G. Van den Mooter

Physical stabilisation of amorphous ketoconazole in solid dispersions with polyvinylpyrrolidone K25.

The glass forming properties of ketoconazole were investigated using differential scanning calorimetry (DSC), by quench cooling liquid ketoconazole from T(m)+10 to 273.1 K, followed by subsequent heating at 5 K/min to T(m)+10 K. It was shown that liquid ketoconazole forms a glass which did not recrystallise following reheating, indicating its stability; T(g) was found to be 317.5+/-0.3 K. However, the presence of a small amount of crystalline ketoconazole was able to convert the amorphous drug back to the crystalline state: the addition of only 4.1% (w/w) of crystalline material converted 77.1% of the glass back to the crystalline state, and this value increased as the amount of added crystals increased. PVP K25 was found to be highly effective in the prevention of such recrystallisation, but only if the amorphous drug was formulated in a solid dispersion, since physical mixing of amorphous ketoconazole with the polymer resulted in recrystallisation of the former compound. Storage of the solid dispersions for 30 days at 298.1 K (both 0 and 52% RH) in the presence or absence of crystals did not result in recrystallisation of the amorphous drug. Solid dispersions formed compatible blends as one single T(g) was observed, which gradually increased with increasing amounts of PVP K25, indicating the anti-plasticising property of the polymer. The values of T(g) followed the Gordon-Taylor equation, indicating no significant deviation from ideality and suggesting the absence of strong and specific drug-polymer interactions, which was further confirmed with 13C NMR and FT-IR. It can be concluded therefore that the physical mechanism of the protective effect is not caused by drug-polymer interactions but due to the polymer anti-plasticising effect, thereby increasing the viscosity of the binary system and decreasing the diffusion of drug molecules necessary to form a lattice.

Physico-chemical characterization of solid dispersions of temazepam with polyethylene glycol 6000 and PVP K30

Abstract In order to increase the dissolution of temazepam, solid dispersions were prepared using polyethylene glycol 6000 (PEG 6000) and polyvinylpyrrolidone K30 (PVP K30). Dispersions with PEG 6000 were prepared by fusion-cooling and co-evaporation, while dispersions containing PVP K30 were prepared by co-evaporation. In contrast to the very slow dissolution rate of pure temazepam, the dispersion of the drug in the polymers considerably enhanced the dissolution rate. This can be attributed to improved wettability and dispersibility, as well as particle size reduction and decrease of the crystalline fraction of the drug. The aqueous solubility of temazepam was favoured by the presence of PEG 6000. The negative values of the Gibbs free energy and enthalpy of transfer explained the spontaneous transfer from pure water to the aqueous polymer environment. It was found that temazepam was decomposed in the presence of aqueous solutions of PVP K30 to at least two unidentified degradation products. Drug–polymer interactions in the solid state were investigated using differential scanning calorimetry, X-ray powder diffraction, and fourier-transform infrared spectroscopy. PEG 6000 gave a eutectic system in which liquid polymer could dissolve approximately 10% of temazepam. On the other hand, X-ray powder diffraction patterns and thermal analysis indicated that the drug was in the amorphous state up to a concentration of 40% w/w when dispersed in PVP K30; the infrared spectra indicated solid state interactions between the OH of temazepam and the CO of PVP K30.

Mechanism of increased dissolution of diazepam and temazepam from polyethylene glycol 6000 solid dispersions

Solid dispersion literature, describing the mechanism of dissolution of drug-polyethylene glycol dispersions, still shows some gaps; (A). only few studies include experiments evaluating solid solution formation and the particle size of the drug in the dispersion particles, two factors that can have a profound effect on the dissolution. (B). Solid dispersion preparation involves a recrystallisation process (which is known to be highly sensitive to the recrystallisation conditions) of polyethylene glycol and possibly also of the drug. Therefore, it is of extreme importance that all experiments are performed on dispersion aliquots, which can be believed to be physico-chemical identical. This is not always the case. (C). Polyethylene glycol 6000 (PEG6000) crystallises forming lamellae with chains either fully extended or folded once or twice depending on the crystallisation conditions. Recently, a high resolution differential scanning calorimetry (DSC)-method, capable of evaluating qualitatively and quantitatively the polymorphic behaviour of PEG6000, has been reported. Unraveling the relationship between the polymorphic behavior of PEG6000 in a solid dispersion and the dissolution characteristics of that dispersion, is a real gain to our knowledge of solid dispersions, since this has never been thoroughly investigated. The aim of the present study was to fill up the three above mentioned gaps in solid dispersion literature. Therefore, physical mixtures and solid dispersions were prepared and in order to unravel the relationship between their physico-chemical properties and dissolution characteristics, pure drugs (diazepam, temazepam), polymer (PEG6000), solid dispersions and physical mixtures were characterised by DSC, X-ray powder diffraction (Guinier and Bragg-Brentano method), FT-IR spectroscopy, dissolution and solubility experiments and the particle size of the drug in the dispersion particles was estimated using a newly developed method. Addition of PEG6000 improves the dissolution rate of both drugs. Mechanisms involved are solubilisation and improved wetting of the drug in the polyethylene glycol rich micro-environment formed at the surface of drug crystals after dissolution of the polymer. Formulation of solid dispersions did not further improve the dissolution rate compared with physical mixtures. X-ray spectra show that both drugs are in a highly crystalline state in the solid dispersions, while no significant changes in the lattice spacings of PEG6000 indicate the absence of solid solution formation. IR spectra show the absence of a hydrogen bonding interaction between the benzodiazepines and PEG6000. Furthermore, it was concluded that the reduction of the mean drug particle size by preparing solid dispersions with PEG6000 is limited and that the influence of the polymorphic behavior of PEG6000 (as observed by DSC) on the dissolution was negligible.

Azo polymers for colon-specific drug delivery

Abstract In order to develop a colon-specific drug delivery system, copolymers of 2-hydroxyethyl methacrylate and methyl methacrylate were prepared in the presence of bis(methacryloylamino)azobenzene. The conditions of polymerization were optimized to prevent crosslinking. Film coatings were prepared with the azo polymers. The films were insoluble in simulated gastric and intestinal juice. Dependent on the of the hydrophilic groups in the polymers, the films were more or less permeable to water. In vitro and in vivo tests prove that it is possible to use the polymers to deliver drugs to the large intestine. Due to the presence of the azo compound, the azo polymer coatings can be degraded by intestinal bacteria.

Improvement of the dissolution rate of artemisinin by means of supercritical fluid technology and solid dispersions

The purpose of this study was to enhance the dissolution rate of artemisinin in order to improve the intestinal absorption characteristics. The effect of: (1) micronisation and (2) formation of solid dispersions with PVPK25 was assessed in an in vitro dissolution system [dissolution medium: water (90%), ethanol (10%) and sodium lauryl sulphate (0.1%)]. Coulter counter analysis was used to measure particle size. X-ray diffraction and DSC were used to analyse the physical state of the powders. Micronisation by means of a jet mill and supercritical fluid technology resulted in a significant decrease in particle size as compared to untreated artemisinin. All powders appeared to be crystalline. The dissolution rate of the micronised forms improved in comparison to the untreated form, but showed no difference in comparison to mechanically ground artemisinin. Solid dispersions of artemisinin with PVPK25 as a carrier were prepared by the solvent method. Both X-ray diffraction and DSC showed that the amorphous state was reached when the amount of PVPK25 was increased to 67%. The dissolution rate of solid dispersions with at least 67% of PVPK25 was significantly improved in comparison to untreated and mechanically ground artemisinin. Modulation of the dissolution rate of artemisinin was obtained by both particle size reduction and formation of solid dispersions. The effect of particle size reduction on the dissolution rate was limited. Solid dispersions could be prepared by using a relatively small amount of PVPK25. The formation of solid dispersions with PVPK25 as a carrier appears to be a promising method to improve the intestinal absorption characteristics of artemisinin.

Drug absorption studies of prodrug esters using the Caco-2 model: evaluation of ester hydrolysis and transepithelial transport

Abstract The design of lipophilic ester prodrugs is a widely used approach to obtain enhanced oral delivery of poorly membrane permeable compounds. The present study was conducted in order to assess the influence of intestinal metabolism on transepithelial flux of prednisolone prodrugs using the Caco-2 system. In addition, distribution of esterase activity along the GI tract was evaluated using homogenates of scraped intestinal mucosa from various parts of small intestine and colon of rat and pig. Prednisolone acetate (lipophilic prodrug) and prednisolone hemisuccinate (hydrophilic prodrug) were selected as model compounds for transport studies. In transport studies using prednisolone acetate (100 μ M), almost complete ester hydrolysis and an increased transepithelial flux of prednisolone were observed. Virtually no transport nor metabolism was observed when the hemisuccinate ester was used, illustrating its poor ability to cross membranes. Incubation studies with purified carboxylesterase showed that prednisolone acetate was rapidly degraded ( t 1/2 =2.94 min), while prednisolone hemisuccinate degradation was very low. Studies on site dependency of esterase activity using p -nitrophenyl acetate as a substrate showed an important interspecies difference, rat intestine possessing much higher activity than pig intestine, and a gradual decrease of esterase activity along the GI tract for the two species tested. Esterase activity in Caco-2 monolayers was twice as high as observed in colon of rat and pig, but much lower than activities measured in the small intestine. It can be concluded that the rat may not be a suitable choice for oral bioavailability studies of ester prodrugs; it may also be advantageous to target ester prodrugs of hydrophilic compounds to the colon, thus preventing significant accumulation of the parent compound inside the mucosal cells.

Physical stability of solid dispersions of the antiviral agent UC-781 with PEG 6000, Gelucire 44/14 and PVP K30.

This paper describes the physical stability of solid dispersions of UC-781 with PEG 6000, Gelucire 44/14 and PVP K30 prepared by the solvent and melting methods. The concentration of the drug in the solid dispersions ranged from 5 to 80% w/w. The solid dispersions were stored at 4-8 and 25 degrees C (25% RH), then their physicochemical properties were analysed by differential scanning calorimetry (DSC), X-ray powder diffraction and dissolution studies as a function of storage time. The DSC curves of solid dispersions of UC-781 with PVP K30 did not show any melting peaks corresponding to UC-781 after storage, indicating no recrystallization of the drug. The DSC data obtained from PEG 6000 and Gelucire 44/14 showed some variations in melting peak temperatures and enthalpy of fusion of the carriers. It was shown that the enthalpy of fusion of PEG 6000 in the dispersions increased after storage; it was more pronounced for samples stored at 25 degrees C compared to those at 4-8 degrees C indicating the reorganization of the crystalline domains of the polymer. Similarly, the enthalpy of fusion of Gelucire 44/14 in the solid dispersions increased as a function of time. Dissolution of UC-781 from all solid dispersions decreased as a function of storage time. While these observations concurred with the DSC data for all solid dispersions, they were not reflected by X-ray powder diffraction data. It was concluded that it is the change of the physical state of the carriers and not that of the drug, which is responsible for the decreased dissolution properties of the solid dispersions investigated.

PLGA nanoparticles and nanosuspensions with amphotericin B: Potent in vitro and in vivo alternatives to Fungizone and AmBisome.

This paper describes the development of poly(D,L-lactide-co-glycolide) (PLGA) nanoparticles (NPs) and nanosuspensions with the polyene antibiotic amphotericin B (AmB). The nanoformulations were prepared using nanoprecipitation and were characterised with respect to size, zeta potential, morphology, drug crystallinity and content. Standard in vitro sensitivity tests were performed on MRC-5 cells, red blood cells, Leishmania infantum promastigotes and intracellular amastigotes and the fungal species Candida albicans, Aspergillus fumigatus and Trichophyton rubrum. The in vivo efficacy was assessed and compared to that of Fungizone and AmBisome in the acute A. fumigatus mouse model at a dose of 2.5 and 5.0mg/kg AmB equivalents. The developed AmB nanoformulations were equivalently or more effective against the different Leishmania stages and axenic fungi in comparison with the free drug. The in vitro biological activity, and especially hemolytic activity, clearly depended on the preparation parameters of the different nanoformulations. Further, we demonstrated that the superior in vitro antifungal activity could be extrapolated to the in vivo situation. At equivalent dose, the optimal AmB-loaded PLGA NP was about two times and the AmB nanosuspension about four times more efficacious in reducing the total burden than AmBisome. The developed AmB nanomedicines could represent potent and cost-effective alternatives to Fungizone and AmBisome.

Characterization of glassy itraconazole: a comparative study of its molecular mobility below Tg with that of structural analogues using MTDSC

The objective of the present study was to estimate the molecular mobility of glassy itraconazole below the glass transition, in comparison with structural analogues (i.e. miconazole and ketoconazole).Glassy itraconazole and miconazole were prepared by cooling from the melt. The glassy state of the drug was investigated with modulated temperature DSC using the following conditions: amplitude +/-0.212 K, period 40 s, underlying heating rate 2 K/min. The glass transition was determined from the reversing heat flow and occurred at 332.4 (+/-0.5) K and 274.8 (+/-0.4) K for itraconazole and miconazole, respectively. The jump in heat capacity at the glass transition was 303.42 (+/-3.43) J/mol K for itraconazole and 179.35 (+/-0.89) J/mol K for miconazole. The influence of the experimental conditions on the position of the glass transition of itraconazole was investigated by varying the amplitude from +/-0.133 to +/-0.292 K and the period from 25 to 55 s, while the underlying heating rate was kept constant at 2 K/min. Glass transition temperature, T(g), was not significantly influenced by the frequency of the modulation nor by the cooling rate. However, the relaxation enthalpy at the glass transition increased with decreasing cooling rate indicating relaxation during the glass formation process. To estimate the molecular mobility of the glassy materials, annealing experiments were performed from T(g)--10 to T(g)--40 K for periods ranging from 15 min to 16 h. Fitting the extent of relaxation of glassy itraconazole to the Williams--Watts decay function and comparing the obtained values with those of amorphous miconazole and ketoconazole indicated that the molecular mobility is influenced by the complexity of the molecular structure. The more complex the structure, the more stable the amorphous state.

Thermal Properties of Hot-Stage Extrudates of Itraconazole and Eudragit E100. Phase separation and polymorphism

Solid dispersions of itraconazole and eudragit E100 were prepared by hot-stage extrusion. Analysis of the physical structure revealed the existence of different phases, depending on the manufacturing condition. Extrudates prepared at 453 K existed as a molecular dispersion of itraconazole in eudragit E100 when the drug concentration did not exceed ca. 13% mass/mass. At higher concentrations, a second phase consisting of pure glassy itraconazole emerged. In other dispersions prepared at 413 K, the second phase consisted of pure crystalline itraconazole. The difference can be attributed to the relation of the process-temperature to the melting point. Heating of both dispersions induced cold crystallization. Extrudates prepared at 453 K showed comparable behavior before and after milling, with the exception that unmilled dispersions with a drug load of ≥60% mass/mass recrystallized upon heating into a polymorphic modification of itraconazole (Tm=431 K). Upon further heating the polymorph recrystallized to the stable crystalline form (Tm=441 K).