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ASPECTS OF SUSPENSION

FORMULATION AND PROBLEM

SOLVING IN CO-SOLVENCY

MPH 205

FORMULATION AND

MANUFACTURE OF MEDICINE

GROUP: F

SUB-GROUP: 2

LECTURE: DR PAUL CARTER

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ABSTRACT

The aim of the experiment was to investigate the principal factors which affect the

wetting and flocculation or deflocculation of particles dispersed in aqueous media. The

experiment is also to compare the behaviour of a hydrophobic and hydrophilic solid in

the presence of ionic surfactants and electrolytes. It takes a certain concentration of surfactant to aggregate the particles substantially enough into a flocculated suspension.

Any concentration above or below this gave a deflocculated suspension. In conclusion,

the pharmaceutical industry use controlled flocculation in the manufacture of suspensions, to ensure that ‘caking’ does not occur and that patients always get the

correct dose of drug per ml of suspension.

INTRODUCTION

A definition of a pharmaceutical suspension is a coarse disperse system in whichinsoluble particles, generally greater than 1µm in diameter, are dispersed in a liquid

medium, usually aqueous.An aqueuos suspension is a useful formulation system for administering an

insoluble or poorly soluble drug. The large surface area of dispersed drug ensures a high

availability for dissolution and also absorption. Suspensions contain one or moreinsoluble medicaments in a vehicle, with other additives such as preservatives, flavour,

colours, buffer and stabilizers. Pharmaceutical suspensions tend to be coarse dispersions

rather than true colloids, although there are many submicron polymer dispersions

available. Drugs in suspensions are prepared mainly for oral, intramuscular or subcutaneous use.

An acceptable suspensions possesses certain desirable qualities, among which arethat the suspended material should not settle too rapidly, particles that do settle to the bottom of the container must not form a hard mass but should be readily dispersed into a

uniform mixture when the container is shaken and that the suspension must not be too

viscous to pour freely from the bottle or to flow through a syringe needle. Problems mayarise when drugs are dispersed in a liquid such as sedimentation, caking, flocculation and

particle growth. Formulation of pharmaceutical suspensions to minimize caking can be

achieved by the production of flocculated systems. A flocculation is a cluster of particlesheld together in a loose open structure. A suspensions consisting of particles in this state

is termed flocculated. There are many states of flocculation and deflocculation.

Unfortunately flocculated systems clear rapidly and the preparation often appears

unsightly, so a partially deflocculated formulation is the ideal pharmaceutical. Viscosityof suspensions is affected by flocculation. A deflocculated system has its particle disperse

throughout the solution. This is because there are forces of repulsion between the

particles of quite a large magnitude. This allows the particles to remain separated. Therate of sendimentation depends on the size of particles.

A suspension in which all the particles remain discrete would in terms of DLVO

theory, be considered to be stable. However, with pharmaceutical suspensions, in whichthe solid particles are very much coarser, such a system would sediment because of the

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size of the particles. The electrical repulsive forces between the particles allow them to

slip past one another to form a close-packed arrangement at the bottom of the container,

with the small particles filling the voids between the larger ones. The supernatant liquidmay remain cloudy after sedimentation owing to the presence of colloidal particles that

remain dispersed. Those particles lower most in the sediment are gradually pressed

together by the weight of the ones above. The repulsive barrier is thus overcome,allowing the particles to pack closely together.

Caking of the suspensions, which arises on close packing of the sedimented

particles, cannot be eliminated by reduction of particle size or by increasing the viscosityof the continuous phase. Fine particles in a viscous medium settle more slowly than

coarse particles but, after settling, they fit to form a more closely packed sediment which

may be difficult to redisperse. Particles in a close-packed condition brought about by

settling and by the pressure of particles above thus greater forces of attraction.Flocculating agents can prevent caking while deflocculating agents increase the tendency

to cake.

EXPERIMENTAL

Materials

• Light kaolin

• Phenolphthalein

• SDS (sodium dodecyl sulphate): cmc 8 X 10-3 moldm-3

• HTAB(hexadecyltrimethylammonium bromide)0.5% w/v: cmc 9 X 10-4 moldm-3

• AlCl3 (aluminium chloride) solution 0.5% w/v

Method

(a) The effect of cationic surfactant on a suspension of hydrophilic kaolin particles.

8 X 1g samples of kaolin were weighed out and 1g of kaolin was transferred toeach of 8 measuring cylinders. The burette was filled with HTAB solution which was

prepared by lab assistant and placed in a water bath temperature set to 27oC. Quantities of

0.5% w/v HTAB solution were added as shown in Table 1 in result section. Distilledwater was added up to 25ml mark using a pipette. Each cylinder was gently inverted once

or twice to disperse kaolin then was allowed to stand. Once sendimented, the

sedimentation volume was recorded and the sedimentation volume ratio was calculated

and the appearance of the supernatant was described. The results were recorded in table 2in the result section. After that, each cylinder was inverted again to redisperse the

suspensions and the ease of redispersion was recorded in Table 3 in result section. The

last part of this part of the experiment was to look at microelectropheresis. Schematicdiagrams of the kaolin surface and the orientation and absorption of HTAB in the

suspension K1, K3 and K7

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(b) Demonstration of controlled flocculation using an electrolyte.

0.5g of phenolphthalein was weighed out into a 25ml measuring cylinder and

made up to the 25ml mark with distilled water using a pipette. The cylinder was shake

and inverted several times. A 1g sample of phenolphthalein was then accurately weighedand transferred to a measuring cylinder and made up to 25ml with 0.5% w/v SDS

solution. 0.5% w/v AlCl3 was then added to the cylinder containing the SDS in a stepwise

fashion in which the exact quantities are shown in Table 4 of the result section. After each addition of AlCl3, the cylinder was inverted several times to ensure good mixing.

The flocculation and sedimentation were then observed.

RESULTS(a) The effect of cationic surfactant on a suspension of hydrophilic kaolin particles.

Table 1: Composition of suspensions K1 to K8

Cylinder 0.5% w/v HTAB (ml)Overall HTAB concentration

( % w/v ) ( moldm-3 )

K1 0.00 0.00 0.00

K2 0.50 0.01 2.74 X 10-4

K3 1.00 0.02 5.49 X 10-4

K4 2.00 0.04 1.10 X 10-3

K5 5.00 0.10 2.74 X 10-3

K6 10.00 0.20 5.49 X 10-3

K7 15.00 0.30 8.23 X 10-3

K8 25.00 0.50 1.37 X 10-3

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Table 2: Sedimentation volume (Vs), sedimentation volume ratio (R) and

appearance of supernatant of slightly agitated suspensions.

Table 3: Ease of

redispersion of agitated suspensions.

Ease of redispersion : 1 8

From particle microelectrophoresis studies, the following observation was obtained.

Suspension Vs ( mL ) R Appearance of supernatant

K1 < 1 < 0.04 Very cloudy among K1 to K3

K2 1.00 0.04 Cloudy than K3

K3 5.00 0.20 Less cloudy among K1 to K3

K4 14.00 0.56 Cloudy

K5 8.00 0.32 Cloudy but less than K4

K6 1.50 0.06 Cloudy

K7 1.00 0.04 Less cloudy than K6

K8 < 1 < 0.04 Less cloudy than K6 and K7

SuspensionEase of

redispersion

K1 1

K2 2

K3 5

K4 8

K5 7

K6 6

K7 4

K8 3

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Suspension No. Charge on particle

K1K3

K7

-vezero

+ve

Schematic diagram of the kaolin surface and the orientation of any adsorbed HTAB

present in suspensions K1, K3 and K7

K1

- The particles have negative charges

because it contain hydrophilic lightkaolin

K3

- Contain hydrophilic light kaolin of

cationic surfactant HTAB. The +ve

charge from HTAB neutralize the – ve charge from kaolin. The particle

has zero charge.

K7

- At K7, it contains large amount of cationic surfactant HTAB. The extraHTAB builds up as a second layer

around the kaolin molecules.

Therefore the particles have positive

charge.

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(b) Demonstration of controlled flocculation using an electrolyte.

( i ) Particles aggregate and come to surface. Some form a layer at the bottom.

Suspension is flocculated.

( ii ) Suspension is cloudier. Fewer particles at the top and bottom. Suspensionis deflocculated.

Table 4: Details of quantities of AlCl3 to addSuspension Total 0.5%w/v SDS (ml) Total AlCl3 added (ml)

P1 25 0

P2 25 2

P3 25 3

P4 25 4

P5 25 5P6 25 6

P7 25 7

P8 25 10

P9 25 20

Table 5: Sedimentation rate of each suspension Suspension State of flocculation Sedimentation rate

P1 deflocculation very slow

P2 deflocculation slow

P3 some flocculation slow

P4 some flocculation slow/medium

P5 some flocculation medium

P6 more flocculation medium

P7 a lot of flocculation medium

P8 a lot of flocculation fast

P9 a lot of flocculation fast

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Schematic diagrams of phenolphthalein surface and the orientation of any adsorbed SDS

or AlCl3 present in suspensions P1 to P9.

Calculation for quantities of 0.5% w/v HTAB solution that need to be added

C1V1 = C2V2

C1 = 0.5% w/v

= 0.5g in 100ml

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V1 = volume of HTAB (ml)

C2 = overall HTAB concentration (moldm-3)

V2 = volume of distilled water = 25ml

For example, K1: C1V1 = C2V2

0.5(0.5) = C2 (25)

C2 = 0.01 g in 100 ml

In moles = 0.01 / 364.46 moles= 2.7438 X 10-5moles in 100ml

Therefore in moldm-3 = 2.74 X 10-4 moldm-3

DISCUSSION

As stated in the introduction, a suspension is defined as a coarse disperse system

in which insoluble particles, generally greater than 1µm in diameter, are dispersed in a

liquid medium, usually aqueous. They allow drugs with poor solubility to be

administered successfully and easily absorbed in the body. The theory behindsuspensions states that smaller particles produce better suspensions. Electrostatic forced

also play a role in the formulation of suspensions; these are what can cause a system to become flocculated or deflocculated.

In a flocculated suspension, the sedimentation rate is rapid and the particles are

easily redispersed. This is due to the flocs which the particles form and these only loosely

pack together at the bottom of the container. Therefore, a flocculated system is used whenformulating suspension to give an even distribution of drug throughout the suspension.

However in a deflocculated system, there are only few attractive forces between

the particles and for this reason they do not form flocs. They have a slow rate of sedimentation which can be timed by assessing the cloudiness of the supernatant. This is

because the particles size is so small. When the sediment does eventually form caking

can occur due to the lack of trapped liquid in the particles. This caking cannot be reversed

that is the particles will not redisperse due to the bonding between the particles when theyreach the bottom of the container.

The first effect looked at in experiments was the sedimentation volume,

sedimentation volume ratio and the appearance of the supernatant after the suspensionhad been slightly agitated. From the result table 2, we can say that as the concentration of

HTAB increases, the cloudiness of the supernatant decreases. This shows that at a

deflocculated system is formed at low concentrations of HTAB as the supernatant iscloudy. And when more HTAB is added, it causes the system to become more

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flocculated. As HTAB is a cationic surfactant, it reduces the steric repulsive forces

between the particles, allowing the attractive forces to have a greater effect forming flocs

and allowing a faster sedimentation time. And because these flocs form all the particlesare trapped within these and settle at the bottom making the supernatant clearer.

Table 3 shows the ease of redispersion after sedimentation for the particles. Again

suspensions K4 and K5 redispersed with K1 to K3 being the most difficult to redisperse.This again proves that the greater amount of HTAB added the more flocculated the

suspension becomes as flocculated systems redisperse easier due to the flocs only weakly

settle at the bottom and do not bond and cake.HTAB cause flocculation to occur by neutralizing the charge on the hydrophilic

kaolin particles. In some cases, adhesion between the particles and the container can

occur above the liquid height. Additives such as surfactants modify the adhesion of these

particles in the suspension by adsorption, thus changing the interaction forces betweenthe particles and container.

The deflocculation in the system occurs because the cationic surfactant increases

the negative charge in the system which leads to repulsion. This leads to a slow rate of

sedimentation, and when sediment does eventually form the particles physically bond toeach other causing caking occur. When the suspension is agitated to be redisperse, the

force between the particles are greater that the forces of the agitation and therefore thecake does not break up and the particles do not redisperse.

The zeta potential of the particles is also reduced with increasing concentration of

cationic surfactant. This displaces the DLVO plot, the suspensions where all the particles

are discreet in stable suspension and this causes a floc to form. If the concentration isincreased beyond this point, it causes the reverse to happen. The zeta potential will

increase and the floc will not form.

We then looked at the control of flocculation using an electrolyte. Table 5 showsthe observations made from these experiments. Phenolphthalein particle are not easily

wetted as they have low contact angle and are hydrophobic, so when in a suspension they

clump together to form a cake at the bottom of the container. SDS is a surfactant and isadded to the suspension to help overcome this problem. However at low concentration

the SDS cannot aid the wetting of phenolphthalein. But as the concentration of SDS is

increased, the system becomes flocculated. The SDS contains sulphate ions which givesthe suspension an overall charge. AlCl3 is added to counteract this and make the

suspension neutral again. It dissociates in water to give Al3+ and 3Cl-ions. The aluminium

ion is a power anion due to its trivalent nature. It reduced the repulsive forces between

particles and this in turn causes increased attraction. This leads to aggregation, whichleads to an increased particle size, sedimentation rate and a greater sedimentation:

volume ratio. This is backed up by stokes law in which it is stated that an increased

particle size leads to an increase in sedimentation. The sediment formed in theseexperiments is easily redispersed.

In suspensions being formulated for patient use, the pharmaceutical industry

produce suspensions which are partially flocculated that is the particles may formsediment at the bottom of the container because of aggregation, but they are easily

redispersed. This would not happen if the suspension was deflocculated, a cake would

form which could not be redispersed. Therefore patients should also be told to shake the

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container to disperse the drug before administration so that they receive the correct dose

of drug.

CONCLUSION

These experiments have shown that in the formulation of suspension, the addition

of cationic surfactant for example HTAB increases the flocculation of particles and

makes them easier to redisperse. And that the addition of an electrolyte also increases the

flocculation of particles in the system. And these details are applied when suspensions are being formulated in industry so that the particles can be easily redisperse and the patient

receives a uniform dose each time.

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