Fabienne Espitalier

Effect of ultrasound on the induction time and the metastable zone widths of potassium sulphate

Abstract A study of cooling crystallisation of a potassium sulphate solution in a batch reactor is described in this paper. The effect of ultrasound on primary nucleation was investigated by measures of induction time and metastable zone width of unseeded solutions. The appearance of crystals is detected by conductivity measurements. The experimental results show that ultrasound has an effect on the primary nucleation of potassium sulphate. Ultrasound allows induction time and metastable zone width to be significantly reduced.

Physicochemical characterization of d-mannitol polymorphs: The challenging surface energy determination by inverse gas chromatography in the infinite dilution region

Nowadays, it is well known that surface interactions play a preponderant role in mechanical operations, which are fundamental in pharmaceutical processing and formulation. Nevertheless, it is difficult to correlate surface behaviour in processes to physical properties measurement. Indeed, most pharmaceutical solids have multiple surface energies because of varying forms, crystal faces and impurities contents or physical defects, among others. In this paper, D-mannitol polymorphs (α, β and δ) were studied through different characterization techniques highlighting bulk and surface behaviour differences. Due to the low adsorption behaviour of β and δ polymorphs, special emphasis has been paid to surface energy analysis by inverse gas chromatography, IGC. Surface energy behaviour has been studied in Henrys domain showing that, for some organic solids, the classical IGC infinite dilution zone is never reached. IGC studies highlighted, without precedent in literature, dispersive surface energy differences between α and β mannitol, with a most energetically active α form with a γ(s)(d) of 74.9 mJ·m⁻². Surface heterogeneity studies showed a highly heterogeneous α mannitol with a more homogeneous β (40.0 mJ·m⁻²) and δ mannitol (40.3 mJ·m⁻²). Moreover, these last two forms behaved similarly considering surface energy at different probe concentrations.

Modelling of multiple-mechanism agglomeration in a crystallization process

A three-level agglomeration model coupled with crystal growth is developed. It accounts for Brownian, laminar, and turbulent agglomeration. The desupersaturation profiles, the particle size distributions, the average sizes, and variances (or standard deviations), as well as the instantaneous agglomeration degrees for each mechanism, can be calculated as functions of time. The model is applied to the crystallization of an amorphous solid into a crystalline polymorph in a batch crystallizer. A runaway phenomenon is detected for agglomeration when crystals are switching over from the Brownian regime to the laminar one: this switchover significantly affects the desupersaturation curve and the crystal shapes.

Experimental study of sono-crystallisation of ZnSO4·7H2O, and interpretation by the segregation theory

Power ultrasound is known to enhance crystals nucleation, and nucleation times can be reduced by one up to three orders of magnitude for several organic or inorganic crystals. The precise physics involved in this phenomenon still remains unclear, and various mechanisms involving the action of inertial cavitation bubbles have been proposed. In this paper, two of these mechanisms, pressure and segregation effects, are examined. The first one concerns the variations of supersaturation induced by the high pressures appearing in the neighbourhood of a collapsing bubble, and the second one results from the modification of clusters distribution in the vicinity of bubble. Crystallisation experiments were performed on zinc sulphate heptahydrate ZnSO(4)·7H(2)O, which has been chosen for its pressure-independent solubility, so that pressure variations have no effect on supersaturation. As observed in past studies on other species, induction times were found lower under insonification than under silent conditions at low supersaturations, which casts some doubts on a pure pressure effect. The interfacial energy between the solid and the solution was estimated from induction times obtained in silent conditions, and, using classical nucleation theory, the steady-state distribution of the clusters was calculated. Segregation theory was then applied to calculate the over-concentrations of n-sized clusters at the end of the collapse of a 4 μm bubble driven at 20 kHz by different acoustic pressures. The over-concentration of clusters close to the critical size near a collapsing bubble was found to reach more than one order of magnitude, which may favour the direct attachment process between such clusters, and enhance the global nucleation kinetics.

Theoretical model of ice nucleation induced by acoustic cavitation. Part 1: Pressure and temperature profiles around a single bubble

This paper deals with the inertial cavitation of a single gas bubble in a liquid submitted to an ultrasonic wave. The aim was to calculate accurately the pressure and temperature at the bubble wall and in the liquid adjacent to the wall just before and just after the collapse. Two different approaches were proposed for modeling the heat transfer between the ambient liquid and the gas: the simplified approach (A) with liquid acting as perfect heat sink, the rigorous approach (B) with liquid acting as a normal heat conducting medium. The time profiles of the bubble radius, gas temperature, interface temperature and pressure corresponding to the above models were compared and important differences were observed excepted for the bubble size. The exact pressure and temperature distributions in the liquid corresponding to the second model (B) were also presented. These profiles are necessary for the prediction of any physical phenomena occurring around the cavitation bubble, with possible applications to sono-crystallization.

Theoretical model of ice nucleation induced by inertial acoustic cavitation. Part 2: Number of ice nuclei generated by a single bubble

In the preceding paper (part 1), the pressure and temperature fields close to a bubble undergoing inertial acoustic cavitation were presented. It was shown that extremely high liquid water pressures but quite moderate temperatures were attained near the bubble wall just after the collapse providing the necessary conditions for ice nucleation. In this paper (part 2), the nucleation rate and the nuclei number generated by a single collapsing bubble were determined. The calculations were performed for different driving acoustic pressures, liquid ambient temperatures and bubble initial radius. An optimal acoustic pressure range and a nucleation temperature threshold as function of bubble radius were determined. The capability of moderate power ultrasound to trigger ice nucleation at low undercooling level and for a wide distribution of bubble sizes has thus been assessed on the theoretical ground.

High bubble concentrations produced by ultrasounds in binary mixtures.

It was discovered that simultaneous insonification and air blowing of different aqueous binary solutions such as water/sodium-dodecyl-sulphate (SDS), water/methanol or water/potassium-sulphate yields a very concentrated bubble cloud invading the whole vessel in a few seconds. After the end of insonification, this cloudiness remained in the solution for about 1 min. The phenomenon was investigated by computer-treatment of solution pictures recorded every second after the end of insonification. Turbidity appeared to increase with ultrasound power, and also with SDS concentration. During the disappearance of the cloud, a turbidity front appeared rising and spreading upward. This front was studied in the characteristic plane and interpreted as a spatial segregation of different bubble sizes rising with different terminal velocities. The bubble sizes involved were estimated to about 10 microns. Adsorption of surface active species are invoked to explain the cloud formation and its abnormally slow disappearance, but the occurrence of the phenomenon for potassium-sulphate salt remains unexplained.

Liquid anti-solvent recrystallization to enhance dissolution of CRS 74, a new antiretroviral drug.

Abstract This study concerns a new compound named CRS 74 which has the property of inhibiting Human Immunodeficiency Virus (HIV) protease, an essential enzyme involved in HIV replication process. It is proved in this study that the original CRS 74 exhibits poor aqueous solubility and a very low dissolution rate, which can influence its bioavailability and clinical response. In an attempt to improve the dissolution rate, CRS 74 was recrystallized by liquid anti-solvent (LAS) crystallization. Ethanol was chosen as solvent and water as the anti-solvent. Recrystallized solids were compared with the original drug crystals in terms of physical and dissolution properties. Recrystallization without additives did not modify the CRS 74 dissolution profile compared to the original drug. CRS 74 was then recrystallized using different additives to optimize the process and formulate physicochemical properties. Steric stabilizer in organic phase ensured size-controlling effect, whereas electrostatic stabilizer in aqueous phase decreased particle agglomeration. Cationic additives avoided drug adsorption onto stainless steel T-mixer. In general, additive improved drug dissolution rate due to improvement of wetting properties by specific interactions between the drug and the additives, and ensured continuous production of CRS 74 by electrostatic repulsion.

Prediction of the acoustic and bubble fields in insonified freeze-drying vials

The acoustic field and the location of cavitation bubble are computed in vials used for freeze-drying, insonified from the bottom by a vibrating plate. The calculations rely on a nonlinear model of sound propagation in a cavitating liquid [Louisnard, Ultrason. Sonochem., 19, (2012) 56-65]. Both the vibration amplitude and the liquid level in the vial are parametrically varied. For low liquid levels, a threshold amplitude is required to form a cavitation zone at the bottom of the vial. For increasing vibration amplitudes, the bubble field slightly thickens but remains at the vial bottom, and the acoustic field saturates, which cannot be captured by linear acoustics. On the other hand, increasing the liquid level may promote the formation of a secondary bubble structure near the glass wall, a few centimeters below the free liquid surface. These predictions suggest that rather complex acoustic fields and bubble structures can arise even in such small volumes. As the acoustic and bubble fields govern ice nucleation during the freezing step, the final crystals size distribution in the frozen product may crucially depend on the liquid level in the vial.

Inverse gas chromatography a tool to follow physicochemical modifications of pharmaceutical solids: Crystal habit and particles size surface effects.

Powders are complex systems and so pharmaceutical solids are not the exception. Nowadays, pharmaceutical ingredients must comply with well-defined draconian specifications imposing narrow particle size range, control on the mean particle size, crystalline structure, crystal habits aspect and surface properties of powders, among others. The different facets, physical forms, defects and/or impurities of the solid will alter its interaction properties. A powerful way of studying surface properties is based on the adsorption of an organic or water vapor on a powder. Inverse gas chromatography (IGC) appears as a useful method to characterize the surface properties of divided solids. The aim of this work is to study the sensitivity of IGC, in Henrys domain, in order to detect the impact of size and morphology in surface energy of two crystalline forms of an excipient, d-mannitol. Surface energy analyses using IGC have shown that the α form is the most energetically active form. To study size and shape influence on polymorphism, pure α and β mannitol samples were cryomilled (CM) and/or spray dried (SD). All forms showed an increase of the surface energy after treatment, with a higher influence for β samples (γs(d) of 40-62 mJ m(-2)) than for α mannitol samples (γs(d) of 75-86 mJ m(-2)). Surface heterogeneity analysis in Henrys domain showed a more heterogeneous β-CM sample (62-52 mJ m(-2)). Moreover, despite its spherical shape and quite homogeneous size distribution, β-SD mannitol samples showed a slightly heterogeneous surface (57-52 mJ m(-2)) also higher than the recrystallized β pure sample (∼40 mJ m(-2)).