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Sustainable Approaches in Pharmaceutical Sciences, First Edition. Edited by Kamal Shah, Durgesh Nandini
Chauhan, and Nagendra Singh Chauhan.
© 2024 John Wiley & Sons Ltd. Published 2024 by John Wiley & Sons Ltd.
121
7
Green Chemistry in the Development of Functionalised
Hydrogels as Topical Drug-Delivery Systems
Maha Mohammad AL-Rajabi
1,2
and Teow Yeit Haan
3,4
1
Faculty of Chemical Engineering & Technology, Universiti Malaysia Perlis (UniMAP), Arau, Perlis, Malaysia
2
Centre of Excellence for Biomass Utilization (CoEBU), Universiti Malaysia Perlis (UniMAP), Arau, Perlis, Malaysia
3
Department of Chemical and Process Engineering, Faculty of Engineering and Built Environment, Universiti Kebangsaan
Malaysia, Bangi, Selangor Darul Ehsan, Malaysia
4
Research Centre for Sustainable Process Technology (CESPRO), Faculty of Engineering and Built Environment, Universiti
Kebangsaan Malaysia, Bangi, Selangor Darul Ehsan, Malaysia
7.1 Introduction
A drug-delivery system (also known as a drug-delivery medium, device, or vehicle) is defined as
a formulation that introduces a therapeutic agent, active ingredient, or drug into the body and
enhances its safety and efficaciousness by regulating its release profile [1]. Such a system acts as
an interface between the drug and the patient, and may assume the form of either a formulation
of the drug or a device used to deliver the drug. It is crucial to recognise this differentiation
between the drug and the device, as it forms the basis for regulatory control of drug-delivery
systems by supervisory agencies [1]. The process of drug delivery comprises the encapsulation
of a drug for administration, from which its active ingredients are released, followed by their
distribution across cellular membranes to the intended anatomical sites [1].
Drug-delivery systems may be categorised according to their routes of administration:
systemic or topical. Systemic drug delivery introduces active ingredients into the systemic
circulation of the human body in order to reach the diseased organs. This includes the oral,
parenteral, or pulmonary (inhalation) routes [1]. Conversely, topical drug delivery introduces a
CONTENTS
7.1 Introduction, 121
7.2 Conventional Topical Drug-Delivery Systems, 123
7.3 Hydrogels, 124
7.4 Tailored Hydrogels for Topical Drug Delivery, 132
7.5
Adoption of Green Chemistry in Developing Functionalised Hydrogels, 135
7.6 Conclusion, 145
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7 Green Chemistry in the Development of Functionalised Hydrogels as Topical Drug-Delivery Systems122
drug-delivery system to the human body through direct administration to the diseased organs.
Under this mode of localised treatment, the drug is not targeted for systemic delivery; instead,
topical drug delivery involves the ophthalmic, rectal, vaginal, or dermatological routes [2].
The human skin represents a crucial route of drug delivery, given that it is one of the most
accessible anatomical parts [3]. As the body’s largest organ, it measures about 1.7 m
2
and
accounts for about 10% of the total body mass. The skin primarily functions as a barrier between
the body and the environment, offering protection against chemicals, ultraviolet radiation,
microbes, and allergens, and retaining moisture. Additionally, it is involved in homeostasis,
controlling both blood pressure and body temperature. The skin further aids in sensing and
detecting environmental stimuli including temperature, pressure, and pain. Though ideal for
drug delivery, the skin hinders the penetration of most chemical compounds. Anatomically,
the human skin comprises four parts: the stratum corneum, viable epidermis, dermis, and sub-
cutaneous tissues. Other anatomical features include sweat glands and hair follicles [1].
Dermatological or topical conditions have been reported as one of the top 15 disorders
for which prevalence and medical spending have risen over the last decade [3]. The out-
come of topical drug therapy is governed by the choice of drug-delivery system. Advances
in biomedical sciences, alongside a growing market for dermatological products, have pro-
moted the development of improved topical drug-delivery systems [3]. Topically delivered
drugs are numerous, such as corticosteroids, antifungals, antivirals, antibiotics, antiseptics,
anaesthetics, and antineoplastics [2].
Drug delivery represents a challenge in topical pharmaceuticals for treating burn
wounds, ulcerations, and lesions. Conventional topical dosage forms are classified into
semi-solids (ointments, creams, and pastes); liquids (lotions, emulsions, suspensions, and
solutions) [4, 5]; and solids (conventional dry dressings and gauzes) (Figure 7.1).
Topical drug delivery medium
Liquids
Semi-solids
Solids
Emulsion
(lotion)
Suspension
Solution
Cream
Ointment
Paste
Dry dressings
Powders
Cotton wool
Bandages and
gauzes
Oil-in-water cream
Water-in-oil cream
Aqueous
vehicle
Alcoholic
vehicle
Oil vehicle
Figure 7.1 Typical examples of conventional topical drug-delivery media. Source: Maha AL-Rajabi,
data adapted from [6].
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7.2 Conventional Topical Drug-Delivery Systems 123
Since the 1950s, drug-delivery systems have undergone continuous progress, with the
ultimate objective of providing and sustaining therapeutic concentrations of a drug at the
intended biological site [7]. Among various modern drug-delivery media, hydrogels have
offered promising potential. Their merits are twofold. First, they are able to retain water in
substantial volumes (up to 99% of their mass) [8]. Secondly, they spontaneously respond to
extraneous triggers including temperature [9], pH [10], ionic strength [11], light [12], and
electric and magnetic fields [13]. Thermo-responsive or temperature-sensitive polymers
represent the most widely explored group of environmentally sensitive polymers, given
their ease of control and preparation and their practical applications [14]. In this regard,
their thermal sensitivity makes them ideal for formulating functionalised thermo-respon-
sive hydrogels. Notably, the phenomenon of phase transition is observed for thermo-
responsive polymers at specific temperatures, at which they undergo a sudden change in
solubility. Accordingly, given their phase transition at physiological temperatures, thermo-
responsive hydrogels have found much potential in biomedical applications, especially for
topical delivery of pharmaceuticals [15].
Sustainable or green chemistry is an area for which the primary focus is on the design of
chemical processes and products that minimise the deployment and generation of hazard-
ous substances. With rising concerns over sustainability across the globe, the adoption of
green chemistry as exemplified by the development of functionalised hydrogels represents
a feasible and promising step. Such adoption can be undertaken in a wide range of con-
texts, such as deploying renewable and sustainable resources, and preferring safer solvents
and less hazardous chemicals in synthesising hydrogels. Among available sustainable and
renewable polymers used in hydrogel synthesis, cellulose is the most favourable, given its
natural abundance, low cost, biodegradability, and biocompatibility. In this chapter, the
use of bio-cellulose in synthesising functionalised hydrogels is detailed.
7.2 Conventional Topical Drug-Delivery Systems
The most conventional and established topical drug-delivery medium is the semi-solid dos-
age form, for which the classification is unfortunately vague and ill-defined [6]. A cream
has been suggested to be defined as a semi-solid, emulsion-derived formulation, compris-
ing less than 50% of polyethylene glycol or hydrocarbons as the medium, and more than
20% water and volatiles [16]. Creams can be classified into the oil-in-water formulation, for
which water is the continuous phase (i.e. vanishing creams), and the water-in-oil formula-
tion, for which oil is the continuous phase (i.e. oily creams). Vanishing creams are appro-
priate for water-soluble drugs, while their oily counterparts are appropriate for lipid-soluble
ones [17].
On the other hand, an ointment is usually defined as a formulation comprising more
than 50% polyethylene glycol or hydrocarbons as the medium and less than 20% water.
Ointments act as the vehicle for topical delivery of active ingredients, offer skin protection,
and act as an emollient [18]. They typically contain a drug emulsified, dissolved, or dis-
persed in an ointment-derived carrier; additionally, they are greasy [19]. The last type of
semi-solid dosage form, a paste, can be viewed as a semi-solid formulation with approxi-
mately 20–50% finely dispersed solids in an oily medium of stiff consistency [20].
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7 Green Chemistry in the Development of Functionalised Hydrogels as Topical Drug-Delivery Systems124
A liquid dosage form is another important conventional drug-delivery medium.
Emulsions, also known as lotions, usually contain a water-based medium, with the water
and volatiles exceeding 50% by proportion [16]. On the other hand, topical suspensions are
defined as a two-phase medium consisting of 0–20% of solids dispersed in a liquid [4],
which is typically water or alcohol based. Topical solutions, the last liquid dosage form, are
defined as a homogeneous, translucent liquid medium for topical drug delivery. Topical
solutions typically contain an alcohol- or water-based vehicle, although this role is at times
played by an oil-based vehicle. Such solutions may contain a gelling agent for thickening
their consistency [21].
Besides semi-solid and liquid formulations, solid dosage forms have also proven effective in
topical drug delivery. They can be classified into powders and dry dressings. Powders are inert
and insoluble solids, with utility in covering ulcers and wounds, absorbing moisture, decreas-
ing friction, and discouraging microbial growth [22]. On the other hand, wound appliances and
dressings constitute a significant segment of the global market for wound treatment.
Conventional dressings with differing degrees of absorbency, as exemplified by bandages,
gauzes, and cotton wool, have presented practical value in wound management [23].
Table 7.1 summarises the appearances, advantages, and disadvantages of conventional
topical drug delivery media. Generally, topical semi-solid and liquid preparations register
suboptimal retention on skin or wound surfaces, for which multiple applications are thus
warranted [24]. Moreover, traditional drug-delivery media present inconvenience in
administration: some dosage forms have to be rubbed in topically to disperse the formula-
tion [25], causing pain, inflammation, and irritation. Notwithstanding their ease of appli-
cation, traditional dry dressings do not support the moisture-rich condition essential for
wound healing [26]. Furthermore, conventional methods have been associated with hap-
hazard kinetics, under which drug release can be inappropriately rapid and excessive topi-
cal concentrations may induce toxicity [27]. To overcome such shortcomings, a viable
alternative dosage form – hydrogels – has been introduced [26].
7.3 Hydrogels
Hydrogels are three-dimensional intermeshing structures of chemically or physically
cross-linked polymeric chains of either synthetic or natural origin. Given their ability to
swell/de-swell and be absorbed, hydrogels can release substantial amounts of retained
water, solvents, or bodily fluids without themselves being dissolved [33]. The first study on
hydrogels in 1960 revolved around polyhydroxyethylmethacrylate, which demonstrated a
high swelling ratio and was used in biomedical application [34].
7.3.1 Methods of Synthesising Hydrogels
Common approaches to synthesising hydrogel involve cross-linking by chemical or physi-
cal means (Figure 7.2) [35–38]. Physically cross-linked hydrogels result from molecular
entanglement and other forces (Figure 7.3). These forces contribute to the cross-linking
through hydrogen bonding, amphiphilic graft and block polymers (hydrophobic interac-
tions), crystallisation, and electrostatic interactions (Figure 7.4, A–D). The chief advantage
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Table 7.1 Appearance, advantages, and disadvantages of conventional topical drug-delivery media.
Conventional topical
drug-delivery medium
Appearance and
sensation Pros Cons References
Semi-solids
Cream Opaque, thick, not
greasy to mildly
greasy; tendency to
mostly evaporate or
be absorbed on
topical application
Appropriate for use on most skin areas; tendency
to cause less irritation
Most appropriate for sensitive and/or dry skin
Offers moisturising and emollient effects
Can be spread more easily and are less oily than
ointments
May cause a greasy feel, given its
thickness
Less moisturising than ointments
Suboptimal retention on the wounds or
skin surfaces
Inconvenient application
[16, 18,
24, 25, 28,
29]
Ointment Clear or opaque,
thick, greasy;
tendency not to
evaporate or be
absorbed on topical
application
Appropriate for very dry skin
Typically free from preservatives
Offers greater potency and better drug
permeation
Efficacious on lesions with thickened skin
Enhances skin hydration and maintains
temperature
Water insoluble, thus can be challenging
to wash off
Can be viewed as greasy or messy to use
Greasy or oily texture, thus can be less
cosmetically or aesthetically appealing
Cannot be spread easily
Suboptimal retention on wounds or skin
surfaces
Inconvenient application
[16, 18,
24, 25, 29]
Paste Opaque, thick, greasy
to mildly greasy;
good adhesion to the
skin, affording a
protective barrier
Less greasy and more absorptive than ointments
Does not soften and flow easily
Usually inappropriate for hairy
anatomical parts, given its stiffness
[18, 20,
30]
(Continued)
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Conventional topical
drug-delivery medium
Appearance and
sensation Pros Cons References
Liquids
Emulsion (lotion) Opaque, non-viscous,
non-greasy; tendency
to rapidly evaporate
with a cooling effect
on topical application
Appropriate for all skin types
Feels less weighty
Favoured for large or hairy intertriginous
anatomical parts (e.g. armpits, feet, and groin)
Affords a cooling effect when the water-based
phase vaporises
Convenient application to hairy areas
Can be spread easily
May irritate the skin (e.g. excessive
drying and burning)
Less moisturising than ointment or
cream
[16, 18]
Topical suspension Shaking required
prior to use, given
sedimentation of
solids
Affords a soothing, cooling effect to skin on
application
Convenient application
More drying than ointment or cream
Alcohol-derived formulations may sting,
especially for skin with eczema or
abrasions
Requires to be shaken prior to use
[16, 22]
Topical solution Clear, non-viscous Easy to spread
Leaves minimal residue
Very simple to produce
Alcohol-derived formulations may
irritate skin (dryness or stinging)
Does not offer skin protection
Less moisturising
[16, 22]
Table 7.1 (Continued)
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Conventional topical
drug-delivery medium
Appearance and
sensation Pros Cons References
Solids
Powders Mixed or dry solids Action is dry and absorption of fatty acids
produces a deodorant and releasing effect
Light, fluffy powders may be inhaled by
patients if proper care is not taken
Drying effects are often seen for powders
[31, 20]
Dry dressing Fine mesh gauze
with a supplement to
enhance occlusion
with non-adherent
characteristics
Promotes dryness of the wound through airing
and evaporation of exudates and wards off
microbes
Convenient to use
Does not support a moisture-rich
condition for wounds to heal
Dressing changes are frequently
required
There has to be intact skin surrounding
the site being dressed, which may not be
the case for large donor sites, e.g. burns
Wound contraction may be hindered by
dressing-induced occlusion
Dressing removal disruptive of
formation of new epithelia
[23, 26,
32]
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7 Green Chemistry in the Development of Functionalised Hydrogels as Topical Drug-Delivery Systems128
of physically cross-linked hydrogels is their biocompatibility, given the lack of toxic chemi-
cal cross-linkers [39]. Additionally, the preparation conditions required for their synthesis
are relatively mild [36]. However, notable shortcomings include the inconsistent perfor-
mance of the hydrogels and the often reversible physical cross-linking [39]. Conversely,
chemically cross-linked hydrogels formed by non-reversible cross-linking can be synthe-
sised using enzymes, different cross-linking agents, free radical polymerisation, and high-
energy radiation (Figure 7.4, E–I) [35, 39, 40]. Unlike their physically cross-linked
counterparts, chemically cross-linked hydrogels are stable against degradation and register
improved mechanical properties [41]. However, cross-linking agents have their drawbacks,
given their potential toxicity, environmental implications, and likelihood of undesirable
reactions with bioactive substances in the hydrogel matrices [42].
Physical cross-linking:
Molecular entanglement
Physical cr
oss-linking:
Secondary forces
Chemical cr
oss-
linking
Hydrogel
Figure 7.3 Physical and chemical cross-linking of hydrogel. Source: Ullah, F. et al., 2015 /
Reproduced with permission from Elsevier.
Chemical cross-linking
Chemical
reaction
Enzymes
Synthesis methods of hydrogels
Physical cross-linking
Hydrogen
bonding
Amphiphilic graft and block
polymers (hydrophobic
interaction)
Crystallization
Cross-linking with covalent
cross-linker (aldehydes)
By condensation
reactions
Free radical
polymerization
High energy
radiation
Electrostatic
interactions
A
B
CD
E
FG
H
I
Figure 7.2 Synthesis methods of hydrogels. Source: Maha AL-Rajabi, data adapted from [36].
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