The oriented processes for extraction and recovery of paracetamol compound across different affinity polymer membranes. Parameters and mechanisms

Accepted Manuscript

Research paper

The oriented processes for extraction and recovery of paracetamol compound across different affinity polymer membranes. Parameters and mechanisms E.H. El Atmani, A. Benelyamani, H. Mouadili, S. Tarhouchi, S. Majid, K. Touaj, L. Lebrun, M. Hlaibi

PII: S0939-6411(16)30983-3

DOI: http://dx.doi.org/10.1016/j.ejpb.2017.06.001

Reference: EJPB 12527

To appear in: European Journal of Pharmaceutics and Biophar- maceutics

Received Date: 20 December 2016 Revised Date: 20 April 2017 Accepted Date: 1 June 2017

Please cite this article as: E.H. El Atmani, A. Benelyamani, H. Mouadili, S. Tarhouchi, S. Majid, K. Touaj, L.

Lebrun, M. Hlaibi, The oriented processes for extraction and recovery of paracetamol compound across different affinity polymer membranes. Parameters and mechanisms, European Journal of Pharmaceutics and Biopharmaceutics (2017), doi: http://dx.doi.org/10.1016/j.ejpb.2017.06.001

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The oriented processes for extraction and recovery of paracetamol compound across different affinity polymer membranes.

Parameters and mechanisms

E. H. EL ATMANI¹, A. BENELYAMANI³, H. MOUADILI¹, S. TARHOUCHI¹, S. MAJID¹, K. TOUAJ^1,2, L. LEBRUN² and M. HLAIBI^1,2

1 Laboratoire Génie des Matériaux pour Environnement et Valorisation (GeMEV), Equipe I3MP, Faculté des Sciences Aïn Chock, B.P. 5366, Maârif, Casablanca, Maroc.

2 Laboratoire Polymères, Biopolymères, Surfaces (PBS), UMR 6270 du CNRS, Faculté des Sciences et Techniques, F-76821 Mont-Saint-Aignan, France.

3 Laboratoire de recherche et développement AFRIC-PHAR, Route régionale Casablanca/Mohammedia N° 322, Km 12, Aïn Harrouda 28630, Casablanca-Maroc

Project: PPR2 (MESRSFC – CNRST)

___________________________________________________________________________________________________________

Abstract

Membrane processes represent one of the most promising technologies for separation and extraction in modern industries, because they have several advantages. Today these processes are an important research topic, including affinity polymer membranes that are highly efficient for oriented processes.

Three affinity polymer membrane types containing lipophilic compounds, methyl cholate (MC) and cholic acid (CA) as extractive agents were prepared and characterized. They have been used to extract active ingredient paracetamol (acetaminophen), from concentrated solutions (0.08 to 0.01 M). Substrate acetaminophen is an important active ingredient and its recovery as a pure compound, is very useful for the pharmaceutical industry. These affinity polymer membranes were adopted to perform experiments on a facilitated extraction process of this substrate at different medium acidities and temperatures. Macroscopic parameters, permeabilities (P) and initial fluxes (J0) for a facilitated extraction of this substrate through each membrane were determined. The results indicate that values of initial fluxes (J0) of the extracted substrate are related to its initial concentration C0 by a saturation law, which allowed to determine microscopic parameters, apparent diffusion coefficients (D*) and association constants (Kass) of formed entity (substrate - extractive agent) (ST).

The results show a clear influence of temperature and acidity factors on the evolution of these parameters and membrane performances in this studied process. Activation parameters (Ea, ΔH^≠, and ΔS^≠) were determined and the values indicate that high performances of these membrane types are certainly related to the movement nature of the substrate across the organic phase, and the structures of the substrate and the extractive agent.

Keywords: affinity polymer membranes; oriented process; facilitated extraction; permeability; flux;

apparent diffusion coefficient; association constant; activation parameters.

* Corresponding author: Miloudi HLAIBI

Address: Laboratoire Génie des Matériaux pour Environnement et Valorisation (GeMEV), Equipe I3MP, Faculté des Sciences Aïn Chock, B.P. 5366, Maârif, Casablanca, Maroc.

E-mail address: [email protected].

1. Introduction

Currently, liquid discharges of fine chemical industry, pharmaceutical industry and hospitals, represent an emission source of several toxic and highly polluting substances to the aquatic environment and water resources, on account of the number of patients treated, the quantity and the diversity of drugs, particularly, anesthetics, antibiotics, analgesics, anti- inflammatory and anti cancerous. This urban pollution influences the ecological balance in the environment, and threatens especially aquatic organisms and human health [1,2] . Indeed, the treatment of these discharges is a major issue for the modern pharmaceutical industry in order to meet environmental challenges by developing new effective technologies of separation and extraction which will enable the treatment of industrial waste, especially recovery of value- added molecules, and thus the valuation of these releases.

Today, membrane processes are among the most promising technologies for extraction, separation and recovery in different areas of modern industries [3-8], view their advantages compared to other techniques such as liquid - liquid extraction, column chromatography, or resin separation, notably the use of large quantities of solvents [9-12]. Polymer membrane processes have become a viable and interesting alternative to conventional solvent extraction methods for selective separation of substrates such as organic compounds and metals from aqueous solutions, since it combines extraction and stripping operation in a single stage. In the last 30 years several membrane separations techniques have been explored with the aim to reduce the needed energy and reactants of solvent extraction separation, and hence the economic and environmental impact. These membrane processes are now the subject of several studies, including the most appropriate affinity membranes for purification and extraction of organic molecules [13-23], in particular, supported liquid membranes (SLMs), grafted polymer membranes (GPMs) and polymer inclusion membranes (PIMs) [24-33].

The studies presented in this manuscript are to determine the parameters and to elucidate the mechanisms related to the facilitated extraction process of paracetamol compound. This oriented process was carried out through three membrane types, containing substantially the same extractive agent with the same interaction site, consisting of three OH groups oriented in the same direction, a SLM membrane containing methyl cholate, and two membranes GPM and PIM, with cholic acid. For these studies, we conducted development and characterization of these membranes, which were subsequently adopted to examine the influence of initial substrate concentration, acidity and temperature of medium, on the

changing parameters related to facilitated extraction process of paracetamol substrate across these affinity polymer membranes.

Acetaminophen, is an active substance (active ingredient) used in many medicines as analgesic and antipyretic (anti-fever) [34]. It is indicated in the treatment of low to moderate intensity symptoms, alone or in combination with other analgesics, because it has few side effects and contraindications, except in fatal overdose. Currently this active ingredient is part of the composition of more than 60 specialties in the world and global consumption exceeds that of aspirin which has many side effects [35,36]. For these medical and commercial reasons, this compound is of major benefit to the pharmaceutical industry. Therefore, the operation on its extraction and its recovery from industrial waste is a capital need.

Acetaminophen is an organic compound of simple structure (Fig. 1), it is a molecule belonging to the family of anilides, derivative from aniline, having a benzene ring, common to many compounds with antipyretic and analgesic properties. The molecule consists of a benzene ring substituted by a hydroxyl group and an amide group in the para position.

Paracetamol has no asymmetric carbon atoms and has no stereoisomers.

Figure 1: Paracetamol: 1-hydroxy-4-acetaminobenzene

Acetaminophen is an acid organic fat soluble compound (pKa = 9.5), it is found in its ionized form in the stomach and small intestine which will facilitate its absorption. Its action mechanism is different from that of aspirin, paracetamol does not inhibit prostaglandin synthesis at the peripheral level, but inhibits it centrally [37,38]. Acetaminophen is one of the most consumed drugs in the world, today there are different industrial synthesis methods, most using acylation of para-aminophenol with acetic anhydride, according to the following reaction:

On the other hand, this compound has a maximum absorption band in U.V.-Visible at 240 nm.

For the extraction, recovery and purification of this compound, we adopted the techniques based on membrane processes, as an environmentally friendly alternative with minimal energy consumption and a considerable reduction in the volume of used solvents, extractive agents and generated waste. These methods are applicable in several sectors, such as environment, energy, health, water treatment, cosmetic, food, chemical, pharmaceutical industries [39,40], and for most systems, we work on continuous systems, and we can extract various substances, less stable and very sensitive to temperature. Depending on their composition, structure, morphology, there is a wide range of membranes [41]: mineral or inorganic membranes, composite membranes for various applications, organic polymer membranes usually used for micro and nano filtration, and affinity polymer membranes for the oriented processes of extraction, purification, separation and recovery of components.

In general, an affinity polymer membrane is defined as a thin polymer layer containing one or more extractive agents (Fig. 2), which acts as a selective barrier, permitting the separation of substances by action of a chemical reaction. Indeed, the substrates which can interact with the extractive agents; can diffuse through the membrane phase, whereas those which do not interact with these agents cannot diffuse through the membrane. Thus, this type of membrane processes acts as a selective barrier, allowing the selective extraction and separation of organic compounds according to their structures and their affinities to interact specially with some extractive agents.

Figure 2: Simplified scheme of an affinity polymer membrane.

Several economic and industrial activities adopt the affinity polymer membranes techniques for various applications. In the chemical industry they are used for the separation and recovery of various organic and inorganic compounds, the separation of gas mixtures, the treatment of water polluted by heavy metals, especially discharges from the nuclear industry….These techniques based on the membrane processes can give clear and important advantages compared to other techniques of separation and extraction, in particular for the selectivity parameter.

To conduct the studies on this oriented process for facilitated extraction of paracetamol compound, three affinity polymer membranes have been developed and adopted, a supported liquid polymer (SLM), a grafted polymer membrane (GPM) and a polymer inclusion membrane (PIM), with methyl cholate and cholic acid as extractive agents, having the same binding site consisting of three hydroxyl groups (OH3, OH7 and OH12) (Fig. 3).

Figure 3: Structure of methyl cholate ester with triol binding site

2. Kinetic and thermodynamic models for determining the parameters

To determine the different parameters relating to the studied process and to quantify the performance of each of the used membranes, several published studies [25, 30-32] have shown that for these membrane types, and in the experimental conditions adopted where substrate is in excess relative to the extractive agent, A kinetic model based on Fick's first law, and a thermodynamic model based on the reversible interaction reaction substrate - extractive agent, the second Fick law, and according to saturation law of the extractive agent by substrate, allow to establish the following relationships (Eqs 1 and 2)

P × (t-tI) = (l × V/S) [1/2 × Ln (C0/(C0 -2CR)] (1) 1/J₀ = (l/D*) × [(1/[T]₀) × (1/K_ass) ×(1/C₀) + (1/ [T]₀) ] (2)

l: membrane thickness, S: membrane active area and V: receiving phase volume.

C0, CR and [T0]: respectively, substrate initial concentration in the feed phase, substrate concentration in the receiving phase at time t and fixed concentration of the extractive agent in organic phase.

P: membrane permeability, J0: substance initial flux across the membrane, Kass: association constant of entity ST (substrate – extractive agent) and D*: apparent diffusion coefficient of the substrate S through the membrane phase.

The above relations show, firstly, that the term - Ln(C0-2CR) is a linear function versus time and the slope (a) value of the obtained straight line, calculates the macroscopic parameter values (P and J0) according to the expressions in Eq. 3. Secondly, the values of slope (p) and

intercept (OO) on the lineweaver-Burk straight line (1/J0 = f(1/C0) (Eq. 2), allow to determine the microscopic parameter values (Kass and D*) according to the expressions in Eq. 4.

P = a x V x l/2S and J₀ = P x C₀/l (3) K_ass = intercept (OO)/slope (p) and D* = (l/OO x [T₀]) (4)

The values of P and J0 parameters are used to quantify the membrane performance and show the initial flux (J0) as a function of the extractive agent concentration in the membrane organic phase, and changes according to a saturation law with the initial concentration C0 of the substrate. Similarly, the values of Kass and D* parameters are used to elucidate the mechanism on this oriented process, and to show that the mechanism of migration of the substrate through the membrane phase is based on the interaction of the substrate (S) with the extractive agent (T) to form an unstable entity (ST), and this migration step is the rate- determining step.

To explain the results and to obtain more information on this facilitated extraction process, we determined activation parameters (Ea, ΔH^≠ and ΔS^≠) related to the transition state of the interaction reaction of substrate (S) with extractive agent (T) to form entity (ST) during the rate-determining step. Indeed, different studies [42,43,44] have shown that initial flux J0

evolves with temperature according to Arrhenius relationship (Eq. 5) J₀(T) = A_j exp (-E_a/RT) (5)

R: Ideal gas constant (8.314 J.mol^-1.K^-1), Aj: pre-exponential term and Ea: activation energy.

After linearization of the expression above, according to the following equation:

LnJ0 = - (Ea/R) × (1/T) + LnAj (6)

Ea and Aj parameters are determined from slope (p) and intercept (OO) of the linear function Ln(J0) = f(1/T). According to transition state theory (Eyring theory), the values of these parameters are used to calculate activation enthalpy ΔH^≠ and entropy ΔS^≠ for the transition state, from the following expressions (Eq. 7).

ΔH^≠ = E_a – 2500 (J. mol^-1) and ΔS^≠ = R (LnA_j – 30.46) (J.mol-1. K-1) at 298 K (7) Analysis of the results indicates that determination of these activation parameters (Ea, ΔH^≠ and ΔS^≠) is essential for understanding the mechanism for these oriented processes through

affinity polymer membranes. Indeed, the activation parameter values allow to confirm the membrane performances and to specify the association nature of substrate with extractive agent at its diffusion through the membrane phase.

3. Experimental section

The experimental part of our studies is to examine the influence of the following factors, initial concentration C0 of the substrate, acidity and temperature of the medium, on the evolution of macroscopic (P and J0) and microscopic (Kass and D*) parameters relating to oriented process of the facilitated extraction of paracetamol substrate through three affinity polymer membrane types. Acetaminophen compound, as well as the extractive agents, methyl cholate ester (MC) and cholic acid (CA) are purchased from ICN Biomedicals. All polymers, polysulfone Udel (PSU), polyvinyl alcohol (PVA), polyvinyl-pyrrolidone (PVP), solvents and other reagents HNO₃, HCl and NaOH, are commercial products (Aldrich, Fluka) of the purest available grade for analysis used as received.

3.1. Materials and equipments

The used cell to perform the experiments relating to process under study consists of two glass compartments divided by adopted membrane (M). Feed compartment (F), containing the solution of paracetamol substrate at studied concentration C₀ (0.08 to 0.01 M) and receiving compartment (R) containing distilled water. The system is immersed in a thermostatic bath (TB) in order to conduct experiments at a constant temperature. A multi stirrer (MS) is used to provide agitation and homogeneity of both aqueous phases (Fig. 4). To determine and monitor the substrate concentration in receiving phase C_R, several (seven) samples collected at regular time intervals from the receiving phase, were measured and analyzed at absorption maximum wavelength (ƛmax = 240 nm), using a UV-Visible spectrophotometer (Rayleigh. U.V. - 2601).

The acidity of aqueous solutions (feed and receiving) was measured using a pH meter (HANNA Instruments HI 8519N), and the pH of these aqueous phases is adjusted with a concentrated solution of hydrochloric acid (HCl) analytical quality. Similarly, an electronic micrometer (Mitutoyo) was used to measure the thickness of the prepared membranes, needed to determine extractive agent concentration [T0] contained in each of the adopted membranes.

Figure 4: Cell with two compartments, adopted for oriented processes through affinity membranes.

In order to analyze the composition and morphology of prepared membranes, an IR spectrophotometer (AVATAR 360 FTIR ESP) was used for plotting spectra (FTIR) to identify the presence of extractive agent into the polymer matrix of the membrane. Similarly a scanning electron microscope (ZEISS EVO40 EP) yielded different images to study the morphology and observe the porosity of different developed membranes.

3.2. Preparation of affinity polymer membranes

To achieve our different experiences on the studied process, we have prepared the following three affinity polymer membranes: supported liquid membrane (SLM), grafted polymer membrane (GPM) and polymer inclusion membrane (PIM).

- SLM adopted in our studies was prepared and conditioned as described in previous studies [24,25,30,33,45,46]. The used polymeric support is a flat sheet of poly(vinylidene difluoride) (PVDF), with 100 µm as thickness, 60% of porosity, 0.45 µm for pore diameter, and 9.62 cm² as membrane active area. This polymeric support was impregnated with an organic phase of a toluene solution containing 10^-2 M of methyl cholate ester as extractive agent. Once the membrane has been developed and conditioned, it was adopted to conduct the facilitated extraction process of paracetamol substrate.

- The adopted GPM to carry out studies on this oriented process of facilitated extraction of acetaminophen substrate was prepared by the phase inversion method [47]. Indeed, a precise amount (3g) of polysulfone polymer is dissolved by stirring (12 hours) in 12.5 ml of DMF at a temperature of 25 to 30 °C. To this homogeneous solution we added 0.6 g of polyvinyl- pyrrolidone polymer until completely dissolved. Then a precise weight of the sodium cholate extractive agent is added to this homogeneous solution (PSU-PVP-DMF). The obtained solution was isolated from air, stirred for 4 days at a fixed temperature (75 °C), to achieve the grafting step of the extractive agent to polymeric chains of the PSU, and get a completely homogenous viscous solution. The resulting solution was cast on a glass plate, spread with a ruler, and then this plate was immersed quickly in a bath containing distilled water. DMF solvent leaves the matrix of the spread viscous solution and a rigid membrane is obtained in the form of a sheet (phase inversion method). The obtained membrane left in water for 48 hours to remove all organic solvent (DMF). After this operation, the membrane is dried, its

mass, thickness (l = 181 µm), and total area were measured and the extractive agent concentration [T0] = 0.251 mol. L^-1 was calculated for this developed GPM membrane type.

- For the preparation of the PIM membrane, 10 g of polyvinyl alcohol (PVA) was mixed with 20 ml of Dimethyl sulfoxide (DMSO) and 80 ml of distilled water (ED), in a well closed bottle to prevent evaporation of the solvent. The mixture was stirred for 24 hours at a temperature of 120 ° C to dissolve the PVA in the solution. Precise amounts (0.5 g) of cholic acid extractive agent and (0.5 ml) of tributyl phosphate plasticizer (97%) were added to this homogeneous solution of PVA, with vigorous stirring for 6 hours at 60 °C. Then, the obtained solution was poured into a kneaded box, which was placed in an oven at a temperature of 70 to 80 °C, until the vulcanization step by complete evaporation of solvent. After these steps, a membrane as a solid flat sheet was obtained, its thickness was measured l = 137 µm, and extractive agent concentration [T0] = 0,171 mol. L^-1 was calculated for this elaborated PIM membrane type.

4. Results and discussion

Before adopting these membranes for the facilitated extraction process of acetaminophen substrate under different experimental conditions, various studies relating to their compositions and their morphologies were performed.

4.1. Analysis and characterization of developed membranes

SLM membrane type is fully characterized, 100 µm of thickness, 60% of porosity, 9.62 cm2 of active area, and an extractive agent concentration [T0] = 0.01 M of methyl cholate ester. However, for developed GPM and PIM membranes, IR and SEM studies were carried out and an example of IR spectrum and SEM images for developed GPM membrane are represented by the following figures (Figs. 5 and 6) :

Figure 5: Spectra FTIR-ATR for the different compounds used for the development of GPM membrane

Figure 6: SEM micrographs: a) polymer support surface (PSU), b) GPM membrane surface (PSU- AC) c) GPM membrane cross-section (PSU-AC)

Analysis of the spectra (Fig. 5) clearly shows the presence of two resonance bands at v = 3400 cm^-1 and v = 1700 cm^-1, relating respectively to the vibration of OH groups and carbonyl function C=O. This result indicates that cholic acid agent is present and has integrated the polymeric support of developed GPM membrane perfectly. In addition, the GPM membrane spectrum indicates the reduction of the band between 1395 and 1440 cm^-1, characteristic of C- OH bond of the carboxylic acid function in extractive agent cholic acid (CA). This important result confirms the grafting of the extractive agent to polymeric support PSU through the COOH group of cholic acid. Similarly, observation and study of SEM images (Fig. 6) show that the porosity of this prepared GPM membrane is homogeneous and increase with the added amount of co-polymer PVP and with the extractive agent concentration contained in the membrane phase.

The same techniques and studies have to characterize the uniformity of the obtained PIM membrane porosity, its change with the amount of extractive agent contained in the membrane phase. On the other hand, these studies clearly indicate that cholic acid agent is entrapped in the polymer matrix of the developed membrane.

Accordingly, once these three membrane types were analyzed and characterized, they were adopted to carry out several experiments related to the oriented process of facilitated extraction of acetaminophen under different experimental conditions.

4.2. Influence of initial substrate concentration C0

Facilitated extraction process of paracetamol substrate was performed at different initial concentrations C0 (0.08, 0.04, 0.02 and 0.01 M) for each of the adopted membranes. To examine the influence of the substrate initial concentration C0 on the evolution of different parameters (P, J₀, K_ass and D*), several experiences related to the studied process were performed at pH = 3 and T = 298 K, values of C_R concentration in receiving phase were determined versus time, and the straight lines obtained for the evolution of the term -Ln(C0- 2C_R) (Eq. 1) with the time are grouped into the graphs of the next figure (Fig. 7):

Figure 7: Evolution of kinetic law -Ln(C0-2CR) for the oriented process of facilitated extraction of paracetamol substrate at pH = 3 and T = 298 K, across adopted membranes: SLM, PIM and GPM.

This linear evolution of the function -Ln(C₀–2C_R) = f(t), clearly indicates that results for the studied process, adapt perfectly to the developed kinetic model, for which diffusion of the substrate through the membrane phase is a rate-determining step, for the mechanism of this oriented process. The slope values of these line segments were used to calculate the values of macroscopic parameters P and J₀, according to the expressions in equation 3, and all obtained results for adopted membranes are summarized in the next table:

Table 1: Evolution of parameters (P and J0), depending on the initial concentration C0, for facilitated extraction process of acetaminophen substrate.

Analysis of these results indicates firstly, that the used membranes are effective for this oriented process, and SLM membrane type is the most efficient for the facilitated extraction of paracetamol substrate. Secondly, these results show that P and J0 parameters vary inversely, and when the concentration C0 decreases in the feed phase, permeability parameter P increases, and flux parameter J0 through the membrane decreases.

4.3. Acidity influence on feed and receiving aqueous phases

The acidity of feed and receiving aqueous phases is very important; to examine its influence on the evolution of the performance of each adopted membrane, for facilitated extraction process of acetaminophen substrate, several experiments were performed for different initial concentrations C0 and at three acidities (pH = 1, 2 and 3). For these experiments, P and J0 parameters were determined, and the values of initials fluxes J0, allowed to represent according to Lineweaver-Burk method, the straight lines on the evolution of function 1/J0 = f(1/C0) (Eq. 2), for adopted membranes and at studied acidities. The values of slopes and intercepts of these various line segments represented by the graphs in figure 8, were used to calculate the values of Kass and D* microscopic parameters according to the terms in equation 4, and all results are summarized in table 2:

Figure 8:Lineweaver-Burk representations (1/J0 = f(1/C0)), for facilitated extraction process of acetaminophen substrate through three membrane types (SLM, PIM, GPM).

Table 2: Inflluence ofacidity factor on the evolution of Kass and D* parameters related to facilitated extraction process of paracetamol substrate across developed membranes at T = 298 K.

Data in table 2, allow for several findings, initially the model is verified, and diffusion of substrate through the membrane phase is based on the balanced reaction (association/dissociation) of substrate S and extractive agent T, with the formation of an unstable entity (ST). Secondly, these results help explain the performance of these affinity polymer membrane types, and show that the more the entity (ST) is unstable (low K_ass), the more the membrane is permeable. Indeed, the most efficient SLM membrane with the highest values of apparent diffusion coefficient D*, corresponds to the lowest values of association constant Kass. In addition, these experimental results for this oriented process, indicate that Kass and D* microscopic parameters are specific, vary inversely, and their values are very important to understand the movement nature of the substrate through the membrane phase.

Finally, these results show that extraction of acetaminophen substrate is more effective at low acidity (pH = 3) and this is certainly due to the structure of this substrate compound.

4.4. Analysis of the temperature factor influence

Studies of the temperature factor influence on the evolution of different parameters relating to facilitated extraction phenomenon of acetaminophen substrate through the affinity polymer membranes are necessary and very important to explain the performance of these membranes, and to elucidate mechanisms related to this oriented process through the adopted membrane types. To examine this influence, several experiments on study process, were conducted to better acidity (pH = 3) and at three temperatures 298, 303 and 308 K. The kinetic law - Ln(C₀-2C_R) = f(t), well suited to experimental results, can treat these results and determine the values of P and J0 parameters for the three studied temperatures. Table 3 summarizes the obtained values for these macroscopic parameters.

Table 3: Evolution of P and J0 parameters according to temperature factor for facilitated extraction process of paracetamol substrate through developed membranes

These results indicate a clear evolution of P and J0 macroscopic parameters according to temperature factor, and show that the increase of this important factor causes an increase in membrane performance. In this temperature interval 298-308 K, a better evolution of the P parameter for GPM membrane is observed, while high performance is maintained for SLM membrane. To understand, explain these results and identify the movement nature of substrate S through the membrane phase, it is necessary to study the temperature factor influence on changing Kass and D* parameters. The presentations according to Lineweaver-Burk method of function 1/J0 = f (1/C0) (Eq. 2), allow to obtain the straight lines indicated by graphs in the next figure (Fig. 9).

Figure 9: Lineweaver-Burk representations (1/J0 = f(1/C0)) for facilitated extraction process of acetaminophen substrate across adopted membranes, at studied temperatures.

Slopes and intercepts for these straight line segments were used according to the terms in equation 4, to determine the values of Kass and D* parameters. The obtained values for these microscopic parameters (K_ass and D*), at three studied temperatures, are grouped in the following table:

Table 4: Influence of temperature factor on the evolution of Kass and D* parameters to facilitated extraction process of acetaminophen substrate through the adopted membranes.

Analysis and study of these results allow several findings. They confirm and explain the performance of these membrane types, Kass and D* parameters vary inversely, and high performance of SLM membrane type is confirmed for this studied process. These microscopic parameters are specific and depend on the membrane type, and generally low values of the association constant (Kass), corresponding to an effective membrane (high D*). On the other hand, an increase in temperature factor causes a decrease in stability of substrate – extractive agent entity (ST), and more rapid diffusion of substrate S through the membrane phase. This significant finding shows that movement of substrate (S) through the membrane organic phase is based on its interaction with extractive agent (T) in opposite reactions (association /

dissociation) whose rates increase with temperature. Accordingly, the passage of acetaminophen substrate through the membrane phase is an apparent diffusion movement, in successive jumps of substrate molecules from one site to another of extractive agent (Fg. 10).

Figure 10: Apparent diffusion movement of substrate by successive jumps from one site to another of extractive agent across the membrane organic phase.

To confirm these results and elucidate the real mechanism relating to studied process through each adopted membrane type, we determined values of activation parameters (E_a, ΔH^≠ and ΔS^≠) for the transition state of the substrate diffusion step across the membrane phase (rate-determining step). Values of initial flux parameter (J₀) were used to represent the function LnJ0 = f(1/T) from the expression LnJ0 = -Ea/R×(1/T) + LnAj provided by transition state theory (Eq. 6). The values of slopes and intercepts of obtained straight segments were used to determine the parameter values of E_a and A_j, so the activation parameter values of ΔH^≠ and ΔS^≠ were determined at 298 K according to expressions in equation 7. All obtained data are presented according to different scales by the histograms in the next figure.

Figure 11: Evolution of activation parameters for the facilitated extraction oriented process of paracetamol through membrane types, SLM, PIM and GPM

Analysis of these results provides more essential information. First, the low values of ΔH^♯ and the negative values of ΔS^♯ indicate that transition state [ST]^♯ of the diffusion step of substrate S by association with extractive agent T across the membrane phase (rate- determining step), is a state that requires little energy and whose structure is close to that of the pseudo formed entity (ST). This finding indicates an early state for this transition step, and explains the good performance of these membrane types for the studied process.

Secondly; the very low values of Ea and ΔH^♯ parameters show that this oriented process for facilitated extraction of paracetamol substrate through these membranes, which requires little energy, is certainly much more structural, based on the structures of substrate and extractive agent, and the orientations of their interaction sites. This latter interpretation is very important

because it helps to explain the high performance of SLM membrane type against these counterparts PIM and GPM. On the other hand, it allows elucidating the mechanism of this oriented process through each of the adopted membranes. Indeed, for SLM membrane, the substrate and extractive agent are in free movement in the organic phase, with favorable orientations for their interaction sites, which require little energy (Fig. 11). Therefore, to this membrane type (SLM) which is most efficient, the diffusion of paracetamol molecules through the membrane phase is done according to a mechanism of jumps from one site to another of extractive agent, known as mechanism by successive jumps on mobile sites. In contrast to PIM and GPM membranes that are a little less efficient, the extractive agent molecules are fixed in the membrane phase, their movement is very restricted, the orientation of their sites is well defined, and their interactions with the substrate molecules require more energy (Fig. 11). Therefore, the diffusion of paracetamol substrate molecules through these membrane types is slightly slower, and is done according to a mechanism by jumps from one site to another of extractive agent, known as mechanism by successive jumps on fixed sites.

All obtained results for this oriented process on the facilitated extraction of paracetamol substrate, indicate that the reactions (association / dissociation) of substrate S with extractive agent T in the membrane phase and the formation of an intermediate entity (ST), is a determining step for carrying out this process through these membrane types. Negative and very similar values of activation entropy parameter ΔS^♯ (Fig. 11), clearly show that the transition state is identical [ST]^♯, and the formation of this unstable entity (ST) is performed on the same interaction sites (substrate / extractive agent), and its structure is identical independently from the adopted membrane type (Fig. 12).

Figure 12: Interaction sites and structure of intermediate entity (ST)

5. Conclusion

To carry out studies on the facilitated extraction oriented process of paracetamol compound across three membrane types, we conducted several experimental works. Initially, we developed and characterized three affinity membrane types SLM, PIM and GPM with the

same extractive agent. Then, these membranes were adopted to perform the various experiments relating to the studied process. Macroscopic parameters, permeability (P), initial flux (J₀) and microscopic parameters, association constant (K_ass), apparent diffusion coefficient (D*) related to this facilitated extraction process of acetaminophen substrate through these membranes were determined. The microscopic parameters are specific to the studied process, the adopted membrane type and especially the nature of substrate and extractive agent components and their structures. The values of these parameters which have been determined for this oriented process are unpublished. They help explain the performance of membranes and especially to understand the movement nature of the substrate through the membrane phase. The influence of different factors, initial concentration C0, acidity and temperature, on the evolution of these parameters was examined and obtained results were analyzed. The results indicate that for this process, SLM membrane is the most effective, compared to its counterparts PIM and GPM [D*SLM/D*PIM or GPM ≈ 100]. Among these factors, the temperature influence is very important and an increase of medium temperature, causes a significant increase in the apparent diffusion coefficient D*, which results in improvement of the performance of each used membrane for this studied process. The reverse evolution of Kass and D* parameters for the studied process has shown that the substrate movement during its migration through the membrane phase is done according to equilibrium reactions (association / dissociation) between the substrate and the extractive agent through their interaction sites.

Finally, these important studies on temperature influence, allowed also to determine the activation parameters (E_a , ΔH^♯ and ΔS^♯) of the rate-determining step (diffusion of substrate through the membrane phase), relating to the studied process. The original values of these parameters allow for two main interpretations: first, the studied process is a process that is much more oriented by the structures of substrate and extractive agent, not by the reaction medium energy. The second interpretation is very important; the structure of unstable intermediate entity (ST), necessary for the migration of substrate through the membrane phase is the same, independently of the adopted membrane type.

Acknowledgments

The works in this manuscript are conducted within the framework of a PPR2 project, funded by the Ministry of Higher Education and Scientific Research (MESRSFC) and the Nat ional Center of Scientific and Technical Research (CNRST). We would like to thank both organizations for their financial support.

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Figure legends

Figure 1: Paracetamol: 1-hydroxy-4-acetaminobenzene

Figure 2: Simplified scheme of an affinity polymer membrane.

Figure 3: Structure of methyl cholate ester with triol binding site

Figure 4: C

ell with two compartments, adopted for oriented processes through affinity membranes.

Figure 5

: Spectra FTIR-ATR for the different compounds used for the development of GPM membrane

Figure 6: SEM micrographs: a) polymer support surface (PSU), b) GPM

membrane surface (PSU-AC) c) GPM membrane cross-section (PSU-AC)

Figure 7:

Evolution of kinetic law -Ln(C

0

-2C

R

) for the oriented process of facilitated extraction of paracetamol substrate at pH = 3 and T = 298 K, across adopted membranes: SLM, PIM and

GPM

.

Figure 8: Lineweaver-Burk representations (1/J0 = f(1/C0)), for facilitated extraction process of acetaminophen substrate through three membrane types (SLM, PIM, GPM).

Figure 9: Lineweaver-Burk representations (1/J0

= f(1/C

0

)) for facilitated extraction process of acetaminophen substrate across adopted membranes, at studied temperatures.

Figure 10:

apparent diffusion movement of substrate by successive jumps

from one site to another

of extractive agent across the membrane organic

phase.

Figure 11:

Evolution of activation parameters for the facilitated extraction oriented process of paracetamol through membrane types, SLM, PIM and GPM

Figure 12:

Interaction sites and structure of intermediate entity (ST)

Fig. 1:

Fig. 2:

Fig.3:

Fig.4:

Fig.5:

Fig.6:

a b c

Fig. 7:

(a)

(b)

Fig 8:

Fig.9:

Fig.10:

Fig.11:

Fig. 12:

Table 1:

Evolution of parameters (P and

J0

), depending on the initial concentration C

0

, for facilitated extraction process of acetaminophen substrate.

Substrate Concentration

C0

SLM membrane PIM membrane GPM membrane

^{P x 107 J0 x 105 P x 107 J0 x 105 P x 107 (cm2.}

s-¹)

J₀ x 10⁵

^{(cm2. s-1) (mmol. cm}1 ^{-2. s-}

)

(cm². s-¹) ^{(mmol. cm-2.s-1) (mmol. cm-2. s-}

1)

0,08 M 20,219

±0,0068

1,618

±0,0027

17,59

±0,0055

1,027

±0,0018

16,397

±0,0048

0,725

±0,0012 0,04 M 20,306

±0,0068

0,812

±0,0024

18,293

±0,0057

0,534

±0,0015

17,295

±0,0051

0,382

±0,0011 0,02 M 20,456

±0,0069

0,409

±0,0022

18,948

±0,0059

0,277

±0,0015

18,129

±0,0053

0,200

±0,0011 0,01 M 20,506

±0,0069

0,205

±0,0021

19,412

±0,0060

0,142

±0,0015

18,973

±0,0055

0,105

±0,0011 pH = 3 , T = 298 K, Standard deviation(P)=1,3*10^-8 and Standard

deviation(J0)=8,5*10^-8

Table 2: Inflluence ofacidity factor on the evolution of Kass and D* parameters related to facilitated extraction process of paracetamol substrate across developed membranes at T = 298 K.

pH SLM membrane PIM membrane GPM membrane

D* x 10⁵ Kass D* x 10⁷ Kass D* x 10⁷ Kass

^{(cm2. s-1) (cm2. s-1) (cm2. s-1)}

1 14,146 ±0,28 1,229 33,905 ±0,79 3,962 20,781 ±0,66 3,337 2 64,103 ±1,28 0,304 56,421 ±1,32 2,5 23,113 ±0,74 3,216 3 81,301 ±1,63 0,253 76,569 ±1,79 1,815 26,222 ±0,84 2,989

Table 3:

Evolution of

P and J0

parameters according to temperature factor for facilitated extraction process of paracetamol substrate through developed membranes

T °K C0 SLM membrane PIM membrane GPM membrane

(mol. L^-1)

^{P x 107 J0 x 105 P x 107}

(cm². s-¹)

J0 x 10⁵ P x 10⁷ (cm². s-¹)

J0 x 10⁵

^{(cm2. s-1) (mmol. cm-2. s-1) (mmol. cm-2.s-1) (mmol. cm-2. s-1)}

298 °K

0,08 20,219

±0,0068

1,618

±0,0027

17,590

±0,0055

1,027

±0,0018

16,397

±0,0048

0,725

±0,0012 0,04 20,306

±0,0068

0,812

±0,0024

18,293

±0,0057

0,534

±0,0015

17,295

±0,0051

0,382

±0,0011 0,02 20,456

±0,0069

0,409

±0,0022

18,948

±0,0059

0,277

±0,0015

18,129

±0,0053

0,200

±0,0011 0,01 20,506

±0,0069

0,205

±0,0021

19,412

±0,0060

0,142

±0,0015

18,973

±0,0055

0,105

±0,0011

303 °K

0,08 20,644

±0,0069

1,652

±0,0028

18,788

±0,0058

1,097

±0,0018

17,273

±0,0051

0,763

±0,0012 0,04 20,744

±0,0070

0,830

±0,0024

19,212

±0,0060

0,561

±0,0016

18,065

±0,0053

0,399

±0,0014 0,02 20,806

±0,0070

0,416

±0,0023

19,883

±0,0062

0,290

±0,0016

18,910

±0,0055

0,209

±0,0011 0,01 20,888

±0,0070

0,209

±0,0022

20,451

±0,0063

0,149

±0,0015

19,66

±0,0058

0,109

±0,0011

308 °K

0,08 21,413

±0,0072

1,713

±0,0029

19,428

±0,0060

1,134

±0,0019

18,424

±0,0054

0,814

±0,0013 0,04 21,450

±0,0072

0,858

±0,0025

19,723

±0,0061

0,576

±0,0017

18,984

±0,0056

0,420

±0,0012 0,02 21,544

±0,0073

0,431

±0,0023

20,355

±0,0063

0,297

±0,0016

19,375

±0,0057

0,214

±0,0011 0,01 21,606

±0,0073

0,216

±0,0023

20,93

±0,0065

0,153

±0,0016

20,335

±0,0059

0,112

±0,0012 pH = 3 , Standard deviation(P)=1,3* 10^-8 and Standard deviation(J0)=8,5*10^-8

Table 4:

Influence of temperature factor on the evolution of

Kass

and

D*

parameters to facilitated extraction process of acetaminophen substrate through the adopted membranes.

SLM membrane PIM membrane GPM membrane

T °K

^{D* x 105 Kass D* x 107 Kass D* x 107 Kass}

^{cm2. s-1 cm2. s-1 cm2. s-1}

T=298 °K 81,3 ±1,62 0,25 76,57 ±1,79 1,82 26,41 ±0,84 2,94 T=303 °K 97,09 ±1,94 0,22 82,1 ±1,92 1,78 30,83 ±0,98 2,49 T=308 °K 115,25 ±2,31 0,19 90,58 ±2,12 1,75 37,17 ±1,18 2,23 pH = 3

Graphical abstract

Highlights

- The oriented processes across different affinity polymer membranes

- Methyl cholate and cholic acid, effective extractive agents for the facilitated extraction and recovery of paracetamol.

- Determination of parameters: macroscopic (P and J

0

) and microscopic (K

^ass

and D*)

- Mechanisms by successive jumps on mobile or fixed sites