Pharmaceutical Suspensions

Suspensions are heterogeneous systems consisting of two phases. The continuous or the external phase is generally a

liquid or semisolid. The dispersed or the internal phase is made up of

particulate matter that is essentially insoluble in, but dispersed throughout the continuous phase.

The insoluble matter may be intended for physiologic absorption or for internal or external coating functions.

The dispersed phase may be composed of discrete particles or it may be a network of particles resulting from particle-particle interaction.

The system is thermodynamically unstable esp. for hydrophobic drugs.

Classification Based On rout of administration

Oral suspension (Antibiotics and antacids).Externally applied suspension (Calamine lotion).Parenteral suspension (Procaine penicillin G, Protamine Zinc-Insulin suspension).

Based On Proportion Of Solid Particles Dilute suspension (2 to10%w/v solid). Concentrated suspension (50%w/v solid).

Based On Electrokinetic Nature Of Solid ParticlesFlocculated suspension. Deflocculated suspension.

Based On Size Of Solid Particles

Colloidal suspension (< 1 micron) (examples: aluminium hydroxide and magnesium hydroxide suspensions).

Coarse suspension (>1 micron) A solid in liquid dispersion in which the particles are above colloidal size is termed a coarse suspension.Nano suspension (10 nm).

Applications Drug in suspension exhibits higher rate of bioavailability than other dosage forms.

bioavailability is in following order:Solution > Suspension > Capsule > Compressed tablet > Coated tablet.

Suspension have better bioavailability than solid dosage forms because of the absence of the disintegration limiting step.

If the drug is insoluble or poorly soluble in a suitable solvent, such as water (Hydrocortisone Acetate and Neomycin eye drops).

Some active ingredients are required to be present in the GI tract in a finely divided form to provide a desired high surface area for adsorption of toxins or to neutralize excess acidity (Kaolin, magnesium carbonate, magnesium trisilicate).

Suspension can mask the unpleasant/ bitter taste of drug. E.g. Chloramphenicol palmitate, particularly if the drug particles are coated E.g. : cefuroxime (Zinnat ).

X-ray contrast agent are also formulated as suspension administered either orally or rectally..E.g. Barium sulphate for examination of alimentary tract. Due to the relatively high atomic number (Z = 56) of barium, its compounds absorb X-rays more strongly than compounds derived from lighter nuclei.

Applications

Suspensions can improve chemical stability of certain drugs.

Drug highly degradable in the presence of water are easily and

rapidly degraded if formulated as solution because the drug is at the molecular level, therefore the insoluble derivative can be formulated as a suspension (insoluble calcium salt of oxytetracycline HCL in an aqueous vehicle ).

Further improvement of drug stability can be achieved by dry or reconstituted suspensions: dry powders to which a vehicle is added at the time of dispensing, therefore the prolonged contact between the solid drug particles and the dispersion medium can be minimized thus enhancing stability (Amoxicillin trihydrate salt).

Furthermore, A drug that degrades in the presence of water may be suspended in a non-aqueous vehicle (Phenoxymethylpenicillin, Tetracycline HCL suspended in fractionated coconut oil for ophthalmic use).

Applications

Duration and onset of action can be controlled.

E.g.Protamine Zinc-Insulin suspension and Isophane insulin. Insulin when given IM solution shows rapid absorption and rapid elimination from the body. When converted into insoluble form and given as suspension it shows slow dissolution and absorption and thus its action is prolonged with less frequency of administration. Insluin forms insoluble complex with protamine and zinc or with isophane. By varying the size of dispersed particles the duration of activity can be controlled.

To prolong activity even further, the drug may be suspended in fixed oils such as arachis or sesame oil.

Applications

Vaccines, for induction of immunity are often formulated as dispersions of killed micro-organisms or toxoids adsorbed on to a substrate of aluminium hydroxide or phosphate. Thus achieving a prolonged antigenic stimulus resulting in a high antibody titre.

Patients having difficulty in swallowing solid dosage forms. The adsorptive properties of fine powders are used in the

formulation of some inhalations. Volatile components such as menthol and eucalyptus oil are adsorbed onto light magnesium carbonate to have a more prolonged release.

Aerosol systems where the drug is suspended in a mixture of propellants.

Suspensions of drugs can also be formulated for topical application (Calamine Lotion BP).

Suspensions of semisolid consistency, where the drug is suspended in a paraffin base (paste) or an emulsion base (Zinc Cream BP).

Physical stability

• Almost all suspension systems separate on standing, and the formulator’s main concern is not to eliminate separation but rather to:

– Decrease the rate of settling. – Permit easy resuspendability of any settled particulate matter.

• A satisfactory suspension must remain sufficiently homogeneous for at least the period of time necessary to remove and administer the required dose after shaking its container.

Physical Stability

Flocculation: In which particles are

held to each other by weak forces,

in the form of loose agregate (flocs). These are characterized by a

fibrous, fluffy, open network of aggregated particles.

The aggregates tend to settle quickly to form a high sediment height.

The sediments are easily redispersible because the particles constituting individual aggregates are sufficiently far apart from one another to preclude caking.

Flocculated suspensions The suspension shall form loose

networks of flocks that settle

rapidly, do not form cakes and

are easy to resuspend.

This form is inducted and desirable in the socalled flocculated suspensions becauseparticles can be easily redispersed by slightshaking and thus it is pharmaceuticallyacceptable. .

Physical stability

Coagule (closed aggregate):A coagule is a system of tightlypacked solid particles with verysmall interparticulate distances,thus resulting in stronginterparticulate attraction andconsequently cannot beredispersed by slightshaking. Accordingly, dosinguniformity will not be achieved uponusing the same bottle as a resultof this aggregation. This formcould happen in the socalled deflocculated suspensionsand should be totally prevented.

In deflocculated suspensions: Individual particles could settles slowly with high packing, which result in formation of cakes that is difficult or even impossible to resuspend.

Because they are not reversible by shaking, coagulation and caking are not pharmaceutically acceptable.

Physical Stability

Sedimentation: Velocity of sedimentationis expressed by Stoke’sequation:

Where, vsed. = sedimentation velocity in cm / sec. d = diameter of particle r = radius of particle. ρs= density of dispersed phase. ρo= density of dispersing media. g = gravitational force.ηo= viscosity of disperse medium in poise.

Brownian movement (motion)

Gravity

Brownian movement counteracts sedimentation and sedimentation equilibrium is achieved when gravity is neutralized by Brownian movement meaning no sedimentation.

2-5 m

Brownian Movement: random movement in all directions and is exhibited by small sized particles.

Thermodynamic stability

Surface Energy (G): quantifies the

disruption of intermolecular bonds that

occur when a surface is created. The

surface energy may therefore be

defined as the excess energy at the

surface of a material compared to the

bulk.

= Surface Area (A) Interfacial tension ()

Surface Energy (G)

Size reduction

Low surface area and

low G

High surface area and high G

Thermodynamic stability

A system is in thermodynamic stability when surface energy is zero. This would be achieved in suspensions when the interfacial tension between the dispersed particles is zero. However, because the interfacial tension in suspensions is positive, free energy is positive and thus suspensions are thermodynamically

unstable.

Drug solutions are thermodynamically stable because of zero interfacial tension and thus the drug dissolves because of this zero interfacial tension.

Factors affecting thermodynamic stability

Particle size of the

dispersed phase

Thermodynamic

stability

Coarse suspensions >

colloidal suspensions >

Nano-suspensions.

Interfacial tension

Suspensions ofhydrophobic drugsare lessthermodynamicallystable than ofhydrophilic drugs.

Thermodynamic stability

Any system tends to reduce the surface free energy by reducing the surface area. Which is achieved in suspensions by agglomeration and particularly coagulation. Thus when the suspension settles to form a sediment, the system becomes more thermodynamically stable despite it becoming more pharmaceutically unstable.

Thermodynamic stability

Pharmaceutical

stability

Thermodynamic

stability

Crystal growth

In a suspension, there is equilibrium between molecules going into solution (dissolution) and molecules going out of solution (crystallization). This is particularly true if the drug at the set conditions is slightly soluble (not practically insoluble). dissolution tends to be faster from small particles because of their high surface area than from large particles. On the other hand crystallization tends to be more on the coarse particles than on the small ones. This is illustrated in the next slide. With time the small particles get smaller (dissolution from them is higher than crystallization on them), and they may ultimately disappear; contrary to this, the large particles become coarser. Thus, there will be a shift in particle size distribution to a larger mean size with narrower distribution.

Dissolution

Crystallization

For small particles

For coarse particles

Crystallization

Dissolution

Crystal growth is accelerated by the following: 1. Wide size distribution.

2. Temperature fluctuations: the temperature fluctuations during storage is of importance especially when suspensions are subjected to temperature cyclings of 20oC or more. This effect depend on:

The magnitude of temperature change. The time interval (rate of heating and cooling). The effect of temperature on the drug’s solubility and subsequent re-

crystallization.

3. Solid state: A change in the crystalline structure of the dispersed solid or a change in the crystal habit may be the reason for crystal growth.

Amorphous to crystalline form. Metastable to a more stable form. Anhydrous to a hydrated form.In addition amorphous and unstable polymorphs because of their higherwater solubility, they encourage crystal growth more than a stablepolymorph.

4. Sedimentation enhances the potential for crystal growth by increasing the particle concentration and decreasing the mean free diffusion path of the solute

molecules.

Prevention of crystal growth

Set the suspension conditions for minimal drug solubility. E.g. Choose acidic pH for weakly acidic drug and alkaline pH for weakly basic drugs for minimal drug ionization and solubility. The higher the solubility, the higher the dissolution that is in equilibrium with high crystallization rate.

Try to narrow the size distribution as much as possible. Usually, before dispersing the drug in a dispersing medium, the raw material is size reduced. During size reduction use an equipment with classifier. Suspension homogenization after preparation is also helpful.

Choose more stable polymorph than an amorphous or less stable polymorph. This is for two reasons:

A. Solubility.B. Polymorphic transformation. Avoidance of the use of high energy milling during particle size

reduction.o Avoidance of temperature extremes during storage.

Prevention of crystal growth

When ingredient (s) are chosen for certain purpose. However, such ingredients they can solubilize the drug. The concentration of such ingredients should be limited to fit the purpose. Excess concentration of such ingredients can solubilize the drug and encourage crystal growth

E.g. 1. Wetting agents are added to prevent lump formation during suspension production for hydrophobic drugs.

E.g. 2. Humectants in topical suspensions (Polyols).

o Many pharmaceutical gums can get adsorbed on the surface of the particles in the suspension and can be used to inhibit crystal growth.

o Incorporation of protective colloids (cellulose derivatives)

which form film barriers around the particles.o Increase the viscosity of the vehicle to retard particle dissolution and

subsequent crystal growth.

Electrical properties of solid-liquid interfaces(Electrokinetics)

Particles dispersed in liquid media may become charged by either of the following ways:

Selective adsorption of a particular ionic species present in solution. This ion may be a part of an electrolyte (Na, K, phosphate, Ca etc) that is added into solution or, in the case of pure water, the hydronium or the hydroxyl ions produced by the ionization of water.Most particles in water acquire a negative charge due to the preferential adsorption of hydroxyl ions.

Ionization of groups that are situated on the surface of the particle (-COOH, -NH2, etc.) depending on the pKa of the group and the pH of the medium.

If we considered a solid surface a-a' (figure next slide ) in contact with an aqueous solution of an electrolyte and that some of the cations (15 +ve) are adsorbed onto the surface giving it a positive charge. These ions are referred to as primary ions or potential determining ions. They give the surface charge of the solid particles.

The rest of the solution will have the rest of the cations plus the total number of anions added.

Near the positively charged surface, the anions are attracted to the positive charge on the surface by electric forces while the cations are being repelled at the same time. This is an attempt to achieve electroneutrality. These ions in this layer are called counter ions, as they have an opposite charge to the potential determining ions. They are adsorbed into a liquid layer adjacent to the solid surface a-a', which is called Stern layer (from a-a' to b-b' in the figure ) this layer is tightly bound to the solid surface.

Electrokinetics

Electrokinetics

Assuming that anions with total

7- ve have been adsorbed and are present in the stern layer, did the system achieve

electroneutrality at b-b ?'

Answer is No, as at b-b', 8 +ve is the net charge .

Electrokinetics

To achieve further electroneutrality, another liquid layer will be formed and extend from b-b' to c-c'. This layer is called diffuse layer and with the stern layer, both are called electrical double layer. Unlike the stern layer this layer is loose and not tightly bound to the stern layer. Ion adsorption into the diffuse layer is governed by the following:

A. Achieving electroneutrality: because electroneutrality was not achieved at b-b', further anions (-ve) will be adsorbed into the diffuse layer to achieve so.

B. Screen effect: the counter ions in the stern layer will act as screen that would reduce the electrostatic attraction between the charged solid surface and counter ions away from the surface. Instead, the counetr ions in the stern layer will bring into the diffuse layer positively charged ions.

A and B will lead to mixed adsorption (+ve and -ve ions) into the diffuse layer.

Electrokinetics

In the previous figure 12 -ve ions and 4 +ve ions were adsorbedinto the diffuse layer. Was electroneutrality achieve at c-c'. Theanswer is Yes, as the 12 -ve neutralize the excess +8 at b-b' andthe 4 +ve in the diffuse layer. Thus the excess negativeadsorption into the diffuse layer brought electroneutrality at c-c'

It can be concluded from the previous case that when a suspendedparticle acquires a charge, the system will neutralize this charge andelectroneutrality will be achieved at certain point from the solidsurface, that happened to be at c-c' in the previous example.

Beyond c-c' until reaching the bulk there will be even distribution of

negatives and positives with electroneutrality.

Despite the whole system in the previous example was electroneutral, there are regions with excess charge (from a-a' to c-c') with respect to the electroneutral regions. With excess charge in these regions potentials exist at any point within these regions. However, as we go from the solid surface potential decrease until it becomes zero at c-c'.

The potential drops rapidly initially, followed by gradual decrease as distance from the solid surface increases, this is because of the screen effect.

Electrokinetics

Electrokinetics

The potential at the solid surface aa\ is called the electrothermodynamic (Nernst) potential E.

E is defined as the difference in potential between the actual surface and the electroneutral region of the system.

The potential at the shear plane bb\ is called the electrokinetic or zeta (ζ) potential.

ζ is defined as the difference in potential between the shear surface of the solid and the electroneutral region of the system.

Zeta potential is positive because counter ions adsorbed onto the stern layer were insufficient to neutralize the solid surface.

Suppose that potentials in the previous example can be calculated based on the difference in the number of ions, what are the values of Nernst and Zeta? Answer: Nernst = +15 and zeta = +8. In addition the potential at c-c' is zero because of the electroneutrality. A plot for potential versus distance a way from the solid particles for the previous example is given in the slide.

Effect of electrolyte

As the concentration of an electrolyte is increased in a colloidal system, the screening effect of the counterions is also increased and the potential falls off rapidly with distance because the thickness of the double layer shrinks.

When the valency of the counter ion is increased, while the total concentration of the electrolyte is held constant, the potential drop is fast and the double electrical layer thickness decreases.

Both factors reduce the zeta potential.

Zero zeta potential

Suppose in the previous case the electrolyte concentration was increased resulting in ion adsorption of 15 -ve into the stern layer. In this case potential drops rapidly to zero at b-b' as zeta potential. Nernst potential will remain the same, because the solid surface charge was the same. The potential versus distance plot would be as the following:

Excess counter ions adsorption Suppose in the previous case the electrolyte concentration was

increased resulting in ion adsorption of 25 -ve into the stern layer. In this case potential drops rapidly to zero before reaching b-b' and then will further drop as a result of excess -ve adsorption beyond, resulting in negative zeta potential. However, the system will neutralize this excess negative charge at b-b' to achieve neutrality at certain point away from b-b'. Again Nernst potential will remain the same. The potential versus distance plot would be as the following:

When solid surface is negatively charged

nd

Significance of zeta potential

Because the tightly bound layer moves with the solid surface (shear plane is not the solid surface), the net charge of the solid surface and this layer (not the solid surface charge) is what govern particle-particle repulsion as two particles approach each others. Accordingly, Zeta potential has practical application in the stabilization of systems containing solid particles, since this potential, rather than the Nernst potential, governs the degree of repulsion between dispersed particles. If the Zeta potential is high (highly positive or negative), particles will experience high electrical repulsion that would exceed the attractive forces, and thus the dispersed particles will remain as monodispersed with no flocculation. On the other hand, if it is low, repulsion would be minimum, which would allow for attractive forces to slightly exceed the repulsive forces. This will result in rapid flocculation after shaking.

Flocculated and deflocculated suspensions

When the absolute value of zeta potential is high (more than 25 mv or less than -25 mv), repulsive forces highly exceed attractive forces, thus deflocculated suspension is obtained. When zeta potential is low and around zero (between –25 mv to 25 mv), attractive forces slightly exceed repulsive forces an thus flocculated suspension is obtained.

Real case on how controlled flocculation can be achieved

Bismuth subnitrate particles acquire a positive charge in water at 0% phosphate, and thus high positive zeta potential (around =90 mV) was found for the suspension (see figure next slide). This suspension is deflocculated with slow sedimentation and caking for the formed sediment. When phosphate counter ions are added as potassium phosphate into this suspension at increasing concentrations zeta potential drops slowly with the increase in counter ion concentration until reaching values between +25 mV and -25mV (region B).

Within this region the low zeta potential values result in rapid flocculation and large sediment volume with no caking. Thus region B is the non caking zone. When zeta potential values are higher than +25 mV (region A), the region is called caking zone. When excessive concentration of phosphate are added zeta potential drops below -25mV (region C) resulting in another caking zone.

CA B

Case study

A drug when formulated as suspension in water acquired a -ve charge on its solid surface as a result of carboxylate ionization. If the zeta potential for this suspension was -85 mv. If NaCl was added as a source for counterions at increasing concentrations. The series of suspensions with different NaCl concentrations prepared were measured for zeta potential and the results are shown in the right table. Answer questions in the next slide.

NaCl (mM) Zeta potential (mV)

0 -85

0.001 -67

0.01 -45

0.1 -13

0.2 +5

0.3 +35

0.4 +45

0.5 +69

What are the counter ions adsorbed into the tightly bound layer ?

Answer: Na+

What is the plot for zeta potential versus NaCl concentration?

What is the plot of potential versus distance a way from the solid surface for suspension representing the beginning of region A of the previous plot?

What is the plot of potential versus distance a way from the solid surface for suspension representing the middle of region B of the previous plot?

What is the plot of potential versus distance a way from the solid surface for suspension representing the far point of region C of the previous plot?

bound

If the experiment was repeated by using CaCl2 or AlCl3 as sources for counterions. Compare the plots of zeta potential versus electrolyte concentration with that of NaCl with explanations.

Since Ca is divalent and Al is trivalent, while Na is monovalent, as valency of counter ion is increased, potential falls more rapidly and zero zeta potential values are achieved at lower electrolyte concentration when valency is higher .

Deflocculated suspension

As a result of high zeta potential and high repulsion that highly exceed attractive forces (such as Van der waals forces), particles remain as separate entities (monodispersed). Particle show slow sedimentation that is dependent on each individual particle size. Coarse particles sediment first because of their large diameter.

As they reach the bottom they have voids among them. The voids are filled with subsequently sedimented finer particles. The sediment is formed slowly with short distance among the sedimented particles (high-close packing). Close arrangement of the sedimented particles and packing gives small sediment volume relative to the volume of the whole suspension.

The supernatant is often cloudy due to presence of ultra fine particle that remain suspended in the supernatant for long time because of their very small diameter and brwonian movement.

Deflocculated suspension

Because of the small sediment volume and large-cloudy supernatant with no distinct boundary between the supernatant and the sediment, patient may not visually detect sedimentation and in this case the appearance of suspension is falsely appealing to him.

The coagulation of the particles in the small sediment likely would result in cake formation. Cake formation is further increased as the distance between particles would further shorten due to the fact that particles lowest the sediment will be pressed by the weight of the ones above. Caking can be further worsen by dissolution and crystallization, both lead to crystal bridging. In crystal bridging, particle surface crystal growth occurs on two or more particles simultaneously and results in the steady formation of crystal-linked particles.

This leads to the ultimate formation of a highly linked sediment similar to concrete. Caking is not pharmaceutically acceptable, because it is not reversible by shaking.

Flocculated suspension

Because of low zeta potential, attractive forces slightly exceed repulsive force which induce rapid flocculation after shaking. The formed floccules will engage all particle sizes (coarse and fine) and thus sedimentation will depend on floccule size rather than individual particle size.

Because floccule size is much larger than individual particle size

sedimentation is rapid. The rapid formation of loose floccule with long interparticulate distance and the rapid sedimentation that will not allow for close packing, both will lead to the formation of a voluminous, spongy-highly porous sediment.

Flocculated suspension

The sediment will encompass most of the total suspension volume. Because ultra fine particle will sediment as floccules, the supernatant will be clear, however small, distinct boundary would be present between the supernatant and the sediment, which is not appealing to the patient.

However, caking will not happen in the loose-voluminous sediment which can be easily redispersed by shaking. Thus sediment formation in flocculated suspension is considered pharmaceutically acceptable, even with the supernatant being clear.

Which suspension type is preferred by formulators?

With controlled flocculation, the ultimate result for flocculated suspension is rapid flocculation and fast sedimentation with an easy reconstitution of the formed sediment.

When flocculation is prevented in deflocculated suspensions, any sedimentation likely will lead to caking which is not acceptable. Thus sedimentation has to be totally prevented in such suspensions, which may be achieved by the following:

1. Reducing the particle size as much as possible.

2. Making the density of the suspended particle close to that of the suspending medium. Density of most organic drug lies between 1.1 and 1.5 g/ml, while the most widely used dispersing medium, water, has a density of 1.0 g/ml. One way, though it is not very practical, is to include vehicles which have higher density than water, such as sorbitol solution (d = 1.29), Syrup (d = 1.31), and high fructose syrup (d = 1.4). These ingredients also have high viscosity, which would further retard drug sedimentation.

3. Increasing the viscosity of the dispersing phase. Using suspending agent, of which the molecular structure entraps

the drug particles and severely retards their sedimentation, is known as structured vehicle. This is particularly useful when the suspending agent forms a thixotropic system meaning it forms gel upon standing, while becomes thin by shaking (becomes fluid enough) for pouring or injection.

The previous measures to prevent sedimentation in deflocculated suspension may fail on shelf as a result of changes in the dosage form such as crystal growth, precipitation of the suspending agent with loss of viscosity due temperature or pH changes. For this reason, deflocculated suspensions have been found not workable by many investigators and flocculated suspension are preferred by many formulators.

Ingredients used in pharmaceutical suspensions

Drug:

A. Particle size:

• Usually the drug raw material is subjected to particle size reduction before suspension production. The most efficient equipment for size reduction is fluid-energy mill. It can achieve size as low as 10 micrometer.

• When we need a size in the colloidal or nano region, no size reduction equipment can achieve this small size. To produce a colloidal or nanosuspension, a process is performed which is called controlled crystallization.

Ingredients used in pharmaceutical suspensions

• In controlled crystallization the drug is made as solution by a reaction with strong base or strong acid. If the drug is neither weak acid or weak base a drug solution can be made in an anhydrous solvent.

• The drug solution is dropped into a crystallization medium containing a stabilizer (Surfactant, such as Tween 80 or polymer, such as polyvinyl alcohol (PVA)) with stirring or homogenization. The stabilizer makes a protective layer around the formed layer to stabilize their size and prevent aggregation.

• By optimizing the crystallization conditions, which are rate of addition, stirring rate of the crystallization medium, stabilizer type, and stabilizer concentration, a controlled crystal size can be achieved.

B. Wettabiltty: For a suspension to exist, there must be some degree of

compatibility between the external and internal phases. One aspect of that is the capacity of the external (continuous) phase

to wet the particulate matter of the internal (disperse) phase. When a strong affinity exists between a liquid and a solid, the liquid

easily forms a film over the surface of the solid.

When this affinity does not exist or is weak, the liquid has difficulty displacing the air or other substances surrounding the solid.

As a result an angle of contact exists between the liquid and the solid.

The contact angle θ is specific for any given system and results from an equilibrium involving three interfacial tensions acting at interfaces between liquid and vapor, solid and liquid, and solid and vapor phases. These tensions are caused by unbalanced intermolecular forces in the various phases.

As the drug is more hydrophobic the higher the contact angle between its solid particles and the aqueous dispersing medium because of the high interfacial tension, and thus during suspension preparation the drug will refuse to be dispersed as single particles and will form large lumps. Accordingly for hydrophobic drugs, the addition of wetting agents is usually a must.

On the other hand, hydrophilic drugs with low contact angle and interfacial tension with the aqueous dispersing medium are easily to be wetted and do not require the addition of wetting agent.

List of hydrophilic and hydrophobic drugs are listed in the following table. Notice in the table that Talc is hydrophilic, but this does not mean it is water soluble.

Also notice that all the hydrophobic drugs are organic, while all the hydrophilic drugs are clays, such as antacids. The later substance usually swell to high extent without being solubilized, and thus they increase the viscosity of aqueous suspensions. Contrary to this, organic hydrophobic drugs do not.

Wetting agents

• Wetting agents lower interfacial tension and contact angle and consequently there will be easier replacement of air among particles with liquid, and easier spreading of liquid on the surface of individual particles. Thus air is escaped from voids among drug particles and the wetted drug would sink as individual wetted particle or wetted mass for further wetting.

• Wetting agents are usually Surfactants: The mechanism of action of surfactants involve the preferential adsorption of the hydrocarbon chain by the hydrophobic surface, with the polar moiety of the surfactant being directed towards the aqueous phase.

• The most widely used wetting agents. Anionic (SLS) or nonionic

surfactants (Tweens and pluronics) are used. Best surfactants are with an HLB of 7-10. Most surfactants except pluronics have bitter taste, nevertheless polysorbate 80 (Tween 80) is the most widely used despite its bitter taste. The usual concentration of wetting agents is from 0.05-0.5%. Higher concentrations my solubilze the drug, which may enhance crystallization growth, and enhance foaming.

The dispersion of hydrophobic solids is also improved by: Hydrophilic polymers such sodium

carboxymethylcellulose. Water insoluble hydrophilic materials (bentonite,

aluminum-magnesium silicate or colloidal silica either alone or in combination).

These materials also exert viscosity-building effects depending on the specific type and concentration used.

At higher concentrations an undesirable gelling may be observed in the case of liquid suspensions in comparison to the desired degree of viscosity or thixotropy.

Suspending agents (viscosity imparting agents or thickening agents):

They are used in deflocculated suspension to prevent sedimentation by increasing viscosity as much as possible. Increasing viscosity beyond certain limit may result in non-pourable liquid suspension or difficult spreading and rubbing of a topical suspension. In flocculated suspension they are used at low concentration to maximize the sedimentation volume ad thus minimize the clear supernatant. High viscosity hinders the re-dispersibility of the sediments.

Suspending agents are classified as the following:

A. Natural: E.g. Acacia, tragacanth, alginic acid, carrageenan, locust bean gum, guar gum, gelatin.

B. Cellulose derivatives (Semisynthetic):

• Water soluble: Methylcellulose, HPMC and Hydroxypropyl cellulose (which are non ionic), Sodium carboxymethyl cellulose (anionic). They give high viscosity in water that is dependent on concentration and molecular weight.

• Water insoluble: Ethylcellulose (nonionic), its dispersion in water is of low viscosity. Soluble in common organic solvents (e.g. ethanol and glycerin) and thus used mainly in non-aqueous suspensions.

C. Synthetic: • Crabopol (Carbomer): polyacrylic acid (Polyanion). Offered as fluffy, white, dry powders (100% effective). The

carboxyl groups provided by the acrylic acid backbone of the polymer are responsible for many of the product benefits. It forms a dispersion in water with low viscosity as a result of low carboxylate ionization. When strong base, such as triethanolamine or isopropanol amine is added to this dispersion with stirring the polymer ionizes and dissolve to give a clear gel. Crabopol is insoluble at pH <4.0 because of low ionization.

• Polyvinylpyrrolidone (PVP):

Non-ionic, soluble in water and some organic solvents

such as ethanol.

• Polyvinyl alcohol (PVA):

Non ionic, water soluble, slightly soluble in ethanol.

Flocculating agents: A. Electrolytes: the most widely used flocculating agents: valence

ions having an opposite charge to that of the suspended particles. Proper use of electrolyte (conc. and type) can reduce Zeta potential to around zero; thus shifting the interparticulate repulsion toward attractive Van der Waal forces. Flocculation efficiency increases with the increase in the valency of the ion. Trivalent ions are more effective than divalent, and divalent are more effective than monovalent (why?). For example Aluminum chloride is more effective than Calcium chloride, which is more effective than sodium chloride in reducing the Zeta potential of negatively charged solid particles.

B. Polymers: at low concentration, hydrocolloids with high molecular weight can bridge solid particle by adsorption at the solid-liquid interface, and projecting into the bulk to attach to another particle. However, at high concentration they would be adsorbed as multimolecular film; they would act as protective hydrocolloids against flocculation (steric hindrance against flocculation). For example, the effect of concentration of ionic polysaccharides on flocculation of sulfaguanidine suspension was studied; it was observed that the sedimentation volume increased as the polymer concentration was increased, but as concentration was increased further, sedimentation volume was decreased.

Humectants and Cosolvents: Glycerin, propylene glycol, low Mwt PEGs and sorbitol.

-They prevent cap locking due to crystallization of sucrose on the bottle nick in oral suspensions.

-Some of them act as sweetener, such as glycerin and sorbitol.

-Used as humectants in topical suspensions.

-They would also allow the incorporation of water insoluble inactive ingredients, such as water insoluble preservatives and antioxidants by acting as cosolvents for these ingredients.

-Excess concentration, however, should be avoided, because they may solubilize the drug, and thus encourage crystal growth.

Sweeteners: Glycerin, sorbitol, sucrose and high fructose syrup. They also increase viscosity of the suspension and thus act as suspending agents. They also reduce the density difference between the suspended particle and the vehicle.

Preservatives: The naturally occurring suspending agents such as tragacanth, acacia,

xanthan gum are susceptible to microbial contamination. If suspension is not preserved properly then the increase in microbial activity may cause stability problem such as loss in suspending activity of suspending agents, loss of color, flavor and odor, change in elegance etc. Antimicrobial activity is potentiated at lower pH.

Preservatives are included in pharmaceutical dosage form to control the microbial bioburden of the formulation.

Ideally, preservatives should exhibit the following properties:

* Possess a broad spectrum of antimicrobial activity encompassing Gram-positive and Gram-negative bacteria and fungi. * Be chemically and physically stable over the shelf-life of the product. * Have low toxicity. * Should not be adsorbed on to the container. * Should be compatible with other formulation additives. * Its efficacy should not be decreased by pH.

Chemical structure and some properties of parbens commonly used as preservatives are given next slide.

Group of alkyl esters of p-hydroxybenzoic acid with an effective pH range of 4.0 to 7.0.

Most active against yeast, molds, and gram positive bacteria.

Antimicrobial activity decreases above pH 7 due to the formation of the phenolate anion.

Being esters, parabens undergo hydrolysis in weak alkaline and strongly acidic solutions.

Parabens work more effectively in combinations.

Parabens

As alkyl chain length of the paraben ester group increases,antimicrobial activity increases but water solubility decreasesand oil solubility increases.

Based on animal data they estrogenic activity that may beassociated with breast cancer is a concern. This activity of parabens increases with length of alkyl group.

Factors affecting preservative efficacy in oral suspension 1. The pH of the formulation: The pH of the formulation. In some

aqueous formulations the use of acidic preservatives, e.g. benzoic acid, sorbic acid, may be problematic. Active form of preservative may be ionized or unionized form. For example active form of benzoic acid is undissociated form. The pKa of benzoic acid is 4.2. Benzoic acid is active below pH 4.2 where it remains in unionized form. The activity of the unionised form of the acid in this respect is due to the ability of this form to diffuse across the outer membrane of the microorganism and eventually into the cytoplasm. The neutral conditions within the cytoplasm enable the preservative to dissociate, leading to acidification of the cytoplasm and inhibition of growth. In antacid suspensions, because the pH is 6-7, therefore parabens, benzoates and sorbates become less active. In antacids other measures are usually taken such as chlorination, ozonization of water or even pasteurization of the suspension to ensure preservation.

2. The presence of micelles: If the preservative exhibits lipophilic properties (e.g. the unionised

form of acidic preservatives, phenolics, parabens), then partition of these species into the micelle may occur, thereby decreasing the available (effective) concentration of preservative in solution.

Reconstitutable suspensions (Dry suspensions)

The most common reason for formulation of suspensions for reconstitution is inadequate chemical stability of the drug in an aqueous vehicle. Reconstituted suspension of penicillin has a maximum shelf life of 14 days. The manufactured dry mixture, however, has shelf life of at least 2 years. Another reason for reconstitution is to avoid problems of physical stability, such as pH change, crystal growth and polymorphic transformation. Nearly all of drugs formulated in this manner are antibiotics. Ingredients used in such suspension are identical to those used in liquid suspension. Other ingredients, may be necessary, such as intragranular disintegrant when the suspension is manufactured using wet granulation. The reconstituble suspension must be easily reconstituted and poured by the patient, for example the drug and suspending agent should disperse by hand shaking; carbomer and methyl cellulose are not recommended. The combination of microcrystaline cellulose and Na CMC (Known commercially as Avicel RC 591 for FMC) is common suspending agent. Flocculating agents are not commonly used in suspensions for reconstitution, because these products are redispersed frequently enough to prevent caking; they do not stand on shelf as liquid suspensions and the patients use them for limited period of time with shaking every time of use.

Sucrose at concentration of 60% is usually included as suspending agents and to aid the preservation (why?).

Anticaking agents, such as silica gel is usually included; the reason is powder agglomeration due to moisture uptake, causing poor powder flow, and even caking before reconstitution because of partial fusing of particles, due to the presence of soluble ingredient, such as sucrose. Consequently, dispersaibility of suspension upon reconstitution may become a problem.

Production of suspension for reconstitution

They can be produced by granulation or dry blending. Granulation is costly and may present the drug for degradation by heat, however it would present less segregation and mixing problems. Dry blending is more economical, and eliminates the effect of heat of drug, however, more mixing problems, such as segregation would happen. This is particularly true when the particle size of drug is very different from the size of excepients. Also the flow for granulated products is better, which would facilitate filling during production and dispersability upon reconstitution .