Preparation of pH-sensitive particles by membrane contactor

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Colloids and Surfaces A: Physicochem. Eng. Aspects 315 (2008) 13–22

Preparation of pH-sensitive particles by membrane contactor Nida Sheibat-Othman, Tim Burne, Catherine Charcosset ∗ , Hatem Fessi LAGEP, UCBL/CNRS-CPE, Bˆat 308, 43 Blvd. du 11 Nov. 1918, 69622 Villeurbanne Cedex, France Received 20 March 2007; received in revised form 15 June 2007; accepted 5 July 2007 Available online 11 September 2007

Abstract In this work, pH-sensitive particles are synthesized using a membrane contactor technique. The polymer (Eudragit® L100 or Eudragit® E100) is dissolved in water at a set pH and is then passed through the pores of a membrane into a continuous phase of a different pH. Contact with the continuous phase causes the pH-sensitive polymer to precipitate. The final particle size distribution (PSD) using this membrane contactor technique is compared to that of a similar batch process. The influence of the different parameters of the process (pressure, cross-flow velocity, concentration of polymer and temperature) on the PSD are studied. The results allow analysis of the different forces controlling the formation of droplets at the membrane pores. © 2007 Elsevier B.V. All rights reserved. Keywords: Membrane contactor; Membrane emulsification; pH-sensitive microspheres; Poly(methacrylic acid and methacrylate) copolymer

1. Introduction Encapsulation and particulate formulations were found to achieve better pharmaceutical profiles and to increase the oral bioavailability and solubility of several drugs. Particulate oral delivery systems can improve the therapeutic efficacy of the drug and decrease its side effects. pH-sensitive polymeric supports, such as hydroxylpropylmethyl cellulose phthalate, methacrylic acid and methyl methacrylate copolymers and cellulose acetate phthalate are commonly used for the coatings of tablets or the preparation of controlled-release formulations. The advantage of these supports is that they exhibit a pH-dependent solubility which increases the drug absorption in specific areas of the gastrointestinal tract. Acrylic polymers (such as Eudragit® E100 and L100) can dissolve rapidly upon deprotonation of carboxylic acid groups at specific pH values. Preparation of polymeric particles such as Eudragit® L100 is usually done using organic solvents. The simple emulsion solvent evaporation/extraction technique is used for encapsulating hydrophobic drugs (oil/water) and the double emulsion (water/oil/water) microsphere preparation technique is used for the encapsulation of hydrophilic drugs. In these techniques, the polymer is first dissolved in an organic solvent and then a

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non-solvent is added to precipitate the polymer to form the pHsensitive particles (see for instance Agarwal et al. [1], Breitkreutz [2] and Eerik¨ainen and Kauppinen [3]). Dai et al. [4] used the quasi-emulsion solvent diffusion technique which avoids using toxic organic solvents. However, a long-term contact of the protein with the organic solvent may lead to its degradation. Therefore, Chern et al. [5] produced pH-sensitive particles by adjusting the pH of the fabrication medium and studied the effect of salts on the precipitation of the polymer and particle sedimentation. In some cases, both a change of the solvent and the pH are provoked to precipitate the pH-sensitive particles [6]. The objective of this work is to produce pH-sensitive particles using a membrane contactor by controlling the pH value of the medium avoiding therefore the addition of organic solvents. Membrane contactor processes have been employed for the preparation of monodisperse entities, for instance emulsions (in this case the process is called membrane emulsification), particles or core–shell microcapsules. The preparation of multiple emulsions was recently studied by Vladisavljevi´c et al. [7] and Scherze et al. 2005 [8]. Reviews on membrane emulsification are proposed by Joscelyne and Tr¨ag˚ardh [9], Charcosset et al. [10] and Graaf et al. [11] as examples. In some processes, emulsification is followed by a polymerization (see for instance Ma et al. [12,13] and Omi et al. [14]). Chu et al. [15] used membrane emulsification followed by interfacial polymerization to produce core–shell microcapsules. In other processes,

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Nomenclature Symbols Am area of the membrane (m2 ) surface area of the pore (m2 ) Ap Dd flow rate of the dispersed phase (kg/s) Fγ interfacial tension force (N) FB buoyancy force (N) FD viscous drag force (N) FI inertial force (N) dynamic lift force (N) FL Fsp static pressure difference force (N) Kf permeability due to membrane fouling (m2 ) Lm membrane thickness (m) md mass of the phase passing through the membrane (kg) n number of cylindrical pores of the membrane Pcap capillary or critical pressure (Pa) Pd dispersed phase pressure (Pa) PE feed pressure at the entrance of the membrane module from the side of the dispersed phase (Pa) rD radius of the droplets (m) rP radius of the pores of the membrane (m) Rf resistance due to membrane fouling (m−1 ) P1,i axial pressure loss in the dispersed phase (Pa) Ptm transmembrane pressure difference (Pa) Greek symbols γ interfacial tension between the two phases (N/m) θ contact angle of droplets with the continuous phase μd dynamic viscosity of the dispersed phase (Pa s) ρd density of the dispersed phase (kg/m3 ) τw wall shear stress (Pa)

the polymerization occurs directly in the membrane contactor [16]. Fairly uniform and stable entities can be obtained if prepared by membrane contactor processes under adequate operating conditions. This is in contrast to conventional batch emulsification methods (for instance mechanical stirring method) in which it is more difficult to obtain a narrow particle size distribution (PSD). Therefore, less surfactant is required in membrane emulsification. The stirring rate in conventional emulsification methods affects the coalescence between the particles during the preparation, which in turn affects the stability of the resulting particles or droplets. The PSD is very important, especially in terms of the interaction with biological cells, if the particles contain active agents (drugs, proteins, enzymes, etc.) and monodisperse particles are usually required. Furthermore, the advantage of the membrane contactor process is that the PSD can be controlled easily by changing the membrane pore size or the operating conditions (pressure, cross-flow velocity, viscosity and temperature of the dispersed phase). Another important advantage of membrane contactors is their ability to easily scale-up for indus-

trial applications, by increasing the available membrane area and using several membrane devices. The objective of this work is to produce pH-sensitive particles using the membrane emulsification technique. The preparation does not involve any organic solvent. The particles are precipitated by changing the pH of the medium. The effect of the process parameters on the PSD is studied. The particles’ properties are compared to those produced in a stirred tank reactor under different working conditions. 2. Materials and methods 2.1. Materials Poly(methacrylic acid-co-methyl methacrylate) copolymers: Eudragit® L100 and Eudragit® E100 were kindly provided by R¨ohm (Darmstadt, Germany). NaOH and HCl were purchased from Sigma–Aldrich. Deionised water is used throughout the work. Eudragit® L100 consists of a 1:1 ratio of methacrylic acid and methyl methacrylate. It is soluble at a pH greater than 5.2, since the acidic groups it contains resist the acidic medium but are ionised in a basic medium. Therefore, Eudragit® L100 is dissolved in a basic medium using NaOH at room temperature and is introduced into an acidic medium containing HCl to cause particle formation by precipitation. The acidic phase contains a surfactant that allows stabilization of the formed particles (polyvinyl alcohol). HCl is the acid used to cause particle formation since it ensures a rapid precipitation of smaller particles with a better monodispersity than citric acid for example. In order to ensure a complete precipitation of the Eudragit® L100, the final pH of the medium is maintained below pH 2 in all experiments. Eudragit® E100 consists of copolymer with a 1:2:1 ratio of methyl methacrylate, N,N-dimethylaminoethyl and butyl methacrylate monomer. It is soluble at a pH less than 5.2 due to its tertiary amine groups. Therefore, it is dissolved in the acidic phase containing HCl and is introduced in the basic phase for particle formation. The surfactant is dissolved, in this case, in the basic phase. The final medium pH attains 11. Typical formulas for particle formation in the batch process are shown on Tables 1 and 2 for a 250 ml reactor. For the membrane process, the same ratios are used with the total mass multiplied by 8. The particle size was measured using a diffraction laser instrument (LS230 Coulter® ).

Table 1 Formula with Eudragit® L100 Dispersed phase

Continuous phase

Component

Amount

Component

Amount

NaOH (%) Eudragit® L100 (%)

1.248 1

PVA (%) HCl (%)

0.5 0.1248

Water (ml) pH

125 0.9

Water (ml) pH

125 12

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are opened. The dispersed phase flux (J) is measured continuously. The experiment is stopped when air bubbles start to appear in the tube connecting the pressurized vessel to the membrane device which means that the dispersed phase vessel is empty. At the end of the experiment, a sample in the preparation is taken for size analysis. The membrane is rinsed by flushing 2.5 l pure water in the membrane module (transmembrane pressure 3 bar) and the membrane permeability is verified. 2.4. Modelling elements Fig. 1. The membrane process for the preparation of pH-sensitive particles.

2.2. Batch process A 250 ml reactor was used to prepare the particles in the batch process. The reactor was equipped with a stirrer and baffle. A jacket allows the reactor temperature to be controlled. All batch preparations took place at ambient temperature. The pH-sensitive particles were prepared by precipitation provoked by changing the pH of the medium in the absence of any organic solvent. The pH of the solution was adjusted using HCl and NaOH. The continuous phase is first introduced to the reactor and then the dispersed phase is introduced as a shot under stirring.

In the membrane emulsification process, the dispersed phase is forced to permeate through the pores of a microporous membrane where a continuous phase is circulating. As the dispersed phase exits the pores of the membrane, it takes the form of droplets that shear off after a certain time. This time and therefore the droplet size depend on the axial and vertical forces exerted upon the droplet. In order to model the process, the flux through the membrane and the forces acting upon the droplet are considered. 2.4.1. Flux of the dispersed phase The average permeate flux of the dispersed phase through the membrane (Jd ) is usually represented by Darcy’s law that can be written either as a function of the membrane permeability Km or its resistance Rm (for more details see Gehlert et al. [17]):

2.3. Membrane process The membrane contactor set-up used for the preparation of microparticles is illustrated in Fig. 1. The membrane is composed of Al2 O3 –TiO2 (Rhodia Orelis, France) and is tubeshaped of length 40 cm, external diameter 10 mm, inner diameter 6 mm. Therefore, the active membrane surface is 7.5 × 10−3 m2 . The average pore size is 0.2 ␮m. The formulations used in the membrane contactor are obtained from those of the batch process (Tables 1 and 2) with an increase by a factor of 8. The dispersed phase, containing the dissolved Eudragit is contained within a pressure-tight 5 l vessel that is placed on a balance and forced to permeate through the membrane into the continuous phase by pressurising the vessel using nitrogen gas (1–7 bar). The continuous phase containing water and emulsifier (PVA) is stored in a 5 l beaker under stirring. It is circulated through the membrane device at different flowrates using a pump. At time t = 0, the valves connecting the pressurized vessel to the nitrogen bottle and to the filtrate side of the membrane device Table 2 Formula with Eudragit® E100 Dispersed phase

Jd (t, z) =

Km + Kf Ptm (t, z) 1 Ptm (t, z) = Lm μd Rm + Rf (t, z) μd (1)

where Lm is the membrane thickness, Ptm the transmembrane pressure difference and μd is the dynamic viscosity of the dispersed phase. Kf and Rf are respectively the permeability and resistance due to membrane fouling that affects the permeate flux mainly from the side of the continuous phase. The permeability and resistance of the membrane are determined by pure water flux tests. They also may be evaluated using the following relationship for a membrane with n cylindrical pores with mean radius rP (Hagen–Poiseuille equation): Km =

nrP2 8π

The flow rate of the dispersed phase (Dd ) is obtained by derivation versus time of the mass that passed through the membrane (md ). The permeate flux is calculated by dividing the flow rate by the area of the membrane (Am ) times the density of the dispersed phase ρd : m ˙ d (t, z) = Dd (t, z),

Continuous phase

Component

Amount

Component

Amount

HCl (%) Eudragit® E100 (%)

0.5 1

PVA (%) NaOH (%)

0.5 1.248

Water (ml) pH

125 0.9

Water (ml) pH

125 12

(2)

Dd (t, z) = Jd (t, z)Am ρd

(3)

The pressure in the continuous phase Pc is equal to the atmospheric pressure. In order to ensure a positive permeate flux, the pressure applied to the dispersed phase (Pd ) has to be higher than the sum of the pressures of the continuous phase and the capillary pressure Pcap , or critical pressure, caused by the curved interface of the dispersed phase at the output of the membrane

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• Fsp : the static pressure difference force is due to the pressure difference between the dispersed phase and the continuous phase at the membrane surface. • FD : the viscous drag force is created by the continuous phase flowing past the droplet parallel to the membrane surface. • FL : the dynamic lift force results from the asymmetric velocity profile of the continuous phase near the droplet. • FB : the buoyancy force is due to the density difference between the phases. • FI : the inertial force is associated with the mass of the fluid flowing out from the opening of the pore.

Fig. 2. Profile of the formation of droplets using membrane emulsification.

pores (see Fig. 2): Ptm (t, z) = (PE − P1,i ) − Pc − Pcap   

(4)

Fγ = 2πγrP = FD + FB ,

Pd

PE is the feed pressure at the entrance of the membrane module from the side of the dispersed phase and P1,i is the axial pressure loss in the dispersed phase. The capillary pressure of the membrane can be obtained by the following relationship assuming cylindrical pores: Pcap =

2γ cos θ rP

(5)

where γ is the interfacial tension between the two phases and θ is the contact angle of droplets with the continuous phase. It should be noted, however, that this relationship was developed for non-viscous solutions. It is obvious that the critical pressure increases with the viscosity of the dispersed phase even if it cannot be calculated by this equation. In viscous solutions, Ma et al. [13] found that the droplet polydispersity and the capillary pressure increased (from 5e3 to 20e3 Pa) with the concentration of polymer in the dispersed phase that was increased up to 20% (w/v). Therefore, with the concentrations of polymer studied in this work, the capillary pressure was found to be negligible in front of the transmembrane pressure and was neglected in Eq. (4). 2.4.2. Droplet formation Droplet formation at the output of the membrane pores is a result of several forces acting on the droplet as shown in Fig. 3 (for more details see for instance Rayner and Tr¨ag˚ardh [18] and Rayner et al. [19]): • Fγ : the interfacial tension force represents the effects of dispersed phase adhesion around the edge of the pore opening.

Fig. 3. Various forces acting on a droplet forming at the output of a pore.

The most important forces are:

Fsp = (Pd − Pc )Ap =

rP 2γ 2 πr = Fγ , rD P rD

2 FD = 6πrD τw

(6)

where rP and rD are the radius of the pores and the droplets, Ap the surface of the pore and τ w is the wall shear stress. This allows estimating the radius of the droplet as a function of the different forces:   rP γ Fγ F γ rP = = (7) rD = 3τw 6πτw Ptm AP This shows that the radius of the droplet is proportional to the ratio of the interfacial tension force to the static pressure difference force. It is inversely proportional to the wall shear stress due to the flux of the continuous phase and is proportional to the radius of the pore. It is worth noting that droplets might be deformed by the difference of the cross-flow velocity between the membrane surface and the centre of the droplet (see Abrahamse et al. [20]). In this work, only the main forces given by Eq. (6) are considered and droplet deformation is neglected. Also, the calculations are done assuming a homogeneous PSD using the mean value of the droplets diameter and assuming a homogeneous pressure in the membrane. 3. Results and discussion The solubility of the polymer depends on the carboxyl content per molecule of polymer. The greater the number of carboxyl groups the polymer chain has, the more hydrophilic it is. For instance, Eudragit® L100 contains more carboxyl groups than Eudragit® S100 and therefore it precipitates at a lower pH value. Eudragit® L100 is soluble at pH greater than 5 and starts to precipitate at pH 5.2 [5]. At high pH values, the carboxylic groups are transformed to carboxylate groups and the polymer dissolves. Particles are first prepared in a batch reactor in order to investigate these phenomena and fix the main concentrations and type of emulsifier. Trials using the membrane emulsification technique are then undertaken, based upon the batch results.

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stirring rate was first studied with Eudragit® L100 using PVA as an emulsifier. Fig. 5 shows that the mean particle size decreases if the stirring rate is increased importantly. Almost the same distribution was, however, obtained with the stirring rates of 500–1000 rpm but bigger particles are obtained under 250 rpm and significantly smaller particles under 1500 rpm. Therefore, with Tween 80 only the stirring rates of 500 and 1500 rpm were studied. Again, a significant decrease in the particle size was obtained with 1500 rpm. An increased stirring speed also decreases the polydispersity of particles as shown by the figure. This shows that the PSD is not only a function of the different concentrations but also of the process of preparation which leads us to consider using the membrane emulsification process.

Fig. 4. Influence of the concentration of Eudragit® L100 on the PSD in the batch process.

3.1. Particle preparation by batch emulsification 3.1.1. Influence of the concentration of polymer The concentration of Eudragit® L100 in the dispersed phase was varied and its influence on the PSD was studied. This parameter is key to the encapsulation process since it affects the efficacy of encapsulation. In general, increasing the concentration of polymer increases the encapsulation efficacy. However, the concentration of polymer may affect the rate of release since it affects the permeability of the microspheres and therefore this parameter is to be chosen wisely. Also, increasing the concentration of polymer increases the viscosity of the dispersed phase and therefore decreases the permeate flux in the membrane process which increases the preparation time. With Eudragit® L100, increasing the concentration of polymer was found to form aggregates as shown in Fig. 4. The PSD is higher and broaden with higher polymer concentration. 3.1.2. Influence of the stirring speed Stirring has an important influence on the PSD. Increasing the stirring speed leads to the droplets division which usually leads to the formation of smaller particles but can also contribute to shear aggregation causing particle coagulation. The

3.1.3. Influence of the concentration of emulsifier The emulsifier lowers the interfacial tension between the droplets and the continuous phase. It ensures stabilization of the formed particles and prevents them coalescing, thus allowing the particle size to be kept to a minimum. During the formation of the droplet at the output of the membrane pores, the emulsifier lowers the minimum emulsification pressure which affects the interfacial tension and therefore the duration of the formation of the droplet on the membrane pores and therefore its size. Two emulsifiers are used in this work: PVA and Tween 80. The influence of the concentration of emulsifier is studied under a stirring rate of 500 rpm. This stirring rate was chosen arbitrarily as can be seen from Fig. 5, the stirring rates of 500–1000 rpm gave almost the same distribution with PVA but smaller or bigger particles could be obtained with the stirring rates of 250 or 1500 rpm. Fig. 6 shows that the concentration of emulsifier does not have a clear effect on the PSD with both Eudragit® L100 and E100 except for 0.03% PVA with Eudragit® L100 where smaller particles are obtained which contradicts our predictions. However, the mean particle size measured by number of particles rather than volume was equivalent at about 10 ␮m for all experiments with PVA. The influence of the emulsifier concentration should be investigated for higher ranges in order to conclude. The Tween 80 (Polysorbate 80) emulsifier was used with Eudragit® L100 to compare emulsifiers. It was found that high concentrations of Tween 80 lead to the formation of bigger

Fig. 5. Influence of the stirring speed on the PSD in the batch process with Eudragit® L100 using two emulsifiers concentrated at 0.5% (PVA and Tween 80).

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Fig. 6. Influence of the concentration of PVA on the PSD in the batch process under a stirring speed of 500 rpm.

particles than using PVA. Fig. 7 shows that the volume of PSD is broader with increasing the concentration of Tween 80. The mean number of PSD was again equivalent in all experiments = 0.1 ␮m. It would be interesting to investigate the interaction between this emulsifier and the polymer particles. 3.2. Particle preparation by membrane contactor One interest of using membrane emulsification comes from its capacity of producing monodispersed entities which is essential in controlling the product quality. This is constrained by a rapid precipitation and stabilization of these entities after passing through the membrane pores in order to avoid their coalescence. In this work, the influence of different process parameters on the PSD was studied: the concentration of polymer, the pressure, the cross-flow velocity and the temperature of the dispersed phase. 3.2.1. Influence of the concentration of polymer In the batch process, the concentration of polymer seemed to affect the presence of aggregates. In the membrane process, the

Fig. 7. Influence of the concentration of Tween 80 on the PSD (Eudragit® L100) in the batch process with a stirring speed = 500 rpm.

concentration of polymer affects the viscosity of the dispersed phase and therefore the permeate flux. This decreases the force of entry in the membrane (Fsp ) with respect to the tangential one (FD ) which helps to tear off the droplets from the membrane pores and leads to the formation of smaller droplets as given by Eq. (7). The effect of the Eudragit® L100 concentration on the diameter of the droplets is shown in Fig. 8. The Eudragit® L100 concentration is varied from 0.5 to 3% (w/v). The figure shows that increasing the concentration of Eudragit® L100 in the dispersed phase greatly increases the introduction time and decreases slightly the mean particle size. It is worthy to compare this component with the batch process shown in Fig. 4. It can be seen that the particle size depends on the polymer concentration more importantly in the batch process than in the membrane process. Fig. 9 compares for instance the PSD with 0.5% and 2% Eudragit® L100 (the same result is obtained with 3%). It can be seen that with 0.5% polymer, the batch process gives a distribution with higher mean value and larger polydispersity (2.4 ␮m in the membrane process and 4.7 ␮m in the batch process). This difference is amplified with 2% polymer where almost two populations are obtained in the batch process and the mean value difference with the membrane process is increased (1.5 ␮m in the membrane process and 13 ␮m in the batch process). This shows an interest in using the membrane process with high polymer concentrations since it maintains the ability of producing small particles and a good polydispersity under these conditions. Fig. 10 shows the global membrane resistance obtained during these experiments. The initial membrane resistance is estimated at 1.3e7 m−1 . No fouling is observed with the concentrations up to 2% polymer. However, with a polymer concentration of 3%, the membrane resistance increases with time which indicates a partial fouling of the membrane pores. It was found in this work that the resistance mainly depended on the permeate flowrate and the viscosity of the dispersed phase (the same mass is introduced in all experiments). Long introduction times lead to membrane fouling. The main parameter affecting the particle size in this case is the viscosity of the dispersed phase. Increasing the concentration of polymer in the dispersed phase increases its viscosity which

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Fig. 8. Influence of the concentration of Eudragit® L100 on the PSD (mass flowrates = 5, 1.7, 0.18, 0.05 g/s with the concentrations 0.5%, 1%, 2% and 3% respectively).

Fig. 9. Comparison of the PSD obtained in the batch and in the membrane processes with different concentrations of Eudragit® L100.

decreases the permeate flowrate and therefore the droplet size. Since the model used to predict the droplet size in this process is that of an emulsification membrane, this leads to an interfacial tension force that decreases slightly with the polymer concentration, due to the decrease in the droplet size. However, since both phases are liquid and almost miscible at the very beginning of the formation of the droplet, calculation of the interfacial tension is not straightforward. Moreover, a slight variation in the pressure was noticed during the experiments. Less viscous solu-

tions have shown a faster decrease in the pressure. This might explain the fact that the particle size decreases when increasing the viscosity of the dispersed phase. An accurate control of the pressure is necessary in order to decouple the effects of these parameters. 3.2.2. Influence of the pressure The pressure affects the permeate flowrate and therefore the droplet size. A high pressure is preferred in order to reduce the

Fig. 10. Membrane global resistance as a function of the concentration of Eudragit® L100 (the membrane resistance at the beginning of the reaction is estimated at 1.3e7 m−1 ).

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Fig. 11. Estimation of the resistance (for Eudragit® L100) and Fγ − Fsp as a function of the transmembrane pressure.

Fig. 12. Influence of the pressure of the dispersed phase on the PSD.

preparation time. However, a pressure which is too high leads to jets of the dispersed phase passing through the membrane which gives large droplets and a large PSD. Therefore, a compromise is to be found. Particle preparation in the membrane process was done under pressures of 2, 4 and 6 bar in the dispersed phase. It was found that the permeate flux of the dispersed phase increased with increasing the pressure, especially with Eudragit® L100. An increasing permeate flowrate was also obtained with time. This

can be due to the time necessary to homogenise the pressure in the membrane (especially that time 0 corresponds to the time when the dispersed phase begins to circulate in an empty tube before entering the membrane). The global membrane resistance was close to the membrane resistance (1.3 e7 m−1 ) for all experiments except for that taking place under 2 bar with Eudragit® L100 that took longer time as shown in Fig. 11 where a higher resistance was detected during the first 200 s of the experiment. The main force affecting the particle size in this case is given by

Fig. 13. Influence of the tangential velocity on the PSD of Eudragit® L100 particles.

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Fγ − Fsp that increases with the transmembrane pressure which should lead to an increase in the droplet size. Increasing the permeate flux increases the perpendicular force with respect to the tangential one. This promotes the growth of the droplets on the pores of the membrane. A rapid stabilization of the droplets is necessary in order to detect this difference at the end of the preparation. Fig. 12 shows that increasing the pressure leads to reducing the polydispersity of the particles with Eudragit® L100. With Eudragit® E100, we observe a slight displacement of the PSD to bigger sizes when increasing the pressure. 3.2.3. Influence of the tangential velocity Increasing the cross-flow velocity of the continuous phase increases the ratio of tangential force (FD ) to the perpendicular one corresponding to the entry in the membrane (Fγ − Fsp ). This leads to a decrease in the droplet size. This phenomenon is observed during the preparation of Eudragit® L100 particles as shown in Fig. 13. It can be seen that the PSD is narrower with higher cross-flow velocity and is displaced to smaller sizes. The mean particle size is inversely proportional to the wall shear stress. Fig. 14 shows that the global resistance is close to that of a clean membrane (1.3 e7 m−1 ) with small tangential velocities (0.575 and 1.15 m/s) but becomes significant at higher velocities. This can be explained by a rapid precipitation of polymer close to the surface of the membrane due to the high cross-flow velocity. 3.2.4. Influence of the temperature The temperature can be an interesting tool to control the viscosity of the dispersed phase. Increasing the temperature of the dispersed phase decreases its viscosity and accelerates its movement through the pores of the membrane. This is supposed to increase the permeate flux and therefore the PSD. However, the temperature cannot be increased importantly since it might cause degradation of any actives to be encapsulated by the pHsensitive particles. Also, the temperature affects the solubility of the different components, specifically the emulsifier, and might

Fig. 14. Estimation of the resistance as a function of the tangential velocity.

Fig. 15. The membrane global resistance as a function of the temperature of the dispersed phase.

modify its nature which might have an undesirable effect on the PSD. Two experiments were undertaken using 25 and 40 ◦ C. In the second experiment, only the dispersed phase was heated up to 40 ◦ C. An increasing permeate flowrate was obtained during this experiment. This can be explained by the time necessary to homogenise the membrane temperature. Once heated, the global resistance decreases to a value lower than that estimated for the membrane at the beginning of all experiments at ambient temperature (1.3 e7 m−1 ) (Fig. 15). The membrane resistance seems therefore to decrease with temperature. Fig. 16 shows the PSD obtained at 25 and 40 ◦ C. It can be seen that slightly bigger particles are obtained when increasing the temperature of the dispersed phase. This contradicts our estimations since the interfacial tension decreases with temperature which should give smaller particles under the same pressure. This phenomenon can be explained again by the rapid decrease in the pressure difference with less viscous solutions as discussed in Section 3.2.1.

Fig. 16. Influence of the temperature of the dispersed phase on the PSD.

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4. Conclusion In this work, pH-sensitive particles for encapsulation of pharmaceutical actives were produced successfully in a batch process and in a membrane contactor. The major advantage of this technique is that no organic solvents are used in the precipitation of the particles. The pH sensitivity of the polymer is used to provoke the precipitation of the particles once they have been dispersed by the stirring (batch process) or formed at the output of the membrane pores. While investigating the different process parameters, it could be found that the type of emulsifier has an important effect on the PSD but the concentrations of emulsifier studied in this work did not seem to have a direct effect on the PSD. In the membrane process, it was found that the fouling resistance is dependent on the duration of introducing the dispersed phase. The concentration of polymer, the transmembrane pressure, the cross-flux velocity and the temperature have an influence on the PSD. It was found that the PSD could better be controlled in the membrane process than in the batch process especially with high polymer concentrations. Using the membrane avoids the formation of aggregates of polymer particles. The model developed for membrane emulsification was found to be adequate if the polymer starts precipitating on the membrane pores. This model can be useful in order to predict and control the particle size by manipulating the viscosity of the dispersed phase (by controlling the temperature or the concentration of polymer) and the velocity of the tangential flowrate. It would be interesting to study the influence of the pH on the permeate flowrate, especially the idea that the membrane surface properties might be affected by the pH value which would also affect the PSD. The influence of the porosity of the membrane on the coalescence of particles has also to be optimised. Finally, the efficiency of encapsulation in both processes would be interesting to study as a function of the different process parameters.

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Acknowledgement The authors would like to acknowledge the contribution of the master candidate Kamel Chibout to the present paper. References [1] V. Agarwal, I.K. Reddy, M.A. Khan, Polymethacrylate based microparticulates of insulin for oral delivery: preparation and in vitro dissolution

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