Investigation and modelling approach of the mechanical properties of compacts made with binary mixtures of pharmaceutical excipients.

Three pharmaceutical excipients (microcrystalline cellulose, lactose, anhydrous calcium phosphate) and their binary mixtures were compacted to form compacts of various mean porosities. Some mechanical properties (Young's modulus, tensile strength and Brinell hardness) were studied on these compacts. The mechanical properties of the binary mixtures were not proportional to the mixture composition expressed in mass. More, for all the properties, a negative deviation was always observed from this linear relationship. In reference to a composition percolation phenomenon, critical mass fractions were detected from the graph mechanical property vs. mass composition of a mixture. The results obtained with Brinell hardness differed from the results of the Young's modulus and the tensile strength, i.e. the most plastic material in the binary mixture controlled the mixture behaviour. Secondly, a predictive model based on a statistical approach was proposed for the Young's modulus and the tensile strength. The validity of this model was verified on experimental data, and an interaction parameter used to characterize the affinity of the two compounds was calculated. Finally, the X-ray tomography technique was applied to the compacts of cellulose/phosphate mixtures to obtain cross-sections images of the compacts. The analysis of the cross-sections images allowed explaining the no linear relationship of the different mechanical properties results observed on these binary mixtures.

Compaction behaviour and new predictive approach to the compressibility of binary mixtures of pharmaceutical excipients.

The compressibility of three pharmaceutical excipients (microcrystalline cellulose, lactose and anhydrous calcium phosphate) and their binary mixtures was studied. The aim of this work was to observe the impact of the mass composition of the mixture on the compressibility. The single-compound materials and their mixtures were compacted using instrumented presses. It allowed obtaining compression cycles (i.e., force-displacement curves) which were associated with energy measurements (specific compaction energy, Esp cp and specific expansion energy, Esp exp). It was observed that for the mixtures studied, the change of Esp cp with the mass composition could be fitted using a linear relationship (it was not the case with Esp exp). A linear relationship between the porosity of mixture's compacts and the mass composition was also obtained. Heckel's plots were then obtained for the three excipients and the mixtures. The mean yield pressure was calculated with the "in-die-method" and the "out-of-die method". A proportional relationship was not valid for the mean yield pressures. But, a predictive approach was proposed in order to obtain indirectly the mean yield pressure of a binary mixture if the data of the single materials were known. It used the linear mixing rule observed with the porosity. The validity was verified and compared with the experimental values. This comparison showed that it was possible to predict the mean yield pressure of binary mixtures from the accessible data of the single excipients.

Evolution of the interaction of a new chemical entity, eflucimibe, with gamma-cyclodextrin during kneading process.

The aim of this study was to enhance the low solubility of eflucimibe, a new chemical entity which can be used as medicine to treat dyslipidemiae, by complexation with gamma-cyclodextrin. The complex was prepared using kneading method. The interaction evolution was studied during process by comparison of the semi-solid and physico-chemical states of the product. The evolution of the semi-solid state was followed by torque measurement when the evolution of physico-chemical state was studied by differential scanning calorimetry, infrared spectroscopy and by determination of the drug solubilisation profile. The interaction, which occurs during the process, is characterised by a modification of the product consistency and by a disappearance of the drug endothermic peaks, a disappearance of a drug spectral band and a widely improvement of the drug solubilisation profile. Indeed, after complete interaction, the drug quantity solubilised in specific conditions increased about 44-fold compared to those of untreated drug. Moreover, the comparison of the physico-chemical and semi-solid states during kneading process clearly shows that when the interaction takes place, a solidification of the paste occurs. The results of these works suggested that the formation of new solid phase allows an enhancement of the solubility of eflucimibe.

Compaction of crystallographic forms of pharmaceutical granular lactoses. I. Compressibility.

Physico-chemical properties of a substance including the compaction behaviour are directly connected with the crystalline structure. The aim of this work is to compare the compaction behaviour in a group of excipient and in this first part, to display the influence of lactose structures on the compressibility. alpha-Lactose monohydrate (LalphaM), anhydrous beta-lactose (LbetaA), anhydrous alpha-lactose (LalphaA) and partly amorphous lactose (FF) were compressed using instrumented presses to investigate the densification behaviour under pressure. Force-displacement curves were associated to two energy parameters, specific cycle energy and specific expansion energy. This approach was used to class the four lactose species. It is possible to differentiate three groups with the specific energy cycle, FF, LalphaA/LbetaA and LalphaM in decreasing order of this energy. At the same time, the values of specific expansion energy are relatively low for FF and LalphaA contrary to LalphaM and LbetaA. Then, Heckel's plots were obtained with two compact geometries and the mean yield pressure was calculated from the in-die-method and the out-of-die-method. Two lactoses seem to differ, LalphaM appears to be the most ductile whereas LalphaA is more brittle than the others. Finally, it is concluded, that in the case of lactoses, pseudopolymorphism seems to affect the compressibility more than anomerisation or partial amorphisation.

Water state characterization, swelling behavior, thermal and mechanical properties of chitosan based networks.

Two kinds of chitosan-based hydrogels, a crosslinked chitosan reference gel and a chitosan-poly(ethylene oxide) semi-interpenetrating network (semi-IPN), with potential pH-sensitive swelling and drug delivery properties are characterized. Swelling studies were performed on the two kinds of hydrogels by differential scanning calorimetry (DSC) at pH 1.2 and by the gravimetric method at pH 1.2 and pH 7.2. Both methods lead to similar results. If pH-dependent swelling properties were observed with both hydrogels, they were however improved for the semi-IPN. The amount of bound water in the xerogels could be determined from DSC measurements and a thermogravimetric analysis. The results obtained by both techniques were in good agreement and indicated that the semi-IPN contained more bound water than the reference gel probably due to the presence of the hydrophilic poly(ethylene oxide) chains. Young modulus of the swollen hydrogels was determined by indentation analysis. The semi-IPN displayed improved mechanical properties compared to the reference gel.

Definition of a solvent system for spherical crystallization of salbutamol sulfate by quasi-emulsion solvent diffusion (QESD) method.

In this paper we describe how the spherical crystallization process by QESD method can be applied to a water-soluble drug, salbutamol sulfate. The type of solvent, antisolvent, and emulsifier and the concentration of emulsifier to be used for the production of spherical particles with a size range 80-500 microm are determined. Furthermore, the solvent/antisolvent ratio and the temperature difference between them (Delta T) are studied. It was observed that, in the case of salbutamol sulfate, the Delta T value has no influence on the formation of spherical particles. A very large metastable zone of salbutamol sulfate in water could explain this phenomenon. Finally, the influence of emulsifier concentration and of maturation time on the size of spherical particles is studied. The results show that these two parameters must be fixed to control the size of the recovered particles.

Magnetic resonance imaging investigation of the mixing-segregation process in a pharmaceutical blender.

Magnetic Resonance Imaging (MRI) was used to study the mixing process of binary mixtures of free flowing sugar beads in a Turbula mixer. In order to make particles MRI-sensitive, some reference beads were doped with an organic oil. Doped and undoped particles were mixed and MRI was used to non-destructively image the particle bed for a given number of mixer rotations (NR), bead diameter ratio (R=d(ref)/d(i)) and rotation speed (V). All the results were quantified on the basis of image analysis to characterise the degree of mixing. Studies showed that for binary mixtures of identical particle size, the mixing was complete after 30 rotations, whereas for beads of different size (R=2.8) a segregated steady state was obtained after nearly 10 rotations. Experiments revealed that segregation appeared as soon as R=0.9. Moreover, the lower the rotation speed, the more segregated the final state was. It appeared that for a filling level greater than 80%, dead regions appeared in the centre of the powder bed. In conclusion, when the particles are non-cohesive, the Turbula blender perfectly mixes identical beads but segregation occurs for beads of different size after just a few rotations.

Design of triptorelin loaded nanospheres for transdermal iontophoretic administration.

Triptorelin is a decapeptide analog of luteinizing hormone releasing hormone, currently used for the treatment of sex-hormones dependents diseases. The aim of this work was to prepare triptorelin-loaded nanospheres useful for transdermal iontophoretic administration. Nanospheres were prepared with the double emulsion/solvent evaporation technique. The effect of three parameters on the encapsulation efficiency has been determined: the role of the pH of the internal and external aqueous phases, the nature of the organic solvent and the effect of three different poly(lactide-co-glycolide) (PLGA) co-polymers. Particle size, zeta potential and release kinetics were also determined. The encapsulation efficiency varied from 4 to 83% reaching the maximum value when both the internal and the external water phases were brought to pH 7 (isoelectric point of the peptide), methylene chloride was used as solvent of the copolymers and PLGA rich in free carboxylic groups was employed. The release profiles obtained with this co-polymer were characterized by the absence of burst effect. This behavior as well as the high encapsulation efficiency was explained by an ionic interaction occurring between the peptide and the co-polymer. This supports the already expressed theory that the release of peptides and proteins from PLGA nanospheres is also governed by the affinity of the encapsulated molecule versus the polymer. The obtained nanoparticles, regarding their size, amount encapsulated and zeta potential, were shown to be suitable for transdermal iontophoretic administration.

Power consumption profiles in high-shear wet granulation. II: Predicting the overwetting point from a spreading energy.

Granulation is an important process in the pharmaceutical industry for the preparation of solid dosage forms. For high-shear wet granulation, the process endpoint is monitored using the device power consumption. However, granulation is very sensitive to variations in the feed product physicochemical properties and, in some cases, power consumption profiles can not be used for process control. In this paper, a model is proposed to predict the granulation overwetting point from the spreading energy of the liquid binder on the powder. This energy is independently calculated from measurements of the powder true surface area, liquid binder surface tension, and liquid contact angle on the powder surface.

Power consumption profiles in high-shear wet granulation. I: Liquid distribution in relation to powder and binder properties.

Wet granulation processes frequently rely on the device power consumption profile to monitor the process endpoint. This work shows how the observed power consumption relates to the physical properties of the mass. The liquid binder was traced with a fluorescent marker and the liquid distribution could be followed during the process. It was found that primary agglomerates form in the reactor, the shape and composition of which depend on the wettability of the starting powders by the liquid binder. An increase of the device power consumption is conditional to the disruption of these primary agglomerates. Increasing the viscosity of liquid binders up to 250 mPa. s had no significant effect on the power consumption. Eventually, the lower surface tension liquid binders yielded greater energy consumption, indicating that interparticle friction forces had a great impact on the device power consumption.

Release of mifepristone from biodegradable matrices: experimental and theoretical evaluations.

Diffusion of mifepristone in poly [(D,L) lactide-co-glycolide)] films was studied by release experiments. Five 50/50 copolymers of increasing molecular weights were used. The degradation effects were shown by gel permeation chromatography (GPC). Release kinetics show the effect of copolymer molecular weights on diffusion and degradation properties of loaded films. A new theoretical model for drug release from a biodegradable matrix was proposed with two assumptions: correlation of the diffusion coefficient with the polymer molecular weight and existence of a first order degradation kinetic. Higuchi's equation is verified at early time and the diffusion coefficient in the non-degraded polymer can be measured. The degradation constant is determined at long time and is compared with the results of GPC.

A study of the adhesive-skin interface: correlation between adhesion and passage of a drug.

The phenomena taking place at the patch-skin interface, in particular the adhesion of a pressure sensitive adhesive (PSA) film loaded with drug and the partition of the drug between the patch and the skin were correlated. The kinetics of adhesion as well as those of drug passage were studied in detail. Adhesion data were collected from peel test either on skin or on a polymer model. Passage of the drug was studied in a simple system composed of PSA film stuck on skin. In some experiments the film was left on the skin throughout the experiment; in others, it was periodically removed and stuck on again to keep the adhesion force constant during the whole of the experiment. We observed a rapid increase of the drug content in the skin until a plateau was reached. One adhesion for the whole experiment or several adhesions gave a similar curve. The main difference was the rate of increase of skin drug content and the value of the plateau. Different hypotheses concerning the relationship between the adhesion of this PSA and changes in the flux of drug have been put forward. However, it is difficult to extrapolate from this model to the in vivo situation because of variation both between individuals and with time.

Physical evaluation of a new patch made of a progestomimetic in a silicone matrix.

The adhesion of a new Transdermal Therapeutic System (TTS) made of silicone and loaded with a progestomimetic drug was characterised. The goal of this study was to use well-known methods or to adapt them to collect representative data. Individually, methods such as surface tension, peel test and rheology are already widely used. Results show that the choice of a substrate for peel tests can be made in the light of surface tension data and that polymers like poly(tetrafluoroethylene) (PTFE) are good alternatives to skin. Peeling characterisations are made a function of thickness of films, drug content in active, conditions of preparation and conditions of use such as pressure. Dynamic rheology is more difficult to link to other methods as it mainly reflects internal phenomena and properties that arise in the bulk, as opposed on its surface. Master curves enable results to be used more easily, but the theories to interpret the data are still not powerful enough to replace peel testing.

Controlled release of vancomycin from poloxamer 407 gels.

The purpose of this study was to investigate Poloxamer 407 25% (w/w) formulations aimed at prolonging the residence time of vancomycin, a time-dependent antibiotic, in a body site with a high infectious risk. Reversible thermal gelation of the formulations permitted their local injection in liquid form and in situ gelation as they warmed to body temperature. Neither the rheological properties of the Poloxamer matrices nor the antibacterial activity of vancomycin was altered by their combination. In vitro, the dispersed form exhibited prolonged release, with a lower diffusion coefficient of vancomycin compared to the solubilized form (4.7x10(-8) vs 2. 1x10(-7) cm(2) s(-1)131 mg l(-1) for the solubilized form), followed by lower but effective antibacterial levels for at least 8 days. Controlled-release profiles, good preservation of vancomycin activity, good tolerability in rats, and ease of administration suggest that Poloxamer 407 may be useful as a vancomycin delivery vehicle for local prophylaxis of infections, especially in prosthetic surgery.

Rheological characterization of pharmaceutical powders using tap testing, shear cell and mercury porosimeter.

Most of the pharmaceutical processes involved in the manufacturing of so lid dosage forms are connected with powder flow properties, at least for some of the intermediate steps. Powder flow characteristics are commonl y investigated by various measurements, such as handling angles, tap tes ting, shear cell measurements, etc. All these approaches allow the calc ulation of indices characterising powder flowability. Unfortunately, th ese methodologies are highly product consuming, which is a limitation in the first steps of a novel drug development, when only a small amount of product is available. The use of mercury porosimetry to evaluate compre ssibility and flow properties of powders could be a new and alternative approach to obtain insight in the rheological properties of granular med ium by the interpretation of the first part of programs (low pressures) . We have developed such an evaluation and compared the results obtaine d with those given by tap testing and shear cell measurements, applied t o four excipients for direct tabletting and three different drugs. Merc ury porosimetry turned out to be a sensitive technique, able to providequantitative information about powder flow properties, complemen ted by an evaluation of particles micro porosity and size distribution, in a single step. These characterisations are obtained with only approx imately 250mg of bulk powder compared to high quantities ( >100g) needed for other methods.

Percutaneous absorption of sunscreens from liquid crystalline phases.

The purpose of the present study was to investigate the effects of two nonionic surfactants with liquid crystalline structures on the cutaneous availability of two sunscreens. Three liquid crystalline structures were investigated: lamellar, hexagonal and cubic. The diffusion of sunscreens within the liquid crystals was determined by measuring transport kinetics into an unloaded surfactant medium from a similar system loaded with the sunscreens. The diffusion coefficients were the greatest in the cubic systems for benzophenone-4 (a hydrosoluble sunscreen) and in lamellar systems for octyl methoxycinnamate (a liposoluble sunscreen). So the diffusion in this surfactant systems was strongly dependent on the structure of the liquid crystal and on the physicochemical properties of the solute. The transcutaneous fluxes were determined using a Franz-type diffusion cell. The liquid crystalline vehicles modified the transcutaneous fluxes of benzophenone-4 but did not change those of octyl methoxycinnamate. The solute diffusion within the vehicle was not the rate-determining step for transcutaneous permeation for either sunscreen. The diffusion of benzopenone-4 within the stratum corneum and that of octyl methoxycinnamate within the dermis could be the rate-determining steps for their transcutaneous permeation. These two steps could be affected differently by nonionic surfactant vehicles.

Powder dynamic contact angle data in the pharmaceutical industry.

Formulation scientists generate physicochemical data that are used in process modelling and in the prediction of end-product quality. In this respect, contact angles are of particular importance as the surface energy of substances influences their processability and bioavailability. Dynamic contact angle (DCA) analysis represents a straightforward wettability assay. Now fully adapted to powders, DCA analysis also proves to be more efficient than other methods for wettability determination.

Structural parameters involved in the permeation of propranolol HCl by iontophoresis and enhancers.

The purpose of this work was to study the effect of iontophoretic transport of Propranolol hydrochloride on the lipidic organization of the stratum corneum pretreated under passive or iontophoretic conditions by two model penetration enhancers, sodium lauryl sulfate and hexadecyl trimethylammonium bromide. Characterization of human stratum corneum was performed by X-ray diffraction, attenuated total reflectance-Fourier transform infrared (ATR-FTIR) spectroscopy and differential scanning calorimetry (DSC). The structural properties were compared with the iontophoretic permeability of propranolol hydrochloride on human stratum corneum. The iontophoretic fluxes of propranolol hydrochloride were effectively increased by two-fold in stratum corneum pretreated with sodium lauryl sulfate. In contrast, they were halved in stratum corneum pretreated with hexadecyl trimethylammonium bromide. These results could be related to changes in the electrical and structural properties of the stratum corneum after incorporation of these enhancers.

Liposomes dispersed within a thermosensitive gel: a new dosage form for ocular delivery of oligonucleotides.

PURPOSE: The main goal of this study was to develop an ocular controlled release formulation of a model oligonucleotide (pdT16), contained within liposomes dispersed within a thermosensitive gel composed by poloxamer 407. METHODS: The influence of the poloxamer concentration 2% or 27% on the stability of the liposomes (PC: CHOL and PC: CHOL: PEG-DSPE) was investigated. The in vitro release profiles of pdT16 from various poloxamer formulations (free pdT16 dispersed within 20% and 27% poloxamer gels, pdT16 encapsulated within liposomes dispersed within 20% and 27% poloxamer gels) were realized using a membrane-free release model. RESULTS: The dispersion of liposomes within a dilute 2% poloxamer solution resulted in a great leakage of pdT16 from liposomes. However, the destabilization effect of poloxamer was reduced when higher concentration (27%) was used. Poloxamer dissolution was found to control the release process of pdT16, whereas the dispersion of liposomes within 27% poloxamer gel was shown to slow down the diffusion of pdT16 out from the gel. CONCLUSIONS: The dispersion of liposomes within a 27% poloxamer gel presented an interesting system to control the release of a model oligonucleotide compare to a simple gel.

Rodent malaria prophylaxis by transdermal delivery of primaquine.

The efficacy of a new transdermal delivery system of primaquine in order to obtain causal prophylaxis against sporozoite-induced Plasmodium yoelii infection was evaluated. A single administration of a 1.0 cm2 transdermal delivery system containing 5.0 mg of primaquine was able to protect 100% of treated mice. This result suggests that the transdermal route may be a very interesting approach for malaria prophylaxis and should encourage further studies in order to determine the absolute bioavailability of the drug as well as its dose-effect relationship.