Outcomes of this lecture 1- Definition and Classification of dispersed systems 2- Pharmaceutical and medical application of suspensions 3- Formulation of Suspensions 4- Suspension formulation additives 5- Stability of suspensions

Dispersed Systems Classification of Dipersed Systems on the basis of particle size: 1- Molecular Dispersion less than 1 nm 2- Colloidal Dispersion 1 nm to 0.5 um 3- Coarse Dispersion greater than 0.5 um

Types of disperse systems A true solution - mixture of two more more components that form a homogenous molecular dispersion, i.e. a one-phase system, the composition of which can vary over a wide range. A colloidal dispersion - represents a system havin a particle size intermediate between that of a true solution and a coarse dispersion, roughly 10Å to 5000Å (0.1mm = 1000Å) A coarse dispersion the diameter of the particles in emulsions and suspensions for the most part being larger than 0.1mm(1000Å).

Pharmaceutical dosage form of Coarse Dispersion: 1- Suspensions 2- Emulsions 3- Semisolids

Suspensions Definition: A dispersion of finely divided, insoluble solid particles (the disperse phase) in a fluid or liquid medium (the dispersion medium).

Suspensions are heterogeneous system consisting of two phases: Continuous or external phase; is generally a liquid or semi solid, Dispersed or internal phase; is made up of particulate matter, that is essentially insoluble in, but dispersed throughout, the continuous phase.

Size of suspended particles: Particles with diameters greater than 0.5 micron (human hair has a diameter of about 75 micron). Systems with particles smaller than 0.5 micron are considered to be colloidal.

Pharmaceutical Advantages of suspensions: To administer an insoluble compound as a liquid. To lessen the unpleasant taste of an insoluble compound by: formulating a vehicle in which the drug is not soluble using an insoluble form of the drug (ie. salt form or prodrug) adsorbing the drug onto an insoluble carrier To modify the release rate of the drug. To improve the stability by reducing the fraction of drug in solution.

Pharmaceutical and medical application of suspensions: 1- Oral dosage forms; amoxicilin, ampicilin, AlMg sulphate, … 2- Topical dosage forms; dermatologic materials; zinc cream, calamine lotion, … 3- Parenteral dosage forms, dexamethazone, …. 4- Ophtalmic dosage forms; eye drops; hydrocortisone, neomycin,… 5- Inhaler dosage forms; aerosols; antiseptics, antibiotics, dermatological steroids. 6- Vaccines; cholera, diphtheria, tetanus vaccines. 7- Diagnostic products; some X-ray contrast media, barium sulphate,…

Physical properties of suspensions: The suspended material should not settle rapidly. The settled particle must not form a hard cake. The settled particle should be easily redispersed and resuspended. The suspension must have optimum viscosity. The suspended particles should be small and uniformly sized.

Formulation of Suspensions: Theoretic Consideration; Select appropriate ingredients Use appropriate mixing and milling equipments Understanding concepts of Particle size, wetting, Particle interaction, Electrokinetics, Aggregation, Sedimentation

Particle Size Control; Before suspension formulation: It is necessary to insure that the drug and ingredients particles are suitably subdivided prior to formulation. Small particles have retarded sedimentation rate Large particles impart a gritty texture

Particle Size Control; After suspension formulation: There is possibility of crystal growth which occurs on storage. In change of temperature for dissolving of drug and ingredients In use of different polymorphic forms of a drug

Wetting; Since, a suspension is essentially an incompatible system, but to exist at all, it requires some degree of compatibility and good wetting of the suspended materials is important in achieving this end. In strong affinity between a liquid and a solid, the liquid easily forms a film over the surface of the solid (wetting will happen easily). In weak or nonexistent affinity, the liquid has difficulty displacing the air or other substances surrounding the solid (importance of contact angle).

Solid nature in aqueous suspension: Hydrophilic (Lyophilic or solvent-loving) which are easily wet by water or other polar liquids, so there is no need for wetting agents. Hydrophobic (Lyophobic) which repel water but can usually be wetted by non-polar liquids

Mechanism of wetting: To ensure adequate wetting the interfacial tension between the solid and the liquid must be reduced so that the adsorbed air is displaced from the solid surfaces by the liquid.

Wetting agents: A) Surface active agents The hydrocarbon chains would be adsorbed by the hydrophobic particle surfaces while the polar groups would project into the aqueous medium becoming hydrated. Surfactants possessing an HLB value of between about 7 and 9 would be suitable for use as wetting agents.

Most surfactants are used at concentrations of up to about 0 Most surfactants are used at concentrations of up to about 0.1% as wetting agents includes: For oral use: polysorbates (Tweens) and sorbitan esters (Spans). For external application: sodium lauryl sulphate, sodium dioctylsulphosuccinate and quillaia extract. For parenteral administration: polysorbates, polyoxyethylen/polyoxypropylene copolymers (Pluronices) and lecithin.

* Disadvantages of surfactants wetting agent: a) Excessive foaming b) Possibility of formation of a deflocculated system

B) Hydrophilic colloids - Behave as protective colloids by coating the solid hydrophobic particles with a multimolecular layer and impart a hydrophilic character to the solid and thus promote wetting. Most Hydrophilic colloids are used as wetting agents includes: = Acacia = Alginates = Cellulose derivatives = Bentonite = Colloidal silica = Tragacanth

C) Solvents Materials such as alcohol, glycerol and glycols which are water miscible will reduce the liquid/air interfacial tension. The solvent will penetrate the loose agglomerates of powder displacing the air from the pores of the individual particles thus enabling wetting to occur by the dispersion medium.

D) Other Materials include: Hydrophilic polymers such as carboxymethylcellulose Aluminum-magnesium silicates lanolin derivatives

Solid Particle Interactions and behavior in suspensions: Lyophobic (hydrophobic) = nonwetting, sensitive to the addition of salts Lyophilic (hydrophilic) = wetting, not sensitive to the addition of salts The behavioral difference between these classes is their sensitivity to the presence of electrolytes. The stability of lyophobic particles will reduce by lowering the repulsive potential of the electerochemical double layer or by decreasing the degree of hydration.

Stages of suspension preparation: Change of solid particle size to suitable size Wetting of solid particles Adding other ingredients such as flocculating agents, dispersants, thickeners, preservatives, flavoring, …

preparation of a suspension Wetting and Dispersion of the Active Ingredient. Stabilization of Dispersed Solid. Preparation of the Vehicle. Addition and Dispersion of Active Ingredient in Vehicle. Addition of Remaining Ingredients and Final Mixing.

Suspension Formation: 1- Precipitation Methods: A) 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. Ethanol, methanol, propylene glycol, and polyethylene glycol are the example of organic solvents.

Important considerations in this method are: Particle size control Correct polymorphic or hydrate form of the crystal of solid particles which obtained from this method. For example precipitation of prednisolone in aqueous methanol gives sesquihydrate product, but in aqueous acetone gives metastable anhydrous crystalline product which is easily suspended in water.

Influence of the solvent on crystal characteristic. Possible preparation under sterile conditions Inherent solvent entrapment and subsequent toxicity The volume ratio 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, freeze drying) The washing of the precipitate

B) Precipitation effected by changing the pH of the medium This technique 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 weakly acid solution of hydrochloric, citric, or acetic acids, the estradiol is precipitated in fine state of subdivision. Insulin suspensions and Adrenocorticotropin zinc suspensions are prepared in a similar manner.

In this method the type of crystal or polymorphic form depends on some factors such as: The concentrations of acid and base The degree and type of fluid shear imparted to the system.

C) Double decomposition method This method involves only simple chemical reaction, although some of the aforementioned physical factors also come into play. For example suspension of zinc polysulfide will prepare by mixing zinc sulfite and sulfurated potash solution.

2) Dispersion Methods: A suspension is prepared on the small scale by grinding or levigating the insoluble material in the mortar to a smooth paste with a vehicle containing the dispersion stabilizer and gradually adding the remainder of the liquid phase in which any soluble drugs may be dissolved. The slurry is transferred to a graduate, the mortar is rinsed with successive portions of the vehicle, and the dispersion is finally brought to the final volume. On a large scale, dispersion of solids in liquids is accomplished by the use of colloid mills. Dough mixers, pony mixers, and similar apparatus are also employed.

Flocculating Agents: 1) Electrolytes: Addition of an inorganic electrolyte to an aqueous suspension will alter the zeta potential of the dispersed particles. If this value is lowered sufficiently then flocculation will occur. The ability of an electrolyte to flocculate hydrophobic particles depends on the valency of its counter ions (monovalent, divalent or trivalent ions). The most widely used electrolytes as flocculating agents include: The sodium salts of acetates, phosphates and citrates

2) Surfactants: Ionic surfactants may cause flocculation by neutralization of the charge on each particle, Non-ionic surfactants will have little effect on the charge density of a particle but may, because of their linear configurations, adsorb on to more than one particle thus forming a loose flocculated structure.

3) Polymeric flocculating agents: The linear branched chain molecules will form a gel-like network within the system and become adsorbed on to the surfaces of the dispersed particles thus holding them in a flocculated state. The most widely used polymers as flocculating agents include: Starch, alginates, cellulose derivatives, tragacanth, carbomers and silicates

Viscosity modifiers of suspensions: 1) Acacia gum (gum Arabic) This natural gum is used as a thickening agent Its value as a suspending agent is largely due to its action as a protective colloid It is not very satisfactory as a suspending agent for dense powders ( It is often combined with tragacanth, starch and sucrose)

Disadvantages of Acacia: Acacia mucilage becomes acidic on storage due to enzyme activity Acacia mucilage contains an oxidize enzyme which may cause deterioration of active agents which are susceptible to oxidation Because of its stickiness it is rarely used in preparations for external use.

2) Tragacanth Its thixotropic and pseudo plastic properties make it better thickening agent than acacia It will form viscous aqueous solution It can be used for internal and external products It is stable over a pH range of 4-7.5

Disadvantages of tragacanth: It takes several days to hydrate fully after disperssion in water, so the maximum viscosity will achieved after this time Its viscosity is also affected by heat

3) Alginates They are most viscous immediately after preparation They exhibit a maximum viscosity over a pH range of 5-9 Sodium alginate (Manucol) is the most widely used material in this class

Disadvantages of Alginates: Alginate mucilage must not be heated above 60 °C as depolymerization occurs with a consequent loose in viscosity At low pH they will precipitate incompatible with cationic materials and heavy metals

4) Starch * Rarely used on its own as a suspending agent * It is one of the constituents of Compound Tragacanth Powder BP * It can be used with sodium carboxymethylcellulose * Sodium starch glycollate (Explotab, Primojel) is used in the preparation of suspensions

5) Methylcellulose (Celacol): This is a semisynthetic polysaccharide and is produced by the methylation of cellulose Several grades are available depending on their degree of methylation and on the chain length The longer the chain the more viscous is its solution It is more soluble in cold water than in hot water

It is stable over a wide range of pH, from 3 to 11 It is non-ionic and are compatible with many ionic derivatives On heating become progressively hydrated an eventually gel at about 50 C and on cooling the original form is regained

6) Hydroxyethylcellulose (Natrosol 250) It exhibits the same properties as methylcellulose It is soluble in both hot and cold water It will not form gel on heating

7) Sodium carboxymethylcellulose (SCMC) (Edifas, Cellosize) It is widely used at concentrations up to 1% in products for oral, parenteral or external use. Produces clear solutions in both hot and cold water It is stable over a pH range of about 5-10

Disadvantages of SCMC It is incompatible with polyvalent cations Will precipitate at low pH Heat will reduce the viscosity

8) Microcrystalline cellulose (Avicel) It is a widely used suspending agent often with 8 to 11% SCMCadded to aid its dispersion and to act as a protective colloid It will disperse readily in water (but are not soluble) to produce thixotropic gels

9) Bentonite It hydrate rapidly, absorbing up to 12 times its weight of water particularly at elevated temperatures The gel formed is thixotropic and therefore has useful suspending properties It is used at concentration of up to 2 or 3% in preparations for external use It may contain pathogenic spores (sterilization needed)

10) Magnesium aluminium silicate (Veegum) It exhibits the same properties as Bentonite It can be used both internally and externally at concentration of up to 5% It is stable over a pH range of 3.5-11%

11) Hectorite It exhibits the same properties as Bentonite It can be used at concentrations of 1-2% for external use Laponites, which are synthetic hectorites do not exhibit the batch variability or microbial contamination, can be used internally

12) Carboxypolymethylene (Carbopol): It is totally synthetic copolymer of acrylic acid and allyl sucrose It is used at concentrations of up to 0.5% mainly foe external application When dispersed in water it forms acidic, low viscosity solutions which, when adjusted to a pH of between 6 and 11, become highly viscous.

13) Colloidal silicon dioxide (Aerosil) It is a finely divided product but will aggregate when dispersed in water and will forming a three-dimensional network. It can be used at concentrations of up to 4% for external use It has also been used for thickening non-aqueous suspensions

Suspension formulation additives 1) Buffers: The inclusion of buffers may be necessary in order to maintain chemical stability, control tonicity or to insure physilogical compatibility Addition of electrolytes may have profound effects on the physical stability of suspensions.

2) Density modifiers: If the disperse and continuous phases both have the same densities then sedimentaion would not occur, So we add this agents to bring the density of two phases closer together. Sucrose, Glycerol or propylene glycol are used as density modifiers

3) Flavours and Perfumes These agents can be obtained from: 1) Natural sources: fruit juices, aromatic oils such as peppermint and lemon oils, herbs and spices 2) Synthetic sources: citric acid, glycine, monosodium glutamate

Due to the high surface area of the dispersed powders, adsorption of these materials may occur thus reducing their effective concentration. Inclusion of these adjuvant may alter the physical characteristics of the system

Taste of product Suitable masking flavour Salty Apricot, peach, vanilla Bitter Anise, mint, chocolate Sweet Vanilla, fruits, berries Sour Citrus, raspberry, liquorice

Advantages of flavours Reducing unpleasant taste Enabling identification of products to be achieved easily Increasing patient compliance

4) Colours Once a suitable flavour has been chosen it is often useful to include a color which is associated with that favor to improve the attractiveness of the product. Enabling identification of products to be achieved easily

These agents can be obtained from: 1) Natural sources: carotenoids, chlorophylls, anthocyanins, riboflavines, caramels, extracts of red beetroot 2) Synthetic sources: amaranth, sodium salts of sulphonic acids

5) Humectants: These agents are used to prevent the product from drying out after application to the skin Glycerol and propylene glycol are examples of suitable humectants which are sometimes incorporated at concentrations of about 5%.

6) Sweetening agents Sucrose: Colorless Very soluble in water Stable over a pH range of about 4 to 8 It will mask the tastes of both salty and bitter drugs It has a soothing effect on the membranes of the throat

Other sweetening agents: Sorbitol, manitol, glycerol, hydrogenated glucose syrup, isomalt, fructose, xylitol, honey, liquorice Artificial sweeteners: - Sodium and calcium salt of saccharin Aspartame Acesulfame potassium Thaumatin

7) Preservatives: The desirable features of a preservatives suitable for use in a suspension is: 1- A wide spectrum of activity against all bacteria, yeast and moulds 2- Bactericidal rather than bacteristatic activity 3- Freedom from toxic, irritant or sensitizing activity 4- High water solubility

5- Compatibility with the other ingredients and with the container 6- Stability and effectiveness over a wide pH range and temperature 7- Freedom from color and odour 8- Retention of activity in the presence of large numbers of micro-organisms

Preservatives Agents Organic acids and their salts - Benzoic acid Parahydroxybenzoeic acid esters - Methyl, ethyl, propyl and butyl esters and their sodium salts Chlorocresol Phenoxyethanol Bronopol Quaternary ammonium compounds Chloroform

Stability of suspensions Sedimentation Deflocculation Crystal Growth

Settling Fbuoyancy Ffriction

Force of Friction Friction is a force that is created whenever two surfaces move or try to move across each other.  Friction always opposes the motion or attempted motion of one surface across another surface. Friction is dependant on the texture of both surfaces. Friction is also dependant on the amount of contact force pushing the two surfaces together

Settling Cont’d eventually Ff = Fb and reach terminal velocity Stokes’ Law v = terminal velocity (cm/s) d = diameter (cm) s = density of dispersed phase o = density of continuous phase o = viscosity of continuous phase (Pa s)

Example How fast will a 50 mm particle of density 1.3 g/cm3 settle in water (h = 1.0 cP)? How fast will it settle in a 2 w/v% methylcellulose solution of viscosity = 120 cP? How fast will it settle if you reduce its particle size to 10 mm?

Stability of suspensions Coagulation; reduce the forces acting to keep the particles apart after they contact each other (i.e., lower repulsion forces). Flocculation; process of bringing destabilized particles together to allow them to aggregate to a size where they will settle by gravity.

Flocculation and Coalescence Collision and sticking (reaction) Stir or change chemical conditions FLOCCULATION Rehomogenization Film rupture COALESCENCE

Flocculation & Deflocculation Flocculation is the formation of light, fluffy groups of particles held together by weak Van der Waal's forces. Deflocculation is the absence of association which occurs when repulsive forces between particles predominate. Particles repel each other and remain as discrete, single particles.

Flocculated Condition weakly bonded to form fluffy conglomerates 3-D structure (gel-like) settle rapidly but will not form a cake - resist close-packing easily re-suspended forms a clear supernatant

Deflocculated Condition repulsion energy is high particles settle slowly particles in sediment compressed over time to form a cake (aggregation) difficult to re-suspend caked sediment by agitation forms a turbid supernatant

Flocculation & Deflocculation Deflocculated Flocculated Particles exist in suspension as separate entities. Particles form loose aggregates. Rate of sedimentation is slow. Rate of sedimentation is high. A sediment is formed slowly. A sediment is formed rapidly. The sediment becomes very closely packed, is difficult to redisperse. The sediment is loosely packed, is easy to redisperse.

Controlled Flocculation electrolytes most widely used reduce zeta potential decrease force of repulsion change pH bridge formation alcohol reduction in zeta potential surfactants form adsorbed monolayers on particle surface efficacy is dependent on charge, concentration

Controlled Flocculation polymers adsorb to particle surface bridging viscosity, thixotropy protective colloid action most effective

Evaluating Suspensions two parameters sedimentation volume, F = Vu/Vo Vu = final sediment volume Vo = initial dispersion volume want F =1 degree of flocculation,  = Vu/Vu Vufinal sediment volume of deflocculated suspension other parameters : redispersibility, particle size, zeta potential, rheology

Other Considerations temperature don’t dilute raising T often causes flocculation of sterically stabilised suspensions freezing may result in cake formation fluctuations in T may cause crystal growth allow suspension stored in fridge to come to room T before redispersing don’t dilute reduces palatability, effectiveness of flocculating & suspending agents change in pH (stability) manufacturer will no longer accept legal responsibility for consequences

Suspensions In Brife coarse dispersion in which insoluble solid particles (10-50 µm) are dispersed in a liquid medium routes of administration : oral, topical (lotions), parenteral (intramuscular), some ophthalmics used for drugs that are unstable in solution (ex. antibiotics). allow for the development of a liquid dosage form containing sufficient drug in a reasonably small volume

Oral Suspensions for elderly, children etc., liquid drug form is easier to swallow liquid form gives flexibility in dose range majority are aqueous with the vehicle flavored and sweetened. supplies insoluble, distasteful substance in form that is pleasant to taste examples antacids, tetracycline HCl, indomethacin

Topical Suspension (Lotions) most often are aqueous intended to dry on skin after application (thin coat of medicianl component on skin surface) label stating “to be shaken before use” and “for external use only” examples : calamine lotion (8% ZnO, 8% ZnOFeO) hydrocortisone 1 - 2.5 % betamethasone 0.1%

Ophthalmics used to increase corneal contact time (provide a more sustained action)

Intramuscular formation of drug depots (sustained action) examples : Procaine penicillin G Insulin Zinc Suspension addition of ZnCl2 suspended particles consist of a mixture of crystalline and amorphous zinc insulin (intermediate action) Extended Insulin Zinc Suspension solely zinc insulin crystals  longer action contraceptive steroids

Disadvantages uniformity and accuracy of dose - not as good as tablet or capsule adequate particle dispersion sedimentation, cake formation product is liquid and bulky formulation of an effective suspension is more difficult than for tablet or capsule

Formulation Criteria specific to lotions : slow settling and readily dispersed when shaken constant particle size throughout long periods of standing pours readily and easily OR flows easily through a needle specific to lotions : spreads over surface but doesn’t run off dry quickly, remain on skin, provide an elastic protective film containing the drug acceptable odor and color common : therapeutic efficacy, chemical stability, esthetic appeal

Suspension Formulation Examples Pediatric Cold Suspension Containing acetaminophen, pseudoephedrine HCl, and chloropheniramine maleate

Ingredients g/100 mL: 1- Acetaminophen USP Powder 3.2 2- Pseudoephedrine HCl USP 0.3 3- Chlorpheniramine Maleate USP 0.02 4- High Fructose Corn Syrup 55 73.0 5- Purified Water USP 20.0 6- Sorbitol Solution USP 70% 20.0 7- Glycerin USP 10.0 8- Xanthan Gum NF 0.14

9- Microcrystalline Cellulose/Sodium 0.56 10- Carboxymethylcellulose Mixture NF (Avicel) 11- Sodium Carboxymethylcellulose NF 0.03 12- Butylparaben NF 0.025 13- Sodium Benzoate NF 0.2 14- Propylene Glycol USP 0.25 15- Malic Acid NF 0.076 16- Citric Acid USP (Anhydrous Powder) 0.038 17- Coloring 0.002 18- Artificial Grape Flavoring 0.2

MANUFACTURING PROCESS 1. 1000 grams of the sorbitol solution and 975 grams of the purified water were poured into an appropiate size stainless steel container. 28 grams of the microcrystalline cellulose/sodium carboxymethylcellulose mixture (Avicel.RTM. RC 591) was added while mixing with a high-shear mixer for a period of 25 minutes. At the conclusion of the hydration period, 10.0 g of sodium benzoate and 1 gram of chloropheniramine maleate were added and mixed until dissolved in the mixture.

2. The solution formed in step 1 was added to an appropriate size stainless steel container containing 3500 grams of the high fructose corn syrup and mixed with a high shear mixer.

3. 7 grams of xanthan gum, 1.5 grams of sodium carboxymethylcellulose and 500 grams of glycerin were added to an appropriate size stainless container and mixed with a high shear mixer. This mixture was then combined with the solution formed in step 2 and mixed with a high shear mixture. 4. 12.5 grams of propylene glycol and 1.25 grams of butylparaben were mixed in a glass beaker and then added to the solution formed in step 3.

5. 15 grams of pseudoephedrine HCl were added to the admixture produced in step 4 and mixed with a high shear mixer until all of the pseudoephedrine HCl was dissolved. 6. 160 grams of the acetaminophen powder was poured into the admixture produced in step 5 and mixed with the high mixer until the acetaminophen was evenly dispersed.

7. 0.1 gram of the coloring was dissolved in 25 grams of the purified water and mixed into the admixture produced in step 6. 1.9 grams of citric acid 3.8 grams of malic acid, and 10 grams of the flavoring were then added and mixed until completely dissolved in the admixture.

8. The final volume of the admixture was adjusted to the final 5 liter volume by adding high fructose corn syrup and then mixed with the high shear Scott mixer. The resulting suspension was then deaerated in an automatic vacuum deaerator.

Prepare a suspension formulation of prednisolone acetate (Describe reasons for choosing different ingredients and the application of each one).