Open Access
Original Article, Biomed Biopharm Res., 2022; 19(1):82-113
doi: 10.19277/bbr.19.1.285; PDF version here [+] Portuguese html version [PT]  


Ionic exchange membranes in the pharmaceutical industry – Review

Ana Morais 1,2, Belen Batanero 2, Patrícia Rijo 1,3 and Marisa Nicolai 1

1CBIOS-Universidade Lusófona’s Research Center for Biosciences & Health Technologies, Campo Grande 376, 1749–024 Lisboa, Portugal; 2Universidad de Alcalá. Departamento de Química Orgánica y Química Inorgánica. Instituto de Investigación en Química “Andrés M. del Rio” (IQAR) Campus Universitario. Fac. Farmacia, km 33,6 A2, 28805 Alcalá de Henares (Madrid) España; 3iMed.ULisboa – Research Institute for Medicines—R&D Unit at Faculty of Pharmacy, University of Lisbon, Av. Prof. Gama Pinto, 1649-003 Lisbon, Portugal

*corresponding author: This email address is being protected from spambots. You need JavaScript enabled to view it.



In line with the longer life expectancy, the pharmaceutical sector, responsible for the continuous development, production and supply of new drugs to cope with the population’s healthcare, has been consistently growing. This scenario illustrates the use of some innovative technologies in industrial processes as the major contributing factor. Amongst these technologies, membrane separation technology stands out. This technique affords the filtration and separation of biological molecules at the nanoscale, resulting in a more expedited manufacturing process and a higher purified end product. Depending on the driving force applied, the separation process involves different approaches, feed stages, different pores’ sizes or permeates. In the scope of membrane separation technology, electrodialysis (ED) uses an electrical potential difference as the driving force to separate ions based on their charge. In this sense, ion-exchange membranes are the most widely used separation materials in purifying systems as they have the advantage of partitioning species of different charges. The present study evaluates two ion-exchange membranes' aptitude as separators for ED filtration of some industrial chemical processes.


Keywords: Ionic-exchange membranes, separation technology, pharmaceutical industry wastewater treatment, electrodialysis

Received: 18/03/2022; Accepted: 28/04/2022



According to the National Institute on Aging, (1) the population's average life expectancy has increased significantly over the last hundred years. However, according to the globalisation phenomena associated with the changes from traditional diets to processed food products manufactured on a mass scale and new lifestyle habits, this rise has not been followed by healthy life expectancy.

Although the reliable healthcare provided by technological development in medical and pharmaceutical areas, some harmful unhealthy habits, sedentary lifestyle, and dietary shifts to weaker-nutrition fatty diets are some risk factors contributing to the emergence of some chronic health problems.

Alongside the technological development in medical healthcare, the pharmaceutical industry has been evolving both in more localised therapeutics and into a more complex molecular synthesis approach.

The pharmaceutical industry responsible for the research, manufacturing, and trade of medicines and other healthcare products aims to contend and overpass many of the population’ health issues. Therefore, in acquiescence with the globalising and population average life expectancy, the pharmaceutical industry has been likely evolving persistently over the years.

Over time, the aforementioned pharmaceutical development has contributed to the current innovative technologies.

Environmental concerns and current legislation (2) have triggered the demand for high-efficiency industrial processes with concurrently reduced capital commitments, making membrane-based technologies one of the most widely used engineering in the pharmaceutical industry.

These technologies have provided valuable assistance in developing advanced products and great support from an economic point of view in the manufacturing procedure of such outputs.

Membrane separation technology used in specific pharmaceutical sectors

Membrane separation methodology is a barrier operation where the boundary is a semipermeable membrane that selectively allows some components to cross through the membrane while excluding others upon the action of a driving force.

Additionally, it grants some elements to penetrate more swiftly into the membrane than others, segregating those elements in the fluid (3).

The membrane partition procedure may be set into six different filtration systems, depending on the target goal: microfiltration (MF), ultrafiltration (UF), nanofiltration (NF), reverse osmosis (RO), pervaporation (PV), and electrodialysis (ED).

In the following work, the main focus will be on the electrodialysis separation technique. Wherein driving force behind the migration of ions across the membrane is a potential difference applied on both sides of the membrane.

The membrane-separation techniques are also widely used in medical devices like haemodialysis (“artificial kidney”), blood oxygenators (“artificial lung”), and other facilities for controlled drug delivery. However, the type of membranes employed in such systems is not under the scope of the present study.

Ionic exchange membranes

The membrane that has gained a prominent place among technological innovations in large-scale chemical processes is the ionic exchange membrane (IEM) (4). These charged membranes are widely used, driving laboratory developments towards improved efficiency, especially nanofiltration and electrodialysis.

Generally, this kind of polymeric membrane is made of highly swellable cohesive gels (e.g., polystyrene) on a polymer backbone to which a charged functional group is attached.

Such polymeric structure is usually made by the polymerisation of functional monomers together with crosslinking agents.

Ionic exchange membranes could be divided into four broad categories:

  • Perfluorinated ionomers,
  • Non-fluorinated hydrocarbons,
  • Sulfonated polyarylenes, and
  • Acid-base complexes.

These membranes can be labelled homogeneous (5) if the polymer framework already holds the functional sites to sustain the ion-exchange groups. Or else as heterogeneous (5) if charged groups are restrained in limited domains distributed through the membrane matrix.

In this last frame, two different polymers are involved: Beyond the structural matrix polymer, there is another ion-exchange resin, usually finely ground, which is used to carry the functional sites.

Compared to homogeneous IEM, heterogeneous IEM presents improved characteristics, such as higher chemical stability, superior mechanical properties, and relatively low production cost (5).

This type of polymeric structure with a functional group is often exploited as a selective barrier for specific ions and prevents the passage of other ions or molecules. Thus, the ideal IEMs are expected to be highly permselective and hold low electrical resistance (i.e., high conductivity) (5). Both parameters rely on the mobility of ions and other neutral species across membranes.

The ionic conductivity is closely related to the ability of membranes to transport ionic species, and selectivity is the ability of a membrane to separate ions.

Depending on the charge of the functional group in the polymer structure, the membrane may allow a favoured passage of cations or anions.

Therefore, IEM can be referred to as cation-exchange membranes when it carries negatively charged sulfonate groups (SO32-) and anion-exchange membranes when its polymer structure supports cationic groups such as quaternary ammonium (NR4+).

The polymeric material of the IEMs must satisfy the requirements claimed for the separation ED process, such as:

  • Good ionic conductivity,
  • Improved chemical and thermal stability,
  • Permeability for desired certain species.

The role of the cationic exchange membrane (CEM) is to be selectively permeable to cations, preferably protons moving from the anode to the cathode. As most popular, the Nafion® N-117 membrane (DuPont, Wilmington, DE, USA) is a widely used CEM due to its high specificity toward protons and other small cations (6).

Nevertheless, this membrane material has limitations, including its weak mechanical strength and high cost, making it unsuitable for long-term studies. Therefore, its replacement with more resistant polymer materials and more moderate production cost is highly desirable.

Similarly, the anion-exchange membrane (AEM) is rather selective for the passage of anions, albeit from both compartments.

In addition, the alkaline environment enclosing AEM allows the selection of non-precious metals as the catalyst material for the evolution of hydrogen and oxygen during its use in water electrolysis.

In accordance, AEM is often used to produce green hydrogen by water electrolysis (7).

This kind of IEM is an essential component in microbial desalination systems, allowing the preferential passage of anions.

In ED, the ionic conductivity (8) characterises the ion transport rate and determines the ohmic losses in membranes during separation electrodialysis processes.

The permselectivity and conductivity of the membranes are, to some extent, in contrast to each other since the growth in moisture content of membranes resulting from their use in liquid separation promotes a simultaneous rise in conductivity and a decrease in the selectivity of transport processes.

Polymeric membranes must satisfy several criteria to intensify ED efficiency:

  • High ionic conductivity to provide high currents with minimal resistive losses;
  • Minimal or no electronic conductivity;
  • Good mechanical strength and stability;
  • Chemical and electrochemical stability under operating conditions;
  • Adequate moisture level;
  • Extremely low fuel or oxidant permeability to maximise the Faraday efficiency of the electrochemical process (aka Coulomb or current efficiency);
  • Cost-effectiveness.

From a competitive perspective, it is also necessary to ensure the membranes’ properties employed during the pharmaceutical industry’s separation methods to satisfy the low internal resistance, good separation, and adequate physical strength.

High-performance, low-cost commercial ionic exchange membranes

In the scope of another sector, the transport properties of two ionic exchange membranes were analysed in a study by Morais et al. (9)

Effectively, two commercially available ion-exchange membranes were investigated as laboratory-assembled fuel cells separators in the scope of the energy supply/source context: the cationic exchange membrane CMI-7000S and the anionic exchange membrane, AMI-7001S (both Membranes International Inc., Ringwood, NJ, USA).

Some electrochemical parameters were also collected.

In this work (9), the operation of IEMs as electrodialytic cell separators were assessed by analysing the performance of laboratory-made fuel cells (Pt, NaBH4/commercial membrane separator/H2O2 + Pt).

Therefore, the anion- and cation-exchange membranes’ performance was appraised by recording the electrochemical parameters in a PAR 273A potentiostat/galvanostat during the fuel cells’ performance. Specifically, the fuel cell:

  • Polarisation;
  • Power density;
  • Stability.

For a more comprehensive evaluation of the studied membranes, the collected data were then used to determine some other essential electrochemical parameters like the energy densities and specific capacities of the electrochemical system of the fuel cell.

The evaluation of IEMs as separators of an electrochemical system (9) was made at room temperature. The membranes used to separate the acidic and alkaline chambers (the anolyte/ the catholyte compartments each of 75 cm3) hold an active area of ca. 30 cm2.

For the electrochemical parameter evaluation, a Pt electrode was used as both anode and cathode, and a saturated calomel reference electrode (SCE) to measure the anode/cathode overpotentials during the cell discharge.


In the Morais et al. experiments (9), the assembled fuel cell (drawn in Figure 1) had highly opposing pH electrolyte solutions, making them very reactive, so the separating membranes must ensure their segregation. The anolyte solution consisted of 1 M NaBH4 with 4 M NaOH (highly alkaline solution) and the catholyte on 3 M H2O2 with 1 M HCl (considerably acid mixture).

Pre-treatment of polymeric membranes

Both polymeric membranes were activated by a pre-treated through dipping into deionised water for 24 h with water being changed twice during that period, followed by immersion in a solution of NaOH (4 M) for two hours.

Membranes’ characterisation

The morphology of the surface and cross-section of the membranes were analysed by field-emission gun scanning electron microscopy and revealed that both surfaces presented a certain degree of roughness, and their topography was clean of foreign material.

The cross-section observations revealed the presence of densely packed microfiber within the structure of both membranes, with the anionic membrane (AMI-7001S) showing additional filaments among the microfibers.

Working principle of IEMs in the ED separation process

Electrodialysis is one of the most used electrically driven membrane separation processes among industrial synthesis (10). It involves an electrochemical membrane process, which conveys the pertinent ions through perm-selective membranes under the effect of a direct electric current field (drawn in Figure 2).

Three types of selective membranes may assist the electrodialytic separation process: cation-exchange, anion-exchange, and bipolar membranes.

Ionic exchange membranes operate according to the principle of Donnan exclusion (11), i.e., only allowing the transference of oppositely charged ions. Conversely, the transfer of ions of the same charge as the immobilised ionic group at the membranes’ surface is mostly blocked (Figure 2).

The ions that compose an aqueous solution may be carried across the boundary layer (12) of an ionic exchange membrane under three routes of mass transport: diffusion, migration, or convection.

Nevertheless, when a bulk solution is under unforced flow, gravitational or electroconvection forces provide the ions from the bulk solution towards the surface of the IEM through a boundary layer there formed (12).

When the boundary layer is formed on an AEM, convection converts to migration and diffusion and is responsible for the electric current transport. When it is over a CEM, the convection only converts to migration and carries an electric current (12).

While the anodic and cathodic reactions occur in each EC cell chamber, the electric field is build-up, thereby gathering the resulting ions at the surface of the ion-exchange membrane used as a separator. Such a situation fosters the ions’ transference by migration.

Therefore, it is possible to conclude that migration is the main mass transport approach for the ions to be segregated under an ED system.

Nevertheless, some diffusional crossover of neutral species through a membrane occurs to a certain extent (especially through the AEM) and occurs due to the concentration gradient between the anode and the cathode compartments.

The CEM is embedded with functional groups (FGs) of negative charge; therefore, it essentially attracts positive charges, and the other way around occurs in the AEM. Especially in strong acid cationic exchange membrane (as CMI-7000S with HSO3 as FG), the repulsive force between the ion-exchange functional groups (SO3-) and the co-ions (OH-, ions with the same charge as the functional group of IEM) is relatively high.

In this case, the water dissociation reaction is restrained, and the charge balance is made by ionic migration through the polymeric membrane (12).

Some point after the ionic transference, the concentration gradient becomes relatively high; therefore, the diffusion crossover of some neutral species like the NaOH, HCl, or organic compounds also takes place to a certain extent, aiming the system to reach an equilibrium state.

Conversely, in the strong base anionic exchange membrane (AMI-7001S with quaternary ammonium as FG), the repulsive forces between those ion-exchange group species (N+(CH3)4) and the co-ions (H+) are relatively low. As a result, the water molecular dissociation is not suppressed.

In the case of the analysed electrochemical fuel cell system (9), where a highly strong acid and base were used as electrolytes, the charge transfer relied on the type of membrane used as a separator:

  1. In the case of AMI-7001S, OHand Clanions migrate from the cathodic to the anodic compartment to keep the cell charge balance;
  2. Conversely, Na+cations cross through the CMI-7000S in the cathode direction, keeping the charge balance (almost no H+in the solution because the dissociation of H2O2 is inhibited).

Although AMI-7001S and CMI-7000S are charge selective membranes, which allow the preferential passage of oppositely charged species, there is a limit to an ion migration toward the oppositely charged compartment whenever both IEMs are used as separators (dashed arrows depicted in Figure 2).


In Morais et al. study (9), the higher power density of the thinner 0.18 mm thick Nafion® N-117 membrane was prominent, compared to the 0.45 mm AMI-7001S and CMI-7000S analysed membranes.

The membranes thickness strongly influences the membrane’s electrodialysis separation process.

Accordingly, a higher thick polymer membrane grants a greater strength and endurance on its usage during the separation process, and it further reduces the unwanted reactants to crossover.

Furthermore, thicker membranes also have a more extended pathway for ion transport during the electrodialysis; therefore, they show a higher ionic resistance.

Conversely, the peak power density of an electrochemical system increases inversely with the thickness of the membrane used to split the electrochemical cell. It occurs because ions must cross a higher average free path between the anodic and cathodic compartments.

Thus, the thickness of the polymeric membrane has a significant impact on the performance of the electrodialysis separation cell.


In the energy-supply research scope, the fuel cell electrode potentials recorded in Morais et al. (9) show an excellent behaviour of both EMIs employed. Nevertheless, energy supply approach, the CMI-7000S membrane exhibits a better power cell performance than the AMI-7001S. This result highlights the higher ohmic resistance of the AMI-7001S reported in Table 1.

Such improved behaviour of CMI-7000S membrane is reflected in other analysed parameters.

As the current density showed a slower decay over time and fuel cell potentials with longer-term durability, which is verified by:

From laboratory-made electrochemical cells performances, it was prominent that the current density relies on pH fluctuation on each of the cell compartments,

The faster decay observed in fuel cell voltage with the AMI-7001S as separator results from the higher decline in the cathodic electrical potential,

Usually, the ion-exchange membranes are sensitive to OH radicals produced during H2O2 catalytic decomposition, with membranes durability constrained by those radicals.

After repeated electrochemical tests, no fouling or physical degradation of the two investigated MPIs was found.

Therefore, it is worth noting that no physical/mechanical degradation of the two membranes was visible during and after extensive use.

Pharmaceutical sectors

Pharmaceutics (13) are a milestone in human scientific development, as they have enabled the cure of millions of deadly diseases, improved the quality of life, and prolonged the population’s life span.

Those pharmaceuticals include a massive group of chemical compounds that bind to specified human and animal receptors, aiming for a particular therapeutic activity (through various mechanisms of action) in a given target organism. These specific mechanisms of action can also affect both prokaryotic and eukaryotic cells of organisms found in the environment (13).

The biological stability and resistance to biodegradation of medicines increase their performance in the prokaryotic aquatic environment by increasing their half-life in the body. Such a situation makes these chemical compounds environmentally persistent.

The environmental persistence of pharmaceuticals and their bioaccumulation promotes the increase of possible toxic and carcinogenic effects on organisms (animals, flora, and fauna).

In addition to human medication, there is also medication for veterinary therapy and enhancement of animal reproductive systems, which use various hormonal compounds and antibiotics.

Therefore, pharmaceuticals have emerged as a new class of environmental contaminants in recent decades, with pharmacologically active compounds exerting toxic effects on numerous organisms whenever by-products of the pharmaceutical industry are disposed of in the environment.

To sustain the development and improvement of chemical and biochemical industries of the pharmaceutical sector, the production of some compounds with diverse bioactivities (antimicrobial, antibacterial and antifungal) claims the implementation of innovative methods for their production.

Regarding the procedure adopted by many industrial chemical syntheses, extraction and the treatment of the resulting fermentation broth are required (14).

In fact, many pharmaceutical formulations make use of fermentation techniques during the development of their active ingredients. In principle, all fermentation processes of the pharmaceutical industry take advantage of membrane separation technology.

Such is the case for carboxylic acids (15) and several organic acids (16) that need to be extracted from their broth to proceed to their crystallisation after the fermentation process. These extraction steps use the benefits of the electrodialysis system, among others.

Given that more than 95% of pharmaceutical manufacturing concerns liquid partitioning, the most widely used separation procedure within the industrial processes embraces the concentration and purification of pharmaceutical products.

In light of this, membrane separation technology has been predominantly employed for (3) chemical separation, improvement of synthesis processes, wastewater purification, and waste/solvent recovery (Figure 3).

IEM may drive laboratory developments towards their improved efficiency, including medicine production

The isolation and purification steps of medicines adopt membrane separation technology, in which various purification methods refine their respective fermentation broths.

Namely, the membrane separation process is widely used in antibiotics industrial-scale production, where various fungi and bacteria foster the development of active antimicrobial substances of such drugs. (13, 17).

Ionic exchange membranes are suitable for a single membrane and bipolar membrane electrodialysis (BM ED) processes, which have been developed to convert salts into corresponding acids and bases.

Consequently, ED processes have also been found to be suitable and cost-effective for the recovery of organic acids or amino acids from their respective salt (18).

Bipolar membranes (BMs) comprise a unique form of ion-exchange membranes established by a cationic and anionic exchange layer, which allows the production of protons and hydroxide ions through the dissociation of the water molecule.

In addition, the electro-hydrolysis of water, which produces H+ and OH ions, may also be exploited to transport components used to produce organic acids such as particular daily vitamin supplements, which leads to economic and environmental benefits (19, 20).

According to the specific requirements and the ED process steps, the ED technique uses several separating membrane models in some membrane separation processes. For instance, AEM served as a barrier in the three-compartment configuration of (Anode-AEM1-Membrane Ultra-Filtration-AEM2-Cathode) ED with ultrafiltration membrane (ED/UF) system (21), for the separation of chitosan oligomer under applied electric field strength.

Chitosan is a natural co-polymer with a considerable biomedical value since it possesses anti-tumour and antimicrobial activities widely used to resolve some osteoarthritis– gastritis health problems (22).

An effective oligomer separation (dimer from the trimer and tetramer) was achieved by ultrafiltration membrane area under applied electric field strength of 2.5 V/cm.

Carboxylic acids functional group adjusts drug bioavailability

Drug absorption (23) relies on drug hydrophilic/hydrophobic balance value, which depends upon polarity and ionization.

Highly polar or strongly ionized drugs cannot efficiently cross the cell membranes of the gastrointestinal barrier. An intravenous route should therefore be followed for taking these types of drugs. Nevertheless, the associated disadvantage is their prompt elimination from the organism.

On the other hand, non-polar drugs are poorly soluble in aqueous media and hence poorly absorbed through cell membranes. If taken intravenous, they will most probably be retained within fat tissues.

In order to overcome this problem, the drug polarity and/or ionization must be altered by changing its substituents.

One way of suppressing this is to alter drug pKa with the addition of a carboxylic acid that may withdraw electrons from the drug ring structure (24).

Carboxylic acids are the most common organic acids large scale used in pharmaceutical drugs (25), chemical (26) and food industry (27). Namely in the production of Nonsteroidal Anti‐Inflammatory Drugs (NSAIDs), in coatings and polymer industry as solvents, or still as food additives as antimicrobial and flavouring agents.

The carboxylic acids most widely found among pharmaceuticals are :

  • 2-aryl-propionic acid, a propionic acid derivative as one of the most widely used nonsteroidal anti-inflammatory drugs class (NSAIDs).
  • Citric acid is commonly used as a preservative excipient in pharmaceutical preparations to preserve their drug active substance stability due to its antioxidant properties.
  • 4-Toluenesulfonic acid as counter-ions during the synthesis of the alkaline drug, given the combination of its hydrophilic nature and high acidic properties.
  • Salicylic acid is the raw material of aspirin production and skin formulations since it facilitates the outer layer of skin removal.
  • Itaconic acid has a renewable dicarboxylic structure used in the preparation of biocompatible hydrogels essential for the controlled release of some drugs within the organism.
  • Ascorbic acid is widely used as an antioxidant agent in preventing and treating several oxidative damages to the human organism.

Currently, the bio-based economy inspires an improvement in current industrial processes. Such is the large-scale production of citric acid, lactic acid, D-gluconic acid, itaconic acid, and 2-keto-L-gulonic acid. In addition, it provides the development of new fermentative approaches for the production of carboxylic acids.

However, there is a financial concern in industrial production’s raw materials and processing costs, which comprise a high portion of the total production costs. Thus, it is essential to improve the segregation and recovery systems associated with the biological production of carboxylic acids by making them competitive.

  • The fundamental requirements of a good ED separation process on an industrial scale are:
  • High purity (most carboxylic acids requires >99.5% degree purity);
  • Owning a high degree of recovery (90-100% yield);
  • Require low energy and chemical consumption in the course of the recovery process;
  • Involve a modest investment, with worth efficient mass and heat transfer guarantee by the recovery equipment;
  • Sustainability (provides a viable solution for the retrieval of various industrial reagents).

The production of carboxylic acids (16, 28, 29, 30) may proceed by a conventional chemical/electrochemical approach or by large-scale biotransformation of the carbohydrates through fermentation by strain cultures.

Nevertheless, as the fermentation process uses renewable resources as raw materials assured by the biosphere, it is preferred over the conventional procedure for producing the organic acids because the fermentation products have a higher degree of health safety.

Although more ecologically friend, the fermentation method requires more steps to succeed during the preparation of the organic acid as the fermentation broth has several ingredients to recover/separate.

In fact, both techniques of organic acids manufacturing require competitive environmental and economic procedures, with the membrane separation technology proving their advancement in separation and purification.

Recovery of carboxylic/organic acids from fermentative broth

In the following paragraphs, some industrial recovery processes (15,16) implemented during the production of essential carboxylic/organic acids used in particular pharmaceutical products are described.

The lactic acid (31) is a valuable component for implantable drug delivery and comes from an anaerobic fermentation by the strain Escherichia coli.

Lactic acid enables the preparation of the polylactic acid biopolymer (PLA), which is considered a potential candidate for a skin-dissolving polymeric matrix, releasing drugs into the body and subsequently absorbed by the body.

Lactic acid extraction from its fermentation broth may be accomplished by different ED configuration systems.

By demineralizing its salt (32), making use of a two-compartment electrodialytic stack in which two AEM and one CEM operate, according to Figure 4.

The lactic acid may also be efficiently recovered from its fermentation broth (33) through a bipolar membrane (BM) electrodialysis unit (Figure 5).

Under this electrodialytic separation system (33), Börgardts et al. reported an economical process of lactic acid production from whey, suitable for industrial scale.

The three-component bipolar cell electrodialytic configuration allows the separation of lactate from other uncharged components and further conversion to lactic acid.

Two commercial homogeneous Neosepta (ASTOM, Tokyo, Japan) cation-exchange (CMX) and anion-exchange (AMX) membranes were employed in this ED configuration, with main characteristics reported in Table 2.

Globally the process consists mainly of the milk protein concentration by ultrafiltration, then converting this lactose into lactate by fermentation with lactic acid bacteria and subsequent microfiltration by ceramic membranes.

Finally, in the recovery of the lactate ion from its fermentation broth, one should convert it into free lactic acid by bipolar electrodialysis.

This cyclic operation made it possible to obtain concentrations of less than 1 g l l-1 of lactate in the dilution chamber while it achieved a 200 g l l-1 of free lactic acid in the concentrate chamber.

Nevertheless, since this is still a high-cost process, some previous broth concentration is necessary (36) and could be performed by using the ED stack schematically portrayed in Figure 6.

This BM ED procedure has been widely applied in the production of several pertinent organic acids for the pharmaceutical sector (16), such as:

  • Propionic acid;
  • Citric acid;
  • 4-Toluenesulfonic acid;
  • Salicylic acid;
  • Itaconic acid;
  • Ascorbic acid.

Alternatively, organic acids production may also be accomplished by the co-ion replacement (37) by using a unique form of a selective IEM. In such a case, the lactic acid production is performed by sodium lactate organic salt desalination through the ion substitution reaction of Na+ for H+. In these circumstances, the ED unit has two compartments for the acid and feed streams.

For the proton exchange reaction to occur, choosing a CEM for the ED-stack arrangement between the anode and the cathode is more convenient, as depicted in Figure 7.

Under the electric current, protons supplied by the acid stream are driven into the feed stream compartment, where they react with the negatively charged lactate anion and turn it to its neutral form.

As a result, the inorganic sodium cations Na+ from the feed stream are equally transferred by the CEM towards the acid compartment, achieving/reaching its electroneutrality.

IEMs employed for chemical purification and recovery in pharmaceutical industry wastewater treatment

The ecological footprint of a drug (13) is nowadays maximum, with pharmaceutical residues being considered “compounds of emerging concern” and causing considerable fear, as these residuals have a large impact on human health and ecosystems.

Physical and chemical methods are among the several techniques used in removing pharmaceuticals from wastewater. Most physical methods move pharmaceuticals from an aqueous phase to a solid phase.

“Physical membrane separation technologies” are an efficient/advanced method available and appear to be the most widely viable pharmaceutical removal method.

The pharmaceutical industry pollutants have become one of the biggest threats to aquatic life with the accumulation of drugs released creating an additional development of antibiotic-resistant microbial strains that afterward reflect on human and animal health (38).

One of the most attractive proceedings used for the comprehensive removal of these pollutants is the cooperative approach that joins a decomposition procedure (e.g., the Fenton reaction) with membrane separation technology (39).

Usually, the wastewater treatment makes use of a bipolar membrane ED system. The bipolar membrane combines an AEM with a CEM that splits available water in the thin layer between these membranes into H+ and OH- ions (40).

This situation creates a pH difference on both sides of the bipolar membrane, setting the base for an attractive series of separations or combined reactions with partitions. The catalysis by ionically charged groups on the ion-exchange membranes fosters the water split that accounts for the pH imbalance.

The dissociative reaction of water is caused by the electric potential built up in the charged membrane layer (which acts as activation energy).

The ions generated by the water dissociation (H+ and OH) are immediately taken up by the ion transport driven by the applied potential during the ED separation process. Significant pH changes thus occur on the concentrated and diluted sides of the ion-exchange membrane used (40).

During the wastewater treatment by the ED membrane process, the ions are driven to cross the AEM and CEM in opposite directions.

Due to the sequential arrangement of both types of membranes in an ED stack, there is a bias of some concentrate and dilute ED compartments’.

At some point, the ion transport towards the concentrate compartment occurs against the concentration gradient at the membrane surface (12), resulting in two types of regressions in the ED process:

1st - The rise of the flux of the ionic species that return by diffusion, given the high concentration gradient that is developed, which the flux of the transported species follows Fick’s law of diffusion (according to the equation below):

where Jx is the flux in the direction of the xx axis, D is the diffusion coefficient of ionic species (m2/s), and dC/dx is the concentration gradient (kg/m4).

Such an ED back-process continues until the ionic flux against the concentration gradient equals the ionic returning diffusion flux, which corresponds to the maximum electrodialytic effect obtained.

2nd - Once the ions in the dilute compartment are depleted, it becomes difficult to remove further ions since insufficient ions are available to transfer electrical charge.

The electrical resistance will increase dramatically when the ions are entirely exhausted in the diluted compartment. From this point on, the remaining energy in the system is then used to split the water:

Therefore, any additional transport is limited to OH- and H+, which is not a useful effect and decreases the efficiency of the ED system.

The electric potential intensity is more prominent in a strong acid CEM (like CMI-7000S sulfonic acid as FG) than in the strong alkaline AEM (likewise the AMI-7001S that has quaternary ammonium as FG) (12).

Therefore, the intensity of the water splitting is more constrained when a CEM is employed instead of an AEM.

In addition, the AEMs with positively charged ion-exchange groups readily attract bacteria during anaerobic wastewater treatment with microorganisms (41), accordingly, are the most often used in wastewater treatment.

Within the scope of desalting water by membrane technology, Zheng et al. (41), inspired by mussel-adhesion, have functionalised a homogeneous AEM towards their monovalent anion selectivity between Cl and SO42− at a constant current.

Therefore, the Zeng group prepared a modified AEM by deposition a polyelectrolyte that improved the separation selectivity of monovalent ions during a four-cell ED apparatus used to separate Cl- from SO42-(Figure 8).

Such adaptation was accomplished by installing oxidised dopamine onto the membrane’s surface, forming a polymer-like coat with high adhesive strength.

In this ED system, homogeneous IEMs of polyamide matrix structure with a very low electrical resistance (purchased from Fujifilm Corp, Tokyo, Japan) were used as background polymer membranes (Table 3).

Additionally, the antibacterial action during the wastewater treatment was also amplified by incorporating silver nanoparticles onto the membrane surface.

Aiming to verify the feasibility of the ED process using ultrafiltration membrane in the purification of wastewater from the pharmaceutical industry, Lu et al. (13) investigated a proposal ne

The proposed ED separation process made use of a stack whose configuration consisted of several ion-exchange membranes (AEM and CEM) alternated with ultrafiltration membranes (UF).

The resulting EDUF configuration proved to be effective in separating similarly charged ions by separating penicillin-G- anions from SO42- anions and recovering some ions from the same “wastewaters” (Figure 9).

By combining two different ED/UF membrane separation processes, antibiotic recovery and wastewater treatment have improved the biodegradability of drug synthesis wastewater.

This study allowed the development of an efficient ED technology for wastewater treatment from chemical production on an industrial level, thus making it an environmentally friendly route for the pharmaceutical industry.

In the same industrial recovery vein, Prakash et al. (11) have investigated the application of two types of CEM for the recovery of a widely used Alum-based coagulant from water treatment plants by using the Donnan membrane process: the homogeneous Nafion® N-117 membrane and the heterogeneous Ionac-3470 (Lanxess AG, Cologne, Germany).

Such an alum-based coagulant sustains the efficient removal of suspended solids and residuals colloidal particles in wastewater treatment.

The main properties of the explored strong-acid cation-exchange membranes are summarized in Table 4.

As previously mentioned, the “Donnan process” is driven by an electrochemical potential gradient, avoiding possible hindrances regarding the high turbidity of natural organic matters in the waste sludge during the recovery of the alum.

Therefore, no perceptible membrane fouling was distinguished, even after multiple runs over long hours of electrodialysis operation.

Nevertheless, the alum recovery with homogeneous Nafion® N-117 membrane was over three times greater than that of heterogeneous Ionac-3470 under similar conditions.

Despite the Nafion® N-117 membrane has proved to be highly efficient in heavy metals and pollutants removal from industrial streams aqueous solutions; this membrane sustains some drawbacks:

  1. a) It requires a pre-treatment with H2O2and HCl to activate, which in turn generates hazardous wastes;
  2. b) It is a high-cost manufacturing membrane, hindering its widespread use in commercial and industrial devices.


As previously stated, membrane separation technology assists in developing innovative products more expeditiously and cost-effectively. Hence, cost is a relevant property of membranes when scaling dialysis systems.

For superior ED segregation, in addition to high conductivity and permselectivity, high mechanical strength and an economical membrane option are also desired.

Taking the approach of Morais et al. as an example, (9) it has been verified that the ion-exchange membranes analysed under the scope of energy supply (9) can be an excellent alternative to membranes used in chemical membrane separation processes.

Both membranes analysed, AMI-7000S and CMI 7001S, displayed favourable characteristics for performing ED separation, such as high permselectivity and relatively low electrical resistance (Table 1).

On the other hand, the higher thickness of the membranes strongly influences the ED separation, giving a higher resistance and reducing the crosslinking of unwanted reagents.

It was noted that the fuel cell employing a CMI-7000S membrane exhibited better power cell performance than the AMI-7001S. This behaviour may be ascribed to the higher ohmic resistance of the AEM (Table 1).

This better performance of the cation exchange membrane CMI-7000S influences other essential properties for ED separation, such as the slower decline in the current density over time, which points to higher stability in the ion transfer between the ED cell compartments.

Indeed, the research of Prakash et al. (11) determined that heterogeneous cation exchange membranes have advantages over homologous homogeneous ones (e.g., Nafion® N-117) since they have similar dialysis results well as being easier to use and less expensive.

It should also be noted that although the lower thickness of homogeneous separation membranes (33, 41) allows them to achieve a higher power density and performance at the beginning of electrodialysis.

Nevertheless, given the periodicity of industrial dialysis processes, the membrane thickness is an essential parameter, and thus the higher thickness of the heterogeneous membranes (9) affords a greater mechanical strength.

Considering the above reflections, the two commercially viable low-cost membranes investigated by Morais et al. offer an attractive option for the membrane separation process at an industrial scale, representing an interesting alternative for future research in pharmaceutical industry processes similar to those referred to in this paper.


The authors would like to express their gratitude to Research Support Funding by the PADDIC (doctoral fellowship to A.M.) In addition, to the Foundation for Science and Technology (FCT, Portugal), for financial support through projects UIDP/04567/2020 and UIDB/04567/2020.

Author Contributions

A.M., conceptualization, investigation, experimental implementation, data analysis, original draft preparation, and editing; M.N. and B.B., data analysis and review; P.R., supervision and final redaction.

Conflict of interest

The senior editor co-authoring this manuscript had no participation in the review nor in the decision process. All authors declare there were no financial and/or personal relationships that may present a potential conflict of interest.



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