Suspensions

• Dispersion system consist of (1)- particulate matter (dispersed phase) (2)- continuous medium (dispersion medium) • Classification of dispersed systems (based on particle size)

1 Molecular  dispersion 2 Colloidal dispersion 3 Coarse dispersion

< 1 nm 1nm- 0.5 mm > 0.5 mm

Oxygen molecules, glucose solution Natural polymers Suspension and emulsion

Definition of suspension su spension : Pharmaceutical Pharmaceuti cal suspensions suspens ions are uniform unifor m dispersions of solid drug particles in a vehicle in which the drug has minimum solubility. Particle size of the drugs may vary from one formulation to the other depending on the physicochemical characteristics of the drug and the rheological properties of the formulation. • A suspension containing particles between 1 nm to 0.5 µm in size is called colloidal suspension. When the particle size is between 1 to 100 µm, the suspension is called coarse suspension. Most of the  pharmaceutical suspensions suspensions are coarse suspension. • Majority of the marketed suspensions are available as dry powders that must be reconstituted before administration but occasionally some  products in the market market are ready-to-use. The first products are not very stable once reconstituted; must be used within 7 to 10 days. •

 Examples  Examples of Pharmaceuti Pharmaceutical cal Suspensions: Suspensions: A. Antacid oral suspensions Antibacterial oral suspension

B. C. D. E.

Dry powders powders for oral oral suspensio suspension n (antib (antibiotic iotic)) Analg Analgesi esicc oral oral suspe suspensi nsion on Anth Anthelm elment entic ic oral oral suspe suspensi nsion on Antic Anticonv onvulsa ulsant nt oral oral susp suspen ensio sion n 1

F. Anti Antifu fung ngal al oral oral sus suspe pens nsio ion n  Pharmaceuti  Pharmaceutical cal applic applications ations of suspensio suspensions: ns: 1) Insoluble Insoluble drug drug or poorly solubl solublee drugs which which required required to be given orally in liquid dosage forms ( in case of children, elderly, and  patients have difficulty difficulty in swallowing swallowing solids dosage forms) 2) To over come come the instabilit instability y of certain drug drug in aqueous aqueous solution: solution: a. Insoluble Insoluble derivativ derivativee formulate formulated d as suspension suspension An example is oxytetracycline HCL ⇒ calcium salt (instable) (stable)  b. Reduce the contact time between solid drug particles and dispersion media ⇒ increase the stability of drug like  Ampicillin  Ampicillin  by making it as reconstituted reconstituted powder. c. A drug that degraded in the presence of water  ⇒ suspended in non-aqueous vehicles. Examples are  phenoxymet  phenoxymethypen hypencillin cillin// coconut oil and tetracycline HCL tetracycline HCL// oil 3) To mas mask k the the tast taste: e: Examples are parace are paracetamol  tamol suspension suspension (more palatable) and chloramphenicol palmitate. 4) Some material materialss are needed needed to be present present as finely finely divided divided forms forms to increase the surface area. Fore example, Mg carbonate and Mg trisilcate are used to adsorb some toxins 5) Suspension Suspension can can be used topical topical applic application ations: s: An example is calamine lotion Bp ⇒ after evaporation of dispersing media; the active agent will be left as light deposit 6) Can be used for parentral administration ⇒ intramuscular (i.m.) to control arte of absorption 7) In vacci accine ness Absorbed antigen

Aluminum hydroxide

e.g. Diphtheria and Tetanus vaccines

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8) X-ray contrast media: an example is oral and rectal administration of   propyliodone 9) In aerosol ⇒ suspension of active agents in mixture of  propellants Qualities of ideal suspension: A well-formulated suspension should have the following properties: 1) The dispersed particles should not settle readily and the settle should redispersed immediately on shacking. Ideally, the particles in a suspension should not sediment at any time during the storage period. Unfortunately, the present technology does not allow us to prepare such a suspension. Since one cannot completely avoid the sedimentation of particles, it is desirable that the particles should settle slowly. The easy redispersion of sedimented particles in a suspension is important for the uniformity of dose. 2) The particle should not form a cake on settling 3) The viscosity should be such that the preparation can be easily poured. A highly viscous suspension would make pouring difficult. 4) It should be chemically and physically stable 5) It should be palatable (orally) 6) It should be free from gritting particles (external use)

FACTORS TO BE CONSIDERED A- Wetting of the particles:

Solid  particles

Hydrophilic can be dispersed easily

Suspending media Difficult to disperse and float on the surface due to hydrophobic surface or  entrapped air 

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• It is difficult to disperse solid particles in a liquid vehicle due to the layer of adsorbed air on the surface. Thus, the  particles, even high density, float on the surface of the liquid until the layer of air is displaced completely. The use of wetting agent allows removing this air from the surface and to easy penetration of  the vehicle into the pores. Alcohol, glycerin, and propylene glycol are frequently used to remove adsorbed air from the surface of   particles when aqueous vehicle is used to disperse the solids. When the particles are dispersed in a non-aqueous vehicle, mineral oil is used as wetting agent. Irrespective of the method of preparation, the solid particles must be wetted using any of the suitable wetting agents before the dispersion in the vehicle. Solid particles that are not easily wetted by aqueous • vehicle after the removable of the adsorbed air are referred to as hydrophobic particles. It is necessary to reduce the interfacial tension between the particles and the vehicle by using surface-active agents to improve the wettibility. Sodium lauryl sulfate is one of the most commonly used surface-active agents. Hydrophilic particles are easy to disperse in the aqueous vehicle once the adsorbed air is removed. Hydrophilic particles do not require the use of surfaceactive agents. The main function of wetting agents: (1)- to reduce the • contact angle between surface of solid particles and wetting liquid via displace the air in the voids (2)- surfactant Examples of wetting agents are tragcanth mucilage, • glycerin, glycols, bentonite and polysorbates. Excessive amounts of wetting agents can cause foaming • or undesirable taste or odor. Contact angle can be used to measure wettibility, if the • angle approximately equal or more than 90 0, particles are floating well out of fluid. B-Particle size:

• Particle size of any suspension is critical and must be reduced within the range as determined during the preformulation study. • Too large or too small particles should be avoided. Larger particles will settle faster at the bottom of the container and too fine particles will easily form hard cake at the bottom of the container.

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• The particle size can be reduced by using mortar and pastel but in large-scale preparation different milling and pulverization equipments are used. • Limitation in particle size reduction (after reaching a certain particle size): 1. Expensive and time consuming 2. Movement of small particles due to brownian motion cause  particles to aggregate, settle, form hard cake that it is difficult to redispersed C-Sedimentation:

• Sedimentation of particles in a suspension is governed by several factors: particle size, density of the particles, density of the vehicle, and viscosity of the vehicle. The velocity of sedimentation of particles in a suspension can be determined by using the Stoke's law:

v =

d2 (p1-p2) g 18 η

Where: v = velocity of sedimentation d = diameter of the particle g = acceleration of gravity ρ 1 = density of the particle ρ 2 = density of the vehicle η = viscosity of the vehicle •

According to the Stoke's equation, the velocity of sedimentation of   particles in a suspension can be reduced by decreasing the particle size and also by minimizing the difference between the densities of  the particles and the vehicle. Since the density of the particles is constant for a particular substance and cannot be changed, the changing of the density of the vehicle close to the density of the  particle would minimize the difference between the densities of the  particles and the vehicle. The density of the vehicle of a suspension can be increased by adding the following substances either alone or in

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combination: polyethylene glycol, polyvinyl pyrolidone, glycerin, sorbitol, and sugar. • The viscosity of the vehicle also affects the velocity of sedimentation. It decreases as the viscosity of the vehicle increases. The viscosity and density of any vehicle are related to each other, so any attempt to change one of these parameters will also change the other one. D-Electrokinetic Properties

• Dispersed solid particles in a suspension may have charge in relation to their surrounding vehicle. These solid particles may become charged through one of two situations. 1. Selective adsorption of a particular ionic species present in the vehicle. This may be due to the addition of some ionic species in a polar solvent. Consider a solid particle in contact with an electrolyte solution. The particle may become  positively or negatively charged by selective adsorption of  either cations or anions from the solution. 2. Ionization of functional group of the particle. In this situation, the total charge is a function of the pH of the surrounding vehicle.

Surface

Counterion

Shear plan

 b-

c-

a+ + + + + + + + + + +

-

a

+

-

+

+

+

+

-

+

-

+

-

+ +

+

 b

-

-

-

+

-

+

-

+

-

+

-

+

+

+

-

+

+

-

+ + +

+

-

Diffusion layer 

6

+

+

c

Tightly  bound layer 

d-

+

-

d

Electro-neutral region

• In the above figure, the particle is positively charged and the anions present in the surrounding vehicle are attracted to the  positively charged particle by electric forces that also serve to repel the approach of any cations. The ions that gave the particle its charge, cations in this example, are called potential-determining ions. Immediately adjacent to the surface of the particle is a layer of tightly  bound solvent molecules, together with some ions oppositely charged to the potential-determining ions, anions in this example. These ions, oppositely charged to the potential-determining ions, are called counterions or gegenions. These two layers of ions at the interface constitute a double layer of electric charge. The intensity of the electric force decreases with distance from the surface of the particle. Thus, the distribution of ions is uniform at this region and a zone of  electrolneutrality is achieved. E-Nernst and zeta potential-

• The difference in electric potential between the actual surface of the  particle and the electroneutral region is referred to as Nernst potential. Thus, Nernst potential is controlled by the electrical potential at the surface of the particle due to the potential determining ions. Nernst  potential has little effect in the formulation of stable suspension. • The potential difference between the ions in the tightly bound layer  and the electroneutral region, referred to as zeta potential (see the figure), has significant effect in the formulation of stable suspension. Zeta potential governs the degree of repulsion between adjacent, similar charged, solid dispersed particles. • If the zeta potential is reduced below a critical value, the force of  attraction between particles succeed the force of repulsion, and the  particles come together. This phenomenon is referred to as flocculation and the loosely packed particles are called floccule. F-Deflocculation and flocculation:

• Deflocculation of particles is obtained when the zeta potential is higher than the critical value and the repulsive forces supersede the attractive forces.

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• The addition of a small amount of electrolyte reduces the zeta  potential. When this zeta potential goes below the critical value, the attractive forces supersede the repulsive forces and flocculation occurs. • The following table illustrates the relative properties of flocculated and Non-flocculated suspension

Flocculated 1. Particles forms loose aggregates and form a network like structure 2. Rate of sedimentation is high 3. Sediment is rapidly formed 4. Sediment is loosely packed and doesn’t form a hard cake 5. Sediment is easy to redisperse 6. Suspension is not pleasing in appearance 7. The floccules stick to the sides of  the bottle

Non-flocculated 1. 2. 3. 4.

Particles exist as separate entities Rate of sedimentation is slow Sediment is slowly formed Sediment is very closely packed and a hard cake is formed 5. Sediment is difficult to redisperse 6. Suspension is pleasing in appearance 7. They don’t stick to the sides of the bottle

• It should be noted that the deflocculated suspensions should be avoided because of the formation of irreversible solid hard cake. Although flocculated suspensions sediment faster and form a clear  supernatant, these are easy to redisperse. • The following figure shows the effect of period of standing on flocculated and deflocculated suspension:

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G-Thixotropic suspension-A thixotropic suspension is the one that is viscous during storage but loses consistency and become fluid upon shaking. A well-formulated thixotropic suspension would remain fluid long enough for the easy dispense of a dose but would slowly regain its original viscosity within a short time.

Method of preparation

The preparation of suspension includes three methods: (1) use of controlled flocculation and (2) use of structured vehicle (3)- combination of both of the two pervious methods. The following is the general guidelines to suspension formulation:

Particles Addition of wetting agent and dispersion medium Uniform dispersion of deflocculated particles

A Incorporation of  structured vehicle

B

C

Addition of  flocculating agent

Flocculated suspension as final product Deflocculated suspension in structured vehicle as final product

Addition of  flocculating agent Flocculated suspension Incorporation of  structured vehicle Flocculated suspension in structured vehicle as final product

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A-Structured vehicle

• Structured vehicles called also thickening or suspending agents. They are aqueous solutions of natural and synthetic gums. These are used to increase the viscosity of the suspension. • Methyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, acacia, gelatin and tragacanth are the most commonly used structured vehicle in the pharmaceutical suspensions. These are nontoxic, pharmacologically inert, and compatible with a wide range of  active and inactive ingredients. • These structured vehicles entrapped the particle and reduces the sedimentation of particles. Although, these structured vehicles reduces the sedimentation of particles, not necessarily completely eliminate the particle settling. Thus, the use of deflocculated particles in a structure vehicle may form solid hard cake upon long storage. • The risk of caking may be eliminated by forming flocculated particles in a structured vehicle. •  Note that too high viscosity isn’t desirable and it causes difficulty in  pouring and administration. Also, it may affect drug absorption since they adsorb on the surface of particle and suppress the dissolution rate. • Structured vehicles are pseudoplastic or plastic in their rheological  behaviors • In the following table is summary of suspending agents

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Table summary of suspending agent

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B-Controlled flocculation

• Controlled flocculation of particles is obtained by adding flocculating agents, which are (1)-electrolytes (2)- surfactants (3)- polymers Typical Flocculation agents

1-Addition of electrolyte to control flocculation

• Most frequently used flocculating agents are electrolytes, which reduce the zeta potential surrounding the solid particles. This leads to decrease in repulsion potential and makes the particle come together  to from loosely arrange structure (floccules). • The flocculating power increases with the valency of the ions. As for  example, calcium ions are more powerful than sodium ions because the velency of calcium is two whereas sodium has valency of one. • The following figure shows the flocculation of a bismuth subnitrate suspension by means of monobasic potassium phosphate (flocculating agents).

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The particles of bismuth subnitrate are positively charged originally. By addition of electrolyte (phosphate, -ve) the zeta potential fell down near zero. At this neutralization value noted absence of caking. Continuing adding of negatively charged electrolyte resulted in changing the overall zeta potential of particles to negative and formation of cake.

2-Addition of surfactant to control flocculation

• Both ionic and non-ionic surfactants could be used to control flocculation • Surfactant adsorbed on the surface of solid particle leading to neutralization or reversing the surface charge • Since most of surfactants act as wetting agents and flocculating agents, the amount of surfactant to be added should be calculated  based on this fact.

Example of surfactant used as flocculating agents

3- Addition of polymers to control flocculation

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• Polymers are long-chained, high molecular-weight compounds containing active groups spaced along their length. • These agents promote flocculation through adsorption of part of the chain on the surface of particle and the remaining part project out into the dispersion medium. Formation of bridge between the projected  parts leads to formation of floccules (see the following figure)

Projection out into dispersion medium

Adsorption on the surface of particles

Solid particle

Solid particle

Formation of bridge between particles

• Hydrophilic polymers also act as protective colloids resulting in coated particles have fewer tendencies to form cake. • Polymers exhibits pseudoplastic flow in solution that promotes the  physical stability of suspension • Some polymers like gelatin stabilize the suspension based on the pH and ionic strength of dispersion medium (carry charge) • An example of polymer is xanthan gum • Positively charged Liposomes (vesicles of phospholipids) adsorbed on negatively charged particles to prevent caking formation.

B- Flocculation in structured vehicles

• Sometimes suspending agents can be added to flocculated suspension to retard sedimentation • Examples of these agents are Carboxymethylcellulose (CMC), Carbopol 934, Veegum, and bentonite 14

• It should be noted that physical incompatibility can limit the addition of suspending agent Most of hydrophilic colloids are negatively charged

Positively charged  particles

 _ 

 Negatively charged  particles

-

+

Addition of  electrolyte - - +- -

 _   _ 

-

+ - -  _ 

+ +

+

Addition of  suspending agent

+  _  +

 _ 

Compatible

+

 _ 

 _  +

-

 _ 

+

+ +  _   _ 

Incompatible

Particle settle rapidly

• Under this circumstance, the formulator can protect particle by changing sign of particle from negative to positive using protective colloids. This is illustrated by the following figure:

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Ready to use suspension and extemporaneous preparation

• Ready to use suspension is manufactured as you learn in this class • Extemporaneous suspension is unordinary preparation that pharmacist wants to prepare to a water-insoluble drug that exists in tablet or  capsule for situations when liquid dosage from is needed. The following steps could be done to prepare extemporaneous suspension: 1. 2. 3. 4.

Put the tablet or capsule content in mortar and crush it Add the suspending vehicle slowly with mixing You could add any flavoring agent or coloring agent available Example of ready available suspending agents are Roxanes diluent and Cologel

Evaluation of suspensions

Suspensions are evaluated by determining their physical stability. Two useful parameters for the evaluation of suspensions are sedimentation volume and degree of flocculation. The determination of sedimentation volume provides a qualitative means of evaluation. A quantitative knowledge is obtained by determining the degree of flocculation. 1. Sedimentation volume: (F), sedimentation volume of a suspension is

expressed by the ratio of the equilibrium volume of the sediment, V u, to the total volume, V o of the suspension. F = Vu/Vo The value of F normally lies between 0 to 1 for any pharmaceutical suspension. The value of F provides a qualitative knowledge about the  physical stability of the suspension.

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F= 1 F =0.5 F >1

No sedimentation, no clear  supernatant 50% of the total volume is occupied  by sediment Sediment volume is greater than the original volume due to formation of  floccules which are fluffy and loose

2. Degree of flocculation: (ß), degree of flocculation is the ratio of the

sedimentation volume of the flocculated suspension, F, to the sedimentation volume of the deflocculated suspension, F ∞ ß = F / F∞ (Vu/Vo) flocculated ß = -------------------(Vu/Vo) deflocculated When the total volume of both the flocculated and the deflocculated suspensions are same; the degree of flocculation, ß = (V u)floc/(Vu)defloc .The minimum value of ß is 1; this is the case when the sedimentation volume of  the flocculated suspension is equal to the sedimentation volume of 

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deflocculated suspension. ß is more fundamental parameter than F since it relates the volume of flocculated sediment to that in a deflocculated system Rheological consideration: viscosity of suspension affects and controls the settling of dispersed particle. It, also, affects pouring the product from bottle and spreading qualities in case of lotion. Best viscosity for suspension is to  be high during storage to prevent sedimentation and to be low at high shear  to ease the administration. Thus, pseudoplastic/ thixotrpic and plastic/ thixotropic suspending agents could be use for this purpose. Combination of  two suspending agents can enhance the stability of suspension Ingredients of suspension: 7. Active ingredient 8. Wetting agent 9. Suspending agent 10.Flocculated agent 11.Protective colloid 12.Sweetener 

1. 2. 3. 4. 5. 6.

Preservative Buffer system Color agent Flavor agent Antifoaming agent Preservative

Typical buffering agents, flavors, colorants, and preservative used in suspensions: Class

Agent

Buffer 

Ammonia solution Citric acid Fumaric acid Sodium citrate

Flavor 

Cherry Grape Methyl salicylatte Orange Peppermint

Colorant

D &C Red No. 33 FD &C Red No. 3 D &C Yellow No. 33

Preservative

Butylparaben Methylparaben Propylparaben 18 Sodium benzoate

Packaging and Storage of Suspensions: 1) Should be packaged in wide mouth containers having adequate air space above the liquid. 2) Should be stored in tight containers protected from: freezing, excessive heat & light 3) Label: "Shake Before Use" to ensure uniform distribution of solid  particles and thereby uniform and proper dosage. 4) Stored in room temperature if it is dry powder (25 0C). It should be stored in the refrigerator after opening or reconstitute (freezing should be avoided to prevent aggregation)

Stability of suspension

A-Physical stability: Appearance, color, odor and taste  pH Specific gravity Sedimentation arte Sedimentation volume Zeta potential measurement Compatibility with container  Compatibility with cap liner  Microscopic examination Determination crystal size Determination uniform drug distribution B-Chemical stability:

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1. Degradation of active ingredient 2. Viscosity change 3. antimicrobial activity: a. Incompatibility with preservative  b. Degradation of preservative c. Adsorption of preservative onto drug particle

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