PS-Section 9 1/16/07...Gels are by definition, “semi-solid systems consisting of either suspensions made up of small inorganic particles or large organic molecules interpenetrated

Section 9

Suspensionsby Drs. Clyde M. Ofner and Roger l. Schnaare

Table of Contents

Suspensions ..................................................................................................................................1Table of Contents ....................................................................................................................1

Introduction and Background........................................................................................................3Definitions ................................................................................................................................3Uses of Suspensions................................................................................................................3

Formulations ..................................................................................................................................4Typical Ingredients....................................................................................................................4

Drug ....................................................................................................................................4Wetting Agent ....................................................................................................................4Suspending Agent ..............................................................................................................4Protective Colloid ..............................................................................................................5Flocculating Agent..............................................................................................................5Sweetener ..........................................................................................................................5Preservative ........................................................................................................................6Buffer ..................................................................................................................................6Flavor ..................................................................................................................................6Color ..................................................................................................................................6Sequestering Agent ............................................................................................................6

Typical Formulations ................................................................................................................7Antacid/Antiflatulent Formula (cellulose gums and Avicel® suspending agents) ..............7Sulfamethazine Suspension (synthetic polymer suspending agent)..................................7Sulfamethazine Suspension (clay and cellulose gum suspending agents)........................8Benzoyl Peroxide Suspension (cellulose and natural gums suspending agents) ..............8Sterile Triamcinolone Diacetate Aqueous Suspension (synthetic polymer) ......................9Prednisolone Acetate Ophthalmic Suspension (cellulose gum suspending agent) ..........9

Steps in Suspension Preparation ................................................................................................10Wetting of Drug ......................................................................................................................10

Surfactants ......................................................................................................................10Solvents – Polar and Nonpolar ........................................................................................10Levigation ........................................................................................................................10

Dispersing Suspending Agent................................................................................................10High Shear ........................................................................................................................10Heat ..................................................................................................................................10Non-polar Liquids ............................................................................................................10Water Soluble Ingredients ................................................................................................10

Combined Drug and Suspending Agent ................................................................................11Other Ingredients....................................................................................................................11

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Final Processing ....................................................................................................................11Published Processing Guidelines ..........................................................................................11

DuPont Problem Solver, 1984 (excerpted) ......................................................................11Nash (paraphrased) ..........................................................................................................11

How Suspensions Behave ..........................................................................................................12Sedimentation ........................................................................................................................12

Factors – Stoke’s Law ......................................................................................................12Particle Size............................................................................................................................12Density Difference ..................................................................................................................12The Gravitational Constant, g ................................................................................................12Viscosity ................................................................................................................................12Dynamic Suspension Interactions..........................................................................................13Flocculation ............................................................................................................................13

Charge Repulsion – zeta potential ..................................................................................13Polymer Adsorption ..........................................................................................................14Caking ..............................................................................................................................14

Crystal Growth........................................................................................................................15Retardation ......................................................................................................................15Polymorphic Changes ......................................................................................................15

Controlling the Properties of a Suspension ................................................................................16Sedimentation ........................................................................................................................16

Suspending Agents and Type of Flow..............................................................................16Pseudoplastic vs. Thixotropic ..........................................................................................16Yield Value ........................................................................................................................16

Electrostatic Flocculation ......................................................................................................17Deflocculated vs. Flocculated Formulations: A Structured Vehicle Approach ......................18

A Universal Approach ..................................................................................................................19Experimental Suspension Parameters ........................................................................................20

Zeta Potential ........................................................................................................................20Density....................................................................................................................................20Viscosity ................................................................................................................................20Sedimentation ........................................................................................................................20Redispersibility ......................................................................................................................20Particle Size............................................................................................................................20

Reconstitutable Suspensions ......................................................................................................21Introduction ............................................................................................................................21Formulations ..........................................................................................................................21Typical Formulations ..............................................................................................................21Preparation ............................................................................................................................21

Powder Blends ................................................................................................................21Granulated Products ........................................................................................................21Combination Products......................................................................................................21

References ..................................................................................................................................22Selected Readings ......................................................................................................................22

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Introduction and Background

Definitions

Suspensions are pharmaceutically stable dispersions of a finely divided solid in a liquid vehicle, usually an aqueous solution. The USP1 defines suspensions as “finely divided, undissolved drugs dispersed in liquid vehicles” and can be ready-to-use, e.g.,Trisulfapyrimidines Oral Suspension or for reconstitution, e.g., Tetracycline OralSuspension. In the latter case, the drug is mixed with other ingredients in the dry state and reconstituted with water at the time of dispensing to the patient.

The USP also defines several dosage forms thatare essentially suspensions but historically arereferred to by other names. For example;

Gels are by definition, “semi-solid systems consisting of either suspensions made up of small inorganic particles or large organic molecules interpenetrated by a liquid.” Thesecan be suspensions if composed of “a two-phase network of small discrete particles,”e.g.,aluminum hydroxide gel or a magma if composed of relatively large particles, e.g., bentonite magma.

The term gel also refers to a “single-phase dispersion of organic macromolecules uniformly distributed throughout a liquid in sucha manner that no apparent boundaries existbetween the dispersed macromolecules and theliquid”, e.g., gelatin gel. These gels are clearlynot suspensions in that the dispersed material is soluble.

Lotions are fluid emulsions or suspensions intended for external application.

Milks are suspensions with a larger particle size than gels, e.g., Milk of Magnesia. The distinction between two-phase gels, magmasand milks is largely historical.

Today all of these preparations are referred to as suspensions.

One other aspect needs to be clarified at thispoint and that is the difference between a suspension and a colloid. Both can bedispersions of a solid in a liquid, however, the particle size of a suspension is such that sedimentation occurs due to the force of gravity, while the particle size of a colloid is small enough so that thermal energy or Brownian motion is sufficient to keep theparticles uniformly dispersed and preventsedimentation.

Uses of Suspensions

Suspensions are basically used to prepareliquid preparations of drugs that cannot be prepared as solutions; either the drug is not soluble or cannot be solubilized by cosolvents,surfactants, etc. They find use in a range ofroutes of administration including topical, oral,parenteral, ophthalmic, otic, and nasal. As adosage form, they offer several advantages:

• Preferred for patients, geriatric and pediatric, who have difficulty in swallowingsolid oral dosage forms such as tablets andcapsules.

• Disagreeable tastes can be often overcomeby purposefully limiting the amount of drug in solution and by flavoring the liquid vehicle.

• Prolonged action can be achieved, for example, in intramuscular injections as well as in oral suspensions.

• Bioavailability is high and generally viewed inthe following order for various oral dosageforms: solutions > suspensions > capsules >tablets.

• Improved chemical stability compared tosolutions.

Table 1. Typical Wetting Agents

Suspending Agent

Suspending agents are materials added to a suspension to increase viscosity and retard sedimentation. There are many materials that fall into this classification and include cellulose derivatives, clays, natural gums, synthetic polymers and a few miscellaneous materials. Most suspending agents are either neutral ornegatively charged and generally effective in a concentration range of 1 to 5%.

Being polymeric in nature, most suspendingagents have hydrophilic and hydrophobicregions in their molecular structure and, as such, can interact with a suspension particle surface. Some adsorption of the suspendingagent to the particle surface almost alwaysoccurs giving the particle surface the solubilitycharacteristics of the suspending agent. As with adsorption of wetting agents, the particlesurface, after adsorption of a suspending agent, will be hydrophilic and either neutral or negatively charged.

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Formulations

Typical Ingredients

Drug

Typically, the particle size distribution is between1 and 50 µm. Ideally, one would prefer a uniformsize; however, in practice, there is always a sizedistribution. With high-speed attrition impactmills the distribution is usually between 10 to 50µm, while fluid-energy mills, can reduce particle size below 5 µm.

The drug surface can be either hydrophilic orhydrophobic. Ionic surfaces such as aluminumhydroxide, are readily wetted and dispersed easily in aqueous vehicles. Most organic drugsform particles with a hydrophobic surface andare difficult to disperse in an aqueous medium.

Wetting Agent

Wetting agents are surfactants that reduce the surface tension of an aqueous medium, coat the surface of suspension particles, and therebyfacilitate the wetting of each particle. The goal is to displace air from the particle surface and to separate each particle from adjacent particlesusing the minimum concentration necessary.

Since wetting agents are surfactants, theyadsorb onto the particle surface and, dependingon the concentration, can partially coat the surface or form a complete monolayer. If the surfactant is charged, the particle surface will,therefore, carry the same charge, whereas if the surfactant is nonionic, the particle surfacewill be hydrophilic but not charged.

Wetting Agent Ionic Charge

Sodium Lauryl Sulfate AnionicDocisate Sodium AnionicPolysorbate 80 Nonionic

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Table 2. Typical Suspending Agents

Suspending Agent Rheologic Ionic ConcentrationBehavior Charge Range (%)

Cellulose Derivatives

Methylcellulose Pseudoplastic/plastic Neutral 1-5Hydroxypropyl Methylcellulose Pseudoplastic Neutral 0.3-2Sodium Carboxymethylcellulose Pseudoplastic Anionic 1-2Microcrystalline Cellulose with Plastic/thixotropic Anionic 0.5-2

Sodium Carboxymethylcellulose

ClaysBentonite Plastic/thixotropic Anionic 1-6Magnesium Aluminum Silicate Plastic/thixotropic Anionic 0.5-5

Polymers

Carbomer Plastic Anionic 0.1-0.4Povidone Newtonian/Pseudoplastic Neutral 5-10

GumsXanthan gum Plastic/thixotropic Anionic 0.3-3Carrageenan Newtonian/Pseudoplastic Anionic 1-2

Protective Colloid

A protective colloid is a polymeric suspendingagent absorbed on the surface of a hydrophobicsuspension particle giving the particle ahydrophilic surface.

Flocculating Agent

Flocculating agents enable suspension particlesto link together in loose aggregates or flocs.These flocs settle rapidly but form a large fluffysediment which is easily redispersed.

Materials that function as flocculating agentsinclude electrolytes, surfactants, and polymers;the same materials that serve as wetting and suspending agents. The mechanism by whichthey function is involved and will be discussed inmore detail later.

Sweetener

Sweeteners are added to suspensions to produce a more palatable preparation, to cover the taste of the drug and other ingredients.Sorbitol, corn syrup and sucrose are used at

relatively high concentrations and also contribute to the viscosity of the suspension.Other sweetening agents such as saccharin,sodium and aspartame, used in relatively lowconcentrations, do not affect the overall viscosity.

Table 3. Typical Sweetening Agents

Sweetener Comments

Saccharides

Sucrose Up to 80%

Polyols

MannitolCooling effect, considered noncaloric, fairly expensive, can cause diarrhea.

SorbitolHalf as sweet as sucrose, considered noncaloric, can cause diarrhea.

Synthetic

Sodium Saccharin500 times as sweet as sucrose, inexpensive.

AspartameGood acid stability

Buffer

Many chemical buffer systems have been usedin suspensions to control pH. The optimal pH ischosen to minimize solubility of the drug, controlstability of the drug, and to ensure compatibilityand stability of other ingredients.

Flavor

Flavoring agents enhance patient acceptanceof the product, which is particularly importantin pediatric patients.

Color

Colorants are intended to provide a more aesthetic appearance to the final product. As relatively large cations or anions, theseagents may be chemically incompatible withother ingredients. They also need approval by the FDA.

Sequestering Agent

Sequestering agents may be necessary to bindmetal ions to control oxidative degradation ofeither the drug or other ingredients.

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Preservative

Preservatives are required in most suspensionsbecause suspending agents and sweeteners are good growth media for microorganisms.Many preservatives are ionic, such as sodiumbenzoate, and may interact and bind or complex with other suspension ingredients.Bound preservatives are not generally active.Even the activity of neutral preservatives, i.e., the parabens, may be compromised by adsorbing onto the suspension particle surface.Solvents such as alcohol, glycerin and propylene glycol are often used as pre-servatives at concentrations approaching 10%.

Table 4. Typical PreservativesPreservative Concentration Range (%)

Alcohols

Ethanol >20Propylene Glycol 15-30Benzyl Alcohol 0.5-3

Quaternary AminesBenzalkonium Chloride 0.004-0.02

Acids

Sorbic Acid 0.05-0.2Benzoic Acid 0.1-0.5

Parabens

Methylparaben 0.2Propylparaben 0.05

Typical Formulations

Antacid/Antiflatulent Formula (cellulose gums and Avicel® suspending agents)

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Ingredient % by Weight Use

Aluminum hydroxide gel (8.9%) 21.00 Drug

Magnesium hydroxide paste (29.5%) 12.90 Drug

Simethicone 0.37 Antiflatulant

Hydroxypropyl cellulose 0.33 Suspending agent

Methylcellulose 0.03 Suspending agent

Avicel® RC-591 0.11 Suspending agent

Sorbitol 6.00 Sweetener

Citric acid, anhydrous 0.06 Buffer

Methylparaben 0.16 Preservative

Propylparaben 0.03 Preservative

Saccharin sodium 0.02 Sweetener

Flavors 0.12 Flavor

Purified water qs 100.00 Solvent

Preparation

1. Charge the mixing tank with purified water at about 40% of the total water required.

2. Separately disperse the methylcellulose in1.5% of the above purified water, add thesimethicone and add to the mixing tank.

1. Mix the methyl and propyl parabens into a slurry with about 2% of the purified water and add to the mixing tank.

2. Add to the mixing tank in the followingorder; magnesium hydroxide paste, aluminum hydroxide gel, citric acid, saccharin sodium, sorbitol, and flavorings.

3. Add to the mixing tank.

4. Mix Avicel® and hydroxypropyl cellulose withabout 13% of the purified water and add tothe mixing tank.

5. Add the remainder of the purified water tothe desired volume and mix until uniform.

Sulfamethazine Suspension (synthetic polymer suspending agent)

Ingredients % by Weight Use

Sulfamethazine 10.1 Drug

Carbomer 934 0.5 Suspending agent

Sodium lauryl sulfate 0.02 Wetting agent

Sucrose 40.0 Sweetener




Flavor mixture 1.0 Flavor

Citric acid 0.2 Buffer

0.1 N NaOH ~10 mL Adjust pH

Purified water qs 100 mL Solvent

Preparation

1. Hydrate the carbomer for 24 hours in a solution of the sodium lauryl sulfate in 30 mLof water

2. Suspend the sulfamethazine in the abovevehicle with the aid of a mixer.

3. Dissolve the preservatives and sucrose in 40 mL of water by heating.

4. Cool the solution and add the saccharinsodium and citric acid.

5. Add the solution to the suspension in step 2.

6. Add the flavor, adjust the pH to 5.5 and mixin a homogenizer.

Benzoyl Peroxide Suspension(cellulose and natural gum suspending agents)

Sulfamethazine Suspension (clay and cellulose gum suspending agents)

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Sulfamethazine 10.0 Drug

Magnesium aluminum-silicate 0.6 Suspending agent

Sodiumcarboxymethylcellulose 1.3 Suspending agent

Sodium lauryl sulfate 0.02 Wetting agent


Sucrose 40.0 Sweetener



Flavor 1.0 Flavor

Purified water qs 100 Solvent

Preparation

1. Hydrate the magnesium aluminum silicateand sodium carboxymethylcellulose for 24hours in a solution of the sodium lauryl sulfate in 30 mL of water.

2. Suspend the sulfamethazine in the abovevehicle with the aid of a mixer.

3. Dissolve the preservatives and sucrose in 40 mL of water by heating.

4. Cool the solution and add the sodium saccharin.

5. Add the solution to the suspension in step 2.

6. Add the flavor and mix in a homogenizer.


Benzoyl peroxide 5.0 Drug

Hydroxypropyl methylcellulose 1.5 Suspending agent

Xanthan gum 1.5 Suspending agent

Polysorbate 20 5.0 Wetting agent

Isopropyl alcohol 10 Solvent

Phosphoric acid 0.03 pH adjustment


Preparation

1. Add the hydroxypropyl methylcellulose and xanthan gum to water heated to approximately 70°C with stirring.

2. Cool to 50°C and add the polysorbate 20.

3. Cool to 35°C and successively add the isopropyl alcohol, phosphoric acid, and benzoyl peroxide (as a 70% aqueous slurry).

4. Mill to obtain a smooth suspension.

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Sterile Triamcinolone Diacetate AqueousSuspension (synthetic polymer)


Triamcinolone diacetate 4.0 Drug

Polyethylene glycol 3350 3.0 Suspending agent

Polysorbate 80 0.2 Wetting agent

Sodium chloride 0.85 Toxicity agent

Benzyl alcohol 0.9 Preservative

Water for injection qs 100 Solvent

Preparation

(Not considering sterility or presence of pyro-gens)

1. Dissolve the polysorbate 80 in a portion ofthe water for injection.

2. Disperse the triamcinolone diacetate in thepolysorbate 80 solution.

3. Dissolve the polyethylene glycol 3350 in aportion of the water for injection.

4. Add the triamcinolone diacetate dispersion to the polyethylene glycol 3350 solution.

5. Successively add the sodium chloride andthe benzyl alcohol.

6. Adjust to volume with water for injection.

Prednisolone Acetate Ophthalmic(cellulose gum suspending agent)


Prednisolone acetate 1.0 Drug

Hydroxypropyl methylcellulose qs Suspending agent

Polysorbate 80 qs Wetting agent

Sodium chloride qs Tonicity agent

Edetate disodium qs Chelating agent

Benzalkonium chloride 0.01 Preservative

Phosphate buffer qs Buffer

NaOH or HCl qs pH adjustment


Preparation

(sterilization not considered)

1. Dissolve the phosphate buffer, edetate disodium, sodium chloride, and benzalkonium chloride in a portion of the water.

2. Disperse the hydroxypropyl methylcellulosein another portion of water.

3. Disperse the prednisolone acetate in a solution of the polysorbate 80 in water using a high-shear mixer.

4. Add the prednisolone acetate dispersion tothe aqueous solution containing the buffer.

5. Add the hydroxypropyl methylcellulose solution to the combined suspension of the drug and buffer solution.

6. Adjust pH.

7. Adjust to final volume with purified water.

Wetting of Drug

• Surfactants• Solvents - polar and nonpolar• Levigation

Some solid drugs have a polar, hydrophilic surface, i.e., aluminum hydroxide and bentonite,and can be wetted by simply sprinkling the solidon the surface of water and letting the mixturestand overnight. Simple mixing of the hydratedmaterial will disperse the solid uniformly.

Most drugs of organic origin, however, have ahydrophobic surface and require some degreeof assistance to be thoroughly wetted. Thewetting agent can be dissolved in approximatelyhalf the final volume of aqueous vehicle and thedrug sprinkled on the surface of the surfactantsolution and allowed to wet for a period of timefollowed by a mixing step to uniformly dispersethe solid.

Alternately, the drug can be added to thesurfactant solution in small portions withagitation or mixing. Using excessive or highshear has the disadvantage of producing foamwhich may be difficult to dissipate but may benecessary to wet the solid thoroughly. Mixingthe drug with a solid, water soluble componentof the suspension, i.e., sucrose, can often aidin preventing clumping of the drug when addedto an aqueous vehicle.

Drugs may also be wetted by using a water-miscible liquid, such as glycerin or propyleneglycol, to produce a thick, smooth paste orslurry with the drug by levigation. The uniformslurry is then added to the part of the aqueousvehicle or surfactant solution. The wetting agentmay be dissolved in solution prior to adding theslurry or may be mixed with the drug at thebeginning of the levigation process.

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Steps in Suspension Preparation

Dispersing Suspending Agent

• High shear• Heat• Non-polar liquids• Water soluble ingredients

Suspending agents also need to be uniformly dispersed to be fully functional. Since they areall hydrophilic, i.e., clays, simple hydration maybe sufficient for complete dispersion.

Those which are water soluble, i.e., cellulosederivatives, present particular problems. Asthe water soluble suspending agents are addedto water, the outer layer of particles or clumpsof particles start to dissolve producing a thickrubbery gel with the powdered, unhydratedpolymer inside. If this layer is not dispersedquickly, the entire mass of particles will tendto stay as a mass and complete dispersionwill be very slow or nearly impossible. Thisis evident by the appearance of opaque ortransparent fish eye-like clumps.

To avoid this problem, the suspending agentmust be dispersed in the aqueous vehiclebefore the rubbery gel can form. This can bedone by adding the suspending agent to theaqueous vehicle in small portions with highshear, then letting the dispersion stand todissipate the foam or air bubbles.

Alternately, the suspending agent can bedispersed in an organic liquid, such as glycerinor propylene glycol, using the levigation processdescribed above. The suspending agent willeventually solvate in the organic liquid, but thisprocess is much slower than hydration in water.Thus, the slurry must be added to the aqueousvehicle with mixing before the solvation processoccurs in the organic liquid.

The suspending agent can also be mixedwith a solid, water soluble component of the suspension, i.e., sucrose, before being addedto the aqueous vehicle with mixing.

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7. Most suspension vehicles can tolerate theaddition of flavors in the form of oils as long asthe final batch is processed through a colloid mill.

8. Process the batch through a colloid mill tocompletely disperse the drug. The mill willefficiently disperse large, soft agglomerates.

9. Process the batch through deaerating equipment.

10. Avoid excessive water losses, especially ifprolonged heating is required.

11. Avoid excessive shearing and high temperatureswhich can depolymerize colloids.

Nash2 (paraphrased)

1. Dry-grind insoluble particles to the smallest andmost uniform size practical and maintain controlof the crystallographic form of the drug duringbulk chemical manufacture.

2. Where practical, allow suspension particles towet completely, without agitation, in a smallportion of the aqueous component of thesuspending vehicle containing the wetting agentin order to release entrapped air and reduce thenumber of non-wetted agglomerates.

3. Dissolve or disperse the suspending agent in themain portion of the liquid vehicle.

4. Slowly add the slurry of wetted suspensionparticles to the main portion of the suspendingagent(s) with the aid of low shear agitation.

5. Carefully control the addition of electrolytes,acids, bases, buffers, and/or tonicity agents toprevent variations in particle charge.

6. Colloid mills, homogenizers, ultrasonic devices, orpumps should be used only after all additions andadjustments have been completed as a finishingprocedure.

7. All finished aqueous suspensions must becarefully preserved against microbial growth.

Combined Drug and Suspending Agent

Since the drug and suspending agent must be uniformly dispersed during suspension prepara-tion, they can be combined in the dry state anddispersed in the aqueous vehicle using anappropriate method described above.

Other Ingredients

Other water soluble ingredients can be addedto the dispersion of drug and suspending agentduring the stage of adding solvent to finalvolume.

Final Processing

The final product is usually passed through ahomogenizer or colloid mill to ensure an even distribution of all ingredients and the break-upof clumps. Proper wetting of both drug and suspending agents cannot depend on this finalstep. In addition, the suspending agent clumpsand the fish eyes cannot be removed at thisstage.

Published Processing Guidelines

DuPont Problem Solver, 1984 (excerpted)

1. Disperse the drug by slow addition to a water, water-glycol or glycol system containing the wetting agent.

2. Add all other excipients which require solutionin as dilute a system as possible.

3. Make sure that the solvent system exceedssolubility limits of dissolved ingredients.

4. Allow sufficient water for easy dispersion andhydration of suspending agents(s) and protectivehydrocolloids.

5. If more than one drug compound is to beincorporated in the formula, ascertain their compatibility.

6. Use sufficient drug overages to compensate forlosses during manufacture and to maintain labelclaim for the shelf life of the product.

deepikaTypewritten Text

Density Difference

If the difference in density between the suspended particle and suspension mediumcan be matched, the sedimentation rate couldbe reduced to zero. Densities approaching 1.3can be obtained with high concentrations ofsucrose, which is comparable to the crystaldensity of 1.25 for many organic drugs. Thedisadvantage of this approach is that it is difficult to maintain a constant density of a solution which has large changes in density with concomitant changes in temperature.

The Gravitational Constant, g

This parameter is not of much interest sinceit cannot be controlled or changed unless in space flight.

Viscosity

Viscosity turns out to be the most readily controllable parameter in affecting sedimentationrate. While the viscosity in Stoke's Law refers to the viscosity of the fluid through which a particle falls, in reality the viscosity that controlssedimentation is the viscosity of the entire suspension. Thus, doubling the viscosity of a suspension will decrease the sedimentationrate by a factor of 2.

Sedimentation

Factors - Stoke’s Law

Sedimentation will potentially always occur in a pharmaceutical suspension since the particlesize is generally greater than that of a colloidal dispersion. The rate is described by Stoke's Lawfor a single particle settling in an infinite containerunder the force of gravity as follows:

where:

d�/dt = the sedimentation rate in distance/timed = particle diameterρ

2= particle density

ρ1

= suspension medium densityg = acceleration due to gravityη = viscosity of the suspension medium

While Stoke's Law does not quantitativelydescribe sedimentation in a suspension, it doesprovide a clear collection of factors and theirqualitative influence on sedimentation.

Particle size

Reducing particle size can have a significanteffect on sedimentation rate. Since the diameteris squared in Stoke's Law, a reduction in sizeby ¹⁄₂ will reduce the sedimentation rate by (¹⁄₂)2

or a factor of 4.

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How Suspensions Behave

d�=

d2 (ρ2

- ρ1) g

dt 18η

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Since a suspension is composed of manyingredients, it must be kept in mind that all theseingredients interact with each other. Figure 1 isa simple representation of some of the possibleinteractions that affect suspension behavior.

Although the drug in a suspension is describedas being insoluble, there is always a finite solu-bility of a drug in water, i.e., the aqueous vehiclesurrounding the suspension particle will be asaturated solution of the drug. This equilibriumchanges with changes in temperature and hasan influence on crystal growth, polymorphicchanges and chemical degradation.

Figure 1: Dynamic Model of SuspensionInteractions

+ _

+ _

DrugSuspensionParticle

D (saturated solution)

(surfactant micelles)(surfactant monomers)

(polymer)

+ -

+ -

(electrolyte)

D

Surfactants used to wet the suspension particle will exist in an equilibrium between surfactant adsorbed on the particle surface,monomers in solution, and surfactant in micelles.Changes that promote micelle formation, i.e.,surfactant concentration, electrolytes, andsolvent polarity, will also promote adsorptionof the surfactant onto the particle surface.

Likewise, polymers added as protective colloidsand suspending agents will be in equilibriumbetween molecules adsorbed on the suspensionparticle surface and molecules in solution inthe aqueous vehicle. Changes that decreasepolymer solubility, i.e., electrolytes and solventpolarity, will also promote deposition of thepolymer on the particle surface.

Electrolytes that affect the adsorption of surfactants and polymers can themselves beadsorbed onto the suspension particle surfacedirectly affecting the surface charge of the particle.

Flocculation

Charge Repulsion - zeta potential

Suspensions can exist in essentially two states,deflocculated or flocculated, depending on howsuspension particles interact. The deflocculatedstate is defined as the condition where eachsuspension particle exists independently andbehaves as a single particle. Flocculation is thestate where suspension particles attract eachother and form loosely bound aggregates orflocs. These flocs behave as a unit but are easilybroken up with shear.

Deflocculation occurs when the particles eitherrepel each other or have no reason to aggregate.Figure 2 depicts an electrostatic model of flocculation. In Figure 2A., each particle carries a positive charge of such magnitude that theparticles repel, hence, this condition would bedeflocculation. Adding negative ions, from a soluble electrolyte, causes the positive charge of the original suspension particles to be “neu-tralized” or “shielded” so that the particles nolonger repel each other but rather aggregateproducing a flocculated state (Figure 2B). Furtheraddition of negative ions can reverse the originalparticle charge and produce negatively particlesand if this negative charge is large enough, theparticles will again repel each other and become deflocculated (Figure 2C).

Dynamic Suspension Interactions

Polymer Absorption

A suspension can also be deflocculated andflocculated by polymers adsorbed on the particle surface as depicted in Figure 3.Polymers will almost always be adsorbedon the particle surface and, if the suspensionvehicle provides a good solvent for the polymer, the coated suspension particles will behave ashydrophilic particles. Thus the particles have noreason to aggregate and will be in a deflocculatedstate. The colloid literature calls this condition stabilized, and the polymer functions as a protective coating.

If the suspension vehicle is changed such thatit becomes a poor solvent for the polymer, i.e.,by the addition of electrolyte or a less polarsolvent, then the polymer will become less soluble, polymer molecules will start to interactand, if the changes are severe enough, thepolymer will precipitate. The polymer moleculeson the particle surface will also start to interactcausing an attraction between particles. Thisinteraction will produce a flocculated state.

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Figure 2: Electrostatic Model ofFlocculation

Figure 4: Sediment Volume of aDeflocculated (caked) and a FlocculatedSuspension (not caked)

Figure 3: Polymer Model of Flocculation

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–ions

–ions

A B CPositive Charge Neutral Charge Negative Charge

Deflocculated Flocculated Deflocculated

Caked Sediment Fluffy Sediment Caked Sediment

Good SolventDeflocculated

Poor Solvent/ElectrolyteFlocculated

Caking

The state of flocculation will have a profoundeffect on the physical properties of the suspen-sion as summarized in the following table andfigure. Agglomerations of flocculated particles(flocs) act as large particles but are fluffy andeasily broken up and redispersed. A deflocculat-ed suspension, while settling more slowly thana flocculated suspension, will eventually settlein a dense, hard cake which may be difficultor impossible to redisperse.

0

50

100

0

50

100

Deflocculated Flocculated

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A comparison of properties of flocculated and defloccuated suspension particles follows:

Deflocculated

1. Particles exist as separate entities.2. Sedimentation is slow - particles settle separately.3. Sediment is formed slowly from bottom of container.4. Sediment eventually becomes caked due to weight of succeeding layers of sediment.5. Pleasing appearance - suspended material remains suspended for a relatively long time.

Supernatant remains cloudy.

Flocculated

1. Particles are loose aggregates.2. Sedimentation is rapid - particles settle as large flocs.3. Sediment is formed rapidly from top of container.4. Sediment is loosely packed and easy to redisperse.5. Somewhat unsightly - obvious, clear supernatant.

Crystal Growth

• Retardation• Polymorphic changes

The equilibrium solubility behavior of the drugin a suspension can result in a change in particlesize and a change from one polymorphic formto another more stable form. As changes intemperature occur, the solubility of the drugchanges; drug continually dissolves andrecrystallizes.

The term Ostwalt ripening refers to the growthof large particles at the expense of smaller onesin a suspension composed of a relatively wideparticle size distribution. The net result is thatthe size distribution narrows. In a suspensionwith a relatively narrow size distribution to beginwith, the size distribution tends to broaden.These changes will occur until an equilibriumcondition is established.

Nash2 offers some guidelines for limiting thesetypes of changes.

• Select particles with a narrow range of sizes.• Use the most stable crystalline form of the

drug.• Avoid the use of high energy milling.• Use a wetting agent to reduce the interfacial

tension between the solid and suspendingvehicle.

• Use a protective colloid to inhibit dissolution.• Increase the viscosity of the vehicle to retard

dissolution.• Avoid temperature extremes during product

storage.

16

Controlling the Properties of a Suspension

Sedimentation

• Suspending agents and type of flow• Pseudoplastic vs. thixotropic• Yield value

As discussed with Stoke's Law, one of the mostreadily available ways to control sedimentationis to increase the viscosity of the suspensionvehicle. This can be done either by the selectionof the suspending agent or by increasing theconcentration of the suspending agent.Viscosity behavior of a suspending agent isdescribed by a flow curve constructed by plotting shear stress as a function of shearrate from any viscometer depicted in Figure 5.A Newtonian fluid (Figure 5A), e.g., most pure liquids, is characterized by a linear flow curve.These liquids have a constant viscosity calculated as the ratio of the shear stressover shear rate or the slope of the flow curvedefined as the apparent (ηa) and differentialviscosity (ηd), respectively.

ηa =

Shear Stress

Shear Rate

=d (Shear Stress)η

d d (Shear Rate)

Figure 5: Rheological Flow Curves:A - Newtonian, B - PseudoplasticC - Plastic, D - Plastic with Thixotropy

Figure 6: Viscosity vs Shear Rate

She

ar S

tres

s

Shear Rate

A B

DC

Almost all suspending agents have a flowbehavior described as non-Newtonian. Cellulosederivatives and soluble polymers have a flowbehavior described by the term pseudoplastic.With either definition of viscosity, it can be seenfrom the flow curve in Figure 5B that viscositydecreases with shear rate for a pseudoplasticfluid as illustrated by the upper curve in Figure 6.

0

10

20

30

40

50

60

70

700500 600400

Shear Rate

Vis

cosi

ty

17

Electrostatic Flocculation

Martin3 has shown that the flocculation of a suspension can be controlled by adjusting the surface charge of a suspension as measured bythe zeta potential. Figure 7 summarizes theseobservations by illustrating the interrelationshipbetween sedimentation volume, caking, andzeta potential.In water, bismuth subnitratehas a positively charged surface with a zetapotential high enough so that the particlesrepel each other. At this point the suspensionis deflocculated and will eventually producea caked sediment.

This behavior is advantageous for suspensionssince during sedimentation the settling particlegenerates a low shear rate, the correspondingviscosity is high, and sedimentation is inhibited.Conversely, when the suspension is shakenvigorously, a high shear rate is generated, theviscosity is decreased, and the suspensionflows or pours easily. This is in contrast to aNewtonian fluid which has a constant viscosityregardless of the amount of shear applied tothe fluid.

Other suspending agents, particularly carbomer,clays, and Avicel® RC, have a plastic flowbehavior. This flow is shear thinning like thepseudoplastic fluids but is also characterizedby a yield value. This yield value is seen as anintercept on the shear stress axis and corre-sponds to the stress that must be placed onthe fluid to cause it to flow (Figure 5C).

If the yield value of the suspending agent isgreater than the stress exerted on the fluidby the suspension particle, the suspensionparticle cannot move through the suspensionand sedimentation cannot take place. Thetheoretical minimum yield value required topermanently suspend a particle can be calculated from the following equation:

where:YV

t= is the calculated or theoretical yield

valueVp = is the particle volume given by π d3/6A = is the cross sectional area of the

particle, π d2/4 and the other terms areas defined in Stoke's Law

Some suspending agents have a time dependentflow behavior (Figure 5D), called thixotropy, whichis characterized by ahysteresis loop in the flowcurve. A thixotropic fluid has a structure that isbroken down by shear as in a plastic or pseudo-plastic fluid; however, the rebuilding of structureafter shearing is stopped takes a finite time. Thisis advantageous in that, in addition to the fluid

YVt

=Vp (ρ2 - ρ1 ) g

A

being shear thinning and may have a yield value,the slower structure buildup allows the fluid tobe processed easily for a period of time.

The viscosity relationship for a thixotropic fluid is depicted in Figure 6 where the upper curve corresponds to the viscosity measured at increasing shear rate and the lower curve to viscosity measured at decreasing shear rate.

Figure 7: Caking Diagram Shows theFlocculation of a Bismuth SubnitrateSuspension by Means of the FlocculatingAgent, Monobasic Potassium Phosphate2

+ _

+_

+_+

_+_

+_

+ _

_+ _

__

__

__

_+

+

++

+

+

+

+

Concentration KH PO2 4

_

+

_100

_

_

0.03

0.04

00

Caking Zone Noncaking Zone Caking Zone

App

aren

t zet

a po

tent

ial

zeta potential Curve

V3/V4 Curve

V1 - V2Ratio

Caked Not Caked Caked50 Concentration KH2PO4

deflocculated suspension by controlling the electrolyte concentration of the suspension.

Deflocculated vs. FlocculatedFormulations: A Structured VehicleApproach

Swarbrick4 describes a scheme for alternativeapproaches for preparing suspensions. In thisscheme, the suspension can be either flocculated or deflocculated as long as a structured vehicle is used. The structured vehicle is characterized by having a yield value and thixotropic flow which prevents sedimentation regardless of the state of flocculation so that a caked sediment cannot be formed.

18

Figure 8: Alternative Approaches to the Formulation of Suspensions

As the electrolyte is added, the HPO42- ion isattracted to the positively charged surface thusshielding and lowering the zeta potential. Thesurface charge is not sufficient for the particlesto repel each other and the suspension flocculates. The sediment produced is looseand fluffy and can be redispersed easily byshaking. Further addition of electrolyte producesa negative surface charge, the suspensionbecomes deflocculated, and will eventuallyproduce a caked sediment. Martin's experimentswere carried out in dilute suspensions of bismuthsubnitrate in water with added electrolyte. In areal suspension, concentrations of drug aremuch higher and the suspension contains manyother ingredients that can affect surface chargeand characteristics. Nevertheless, one can in practice produce either a flocculated or

Particles

Addition of wetting and dispersion medium

Uniform dispersion ofdeflocculated particles

A B C

Incorporation of Addition of flocculating agent Addition ofstructured vehicle flocculating

Flocculated suspension agentas final product

Flocculatedsuspension

Deflocculated suspensionin succeeding vehicle as Incorporation of

final product structured vehicle

Flocculated suspensionin structured vehicle as

final product

19

A Universal ApproachPlaizier-Vercammen and Janssens5 haveproposed a universal method of formulating suspensions. They acknowledge the effect ofa zeta potential or surface charge on the stateof flocculation but point out that zeta potentialsare measured in dilute dispersion and do notreflect quantitatively the zeta potential in a realsuspension.

As pointed out in Figure 1, there are many components in a suspension formulation thataffect the surface properties of each suspensionparticle. While the zeta potential relates to therelative surface charge in sign and magnitude, itcannot be relied upon to describe the behaviorof a formulated suspension.

Plaizier-Vercammen and Janssens suggestthat the suspension be formulated varying the concentration of charged surfactant to vary thezeta potential. All of the ingredients should beincluded so that the overall effect can be seen.

Such an approach is illustrated in Figure 9 fora bismuth subcarbonate suspension preparedin water and in 3% Avicel® RC-581 as a suspending agent and sodium dioctylsulfosucci-nate as an anionic surfactant. In water, thesediment volume decreases with increasingsurfactant concentration clearly suggestingan increase in zeta potential with increasingsurfactant concentration. The last three samplesat the highest surfactant concentration arecaked, which is consistent with a deflocculatedsuspension.

With Avicel® RC-581, the sediment volume stays relatively constant up to 0.1% surfactant concentration, then decreases slightly. However,none of the samples prepared with the suspend-ing agent were caked, suggesting a flocculatedsuspension, at least at the lower surfactant con-centration. At higher surfactant concentrations,the samples could be either flocculated ordeflocculated with the suspending agent supplying a sufficient yield value to prevent sedimentation and caking.

Figure 9: Sedimentation Behavior of a Bismuth Subcarbonate Suspension in Water and in 3% Avicel® RC-581

0

0.2

0.4

0.6

0.8

1

0.000 0.001 0.010 0.100 0.500 1.000

Rel

ativ

e S

edim

ent

Volu

me

% Surfactant Concentration

Caked

Water3% Avicel®

Regardless of the mechanism of particle interaction in this illustration, physically stableand useful suspensions could be preparedwith 3% Avicel® RC-581 with a surfactant concentration ranging from 0 to 0.1%.

This universal method can be summarized andextended as follows:

• Prepare the suspension formulation with reasonable ingredients at reasonable levels.

Vary the formulation composition to get a subjectively suitable product regarding appearance, viscosity, and sedimentation.

• Select one formulation factor such as electrolyte, surfactant, or solvent and varyits concentration to obtain a variation inthe sedimentation rate or volume.

This systematic variation will producechanges in all of the equilibria describedin Figure 1 so that changes represent acomposite effect of the entire formulation.

• Select a concentration of this ingredient tomaximize sediment volume and minimize sedimentation rate.

Zeta Potential

Determined from the electrophoretic mobility indilute dispersion. Generally, reflects the relativesurface potential of the undiluted suspensionbut not a quantitative measure.

Density

A measure of air incorporated into the suspension during preparation.

Viscosity

Need to determine flow properties over a rangeof shear rates to identify the type of flow, thechange in viscosity with shear rate, degree oftime dependency (thixotropy), and the presenceof a yield value.

Sedimentation

Rate of sedimentation, relative volume of sediment, and quality of the sediment.

Redispersibility

Measured by the number of rotations of thesuspension container required to redisperse anysediment. An indirect indicator of flocculation.

Particle Size

Measure as a function of time. Some changecan be expected over a period of time untilan equilibrium is established.

20

Experimental Suspension Parameters

21

Preparation

The preparation of suspensions for reconstitutioninvolves dry powder and granulation processesthat are described in other sections of this publi-cation. In general, the products fall into one ofthree classes; powder blends, granulations, ora combination of the two.

Powder Blends

Traditional powder mixing processes are involvedtaking precautions when incorporating smallquantities of ingredients to ensure uniformity.

Powder blends have the advantage of using relatively simple equipment, are least likely tohave chemical and stability problems becauseno heat or solvents are used, and normallyhave a low moisture content.

They are, however, prone to uniformity problems,poor flow and demixing.

Granulated Products

All of the ingredients are processed by granulation, usually a wet granulation process.They have the typical advantages of granulations, i.e., improved appearance,improved flow characteristics, less segregationproblems, and less dust generation during filling.

Disadvantages include increased cost due tomore processing steps, higher residual moisturecontent, stability problems with ingredientssensitive to water during granulation, e.g.,flavors.

Combination Products

These products take advantage of the positive features of the first two methods. Less energyis required if the majority of the diluent canbe added after granulation. Heat-sensitiveingredients, such as flavors, can be addedafter drying the granulation.

Introduction

Suspensions for reconstitution are dry formulations which require mixing with waterprior to administration. Once reconstituted,they must conform to all of the requirementsof a traditional suspension.

This type of dosage form is usually used fordrugs that are not stable in the presence ofwater but need to be dispensed in liquid form.Oral and parenteral products are included in this classification.

Formulations

In general, the number of ingredients should be kept to a minimum in order to decrease the possibility of problems. All ingredients should disperse rapidly on reconstitution, this criterioneliminates several suspending agents whichrequire special mixing procedures for complete dispersion. Sodium carboxymethylcellulose(NaCMC), microcrystalline cellulose withNaCMC, carrageenans, and xanthan gum are typical suspending agents capable of dispersing readily by shaking.

Typical Formulations

Two Commercial Amoxicillin Suspensions forReconstitution.

Reconstitutable Suspensions

Ingredient Function Product 1 Product 1

Active ingredient Amoxicillin trihydrate Amoxicillin trihydrate

Sweetener Sucrose Sucrose, mannitol

Suspending agent Xanthan gum Cellulose, Na CMC

Dessicant Silica gel

Buffer Sodium citrate Sodium citrate, citric acid

Preservative Sodium benzoate

Colorant FD&C Red No. 3 Red No. 28, Red No. 40

Flavor Flavors Artificial flavors

Care must be taken that the particle size distribution of the granulation and non-granulated fractions are controlled to prevent segregation and nonuniformity.

References

1. United States Pharmacopeia, 24th Ed., 1999,US Pharmacopeal Convention

2. R. A. Nash, Pharmaceutical Suspensions,Chapter 1 in Pharmaceutical Dosage Forms:Disperse Systems, Vol. 2, ed, H. A.Lieberman, M M. Rieger, and G.S. Bankereds., Marcel Dekker, Inc., 1996.

3. A.N. Martin and P. Bustamonte, PhysicalPharmacy, 4th ed., Williams & Wilkins, 1993.

4. J. Swarbrick, Coarse Dispersions, Chapter 21in Remington: The Science and Practice ofPharmacy, 19th ed, A. R. Gennaro ed, MackPublishing, 1995.

5. J. A. Plaizier-Vercammen and E. Janssens, AUniversal Method to Obtain Stable and EasilyRedispersible Suspensions, Labo-Pharma -Probl. Tech. 32: 283-7, 1984.

Selected Readings

Remington: The Science and Practice ofPharmacy, 19th ed, A. R. Gennaro ed, MackPublishing, 1995.

A.N. Martin and P. Bustamonte, PhysicalPharmacy, 4th ed., Williams & Wilkins, 1993.

Pharmaceutical Dosage Forms: DisperseSystems, Vol. 1, ed, H. A. Lieberman, M. M.Rieger, and G. S. Banker eds., Marcel Dekker,Inc., 1996.

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