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Paper Coordinator
Content Reviewer
Dr. Vijaya Khader
Dr. MC Varadaraj
Principal Investigator
Dr. Vijaya KhaderFormer Dean, Acharya N G Ranga Agricultural University
Content Writer
Prof. Farhan J Ahmad Jamia Hamdard, New Delhi
Paper No: 05 Product Development 1
Module No: 31 Suspension Part 1:
Development Team
Dr. Gaurav Kumar Jain Jamia Hamdard, New Delhi
Prof Roop K. Khar BSAIP, Faridabad
Prof. Dharmendra.C.Saxena
SLIET, Longowal
Dr. Gaurav Kumar Jain Jamia Hamdard, New Delhi
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Introduction
Biphasic liquids such as suspensions and emulsions are unique dosage forms because many of their
properties are due to the presence of a boundary region between two phases. In suspensions, a liquid and
an insoluble solid, meet to form an interface. In the case of emulsions, two immiscible liquids, usually
oil and water, form an interface. An interface between the liquid and air is also present. Although the
terms interface and surface are often used interchangeably, the latter term usually indicates boundaries
in which one phase is a gas. The most important and fundamental property of any interface is that it
possesses a positive free energy. Essentially, this means that the molecules at the interface are in a higher
energy state than if they were located in the bulk phase (Figure 1). The greater the preference of the
molecule of interest for the bulk, as compared with the interface, the higher the interfacial free energy.
FIG. 1. Diagrammatic representation of the positive free energy of interface.
The primary objective of the formulator is to reduce this positive interfacial free energy value to zero by
various means. One approach is simply to reduce the amount of interface i.e., via flocculating or
aggregating of particles (in case of suspensions) or via coalescence of the globules to form one macro-
phase (in case of emulsions). Another method to reduce interfacial free energy is to vary the composition
of the interface to make it rich in surface active material.
Figure 1 illustrates the types of boundary regions that are discussed in this chapter. The boundary regions
are often complex. Surface active agents, which are molecules with special properties, may be contained
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within a system in various forms: they may be present as single molecules in solution (Figure 2A); they
may also be adsorbed at the air-liquid surface (Figure 2B); they may form a layer at the oil-water interface
(Figure 2C); or they may form oriented clusters in the aqueous phase, which are called micelles (Figure
2D). Attractive and repulsive forces exist between particles, and the outlined region surrounding the
particles in Figure 2 indicates a region of potential interaction.
FIG. 2. Schematic representation of boundary regions encountered in suspensions and emulsions. Key:
A, surface active agent molecules; B, surface active agent oriented at the air-water interface; C, surface
active agent oriented at the oil-water interface; D, micelle; E, suspended particles surrounded by a
region of potential interaction.
In addition, the molecules in the interfacial region are not locked into position but are in constant
motion. The average interfacial residence time for a molecule of a liquid is believed to be approximately
106 sec. Thus, the interfacial region of suspensions and emulsions is a dynamic, clearly identifiable
region between the phases of the system.
When the interfacial region constitutes a large portion of the system—as when the particle size
of the solid phase of a suspension is small or when the globule size of the dispersed phase of an emulsion
is small,—the overall properties of the system are profoundly influenced by the presence of the interfacial
region.
A fundamental thermodynamic equation that describes suspensions and emulsions is as follows:
G A (1)
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Where G is the change in the free energy of the system accompanying a change in interfacial area A,
is the interfacial tension (liquid-liquid for an emulsion or solid-liquid for a suspension), and
temperature, pressure, and composition are constant. The term G represents the work required to
increase the area of the interface by an amount equal to A. Since this work is always positive, a system
always tends toward that state having the lowest possible interfacial area. This state is
thermodynamically stable.
Suspensions are heterogeneous systems consisting of two phases. The continuous or external
phase is generally a liquid or semisolid, and the dispersed or internal phase is made up of particulate
matter that is essentially insoluble in, but dispersed throughout, the continuous phase; the insoluble
matter may be intended for physiologic absorption or for internal or external coating functions.
Suspensions can be classified in various ways based on their physical state as suspension, aerosol
and foam; based on the size of the dispersed particles as molecular dispersion (size <1.0 nm), colloidal
dispersion (0.1 - 0.2 µm) and coarse dispersion (size >0.2 µm); based on behavior of dispersed phase
which may consist of discrete particles (deflocculated suspensions), or it may be a network of particles
(flocculated suspensions), resulting from particle-particle interactions.
Suspensions contribute to pharmacy and medicine by supplying insoluble and often distasteful drugs in
a form that is pleasant to taste, by providing a suitable form for the application of dermatologic materials
to the skin or mucous membranes, and for the parenteral administration of insoluble drugs. Therefore
pharmaceutical suspensions may be classified into three general classes: oral, topical and parenteral
suspensions.
Oral Suspensions.
Oral suspensions are oral liquids containing one or more active ingredients suspended in a
suitable vehicle. Suspended solids may slowly separate on keeping but are easily redispersed.
The solids content of an oral suspension may vary considerably. For example, antibiotic preparations,
antacids and radiopaque suspensions contain relatively high amounts of suspended material for oral
administration. The vehicle may be a syrup, a sorbitol solution, or a gum-thickened, water-containing
artificial sweetener because in addition to ingredients, safety, taste, and mouthfeel are important
formulation considerations. In the case of limited shelf life (low chemical stability of the insoluble drug),
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the dosage form may be prepared as a dry granulation or powder mixture that is reconstituted with water
prior to use.
Topical Suspensions.
Historically, the externally applied ‘‘shake lotion’’ is the oldest example of a pharmaceutical
suspension. Calamine Lotion USP, as well as other dermatological preparations, is closely associated
with the technical development of the pharmaceutical suspension. Because safety and toxicity
considerations are most readily dealt with in terms of dermatological acceptability, many useful
suspending agents were first introduced in topical formulations. In addition, the protective action and
cosmetic properties of topical lotions usually require the use of high concentrations of the dispersed
phase, often in excess of 20%. Therefore, topical lotions represent the best example of suspensions that
exhibit low settling rates. Various pharmaceutical vehicles have been used in the preparation of topical
lotions, including diluted oil-in-water or water-in-oil emulsion bases, determatological pastes, magmas,
and clay suspensions.
Parenteral Suspensions.
The solids content of parenteral suspensions is usually between 0.5 and 5.0%, except for insoluble
forms of penicillin, in which concentrations of the antibiotic may exceed 30%. These sterile preparations
are designed for intramuscular, intradermal, intra-lesional, intra-articular, or subcutaneous
administration. The viscosity of a parenteral suspension should be low enough to facilitate injection.
Common vehicles for parenteral suspensions include preserved 0.9% saline solution or a parenterally
acceptable vegetable oil. The primary factor governing the selection of injectable ingredients is safety.
Ophthalmic suspensions that are instilled into the eye must be prepared in a sterile manner. The vehicle
employed is essentially isotonic and aqueous in composition.
Traditionally, certain kinds of pharmaceutical suspensions have been given separate designations, such
as mucilages, magmas, gels, and sometimes aerosols; also included would be dry powders to which a
vehicle is added at the time of dispensing.
Suspensions form an important class of pharmaceutical dosage forms. These disperse systems
present many formulations, stability, manufacturing, and packaging challenges. Almost all suspension
systems separate on standing. The formulator’s main concern, therefore, is not necessarily to try to
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eliminate separation, but rather to decrease the rate of the settling and to permit easy resuspendability of
any settled particulate matter. A satisfactory suspension must remain sufficiently homogeneous for at
least the period of time necessary to remove and administer the required dose after shaking its container.
For the most part, only aqueous suspensions are discussed, and little attention is paid to oils or aerosol
propellants as suspension vehicles. Also, this discussion is limited to suspensions with particles having
diameters greater than 0.2 micron, approximately the lower limit of resolution of optical microscopes.
Thus, although suspended particles do not exhibit all the properties of colloids, such as the so called
colligative properties, they do have heightened surface properties, that is, whatever surface properties
exist are magnified because of the increased surface area.
Theoretic Considerations
Knowledge of the theoretic considerations pertaining to suspension technology should ultimately
help the formulator to select the ingredients that are most appropriate for the suspension and to use the
available mixing and milling equipment to the best advantage. Some understanding of wetting, particle
interaction, electro kinetics, aggregation, and sedimentation concepts facilitates the making of good
formulatory decisions.
Wetting
A frequently encountered difficulty that is a factor of prime importance in suspension formulation
concerns the wetting of the solid phase by the suspension medium. Certain solids are readily wet by
liquid media whereas others are not. In aqueous suspension terminology, solids are said to be either
hydrophilic (lyophilic or solvent-loving, rarely lyotropic) or hydrophobic (lyophobic). Hydrophilic
substances are easily wet by water or other polar, liquids; they may also greatly increase the viscosity of
water suspensions. Hydrophobic substances repel water but can usually be wetted by nonpolar liquids;
they usually do not alter the viscosity of aqueous dispersions. Hydrophilic solids usually can be
incorporated into suspensions without the use of a wetting agent, but hydrophobic materials are
extremely difficult to disperse and frequently float on the surface of the fluid owing to poor wetting of
the particles or the presence of tiny air pockets.
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When a strong affinity exists between a liquid and a solid, the liquid easily forms a film over the
surface of the solid. When this affinity is nonexistent or weak, however, the liquid has difficulty
displacing the air or other substances surrounding the solid, and there exists an angle of contact between
the liquid and the solid. This contact angle, , results from an equilibrium involving three interfacial
tensions, specifically, those acting at the interfaces between the liquid and vapor phases, at the solid and
liquid phases, and at the solid and vapor phases. These tensions are caused by unbalanced intermolecular
forces in the various phases.
As can be seen in Figure 3, the contact angle varies from 0 to 180° and is a useful indication of wetting.
A low contact angle indicates that adhesive forces between the liquid and the solid predominate and
wetting occurs, while a high contact angle indicates that the cohesive forces of the liquid predominate.
FIG. 3. The use of the contact angle, , to characterize the wetting of a solid by a liquid.
The basic equation that applies to wetting is the Young equation, which is based on the change in free
energy caused by an increase in the area of a solid that is wetted by a liquid. For a small, reversible
change in the position of the liquid on the surface, there is an increase in the liquid-solid interfacial area,
A, and a corresponding decrease in the solid-air interface of A cos . The corresponding free energy
change is given by:
S/ L S/ A L/ AG A A cos A (2)
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As A approaches zero, the ratio G/A approaches zero at equilibrium, so that equation (2) reduces to
the Young equation:
𝛾𝑆/𝐴 = 𝛾𝑆/𝐿 + 𝛾𝐿/𝐴𝑐𝑜𝑠𝜃 (3)
The Young equation states that the contact angle will be <90° if the interaction between the solid and
liquid is greater than the interaction between the solid and air, i.e., S/L > S/A. Under these conditions,
wetting occurs. A general guideline is that solids are readily wetted if their contact angle with the liquid
phase is less than 90°.
The wetting of a solid during the manufacture of a suspension involves the displacement of air
from the solid surface. The first step in the wetting of a powder is adhesional wetting, in which the
surface of the solid is brought into contact with the liquid surface. This step is the equivalent of going
from stage a to stage b in Figure 4. The particle is then forced below the surface of the liquid as
immersional wetting occurs (b to c in Figure 4). During this step, solid-liquid interface is formed, and
solid-air interface is lost. Finally, the liquid spreads over the entire surface of the solid as spreading
wetting occurs. The work of spreading wetting is equal to the work to form new solid-liquid and liquid-
air interfaces minus the loss of the solid-air interface. For the total wetting process, the work required is
the sum of the three types of wetting:
𝑊𝑡𝑜𝑡𝑎𝑙 = −6 𝛾𝐿/𝐴𝑐𝑜𝑠𝜃 (4)
Therefore, the analysis supports the generalization drawn from the Young equation, as wetting occurs
spontaneously, i.e., without any input of work into the system, if the contact angle is <90°.
FIG. 4. The three stages involved in the wetting of a solid : a b, adhesional wetting; b c,
immersional wetting; c d, spreading wetting.
Particle Interactions and Behavior
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Electric double layer
Formulation of a suspension or emulsion necessitates the use of ionic surface active agents as the
suspending agent or the emulsifying agent. The surface active agents are oriented at the oil-water
interface, so that the charged, groups form the outside surface. The presence of charge at an interface has
profound effects on the nature of the interfacial region. Figure 5 presents a model of the interfacial region
of a charged surface and provides a good basis for understanding the behavior of pharmaceutical
suspensions and emulsions.
A layer of ions of opposite charge is sufficiently held together by the charged surface so that the
ions move with the surface (Stern layer). The surface charge is not completely balanced by the Stern
layer, and a second region, the diffuse layer, is necessary for complete balance of the surface charge.
The diffuse layer contains both anions and cations, but ions that are of opposite charge to the surface
predominate, so that in the neighboring area of any charged particle, there exists an ion atmosphere
having a net charge that is opposite to that of the surface. The concept of a diffuse double layer was
developed by Gouy and Chapman to describe the transition from points near the charged surface to the
electrically neutral bulk solution.
FIG. 5. Diffuse double-layer model of a positively charged surface in an aqueous medium.
This mobile layer of ions has a definite thickness, which is approximated by the so-called Debye length
(1/k):
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1 𝑘⁄ = (𝐷𝑘𝑡
2𝑛𝑒2𝑍2)1/2
(5)
Where, D is the dielectric constant of the medium, n is the concentration of ions in the bulk solution
phase, e is the electronic charge, Z is valence, k is Boltzman’s constant, and T is temperature. Beyond
this distance (1/K), the net charge density of the ion atmosphere approaches zero, and the electrical
potential is reduced considerably below its value at the surface. The major factors affecting the thickness
of the double layer are the electrolyte concentration of the solution, n, and the valence, z, of the counter
ions.
The terms lyophobic (hydrophobic) and lyophilic (hydrophilic) were mentioned in the previous
section. These terms are sometimes considered synonymous with non-wetting and wetting, respectively.
The primary behavioral difference between these two classes of materials is their sensitivity to the
presence of electrolytes. Lyophobic materials in suspension are sensitive to the addition of salts, whereas
lyophilic materials are not. Addition of large amounts of electrolyte to a solution of a lyophilic material
results in precipitation of lyophilic material, although dilution with the vehicle reverses the precipitation.
As distinct from lyophilic materials, dilution with the vehicle does not reverses the precipitation of
lyophobic solids. However, in the case of the lyophobic material, one may not observe aggregation, the
desired form of matrix formation during sedimentation. The stability of lyophobic colloids is also
reduced by lowering the repulsive potential of the electrochemical double layer or by decreasing the
degree of hydration.
In addition to the repulsion between particles resulting from the diffuse double layer, the ionic strength
and the valence and size of the ions on the surface and in the double layer influence both the total charge
and the thickness of the double layer; these factors also influence hydration.
The Schulze-Hardy rule states that the valence of the ions having a charge opposite to that of the
hydrophobic particle appears to determine the effectiveness of the electrolyte in aggregating the particles.
The aggregating value or efficiency therefore increases with the valence of the ions. Divalent ions are
ten times as effective as monovalent; trivalent are one thousand times as effective as monovalent. It is
important to remember that this rule is valid only for systems in which there is no chemical interaction
between the aggregating electrolyte and the ions of the double layer of the particle surface.
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Note also, incidentally, that aggregating forces are of sufficient magnitude to overwhelm the
electrostatic repulsion between particles having net charges of the same sign. With respect to actual
electrolyte concentrations used, satisfactory aggregation has been found to occur at the following
approximate ion concentrations: 25 to 150 mmol/L for monovalent ions, 0.5 to 2.0 mmol/L for divalent
ions, and 0.01 to 0.1 mmol/L for trivalent ions. The influence of valence and concentration on the
aggregation of a lyophobic particle suspension can be determined experimentally by either measuring
the change in zeta potential or by observing the degree of aggregation in terms of some measurable
parameter such as sediment height.
Although it is not pharmaceutically useful to a great extent, the Hofmeister or lyotropic series
rule applies to hydrophilic particles in a manner somewhat analogous to the Schulze-Hardy rule, and
takes into account not only the charge but also the ionic size and hydration capability. In order of
decreasing aggregating ability, the monovalent cation and anion progressions are respectively Cs+, Rb+,
NH4+, K+, Na+, Li+, and F+, IO3
–H2PO4, BrO3–, CI–, CIO3, Br–, NO3, CIO4
–, I–, CNS–.
Interparticle Forces
Many observed properties of a disperse system reflect the net force of interaction between the particles
or globules that the system comprises. The following forces have been identified.
1. Electrostatic repulsive forces arise from overlapping of the diffuse double layers of approaching
surfaces. These forces depend greatly on the concentration and valence of electrolyte in solution.
2. Van der Waals attractive forces arise from the electromagnetic fluctuations in the molecules that
make up the surface. These forces are largely independent of the electrolyte.
3. Repulsive hydration forces arise from the structuring of water in the interfacial region. These forces
are independent of electrolyte concentration. At low electrolyte concentration, the contribution of this
force may not be observed, owing to the strong electrostatic repulsive forces. At high electrolyte
concentration, however, the diffuse double-layer interactions are weak, and the repulsive hydration
forces may determine the interaction of the surfaces.
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4. Born repulsive forces are of short range and operate over distances of atomic dimensions. They are
due to the repulsive effects of atomic orbital overlap.
5. Adhesive forces arise when surfaces are in contact. The adhesive forces depend on pH, specific
cations, and the crystallographic orientation of the surfaces.
6. Steric repulsive forces depend on the size, geometry, and conformation of molecules that are
adsorbed on the surface.
Deryaguin, Landau, Verwey and Overbeek recognize the concept of the balance between
electrostatic repulsive and van der Waals attractive forces between particles. Thus, the concept has
become known as the DLVO theory. Figure 6 illustrates the repulsive double layer and attractive van der
Waals forces at three electrolyte concentrations.
FIG. 6. Effect of electrolyte concentration on repulsive double-layer forces and attractive van der Waals
forces. Key: A, low electrolyte concentration; B, intermediate electrolyte concentration; C, high
electrolyte concentration.
At low electrolyte concentration – the repulsive forces predominate so that the particles remain
independent, and the system is considered dispersed.
At high electrolyte concentration – the repulsive forces are greatly reduced, so that the attractive van der
Waals forces predominate. These net attractive forces that the particles encounter cause the formation of
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an aggregate of particles, a process known as coagulation. Thus, the DLVO theory explains the fact that
the addition of electrolyte to a colloidal system causes coagulation.
When the repulsive hydration and Born repulsive forces are considered along with the double-layer
repulsive and van der Waals attractive forces, the net force diagram shown in Figure 7 is obtained.
FIG. 7. Net -potential energy curve for a particle in an electrolyte vehicle.
As two particles approach each other in an aqueous medium of proper electrolyte concentration, a weak
attractive force exists just beyond the range of the double-layer repulsive forces. This attractive region
is called the secondary minimum and is responsible for the particle interaction termed flocculation.
Particles therefore experience attraction at significant interparticle distances (10 to 20 nm) and form the
fibrous, fluffy, open network of aggregated particles known as floccules, as illustrated by Figure 8. Such
a suspension is called flocculated suspension. In this suspension type, the structure of aggregates is quite
rigid, hence, they settle quickly to form a high sediment height and are easily redispersible because the
particles constituting individual aggregates are sufficiently far apart from one another to preclude caking.
The secondary minimum is not observed if the repulsive forces extend further from the surface than
attractive forces. Thus, the adjustment of valence and concentration of the electrolyte can induce
flocculation.
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FIG. 8. An artist’s conception of open-network suspension aggregate.
A repulsive barrier termed the primary maximum separates the secondary minimum from the primary
minimum. The magnitude of the repulsive force at the primary maximum determines whether a
flocculated system will remain flocculated. If the thermal energy in the system is similar to, or greater
than, the repulsive barrier, then the particles in the system are able to move closer together (0.5 to 2.0
nm) and encounter strong attraction due to the primary minimum. The strong attraction in the primary
minimum gives rise to the particle interaction termed coagulation. Other sources of energy, such as
centrifugation or compression of the particles due to freezing may force particles into the primary
minimum by overcoming the primary maximum and may lead to coagulation.
Closed aggregate, or coagule is characterized by a tight packing produced by surface film bonding, as
shown by Figure 9. These aggregates settle slowly to low sediment heights that approach the sediment
density of a dispersed particulate system. Characteristically, sediments composed of closed aggregates
are not easily redispersed. The affinity of surface films to each other is responsible for the tenacity of the
aggregate not only within an individual aggregate, but also to surrounding aggregates. Upon
sedimentation, the aggregates tend to form a single large “film-bonded” aggregate, which is difficult, if
not impossible, to redisperse. The surface films that lead to coagule formation are often surfactants,
gases, immiscible liquids, and in the case of non-aqueous suspensions, water.
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FIG. 9. An artist’s conception of closed suspension aggregate.
At low electrolyte concentration, the interaction curve contains a much larger primary maximum than at
higher ionic strength conditions, and particle interactions are minimized. Such a suspension is called
dispersed, deflocculated or peptized. In this suspension type, the individual particles are dispersed as
discrete entities, as illustrated by Figure 10. This suspension type sediments slowly (as compared with
the closed and open aggregate types), attains the lowest possible sediment height, and owing to the
closeness of the particle surfaces upon sedimentation, possesses a high potential for caking, because of
the ease of formation of extensive crystal bridging.
FIG. 10. An artist’s conception of dispersed suspension form.
Formulation Components
Wetting agents
A frequently helpful pharmaceutical technique for modifying the wetting characteristics of
powders involves the use of surfactants (sometimes with shearing) to decrease the solid liquid interfacial
tension and contact angle between solid particles and the liquid vehicle. Common surfactants used as
wetting agents include: 1) non-ionic type (polyoxyalkyl ethers, polyoxylakyl phenyl ethers, polyoxy
hydrogenated castor oil, sorbitan esters and polyoxy sorbitan esters) and 2) anionic type (docusate
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sodium and sodium lauryl sulfate). The best range for wetting and spreading by non-ionic surfactants is
between a hydrophile–lipophile balance (HLB) value of 7 and 10, although surfactants with values higher
than 10 are often used for this purpose.
Deflocculants and Dispersing Agents
These agents do not appreciably lower surface and interfacial tension; thus, they have little
tendency to create foam or wet particles. Most deflocculants, however, are not generally considered safe
for internal use and as a result the only acceptable dispersant for oral products is lecithin or a lecithin
derivative (naturally occurring mixture of phosphatides and phospholipids). Because lecithins vary in
water solubility and dispersibility characteristics, proper control of product specifications must be
maintained to obtain reproducibility.
A proper surfactant in appropriate concentration improves the dispersion by reducing the
interfacial tension. For example, if surfactants with negative charges are adsorbed on the particles, this
prevents or minimizes aggregation in the presence of positive ions because of the mutual repulsion of
like charges. Examples of such agents include sodium lauryl sulfate and sodium dioctyl sulfosuccinate.
In practice, a nonionic surfactant is usually used to aid the dispersion of the insoluble phase.
Polyoxyethylene ethers of mixed partial fatty acid esters of sorbitol anhydrides (Tweens), the same
compounds without the hydrophilic oxyethylene groups (Spans), higher molecular weight polyethylene
glycols (Carbowaxes), and molecular combinations of polyoxyethylene and polyoxypropylene
(Pluronics), are frequently used in this manner. One must be careful, especially with the nonionic
surfactants, not to use too high a concentration of the agent. Over the critical micelle concentration, intact
micelles are adsorbed to particle surfaces, providing a continuous film for coagule formation, as
discussed previously.
Flocculating Agents
Before aggregating the suspension particles in the open network aggregate, it is important to
ensure that the particles are well dispersed in the aqueous phase or other vehicle. Flocculating agents are
neutral electrolytes that are capable of reducing the z potential of suspended charged particles to zero.
The concentration of added electrolyte necessary to produce the flocculated state corresponds to the
quantification expressed in the Schulze-Hardy rule previously discussed. Monovalent ions such as,
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sodium or potassium chloride in small concentrations (0.01–1%), are often sufficient to induce
flocculation of weakly charged, water-insoluble, organic non-electrolytes. In the case of insoluble, highly
charged, and polyelectrolyte species, similar concentrations (0.01–1%) of water-soluble divalent or
trivalent ions, such as calcium salts, aluminum chloride, sulfates, citrates, and potassium biphosphate,
may be required for floc formation, depending on particle charge (positive or negative).
Suspending Agents
Suspending agents retard settling and agglomeration of the particles by functioning as an energy
barrier, which minimizes interparticle attraction and ultimate aggregation. The general choice of
suspending agents includes (i) protective colloids, (ii) viscosity-inducing agents and, (iii) surfactants.
Some of the suspending agents used to a large extent in formulation include modified cellulose polymers,
proteins such as gelatin, and totally synthetic polymers.
Protective colloids
Suspension systems intended for oral, parenteral, ophthalmic, or topical use may not appear
elegant because they usually exhibit poor drainage in vials or bottles due to the clusters of particles.
These properties may be improved by the addition of protective colloids. Protective colloids differ from
surfactants in that they do not reduce interfacial tension. Their solutions differ in viscosity and are used
in higher concentrations than are surfactants. Protective colloids also differ from other agents in that their
effect is due not only to their ability to increase the zeta potential, but also to their formation of a
mechanical barrier or sheath around the particles.
Viscosity Modifiers
Because the flow of liquid for dispensing and dosing is important, an appropriate control of
viscosity is required to prevent the liquid from running and, at the same time, to allow good dosing
control. Many thickening agents are available including carboxymethyl cellulose (CMC), methyl
cellulose, polyvinylpyrrolidone (PVP), and sugar. Because of the significant opportunities available for
interacting with salts and other formulation ingredients, the viscosity control should be studied in the
final formulation and over the shelf-life of the product [Ková & Fortelný, 1984].
Modified cellulose polymers.
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Sodium carboxymethylcellulose (CMC), methylcellulose (Methocel), and
hydroxypropylmethylcellulose (Methocel, HG) are widely used in oral, topical, and parenteral dosage
forms. Sodium carboxymethylcellulose is an anionic polymer, whereas methylcellulose and
hydroxypropylmethylcellulose are nonionic. Sodium carboxymethylcellulose is used in concentrations
of up to 0.5% in injectable preparations. In oral dosage forms, they are frequently used in higher
concentrations because of the higher solids content of the systems. Sodium carboxymethylcellulose does
have some disadvantages: it is incompatible with a number of electrolytes and quaternary ammonium
compounds, and it forms complexes with certain surfactants. Methylcellulose and
hydroxypropylmethylcellulose gel on heating and are affected by electrolytes. One of the more useful of
the totally synthetic polymers is polyacrylic acid (Carbopol); it is used mostly in external lotion and gel
preparations. After being uniformly dispersed in water, it is neutralized with an organic amine such as
triethanolamine or with inorganic alkali to achieve the desired viscosity in a range from pH 6 to 10. The
material is extremely sensitive to electrolytes, but is suited for use equally in aqueous and non-aqueous
systems. These polymeric agents function primarily as protective colloids and alter the viscosity of the
medium.
Clays.
As a group, the clays (essentially hydrated aluminum and/or magnesium silicates) are also quite
useful in suspension formulating. They hydrate further in water to a high degree to form colloidal
dispersions having high viscosities. The manner in which the members of the group are prepared,
however, has a profound effect on die final product. The clay should always be added to the water with
high shear to effect uniform dispersion and maximum hydration. The pH of aqueous clay dispersions is
somewhat alkaline, in the range of pH 8.5 to 9.5; therefore, they also possess some acid neutralizing
capacity. The viscosity of aqueous dispersions of these agents varies, depending on the type and amount
of solids dispersed. In general 5 to 10% concentrations of the clay form firm opaque gels. Clays can be
formulated in systems in which the pH is between 6 and 11, but they are most stable between pH 9 and
11. Alkaline buffers usually are included to maintain the pH. All dispersions of the clays are drastically
affected by electrolytes in accordance with the Schulze-Hardy rule; ethanol also affects these agents by
dehydrating the colloid, thereby reducing the viscosity. Clay suspensions and gels are excellent media
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for mold and bacterial growth, and should therefore be adequately preserved with nonionic antimicrobial
preservatives. The paraben esters and benzoates are useful, but cationic “quaternary” preservatives are
ineffective. Heat and aging usually increase the viscosity of clay mixtures, but this may become less
significant in the more concentrated systems.
Formulation Adjuvants
Certain aspects of suspension formulation pertain to both aggregate and dispersed suspension
systems and are therefore discussed together. Suspension adjuvants must be considered. These agents
include the preservative, color, perfume, and flavor; they may materially affect the characteristics of the
suspension system. In general, most colors are used in small quantities and are usually compatible;
flavors and perfumes are similarly used and are also usually compatible with the vehicle. To illustrate
that one must be on guard against adjuvant interaction, it is noted that Bean and Dempsey showed that
the adsorptive power of kaolin suspensions can reduce the activity of some preservatives.12 Kaolin hurt
the quaternary benzal-konium chloride (BAK), but not the nonionic and less surface-active m-cresol.
Similarly, it was shown, that procaine penicillin adsorbed the quaternary and that the supernatants of the
BAK systems had less activity than the suspensions; thus, the adsorbent acted as a reservoir.