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Chapter 13
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Nanotechnology and Hydrophobic Drug
Solubilisation
Lewis Dymock and Clare Hoskins
13.1 Introduction
The delivery of hydrophobic drug molecules is a major challenge faced by the
pharmaceutical industry. Currently, it is estimated that 40% of all drug entities
approved for clinical use (Larrañeta et al. 2018) and 90% of drug compounds in
development (Kalepu and Nekkanti 2015) are hydrophobic, meaning they are
insoluble in aqueous-based systems. In order for any drug to be administered either
orally or via most parenteral routes, the drug must first be able to dissolve in aqueous
environments (Bittner and Mountfield 2002; Dahlgren et al. 2022). Without this
ability, either they will not undergo dissolution in order for efficient absorption to
occur (Dahlgren et al.
if dosed via oil-based systems (Desousa 2016).
2022) or cause patients great pain on parenteral administration
13.1.1 Drug Solubilisation
Drug solubility is defined as the maximum amount of drug that will dissolve in a
solvent at a certain temperature and form a solution (Savjani et al.
dissolution rate is a measure of the speed with which a drug goes into solution. In
order to deduce why a drug molecule may be hydrophobic, it is first important to
understand the stages of solubilisation (Fig.
molecule) is placed inside a solvent (aqueous-based system) in its bulk powder form,
the molecules of the drug need to disperse in order to be accommodated within the
L. Dymock · C. Hoskins (✉)
Pure and Applied Chemistry, University of Strathclyde, Glasgow, UK
e-mail: clare.hoskins@strath.ac.uk
© The Editor(s) (if applicable) and The Author(s), under exclusive license to
Springer Nature Switzerland AG 2024
I. F. Uchegbu et al. (eds.), Fundamentals of Pharmaceutical Nanoscience,
https://doi.org/10.1007/978-3-031-59478-6_13
2012a). The drug
13.1). When a solute (in this case a drug
313
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Stage 1
Stage 2
Stage 3
Fig. 13.1 Stages in drug solubility. Stage 1—Drug molecules move away from their bulk form.
Stage 2—Water molecules form tiny cavities. Stage 3—Drug molecules are accommodated within
water cavities resulting in solubilisation
‘cavities’ formed between the molecu les of the solvent (Mittal 2017). Once the drug
molecule has been inserted into these cavities, it is considered as solubilised. There
are a number of factors that affect whether solubilisation can occur; the first is the
nature of the solvent (and its ability to accommodate the drug molecule within its
cavities). The polarity of the solvent can often make a huge difference to the extent of
solubilisation. Solubilisation is a ‘like dissolves like’ phenomenon, whereby polar
solvents such as water-based s
size/shape
of
the
architectures of drug molecules may find it more difficult to accommodate within the
solvent cavities. This inability to reside in the solvent cavities is correlated with the
molecular weight of the drug, with smal ler molecular weight compounds finding it
easier to be inserted wi thin the cavities and become solubilised, as demonstrated
the Noyes–Whitney
This equation utilises a number of characteristics of the drug-solvent system to
determine the dissolution rate (
ystems f
drug
molecule may also have an effect, whereby specific molecular
Equation (Eq.
avour solubilisation of polar compounds. The
).
13.1
dw
DAC
=
dt
dw
, namely, the diffusion constant (D), the surface
Þ
dt
s
σ
by
ð13:1Þ
13 Nanotechnology and Hydrophobic Drug Solubilisation 315
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area of the solid drug (A), the drug concentration in the dissolution layer when
saturated (C
), and the thickness of the diffusion layer (σ). As seen in the equation
s
above, if dissolution was the rate-limiting step in bioavailability, then a change in
A (or C
) will result in a change in the bioavailability.
s
Given that the size of the drug crystal has a direct impact on its solubilisation,
there is huge potential for new high precision milling technologies to form smaller
drug crystals in order to promote solubilisation (Rasenack and Müller
2002). Finally,
temperature has a direct impact on the solubilisation of drug molecules. As the
temperature of the solve nt is increased, the degree of flexibility and movement of the
solvent molecules also increases; this leads to increased scope for cavity formation
and/or an increase in cavity size which can promote more drug crystals being
inserted within the solvent cavities; however, the reverse is also true, and as the
solution cools down, it is important to consider that molecular mobility will reduce
and the solubilisation experienced at elevated temperatures may very well be
reversed, resulting in the drug precipitating back out of solution.
13.1.2 Drug Partitioning
Once in solution, drugs can partition between different phases. When a drug is
placed within two immiscible solvents, the drug will partition into each solvent
according to its affinity for each phase (Kubinyi 1978). This ability to partition is
determined by the partition coef ficient (P) (Eq. 13.2) of the drug. The partition
coefficient is a measure of the hydrophobicity of a drug molecule as is determined by
placing the drug into a mixed solvent system and measuring the concentration of
drug in an oily phase (C
(C
).
w
) compared to the concentration of drug in an aqueous phase
o
However, the partition coefficient is normally expressed in its log form, denoted
as logP. The logP is an important value in pharmaceutical development, as it can
give an indication not only of aqueous solubility, but also the ability of the drug to
cross the lipophilic (non-aqueous) biological membranes, in order to cross epithelial
barriers or enter cells (Soliman et al.
low logP value, it is unlikely to possess a great affinity for the non-aqueous phase,
meaning it will not cross the biological barriers, which is problematic for intracellular trafficking and may result in the drug becoming cleared from the body before
exerting its clinical effect. Conversely, if a drug is highly lipophilic with a large logP
value, this means it does not have any problems crossing those biological barriers,
but it will possess very low aqueous solubility, and this may be its rate-limiting
factor for dosing, particularly when administered via oral routes, as in order for drugs
C
o
P =
C
w
2021
). If a drug is too hydrophilic with a very
ð13:2Þ
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to be administered orally, they must first undergo dissolution into the aqueous-based
gastrointestinal fluid.
13.1.3 Biopharmaceutics Classification Table
The biopharmaceutics classification table (Table 13.1) is a guide for predicting the
oral bioavailability of drug molecules based on their logP values (Florence and
Atwood 2016). Class I and III compounds both exhibit high aqueous solubility,
meaning that they can readily dissolve in the aqueous-based GI fluid; however, their
affinity with the lipophilic phase differs, whereby Class I drugs possess a good extent
of lipophilicity and can permeate biological barriers, whilst Class III compounds do
not, meaning they may require a permeation enhancer in order for effective delivery.
Class II compounds exhibit high permeability of biological compounds; however,
they possess low aqueous solubility. It is this class of compound which typically fail
due to their limited aqueous solubility. Therefore, enhancement of aqueous solubility will overcome the initial barrier to delivery and lead to increased bioavailability.
13.1.4 Traditional Methods of Drug Solubilisation
Traditionally, surfactants have been used to solubilise hydrophobic drugs for pharmaceutical application. These low molecular weight amphiphilic molecules selfaggregate into micelle structures where their hydrophobic tails cluster together in a
core surrounded by their hydrophilic heads, which stabilise them into a micelle
structure (Patel et al.
2020). Hydrophobic drug molecules are capable of entering and
residing within the lipophilic core of the micelle, thus enabling their delivery in
aqueous-based systems. The amount of surfactant required for aggregation is dependent on a number of factors such as surfactant head/tail ratio and type, presence of
electrolytes, pH of solution and temperature. The minimum amount of surfactant
required to form the micelle structures is denoted as the critical micellar concentration (CMC). The exterior hydrophilic shell of the surfactant reacts with the biological milieu allowing absorption into the body whilst the drug cargo resides safely
inside the core. Traditionally used surfa ctants include Tween, Span, sodium dodecyl
sulphate and Cremophor EL (Das et al. 2022). Although surfactants have been used
readily in medicines manufacture, they are not ideal systems as they often possess
Table13.1 Biopharmaceutics
classification table outlining
ability of active ingredients to
dissolve in aqueous media and
partition across biological
membranes
Class Solubility Permeability
I High High
II Low High
III High Low
IV Low
Low
13 Nanotechnology and Hydrophobic Drug Solubilisation 317
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low stability resulting in precipitation of drugs from solution, or the concentration
required to stabilise the drug (excipient: drug ratio) being very high. These factors
can result in off target effects from the vehicle, costly formulations or viscous
preparations which cause pain upon administration.
Other technologies which have been previously used to aid drug solubilisation
include the use of emulsions or microem ulsions, where oil droplets are suspended in
water and stabilised with surfactants, allowing drug cargo to be solubilised within
the oil fraction (Peng et al.
excipient: drug ratios are high, and the formulations have low shelf life and stability.
Cosolvents are another option in the solubilisation of hydrophobic compounds
(Jörgensen et al.
the addition of another solvent into the system can aid in solubility via exploitation
of the drugs logP. Commonly glycerol, ethyl alcohol and propylene glycol are
employed in cosolvent systems. However, the use of cosolvent systems is less
favourable as residual organic solvents or fractions may introduce toxicity to the
formulation. Where other drug molecules are insoluble, formation of their salt
crystals may be employed to enhance solubility. Here, pH manipulation of weakly
acidic or basic drugs forming salt crystals can change solubility profiles, often
leading to enhanced and hence faster dissolution. Salt formation is usually one of
the first trialled methods in solubility enhancement in product development. Finally,
given the role particle size plays in solubility, milling of drug crystals into smaller
entities has also been used for solubility enhancement (Savjani et al.
process is known as micronisation, where the large bulky drug crystals which cannot
be accommodated within the aqueous solvent are milled down to smaller crystal
sizes with a higher surface area. This approach to solubilisation requires expensive
equipment but does not require the use of excipients making it a very attractive route;
however, micronisation is not suitable for all drugs as many deform under compaction or milling, and this can lead to loss of activity.
2020). Where the drug solubility within one solvent is limited,
2011). However, like the surfactant-based systems, the
2012b). This
13.2 Nanotechnology for Hydrophobic Drug Solubilisation
Nanotechnology has played an instrumental lead in the formulation of hydrophobic
drug molecules. Nano-sized carriers are usually defined between 1–300 nm in
dimension, although depending on the system can reach as large as 1000 nm.
Nanotechnology is an umbrella term which incorporates many diverse systems,
but generally the benefits from the use of nanotechnology-based systems over
conventional systems for drug solubilisation are similar. Guo et al. demonstrate
such diversity in systems well in Fig.
used to deliver the hydrophobic compound celastrol (Guo et al.
benefits include higher drug loading efficiency, use of lower excipient quantities,
the ability to load multiple drugs into one system to offer combination therapies
(Kumar et al. 2012). Improvement not only in solubility, but also permeability,
which allows efficacy enhancement not only in Class II, but also in Class IV
13.2, where they describe the technologies
2021). These
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Fig. 13.2 Various types of celastrol-loaded formulations (Guo et al. 2021)
compounds, offering a whole new realm of therapeutics from previously discarded
drug candidates which have previously demonstrated clinical benefit, but suffered
from their poor physicochemical properties. Protection of the drug from premature
degradation, whilst some p rotection is offered by the surfactant-based systems, the
higher stability of the nano-systems allows greater protection meaning greater
on w
efficiency in delivery, often allowing for dose reducti
al.
(Hoskins et
general, are
2012a). Additionally, and very importantly, nanotechnologies in
very easy to tailor to application, this means they can be surface
hich is more cost effective
engineered with specific targeting agents which can offer site-specific cargo delivery, again enhancing efficacy and reduci ng off target effects (Liang et al. 2021).
Each of the technologies are discussed in detail within this book, so only a brief
overview of these will be discussed in this chapter. The main technologies used for
hydrophobic drug solubilisation remain to be the liposome and other lipid-based
systems (Puri et al. 2009
). These nano-carriers rely on the use of naturally occurring
materials, mimicking those already in the body. Each system encapsulates the drug
within the lipid component of their structure, in the case of liposomes this is within
the lipid bilayer, and for solid lipid/multiparticulate lipid nanoparticles this is within
their main lipid body. Polymer-based technologies such as polymer-drug conjugates
or amphiphi lic polymers are synthetic nano-systems which offer the ability to
encapsulate drug compounds within their hydrophobic core, much like the surfactant
systems (Ting et al.
2018). Drugs can be incorporated either by being chemically
bound or encapsulated into the self-assembled aggregate. However, unlike
13 Nanotechnology and Hydrophobic Drug Solubilisation 319
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surfactants, the polymer-based systems offer superior stability and excipient: drug
ratios reduced as much as 10,000 times compared to the use of low molecular weight
surfactants; essentially overcoming some of the challenges associated with cost,
viscosity or toxicity from the carrier (Hwang et al.
meric systems offer a different approach whereby hydrophobic drug molecules can
become physically entrapped inside the highly branched network of the nanostructure, offering safe harbour during transport to their destination site (Choudhary et al.
2017). Other synthetic nano-carriers used for this purpose are cyclodextrins and
calixarenes (Laza-Knoerr et al. 2010;
form cup- or crown-shaped
interior. Drug molecules can enter into the interior cavity of the structures forming
inclusion complexes via hydrophobic–hydrophobic interactions and reside within
these cavities allowing them to form colloidal suspensions. However, with these
technologies, the main drawback is their lack of universal solubilising ability , as they
are normally tailored to one sp
ng
meani
ingredients.
Niosomes and exosomes are also currently the focus of a lot of attention for drug
solubilisation, with niosomes mimicking the liposome structure, with the difference
of their molecular makeup (Gharbavi et al. 2018). Niosomes are composed of
non-ionic surfactants compared with the phospholipid structure of liposomes, but
the mechanism for drug loading and residence is similar. Exosomes are vesicles
which are derived from the body itself, secreted from cells, again mimicking the
liposomal structure, with the added benefit of being manufactured within human
cells, and therefore less likely to undergo immune clearance. Both entities have
shown good promise pre-clinically and are likely to be advancing rapidly towards
the clinic in the next decade.
Finally, nanonisation is the next generation technology from micronisation,
where drug molecules are formed into nanoscale crystals, this may be via high
precision milling, or via laser ablation, to form more soluble forms of the larger
bulk crystal, without the need for any excipient (Da Silva et al.
these main technologies, examples of drugs which have been solubilised within them
and their advantages/limitations is shown in Table 13.2.
they
can
expensive to manufacture, and not transferrable between active
be
molecular architectures, which possess a hydrophobic
ecific d
Hoskins and Curtis
rug entity based on molecular size and shape,
2020). Dendrimer-based poly-
2015). These molecules
2020). A summary of
13.3 Routes of Delivery
Over the past decade, most of the solubilisation nano-systems reported in the
literature or being tested in the clinic have been developed for intravenous cancer
therapy. However, as knowledge has grown in this area, there has been a move
towards other routes of delivery and clinical conditions.
Drug formulations which have been administered intravenously have been shown
to promote longer circulation times once inside the body. This fact may be due to the
protective effect of the nano-carrier acting as a protective ‘sheath’ from drug
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Examples of
drugs which
have been
Method to increase the drug
Low drug loading levels
Key advantages Limitations
Ability to opti-
mise loading and
attempted
Blonanzarin
(Møller et al.
solubility
larly dispersed in the lipid matrix
Risk of drug expulsion on
release
characteristics
Low chronic
2021)
or incorporated into the drug-
enriched shell/core
storage
High water content in
toxicity
Protection of
et al. 2022)
structure
incorporated
drugs
Physical stability
(Nayek et al.
2021)
(Nayek et al.
Instability on drug
entrapment
Ability to opti-
targeting
Change
Long shelf life
2021)
(Ramzan et al.
biodistribution of
2021)
mize loading and
drug
Flavopiridol
(Chen et al.
Hydrophobic drugs are entrapped
in the bilayer
Instability on storage
release
characteristics
Low chronic
2021)
toxicity
(Webb et al.
2020)
Examples of the composition
Nano-
Table 13.2 Summary of main nanotechnologies used for drug solubilisation
systems
Lipid constituents (e.g.) Hydrophobic drugs are molecu-
Solid-lipid
nanoparticles
(SLN)
Labrafec Cilostazol (Bibi
Lipoid Irinotecan
Solutol Gefitinib
CP-Togo Care 450 Ketoconazole
Goat fat Site-specific
Phosphatidylcholines Doxorubicin
Liposomes Phospholipids (e.g.)
13 Nanotechnology and Hydrophobic Drug Solubilisation 321
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(continued)
Relatively high excipient:
drug ratio
Protection of
incorporated
drugs
(Li et al. )2020
Relatively expensive
Site-specific
targeting
2021)
Paclitaxel
(Zeng et al.
Ease of fabrica-
tion/
functionalization
(van den Hoven
et al. 2013)
biodistribution of
drug
Instability on dilution
release
Ability to opti-
mize loading and
Propofol
(Al Ameri et al.
2020)
Hydrophobic drugs are encapsu-
lated within the hydrophobic core
of the polymeric self-assemblies
Instability on storage
characteristics
Low chronic
toxicity
(Alsuraifi et al.
2018)
Protection of
incorporated
drugs
al.
2012b)
(Hoskins et
Site-specific
targeting
(Hoskins et al.
2012b)
Ease of fabrica-
tion/
functionalization
(Velluto et al.
2021)
Change
biodistribution of
drug
Choline glycerolphospholipid Ciprofloxacin
Ethanolamine
glycerolphospholipid
Phosphatidylglycerol Prednisolone
Phosphatidylinositol Change
Phosphatidylserine
Block copolymers
Polymeric
self-
assemblies
PEG-b-poly(aspartic acid) 5-Fluorouricil
PEG-b-poly(D,L-lactide) Paclitaxel
PEG-b-poly(glutamic acid) Griseofulvin
PEO-PPO-PEO (Pluronics) Cyclosporin A
Hydrophobically modified
polymers
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