Pharmaceutical Suspensions Prof. Ibrahim Alsarra

1. Department of Pharmaceutics College of Pharmacy King Saud University PHT 312: Pharmaceutics II Pharmaceutical Suspensions Prof. Ibrahim Alsarra

2. Introduction • Suspensions and emulsions form an important class of pharmaceutical dosage forms, but they also present many formulation, stability, manufacturing and packaging challenges. • The principal objectives of this part of this course are to provide some practical considerations that apply to these systems, and then relate those considerations to formulation methods, evaluation procedures and manufacturing techniques.

3. Introduction • We are talking about two-phase systems. The substance that is distributed is referred to as the suspensoid (if a suspension) the dispersed phase or the internal phase and the vehicle is termed the dispersing phase, the dispersion medium, the dispersive medium, the external phase or the continuous phase. • The particles of the dispersed phase can vary widely in size, even within one formulation, ranging from particles or droplets large enough to be visible to the naked eye down to as small as colloidal dimensions.

4. Introduction • The manufacturer will usually want the dispersed phase particle size to fall in a narrow range to maintain uniformity within each product and from package to package. Most good oral suspensions have a particle size in the diameter range 1 to 50 µm. • Coarse Dispersion: - Suspension: solid drug in liquid vehicle - Emulsion: Liquid drug in liquid vehicle 1)- Oil-in-water emulsions (o/w) 2)- Water-in-oil emulsions (w/o)

5. Solutions ♦ Have small particles ♦ Are transparent ♦ Do not separate ♦ Cannot be filtered Colloids ♦Have medium size particles ♦ Cannot be filtered ♦ Separated with semipermeable membranes Suspensios ♦Have very large particles ♦ Settle out ♦ Can be filtered ♦ Must stir to stay suspended

6. Introduction • Because of their larger particle size range, suspensions and emulsions are more likely to separate from the dispersion medium by settling (sedimentation) or creaming (rising), respectively. • This presents a dosing uniformity problem since the drug is contained in these dispersed particles. If the product has separated, the patient may be overdosing or underdosing, depending on whether the sampled product was high in dispersed phase or low in dispersed phase. • What the manufacturer will aim for is a product that possesses random but reasonably uniform redistribution of the dispersed phase when the container is shaken.

7. SUSPENSIONS • Heterogeneous systems consisting of two phases. The continuous or external phase is generally a liquid or semisolid, and the dispersed or the internal phase is made up of particulate matter which is essentially insoluble in, but dispersed throughout, the continuous phase. Almost all suspension systems separate on standing. • The formulator’s main concern, therefore, is not necessarily to try to eliminate separation, but rather to decrease the rate of settling and to 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.

8. SUSPENSIONS • Advantages to Oral Suspensions: There are several reasons for using oral suspensions to deliver a drug: • Pharmacokinetic modification • Palatability • A liquid dosage form vs. a solid dosage form • Solubility and Stability

9. SUSPENSIONS • Pharmacokinetic modification achievable with suspension forms relates essentially to improved absorption properties. Suspension forms of drugs may be more readily bioavailable than comparable capsule or tablet solid dosage forms because the initial disintegration step is bypassed. On the other hand, significant bioavailability differences among generically equivalent brands of oral suspensions have been occasionally observed. • The fact that in aqueous suspensions the relatively insoluble drug greatly reduces or eliminates taste sensation permits the formulation of palatable oral liquids which would otherwise not be possible due to the bad taste of certain drugs.

10. SUSPENSIONS • Not infrequently a liquid form is preferred over the solid form of a drug: (i) ease of swallowing issue with infants and geriatric patients. (ii) the flexibility in the range of doses (not locked into a particular dose by a tablet formulation). • Since oral suspensions can be prepared by a pharmacist using commonly available suspending agents, the pharmacist must recommend that the extemporaneous product be used within a relatively short time since there is usually no evidence to justify the assumption that long-term stability exists.

11. SUSPENSIONS • Some drugs are not sufficiently soluble in conventional, safe and legally permissible vehicles (e.g., water, syrup, hydroalcoholic mixtures, and water/glycerin blends) to provide the desired dose in a 5 to 15 ml volume. • Chemical stability is often improved if the drug is insoluble in the liquid medium. For this reason, suspensions may be prepared with a water-insoluble derivative of the parent drug. The insoluble derivative may be an ester, as in the case of acetyl sulfisoxazole, or an insoluble salt, as in the case of propoxyphene napsylate. Sometimes the drug itself is sufficiently insoluble so that a suspension may be prepared without derivatization, as is the case of phenytoin in which the free-acid form of the drug (as opposed to the sodium salt) is sufficiently insoluble so that an aqueous suspension may be prepared.

12. Desired features in a pharmaceutical suspension 1. Therapeutic efficacy - if the drug does not exert pharmacological activity after administration, it has failed in its purpose. 2. Chemical stability - no degradation or decomposition of vital components within the formulation during processing, storage, handling or administration. 3. Physical stability - the suspension should not settle too quickly and should be readily redispersed on gentle shaking. 4. The particle size should remain fairly constant throughout the shelf-life of the product. You don't want dissolution or aggregation of the particles within the suspension.

13. Desired features in a pharmaceutical suspension 5. The suspension should pour easily and evenly from the container. 6. The formulation should be aesthetically pleasing to the eye, nose and mouth. The appearance, viscosity, texture and any other properties detected by the senses must be considered.

14. Available Suspension Formulations 1. Ready-to-use Oral Suspension: If that is the case, the formulation requires addition of a wetting or spreading agent prior to introduction of the solid particles to the continuous phase. The wetting agent is even expected to enter the pores of the solid particles which allows the continuous phase to penetrate. Keep in mind that only minimum amount of wetting agent should be used, compatible with producing an adequate dispersion of the particles. Excessive amount may lead to foaming or impart undesirable taste or odor to the product. Alcohol, glycerin and propylene glycol would qualify as wetting agents for oral products.

15. Available Suspension Formulations 1. Ready-to-use Oral Suspension: In large scale production, the wetting agent would probably be added at the same time that the solid is reduced in size in a colloid mill. In this way the surfaces of the particles are coated with the surfactant material prior to its introduction Into the vehicle. The solid is added to a portion of the vehicle which already contains all the soluble components, including color, flavor and preservative. After thorough mixing, more vehicle is added sequentially with blending after each addition. The final product is passed through a colloid mill or other blender to ensure uniformity.

16. Available Suspension Formulations 2. Extemporaneous Preparation: As a pharmacist, you may be called upon to prepare an extemporaneous liquid form of a drug that is available in a solid dosage form, usually as a tablet or capsule. Place the contents of the capsule or the whole tablet into a mortar and crush the material with your pestle. Slowly add a small amount of the vehicle and mix the two to form a paste. Dilute the paste with more vehicle until all of the vehicle has been added to the mortar.

17. Available Suspension Formulations 3. Dry Powders for Oral Suspension: The products that are available as ready-to-use suspensions are labeled "Oral Suspension.” There are dry powder mixtures or granules intended for suspension in an appropriate vehicle prior to administration as a suspension; they bear the title "... for Oral Suspension" to distinguish them from already prepared oral suspensions. The powder mixture must contain any coloring agent, flavoring, sweetener, stabilizing agent, suspending agent (viscosity modifier) and preservative intended for the final formulation that is administered. By including all of these agents in the powder mixture, the vehicle for reconstituting the product can be purified water.

18. Available Suspension Formulations 3. Dry Powders for Oral Suspension: When you as the pharmacist are called upon to reconstitute and dispense such a product: 1. Loosen the powder at the bottom of the container by gently tapping it against a hard surface. 2. Add a small portion of the label-designated amount of purified water and shake until the powder is wetted. 3. Add the remainder of the water in several aliquots. 4. Shake the container to confirm that all of the particles are wetted and suspended.

19. Routes of administration of suspension Suspensions are used to administer insoluble and distasteful substances in a form that is pleasant to taste by providing a suitable form, for the application of dermatological materials to the skin and mucous membrane and for parenteral usage. Thus suspensions can be administered by oral, topical, parenteral and ophthalmic application

20. Oral suspensions Patients who have problems in swallowing solid dosage forms require drugs to be dispersed in a liquid. Oral suspensions permit the formulation of poorly soluble drugs in the form of liquid dosage form. As these suspensions are to be taken by oral route therefore they must contain suitable flavoring and sweetening agents. Drugs, which possess unpleasant taste in solution dosage form like paracetamol, chloramphenicol palmitate can be formulated as palatable suspension as they are suitable for administration to peadiatric patients.

21. Topical suspensions These suspensions are meant for external application and therefore should be free from gritty particles. Example of fluid suspension includes calamine lotion, which leave a deposit of calamine on the skin after evaporation of the aqueous dispersion phase. Zinc cream has a consistency of semisolid. Zinc cream consists of high percentage of powders dispersed in an oily (paraffin) phase.

22. Parenteral suspensions These suspensions should be sterile and should possess property of syringability. Vaccines are also formulated as dispersions of killed microorganisms for example inCholera vaccine or as toxoid adsorbed on tosubstrate like aluminium hydroxide or phosphate for prolonged antigenic stimulus. For Exampleadsorbed Diphtheria and Tetanus toxoid.

23. Ophthalmic suspensions These should also be sterile and should possess very fine particles. Drugs, which are unstable in aqueous solution, are formulated as stable suspensions using non-aqueous solvents. For example fractioned coconut oil is used for dispersing tetracycline hydrochloride for ophthalmic use.

24. Theoretical considerations • The basic concern involves the fact that suspensions settle, and it is necessary to redistribute it before using or dispensing the product. • A desirable suspension should be easily redispersed by shaking, should remain suspended long enough to withdraw an accurate dosage, and should have the desired flow properties. • Before we start discussing the formulation of suspensions, it is of great importance to explain some concepts pertaining to the formulation.

25. (1)- Interfacial phenomenon • Smaller particle size and large surface area is associated with a surface free energy making it thermodynamically unstable. • Thus the particles possess high energy which leads to grouping together to reduce surface free energy thus leading to formation of floccules. These floccules are held together among themselves and within by weak van der waals forces. However in cases where particles are adhered by stronger forces to form aggregates forming hard cake. These phenomena occur in order to make system more thermodynamically stable. • In order to achieve a state of stability the system tend to reduce the surface free energy, which may be accomplished by reduction of interfacial tension that is achieved by use of surfactants.

26. (2)- Wetting • A difficulty that is frequently encountered and a factor of prime importance in suspension formulation concerns the wetting of the solid phase by the suspension medium. • By definition, a suspension is essentially an incompatible system, but to exist at all it requires some degree of compatibility, and good wetting of the suspended materials is important to achieve this end. • When a strong affinity exists between a liquid and a solid, the liquid will easily form a thin film over the surface of the solid. When this affinity is nonexistent or weak, however, the liquid has difficulty displacing the air or other substances surrounding the solid, and there exists an angle of contact between the liquid and the solid.

27. (2)- Wetting…(cont.) • This contact angle, , results from an equilibrium involving three interfacial tensions, specially, those acting at the interfaces between the liquid and vapor phase, at the solid and liquid phases, and at the solid and vapor phases. • Certain solids are readily wet by liquid media whereas others are not. In aqueous suspension terminology, solids are said to be either hydrophilic (water loving) = lyophobic (fat hating) or hydrophobic (water hating) = lypophilic (fat loving). • Hydrophobic substances are easily wet by either water or other polar liquids; they may also greatly increase the viscosity of water suspensions.

28. (2)- Wetting …(cont.) • Hydrophilic solids usually can be incorporated into suspensions without the use of wetting agent, but hydrophobic materials are extremely difficult to disperse and frequently float on the surface of the fluid due to poor wetting of the particles or the presence of tiny air pockets. • A frequently helpful pharmaceutical technique for modifying the wetting characteristics of powders involves the use of surfactants to decrease the solid-liquid interfacial tension.

29. (2)- Wetting …(cont.) • Other materials that can be used to aid dispersion of hydrophobic solids are hydrophilic polymers such as sodium carboxymethylcellulose. • These hydrophilic agents may, if used at too high concentration, cause undesirable gelling instead of just the desired degree of viscosity or thixotropy; the latter term refers to the formation of a gel like structure which is easily broken and becomes fluid upon agitation.

30. (3)- Sedimentation (Settling) rates • Sedimentation and flocculation rates are properties of suspension systems governed by particles size, particle-particle interactions, densities of the particle and the medium, and the viscosities of the continuous phase. • In deflocculated polydispersed systems (i.e. those having many different particle sizes present). • In this case the large particles settle downward more rapidly than the smaller particles, whereas in concentrated deflocculated suspensions the larger particles exhibit hindered settling and the smallest settle more rapidly.

31. (3)- Sedimentation (Settling) rates • In flocculated suspensions, the particles are linked together into flocs which initially settle according to the size of floc and the porosity of the aggregated mass, and therefore, a clear supernatant is formed on settling.

32. (3)- Sedimentation (Settling) rates • The well known Stokes’ relation describes the sedimentation velocity of a particle in suspension: • where v = velocity of the sedimentation or rate of settling in cm/sec; • r = particle radius; • D = particle diameter in cm; • d1 and d2 = density of the particle and the liquid, respectively, in (g/cm3); • g = acceleration due to gravity (gravitational constant) = 980.7 cm/sec2; •  = the viscosity of the medium in poises.

33. (3)- Sedimentation (Settling) rates • The various parameters influencing the rate of settling are contained in the Stokes’ equation. These parameters lead to several manufacturing considerations as well as to the inclusion of certain additives to oral suspension formulations: • Reduction of particle size (Recall, however, that reducing the particle size may also promote caking.) • Solid content - recall that Stokes’ equation is based on a dilute suspension because the presence of other particles hinders settling • Increasing the density of the vehicle (additive) • Increasing the viscosity of the vehicle (within limits since the increase in viscosity also affects flow from the bottle) (additive: suspending agent or viscosity modifier) • Prevention of aggregation/caking (additives: surfactants and flocculating agents)

34. (3)- Sedimentation (Settling) rates (A) -Particle size reduction: • This is usually accomplished by dry milling prior to incorporating the dispersed phase into the vehicle: • Micropulverizers are the high-speed equipment that can rapidly, conveniently and inexpensively produce fine powders in the diameter range 10 to 50 µm. • To achieve particles less than 10 µm in diameter requires a process called jet-milling or micronizing. The particles are carried into compressed air streams where they collide with one another due to the violent turbulence and high velocities present in these systems. These collisions result in fragmentation and the resultant decrease in particle size. • Particles of extremely small dimensions can be produced by spray drying.

35. (3)- Sedimentation (Settling) rates (A) -Viscosity Modifiers: • Carboxymethylcellulose (CMC), methylcellulose, xanthan gum, and bentonite have been used to thicken the continuous phase and help to support the physical stability of the suspension. These agents are poorly absorbed from the GI tract and essentially pass through unchanged. • When polymeric substances and hydrophilic colloids are used as suspending agents, appropriate testing must be performed to ascertain that the substance does not interfere with the absorption of the drug. The usual mechanism is adsorption or sequestering of the drug which interferes with the rate and extent of absorption.

36. (3)- Sedimentation (Settling) rates (A) -Viscosity Modifiers: • To determine if the product is too viscous, the study of flow characteristics, or rheology, comes into play. Viscometers are employed which measure the relative ease or difficulty in rotating spindles through the sample medium.

37. (4)- Surface potential at a surface of particles • Both attractive and repulsive forces exist between particles in a liquid medium. The balance achieved between these opposing forces determines whether or not particles approaching each other actually make contact or repulsed at a certain distance of separation. • The attractive forces are van der Waals’ forces of London dispersion type. The repulsive forces arise from the presence of an electrical potential relative to the surrounding medium.

38. (4)- Surface potential at a surface of particles • both attractive and repulsive forces exist between particles in a liquid medium. The balance achieved between these opposing forces determines whether or not particles approaching each other actually make contact or repulsed at a certain distance of separation. • The attractive forces are van der Waals’ forces of London dispersion type. The repulsive forces arise from the presence of an electrical potential relative to the surrounding medium. • Usually particles acquire a charge as a result of (1) ionization of the molecules at the surface, (2) adsorption of ions by the particles from the surrounding liquid, and (3) a difference in the dielectric constant of the continuous phase and the dispersed particles.

39. (5)- Zeta potential (z or ) • A measurable indication of the potential existing at the surface of a particle. When the zeta potential is relatively high (25 mV or more), the repulsive electrical forces between two particles exceed the attractive London forces. • Accordingly, the particles are dispersed and said to be deflocculated. Even when brought close together by random motion or agitation, deflocculated particles resist collision due to their high surface potential. • The addition of a preferentially adsorbed ion, whose charge is opposite in sign to that on the particle, tends to neutralize the surface potential and leads to a progressive lowering of the zeta potential.

40. (5)- Zeta potential (z or ) • At some concentration of the added ions the electrical forces of repulsion are lowered sufficiently that the forces of attraction predominate. Under these conditions the particles may approach each other closely and form loose aggregates, termed flocs. • Such a system is said to be flocculated. In order to obtain a flocculated, non-caking suspension with the maximum sedimentation volume, the zeta potential must be controlled so as to lie within a certain range (generally less than 25 mV), which can be achieved by the rational use of electrolyte.

41. (6)-Flocculated Systems • When formulating suspensions, it is most important to make sure that the particles are well dispersed in the aqueous phase or other vehicle. • In this type the solid particles of dispersed phase aggregate leading to network like structure of solid particles in dispersion medium. The aggregates form no hard cake. These aggregates settle rapidly due to their size as rate of sedimentation is high and sediment formed is loose and easily redispersible.

42. (7)-Deflocculated Systems • These agents retard settling and agglomeration of the particles by functioning as an energy barrier, which minimizes interparticle attraction and ultimate flocculation. • In deflocculated system the particles are well dispersed and settle singly but more slowly than a flocculated system. The particles, however, have a tendency to form a sediment or cake that is very difficult to redisperse.

44. (8)- Quantitative Expressions of Sedimentation • The sedimentation volume, F, is the ratio of the final, or ultimate, volume of the sediment, Vu, to the original volume of the suspension, V0, before the settling. Thus, • As the volume of the suspension which appears occupied by the sediment increases, the value of F, which normally ranges from nearly 0 to 1, increases. In the system where F = 0.75, for example, 75% of the total volume in the container is apparently occupied by the loose, porous flocs forming the sediment. When F = 1, no sediment is apparent even though the system is flocculated. • This is the ideal suspension for, under these conditions, no sedimentation will occur. Caking also will be absent.

45. (8)- Quantitative Expressions of Sedimentation • Degree of flocculation: a better parameter for comparing flocculated systems is the degree of flocculation, , which relates the sedimentation volume of the flocculated suspension, F, to the sedimentation volume of the suspension when deflocculated, F. • The degree of flocculation is, therefore, an expression of the increased sediment volume resulting from flocculation. in which F is the sedimentation volume of the deflocculated suspension.

46. Some Suspension Products available in Market

47. Important Notes It is critical to add the proper amount of purified water to the product as this determines the dose of the drug in the designated volume to be administered. By using purified water instead of tap water, you avoid the introduction of contaminants to the system which could adversely affect the stability of the preparation. One advantage to these dry powder formulations is the enhanced stability provided to water-sensitive drugs during storage.

48. Administration and Counseling for Oral Suspensions • Most oral suspensions are administered by teaspoon or tablespoon. Make certain that you counsel the patient regarding which to use. • Reconstituted products are usually suspensions and an oversized bottle is necessary to allow a headspace to shake the suspension into for adequate redispersion. • Make clear to the patient that the headspace is not because they have been cheated of drug, but rather to allow room to shake the mixture.

49. Administration and Counseling for Oral Suspensions • Some patients don't understand that the medication is for oral administration. For example, make clear to the patient that the oral antibiotic suspension to treat a middle ear infection is to be taken by mouth and not placed in the ear canal. • If the medication states that the product should be refrigerated, counsel the patient to store it in the refrigerator. Some suspension and emulsion products do not require refrigeration during storage. It probably is dependent on the level of preservative present in the formulation.

50. Administration and Counseling for Oral Suspensions • Some suspensions can interfere with the bioavailability of other oral drugs. • Examples are: Cholestyramine suspension has been shown to decrease the bioavailability of warfarin, digitoxin and thyroid hormones, probably by adsorption of the drug to the suspensoid particles. • Advise the patient to stagger the administration of their oral drugs by several hours when interferences have been reported.