M.T Faucci

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.

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.

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.

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.

Characterization of physicochemical properties of naproxen systems with amorphous β-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.

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.

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

Ground mixtures of ketoprofen (KETO) with native crystalline β-cyclodextrin, amorphous statistically substituted methyl-β-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-β-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 β-cyclodextrin.

Computer-aided molecular modeling techniques for predicting the stability of drug–cyclodextrin inclusion complexes in aqueous solutions

Molecular modeling was used to investigate factors influencing complex formation between cyclodextrins and guest molecules and predict their stability through a theoretical model based on the search for a correlation between experimental stability constants (Ks) and some theoretical parameters describing complexation (docking energy, host– guest contact surfaces, intermolecular interaction fields) calculated from complex structures at a minimum conformational energy, obtained through stochastic methods based on molecular dynamic simulations. Naproxen, ibuprofen, ketoprofen and ibuproxam were used as model drug molecules. Multiple Regression Analysis allowed identification of the significant factors for the complex stability. A mathematical model (r ¼ 0:897) related log Ks with complex docking energy and lipophilic molecular fields of cyclodextrin and drug. 2002 Elsevier Science B.V. All rights reserved.

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.

Compatibility Studies of Multicomponent Tablet Formulations. DSC and experimental mixture design

An experimental mixture design was applied to a differential scanning calorimetry (DSC) study performed to evaluate naproxen compatibility in tablet formulations consisting of four classic excipients (sorbitol, sodium carboxymethylcellulose, poly(ethylene glycol) 20000 and Veegum) each in adequate concentration ranges accounting for the relevant values actually used in pharmaceutical formulations. Twenty-seven different tablets were obtained from as many mixtures prepared according to the experimental design plan and analyzed in a random order by DSC. Statistical evaluation of experimental data enabled correlation of both enthalpy and onset temperature variations of drug melting endotherm (selected as responses indicative of the presence of drug-excipient interactions) with the mixture composition. Variance analysis (Anova) confirmed the reliability of the postulated polynomial model in providing adequate prediction of true system behaviour.