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12. Wei Z, Huang Q.Edible Pickering emulsions stabilized by ovotransferrin–gum arabic par-
ticles. Food Hydrocolloids. 2019;89:590–601.
13. Matubayasi N.Surface tension and related thermodynamic quantities of aqueous electrolyte
solutions: CRC Press, Boca Raton, Florida. 2013:48
14. Geng T, Qiu Z, Zhao C, Zhang L, Zhao X, etal. Rheological study on the invert emulsion uids
with organoclay at high aged temperatures. Colloid and Surfaces. 2019;573:211–221.
15. Khan BA, Akhtar N, Khan HMS, Waseem K, Mahmood T, Rasul A, et al. Basics of
pharmaceutical emulsions: A review. African Journal of Pharmacy and Pharmacology
2011;5(25):2715–2725.
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81© The Author(s), under exclusive license to Springer Nature Switzerland AG 2022
S. A. Khan (ed.), Essentials of Industrial Pharmacy, AAPS Advances in the
Pharmaceutical Sciences Series 46, https://doi.org/10.1007/978-3-030-84977-1_7
Chapter 7
Oral Suspensions
SaeedAhmadKhan, AbdulBaseer, SalarKhan, andMehmoodHussain
Abstract The use of suspension dosage form has a long history for poorly soluble
drugs. Development of stable suspension of the drug product has been a challenge
on many fronts. In this chapter some of the important aspects of stable suspension
formulation are discussed. Particularly, properties related to drug delivery and sus-
pension stability are explained in detail. Suspension with regard to theoretical con-
sideration including occulation, viscosity, particle settling, zeta potential, Ostwald
ripening, and particle aggregation is explained. Discussion relevant to excipients is
also included. Moreover, methods of particle size reduction are introduced, includ-
ing those employed for nanosuspension.
Keywords Electric double layer · DLVO theory · Flocculation · Coagulation ·
Manufacturing of suspension
7.1 Introduction
The dispersion system in which the drug (dispersed phase) is dispersed as nely
divided insoluble particles in the vehicle (dispersion medium) is termed as pharma-
ceutical suspension [1].
The dispersed phase tends to separate on storage; therefore, it is important to
control the process of separation, usually with the help of suspending agent(s) or
surfactant(s). A stable suspension is the one that ensures an accurate dose after
S. A. Khan (*) · M. Hussain
Department of Pharmacy, Kohat University of Science and Technology, Kohat, Pakistan
e-mail: saeekhan@kust.edu.pk
A. Baseer
Department of Pharmacy, Abasyn University, Peshawar, Pakistan
S. Khan
Department of Pharmacy, Abdul Wali Khan University Mardan, Mardan, Pakistan
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82
shaking. Ideally, pharmaceutical suspension should have the following proper-
ties [2]:
– It should exhibit low sedimentation rate.
– It should be easily redispersible on gentle shaking.
– It should be easily dispensed from container.
– It should be acceptable for patients in terms of taste, smell(in case of oral sus-
pensions), and administration.
Advantages Pharmaceutical suspension is used for a variety of pharmaceutical
uses, for instance, drugs having low solubility, e.g., prednisolone, are formulated as
suspensions [3]. Furthermore, the degradation of some drugs, e.g., oxytetracycline,
might be prevented when they are formulated as suspension [1]. Suspension can
also be used to mask the bitter taste of drugs, e.g., chloramphenicol palmitate sus-
pension. Moreover, suspension can be helpful in controlling the release of drugs,
e.g., procaine penicillin. Besides, in some cases, suspension dosage form is the only
option available for administration of drugs, e.g., some vaccines like cholera vac-
cine [4].
Disadvantages Pharmaceutical suspensions may exhibit physical instability, e.g.,
sedimentation and cracking during shelf life. Special formulation measures are
required to minimize instability and to ensure uniform dosing. Moreover, formula-
tion of aesthetically good suspension is very challenging. Besides, suspensions
require careful handling during transport [4].
7.2 Dispersed Particles inaMedium
The particles when dispersed in a medium exhibit electrical charges either due to
ionization of functional groups, e.g., COOH and NH
2,
or by adsorbing ions to its
surface. Once the surface of dispersed particles gets a charge, a phenomenon called
electrical double layer takes place [5], as shown in Fig.7.1. The charged particle
attracts counterions that form an immovable layer around the particle and is called
the stationary layer or stern layer. However, the surface charge of particle is not
completely neutralized. This residual surface charge attracts more counterions from
its surrounded medium so that a second layer of counterions is developed around
the particle. This layer is farther away from the particle surface. The attractive forces
of the particle charged surface get weaker with the distance. Therefore, this second
layer is less ordered and movable and is called diffuse layer. Both anions and cations
are present in diffuse layer, but ions that are of opposite charge to the surface pre-
dominate. There exists an imaginary boundary within the diffuse layer, and inside
this boundary the particle acts as a single entity, called slipping plane. The potential
at slipping plane is said to be zeta potential [6].
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The magnitude of zeta potential shows the degree of electrostatic repulsion
between two nearest particles. However, along with the electrostatic repulsive
forces, van der Waals forces of attraction also exist. The well-known Derjaguin-
Landau- Verwey-Overbeek theory (DLVO theory) suggests that the van der Waals
attractive forces and electrostatic repulsive forces can be superimposed at each
interacting distance between adjacent particles. So the overall energy of interaction
between particles (Vt) is the sum of the energies of attraction (Va) and energies of
repulsion (Vr) [7].
VVV
tar
(7.1)
As shown in Fig.7.2, three main regions may be observed in the total energy of
interaction:
The primary minimum: This is a region of high degree of instability of formula-
tion. In this region, particles exhibit strong attraction and tend to exhibit coagula-
tion (irreversible aggregates).
The primary maximum: In this region, the repulsion interaction between particles
predominates and particles tend to repel each other. The magnitude of repulsion
is dependent on adjacent particles’ zeta potential.
The secondary minimum: in this region, attractive forces predominate over repul-
sive forces; however, as compared to primary minimum, the magnitude of
attraction is less. Consequently, the particles undergo occulation, i.e., the for-
mation of loose aggregates (occules), as shown in Fig. 7.3. The sediment
formed in occulated suspension can be easily redispersed by gentle shaking.
This phenomenon is sometimes exploited for controlled occulation [8].
Fig. 7.1 Diffuse double layer model of a positively charged surface in an aqueous medium
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7.3 Formulation Considerations
The excipients used in formulation of oral suspensions are summarized in Table7.1.
The following section discusses various factors that need to be considered during
formulation of stable pharmaceutical suspension.
Fig. 7.2 Diagrammatic representation of the overall interactive energy between two particles and
their distance of separation
Fig. 7.3 Schematic representation of stable suspension (a), coagulation (b), and occulation (c)
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7.3.1 Chemical Incompatibility
The compatibility of all the ingredients in suspension, i.e., buffers, drugs, and sus-
pending agents should be thoroughly investigated. For instance, carboxymethyl cel-
lulose (CMC) may interact with cationic excipients, e.g., benzalkonium chloride,
and get precipitated. Therefore, the use of CMC should be avoided in the presence
of cationic excipients [9].
7.3.2 Particle Size
Thephysical stability of a suspensions is directlydependent on the particle sizeof
dispersed phase. According to Stokes equation, the rate of sedimentation (V) is
directly proportional to particle size (d) and the difference of particle-vehicle densi-
ties (ρ
s
−ρ
o
) and inversely proportional to viscosity of the vehicle (η):
Table 7.1 Common excipients used in pharmaceutical suspensions
Excipients Examples
Vehicle Puried water (USP)
Glycerin, polyethylene glycol, propylene glycol, and alcohol
Buffers Citric acid/sodium citrate
Acetic acid/sodium acetate
Suspending agents/
viscosity builders
Cellulose derivatives: Sodium carboxymethylcellulose, hydroxypropyl
methylcellulose, etc.
Natural gums: Acacia, tragacanth, guar gum, xanthan gum, etc.
Natural polymers: Chitosan, agar, alginate, etc.
Synthetic polymers: Polyvinylpyrrolidone, carbopol, polyvinyl alcohol,
etc.
Flocculating agents Electrolytes: Sodium chloride, aluminum chloride, potassium
dihydrogen phosphate, etc.
Surfactants: Docusate sodium, sodium lauryl sulfate, sorbitan
monolaurate, etc.
Hydrophilic polymer: Tragacanth, sodium carboxymethylcellulose, etc.
Wetting agents Surfactants: Phosphatidyl choline; sodium dodecyl sulfate; polysorbate
(Tween
®
) 20, 40, 60, and 80; sorbitan esters (Span
®
) 40, 60, and 80;
cetrimide; etc.
Hydrophilic polymers: Gelatin, acacia, cellulose derivatives, etc.
Antimicrobial agents Benzalkonium chloride (also used as surfactant), methyl and propyl
parahydroxybenzoic acid, benzoic acid, etc.
Antioxidants Ethylenediamine tetraacetic acid (EDTA), sodium metabisulte, sodium
sulte, ascorbic acid, etc.
Sweetening agents(in
case of oral
suspension)
Dextrose, fructose, glucose, aspartame, maltose, mannitol, saccharin,
sorbitol etc.
Other excipients Specic colorants and avors may also be used
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Vd
g
so
2
18
(7.2)
where:
V=sedimentation rate
d=particle diameter
ρ
s
=particle density
ρ
o
=vehicle density
g=gravitational force
η=vehicle viscosity
Dissolution of drug can also be affected by particle size. Reduction in particle
size increases dissolution rate of drug; hence the bioavailability of drug may
beincreased.
Moreover, the particle size also depends on the intended route of application. For
instance, too large particle size imparts gritty texture to the pharmaceutical suspen-
sion that can be unfavorable for ophthalmic and topical application. For this reason,
particles size in ophthalmic and topical suspensions is typically around 1μm and
10–100μm, respectively [10].
An ideal suspension has a constant average particle size throughout the shelf life.
However, sometimes a slight increase in storage temperature enables the smaller
drug particles to dissolve. Recrystallization of dissolved drug occurs on the larger
particle surfaces, thus increasing the average particle size. This phenomenon is
called crystal growth or Ostwald ripening [11]. Inclusion of hydrophilic polymers
in formulation can prevent crystal growth by adsorbing on to the surface of dis-
persed drug particles.
7.3.3 Viscosity
Viscosity is the property of a uid to resist the ow (shear deformation). In technical
terms, viscosity (η) is shear stress divided by shear rate.
Shear stress is the force experienced by a cross section of uid to move the uid
layers past each other. Shear rate is the rate at which the uid layers move past
each other.
The uids where shear rate linearly increases with shear stress, i.e., viscosity of
uid remains constant, these are called Newtonian uids, e.g., water and honey.
However, in reality, most of the suspensions exhibit non-Newtonian ow, and the
uid shows a nonlinear relationship between shear stress and shear rate, i.e., the
viscosity of uid varies with shear rate. Non-Newtonian uids are called pseudo-
plastic or shear-thinning uids when with increase in shear rate the viscosity of
uid decreases. However, when uid viscosity increases with increasing shear rate,
the uid is termed as shear-thickening or dilatant uid. In some uids, a certain
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stress level, called yield stress or yield value, is required to initiate ow; these uids
if after the yield stress exhibit Newtonian ow are called plastic uids or Bingham
uids [12]. And if the uid exhibits shear-thinning behavior after yield stress, then
the uids are termed as viscoplastic uids. The ow curves of different type of uids
are given in Fig.7.4.
As mentioned earlier the rate of sedimentation is inversely proportional to the
viscosity. The physical stability of suspension can be improved by increasing the
viscosity. Adding a suspending agent is one of the most common methods of
increasing the viscosity, although too high viscosity is undesirable due to poor pour-
ability and dosing.
7.3.4 Wetting
For preparation of stable suspension, the solid dispersed particles should be com-
pletely wetted by the solvent. Since water is commonly used as vehicle for pharma-
ceutical suspension, therefore particles that are hydrophilic in nature are easily
wetted by water. Contrarily, in hydrophobic materials water does not penetrate into
the inter-particular spaces of powder. Therefore, wetting agent is added to improve
wetting of the hydrophobic powder.The wetting property of material can be assessed
by measuring the contact angle, which is the angle a liquid creates on a solid sur-
face, as shown in Fig.7.5.
Surfactants are frequently used as wetting agents in pharmaceutical suspensions.
Surfactants act as wetting agent by decreasing the solid-liquid interfacial tension.
Fig. 7.4 Graphical
representation of ow
property of various types
of uids
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Surfactants with HLB value 7–9 act as wetting agents [5]. Besides this, hydrophilic
polymers, e.g., carboxymethyl cellulose, etc., are also used as wetting agent.
7.3.5 Mixing
Homogeneous dispersion of drug in vehicle requires efcient mixing. The mixers
employed in manufacturing of pharmaceutical suspension must have the capacity to
mix viscous material. Mixing time must be critically validated, since too much
shearing results in accumulation of air in the bulk liquid.
7.3.6 Size Reduction andHomogenization
As discussed earlier, particle size can affect the sedimentation rate and redispersion
of the sedimented particles. For small scale, the particle size can be reduced by
pestle and mortar. For large-scale manufacturing, homogenizers, such as colloid
mill, piston gap homogenizer, etc., described in Chap.3 Sect. 7.2, are employed.
Typically, homogenization is the last step in manufacturing of almost all types of
pharmaceutical suspensions [13].
7.3.7 Flocculation
Flocculation is a phenomenon whereby small suspended particles form loose aggre-
gates (occules) that can be easily separated by gentle shaking. Flocculation of
particles occurs when repulsive electrical forces in a dispersed system become low
to the extent (i.e., secondary minimum) that the suspended particles can form oc-
cules. The occules settle and produce sediment which is less dense and easier to
redisperse on gentle shaking than a sediment produced by deocculated suspension.
The major difference between occulated and deocculated suspension is given in
Table7.2. It should be noted that too much reduction in repulsive forces may result
Fig. 7.5 Contact angle at hydrophilic and hydrophobic surfaces
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into irreversible aggregates of particles (coagulation). With the use of occulating
agents (e.g., electrolytes, polymers, surfactants, etc.), the occulation process can
be adequately controlled, called controlled occulation [8].
7.3.8 Preservation
Suspensions for oral administration are multidose products; therefore, preservation
against microorganisms is necessary. The limits regarding number and type of
microorganisms in oral solutions and suspensions are specied in various pharma-
copoeias. For instance, the European Pharmacopoeia species that oral products
should be free from E. coli; moreover, the number of aerobic bacteria and fungi per
gram or milliliter should be less than 1000 and 100, respectively.
Additionally, oral suspensions also require preservation against oxidation to
enhance the chemical stability of drug [14]. Antioxidants are compounds (e.g.,
sodium sulte, ascorbic acid, sodium metabisulte, etc.) that get oxidized faster
than the drug, hence preventing oxidation of drug. Chelating agents, e.g., ethylene-
diamine tetraacetic acid (EDTA), citric acid, etc., also act as antioxidant by forming
complexes with heavy metal ions that are involved in oxidative degradation of drugs.
7.4 Industrial-Scale Manufacturing ofSuspension
Pharmaceutical suspension is usually manufactured by two methods:
1. Direct incorporation method
2. Precipitation method
7.4.1 Direct Incorporation Method
According to this method the drug is directly incorporated into previously prepared
vehicle. For simplication the process is divided into various steps.
Table 7.2 Physical attributes of occulated and deocculated suspension
Deocculated suspension Flocculated suspension
Particles are suspended as separate entities Particles are suspended as loose
aggregates
Slow rate of sedimentation Fast rate of sedimentation
The sediment is hard to be redispersed The sediment is easily redispersible
Due to uniform dispersion of relatively smaller
particles, the suspension has a pleasing appearance
Due to dispersed occules, the
suspension has visible distinct phases
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