a r Paper Coordinator - INFLIBNET Centre

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Pharmaceutical sciences

Product Development 1

Suspension Part II

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: 32 Suspension Part II

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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Suspension Part II

Introduction

Suspension Formation

The processes involved in the suspension formation are shown in Fig. 1. The flocculated state

(C) may be reached either directly by wetting and dispersing hydrophobic particles with a suitable

flocculating agent, or else by first wetting and dispersing to produce a disperse or deflocculated state (B)

with a suitable surfactant and then flocculating with a suitable agent such as a hydrophilic colloid or

polyelectrolyte. In contrast to deflocculated or peptized particles, flocculated suspensions (C), which are

considered pharmaceutically stable (although colloidally unstable), can always be redispersed with

gentle agitation. Addition of too much flocculating agent results in over flocculation and tends to produce

agglomerated or coagulated irreversible systems (E). The term plaque (platelike) is used to describe

essentially flat agglomerates, whereas the term coagula (clumplike) are reserved for thicker, three-

dimensional particle masses. In the absence of a protective colloid, the process of crystal growth is

indicated by the arrow connecting (A) to (D).

FIG. 1. Processes involved in the suspensions formation

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Suspension Part II

Precipitation Methods

Three precipitation methods are discussed in this section: organic solvent precipitation,

precipitation effected by changing the pH of the medium, and double decomposition.

Organic solvent precipitation.

Water-insoluble drugs can be precipitated by dissolving them in water-miscible organic solvents

and then adding the organic phase to distilled water under standard conditions. Examples of organic

solvents used include ethanol, methanol, propylene glycol, and polyethylene glycol. Several important

considerations are involved when this method is used. Perhaps the most important factor next to particle

size control is that the “correct” polymorphic form or hydrate of the crystal be obtained. For example,

different forms are obtained when prednisolone is precipitated from aqueous methanol as opposed to

aqueous acetone. Besides the influence of the solvent on crystal characteristics, the following additional

factors may need to be considered: possible preparation under sterile conditions, inherent solvent

entrapment and subsequent toxicity, the volume ratios of the organic to the aqueous phase, rate and

method of addition of one phase to the other, temperature control (cooling rate and drying conditions),

method of drying the precipitate (forced air, vacuum, or freeze drying), and finally, the washing of the

precipitate. Where pertinent, sterilant residues should not be overlooked (e.g., ethylene glycol from

ethylene oxide gas sterilization procedures).

Precipitation by pH.

The method of changing the pH of the medium is perhaps more readily accomplished and does

not present the same difficulties associated with organic solvent precipitation. The technique, however,

is only applicable to those drugs in which solubility is dependent on the pH value. For example, estradiol

suspensions can be prepared by changing the pH of its aqueous solution; estradiol is readily soluble in

such alkali as potassium or sodium hydroxide solutions. If a concentrated solution of estradiol is thus

prepared and added to a weakly acidic solution of hydrochloric, citric, or acetic acids, under proper

conditions of agitation, the estradiol is precipitated in a fine state of subdivision. The type of crystal or

polymorphic form depends on such factors as the concentrations of acid and base and the degree and

type of fluid shear imparted to the system.

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Suspension Part II

Insulin suspensions also may be prepared by a pH change method. Insulin has an isoelectric point

of approximately pH 5. When it is mixed with a basic protein, such as protamine, it is readily precipitated

when the pH is between the isoelectric points of the two components, i.e., pH 6.9 to 7.3. Protamine zinc

insulin (PZI) contains an excessive quantity of zinc to retard absorption. According to the British

Pharmacopoeia of 1958, a phosphate buffer is added to each individual vial containing the acidified

solution of insulin, protamine, and zinc, so that the pH is between 6.9 and 7.3; the preparation is

compounded in the final container by mixing the PZI and the buffer in the filling operation.

Adrenocorticotropin (ACTH) zinc suspensions are prepared in a similar manner. The precipitate formed

in the process is zinc hydroxide or zinc phosphate, on which the ACTH is adsorbed; this combination

results in a long acting preparation when administered. The addition of phosphate salts and organic

phosphate to prepare an even longer acting ACTH preparation is also possible.

When either the change in pH or the organic solvent precipitation method is used to prepare a

suspension, a degree of supersaturation is brought about suddenly in the batch process to give rise to

crystal nucleation and growth, after which the initial supersaturation subsides. Thus, the degree of

supersaturation changes throughout the process, and neither the rate of nucleation nor the rate of crystal

growth is constant; therefore, the particle size distribution is variable. The degree of supersaturation and

the rate of nucleation are greatest at the beginning of the process, so that crystals formed initially become

the largest because they are exposed to the supersaturated solution for the longest period of time. It

appears, therefore, that when less concentrated solutions are used, the particle size distribution is broader

than when more concentrated solutions are used.

Double decomposition.

Making suspensions by double decomposition involves only simple chemistry, although some of

the aforementioned physical factors also come into play. The reader is referred to standard pharmacy

texts to review the preparation of White Lotion (NF XIII), that is, forming zinc “polysulfide” by mixing

zinc sulfate and sulfurated potash solutions.

Dispersion Methods

When the dispersion method is utilized for suspension preparation, the vehicle must be

formulated so that the solid phase is easily wetted and dispersed. The use of surfactants is desirable to

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Suspension Part II

ensure uniform wetting of hydrophobic solids. The use of suspending agents, such as the synthetic

polymeric polyelectrolytes, natural gums, or clay, may be indicated, depending on the specific

application. The actual method of dispersing the solid is one of the more important considerations

because particle size, reduction may or may not result from the dispersion process. If particle-size

reduction occurs, the particles obtained may have different solubilities if a metastable state is involved,

and this may lead to transient supersaturation of the system. A number of dispersion methods are used

to prepare suspension products. For present purposes, there is no need to describe and discuss the

comminuting and shearing equipment commercially available because information on such equipment

is easily obtained. The reader need only recall that much of what has been and will be discussed with

respect to basic suspension technology applies regardless of how the suspension is made.

Preparative Techniques

The actual preparation of suspensions involves choosing the ingredients (utilizing principles

already discussed) and determining the type of manufacturing equipment to be used. Needless to say,

each suspension is a separate case and absolute generalization is not possible. If the suspension is made

by a dispersion process, it is best to achieve pulverization of the solid by a micronization technique. This

involves subjecting the particles to a turbulent air chamber in which they collide with each other and

fracture. Particles under 5 microns are readily obtained. Although it is not widely used for this purpose,

spray-drying also can be considered a method of comminution to produce a finely divided solid phase.

If the suspension is made by controlled crystallization, a supersaturated solution should be formed and

then quickly cooled with rapid stirring. This causes the formation of many nuclei and hence many

crystals; it is just the opposite of letting crystals grow large.

At some time during suspension formation, it is likely that shearing will be desired. This

homogenization can be accomplished by the conventional stator-rotor colloid mills. Ultrasonic

equipment also can be used to effect high intensity mixing, but usually, this technique is not applied

commercially. Of interest, however, is the work of Sheikh, Price, and Gerraughty, who studied the effect

of ultrasound on polyethylene spheres in aqueous suspension.13 The ultrasound reduced the sphere size

only when surfactants were added, especially those having high HLBs. When such agents were used as

additives, the particles were readily dispersed and hence completely surrounded by liquid. Since

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Suspension Part II

ultrasound waves and cavitation shock waves are transmitted to the particles through the liquid medium,

a poor suspension would not be as susceptible to size reduction as a better dispersed one. Excessive

shearing (or high temperatures) may irreversibly damage polymeric materials such as gums, so that

viscosity loss is suffered. Instead of trying to hydrate gums and clays by massive shearing, it is often

better, when possible, to give the material the necessary time to hydrate under conditions of mild

shearing. An alternate procedure is to mix with, or preferably spray the gum with, a chlorinated

hydrocarbon, acetone, or alcohol solution of a wetting agent (e.g., sodium dioctyl sulfosuccinate). About

0.4% (based on the gum weight) of the wetting agent should be added to the gum. This technique can

produce a marked beneficial effect, as wetting of the gum and hence hydration is greatly accelerated.

A final comment is that processing studies in a pilot plant are needed because it is axiomatic that

the scale-up operation from laboratory batches to production lots brings with it many troubles and

unexpected results.

Controlled Flocculation

The aim in the formulation of suspensions is to achieve partial or controlled flocculation. The

main advantages of the stable floc are as follows. The aggregates tend to break up easily under the

agitation of a bottle or vial, or by the flow through a small orifice (hypodermic needle and/or syringe)

and reform an extended network of particles after the force is removed. Flocculation, therefore, imparts

a structure to the suspension with virtually no increase in viscosity. The following examples illustrate

how suspensions may be prepared by controlled flocculation procedures:

1. The wetting agent, (not more than 0.1–0.2% w/v of the final concentration), is dissolved in

approximately half the final volume of aqueous vehicle.

2. Microfine particles of the drug at the desired concentration are uniformily spread over the surface of

the vehicle and drug is allowed to be wetted undisturbed for as long as 16 h.

3. The wetted slurry is passed through a fine wire sieve (100 mesh size) or wetted slurry is passed

through a colloid mill to remove poorly wetted powder.

4. The slurry concentrate of the drug is agitated gently with an impeller-type mixer.

5. To slurry, flocculating agent is added till flocculation end point is reached.

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Suspension Part II

6. To determine the endpoint, small samples are transferred to a graduated cylinder, an equal amount

of vehicle is added and the cylinders are gently shaken and permitted to stand undisturbed. The

sample with the highest ratio of sediment to total suspension volume, exhibiting a clear supernate

and good drainage characteristics is considered to be at the appropriate endpoint.

7. After the flocculation endpoint has been established and verified, the other formulation adjuvants

(preservative, colorant, flavor, buffer, etc.) are added, and the slurry is brought to final volume with

liquid vehicle.

Structured Vehicle

Another technique for the preparation of a stable suspension is based on the concept of the

‘‘structured vehicle,’’ in which the viscosity of the preparation, under static conditions of very low shear,

on storage approaches infinity. The vehicle is said to behave like a ‘‘false body’’ that is able to maintain

the suspended particles in a state of more or less permanent suspension. Structured vehicles are avoided

for the preparation of parenteral suspensions, owing to their high viscosity.

Bingham-Type Plastic Flow.

Vehicles with Bingham type plastic rheological flow are characterized by the need to overcome

a finite yield stress before flow is initiated. Permanent suspension of most pharmaceutical systems

requires yield-stress values of at least 2–5 Pa (20–50 dyn/cm2). Bingham plastic flow is produced by

carbomers. carbomers exhibit a sufficiently high yield value at low solution concentration and low

viscosity to produce permanent suspensions.

Thixotropic Flow.

Thixotropic flow is defined as a reversible, time-dependent, isothermal gel–sol transition.

Thixotropic systems exhibit easy flow at high shear rates and on removing the stress the system is slowly

reformed into a structured vehicle. The usual property of thixotropy results from the breakdown and

buildup of floccules under stress. The primary advantage of thixotropic flow is that it confers pourability

under shear stress and viscosity and sufficiently high yield stress when the shear stress is removed at

rest. Pseudoplastic materials (such as hydroxyethylcellulose, hydroxypropyl methyl cellulose or sodium

carboxymethylcellulose) in combination with a clay (hydrated colloidal magnesium aluminum silicate)

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Suspension Part II

or blends and coprecipitates of sodium carboxymethylcellulose and microcrystalline cellulose exhibit

thixotropic flow.

Emulsion Base.

A waxy-type self-emulsifier develop structure or ‘‘false body’’ in suspension systems. A dilute

emulsion system is not often considered for suspension purposes because of the potential complexities

involved in mixing emulsion and suspension systems. The drug particles are dispersed in the primary

emulsion component prior to dilution with other vehicle components.

Product Development

A generalized consideration of the selection of ingredients and equipments for manufacturing of

suspensions is not possible. If the suspension is to be prepared by dispersion technique, it is better to

pulverize the solids first. The particles are subjected to a stream of turbulent air, which makes them to

colloid with each other and fracture. Particles below 5m sizes are easily obtained. In case of controlled

crystallization technique, the supersaturated solution is quickly cooled with rapid stirring. The later

action ensures the formation of large number of crystals and avoids crystal growth. Homogenization, if

required at any stage, can be accomplished by colloid mills. Although ultrasonic techniques can be used

yet they are of less commercial value.

A few general guidelines are stated below:

Wetting of the particles is better achieved by keeping them in contact with a small portion of

vehicle containing an appropriate quantity of wetting agents without agitation. Suspending agent should

be dissolved or dispersed in main portion of the vehicle and sufficient time and dispersion equipment

should be employed. This helps in attainment of proper viscosity. The slurry of wetted particles should

be added at low shear to main portion of suspending agent, and not the other way round. Electrolyte

addition should be properly controlled to prevent variations in the particle charge. All the finished

suspensions must be carefully preserved against bacterial growth.

Aggregated (open network system)

The controlled aggregate system can be made by using an electrolyte. Schulze – Hardy rule can

be used to determine the amount of electrolyte needed. Electrolytes promote aggregation by reducing

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Suspension Part II

zeta potential, which acts as an electrical barrier between the particles. In some cases in which

incompatibility factors are absent, very small amount of aluminium chloride or potassium bisphosphate

may act as aggregating agent. Surfactants, both ionic and nonionic, can also be used for the purpose. One

must be careful in case of non-ionic surfactants because above critical micelle concentration they tend

to get adsorbed on the particle surface, forming a continuous film, leading to coagule formation. Long

chain high molecular weight polymers act as aggregating agents because part of their chain gets adsorbed

on the particle surface, with the remaining part projecting out into dispersion medium. Bridging between

these latter portions leads to the formation of flocs.

Oral suspensions, due to high solid contents, exhibit poor drainage from bottles. This may be

improved by the use of protective colloids. Protective colloids differ from surfactants in that they do not

reduce interfacial tension. They not only increase the zeta potential but also form mechanical barrier

around the particles. Example of this approach is the use of silica gel, aluminium hydroxide gel etc.

Dispersed System

Individual particles in disperse system are generally dispersed with the aid of an agent that lowers

the interfacial tension. To maintain this state however, a viscosity imparting suspending agent is usually

required as an adjunct [Wen-Yen & Trong-Ming, 1989]. These agents retard settling and agglomeration

of particles by functioning as an energy barrier, which minimizes interparticle interaction and ultimate

aggregation. The general choice of suspending agents includes protective colloids, viscosity inducing

agents, surfactants and dispersing agents. Combination of different types of suspending agent may also

be used to achieve desired rheologic properties.

Stability Considerations

Aggregation

The aggregation of particles in suspension can be termed aggregation or coagulation. The term

‘coagulation’ should be used when the forces involved are primarily physical owing to reduction in the

repulsive forces at double layer. The term ‘flocculation’ can be applied to those cases in which weak

‘bridging’ occurs among the particles. However, since in many pharmaceutical systems the exact nature

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Suspension Part II

of the sources is somewhat obscure, we shall restrict ourselves here to term ‘aggregation’. By using

simple diffusion theory, Von Smoluchowski derived equation for both rapid aggregation (when all

particle – particle collisions results in aggregation) and slow aggregation (in which only a fraction of all

particle-particle collisions results in aggregation) [Kruyt, 1953]. The pharmaceutical scientists are

concerned with slow aggregation, since the aggregation in suspension of drugs is mainly slow. The t1/2

time for the initial number of single particles (singlets) in a suspension to decrease by 50% because of

aggregation is given by

DRNo

t /

4

121

where, D is diffusion coefficient of the singlets, R is gas constant, No is initial number of singlets

and is the collision efficiency.

Types of aggregates

The aggregates in a suspension system can be classified according to their morphology.

Floccule is an open aggregate system. The structure is rigid and settles quickly to form a high

sediment height and is easily redispersible because the particles constituting individual aggregates

are sufficiently far apart from one another to preclude caking. A coagule is a closed aggregate formed

by surface film bonding. The affinity of surface films for each other is responsible for tenacity of the

aggregate not within an individual aggregate, but also surrounding aggregates. Upon sedimentation

the aggregates tend to form a single large film bound 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 case of non-aqueous suspensions, water. The third form is disaggregated

or dispersed form wherein the particles settle as discrete entities. Sedimentation is much slower than

the aggregated systems, attains lowest possible sediment height and possesses a high potential for

caking.

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Suspension Part II

Sedimentation

The pharmaceutical suspension is destined to settle even though one can slow the processes

well within shelf-life times for pharmaceutical products. The rate of settling can be calculated by

Stoke’s law

9

g r 2 =

2 ..

where, v = (terminal) velocity, r = radius of the particle, = the difference in density of the solid

dispersed phase and the density of the liquid dispersion medium, g = a constant due to gravity, and

= viscosity of the liquid.

According to Stoke’s law the rate of sedimentation can be retarded most effectively by

controlling the particle diameter (radius) and viscosity of the medium. However, Stoke’s law is

applicable only to dilute systems (solid content <2%). To take into consideration the concentrated

systems, Higuchi [1958] developed an equation with fewer limitations. He considered settling

phenomenon to be equivalent to movement of liquid medium through the bed of dispersed phase.

Particle Growth

The surface free energy for the small particles is greater than for larger particles. In some

systems, therefore, small particles will be appreciably more stable than the larger ones. For such

systems small fluctuation in the temperature will result in crystal growth as the small particles

dissolve with the rise in temperature; and then crystallize at the surface of the existing particles, with

a temperature drop. Thus the larger particles will grow in size at the expense of the smaller particles.

The suspension will become coarser as the mean particle size spectrum shift to higher values. Many

gums adsorb onto the crystal surfaces and thus can be used to inhibit crystal growth. Freeze – thaw

as well as more elevated temperature cycling tests can provide a useful technique for evaluating

crystal growth and crystal growth inhibitors.

The size distribution of dispersed systems may increase during aging, owing to four principal

mechanisms: Ostwald ripening; polymorphic transformation; crystal habit; and temperature cycling.

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Suspension Part II

Ostwald ripening

Since suspensions are saturated solutions of the particulate substance, small changes in

temperature that occur during shelf storage lead to unexpectedly rapid caking via crystal bridging, much

in the same way that crystal growth yields can be optimized by alternately warming and cooling a mother

crystallization liquor. This process, known as Ostwald ripening, is unavoidable in pharmaceutical

suspensions of the dispersed type. Suspensions of the dispersed type tend to cake easily, owing to the

compact sedimentation that occurs when these suspensions settle.

The basis for Ostwald ripening is found in equation (7) and it applies to the equilibrium solubility

of small particles:

ln𝑆

𝑆0=

2𝛾𝑉

𝑟𝑅𝑇 (7)

where, S0 is the solubility of infinitely large particles, S is the solubility of a small particle of radius r,

is the surface tension, and V is the molar volume of the solid.

Polymorphic transformation

Polymorphism as applied to crystals specifically refers to the different crystal structures the same

chemical compound may have. The difference in the equilibrium solubility of polymorphs provides a

driving force for crystal growth in suspension as the particles of the more soluble polymorph go into

solution and reprecipitate as the less soluble, i.e., more stable, form. This process is accelerated if the

drug powder used to prepare the suspension contains a mixture of polymorphs, or if a seed of the more

stable form is introduced. The rate of conversion of a metastable to a stable polymorph may be rapid or

slow. When this rate of conversion is very slow, it may be feasible to use the metastable form

commercially.

Crystal Habit

Crystal habit may be denned as the outward appearance of an agglomeration of crystals. Although

seemingly trivial, crystal habit can be of great importance in suspension redispersibility, sedimentation,

physical stability, and appearance. For example, sulfisoxazole can be produced in a single geometric

crystal form having relatively similar sizes, but an agglomerate of the crystals can have physical

properties vastly different from those of single crystals. Small clumps of sulfisoxazole crystals may

exhibit little tendency to disperse because of the tenacity of the clump. These clumps may exhibit

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Suspension Part II

retarded dissolution and thus retarded bioavailability rates due to the inability of a dissolution fluid to

penetrate to the interior crystal components of the clump.

Traditionally, crystal habit was classified on the basis of the geometry of the agglomerate (needle,

prism, plate, etc.), but in reality, most crystal habit morphology is of a nondescript form. The relatively

strong, rigid crystalline structure that exists within a crystal is not responsible for the agglomeration of

crystals. Rather, weak van der Waals interactions occurring at crystal surfaces hold the agglomerate of

crystals in form. Mostly, this occurs as non-geometrically classifiable clumps.

The factors controlling crystal characteristics involve basically either the production of a change

in crystal habit (physical shape such as needle, plate, prism) or the production of no change in crystal

habit. When there is no change in the crystal habit, the following factors may still be considered: drug

decomposition leading to salting in or out, pH changes with changes in the particle size distribution, and

the effect of change in temperature. When there is a change in crystal habit, solvation and polymorphism

(presence of one or more crystalline and/or amorphous forms) are of importance. It is also notable that

the rate of physiologic absorption can be greatly altered, depending on which crystalline or amorphous

forms are administered.

Temperature cycling

Temperature cycling may lead to crystal growth, as solubility depends on temperature. In most

cases, solubility is directly related to temperature, so that a slight rise in temperature leads to an increased

equilibrium solubility. A drop in temperature, however slight, results in a supersaturated solution

surrounding each particle. Precipitation occurs to relieve the supersaturation, and crystal growth occurs.

The temperature effects depend on the magnitude of the change in temperature over a given period of

time, the time interval, the effect of temperature on the solubility of the suspended drug, and on

recrystallization phenomena.

Evaluation of Suspension Stability

Since stability testing is discussed elsewhere in the pharmaceutical literature, the only emphasis

here is on the most pertinent aspects of suspension stability. Techniques for the evaluation of

heterogeneous systems generally are complex and are far from being completely satisfactory. Some test

methods are so drastic that the stability information is obtained during an evaluation that destroys the

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Suspension Part II

system being evaluated. Some methods are somewhat empiric in nature, i.e., the exact basis on which

they operate cannot be explicitly defined mathematically. All test procedures suffer some limitations,

and the results, therefore, must be cautiously evaluated and interpreted. As the methodology involved in

the pertinent stability studies is often somewhat complicated, this section of the chapter is more fully

referenced so that further details can be obtained if desired. The purpose here is to point out explicitly

one method, and then indicate only the general nature of some of the other approaches taken. Use of

evaluation techniques permits the formulator to screen the initial preparations made and also to compare

the improved formulations to competitive commercial products. The latter point should not be treated

lightly even though it does not deal with absolute standards.

Sedimentation Volume

Sedimentation volume is the ratio of the ultimate height (Hu) of the sediment to the initial height

(Ho) of the total suspension as it settles in a cylinder under standard conditions. The larger this ratio

better is the suspendibility. For better formulations a plot of sedimentation volume versus time yields

more horizontal, less steep line. In case of highly concentrated suspensions, supernatant available is very

little to determine the Hu and hence a modified experimental method is used. The concentrated

suspensions are diluted with additional vehicle; Hu values for diluted suspensions are determined, Ho

value equals to the original volume of sample before dilution. Sedimentation volumes thus obtained are

plotted against the time and compared for different formulations.

Since redispersibility is one of the major considerations in assessing the acceptability of a

suspension, and since the sediment formed should be easily dispersed by moderate shaking to yield a

homogeneous system, measurement of the sedimentation volume and its ease of redispersion form two

of the most common basic evaluative procedures.

The concept of sedimentation volume is simple. In short, it considers the ratio of the ultimate height (Hu)

of the sediment to the initial height (Ho) of the total suspension as the suspension settles in a cylinder

under standard conditions.

Sedimentation Volume = Hu / Ho

The larger this fraction, the better is the suspendability (Fig. 2). Methods utilizing the

sedimentation volume obtained in a cylinder offer a practical approach to the determination of the

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Suspension Part II

physical stability of suspension systems. Particularly good is the fact that the system remains

undisturbed. Specifically, it is worth knowing how to use the Hu and Ho concepts. The formulator should

obtain the Hu/Ho ratios and plot them as ordinates with time as the abscissae. Note that although the

conventional Hu is called the “ultimate” height of the sediment, ultimate really means the height at any

particular time. The plot just described will at time zero start at 1.0, with the curve then being either

horizontal or gradually sloping downward to the right as time goes on. One can compare different

formulations and choose the best by observing the lines, the better formulations obviously producing

lines that are more horizontal and/or less steep.

FIG. 2. Sedimentation of (a) flocculated and (b) deflocculated suspensions.

Concentrated suspensions.

Another technique that utilizes essentially the same parameters may be used to evaluate highly

concentrated suspensions, which might be difficult to compare because there would be only minimum

supernatant liquid. The technique involves diluting the suspension with additional vehicle, i.e., with the

total formula with all ingredients except the insoluble phase. As an example, one could dilute 50 ml of a

suspension to a volume of 100, 150, or 200 ml. The Hu reading then becomes the volume of sediment in

the diluted sample, and H0 equals the original volume of the sample before dilution. The Hu/Ho ratio

may in this case be greater than 1. Regardless, the ratio is again plotted against time, and comparisons,

between formulas are made as before.

Degree of flocculation

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Suspension Part II

One additional concept should also he considered by the formulator. In all the comparisons just

mentioned, the screening technique results only in a relative ranking; this indicates which preparations

are the better ones. It is also useful, however, to consider the possibility of making an absolute evaluation;

this may be done as follows.

The degree of flocculation is the ratio of sedimentation volume of the flocculated suspension (F) to the

sedimentation volume that would be produced in the ultimate dispersed state (F∞).

Degree of flocculation = F / F∞

To obtain the completely dispersed suspension form, which represents the least void space for

the solid phase and hence the smallest sedimentation volume, electrolytes that promote settling may be

added or the preparation may be centrifuged. The Hu/Ho ratio observed is then the lowest figure

obtainable. This figure serves as a base line and gives some idea of the degree of aggregation obtained

because ratios higher than this minimum represent the existence of the desired aggregated state. In

reference to the plots discussed, it is clear that data that produce a line that quickly drops toward this

reference point do not represent a good suspension, as any aggregation if there is any at all, is too

temporary and infirm.

Another use for Hu/Ho data is possible, and particularly pertinent are the various relationships of

Ward and Kammermeyer.14 In essence, these workers attempted to quantitate settling further using Hu

and Ho values. It is known that the ultimate height of the solid phase after settling depends on the

concentration of solids and the particle size. These workers found that if Ho and Hu readings (taken on a

series of different concentrations of the same solids having a particular average particle size range) are

measured in a certain vehicle, the resulting data form a straight line plot if the logarithm of the weight

percentage of solids is plotted against the ratio Hu/Ho. One can then predict Hu for any given solids

concentration by multiplying Ho by the “relative concentration factor,” i.e., by Hu/Ho.

Redispersibility

As noted, the evaluation of redispersibility is also important. To help quantitate this parameter to

some extent, a mechanical shaking device may be used. It simulates human arm motion during the

shaking process and can give reproducible results when used under controlled conditions. It should be

remembered, however, that the test conditions are not the same as those encountered under actual use,

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Suspension Part II

and further testing should be considered. Nevertheless, the test results are useful and provide guidance

during screening procedures.

Rheologic Methods

A practical rheologic method utilizes a Brookfield viscometer mounted on a helipath stand. The

T-bar spindle is made to descend slowly into suspension, the resistance that spindle meets at various

levels in sediment is measured. This resistance is direct measure of structure formation due to

agglomeration at different levels. Data can be obtained for variously aged and stored samples. A plot of

resistance versus the number of turns a spindle takes may also be useful. Better suspensions show a lesser

rate of increase of resistance with spindle turns, that is, curve is horizontal for a longer period.

In addition to techniques involving sedimentation and redispersibility factors, rheologic methods

can also be used to help determine the settling behavior and the arrangement of the vehicle and particle

structural features for purposes of comparison.

The majority of rheologic investigations of suspension systems have been done at high shear

rates and on systems that must be made uniform before evaluation. For present purposes, the importance

of using low shear rates and undisturbed samples cannot be overemphasized. The prime reason for this

is the fact that die structure achieved on storage is what should be evaluated. A practical rheologic

method involves the use of the Brookfield viscometer mounted on a helipath stand. The T-bar spindle is

made to descend slowly into the suspension, and the dial reading on the viscometer is then a measure of

the resistance the spindle meets at various levels in a sediment. In this technique, the T-bar is continually

changing position and measures undisturbed samples as it advances down into the suspension. This

technique also indicates in which level of the suspension the structure is greater, owing to particle

agglomeration, because the T-bar descends as it rotates, and the bar is continually entering new and

essentially undisturbed material. Data obtained on samples variously aged and stored indicate whether

undesired changes are taking place. Thus, using the T-bar spindle and the helipath, the dial reading can

be plotted against the number of turns of the spindle. This measurement is made on undisturbed samples

of different ages. The results indicate how the particles are settling with time. In a screening study, the

better suspensions show a lesser rate of increase of dial reading with spindle turns, i.e., the curve is

horizontal for a longer period.

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A method combining the use of both rheologic and sedimentation parameters is illustrated by the

work of Foernzler, Martin, and Banker15, who studied the effect of thixotropy on stability. Although this

method does not observe the system under equilibrium conditions and is subject to some challenge, the

authors attempted to predict physical stability by a rheologic evaluation of thixotropy. Incidentally,

Wood used these workers’ data to develop additional correlations.16 It is important to note that the use

of most viscometers and centrifuges in stability studies is not ideal for aggregated systems because their

use destroys the structure formed.

Electrokinetic Techniques

Microelectrophoresis apparatus permits the measurement of the migration velocity of the

particles with respect to the surface electric charge or the familiar zeta potential; the latter has units of

viscosity times electrophoretic mobility, or more familiarly, volts. Stanko and DeKay also evaluated

suspensions by electrokinetic methods and showed that the zeta potential changes upon the addition of

additives and is related to stability. Haines and Martin studied some of the formulation factors that

influence the stability of suspensions. They correlated the zeta potential to visually observed caking; zeta

potential was again determined by microscopic electrophoresis. It was found that certain zeta potentials

produced more stable suspensions because aggregation was controlled and optimized.

Particle Size Changes

The suspensions under evaluation study are subjected to freeze–thaw cycle, which causes particle

growth and may indicate the probable future particle behavior on long storage at room temperature. The

changes in particle size, particle size distribution, and crystal habit are noted. Particle size can be

determined by microscopic means and photomicrographs can serve as permanent records.

Certain adjuvants have a profound effect on physical performance of the suspension under

freeze–thaw conditions. When a low solid content steroid injectable preparation containing sodium

CMC and benzoyl alcohol and other containing CMC, methyl paraben, and propyl paraben were

subjected to freezing and thawing, the former suspension caked badly while the later remained

unaffected. Protective colloids thus may be adversely affected by freezing thawing or elevated

temperatures i.e. gelatin is sensitive to low temperatures whereas methylcellulose is adversely

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affected by higher temperatures. Although freeze thaw cycle studies are useful guides, the best

stability information is still obtained from studies conducted at room temperature.

The freeze-thaw cycling technique is particularly applicable to stressing suspensions for stability

testing purposes. This treatment promotes particle growth and may indicate the probable future state of

affairs after long storage at room temperature. Thus, it is of prime importance to be alert for changes in

absolute particle size, particle size distribution, and crystal habit. With respect to the latter point, Carless

et al. investigated the various crystal forms of cortisone acetate and also noted the acceleration of

sulfathiazole crystal growth in suspensions that underwent temperature cycling. Obviously, the

physiologic availability and thus the therapeutic effect of the active ingredients may be influenced by

such changes. Particle size distributions are sometimes determined by microscopic means. This method

of necessity requires dilute suspensions that are counted with the aid of an ocular grid. In some instances,

photomicrographs may be taken for permanent records. This method is quite tedious, especially when

large numbers of samples are to be evaluated. It is worth noting that certain suspension components, e.g.,

the preservative or the protective colloid, may have a profound effect on the physical performance of the

suspension under freeze-thaw conditions. When a low solids content steroid injectable preparation

containing sodium carboxymethylcellulose (CMC) and benzyl alcohol, and one containing CMC,

methylparaben, and propylparaben, were subjected to freezing and thawing, the former suspension caked

badly, while the latter was unaffected. Protective colloids may thus be adversely affected by freezing,

thawing, or elevated temperatures; for example, gelatin is sensitive to low temperatures whereas

methylcellulose is adversely affected by higher temperatures. Although freeze-thaw cycle studies are

useful guides, the best stability information is still obtained from studies conducted at room temperature.

Electrokinetic Techniques:

Zeta potential has a considerable influence on the physical stability of the suspension. Zeta

potential can be measured by microelectrophoresis, in which a sample of suspension is mounted on a

special microscopic slide across which a known potential is applied. The speed of movement of the

particles across the field is a function of zeta potential and is determined visually. The apparatus is

standardized by use of particles of known zeta potential. Rabbit erythrocytes are commonly used for this

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purpose. Alternatively, more elaborate semi-automated and fully-automated equipments are available.

The zeta potential then can be correlated to stability.

Preservation Stability:

The various ingredients present in the formulation may interact with the preservatives and thus

may lead to either certain chemical incompatibilities or loss of preservative efficacy. Hence to retain

preservation capacity of formulation certain analytical procedures should be developed. One such assay

developed by Schieffer et al. [1984] describes the rationale for using methyl, ethyl, propyl, and butyl

esters of 4-hydroxybenzoic acid in combination with antacids and other pharmaceutical products. The

antacids have high pH values, and hence hydrolysis of the esters occurs, but the decomposition of the

parent compound can be prevented by properly controlling the concentration.

Packaging

Perhaps the final “adjuvant” one should consider is the package. Usually, initial laboratory

screening employs conventional graduates or readily available botdes. When final packaging is

considered, it should be noted that various types of glass are available. The types vary with respect to

their ability to resist water attack, the degree of attack being related to the amount of alkali released from

the glass. The USP should be consulted for further details, as it describes both the tests and standards

that should be met by containers to be used for packaging parenteral and non-parenteral (oral or topical)

products. One point of terminology may be noted: “flint” refers to clear, colorless, brilliant glass.

Originally, it contained lead and was also called “lead” or “crystal” glass; today in commerce, non-lead,

highly color-free, soda-lime-silica glasses, the most common general-purpose transparent glasses, are

also called flint. Parenteral multiple-dose vials may be “flint” (colorless) or amber, and may be silicone-

coated to improve drainage of the suspensions. (Silicone coating also minimizes the leaching of alkali

from the glass.) This technique of silicone coating is used widely for suspensions of steroids and

combinations of penicillin and dihydrostreptomycin. It is also used in preparations with high solids

content, in which formulation modifications cannot measurably improve the drainage of the preparation.

There has been a trend to package suspension systems for oral and topical administration in

polyethylene or other plastic containers. Many factors must be considered when a suspension is evaluated

in such a container. These factors include loss of flavor and perfume, preservative adsorption, and

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leaching into the product of substances from the container. Before evaluative procedures are discussed

per se, it must be stressed that after the initial stability observations are completed, the determination of

the stability of the suspension in the final package is an important step of the product development

procedure.

Stabilizing Suspensions

Various pharmaceutical excipients with different functions can be used for stabilizing

suspensions. The following groups of products can be offered for stabilizing oral and topical suspensions.

Soluble Kollidon products can be used at low concentrations; for example Kollidon 90 F (2-5%) suffices

to stabilize aqueous suspensions. A combination consisting of Kollidon 90 F (2%) and Kollidon CL-M

(5 to 9%) has proved to be an effective system for stabilizing suspensions. Kollidon 30 is also used for

this purpose. It can be combined with all conventional suspension stabilizers (thickeners, surfactants

etc.). The use of Kollidon CL-M as a suspension stabilizer has nothing whatever to do with the principle

of increasing the viscosity. The addition of 5 to 9% Kollidon CL-M has practically no effect in changing

the viscosity, but it strongly reduces the rate of sedimentation and facilitates the redispersibility, in

particular - an effect that is consistent with the low viscosity. One of the reasons for this Kollidon CL-M

effect is its low (bulk) density, which is only half of that of conventional crospovidone (e.g., Kollidon

CL).

The poloxamers, Lutrol F-68 and Lutrol F-127, in concentrations of 2 to 5% of final weight of

suspension, offer a further opportunity of stabilizing suspensions. They also do not increase viscosity

when used in these amounts and can be combined with all other conventional suspension stabilizers.

Nanosuspensions

Nowadays, suspensions with dispersed particles in the range 0.1 to 0.2 microns called as

“nanosuspensions” are widely used as drug delivery systems. Although theoretical and formulation

considerations involved in development of nanosuspensions are similar to those of conventional

suspensions but the nano size range of particle imparts some unique properties to these delivery systems.

At nano dimensions surface properties of the material dominate in lieu of the bulk properties. Particles

at nanosize range undergoes continuous brownian motion and does not follow stokes law. Thus unlike

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conventional suspensions, nanosuspensions do not tend to settle down and are thermodynamically more

stable. The major advantage of pharmaceutical nanosuspensions is their ability to increase the solubility

and in vivo bioavailability of highly water-insoluble drugs.

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a r Paper Coordinator - INFLIBNET Centre