of a 27-run D-optimal matrix. The best background electrolyte was found to be 0.13 M, pH 2.9 Britton-Robinson buffer, containing 10% v/v ethanol. Other optimised parameters were voltage (30 kV) and temperature (30 degrees C). The UV detector for quantitation of otilonium bromide and diazepam was set at 280 nm and 230 nm, respectively. Procaine hydrochloride was used as internal standard and run time was less than five minutes. Validation was performed, for drug substance and drug product, according to ICH3 guidelines. For drug product the recovery for otilonium bromide and diazepam ranged from 98.3% to 101.2% and from 97.1% to 99.0%, respectively; the RSD values found for otilonium bromide and diazepam ranged from 2.4% to 3.0% and from 1.1% to 4.5%, respectively.

Thermal behavior and dissolution properties of naproxen from binary and ternary solid dispersions.

Solid dispersions of 10% w/w naproxen (NAP) in poly(ethylene glycol) (PEG) (4000, 6000, or 20,000) as a carrier with or without incorporation of anionic (sodium dodecyl sulfate; SDS) or nonionic (Tween 80; Tw80) surfactant were prepared by the melting method. Physicochemical characteristics were determined by differential scanning calorimetry (DSC) and X-ray diffraction analysis. The results of dissolution studies showed that drug dissolution properties were better from ternary systems than from binary systems since in the former the wetting and solubilizing effects of surfactant and polymer were additive. No influence of the PEG molecular weight was found. The best performance given by anionic surfactant has been attributed to several factors, such as higher hydrophilicity, better solubilizing power, and most facile interaction with both drug and PEG. No important changes in solid-state characteristics or in drug dissolution properties were found after 30 months storage for dispersions with or without surfactant. Only a slight decrease in initial drug dissolution rate was observed at the highest concentration (10% w/w) of SDS.