Christine Barthélémy

Improved Dissolution Behavior of Fenbufen by Spherical Crystallization

Fenbufen is an analgesic, antipyretic and anti-inflammatory drug that is characterized by poor water solubility, a defect increased by very low wettability. Poor water solubility, particularly at low pH, could decrease absorption in the upper part of the gastrointestinal tract, which would be inconvenient for good bioavailability. Different spherical crystallization processes have been considered as methods to improve fenbufen dissolution behavior. A two-solvent system, in the presence of a bridging liquid, is the only method capable of producing spherical fenbufen crystals. In a first step, fenbufen solubility was considered in different solvents. The drug crystals formed were typically needle shaped. This characteristic was considered as a favorable parameter to obtain spherical crystals. After the selection of the best fenbufen solvent, several ratios of solvent (S)-nonsolvent (NS) (tetrahydrofuran [THF]-demineralized water) were studied. The addition of a bridging liquid (isopropyl acetate) improved spherical crystallization. The results from this method were reproducible batch to batch. The spherical crystals obtained showed a clear improvement in dissolution capacity, probably due to better wettability. Dissolution studies were then carried out on these spherical crystals stored for 1 month at different relative humidities (RHs). The dissolution profiles remained unchanged.

Physical characterization of naproxen sodium hydrate and anhydrate forms

Naproxen sodium (NS) is a nonsteroidal anti-inflammatory drug used in painful and inflammatory diseases. By crystallization from water or by exposure to relative humidities over 43%, the anhydrate form can be hydrated to a dihydrate species. Different techniques have been used to characterize physically anhydrate naproxen sodium (ANS) and hydrate naproxen sodium (HNS): elemental analysis, atomic absorption, electron scanning microscopy, thermomicroscopy, differential scanning calorimetry, Karl Fishers titrimetry, thermogravimetry, spectrophotometric analysis and X-ray diffraction study. The hydration/dehydration mechanism, at different relative humidities, was investigated to evaluate their physical stability. When stored up to 43% relative humidity, ANS shows a good stability, whereas with an increase in relative humidity it is hydrated. HNS equilibrium solubility was determined at different temperatures (21, 26, 31, and 37 degrees C). Due to the metastability and the quick phase changes in the water of ANS, its solubility was calculated from intrinsic dissolution measurements at the same temperatures, as solubility measurements of HNS. Water solubility of ANS is greater than HNS, but the solubility difference decreases when the temperature decreases. This is due to the fact that at higher temperatures the intrinsic dissolution rates (IDR) of ANS are considerably faster and decrease as the temperature falls.

Improved compression properties of propyphenazone spherical crystals.

Spherical propyphenazone crystals were produced by an agglomeration technique using a three solvents system. After selecting the best propyphenazone solvent (ethyl alcohol), non-solvent (demineralized water) and bridging liquid (isopropyl acetate), several of their ratios were tested by a Sheffé ternary diagram. Micromeritic properties of agglomerates such as flowability, were improved and their compression behavior was investigated and compared to that of raw crystals. By compression and densification studies, along with tablet SEM analysis, we have been able to explain the compression mechanism of propyphenazone spherical crystals and have shown that their better tablet/ability can be due to the small size of individual particles in the agglomerates

Impact of multiaccess infusion devices on in vitro drug delivery during multi-infusion therapy.

BACKGROUND: Multiaccess infusion sets allow multiple simultaneous infusions but may induce interference in drug delivery resulting from large variations in the delivery rate of potent drugs. In this study, we sought to understand the influence of multiaccess infusion device properties (dead space volume and antireflux valve [ARV]) on drug delivery during multi-infusion therapy. METHODS: Infusion sets differing in length, dead space volume, and presence of an ARV were assessed. Three drugs were infused simultaneously through different access points, and their concentrations were obtained using UV spectrophotometric analysis of the effluent. Different infusion configurations were compared by assessing (1) the amount of drug delivered to the patient per unit of time, (2) the mean amount of drug delivered to the patient per unit of time during the steady-state infusion (mass flow rate plateau), and (3) flow change efficiency calculated from the ratio of the area under the experimental instant mass flow rate curve to the area corresponding to theoretical instant mass flow rate curve. RESULTS: Infusion sets with lower dead space volumes offered significantly higher flow change efficiency (53.0% ± 15.4% with a dead space volume equal to 0.046 mL 5 min after the start of infusion) than infusion sets with higher dead space volume (5.6% ± 8.2% with a dead space volume equal to 6.16 mL), whatever the flow rate changes. Even in case of large dead space volumes, the presence of an ARV significantly increased the mass flow rate plateau (from 92.4% to 99.3% of the theoretical plateau without and with the presence of an ARV, respectively). CONCLUSIONS: Multi-infusion therapy induces perturbation in drug delivery. These perturbations (lag time, backflow, and bolus) could be reduced by using infusion sets including very low dead space volume and an ARV.

Infusion set characteristics such as antireflux valve and dead-space volume affect drug delivery: an experimental study designed to enhance infusion sets.

BACKGROUND: The ability of an infusion set to deliver a specific amount of drug to the patient can be directly related to the presence of an antireflux valve and dead-space volume. In this study we quantified separately the impact of these 2 components on drug delivery. METHODS: Various infusion sets were assessed differing in length, in dead-space volume, and with or without an antireflux valve. Noradrenalin was infused with a syringe pump simultaneously with a carrier flow. Effluent drug concentration was measured using ultraviolet spectrophotometry. Flow change efficiency (FCE) was calculated from the ratio of the area under the experimental mass flow rate curve to the area under the theoretical instantaneous mass flow rate curve. RESULTS: The FCE for infusion sets with or without antireflux valves were significantly different 10 to 15 minutes after the start of an infusion at flow rates of 7 mL/h for noradrenalin and 35 mL/h to 70 mL/h for the carrier fluid. They were not different with a carrier flow of 115 mL/h. DISCUSSION: These findings suggest that antireflux valves have a significant impact on FCE when the ratio of drug flow rate to carrier fluid flow rate is high. Infusion sets with very low dead-space volume connectors yield better FCE. There is a nonlinear relationship between dead-space volume and FCE 5 to 10 minutes after the onset of drug infusion. CONCLUSION: Care providers must consider dead-space volume and the presence of an antireflux valve when choosing their infusion sets.

Experimental study on infusion devices containing polyvinyl chloride: To what extent are they di(2-ethylhexyl)phthalate-free?

The use of medical devices containing highly criticized phthalates including di(2-ethylhexyl) phthalate (DEHP) has been challenged by European directive 2007/47/CE, put into effect in March 2010. New plasticizers are now being used to soften PVC in medical devices: trioctyltrimellitate (TOTM), di-isononyl-cyclohexan-1,2-dicarboxilate (DINCH) and di(2-ethylhexyl) terephthalate (DEHT). To quantify DEHP in nine DEHP-free medical devices made of PVC softened by alternative plasticizers, high performance liquid chromatography analysis with ultraviolet detection at 220 nm wavelength was achieved. An NMR spectroscopy was performed to confirm DEHP presence. Only two medical devices out of the nine tested were truly without DEHP. One of them showed traces of DEHP exceeding the threshold contamination of 0.1% in plastic mass set by REACH regulations. TOTM plasticizer is still incriminated when polyvinyl-chloride (PVC) is contaminated with DEHP. Manufacturers must verify the purity of their raw material, not only on PVC, but also on other soft plastics entering into the composition of medical infusion devices. The clinical consequences of exposure to certain levels of DEHP have not been evaluated. A solution could be to use alternative PVC-free materials.

The impact on drug mass flow rate of interrupting and resuming carrier fluid flow: an in vitro study on a very low dead-space volume infusion set.

BACKGROUND: Stopping and resuming carrier fluid flow can lead to potentially dangerous transient disturbances in drug mass flow rate. We compared the impact of 2 infusion sets, one with very low dead-space volume and the other with greater dead-space volume, on the amount of drug delivered during stop-and-go carrier fluid flows. METHODS: Two infusion sets, both with antireflux, connected to an angiocatheter and with dead-space volumes of 6.185 mL and 0.071 mL, respectively, were assessed. Two protocols were studied: carrier fluid flow of 90 mL/h associated with noradrenaline infused at 7 mL/h and carrier fluid flow of 350 mL/h with a noradrenaline infusion flow of 65 mL/h. During both protocols, the carrier fluid was stopped and resumed at the same rate 30 minutes later. Effluent noradrenaline concentration was measured using UV spectrophotometry. Flow change efficiency was calculated from the ratio of the area under the experimental mass flow rate curve to the area under the theoretical instantaneous mass flow rate curve. RESULTS: For both flow rate conditions, flow change efficiency was significantly different for the 2 infusion sets during the 10-minute period after stopping carrier fluid flow and the 10-minute period after restarting it. The major phenomena were sudden decreases in drug delivery after stopping carrier flow and sudden, temporary increases when it was resumed. The very low dead-space volume infusion set resulted in significant reduction in changes in drug delivery compared with the standard set, even at high flow rates. CONCLUSION: The use of a very low dead-space volume set attenuates disturbances in drug delivery caused by interrupting and resuming carrier fluid flow.

Influence of crystal hydration on the mechanical properties of sodium naproxen.

The aim of this work is to establish a correlation between water uptake by anhydrous sodium naproxen (ASN) at two different relative humidities and modifications in tableting and densification behaviour under hydration. Water uptake was evaluated at different relative humidities. Models for the hydration kinetics of ASN at 55% and 86%, corresponding to the formation of the dihydrated and tetrahydrated forms, respectively, were evaluated assuming Eyrings dependence on temperature. Tabletability, compressibility, compactibility, and densification behaviour were determined using an instrumented single punch tablet machine. Kinetic data are consistent with a model where water molecules enter the crystal preferentially along hydrophilic tunnels existing in the crystal structure and corresponding to the propionate side chain. Water inclusion perturbs the crystallographic structure, causing slight structural changes according to the amount and associated to an increase in entropy. The interposition of water molecules between sodium naproxen molecules weakens intermolecular bonds, and these sites can behave like sliding planes under compression. Such structural changes may explain the improved compression behaviour and modified densification propensity mechanism. Kinetic data describing the water hydration mechanism of ASN explain in an original way the improved tableting and densification properties under hydration.

P-glycoprotein and cytochrome P450 3A4 involvement in risperidone transport using an in vitro Caco-2/TC7 model and an in vivo model.

The possible involvement of P-glycoprotein (P-gp) and cytochrome P450 (CYP) 3A4 in risperidone transport was investigated using in vitro and in vivo models. Firstly, uptake studies were performed on a Caco-2/TC7 cell monolayer; the effects of 1 microg ml(-1) risperidone on apparent permeability were determined for secretory and absorptive directions, in the presence or absence of various P-gp and CYP3A4 inhibitors (verapamil, ketoconazole, erythromycin), and of an associated multidrug-resistant protein inhibitor (indomethacin). Secondly, on a conscious rat model, risperidone pharmacokinetic parameters, notably absorption parameters, were determined using compartmental and deconvolution methods. Three groups of seven rats received respectively an IV risperidone dose, an oral risperidone dose (PO group) and the same oral risperidone dose after verapamil administration (POV group). No formation of 9-hydroxyrisperidone was observed on Caco-2 cells after risperidone administration; there was no evidence that intestinal CYP3A4 is involved in risperidone metabolising. Risperidone secretory permeation was higher than absorptive permeation. Verapamil increased risperidone absorption permeation and decreased its secretory permeation. Indomethacin did not modify these permeation values. In rats, verapamil led to an increase in both risperidone and 9-hydroxyrisperidone plasmatic concentrations. The fraction absorbed in the verapamil group was 3.18 times higher than in the oral group (65.9% and 20.7% for POV group and PO group). The absorption rate constant was lower in the verapamil group. Our results indicate that P-gp decreases the intestinal absorption of risperidone and that intestinal CYP3A4 is not involved in risperidone metabolism.

The impact of multilumen infusion devices on the occurrence of known physical drug incompatibility: a controlled in vitro study.

BACKGROUND:Drug incompatibility is a problem, especially when managing patients in intensive care units. We designed the present study to assess the impact of multilumen infusion access devices on the occurrence of known physical drug incompatibility through a controlled in vitro study. METHODS:Three infusion devices connected to a single-lumen catheter were studied: a standard set with 2-port manifold and 1-m extension set and 2 multilumen infusion access devices: a 3-lumen extension set and a 9-lumen extension set (Edelvaiss-Multiline™; Doran International, Toussieu, France). For the 9-lumen extension set, 3 infusion access combinations were studied. Furosemide, midazolam, and saline were infused simultaneously through 3 infusion devices. Three concentrations of furosemide were tested. The infusion rate of saline (carrier) was initially set at 100 mL/h and stepwise decreased by 10 mL/h until precipitate formation. Physical incompatibility was assessed by 2 tests: visual inspection and the subvisible particle count test according to the European Pharmacopeia. The lowest saline infusion rate to prevent visible precipitate and attain an acceptable particle count (i.e., to pass “the 2 tests”) was reported for each infusion set. RESULTS:The standard set revealed visible precipitate even at the highest saline flow rate (100 mL/h). The 3-lumen device prevented drug precipitation using the 2 lowest furosemide concentrations with a saline infusion rate that decreased with furosemide concentration. The 9-lumen infusion access device prevented drug precipitation whatever the furosemide concentration for 2 access combinations using saline infusion rates of between 20 and 60 mL/h but not for a third access combination, despite saline infusion rates equal to 100 mL/h. CONCLUSIONS:Infusion device characteristics appear to have an impact on the physical compatibility of the 2 drugs. Under specified conditions, the 9-lumen infusion access device prevents physical furosemide-midazolam incompatibility.