A. Manderioli

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.

Properties of Solid Dispersions of Naproxen in Various Polyethylene Glycols

AbstractSolid dispersions of naproxen in polyethylene glycol 4000, 6000, and 20000, aimed at improving the drug dissolution characteristics, were prepared by both the solvent and melting methods. The drug-polymer interaction in the solid state was investigated using differential scanning calorimetry, hot-stage microscopy, Fourier-transform infrared spectroscopy, and x-ray diffraction analysis. Interaction in solution was studied by phase solubility analysis and dissolution experiments. Computer-aided molecular modeling was used to supplement the results from phase solubility studies. No important chemical interaction was found between naproxen and polyethylene glycol, either in solution or in the solid state, apart from the formation of weak drug-polymer hydrogen bonds. The increase of naproxen dissolution rate from its binary systems with polyethylene glycol could be attributed to several factors such as improved wettability, local solubilization, and drug particle size reduction. No influence of polymer...

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.

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.

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.

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.

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.

Differential scanning calorimetry in compatibility testing of picotamide with pharmaceutical excipients

Abstract Differential scanning calorimetry with the support of X-ray powder diffractometry was used as a screening technique for testing the compatibility of picotamide (4-methoxy-N,N′-bis(3-piridinylmethyl)-1,3-benzenedicarboxamide) in the dehydrated form with various pharmaceutical excipients for solid dosage forms. The effect of dry grinding, wet grinding (i.e. kneading) and ageing on drug-excipient blends in the 1:1 (by weight) ratio on physicochemical and chemical stability of the drug was investigated. Chemical compatibility was in general observed with exception of combinations with tartaric and ascorbic acid, where acid/base interactions induced by heating were responsible for the drug degradation evidenced by the profound modification of the thermal effects of individual components. Analogous modifications (i.e. loss of melting peak of the drug) in mixtures with polyvinylpyrrolidone were due to amorphization of picotamide with no substantial alteration of its chemical integrity. Physical compatibility was seen in the systems with microcrystalline cellulose, corn starch, hydroxypropylmethylcellulose and hydroxyethylcellulose where dehydrated picotamide was stable except under wet grinding conditions. In combinations with sodium carboxymethylcellulose, veegum and arabic gum solid-state phase transformation of dehydrated picotamide to monohydrate occurred also by simple blending, probably because of the weak interaction between excipient and the associated water.

Multicomponent Systems of Econazole with Hydroxyacids and Cyclodextrins

The effect of the type of cyclodextrin (α-, β-, γ-,hydroxypropyl-β-CD) and of hydroxyacid (tartaric, citric, gluconic,malic, lactic) on the solubility enhancement by multicomponent complexationof econazole, a poorly water soluble base-type drug, was studied. A synergisticeffect was found in ternary systems, largely more effective than correspondingbinary complexes and salts. Moreover, the presence of a third component madeeffective the use of γ-CD, which had no solubilizing power in binarysystems. The solubilizing efficiency of multicomponent systems was not relatedto the solubilities of the corresponding salts or binary complexes. Phase-solubility analysis at different temperatures was also used to investigate the interaction of econazole with cyclodextrins, alone or in the presence of hydroxyacid. The best 1 : 1 : 1 molar ratio system was that with α-CD and malic acid which showed the best solubilizing power and the highest stability constant of the ternary complex.Ternary α-CD products, prepared by co-grinding, co-evaporation or colyophilization, were characterized by Differential Scanning Calorimetry and tested for dissolution properties. The higher solubilizing properties of multicomponent systems were reflected in better drug dissolution rates from their solid systems.

Interaction of naproxen with α-, β-, and γ-hydroxypropyl cyclodextrins in solution and in the solid state

Solid combinations of naproxen with amorphous hydroxypropyl derivatives of α-, β-, and γ-cyclodextrin with an average substitution degree per anhydroglucose unit of 0.6 were investigated for thermal behaviour (differential scanning calorimetry), drug crystallinity (X-ray diffractometry), and dissolution rate (dispersed amount and rotating disc methods). Phase-solubility analysis and computer-aided molecular modelling were carried out to study the inclusion complexation of naproxen with hydroxypropyl cyclodextrins. The cavity size of the host is a selective factor for the solubilizing effect, complexing ability, and dissolution rate enhancement on naproxen, hydroxypropyl β-cyclodextrin being markedly the most effective derivative. No relationship was found between the decrease in crystallinity of the drug dispersed in the amorphous carrier matrix and the geometrical features of the cyclodextrin macrocycle.