**4. Applications of alginate metal complexes**

## **4.1 Organic synthesis field**

Click chemistry is a new approach for drug industries based on the chemical reactions with high yields, and stereo-selectivity results with low reaction time. Bahsis et all [22] studied the synthesis of hydrogel catalyst; consist of sodium alginate with copper (II) for the azide-alkyne cycloaddition in the form of spherical beads. The prepared beads showed high catalytic activity for the required interaction.

Pua et al. [23] studied the synthesis of three alginate catalysts for the esterification of oleic acid. Ferric-alginate, Copper-alginate, and Nickel alginate beads were used to esterify the free fatty acid, and Fe- beads were the most successful ones.

In the work of Souza et al. [24], Alg-Cu+2 microspheres were prepared via an ion exchange process, and it was examined as a catalyst for the synthesis of some substituted pyrazoles. The resulted product was in excellent yield, and the catalyst activity still good even after five reactions.

Qiao et al. [25] introduced a new hybrid material of Ni-alginate beads. They distinguished with their remarkable activity and stability as styrene hydrogenation catalyst with recycling ability for 20 times. On the other hand, the ease of this hybrid material preparation allows examining its hydrogenation activity of unsaturated substrates.

### **4.2 Environmental field**

In the past decades, many researchers have been aware of the heavy metals that affected the environment, due to Pollution caused by mining and different manufacturing. The industrial wastewaters clean-up of toxic metals such as Pb, Hg, Ni, Cr, Cd, As is challenging for many research centers [26–28].

Membrane filtration, electrodeposition, ion exchange, and chemical precipitation were the most techniques involved in removing metal from aqueous contaminated solutions. However, there were disadvantages to some of these methods compared to the treatment of complex [29]. Sodium alginate is one of the rawest materials using in synthesis methods as adsorbents to remove heavy metal ions from aqueous solutions.

Gao et al. [30] reviewed the Possibility of developing the sodium alginate as adsorbents, the involved mechanisms in the adsorption process were; electrostatic interaction, ion exchange, reduction, and photocatalytic reduction. In another study, they provide a synthesized sodium alginate adsorbent which showed notable selectivity towards Pd (II). Therefore, they provide selective industrial applications to reduce the Pd (II) from effluents.

Clinoptilolite/Nickel Ferrite/Sodium Alginate Nanocomposite beads were prepared by Bayat et all. [31] via many stages to remove methylene blue dye from water. Pseudo-second-order was the best fit model for adsorption kinetic, and the optimal pH was 5 for methylene blue adsorption.

#### **4.3 Pharmaceutical field**

The development of a drug delivery system is one of the most researcher's concerns. Particularly, in the case of chiral excipients [7, 32–34], which leads to possible steric interactions between chiral excipient and the chiral drug due to enantioselective release. Thus, it could affect the pharmacological and bioavailability studies of chiral drugs. Many chiral excipients were used in several pharmaceutical formulations, and numerous researchers have studied the effect of chirality on the drug release [35] such as ketoprofen [36, 37], propranolol [38, 39], metoprolol [40], tiaprofenic acid [41], ibuprofen [42], salbutamol [43, 44] and verapamil [45] from its formulations.

Sodium alginate can interact with multivalent metal ions leading to the proposed egg-box model [14]. Thus, drug-loaded beads could be prepared by the ionotropic gelation method, this allows the study of drug release behavior.

Alginate's common role in pharmaceutical industries includes gel-forming, stabilizing, and thickening agents. Nowadays, it can play an important role in drugcontrolledrelease [8, 10]. The most frequent use of alginate and/or its derivatives is in oral dosage forms, but the use of alginate metal complex is still under investigation in many cases, especially in the case of studying the drug release behavior. Here, we briefly describe the use of the alginate metal complex in sustained and enantioselective release for some chiral drugs.

#### *4.3.1 Sustained release applications*

Alginates were classified among the most varied biopolymers, due to their flexibility for modification. Thus, it was widely used in food, drugs, and cosmetics. This kind of polymers could be useful as an excipient for sustained and controlled drug delivery. Therefore, many researchers introduced the use of alginate in the pharmaceutical field and biomedical applications. **Table 1** summarizes some examples of the alginate metal complex's application as sustained or prolonged drug release agents.



#### **Table 1.**

*cellulose.*

*Some examples of alginate metal complex application as sustained release agent.*

## *4.3.2 Enantioselective release applications*

Academic researchers recognized the importance of developing chiral drugs and their pharmaceutical industry. Investigation of enantioselective release (ESR) was discussed with two main strategies: 1- chiral interactions between a chiral drug and chiral matrices, 2- key-to-lock strategy with molecular-imprinting polymers [35, 61]. Several publications discussed the ESR, but few of them dealt with the alginate metal complex as a chiral excipient. This review focuses on the alginate complexes and their role in some profens ESR.

As mentioned above, alginate metal complexes have been extensively used in the pharmaceutical field. However, the enantioselective release of chiral drugs from alginate complexes is very rare.

Our previous studies were among the first publications in this field [62–64]. Alginate metal complexes in form of beads were prepared by the ionotropic gelation method. Ketoprofen (KTP) was loaded in the first group of beads [62], and tiaprofenic acid (Tia) was loaded in the second one [63]. In all cases, the resulted beads were characterized; bead size, metal content, shrinkage ratio, drug loading, and loading efficiency were calculated. The in-vitro release was carried out in an aqueous phosphate buffer that resembles gastric medium (6.8–7.4), and the enantioselective release (ESR) was observed in many complexes [62–64].

Beads in the two groups tend to have a metal content higher than the calculated ones. These results may due to the retention of free ions in the resulted network. On the other hand, in both cases, the divalent ion metal beads show a smaller size than the beads with trivalent ones. **Figure 3** shows the drug-loaded beads (KTP and Tia) metal contents compared to blank beads.

*Alginate Metal Complexes and Their Application DOI: http://dx.doi.org/10.5772/intechopen.98885*

#### **Figure 3.**

*Comparison of metal content (mol/100 g) for blank beads (blue column), KTP loaded beads (red column), and Tia loaded beads (green column).*

In order to explore the ESR result, the IR spectrum for all prepared beads types was determined at a range of 4000–400 cm−1 [62, 63]. There was an obvious hydrogen bonding between hydroxyl and carboxyl groups of alginates with the Tia and KTP ketone and carboxylic hydroxyl. The OH signals of KTP and Tia and the alginates' OH combines together in one signal due to hydrogen bonding interaction which could explain the ESR results. More discussion was described in detail in references [62, 63].

ESR comparison between KTP and Tia loaded beads shows a similar ESR behavior for AZnK and AZnT beads as shown in **Figure 4**. In both cases, the ESR > 1 indicating to a stronger interaction with S- enantiomer meaning more

#### **Figure 4.**

*ESR for KTP and Tia from divalent alginate-metal complexes beads as R/S ratio (blue column), racemic release R/S = 1 (red line).*

#### **Figure 5.**

*ESR for KTP and Tia from trivalent alginate-metal complexes beads as R/S ratio (blue column), racemic release R/S = 1 (red line).*

retention of S-enantiomer in contrast to R-enantiomer. **Figure 5** shows that there were not any significant differences between the trivalent loaded beads. In both cases, The ESR was almost =1 with the racemic release. However, ACa beads show an obvious ESR for both KTP and Tia but in a contrasting way. The ESR < 1 in ACaK indicating to strong chiral interaction with R- enantiomer. While ESR > 1 in ACaT indicating to strong chiral interaction with S- enantiomer. These different results in many cases due to the difference in KTP and Tia structures **Figure 6**.

On the other hand, the kinetic simulation of studied beads [63, 64] shows that the best fit models for each enantiomer and the racemic mixture were the same. However, the obtained models differ depending on the type of complexation due to the resulting "egg-box" structure.

*Alginate Metal Complexes and Their Application DOI: http://dx.doi.org/10.5772/intechopen.98885*
