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

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 which insoluble particles, generally greater than 1m 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 more insoluble 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 are that 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 may arise 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 particles held 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. Viscosity of 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. The rate 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 which the solid particles are very much coarser, such a system would sediment because of the

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 liquid may 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 viscosity of 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 to each 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. Distilled water 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 2 in 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. Schematic diagrams of the kaolin surface and the orientation and absorption of HTAB in the suspension K1, K3 and K7

(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 weighed and 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
Overall HTAB concentration ( % w/v ) K1 K2 K3 K4 K5 K6 K7 K8 0.00 0.50 1.00 2.00 5.00 10.00 15.00 25.00 0.00 0.01 0.02 0.04 0.10 0.20 0.30 0.50 ( moldm-3 ) 0.00 2.74 X 10-4 5.49 X 10-4 1.10 X 10-3 2.74 X 10-3 5.49 X 10-3 8.23 X 10-3 1.37 X 10-3

Cylinder

0.5% w/v HTAB (ml)

Table 2: Sedimentation volume (Vs), sedimentation volume ratio (R) and appearance of supernatant of slightly agitated suspensions.
Suspension K1 K2 K3 K4 K5 K6 K7 K8 Vs ( mL ) <1 1.00 5.00 14.00 8.00 1.50 1.00 <1 R < 0.04 0.04 0.20 0.56 0.32 0.06 0.04 < 0.04 Appearance of supernatant Very cloudy among K1 to K3 Cloudy than K3 Less cloudy among K1 to K3 Cloudy Cloudy but less than K4 Cloudy Less cloudy than K6 Less cloudy than K6 and K7

Table 3: Ease of redispersion of agitated

Suspension K1 K2 K3 K4 K5 K6 K7 K8

Ease of redispersion 1 2 5 8 7 6 4 3

suspensions.

Ease of redispersion :

From particle microelectrophoresis studies, the following observation was obtained.

Suspension No. K1 K3 K7

Charge on particle -ve zero +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 light kaolin

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 extra HTAB builds up as a second layer around the kaolin molecules. Therefore the particles have positive charge.

(b) Demonstration of controlled flocculation using an electrolyte. (i) ( ii ) Particles aggregate and come to surface. Some form a layer at the bottom. Suspension is flocculated. Suspension is cloudier. Fewer particles at the top and bottom. Suspension is deflocculated.

Table 4: Details of quantities of AlCl3 to add

Suspension P1 P2 P3 P4 P5 P6 P7 P8 P9 Total 0.5%w/v SDS (ml) 25 25 25 25 25 25 25 25 25 Total AlCl3 added (ml) 0 2 3 4 5 6 7 10 20

Table 5: Sedimentation rate of each suspension

Suspension P1 P2 P3 P4 P5 P6 P7 P8 P9 State of flocculation deflocculation deflocculation some flocculation some flocculation some flocculation more flocculation a lot of flocculation a lot of flocculation a lot of flocculation Sedimentation rate very slow slow slow slow/medium medium medium medium fast fast

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

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 1m 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 behind suspensions 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 when formulating 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 they reach 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 suspension had 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 is cloudy. And when more HTAB is added, it causes the system to become more

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 particles are 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 between the 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 to each 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 the cake 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 is increased 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 shows the 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 is added 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 gives the 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, which leads 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 these experiments is easily redispersed. In suspensions being formulated for patient use, the pharmaceutical industry produce suspensions which are partially flocculated that is the particles may form sediment 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

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.