S. Pinzauti

Utilization of differential scanning calorimetry as a screening technique to determine the compatibility of ketoprofen with excipients

Abstract Differential scanning calorimetry (DSC) was used as a screening technique for assessing the compatibility of ketoprofen with some excipients currently employed in tablet or capsule formulations. The effect of sample treatment (simple blending, cogrinding, compression, kneading) was also evaluated. On the basis of DSC results, ketoprofen was found to be compatible with hydroxyethylcellulose, hydroxypropylcellulose, microcrystalline cellulose, corn starch, arabic gum, colloidal silica, veegum, lactose, glucose, sorbitol and mannitol. Some drug-excipient interaction was observed with palmitic acid, stearic acid and stearyl alcohol and eutectic formation was found with magnesium stearate. Strong solid-phase interaction with polyethylene glycol 6000, polyvinylpolypyrrolidone and even more with polyvinylpyrrolidone K30 was found.

Application of quality by design to the development of analytical separation methods.

AbstractRecent pharmaceutical regulatory documents have stressed the critical importance of applying quality by design (QbD) principles for in-depth process understanding to ensure that product quality is built in by design. This article outlines the application of QbD concepts to the development of analytical separation methods, for example chromatography and capillary electrophoresis. QbD tools, for example risk assessment and design of experiments, enable enhanced quality to be integrated into the analytical method, enabling earlier understanding and identification of variables affecting method performance. A QbD guide is described, from identification of quality target product profile to definition of control strategy, emphasizing the main differences from the traditional quality by testing (QbT) approach. The different ways several authors have treated single QbD steps of method development are reviewed and compared. In a final section on outlook, attention is focused on general issues which have arisen from the surveyed literature, and on the need to change the researcher’s mindset from the QbT to QbD approach as an important analytical trend for the near future. FigureQuality by design guide for analytical method development

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.

Didanosine extended-release matrix tablets: optimization of formulation variables using statistical experimental design.

Statistical experimental design was applied to evaluate the influence of some process and formulation variables and possible interactions among such variables, on didanosine release from directly-compressed matrix tablets based on blends of two insoluble polymers, Eudragit RS-PM and Ethocel 100, with the final goal of drug release behavior optimization. The considered responses were the percent of drug released at three determined times, the dissolution efficiency at 6 h and the time to dissolve 10% of drug. Four independent variables were considered: tablet compression force, ratio between the polymers and their particle size, and drug content. The preliminary screening step, carried out by means of a 12-run asymmetric screening matrix according to a D-optimal design strategy, allowed evaluation of the effects of different levels of each variable. The drug content and the polymers ratio had the most important effect on drug release, which, moreover, was favored by greater polymers particle size; on the contrary the compression force did not have a significant effect. The Doehlert design was then applied for a response-surface study, in order to study in depth the effects of the most important variables. The desirability function was used to simultaneously optimize the five considered responses, each having a different target. This procedure allowed selection, in the studied experimental domain, of the best formulation conditions to optimize drug release rate. The experimental values obtained from the optimized formulation highly agreed with the predicted values. The results demonstrated the reliability of the model in the preparation of extended-release matrix tablets with predictable drug release profiles.

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.

Identification and determination of mainstream and sidestream smoke components in different brands and types of cigarettes by means of solid-phase microextraction-gas chromatography-mass spectrometry

The qualitative and quantitative determination of components of mainstream and sidestream smoke has been performed by solid-phase microextraction-gas chromatography-mass spectrometry. Several brands and types of cigarettes sold in Italy were considered: normal, mild, light, extra light, some with filter and some without. Extraction of the analytes was performed by means of solid-phase microextraction (SPME) and the optimisation of the extraction procedure was performed by experimental design, taking into consideration type of fiber polymer, exposure temperature and time. Sixty-seven components of mainstream and sidestream smoke were identified. The quantified compounds (by means of deuterium-labelled isotopologues) were benzene, toluene, p-xylene, m-xylene, pyridine, o-xylene, limonene, naphthalene, phenol and nicotine. Finally, a comparison between the chemical profile of smoke from the different cigarettes was made.

EXPERIMENTAL DESIGN IN THE DEVELOPMENT OF VOLTAMMETRIC METHOD FOR THE ASSAY OF OMEPRAZOLE

A multivariate strategy was used to optimize an adsorptive stripping voltammetric method for the determination of the antiulcer drug omeprazole. A 3/4 matrix was used for the variable screening while a central composite design was chosen in the subsequent step to evaluate the response surfaces. Simultaneous optimization of the response peak height (hp) and peak half width w1/2), the latter being a peak shape measure, was achieved. The factors accumulation time, pulse amplitude, scan rate and stirring rate were all found to be statistically significant for the response hp, while for the response w1/2 only the stirring rate was found to be significant. The optimized method shows a good linearity between peak height and analyte concentration in the concentration range from 8.33 x 10(-9) M to 1.42 x 10(-7) M with a LOD of 6.5 x 10(-9) M. The mean recovery of omeprazole in capsules was 101.9% with a SD of 2.04 (RSD = 200).

Design of experiments for capillary electrophoretic enantioresolution of salbutamol using dermatan sulfate.

Statistical experimental design was used for the optimization and for robustness evaluation of a capillary electrophoretic method developed for the enantioresolution of salbutamol. Dermatan sulfate was used as chiral selector. The goal of the study was to obtain an efficient and fast separation. An eight-run Plackett-Burman matrix was used during the optimization process for the screening of the factors and to adjust the experimental domain under study. Response surface methodology was adopted after the screening phase to obtain information about how the factors percentage of chiral selector, pH and voltage affected the considered responses resolution and analysis time. The Derringer desirability function, which makes it possible to combine results obtained for properties measured on different scales, was used to simultaneously optimize the two responses. Robustness testing was carried out using a Plackett-Burman matrix. The method was found robust as regards the response resolution while voltage and chiral selector were found to be critical factors for the robustness of analysis time response. The proposed CE method permitted the complete enantioseparation of racemic salbutamol and was applied to its chiral resolution in spiked urine samples.

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.

Experimental design methodologies to optimize the CE separation of epinephrine enantiomers

SummaryA capillary electrophoretic method using a chiral selector was optimized by experimental design for the enantioresolution of epinephrine enantiomers. Two β-cyclodextrins derivatives, namely heptakis-2,6-di-O-methyl-β-cyclodextrin and carboxy-methyl-β-cyclodextrin, respectively neutral and charged, were used as chiral selectors employing an uncoated capillary. By using a statistical experimental design in which all factors are varied at the same time, it was possible to optimize the method with regard to the resolution between peaks and the two migration times. A fractional factorial design and a central composite design were used. A compromise between conflicting goals, such as maximization of resolution and minimization of analysis time, was found by means of a desirability function D. Balancing these goals against each other, the most acceptable solution to the problem was found and the optimized method gave a fast separation with complete resolution between the adrenaline enantiomers. The response surfaces obtained confirmed the robustness of the method.