What is Pharmaceutical Suspension?

Introduction

• A Pharmaceutical suspension is a dispersed system in which the internal phase is dispersed uniformly as finely divided insoluble particles throughout the external phase.
• The internal phase consists of insoluble solid particles having a specific range of size which is maintained uniformly throughout the suspending vehicle with aid of a single or combination of suspending agents.
• The external phase (suspending medium) is generally aqueous in some instances, and may be an organic or oily liquid for non-oral use.
• The term "Disperse System" refers to a system in which one substance (The Dispersed Phase) is distributed, in discrete units, throughout a second substance (the continuous Phase or vehicle).
• Each phase can exist in a solid, liquid, or gaseous state.
• Most suspensions are classified as coarse suspensions which is a dispersion of particles with a mean diameter greater than 1μm (1 to 100 μm). A colloidal suspension is a dispersion of particles with a mean diameter of less than 1μm (0.5μm to 1μm).

The Difference Between Solution & Suspensions

• When the 2 substances totally mix it is called a solution.
• E.g. Solute + Solvent = Solution
• (sugar) + (water) = Solution

• We then say sugar is soluble in water, it has dissolved.

• The particles in a suspension are insoluble
• Sometimes when we mix substances they stay in clusters. We, therefore, say it is insoluble in water.
• E.g. Chalk + Water = Suspension

• Eventually the particles sink to the bottom to form sediment.

Types of Insoluble Solids

• There are two types of insoluble solids which constitute the internal or dispersed phase. These are

1. Diffusible solids – this sediment is sufficiently slowly to enable satisfactory dose removal after redispersion. eg. Light kaoline, magnesium trisilicate.
2. Indiffusible solids - eg. sulphadimidine and chalk. This sediment too rapidly and require the addition of other materials to reduce the sedimentation rate to an acceptable level.

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Sedimentation

• This phenomenon occurs in a dispersed system where the dispersed particles settle at the bottom of the container. This occurs because the particles are too large to remain permanently suspended in the vehicle.
• Therefore suitable suspending agents are added to retard this process.

Suspending Agents

• Suspending agents are substances that are used to keep finely divided insoluble materials suspended in a liquid media by preventing their agglomeration (coming together) and by imparting viscosity to the dispersion media so that the particles settle more slowly. Care must be taken when selecting a suspending agent for oral preparations as the acid environment of the stomach may alter the physical characteristics of the suspension and therefore the rate of release of the drug from suspension.
• Types of suspending agents

Natural Agents

• This class consists of those from.

1. Animal source eg. Gelatine
2. Plant sources eg. Acacia, Tragacanth, Starch, seaweed (Alginates)
3. Mineral sources. eg Bentonite, Kaoline

Semi-Synthetic Agents

• These consist of substituted cellulose (minerals) eg. Hydroxyethylcellulose, Sodium Carboxymethylcellulose, methylcellulose, Microcrystalline cellulose

Synthetic Agents

• They are synthetic polymers eg carboxy polymethylene (carbopol), Polyvinyl Alcohol, and Polyvinyl Pyrrolidone iodine complex (PVC).
• Most suspending agents perform two functions. i.e. besides acting as a suspending agent they also impart viscosity to the solution. Suspending agents form film around particles and decrease interparticle attraction.
• A good suspension should have well-developed thixotropy.
• At rest, the solution is sufficiently viscous to prevent sedimentation and thus aggregation or caking of the particles. When agitation is applied the viscosity is reduced and provides a good flow characteristic from the mouth of the bottle.

Classification of Suspensions

• Based On General Classes 

1. Oral suspension 
2. Externally applied suspension 
3. Parenteral suspension.

• Based On the Proportion Of Solid Particles 

1. Dilute suspension (2 to10 %w/v solid) 
2. The concentrated suspension (50%w/v solid)

• Based On the Electrokinetic Nature Of Solid Particles 

1. Flocculated suspension 
2. Deflocculated suspension

• Based On the Size Of Solid Particles

1. The colloidal suspension (< 1 micron)
2. The coarse suspension (>1 micron) 
3. Nano suspension (10 ng)

Formulation of Suspension

The three steps that can be taken to ensure the formulation of an elegant pharmaceutical suspension are:

1. Control Particle Size: On a small scale, this can be done using a mortar and a pestle to grind down ingredients to a fine powder.
2. Use a thickening agent to increase the viscosity of the vehicle by using suspending agents or viscosity-increasing agents
3. Use of a wetting agent/surfactant

Pharmaceutical Applications of Suspensions

• Suspensions may be used pharmaceutically for several reasons. Some are given below;

1. Suspension is usually applicable for a drug that is insoluble or poorly soluble. E.g. Prednisolone 
2. Suspension to prevent degradation of the drug or to improve the stability of the drug. E.g. Oxytetracycline suspension
3. To mask the taste of bitter or unpleasant drugs when formulated in solution form. Drugs are formulated as suspensions that will be more palatable E.g. Chloramphenicol palmitate suspension
4. Suspension of drug can be formulated for topical application e.g. Calamine lotion.
5. Suspension can be formulated for parenteral application in order to control the rate of drug absorption, E.g. penicillin procaine
6. Vaccines as immunizing agents are often formulated as a suspension. E.g. Cholera vaccine
7. X-ray contrast agents are also formulated as a suspension. E.g. Barium sulfate for examination of the alimentary tract
8. If the drug is unstable when in contact with the vehicle, suspensions should be prepared immediately before handing out to the patient to reduce the amount of time that the drug particles are in contact with the dispersion medium. Eg Amoxicillin suspension
9. Drugs that degrade in an aqueous solution may be suspended in a non-aqueous phase. eg. Tetracycline hydrochloride is suspended in a fractionated coconut oil for ophthalmic use.
10. Lotions containing insoluble solids are formulated to leave a thin coating of medicament on the skin. As the vehicle evaporates, it gives a cooling effect and leaves the solid behind. eg calamine lotion and sulfur lotion compound.
11. Bulky, insoluble powders can be formulated as a suspension so that they are easier to take eg Kaolin or chalk.

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Advantage of Suspension

• Suspension can improve the chemical stability of certain drugs. E.g. Procaine penicillin G
• The drug in suspension exhibits a higher rate of bioavailability than other dosage forms. bioavailability is in the following order, Solution > Suspension > Capsule > Compressed Tablet > Coated tablet
• Duration and onset of action can be controlled. E.g. Protamine Zinc-Insulin suspension
• Suspension can mask the unpleasant/ bitter taste of the drug. E.g. Chloramphenicol palmitate

Disadvantage of Suspension

• Physical stability, sedimentation, and compaction can cause problems.
• It is bulky, therefore sufficient care must be taken during handling and transport.
• It is difficult to formulate 
• A uniform and accurate dose can not be achieved unless the suspension is packed in a unit dosage form.

Basic Requirements of Suspension

• The suspended particles should not settle rapidly and the sediment produced must be easily re-suspended by the use of a moderate amount of shaking.
• Satisfactory pourability.
• Should have an elegant smooth appearance.
• After gentle shaking, the medicament stays in suspension long enough for a dose to be accurately measured.
• Constant particle size and size distribution so that the product is free from a gritty texture.

Flocculated Suspensions 

• Flocculation is a condition that occurs as a result of the lowering of electrical forces of repulsion in a dispersed system so that the force of attraction predominates. Systems under this condition reduced repulsive forces the dispersed particles to approach each other more closely and form aggregates known as flocs In flocculated suspension, formed flocs (loose aggregates) will cause an increase in sedimentation rate due to an increase in the size of sedimenting particles. Hence, flocculated suspensions sediment more rapidly.
• Here, sedimentation depends not only on the size of the flocs but also on the porosity of flocks. In flocculated suspension, the loose structure of the rapidly sedimenting flocs tends to preserve in the sediment, which contains an appreciable amount of entrapped liquid. The volume of final sediment is thus relatively large and is easily redispersed by agitation.

• Most stable pharmaceutical suspensions are flocculated.
• The suspension appears somehow insightful (unappealing) due to its rapid sedimentation and it presents an obvious clear supernatant. This can be minimized by enlarging the volume of the sediments with the use of flocculating agents eg starch, alginates, and carboxy vinyl polymers.
• Since the sediment is loosely structured, caking or claying does not occur.

Deflocculated Suspensions

• A deflocculated suspension is one in which the electrical repulsive forces between particles exceed the attractive forces, and the particles are kept apart as individuals affected only by the suspending vehicle. Even when brought together by random motion, they resist collision due to the high surface tension.
• In deflocculated suspension, individual particles are settling, so the rate of sedimentation is slow which prevents entrapping of a liquid medium which makes it difficult to re-disperse by agitation.
• This phenomenon is also called ‘cracking’ or ‘claying’.
• In deflocculated suspension, smaller particles settle slowly and therefore remain supernatant liquid so the supernatant appears cloudy and has a pleasing granular appearance whereby in flocculated suspension, even the smallest particles are involved in flocs, so the supernatant does not appear cloudy.

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Flocculating Agents

• Flocculating agents decrease the zeta potential of the suspended charged particle and thus cause aggregation (flock formation) of the particles.
• Examples of flocculating agents are:

1. Neutral electrolytes such as KCl, and NaCl.
2. Surfactants
3. Polymeric flocculating agents
4. Sulfate, citrates, phosphates salts
5. Neutral electrolytes e.g. NaCl, and KCl besides acting as flocculating agents, also decrease the interfacial tension of the surfactant solution. If the particles are having less surface charge then monovalent ions are sufficient to cause flocculation e.g. steroidal drugs.
6. For highly charged particles e.g. insoluble polymers and poly-electrolytes species, di or trivalent flocculating agents are used.

Mixing Procedure of Suspensions

• The method of dispensing suspensions is the same for most, with some differences for specific ingredients.

1. Crystalline and granular solids should be finely powdered in the mortar. The suspending agent should then be added and mixed thoroughly in the mortar. Do not apply too much pressure, otherwise gumming or caking of the suspending agent will occur and the heat of friction will make it sticky.
2. Add a little liquid vehicle to make a paste and mix well until smooth and free of lumps. Continue with gradual additions until the mixture can be poured into a bottle. The further liquid is used to rinse all the powder into the bottle where it is made up to volume.
3. When water is prescribed as a vehicle, use freshly boiled and cooled water or potable water where permissible.

Variations

• If the wetting agents are included in the formulation, add them before forming the paste
• If syrup and/or glycerol are in the formulation, use this rather than water to form the initial paste
• If soluble solids are being used, dissolve them in the vehicle before or after making the paste
• Leave the addition of volatile components, coloring or concentrated flavoring tinctures such as chloroform spirit, liquid licorice extract, and compound tartrazine solution until near the end.

Stability of Suspensions

• Factors that contribute to the appreciable stability of a suspension include 

1. Small particle size - reducing the size of the dispersed particle increases the total surface area of the solid. The greater the degree of subdivision of a given solid the larger the surface area. The increase in surface area means also an increase in the interface between the solids and liquids leading to an increase in the viscosity of a system.
2. Increasing the viscosity - increasing the viscosity of the continuous phase can lead to the stability of suspensions. This is so because the rate of sedimentation can be reduced by the increase in viscosity. Viscosity increase is brought about by the addition of thickening agents to the external phase. In water, these must be either soluble or swell. It is important to note that the rate of release of a drug from a suspension is also dependent on the viscosity, of a product. The more viscous the preparation, the slower is likely to be the release of a drug. Sometimes this property may be desirable for depot preparations.
3. Temperature - Another factor that negatively affects the stability and usefulness of pharmaceutical suspensions is a fluctuation of temperature. Temperature fluctuations can lead to caking and claying.

Quality Control of Suspensions

The following tests are carried out in the final quality control of suspension:

1. Appearance Color, odor, and taste
2. Physical characteristics such as particle size determination and microscopic photography for crystal growth
3. Sedimentation rate
4. Zeta Potential measurement
5. Sedimentation volume
6. Re-dispersibility and Centrifugation tests
7. Rheological measurement
8. Stress test
9. pH
10. Freeze-Thaw temperature cycling
11. Compatibility with container and cap liner.

Special Labels and Advice for Suspensions

All pharmaceutical suspensions should be properly labeled. 

1. The most important additional information in addition to the product name and directions for use is the inclusion of the direction “shake the bottle well before use” as some sedimentation of medicament would normally be expected. Shaking the bottle will redisperse the medication and ensure that the patient can measure the accurate dose. 
2. Other labeling information includes directions to store in a cool place and the expiry date.

Container for Suspensions

• Choices of packaging of all pharmaceutical products are an extremely important aspect of ensuring the stability of the product.
• Suspensions should be packed in amber-colored bottles - plain for internal use and ribbed for external use. There should be adequate air space above the liquid to allow shaking and easy pouring. A 5ml medicine spoon or oral syringe should be given when the suspension is for oral use.

Ideal Requirements of Packaging Material

• It should be inert. 
• It should effectively preserve the product from light, air, and other contamination through shelf life. 
• It should be cheap. 
• It should effectively deliver the product without any difficulty

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