1. Pharmaceutical Suspensions
Liquid and Semi-solid Dosage Forms
PHT 3101
Lawrence Imanirampa; MUST(MPS)
24th OCTOBER2012 1

2. Pharmaceutical Suspensions
What is expected from Student at the end of this topic:
To know the nature of suspensions,
Pharmaceutical uses of suspensions,
Properties of an ideal suspension,
Matters related to formulation of suspensions,
Excipients used in suspensions and
Preparation of both internal and external suspensions.

3. What is a Suspension?
A disperse system in which one substance (disperse phase) is distributed in particulate form throughout another (continuous phase/external phase/vehicle).
May contain one or more insoluble medicaments in a vehicle, with other additives (preservatives, flavours, colours, buffers and stabilizers)
Most p'ceutical suspensions are aqueous but an oily vehicle can be used
Are used for oral, inhalation,topical application, ophthalmic preparations, parenteral administration and as aerosols 3

4. Most p’ceutical suspensions are coarse suspensions
dispersion of particles with mean diameter >1 μm
Colloidal suspension
dispersion of particles with mean diameter <1 μm
Most p’ceutical suspensions are coarse suspensions
Phases will separate upon storage, but suspension is considered stable as long as the drug particles re- disperse upon agitation

5. Reasons for using p'ceutical suspensions
Drugs with very low solubility are usually formulated as suspensions
Some people find it difficulty to swallow solid dosage forms, drug be dispersed into liquid form
Drugs with unpleasant taste in their soluble form can be made into insoluble derivatives- formulated as a suspension whc are more palatable(chloramphenicol soluble chlorampenicol palmitate)

6. There is immediate optimal dissolution in git if a drug is relivered in finely divided form,rate of absorption of the drug from a suspension is faster than when delivered in a solid dosage form(slower than the rate from a solution)
Insoluble forms of a drugs may prolong the action of a drug by preventing rapid degradtion of the drug in presence of water(ref.... oxytetracyline----- Hcl.soluble...hydrolyses rapidly and Ca++ salt..insoluble...stable)

7. A drug unstable when in contact with the vehicle, suspensions shd be prepared immediately prior to handing out to the patient in order to reduce the amnt of time that the drug particles are in contact with the dispersion medium(ampicillin suspension water added to pulv or granules, 2/52 day expirely date is give if kept in a frige)

8. Drugs whc degrade in aqueous solutions may be suspended in non- aqueous phase i.e. tetracycline Hcl is suspendedin fractionated coconut oil for ophthalmic use
Bulky, insoluble powders are formulated in this form so as to make them easier to take i.e Kaolin Mixture Paediatric BP, and antacid- Mg Trisilicate Mixture BP.

9. IM,IA or SC injections are formulated as suspensions to prolong the release of the drug
Lotions containing insoluble solids are formulated to leave a thin coating of medicament on the skin,
As the vehicle evaporates , it gives a cooling effect and leaves the solid behind i.e Calamine Lotion BP

10. Advantages of Suspensions
Useful drug delivery system for drugs with a low solubility
To formulate these drugs into solutions may need large volumes of solvent
pptn issues on storage
Are formulated to mask the taste of drugs
Useful for administering drugs to patients who have difficulty swallowing solid dosage forms
Can be formulated to provide controlled drug delivery
E.g. intramuscular injections 10

11. Disadvantages of Suspensions
Suspensions are unstable
Therefore must be designed carefully so that stability is retained over the shelf-life
Is difficult to formulate aesthetic suspensions
Are bulky, and difficult for patients to carry 11

12. Characteristics of a good Pharmaceutical Suspension
Low rate of sedimentation
Disperse phase must be easily re-dispersed with gentle shaking
Flow properties of the suspension should allow it to be easily removed from the container
it should be pourable
It should be aesthetically pleasing
The suspended particles should be small and uniform in size
so product does not have a gritty texture 12

13. Formulation of suspensions
Three steps to be taken to ensure formulation of an elegant p'ceutical suspension are:
Control of particle size(grind ingredients to fine powder)
Use of thickening agent to increase viscosity(suspending/ viscosity- increasing agents)
Use wetting agents

14. The insoluble medicament may be diffusible solids or indiffusible solids:
Diffusible Solids(Dispersible solids
Are insoluble solids that are light and easily wetted by water
Mix readily with and stay dispersed long enough for an adequate dose to be measured
Are easily re-dispersed after settling
i.e.Mg Trisilicate,light Mg carbonate and light kaolin

15. Indiffusible solids
Most insoluble solids are not easily wetted, and may form large porous clumps in the liquid
These solids will not remain evenly distributed in the vehicle long enough for an adequate dose to be measured, i.e oral- ASA,Sulphadimidine, phenobarbitone and chalk,
External use- calamine, hydrocortisone,sulphur & Zinc oxide

16. Sedimentation
The rate of sedimentation is directly proportional to the square of the average diameter of the particles
Large particles sediment faster and will be on bottom
Small sized particles form a cake
Stokes’ Law describes the factors affecting sedimentation rate for particles: 16

17. Where
V= velocity of the spherical particle
r=radius of the particle
6=density of the particle
p=density of the liquid
n=viscosity of theliqiud
G= acceleration due to gravity
get other versions of Stokes equation

18. Basic consequences of this equation are that the rate of fall of a suspended particle in a vehicle of a given density is greater than it is for a smaller particle
Also, the greater the difference in density between the particles and the vehicle, the greater will be the rate of descent
Increasing the viscosity of the dispersion medium the , within the limits so that the suspension is still pourable ,will reduce the rate of sedimentation of a drug

19. Thus a decrease in settling rate in a suspension may be achieved by reducing the size of the particle and by increasing the density and viscosity of the continuous phase

20. Application of Stokes Law
Particles can sediment without being hindered by other particles
That the suspension must be very dilute(0.02%)

21. Reduction of velocity of sedimentation
By decreasing or reducing particle size(r)
Minimize the difference between the densities of particles and vehicle(6-p)
Increasing viscosity (n)of the vehicle(surfactant/suspending agent/ thickening agent)

22. Density alteration or change
Is by addition of the following substances alone or in combination
- polyethylene glycols
- polyvinyl pyrolidine
- glcerine
- sorbitol
- sugar

23. Increase of viscosity Done to reduce sedimentation
Is by addition of suspending agent alone or in combination,eg.,
-methylcellulose
-carboxymethylcellulose
-SCMC
-Acacia
- tragacanth
- bentonite

24. viscosity
Preferably the suspension shd have a high viscosity to prevent sedimentation but has to be dispensed conveniently as well,so viscosity shd'nt be too high
Ideally, a thixotropic viscosity, so that after shaking the viscosity goes down and the suspension can be dispensed easily and then at rest the high viscosity recovers and sedimentation is inhibited

25. To optimise the stability of the suspension, particle size should be minimised
By controlled precipitation or milling
Crystal growth (Ostwald ripening) occurs during storage, and can affect the average particle size
Smaller particles dissolve in the aqueous vehicle if temp ↑ during storage, and then crystallise on the surface of the larger particles when temperature ↓
Average diameter of the suspended particles ↑ 25

26. Crystal growth can be limited by adding a hydrophilic polymer to the formulation
adsorbs onto the surface of each particle.
the formulation should be subjected to temperature cycling (hot, cold, hot, etc)
to monitor changes in particle diameter and physical stability

27. Wetting Insoluble drug particles are hydrophobic and not easily wetted
So vehicle will not readily form a layer around the particle
And Air will remains trapped in the particles
Causes them to float to the surface of the formulation
They wont be homogeneously dispersed 27

28. Wetting: Importance of a Low Contact Angle
Contact angle is the angle at which the liquid/vapour interface meets the surface of the solid
Contact angle defined in terms of the interfacial tensions between the 3 phases:
Liquid (vehicle)/vapour(l/v),
Solid (drug)/vapour (s/v)
Solid (drug)/liquid (vehicle(s/v)
To wet fully with an aqueous vehicle the contact angle, θ, must be low 28

29. Contact angle
YOUNG EQUATION

30. To wet fully with an aqueous vehicle the contact angle, θ, must be low
Liquid (vehicle)/vapour(l/v),
Solid (drug)/vapour (s/v)
Solid (drug)/liquid (vehicle(s/v)
To wet fully with an aqueous vehicle the contact angle, θ, must be low

31. Ways to Reduce Contact Angle
Contact angle can be reduced by decreasing the interfacial tensions between the vehicle and the vapour and between the solid and the vehicle.
Adsorbed air on the solid surfaces needs to be displaced by the liquid
Achieved by the addition of surface-active agents to the formulation
Used at concentrations up to about 0.1%
Oral use:
polysorbates (tweens) and sorbitan esters (spans)
External Use
sodium lauryl sulphate, sodium dioctylsulphosuccinate and quillaia extract
Parenteral Use
polysorbates, lecithin and Pluronics 31

32. Hydrophilic colloids Coat the solid (hydrophobic) drug particles
They give the particles hydrophilic characteristics which promotes wetting
-Acacia,
-bentonite,
-tragacanth
-alginates and
- cellulose derivatives
NB – also used as suspending agents 32

33. Water-miscible solvents
Reduce the liquid/vapour interfacial tension
Penetrate loose powder agglomerates and displace the air so wetting can occur
E.g. alcohol, glycerol and glycols

34. Electrical Properties of Dispersed Particles
Following dispersion within an aqueous medium, particles may acquire a charge due either to:
Ionisation of functional groups on the drug molecule
Adsorption of ions on to the surface of the particle 34

35. Ionisation of Functional Groups on the Drug Molecule
Insoluble drug particles may possess groups at the surface that will ionise as a function of pH
E.g. COOH or NH2
The degree of ionisation is dependent on the pKa of the molecule and the pH of the surrounding solution 35

36. Adsorption of Ions onto the Surface of the Particle
Following immersion into an aqueous solution which contains electrolytes, ions may be adsorbed onto the surface of the drug particle
If there are no added electrolytes, preferential adsorption of hydroxyl ions (OH-) on to the surface of the particle will occur
Hydronium ions (H3O+)are more hydrated than hydroxyl ions, so are more likely to remain within the bulk medium.
Following the adsorption of ions onto the surface, a phenomenon called the electrical double layer is established 36

37. Features of the Electrical Double Layer: The First Layer
It is composed of adsorbed ions on the surface, counter-ions, and bound hydrated solvent molecules
Ions (e.g. cations) are adsorbed onto the surface of the particle, and the anions and remaining cations stay in solution
A potential is generated on the surface of the particle = the Nearnst potential
The ions that are responsible for this potential are called potential-determining ions
Anions are then electrostatically attracted to the (positive) surface of the particle.
These anions will then repel the approach of further anions 37

38. Features of the Electrical Double Layer: The Stern Plane
The boundary between the first and second layers of the electrical double layers
Characterised by:
The adsorbed ions on the surface of the particle
The adsorbed counterions at the surface of the particle
It falls through the centre of the counterion layer
The charge at the surface of the particle is usually greater than at the Stern Plane 38

39. Features of the Electrical Double Layer: The Second Layer
Contains predominantly hydrated counter-ions that are loosely attached to the surface of the particle, and has the following features:
The boundary of the second layer possesses a potential, known as the zeta potential
This is less than the potential at the Stern Plane
If the particle is rotated, this second layer forms the shear plane
I.e. the effective surface
At a certain distance from the surface of the particle, electrical neutrality is restored 39

40. Flocculation
Floccule = a less rigid or loose aggregation of particles held together by fairly weak particle-particle bonds.
Flocculated particles form a lattice that resists complete settling, and are therefore less prone to compaction.
Floccules settle to form a higher sediment volume than unflocculated particles, and the loose structure allows the aggregates to break up and redistribute easily upon agitation 40

41. Physical stability of the suspension:
The condition in which the particles do not aggregate and in which they remain uniformly distributed throughout the dispersion
This is rarely achieved
so if the particles do settle it is important that they should easily be re-suspended by moderate agitation.
Ideally a stable dispersion will be deflocculated
the individual solid particles remain discrete, but sedimentation will occur due to the size of the particles. 41

42. The smaller particles fill the spaces between the larger particles.
Electrical repulsive forces between the particles allow them to slip past each other
forming a close-packed arrangement at the bottom of the container.
The smaller particles fill the spaces between the larger particles.
The particles lower down become pressed together by the weight of the particles above
The particles are now in close contact with each other
Hence the repulsive forces between them have been overcome.
Crystal growth and hydration effects may cause bridges to form between the particles
This physical bonding leads to cake or clay formation which cannot be easily dispersed by agitation alone. 42

43. There is a relationship between the overall energy between two particles and their distance of separation 43

44. The primary minimum The primary maximum The secondary minimum
High attraction between particles.
Particles will irreversibly coagulate, and the formulation will be unstable
The primary maximum
Repulsion between particles, prevents the particles interacting at close distances.
Affected by the presence and concentration of electrolytes
magnitude of primary maximum reduced as electrolyte concentration increased.
Also occurs when ionic surface-active agents are added
The secondary minimum
Attractive forces predominate, but less attraction than at the primary minimum.
Particles at secondary minimum are known as floccules, and the process is flocculation.
Physical stability of the suspension at this point is increased.
The interaction between the particles may be broken by shaking (agitation), so an accurate dose can be given. 44

45. Controlled Flocculation (1)
Particles can be engineered to reside in the secondary minimum in a process called Controlled Flocculation
Flocculated systems have a high sediment volume
There is a large void volume within the floccule structure.
The size of drug particles used in the formulation of suspensions is generally large enough to exhibit a secondary minimum
Enhanced by the non-spherical nature of the particles.
The ability to undergo flocculation increases as the concentration of suspended particles increases
There is a higher chance of particle-particle interactions.
Flocculation can also be induced by the incorporation of electrolytes or surface-active agents into the formulation. 45

46. Controlled Flocculation (2)
The sedimentation volume ratio can be used to assess the flocculation properties of a suspension:
F = Sedimentation volume ratio, Vu = Ultimate settled volume, V0 = Original settled volume
This ratio can be used during formulation, and plotted against the concentration of additive to show the concentration needed for the suspension. 46

47. Rheological Properties
The degree of flocculation affects the rheological properties of a suspension
Viscosity of a flocculated system is higher than a deflocculated system
amount of free continuous phase is reduced as it becomes entrapped in the floccules
Flocculated suspensions exhibit plastic and pseudoplastic flow properties 47

48. Suspending Agents Increase the viscosity of the vehicle
⇒slower sedimentation rate
Most agents can form thixotropic gels
Semi-solid on standing, but flow readily after shaking
Suspending agents should be carefully chosen
Drugs may bind to them
Stomach acidity may alter the physical characteristics of the suspension, and hence the rate of drug release from the suspension 48

49. Types of Suspending Agent
Natural Polysaccharides
Tragacanth
Used for internal and external products
0.2g added per 100ml of suspension
Need to disperse it with the insoluble powders before adding any liquid, or clumping will occur
Stable at pH 4 to 7.5
Takes a few days to fully hydrate in water 49

50. Compound Tragacanth powder BP
Also acacia gum(not very satisfactory), starch (rarely used on its own), agar, guar gum, carrageenan & sodium alginate
Compound Tragacanth powder BP
Contains tragacanth, acacia, starch and sucrose
Easy to use
Use 2g per 100ml of suspension

51. Semi-synthetic Polysaccharides
Types of Suspending Agent
Semi-synthetic Polysaccharides
These are water-soluble celluloses
Methylcellulose = [C6H7O2(OH2)OCH3]n
Longer chain length makes more viscous solutions
Non-ionic and stable over a wide pH range from 3 to 11
Can also use:
hydroxyethylcellulose,
sodium carboxymethylcellulose and
microcrystalline cellulose 51

52. Clays Natural inorganic materials Hydrate readily
Need to be sterilised before use, as may contain spores
Hydrate readily
Absorb 12 times their own weight in water
Form thixotropic gels
Bentonite = Al2O3.4SiO2.H2O
Used at concentrations of 2 – 3 % in external preparations
Magnesium Aluminium Silicate
Insoluble flake
Used at concentrations up to 5% in internal and external preps

53. Synthetic Agents Miscellaneous Agents
Carbomer (carboxyvinyl polymer, carbopol
Synthetic polymer of acrylic acid and allyl sucrose
Used at concs up to 0.5%
Mainly external use, but sometimes internal
Colloidal silicon dioxide (Aerosil, Cab-O-Sil)
Used at concs of up to 4% for external use
Miscellaneous Agents
Gelatin
Used as a suspending and viscosity-increasing agent. 53

54. Other Excipients Buffers Density Modifiers
May be needed to maintain chemical stability of suspension, to control tonicity, or to ensure physiological compatibility
Adding electrolytes may adversely affect the physical stability of the suspension
Density Modifiers
Sedimentation will not occur if disperse and continuous phases have same density
Minor modifications can be made to the aqueous phase by adding sucrose, glycerol or PEG
Flavours, colours and perfumes
See lecture notes for pharmaceutical solutions 54

55. More Excipients Humectants Preservatives Sweetening Agents
Sometimes used in external preparations
Stops product drying out following application to the skin
Glycerol and PEG added at concs of approx. 5%
Preservatives
Used to prevent growth of micro-organisms that may be present in raw materials used, and to prevent in-use contamination
May interact with other components of the suspension
Solubilised by wetting agents
Adsorb onto suspended solids (kaolin or mag. trisilicate)
Interact with polymers
Sweetening Agents
Increase palatability
High concentrations may affect rheological properties and make suspension difficult to pour
Eg sucrose, glycerol or sorbitol 55

56. Small-scale Manufacture of Suspensions: Principles
Control particle size
Use a pestle and mortar to grind the ingredients down into a fine powder
Increase the viscosity of the vehicle
Use suspending agents or viscosity-increasing agents
Use a wetting agent 56

57. Extemporaneous Dispensing of Suspensions
Grind the crystalline and granular solids to a fine powder in a mortar
Add the suspending agent and mix thoroughly
Too much pressure ⇒ gumming or caking
Heat of friction ⇒ stickiness
Add enough of the liquid vehicle to make a paste, and mix this until it is smooth
If using a wetting agent, add it before making the paste
If suspension includes sucrose or glycerol, use these to make the paste
Soluble solids may be incorporated before or after making the paste
Gradually add more liquid, until the mixture can be poured into a tared bottle
Rinse the rest of the powder out of the mortar with more of the liquid, and then make it up to volume
NB: Add any volatile components near the end 57

58. General method for the preparation of a suspension containing a diffusible solid

59. Check the solubilities, in the vehicle,of all solids in the mixture
Calculate the quantities of vehicle required to dissolve any soluble solids
Prepare any Double Strength Chloroform Water BP
Weigh all solids on class 11 or electronics balance
Dissolve all soluble in the vehicle in a small glass beaker
Mix any insoluble diffusible powders in porcelain mortar using the doubling-up

60. method to ensure complete mixing
7. Add a small quantities of vehicle(may/may not be a solution) in the mortar and using a pestle to form a smooth paste
8. Add further vehicle in small quantities , and continue mixing until the mixture in the mortar is of possible consistency
9. Transfer the contents of the mortar to a conical measure of suitable size

61. 10. Rinse out the mortar with more vehicle and add any rinsing to the conical measure
11. Add the remaining liquid ingredients to the mixture in the conical measure(think of the presence of a volatile component)
12.Make up to final volume with the vehicle
13. Stir gently, transfer to a suitable container , ensuring that all solid is transferred from the conical measure to the bottle and label ready to be dispensed to the patient.

62. What was presented by student in their groups:
Sedimentation rate and wetting
Physical stability
Prepn of suspension
Packaging/storage
Release of drug from a suspensions
Dry powder forms, commonly used examples

63. END