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8
Suspensions: Theory, Formulation
Considerations, Flocculated
andDeflocculated Suspensions,
andEvaluation of Suspension Stability
AnjaliRajora andKalpanaNagpal
Abstract
Pharmaceutical formulations like suspensions are highly benecial for delivery
of drugs. Several challenges arise during development due to their inherent struc-
tural instability. These formulations typically comprise small solid particles
(sized between 0.5 and 5μm) suspended in a liquid or semiliquid that acts as the
continuous phase and desired carrier. Theoretical concerns linked to pharmaceu-
tical suspensions (such as interfacial properties, surface free energy, and surface
potential along with electric double layer, zeta, and Nernst potential) are concep-
tualized. Certain other crucial aspects like wetting, electrokinetic phenomena,
and DLVO (Derjaguin, Landau, Verwey, and Overbeek) theory with theory of
sedimentation are addressed. From a stability point of view, a comprehensive
understanding of these factors is crucial since both the characteristics of the car-
rying liquid and the properties of dispersed solids impact the solidity of the sus-
pension. This chapter delivers an encompassing survey of pharmaceutical
suspensions, their introduction, classication, theoretical exploration, assess-
ments, and stability considerations. It is an attempt to equip researchers, practi-
tioners, and stakeholders with a comprehensive understanding of leveraging
suspensions for efcient drug delivery.
Keywords
Suspensions · Flocculated suspensions · Deocculated suspensions · DLVO theory
A. Rajora · K. Nagpal (*)
Amity Institute of Pharmacy, Amity University Uttar Pradesh, Noida, Uttar Pradesh, India
e-mail: knchaswal@amity.edu
200
Abbreviations
DLVO Derjaguin, Landau, Verwey, and Overbeek
EDL Electric double layer
L Contact angle
PCS Photon correlation spectroscopy
SDS Sodium dodecyl sulfate
SPOS Single particle optical sensing
V Potential energy
VA van der Waals attraction
V
deoc
Final volume of sedimentation in deocculated suspension
V
oc
Final volume of sedimentation in occulated suspension
V
i
Actual suspension volume
VR van der Waals repulsion
V
s
Final sediment volume
z Zeta
8.1 Introduction
A pharmaceutical suspension is formed when a solid particle can’t dissolve in the
solvent liquid. Generally, these suspensions have particles larger than 0.5μm in
diameter (Jones 2016). A clear distinction between suspensions and dispersions
with smaller particles cannot be made because it is difcult and impractical
(Brunaugh etal. 2019). They come with several advantages like effectively deliv-
ering hydrophobic drugs; giving intramuscular depot therapy; covering up
unpleasant tastes of certain ingredients; avoiding the use of cosolvents; protect-
ing against drug degradation from things like oxidation, hydrolysis, or microbes;
and making it easier for young and elderly patients to take the medicine (Iyer
etal. 2006). Furthermore, compared to solutions, suspensions can take in much
higher drug concentrations (Wong etal. 2008). This study gives a summary of
various suspension-related aspects including suspension theories, their catego-
ries, and their stability aspect. It also touches on some formulation-related sub-
jects (Arora etal. 2022).
The two phases make up heterogeneous systems known as suspensions. Solid
particles that are mostly insoluble in the external phase make up the internal or dis-
persed phase (Jermain etal. 2018). It also contains the continuous phase also called
dispersion medium which is usually in the form of a semisolid (e.g., gels) or liquid
(such as liquid suspensions). Although organic or greasy liquids are occasionally
utilized, an aqueous dispersion medium makes up most pharmaceutical suspensions
(Leleux and Williams III 2014).
A. Rajora and K. Nagpal
201
8.2 Theoretical Considerations
8.2.1 Interfacial Properties
Pharmaceutical suspensions contain a solid phase in the form of tiny fragments
dispersed in the dispersion medium. Because of this, there are many interlinks
within the formulation that inuences the rmness of the suspension. As a result,
change in the physical characteristics of the dispersion largely depends on its sur-
face qualities. Surface free energy plus surface potential is among the important
characteristics of interface (Nutan and Reddy 2010).
8.2.1.1 Surface Free Energy
Solids that have been nely divided frequently have a large surface area and a lot of
free energy there. The relation between surface area and free energy could be
stated as:
∆ ∆GA=
γ
where γ is the interface tension linking the continuous phase and solid phase, ΔG is
the rise in free energy, and ΔA is surface area change. The suspension is more ther-
modynamically stable reected by the lower value of ΔG (Kulshreshtha etal. 2010).
Thus, a system with incredibly small particle due to the huge total surface area is
thermodynamically unstable. The system tends to aggregate to lower the surface
area with the surplus free energy. This free energy can be minimized to prevent
particle grouping, which is achieved by decreasing the interface tension. Addition of
a wetting agent causes its absorption at the interface. As the interfacial tension
decreases, the system will become more stable (Aulton and Taylor 2013).
8.2.1.2 Surface Potential
The existence or nonexistence of a surface potential can generally be used to explain
the strength of lyophobic colloidal systems. Suspension systems can also benet
from this concept (Garad etal. 2010). Surface potential survives when the dispersed
solid particles within suspension have a charge relative to the liquid medium in
which they are suspended. Several processes can lead to charged particulate matter.
The possibility of selective adsorption by solid particles of a certain ionic type exists
if the suspension contains electrolytes. Several processes can lead to charged par-
ticulate matter. The possibility of selective adsorption by solid particles of a certain
ionic type exists if the suspension contains electrolytes. As a result, charged parti-
cles will eventually form. Because of the disproportionate nature of the OH
−
ion, it
is possible, for example, that rubber particles dispersed in water will adsorb more
OH
−
ions than H
3
O
+
ions (Brunaugh etal. 2019). Surfactants are adsorbed on the
interface of liquid and solid. In rare cases, they can ionize and give the particles a
negative or positive charge. For example, sodium dodecyl sulfate (SDS) is an anion
in water medium. Solid objects can also be charged by ionizing their functional
groups. In this case, the total charge is affected by the pH of the nearby vehicle.
8 Suspensions: Theory, Formulation Considerations, Flocculated and Deocculated…
202
Ionizable groups such as -COOH and -NH
2
are found in peptide and protein mole-
cules. Dispersed particles of these compounds will ionize. The pH of the surround-
ing vehicle has a signicant effect on the direction and intensity of ionization
(Bhattacharjee 2016).
8.2.2 Electric Double Layer (EDL)
Once dispersed particles encounter an aqueous electrolyte mixture, they can choose
only one type of charge to adsorb. The particles are often negatively charged when
an anion is absorbed. The ions, in this case the anions that determine the charge on
the particle, are known as co-ions or potential-determining ions as shown in Fig.8.1
(Ohshima 2014). The residual ionic species in the liquid consist of the remaining
anions and sum of the added cations. This means that the dispersion medium will
include more cations than anions. These cations are called counterions or gegenions
because their charge is different from that of the ions that determine the potential.
Electric forces attract them to a negatively charged surface. Once the initial adsorp-
tion is complete, the gegenions also repel any additional approaching anions from
the particle surface. All the ions in the solution are evenly distributed due to these
electrical forces and thermal motion. This creates an equilibrium situation where
Fig. 8.1 Schematic representation showing the electric double layer in a liquid in contact with a
negatively charged particle. The zeta potential is the potential at the slipping plane that separates
the mobile uid from the uid that remains attached to the solute (Barhoum etal. 2018). (Reprinted
from Emerging Applications of Nanoparticles and Architecture Nanostructures, Ahmed Barhoum,
M.Luisa García-Betancourt, Hubert Rahier, Guy Van Assche, Physicochemical characterization of
nanomaterials: polymorph, composition, wettability, and thermal stability, page no 255–278.
Copyright (2018), with permission from Elsevier)
A. Rajora and K. Nagpal
203
certain additional cations move toward the surface and the remaining cations are
transferred away from charged surface as dispersed in reduced amounts (Eyley
etal. 2015).
In the region of the liquid closest to the particles, almost all counterions will be
present. The solvent component that is rmly attached to the particle surface along
with these counterions is called the Stern layer. This layer moves as the particles
move through the continuous phase, so Stern layer is near to the shear plane. The
co-ions, which get adsorbed on the surface of a solid body, are more abundant than
counterions in a compactly bound layer (Ferrar etal. 2020). Thus, the potential in
the shear plane is however negatively charged. Stern layer is surrounded by a diffuse
layer containing additional counterions than co-ions. Relatively mobile ions in this
layer continuously move into and out of the main body of the dispersion medium
due to thermal energy. Electrical neutrality appears wherever the moving diffuse
layer stops. Outside the diffuse layer, the concentrations of counter as well as cova-
lent ions are identical, indicating an electrically neutral state for the rest of the dis-
persion medium. At the liquid-solid interface, the electrical distribution can be
thought of as a charged EDL. Stern layer consists mainly of counterions and is
rmly attached to the surface of the solid. More counterions and greater mobility
are present in the second layer. The EDL thickness rests on the form and number of
ions present in the solution. It’s vital to keep in mind that the suspension is electri-
cally neutral, even though the charges are unevenly distributed in the EDL.Two
additional options are possible (Vo etal. 2020). If the counterion concentration in
the rigidly bound layer is identical to the concentration of cations at the surface of
solid, the shear plane will be electrically neutral, and there will be only one layer of
medium and ions, as opposed to two layers. If the entire charge of counterions in the
Stern layer is greater than the charge derived from the co-ions, the total charge in the
shear plane will be positive rather than negative. Electrical neutrality is attained
where the electrical EDL terminates, and the diffuse layer contains additional co-
ions than counterions (Kulshreshtha etal. 2009). The difference between the con-
centration of positive and negative ions at any given distance from the surface is
used to calculate the charge density at this point (Frigaard 2019).
8.2.3 Zeta andNernst Potential
Electro-thermodynamic potential, surface potential, or Nernst potential refers to the
difference in electrical potential between the real or true surface of the particle and
the electroneutral zone. The electric potential at the particle’s surface thereby pro-
tects the Nernst potential because of the potential-regulating ions. The electrokinetic
or zeta (z) potential is the potential difference between the electroneutral zone and
the shear plane. The z potential, in contrast to the Nernst potential, has a signicant
effect on the establishment of a stable suspension (Hebishy etal. 2015). To neutralize
the charged particles in suspension, an EDL is created. The electrical potential at any
point in the suspension system depends on its precise location, as was explained in
the paragraphs before. The potential in the diffuse layer gradually varies with
8 Suspensions: Theory, Formulation Considerations, Flocculated and Deocculated…
204
increasing distance from the solid object. The strength of the attraction between
neighboring, equally charged particles in a solid dispersion is controlled by the zeta
potential. The van der Waals force, the attractive force between particles, outweighs
the repulsive forces and leads to the formation of occules when the zeta potential
falls to a specic level, which depends on the particular system being examined. We
refer to this process as occulation. Both surface charge and EDL width have an
impact on zeta potentials and surface area. Microelectrophoresis, which involves
watching the movement of particles in a voltage eld using a microscope, can be
used to measure zeta potential (Loftsson 2014; Haines and Martin 1961a).
8.2.4 Wetting
Due to the elevated interface tension among the particles and dispersion medium,
hydrophobic powders exhibit weak adhesion. The contact angle between the liquid
and solid phases is maintained at an unusually high level because of this deforma-
tion. Surfactants can be used to reduce the interfacial tension, thereby reducing the
contact angle and achieving excellent wetting (Haines and Martin 1961b). The
hydrocarbon chain from the surfactants is adsorbed on the lipophilic surface of par-
ticles, while the polar end is retained in the liquid medium. Therefore, the necessary
wetting of solid materials can be accomplished by reducing the interfacial tension.
Young’s equation is used to determine whether a solid has become wet (Haines and
Martin 1961c).
co
sΘ=
−
γγ
γ
sv sl
lv
where γ is the interface tension between vapor (v), solid (s), and liquid phases and
Θ is the contact angle and the contact angle (L). Wetting agents can reduce the con-
tact angle by reducing sl in addition to the lv ratio. Wetting agents can be made
using surfactants having an HLB (Hydrophilic Lipophilic Balance) value of 7–9
(Kayes 1977). Most surface-active agents are employed as wetting agents in con-
centrations up to 0.1%. Polysorbates and sorbitan esters are two commonly used
oral humectants. One of the surfactants that is applied externally is SDS.Lecithin,
in addition to other ingredients, can be part of parenteral drugs along with polysor-
bates and some poloxamers. Excess surfactant can lead to deocculation or foamed
systems, neither of which is considered ideal (Matthews and Rhodes 1968a).
8.2.5 Electrokinetic Phenomena
Four electrokinetic processes, including electroosmosis, sedimentation potential,
electrophoresis, and streaming potential, can exist due to the existence of interfacial
potentials. In fact, all these features are the result of the motion of the charged sur-
face of the adjoining liquid phase (Khan etal. 2022). When a potential difference is
A. Rajora and K. Nagpal
205
applied, charged particles move through the liquid, and this movement is measured
by electrophoresis (Roura and Fort 2004). The z potential of a suspension can be
determined using:
Z
v
e
=× ×
()
×910
4
4
πη
ε
where e is the dielectric constant of the medium, Ƞ is the viscosity of the medium in
poises, Z is the zeta potential of the medium in volts, v is the migration speed of
particles in the electrophoresis tube in cm/s, and E is the potential gradient in V/cm
(Matthews and Rhodes 1968b).
8.2.6 DLVO Theory
The renowned DLVO (Derjaguin, Landau, Verwey, and Overbeek) theory, formu-
lated by Derjaguin, Landau, Verwey, and Overbeek during the 1940s (Derjaguin and
Landau 1941; Verwey and Overbeek 1948), elucidates scenarios in which van der
Waals forces coexist with electrostatic forces (Adair etal. 2001; Kellaway and Najib
1981). This theory operates on the premise that electrostatic double-layer forces and
van der Waals forces act independently. Hence, these forces can be combined or
summed at each interacting distance between two particles (Lieberman etal. 1987).
Several researchers have considered the method of so-called controlled occulation
for the preparation of drug suspensions and this is well-known (Trefalt and Borkovec
2014; Yotsumoto and Yoon 1993). The idea of “controlled occulation” is based on
the knowledge of the so-called DLVO theory of colloidal stability (Pal etal. 2010;
Strum etal. 1978). This implies that the van der Waals attraction (VA) and the repul-
sion (VR) combine to create potential energy (V) because of contact among the two
particles (Venkateshwarlu etal. 1990).
The phrases “coagulation” and “occulation” are often used interchangeably in
the literature to refer to the accumulation of particles in suspensions. The term
“coagulation” should be used only to describe primary minimal aggregation to pro-
vide the most satisfactory denition of these concepts (Short and Rhodes 1973).
The term “occulation” refers to the grouping of particles in a secondary minimum.
The latter term is also used to describe the occlusion of most particles and polymer
bridges caused by interactions between metal ions and polyelectrolytes. It has long
been believed that chemicals such as nonionic surfactants can stabilize a dispersion
if they are adsorbed on the particle surface in the absence of a detectable zeta poten-
tial (Liu etal. 2019). The interaction potential energy should also consider the addi-
tional steric stabilization term Vs (Jangde etal. 2011). Thus
However, the term “controlled occulation” is possibly a misnomer as:
8 Suspensions: Theory, Formulation Considerations, Flocculated and Deocculated…
206
1. It occurs when a secondary minimum is reached and the primary maximum is
reduced by the addition of electrolyte, deepening the secondary minimum
2. It is caused by polymer or metal ion polyelectrolyte bridges
3. Primary minimal coagulation is induced by the addition of electrolyte or other
charged species, the depth of which is limited by the steric effect of the addi-
tional surfactant or polymer, which is more precisely called controlled coagula-
tion (Khan etal. 2022)
The essence of the DLVO theory can be easily understood in Fig.8.2. The gure
depicts the opposite forces: electrical repulsion originating from the electric double
layer and attraction originating from the van der Waals force. These forces are
drawn in opposite directions because of their different natures. If the net energy
curve is consistently above the baseline, this indicates a repulsive state. Conversely,
curves below the baseline show attraction. The highest point of repulsion is called
the energy barrier itself (Kulshreshtha etal. 2010). To facilitate agglomeration, the
two particles on a collision course must possess sufcient momentum to overcome
this barrier. When particles successfully move through repulsion, they are brought
together by the force of attraction. In the future, they can be considered captured by
van der Waals-London forces (Martin 2001).
8.2.7 Theory ofSedimentation
Velocity of sedimentation is represented by Stoke’s equation:
rgdg
Sed
so
so
=
−
()
=
−
()
22
9
2
18
ρρ
η
ρρ
η
Fig. 8.2 Schematic interaction energy versus distance proles of DLVO interaction. The attrac-
tive van der Waals and the repulsive electrostatic potentials form the total interaction energy (Adair
etal. 2001). (Reprinted from Encyclopedia of Materials: Science and Technology, Second edition,
J.H.Adair, E.Suvaci, J.Sindel, Surface and Colloid Chemistry, page no. 1–10. Copyright (2001)
with permission from Elsevier)
A. Rajora and K. Nagpal
207
where d= particle diameter, η=viscosity of the dispersed medium in the poise,
v=sedimentation velocity in cm/s, g=acceleration due to gravity, r=radius of the
particle, ρ
o
=density of the dispersed medium, and ρ
s
=density of the dispersed
phase. Particle size is the most important variable because it is squared in equation.
A modest settling velocity is produced by smaller particles. To reduce settling, one
can increase the viscosity of the medium. Cellulose compounds such as methyl cel-
lulose and hydroxypropyl methyl cellulose are often used as viscosity enhancers
(Cooper and Gun 2002). Natural gums are additional examples (e.g., acacia and
tragacanth). The disparity in densities between the dispersed phase and the continu-
ous phase may have an impact on the rate of settling. Zero denotes the absence of a
delay. Since the density of the dispersed phase cannot be altered, the medium would
need to be made denser (Banker and Rhodes 1979).
8.2.7.1 Limitation ofStoke’s Equation
• Only spherical particles in a highly dilute solution obey Stoke’s equation (0.5–2g
per 100mL).
• The particles should fall freely and independently of each other (without
collision).
• The particles should not have any physical or chemical attraction or afnity to
the dispersion medium, but since most pharmaceutical suspension formulations
are 5%, 10%, or higher in consistency, there is a possibility that particle settling
will be difcult (Ansel etal. 2005).
8.2.8 Important Considerations forSuspension
The creation of a pharmaceutical suspension requires knowledge of the parameters
of the dispersion component and the dispersion medium. When choosing ingredi-
ents for the creation of a suspension, it’s crucial to take the route of administration,
the intended purpose, and any potential side effects into account (Martin and
Swarbrick 1966). The following considerations should be made when making phar-
maceutical suspensions:
1. Suspended material’s nature: In the formulation of a slurry, the boundary quali-
ties of the suspended material are crucial. Low surface tension particles can be
easily wetted by water and suspended as a result. High interfacial tension mate-
rial particles do not wet readily, nevertheless. Surfactants are typically used to
suspend such materials. Surfactants make particles more wettable (Soci and
Parrot 1980).
2. Size of suspended particles: According to Stoke’s rule, a smaller particle size
causes a slower rate of deposition for suspended particles. Processes including
grinding, screening, and crushing can reduce the particle size. The speed and
volume of medication absorption, dissolution, and biodistribution are also inu-
enced by particle size. However, above a certain point, particle size reduction
might cause a compact cake to form during deposition (Ludwing and Van
Ooteghen 1988).
8 Suspensions: Theory, Formulation Considerations, Flocculated and Deocculated…
208
3. Viscosity of the continuous phase: Higher viscosity of the continuous phase
ensures lower sedimentation. Nevertheless, this may negotiate additional neces-
sary properties like syringeability of parenteral suspensions, dispersibility of
topical suspensions, and ease of pourability of oral suspensions. The shear thin-
ning property is extremely necessary as it will offer comparatively higher viscos-
ity of suspension during storage (low shear); and thus, the settling is slow. After
mixing (high shear), the viscocity is lower which permit better pourability of the
suspension from the bottle (Pennington etal. 1988).
8.3 Classification ofSuspensions
Particles suspended within a liquid medium have the potential to experience both
van der Waals forces that attract them and electrostatic forces that repel them.
Consequently, these forces can lead to the dispersion of particles, their clumping
into aggregates, or their formation into clusters. Some differences between occu-
lated and deocculated suspension are shown in Fig.8.3. The interplay of attractive
and electrostatic repulsive forces at the particle’s surface dictates the extent of both
aggregation and clustering processes.
8.3.1 Flocculated Suspension
The structure of occulation is due to a combination of a strong attractive force and
a reduction in electrical repulsive forces between dispersed particles in suspension.
When this happens, the particles come closer to each other with less attraction,
resulting in a loosely aggregated structure known as a occules. The rate of
Fig. 8.3 A comparison of occulated and deocculated suspension
A. Rajora and K. Nagpal