Article

Improving Stability and Absorption of Minerals in Pharmaceutical

Formulations: A Review of Emerging Strategies

Pitriani^1*, Yoga Windhu Wardhana², Anis Yohana Chaerunisaa²

¹Master Program of Pharmacy, Department of Pharmaceutics and Pharmaceutical Technology, Faculty of

Pharmacy, Padjadjaran University, Bandung, West Java, Indonesia

²Department of Pharmaceutics and Pharmaceutical Technology, Faculty of Pharmacy, Padjadjaran University,

Bandung, West Java, Indonesia

Abstract

Minerals are essential for numerous physiological functions. However, their application in

pharmaceutical formulations is often limited by hygroscopicity and low bioavailability, which can

diminish their therapeutic effectiveness. This article reviewa not only highlights these challenges but also

provides an in-depth, up-to-date evaluation of various strategies designed to overcome these limitations,

supported by quantitative data from recent literature. This review article emphasizes the role of co-

processing with excipients and encapsulation technology, which improve mineral stability by creating an

effective moisture barrier, thereby extending product shelf life. Effervescent formulations, through an

acid-base reaction, generate gas that significantly enhances mineral solubility and contributes to

increased bioavailability. Microencapsulation, using a polymer or protein layer, protects minerals from

gastric degradation and allows for controlled release in the intestine, the primary site of absorption.

Chelating peptides form stable complexes with mineral ions, improving their transport and uptake in the

body. Meanwhile, advanced nanoparticle technologies like Solid Lipid Nanoparticles and liposomes

increase the contact surface area, accelerate dissolution, and protect minerals from oxidative

degradation. This review article offers a comprehensive overview of strategies that can significantly

advance the development of more effective and stable mineral-based pharmaceuticals.

Keywords: Bioavailability; hygroscopic; minerals; moisture barrier; stability.

Graphical Abstract

*

Corresponding author

Email addresses: pitriani22001@mail.unpad.ac.id (Pitriani)

DOI: https://doi.org/10.22437/chp.v9i2.46931

Received July 11^th2025; Accepted September15^th2025; Available online November 04^th2025

(https://creativecommons.org/licenses/by/4.0 )

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Introduction

bioavailability, which can negatively affect

the

effectiveness

and

stability

[16].

of

The

Minerals are essential for human health,

both as nutrients needed for the body to

function properly and as key ingredients in

the production of pharmaceutical and

biomedical products [1,2]. For example, they

are used to produce calcium supplements in

the pharmaceutical [3] and serve as imaging

pharmaceutical

preparations

hygroscopic of minerals, which is their ability

to absorb moisture from the environment,

can affect the physical and chemical stability

of

pharmaceutical

preparations.

Additionally, low bioavailability can limit the

body's ability to efficiently absorb minerals,

thereby reducing their therapeutic potential

[17,18]. This approach must take into

account various factors, including particle

size, crystal form, and the use of excipients

that can modify the physical and chemical

properties of minerals for improved stability

and absorption[19]. Various techniques such

as encapsulation in nanoparticles, the use of

binding compounds, and drug delivery

technology based on liposomes can be used

to enhance solubility and improve the

bioavailability of minerals in pharmaceutical

formulations [20,21]. This review article

provides a comprehensive insight into

various formulation methods applied to

enhance

pharmaceutical

microencapsulation, the use of complex

minerals with carriers, and the utilization of

advanced

Furthermore, this review highlights the key

formulation challenges, particularly

agents

Minerals are commonly classified into two

categories: macrominerals and

in

biomedical

diagnostics

[4].

microminerals [5]. Macrominerals include

calcium (Ca), magnesium (Mg), potassium

(K), sodium (Na), chloride (Cl), phosphorus

(P),

and sulfur (S)

whilemicrominerals

include iodine (I), zinc (Zn), selenium (Se),

iron (Fe), manganese (Mn), copper (Cu),

cobalt (Co), molybdenum (Mo), fluoride (F),

and chromium (Cr) [6,7]. These minerals are

required for various physiological functions,

including the formation of strong bones and

teeth, nerve signal transmission, muscle

contraction, and maintaining cardiovascular

health [8–10]. For instance, macrominerals

such as calcium, phosphorus, and fluoride

are vital for bone and dental health, while

magnesium, zinc, and copper serv e as

cofactors in various enzymatic processes

that regulate metabolism and cellular

function [11,12]. Additionally, these minerals

support normal heart rhythms, assist in

hormone production, and play a crucial role

in immune function [12]. Minerals have been

used in the pharmaceutical industry as

active ingredients in various applications,

including nutritional supplements, imaging

agents, advanced drug delivery systems, and

as bioactives in regenerative therapy [13].

However, the integration of minerals in

the

stability

of

minerals

in

formulations,

including

drug

delivery

technologies.

moisture sensitivity and low bioavailability,

which can compromise the physical stability

and therapeutic effectiveness of mineral-

based

products.

Addressing

these

limitations is essential to ensure optimal

delivery, sustained bioactivity, and overall

therapeutic efficacy in clinical use.

Materials and Methods

pharmaceutical

significant challenges, primarily due to

issues with hygroscopicity and low

bioavailability [4,14,15].

formulations

presents

The research methodology in this study is

structured systematically to provide an in-

depth literature review on formulation

strategies aimed at enhancing the stability of

minerals in pharmaceutical formulations.

The methodology framework is designed to

The challenge in formulating minerals lies in

their hygroscopic nature and low

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explore

key

focus

areas

of

mineral

pharmaceutical formulations, and duplicate

articles. In addition, we excluded review

articles, conference abstracts, non–peer-

reviewed papers, and other forms of

secondary publications. These restrictions

ensured that all articles included in the

formulation, specifically how to maintain the

stability

detrimental

bioavailability. The methodology for this

review involved a systematic approach to

identify, analyze, and synthesize existing

literature on mineral formulation strategies,

providing a clear and detailed insight into

this topic.

of

active

interactions,

ingredients,

and

reduce

improve

analysis

represented

original

primary

research. The article selection process

follows the PRISMA (Preferred Reporting

Items for Systematic Reviews and Meta-

Analyses) guidelines, designed to ensure

transparency and quality in the collection

Tools and Materials

and

analysis

of

literature.

Figure

1,

Literature search was conducted using two

primary databases, namely PubMed and

Google Scholar, which allow access to

relevant and literature widely recognized in

biomedical and pharmaceutical research.

Keywords used in the article search included

"Mineral Formulation AND Mineral Stability

illustrating the steps in article selection, from

the initial literature search to the selection of

articles that meet the research criteria (A

PRISMA flowchart). As a result, 31 articles

meeting the inclusion criteria were selected

for further analysis.

AND

Hygroscopic

Mineral

and

AND

"Mineral

Data Presentation and Conclusion Drawing

Bioavailability

Formulation

Hygroscopic

Mineral either individually or in combination.

All articles found were managed using

Mendeley reference management software

Mineral"

OR

Mineral

OR

Stability

Bioavailability

OR

The analyzed data is presented in the form

of tables, graphs, and descriptive narratives,

as commonly done in systematic review

research [22]. All stages of analysis are

carried

out

independently

by

three

to

facilitate

the

organization

and

researchers to ensure objectivity. The results

of each analysis are then compared and

discussed to ensure reliability and reduce

potential bias in data interpretation.

documentation of the literature.

Article Selection Criteria

The articles identified through the initial

search were filtered based on predefined

inclusion and exclusion criteria. Inclusion

Criteria: The inclusion criteria cover articles

published between 2018 and 2025, freely

accessible, and original research discussing

the application of formulation technology to

improve mineral stability in pharmaceutical

preparations. Articles focusing on strategies

to address hygroscopicity and low mineral

bioavailability in pharmaceutical products

are of primary interest. Exclusion Criteria:

The exclusion criteria include articles that

are irrelevant to the topic of mineral stability,

research conducted outside the context of

Research Procedure.

This research procedure prioritizes validity

through the selection of credible, high-

quality

articles.

The

establishment

of

inclusion and exclusion criteria aims to

minimize potential bias and ensure the

accuracy of the data to be analyzed. The data

analysis process is carried out in four main

stages.

Data Reduction: Each selected article is

thoroughly read to understand its context

and identify the key findings within [22]

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Findings Recording: The key points from each

article are recorded based on the conceptual

framework established in this research. The

conceptual framework for this research is

based on two primary challenges in mineral

formulation: hygroscopic nature and low

bioavailability. Accordingly, the findings from

each analyzed article were categorized and

documented based on the formulation

strategies that address these challenges.

Additional findings that contribute to the

formation

of

new

insights

are

also

documented [22].

Thematic Grouping: The notes collected from

various articles are grouped into specific

themes. These themes are then developed

into thematic concepts that describe the

mineral formulation [22].

Figure 1. PRISMA Flowchart

magnesium (Mg), potassium (K), sodium

(Na), chloride (Cl), phosphorus (P), and sulfur

Result and Discussion

(S)

is

required

in

larger

amounts.

Minerals play a vital role in the body,

performing necessary functions ranging

from building strong bones to transmitting

nerve impulses - essential for sustaining

physiological homeostasis and longevity

[23]. The presence of a range of minerals is

essential for various physiological processes,

including acting as cofactors for enzymes

Macrominerals are integral to bone health,

muscle function, and metabolic processes

[3]. For example, calcium intake has been

investigated in relation to a reduced risk of

obesity and certain cancers, though the

evidence remains mixed[24]. Iodine (I), zinc

(Zn), selenium (Se), iron (Fe), manganese

(Mn), copper (Cu), cobalt (Co), molybdenum

(Mo), fluoride (F), chromium (Cr), and boron

(B) are essential for enzymatic functions and

immune responses. For instance, iron is

involved

regulating normal heart rhythms. The role of

macrominerals such as calcium (Ca),

in

hormone

synthesis

and

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crucial for oxygen transport and energy

metabolism [25]. Mineral deficiencies can

lead to health problems such as anemia,

osteoporosis, and muscle weakness [26].

calcium, magnesium, and potassium, often

have low bioavailability when consumed in

conventional pharmaceutical formulations

[34]. This can be due to various factors,

including low solubility, binding with other

components in the digestive system that

hinder absorption, or the body's inability to

efficiently metabolize the minerals [35].

Minerals that are poorly absorbed do not

provide optimal therapeutic benefits [36],

even when administered in sufficient doses.

Therefore, efforts to enhance mineral

bioavailability are crucial to ensure that

mineral-based supplements or medications

can provide significant therapeutic effects

[37].

The

pharmaceutical

significant challenges,

formulation

of

minerals

in

several

high

the

industry

faces

namely

hygroscopicity and low bioavailability. These

two factors not only affect product stability

but also its effectiveness in therapeutic

applications. High hygroscopicity can lead to

various

formulations, including changes in the

physicochemical properties of the

substances, which result in difficulties in

subsequent formulation processes,

instability during storage, and negative

effects on bioavailability [27,28].

issues

in

pharmaceutical

Strategies to Reduce or Control the

Hygroscopicity of Minerals.

Hygroscopicity is the ability of a substance to

absorb moisture from the surrounding

environment [29,30]. Minerals with high

hygroscopic properties tend to undergo

significant physical changes when exposed

to moisture, such as changes in texture,

particle size, or even undesirable chemical

reactions. This is a major problem in

Common formulation strategies applied to

reduce

the

hygroscopic

properties

of

minerals

include

co-processing

with

excipients and encapsulation. Co-processing

with excipients involves combining the active

ingredient with hydrophobic excipients to

reduce the mineral's ability to absorb

moisture. Meanwhile, encapsulation refers

to the process of coating a product with a

wall material to shield it from environmental

pharmaceutical

product stability

formulations,

during storage

where

and

transport is crucial. When minerals absorb

moisture, chemical degradation or changes

in solubility can occur, ultimately reducing

the effectiveness of the active ingredients.

Moreover, improper storage conditions can

accelerate this process, reduce shelf life, and

make the product more prone to damage

[31]. For example, mineral salts such as

calcium and magnesium are highly affected

by high humidity, which can influence

chemical stability and reduce therapeutic

factors [38]. This method presents

a

promising

minerals,

approach

aiming to

for

preserve

enveloping

their

therapeutic function, control their release,

and enhance their solubility. Furthermore,

encapsulation

can

effectively

reduce

hygroscopicity, which facilitates preparation

and extends shelf life. During this process,

minerals are dispersed within a matrix of

wall

materials

and

subsequently

potential

hygroscopicity, low mineral bioavailability is

also significant challenge in

[31,32].

In

addition

to

encapsulated within a particulate structure.

Common encapsulation techniques include

spray drying, freeze drying, and coacervation

[39]. Figure 2 illustrates strategies to reduce

or control mineral hygroscopicity, while

Table 1 summarizes specific formulation

approaches.

a

pharmaceutical formulations. Bioavailability

refers to the extent to which the body can

absorb and utilize active ingredients once

administered. Certain minerals, such as

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Figure 2. Strategies to Reduce or Control the Hygroscopicity of Minerals

Table 1. Application of Strategies to Reduce Hygroscopicity of Minerals

No

Active

Strategy

Polymer

Findings

Ref.

Ingredient

1

Sodium

chloride

Co-processing

with

Pluronic

Significant

hygroscopic growth (>50%)

reduction

in

[32]

excipients

2

Sodium

chloride

Encapsulation

Si0₂

Protects

moisture

particles

and slows

from

air

[40]

down

deliquescence.

Pharmaceutical dosage forms generally

consist of active ingredients combined with

various excipients, which support the

manufacturing process and ensure stability

techniques in pharmaceutical dosage form

manufacturing include wet granulation,

solution-based

methods,

and

physical

blending, followed by drying processes such

as freeze-drying, oven drying, fluidized bed

drying, or air drying [39]. Table 1 provides an

example of co-processing strategies using

excipients to reduce mineral hygroscopicity.

For example, Haddrell et al [32] revealed that

the addition of Pluronic F127, even at low

and

effective

delivery

of

the

active

ingredient. Most excipients used must be

inert, meaning they do not affect the

therapeutic effects of the active ingredient or

cause unwanted changes such as phase

changes

or

reduced

stability

during

production and storage [41]. Excipients can

be added to improve stability and reduce the

hygroscopicity of pharmaceutical dosage

forms by forming protective barriers or

absorbing ambient moisture preferentially.

co-processing with excipients to formulate

the active ingredients with hydrophobic

excipients to divert water away from the

actives and encapsulation to envelop the

active ingredients with polymers via spray-

drying. Some commonly used co-processing

concentrations

(about

1%

by

weight),

effectively reduced the hygroscopic growth

of aerosols, which typically occurs when

aerosols are exposed to environmental

moisture. This finding indicates that F127

can be used to control or reduce the ability

of aerosol particles to absorb moisture,

which in turn can improve the stability of

aerosol products and enhance drug delivery

in nebulizer applications. Bermeo et al [40]

showed that sodium chloride coated with

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SiO₂ acts as an effective physical barrier

hinder the optimal absorption and utilization

against water vapor, protecting particles

of

minerals

in

pharmaceutical

and

from

environmental

moisture

and

nutritional formulations. Therefore, various

approaches have been developed and

significantly slowing down the deliquescence

process. This coating forms a relatively inert

and stable structure, which not only

prevents direct contact between particles

and water vapor but also maintains the

morphological integrity of the particles in

high humidity conditions.

applied

to

significantly

improve

the

bioavailability of active mineral ingredients.

These methods carefully address common

issues such as poor solubility, susceptibility

to degradation, and adverse interactions

within the gastrointestinal tract. Ultimately,

this ensures improved absorption and

Strategies to Enhance the Bioavailability of

Minerals

clinical efficacy.

formulation strategies used to enhance

mineral bioavailability, while Table

Figure 3 illustrates the

2

The

chemical

and

physiological

provides specific applications of these

approaches.

characteristics of the environment often

Figure 3. Strategies to Enhance the Bioavailability of Minerals

Enhancing the bioavailability of minerals is conventional

formulation

approaches

crucial

for

improving

nutritional

and

(effervescent systems, microencapsulation,

pharmaceutical

preparations,

as

and chelating peptides) as well as advanced

physiological barriers often hinder optimal

absorption [71], [72]. Innovative strategies to

nanotechnology-based

(nanoparticles, solid lipid nanoparticles,

mesoporous particles, and liposomes).

carriers

enhance

mineral bioavailability include

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Table 2. Application of Strategies to Enhance the Bioavailability of Minerals

No

1

Active

Ingredient

Ferro

ascorbate

Strategy

Findings

Ref.

[42]

[43]

Formulated

effervescent

Effervescent

into

Bioavailability increased significantly

(>70%) compared to IR tablets (15-30%).

Increased serum magnesium by 0.24

2

Magnesium

mM

(p

<

0.0001)

and

serum

bicarbonate by 3 mM (p = 0.015).

3

4

5

Iron

Microencapsulation

Microencapsulation was most effective,

achieving 29% bioaccessibility of iron.

[44]

[45]

[46]

Magnesium

10.3%

increase

in

magnesium

bioavailability.

Zinc

calcium

and

Microspheres released high amounts

of calcium, phosphorus, and zinc,

distributed throughout the defective

region

6

Calcium

Microencapsulation

Enhances calcium bioavailability by

[47]

improving

performance

Enhances

the

therapeutic

7

8

9

Calcium

Zinc

calcium

bioavailability,

[48]

[49]

[50]

reaching up to 32%.

40% increase in absorption rate.

Zinc-chelating

peptide

Zinc chelation

Zinc

An oyster protein hydrolysates-zinc

complex (OPH-Zn) showed antioxidant

bioactivity

and

enhanced

zinc

bioaccessibility.

10

Iron

Zinc chelation

High iron content (31.3 ± 1.4 to 61.1 ±

4.4 mg Fe/g dried beads) and high EE%

(57.6 ± 7.7% to 78.5 ± 2.9%). Ferrous bis-

[51]

glycinate

chelate

increases

iron

bioavailability by 23%.

11

12

Calcium

Chelating peptides

Calcium solubility of the 65.27% ±

2.75% was significantly higher than that

of calcium chloride (38.99% ± 5.77%).

[52]

[53]

Calcium

reaching 42.47% for the Chelating

peptides -Ca group, which was

absorption

rate

in

rats,

substantially higher than the 31.23%

observed in the control group.

13

Calcium

Chelating peptides

Chelation rate of 78.38%, calcium

[54]

transport

increased

significantly

compared to CaCl₂ in the Caco-2 cell

model and calcium retention: ~88.39%

after 2 hours of simulated gastric

digestion.

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No

Active

Ingredient

Ferrous iron

Strategy

Findings

Ref.

[55]

[56]

14

15

Chelating peptides

Enhancing

retention, and utilization of iron.

Enhancing iron absorption,

the

transport,

cellular

Iron

bioavailability increased from 72.85%

to 81.33%.

16

Calcium

Chelating peptides

The absorption rate for the control

group was only 60.52% and chelating

peptides group was 68-73%.

[57]

17

18

Zinc

Nanoparticles

64.5% increase in zinc bioavailability.

The bioavailability of ZnSO₄ dropped

[58]

[59]

sharply

to

only

28.71%

whereas

ZnPNPs remained comparatively stable

at 44.72%.

19

20

Zinc

Nanoparticles

zinc solubility declined markedly to

approximately 32% within 3 hours. By

contrast, the nanoparticle-mediated

system maintained zinc solubility at

nearly 100% over the same period.

The serum zinc concentration in rats

[60]

[61]

receiving

markedly to 3.67 ± 0.25 μg/mL, in the

control group receiving no zinc

nanoparticle

increased

supplementation (2.32 ± 0.22 μg/mL)

and in the group administered S-ZnO at

the same dosage (2.43 ± 0.14 μg/mL).

The expression of the osteocalcin (OC)

gene was significantly upregulated and

21

22

Zinc

Iron

Nanoparticles

[62]

[63]

strongly

correlated

with

bone

mineralization levels (r = 0.84),

Significantly

bioavailability,

enhance

plasma

zinc

concentrations markedly increased to

1.78 μg/mL.

23

24

Solid

Lipid

SLN protects encapsulated iron in

gastric fluid and releases almost 80% of

iron in intestinal fluid.

Drug release from SLN structure and

ferrous sulfate tablets in phosphate-

buffered saline at pH = 7.4 show higher

and sustained release, almost double

the free drug.

[64]

[65]

Nanoparticles (SLN)

ferrous

sulphate

Solid

Lipid

Nanoparticles (SLN)

25

Iron

Mesoporous

particles

iron

Superior

bioavailability

of

MIP

[66]

compared to commercial iron particles.

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No

Active

Ingredient

Ferrous

Strategy

Liposomes

Findings

Ref.

26

Encapsulation efficiency higher than

97%, optimal short-term and long-term

stability, and excellent bioavailability in

Caco-2 cell lines.

[67]

sulphate

27

28

Cupric

Iron

Liposomes

pH-sensitive copper release, releasing

36/78% and 47/94% of copper at pH

6/4.5

About 9 mg of iron in liposomal form

promotes longer and more consistent

[68]

[69]

iron

release

compared

to

non-

liposomal containing the same iron

amount.

29

Zinc

Liposomes

The liposomal

increase of +14.3 ± 18.5% after 4 hours,

whereas the standard group

group showed an

[70]

experienced a decrease of −6.0 ± 13.1%

(p = 0.0001). After 6 hours, the

liposomal group maintained a slight

increase of +1.0 ± 20.9%, while the

standard

group

saw

a

more

pronounced decrease of −21.0 ± 15.3%.

Effervescent

mechanism ensures that the drug remains in

the optimal absorption site for a longer

Effervescent

formulations

significantly

duration,

bioavailability.

bioavailability

ultimately

Additionally,

the

improving

its

the

increase the bioavailability of various drugs,

especially those that are poorly soluble or

unstable in acidic environments. This system

uses effervescence generated from the

reaction between an acid and a base to

facilitate rapid dissolution and absorption of

the drug [73]. For example, Singh et al [42]

formulated an effervescent preparation with

the active ingredient Ferrous Ascorbate (FA),

which has low bioavailability, solubility, and

stability at higher pH. Their study showed

that the retention time in the stomach for

the effervescent preparation

significantly

conventional

prolonged retention is attributed to the

effervescence, which generates carbon

dioxide (CO₂) and causes the tablet to float,

of

effervescent

formulation also increased significantly

(>70%) compared to conventional tablets

(15-30%). The bioavailability study was

conducted in an animal model. The in vivo

studies, including the gastroretentive study

using

X-ray

radiography

and

the

pharmacokinetic study, were carried out on

healthy rabbits. This approach allowed us to

demonstrate the prolonged gastric retention

and enhanced bioavailability of the floating

tablet formulation. These findings suggest

that formulating the preparation into an

increased

(6

hours)

(<1

compared

hour).

to

This

tablets

effervescent

bioavailability.

demonstrated

form

Quinones

that the

can

enhance

et al

effervescent

its

[43]

formulation significantly increased serum

thereby delaying gastric emptying. This

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magnesium by 0.24 mM (p < 0.0001) and

serum bicarbonate by 3 mM (p = 0.015) in

patients with stage 5D chronic kidney

disease compared with controls receiving

calcium acetate, thereby confirming the

effectiveness of the effervescent dosage

form in enhancing mineral bioavailability.

sulfate solution). The nanocrystalline form

possesses a very high surface area-to-

volume ratio, thereby accelerating the

dissolution of mineral ions (Zn²⁺ and Ca²⁺)

and enabling efficient release. Mi et al [47]

demonstrated

that

microencapsulation

bioavailability by

enhances calcium

improving the therapeutic performance of

formulations for osteoporosis in animal

models, as it protects calcium from gastric

degradation and ensures improved mineral

release and absorption in the intestine.

Aquino et al [48] demonstrated that

Microencapsulation.

Microencapsulation significantly improves

the bioavailability of minerals compounds by

providing a protective layer that enhances

stability and controlled release [74,75,76].

Cian et al [44] used a microencapsulation

method to improve the bioavailability of

iron. This research successfully developed a

microencapsulation method for iron and

ascorbic acid by utilizing protein concentrate

from brewer’s spent grain (BSG) and locust

bean gum as the encapsulating material.

This process used spray drying technology to

enhance the bioaccessibility of iron, which is

essential for ensuring the body can absorb it

effectively. The study showed that the BSG

protein concentrate had a high ability to

chelate iron, helping to keep the iron

dissolved and stable as it passed through the

digestive tract. Microencapsulation was

microencapsulated

calcium

exhibited

significantly higher bioavailability, reaching

up to 32%, compared to calcium chloride

control in an in vitro study.

Chelating Peptides

Peptide chelation is a very effective and

useful strategy for significantly increasing

the bioavailability of essential minerals,

especially iron and zinc [77,78]. This

innovative

process

is

based

on

the

stabilization of the complex between certain

peptides and metal ions, which increases

mineral stability and solubility in the

gastrointestinal tract [78,79]. The basic

principle of chelation is the binding of a

mineral ion with an organic molecule that

acts as a chelating agent. This process forms

a complex, ring-like structure where the

chelating agent's functional groups (such as

carboxyl or amino groups) donate a pair of

free electrons to bond with the mineral ion

[55–57]. By strengthening this soluble and

often more permeable complex, chelating

peptides can identify common inhibitors of

absorption and facilitate more effective

absorption across the intestinal barrier,

which eventually affects more beneficial

mineral utilization in the body. This study

makes use of the inherent peptide biology

compatibility and offers a suitable, safe, and

effective method for maximizing mineral

delivery and addressing deficiency [80]. For

most

effective,

achieving

29%

bioaccessibility of iron under simulated

digestion, which represents more than a

twofold

increase

compared

to

the

unencapsulated control.

Pajuelo

et

al

[45]

showed

that

microencapsulation results in a more stable

and prolonged increase in plasma

concentrations compared to the non-

encapsulated form, with bioavailability up to

10.3% higher. Zelaya et al [46] demonstrated

that zinc-doped carbonated nanocrystalline

hydroxyapatite (Zn-cHA), encapsulated in

alginate

microspheres,

significantly

enhanced the bioavailability of zinc and

calcium in Wistar rats compared with

controls (non-zinc hydroxyapatite and zinc

206

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Chempublish Journal, 9(2) 2025,196-220

example, Syahputra et al [49] used chelating

peptides to enhance zinc bioavailability.

These chelating peptides were synthesized

by hydrolyzing collagen with the bromelain

enzyme, which yielded peptides with high

zinc-chelating ability. The peptides were

then further purified using reverse-phase

high-performance liquid chromatography

(RP-HPLC), and their efficacy in enhancing

zinc absorption was evaluated ex vivo. The

with the peptide NDEELNK and protein

hydrolysates from sea cucumber egg yolk.

Zhang

et

al

[53]

revealed

that

the

complexation of peptides with calcium led to

a significant increase in the apparent calcium

absorption rate in rats, reaching 42.47% for

the CBP-Ca group, which was substantially

higher than the 31.23% observed in the

control group. Wu et al [54] demonstrated

that a pig bone collagen peptide-calcium

study

demonstrated

that

these

zinc-

chelate

significantly

enhances

calcium

chelating peptides have the potential to be a

more effective alternative to current zinc

supplements, increasing zinc bioavailability

by 40%.

bioavailability. The complex showed an

optimal chelation rate of 78.38%, which is

notably higher than that achieved with single

enzymes (42–56%). The chelate was also

proven to increase calcium transport in a

Caco-2 cell model compared to a CaCl₂

control at all time points from 30 to 240

The

research

conducted

by

[50]

demonstrated that zinc chelation with OPH

(oyster protein hydrolysates) results in the

formation of an OPH-Zn complex, which

enhances zinc solubility under specific pH

minutes.

Furthermore,

this

chelate

effectively resisted absorption inhibitors like

phosphate and phytate and exhibited high

stability during digestion, with calcium

conditions

digestion simulations. Furthermore, the

antioxidant activity of OPH remains

and

during

gastrointestinal

retention

remaining

at

approximately

88.39% after 2 hr of simulated gastric

preserved or even increases after chelation

with zinc. The OPH-Zn complex has a

digestion.

potential

These

as

findings

an effective

highlight

its

mineral

nanoparticle

structure,

allowing

for

supplement. Li et al [55] have successfully

demonstrated that the complexation of

peptides with ferrous iron (Fe²⁺) significantly

enhances its transport, cellular retention,

and utilization in an in vitro study using the

improved zinc bioaccessibility by reducing

the potential for zinc precipitation and its

interaction with other components in the

digestive tract. The use of OPH-Zn shows

great potential as a functional ingredient

that can enhance zinc absorption, with the

added benefit of improved antioxidant

activity, which is important for human

health, especially in the prevention of

diseases related to oxidative stress.

Caco-2

cell

model.

Patil

et

al

[56]

demonstrated that chelating with chickpea

can significantly enhance iron binding

efficiency and iron uptake in an in vitro study

using Caco-2 cells. The results show that the

non-fermented

complex

chickpea

had

protein–iron

a mineral

(NCP-Fe)

Cui et al [52], after simulated gastrointestinal

digestion, the calcium solubility of the

NDEELNK–calcium complex (65.27%) was

significantly higher than that of calcium

chloride (38.99%). A substantial increase in

bioavailability of 72.85 ± 1.45%. However,

after 90 hours of solid-state fermentation

with Aspergillus awamori (FCP90-Fe), this

value increased significantly to 81.33 ±

1.23%. Yuan et al [57] demonstrated that

calcium

bioavailability

has

been

supplementation

with

peptide–Ca

demonstrated in vitro using the Caco-2 cell

model, where the uptake of calcium ions was

effectively improved by complexing them

complexes from sunflower seeds (SSP-Ca)

and peanuts (PP-Ca) significantly improved

207

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Chempublish Journal, 9(2) 2025,196-220

calcium bioavailability in female mice on a

low-calcium diet. The absorption rate for the

control group was only 60.52 ± 8.95%, while

supplementation with CaCO₃ was slightly

higher at 65.78 ± 10.30%. The most

significant increase was observed in the L-

SSP-Ca group, with an absorption rate of

75.96 ± 4.26%, followed by the H-SSP-Ca

(73.10 ± 8.96%), and H-PP-Ca (68.31 ±

11.02%) groups.

addresses the limitations of both forms the

poor stability of heme and the poor

absorption of non-heme iron.

Nanoparticles

Nanoparticles represent a transformative

advancement

in

drug

delivery

by

simultaneously

enhancing

aqueous

solubility,

conferring

physicochemical

stability, and ultimately improving the

bioavailability of diverse minerals [85]–[88].

These benefits are primarily achieved

through the reduction of particle size to the

Heme and Non-Heme Iron Sources.

The bioavailability of iron is crucial, and its

absorption and utilization in the human

body are significantly influenced by the

differences between heme and non-heme

iron sources. Heme iron, primarily derived

from animal products such as meat, poultry,

and fish, possesses a unique porphyrin ring

structure. This structure allows for the

absorption intact by the intestine through

nanometer

scale

(1–1000

nm),

which

markedly increases the surface area-to-

volume ratio [89]. The resulting higher

dissolution rate and saturated solubility are

critical determinants for more efficient

absorption. In addition, the nanoscale

dimensions of these particles facilitate

improved penetration across biological

barriers and enable targeted delivery to

specific sites [90,91]. Beyond solubility

highly

inhibitory

effective

routes,

of

bypassing

several

the

food

effects

components that typically interfere with the

absorption of non-heme iron [81]–[84]. In

contrast, non-heme iron, which is prevalent

in plant-based foods (such as legumes, leafy

vegetables, fortified cereals) and animal

products, must be released from food

components before it can be absorbed.

Churio et al [51], demonstrated that alginate

beads containing a mixture of heme and

non-heme iron had a high iron content and

good encapsulation efficiency. These beads

showed higher stability under simulated

gastric conditions, with slower iron release

compared to alginate beads containing only

ferrous fumarate (FF) or ferrous bis-glycinate

chelate (Ferrochel®) (FCH). Most of the iron

release occurred under intestinal conditions,

the site of iron absorption, with higher

release efficiency in the mixed beads. This

study suggests that a combination of heme

and non-heme iron could be an effective

alternative in iron supplementation or

fortification strategies, as this approach

enhancement,

nanoparticles

provide

a

protective microenvironment that shields

encapsulated or adsorbed compounds from

enzymatic degradation, pH fluctuations, and

oxidative stress [92], thereby preserving

their structural integrity and prolonging their

functional lifespan within complex biological

systems [93,94]. Nanoparticle technology

has become a fundamental basis for the

development

of

contemporary

pharmaceutical formulations, as it effectively

addresses solubility and stability challenges,

consequently enhancing bioavailability to

maximize therapeutic potential [85,95].

Cheng et al [58] developed Zn-WPH-COS

(zinc-whey

protein

hydrolysate-chitosan

oligosaccharide) nanoparticles to enhance

the bioavailability of zinc. Zn-WPH-COS was

prepared by combining zinc with whey

protein hydrolyzate (WPH) and chitosan

oligosaccharide

transglutaminase

(COS)

(TGase)

using

generate

to

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Chempublish Journal, 9(2) 2025,196-220

nanoparticles. The study found that Zn-

According to the findings of Olbert et al [61]

WPH-COS

significantly

increased

the

zinc

demonstrated

bioavailability compared to the standard

form (S-ZnO) in an in vivo study conducted

on

oxide

nanoparticles

a significantly

(ZnO-NPs)

enhanced

solubility and dialyzability of zinc compared

to Zn-WPH or ZnSO₄⋅7H₂O, leading to

improved zinc bioaccessibility. This was

achieved thanks to the protection provided

by COS on Zn-WPH, reducing the formation

of zinc precipitates with phytic acid and

enhancing zinc bioavailability. The materials

used in our formulation, whey protein

hydrolysate

oligosaccharide

recognized as safe and have a history of use

in food and biomedical applications. Feng et

al [59] reported that the zinc bioavailability

rats.

After

two

the

weeks

serum

of

oral

zinc

administration,

concentration in rats receiving ZnO-NPs at a

dose of 7 mg/kg increased markedly to 3.67

± 0.25 μg/mL. This value was substantially

higher than that observed in the control

group receiving no zinc supplementation

(2.32 ± 0.22 μg/mL) and in the group

administered S-ZnO at the same dosage

(2.43 ± 0.14 μg/mL). This pronounced

difference confirms that nanoparticles, due

to their extremely small size, are more

efficiently absorbed by the body, thereby

(WPH)

(COS),

and

are

chitosan

generally

of

zinc-enriched

polyphosphate

nanoparticles (ZnPNPs) reached 60.17 ±

3.95% relative to ZnSO₄ (100%) in rats.

However, when calcium and phytate known

strong inhibitors of zinc absorption—were

present, the bioavailability of ZnSO₄ dropped

sharply to only 28.71 ± 2.80%, whereas

ZnPNPs remained comparatively stable at

44.72 ± 3.66%. These findings indicate that

although ZnPNPs are slightly lower than

ZnSO₄ under normal conditions, they are far

more resilient against phytate inhibition,

making them a more effective strategy for

enhancing zinc bioavailability in phytate-rich

cereal-based diets. Feng et al [60] reported

enhancing

mineral

levels

in

the

bloodstream. Terova et al [62] demonstrated

that administering a diet supplemented with

nanoparticle forms of zinc, manganese and

selenium to gilthead seabream (Sparus

aurata)

larvae

over

a

24-day

period

significantly increased total body length

(9.00 ± 0.32 mm) and stress resistance (65.79

± 3.72%) compared to the control group.

Furthermore,

osteocalcin (OC) gene was significantly

the

expression

of

the

upregulated and strongly correlated with

that

casein hydrolysate

mediated

the

bone mineralization levels (r

=

0.84),

and

formation of Zn/CaP nanoparticles, which

effectively prevented zinc precipitation in the

intestinal environment. In the absence of

these nanoparticles, zinc solubility declined

markedly to approximately 32% within 3

indicating

utilization

enhanced

of minerals

absorption

delivered

in

nanoparticle form.

Swain et al [63] demonstrated that zinc

supplementation

nanoparticles

in

the

form

of

hours.

By

contrast,

the

nanoparticle-

(NP-ZnO)

significantly

mediated system maintaining zinc solubility

at nearly 100% over the same period. This

stabilization

availability but also resulted in a significant

enhancement of zinc transport across the

mouse intestinal model, underscoring the

potential of casein-derived nanoparticles to

improve mineral bioavailability.

enhanced bioavailability compared to the

conventional form (ZnO) in weaned piglets.

After 14 days of treatment, plasma zinc

concentrations markedly increased to 1.78

μg/mL in the NP-ZnO group (800 mg/kg),

compared to 1.23 μg/mL in the control group

and 1.33 μg/mL in the conventional ZnO

group. These findings indicate that zinc

not

only

preserved

zinc

209

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Chempublish Journal, 9(2) 2025,196-220

nanoparticles are more efficiently absorbed

by the body.

reducing the crystallinity, and decreasing the

particle size of the minerals [106–108]. This

way, mesoporous materials make the

minerals more soluble and, ultimately, more

easily absorbed by the body [109, 110]. Lin et

al [66] demonstrated that mesoporous iron

particles (MIPs) had excellent potential to

improve iron bioavailability. The study used

Solid Lipid Nanoparticles (SLN)

Minerals essential to the human body often

suffer from low bioavailability due to poor

solubility [97]. Solid lipid nanoparticles

(SLNs), owing to their nanometric size and

Caco-2

absorption, and the results showed that

MIPs had much higher bioavailability

cell

models

to

measure

iron

lipid-based

composition,

enhance

the

surface area of encapsulated minerals,

protect them from degradation processes

such as oxidation, and facilitate improved

absorption [98,99]. This delivery system

offers promising applications in mineral

supplementation, food fortification, and

clinical nutrition [100,101]. Hong et al [64]

developed solid lipid nanoparticles (Fe-SLNs)

based on a W/O/W double emulsion coated

compared to commercial iron particles due

to their high porosity and smaller particle

size. In vivo tests on iron-deficient rats

showed that supplementation with MIPs

significantly increased hemoglobin levels

and red blood cell regeneration.

Liposomes

with

water-soluble

chitosan

(WSC)

to

enhance iron bioaccessibility and stability.

The study showed that Fe-SLNs and WSC-Fe-

SLNs protected encapsulated iron from lipid

Liposomes

formed through surfactant interactions with

an aqueous medium [111,112]. This

are

encapsulation

systems

peroxidation

under

different

pH

and

structure encloses hydrophilic compounds

in the core and hydrophobic compounds in

temperature conditions and could release

nearly 80% of iron in a simulated intestinal

fluid. Coating with WSC also reduced lipid

peroxidation that occurred in pure iron.

the

two

layers.

Surfactants

used

in

liposomes are made from phospholipids,

which carry an electrical charge [113,114].

Bochicchio et al [67] demonstrated that

nanoliposomes enhance the bioavailability

of ferrous sulfate compared to control

formulations in Caco-2 cell models, while

also exhibiting a high iron encapsulation

Hatefi and Farhadian [65] demonstrated that

the encapsulation efficiency reached 92.3%

with a particle size of approximately 358 nm.

The resulting solid lipid nanoparticles (SLNs)

exhibited higher and more sustained drug

release compared to conventional ferrous

sulfate tablets. This study suggests that

ferrous sulfate SLNs can be an attractive

delivery system for oral iron therapy due to

their ability to reduce oxidation and increase

contact time with the mucosal membrane,

ultimately enhancing iron absorption.

efficiency

(>97%),

thereby

maintaining

stability and protecting the compound from

degradation. Pinho et al [68] demonstrated

that the use of pH-sensitive liposomes

containing Cu(II) phenanthroline (Cuphen)

complex can significantly enhance copper

(Cu) bioavailability in colorectal cancer

therapy.

Mesoporous

Ko

et

al

[69]

demonstrated

that

nanoliposomes effectively enhance the

bioavailability of ferrous sulfate and vitamin

E. This is evidenced by a more prolonged

increase in the blood levels of these

Mesoporous materials offer a solution by

encapsulating minerals within their nano-

sized pores [102]–[105]. This mechanism

works by increasing the surface area,

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Chempublish Journal, 9(2) 2025,196-220

nutrients in the group consuming the

liposomal formulation compared to the non-

liposomal control. In the study by Tinsley et

al [70], liposomes in a multivitamin/mineral

(MVM) supplement significantly increased

the bioavailability of iron. The mean area

under the curve (AUC) for iron in the

liposomal MVM was 33.22 mcg/dL × 6 hours,

which was 50% higher than the standard

MVM (19.84 mcg/dL × 6 hours; p = 0.02).

When measuring the percentage change in

serum iron levels from baseline, the

liposomal group showed an increase of

+14.3 ± 18.5% after 4 hours, whereas the

standard group experienced a decrease of

−6.0 ± 13.1% (p = 0.0001). After 6 hours, the

liposomal group maintained a slight increase

of +1.0 ± 20.9%, while the standard group

saw a more pronounced decrease of −21.0 ±

15.3%, which was also statistically significant

(p = 0.0002).

developing delivery systems that are safer,

more efficient, and scalable to maximize the

therapeutic benefits of mineral supplements.

Acknowledgement

-

Author Contributions

Conceptualization,

Methodology, PP; Software, PP; Validation, P,

YWW and AHC; Formal Analysis, P;

PP

and

YWW;

Investigation, P; Resources, P; Data Curation,

P; Writing - Original Draft Preparation, P;

Writing - Review & Editing, P; Visualization, P;

Supervision, AYC; Project Administration,

AYC; Funding Acquisition, AYC.

Conflict of Interest

The authors declare no conflict of interest.

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