Outcomes of this lecture

1. Outcomes of this lecture 1- Definition and Classification of dispersed systems 2- Pharmaceutical and medical application of suspensions 3- Formulation of Suspensions 4- Suspension formulation additives 5- Stability of suspensions

2. Dispersed Systems Classification of Dipersed Systems on the basis of particle size: 1- Molecular Dispersion less than 1 nm 2- Colloidal Dispersion 1 nm to 0.5 um 3- Coarse Dispersion greater than 0.5 um

3. Types of disperse systems • A true solution - mixture of two more more components that form a homogenous molecular dispersion, i.e. a one-phase system, the composition of which can vary over a wide range. • A colloidal dispersion - represents a system havin a particle size intermediate between that of a true solution and a coarse dispersion, roughly 10Å to 5000Å (0.1mm = 1000Å) • A coarse dispersion the diameter of the particles in emulsions and suspensions for the most part being larger than 0.1mm(1000Å).

4. Pharmaceutical dosage form of Coarse Dispersion: 1- Suspensions 2- Emulsions 3- Semisolids

5. Suspensions Definition: A dispersion of finely divided, insoluble solid particles (the disperse phase) in a fluid or liquid medium (the dispersion medium).

6. Suspensions are heterogeneous system consisting of two phases: • Continuous or external phase; is generally a liquid or semi solid, • Dispersed or internal phase; is made up of particulate matter, that is essentially insoluble in, but dispersed throughout, the continuous phase.

7. Size of suspended particles: Particles with diameters greater than 0.5 micron(human hair has a diameter of about 75 micron). Systems with particles smaller than 0.5 micron are considered to be colloidal.

8. Pharmaceutical Advantages of suspensions: • To administer an insoluble compound as a liquid. • To lessen the unpleasant taste of an insoluble compound by: • formulating a vehicle in which the drug is not soluble • using an insoluble form of the drug (ie. salt form or prodrug) • adsorbing the drug onto an insoluble carrier • To modify the release rate of the drug. • To improve the stability by reducing the fraction of drug in solution.

9. Pharmaceutical and medical application of suspensions: 1- Oral dosage forms; amoxicilin, ampicilin, AlMg sulphate, … 2- Topical dosage forms; dermatologic materials; zinc cream, calamine lotion, … 3- Parenteral dosage forms, dexamethazone, …. 4- Ophtalmic dosage forms; eye drops; hydrocortisone, neomycin,… 5- Inhaler dosage forms; aerosols; antiseptics, antibiotics, dermatological steroids. 6- Vaccines; cholera, diphtheria, tetanus vaccines. 7- Diagnostic products; some X-ray contrast media, barium sulphate,…

10. Physical properties of suspensions: • The suspended material should not settle rapidly. • The settled particle must not form a hard cake. • The settled particle should be easily redispersed and resuspended. • The suspension must have optimum viscosity. • The suspended particles should be small and uniformly sized.

11. Formulation of Suspensions: Theoretic Consideration; • Select appropriate ingredients • Use appropriate mixing and milling equipments • Understanding concepts of Particle size, wetting, Particle interaction, Electrokinetics, Aggregation, Sedimentation

12. Particle Size Control; Before suspension formulation: It is necessary to insure that the drug and ingredients particles are suitably subdivided prior to formulation. • Small particles have retarded sedimentation rate • Large particles impart a gritty texture

13. Particle Size Control; After suspension formulation: There is possibility of crystal growth which occurs on storage. • In change of temperature for dissolving of drug and ingredients • In use of different polymorphic forms of a drug

14. Wetting; • Since, 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 in achieving this end. • In strong affinity between a liquid and a solid, the liquid easily forms a film over the surface of the solid (wetting will happen easily). • In weak or nonexistent affinity, the liquid has difficulty displacing the air or other substances surrounding the solid (importance of contact angle).

15. Solid nature in aqueous suspension: • Hydrophilic (Lyophilic or solvent-loving) which are easily wet by water or other polar liquids, so there is no need for wetting agents. • Hydrophobic (Lyophobic) which repel water but can usually be wetted by non-polar liquids

16. Mechanism of wetting: To ensure adequate wetting the interfacial tension between the solid and the liquid must be reduced so that the adsorbed air is displaced from the solid surfaces by the liquid.

17. Wetting agents: A) Surface active agents • The hydrocarbon chains would be adsorbed by the hydrophobic particle surfaces while the polar groups would project into the aqueous medium becoming hydrated. • Surfactants possessing an HLB value of between about 7 and 9 would be suitable for use as wetting agents.

18. Most surfactants are used at concentrations of up to about 0.1% as wetting agents includes: • For oral use: polysorbates (Tweens) and sorbitan esters (Spans). • For external application: sodium lauryl sulphate, sodium dioctylsulphosuccinate and quillaia extract. • For parenteral administration: polysorbates, polyoxyethylen/polyoxypropylene copolymers (Pluronices) and lecithin.

19. * Disadvantages of surfactants wetting agent: a) Excessive foaming b) Possibility of formation of a deflocculated system

20. B) Hydrophilic colloids - Behave as protective colloids by coating the solid hydrophobic particles with a multimolecular layer and impart a hydrophilic character to the solid and thus promote wetting. • Most Hydrophilic colloids are used as wetting agents includes: = Acacia = Alginates = Cellulose derivatives = Bentonite = Colloidal silica = Tragacanth

21. C) Solvents • Materials such as alcohol, glycerol and glycols which are water miscible will reduce the liquid/air interfacial tension. • The solvent will penetrate the loose agglomerates of powder displacing the air from the pores of the individual particles thus enabling wetting to occur by the dispersion medium.

22. D) Other Materials include: • Hydrophilic polymers such as carboxymethylcellulose • Aluminum-magnesium silicates • lanolin derivatives

23. Solid Particle Interactions and behavior in suspensions: • Lyophobic (hydrophobic) = nonwetting, sensitive to the addition of salts • Lyophilic (hydrophilic) = wetting, not sensitive to the addition of salts The behavioral difference between these classes is their sensitivity to the presence of electrolytes. The stability of lyophobic particles will reduce by lowering the repulsive potential of the electerochemical double layer or by decreasing the degree of hydration.

24. Stages of suspension preparation: • Change of solid particle size to suitable size • Wetting of solid particles • Adding other ingredients such as flocculating agents, dispersants, thickeners, preservatives, flavoring, …

25. preparation of a suspension • Wetting and Dispersion of the Active Ingredient. • Stabilization of Dispersed Solid. • Preparation of the Vehicle. • Addition and Dispersion of Active Ingredient in Vehicle. • Addition of Remaining Ingredients and Final Mixing.

26. Suspension Formation: 1- Precipitation Methods: A) Organic solvent precipitation: Water-insoluble drugs can be precipitated by dissolving them in water-miscible organic solvents and then adding the organic phase to distilled water under standard conditions. Ethanol, methanol, propylene glycol, and polyethylene glycol are the example of organic solvents.

27. Important considerations in this method are: • Particle size control • Correct polymorphic or hydrate form of the crystal of solid particles which obtained from this method. For example precipitation of prednisolone in aqueous methanol gives sesquihydrate product, but in aqueous acetone gives metastable anhydrous crystalline product which is easily suspended in water.

28. Influence of the solvent on crystal characteristic. • Possible preparation under sterile conditions • Inherent solvent entrapment and subsequent toxicity • The volume ratio of the organic to the aqueous phase • Rate and method of addition of one phase to the other • Temperature control (cooling rate and drying conditions) • Method of drying the precipitate (forced air, vacuum, freeze drying) • The washing of the precipitate

29. B) Precipitation effected by changing the pH of the medium This technique is only applicable to those drugs in which solubility is dependent on the pH value. For example Estradiol suspensions can be prepared by changing the PH of its aqueous solution; estradiol is readily soluble in such alkali as potassium or sodium hydroxide solutions. If a concentrated solution of estradiol is thus prepared and added to weakly acid solution of hydrochloric, citric, or acetic acids, the estradiol is precipitated in fine state of subdivision. Insulin suspensions and Adrenocorticotropin zinc suspensions are prepared in a similar manner.

30. In this method the type of crystal or polymorphic form depends on some factors such as: • The concentrations of acid and base • The degree and type of fluid shear imparted to the system.

31. C) Double decomposition method This method involves only simple chemical reaction, although some of the aforementioned physical factors also come into play. For example suspension of zinc polysulfide will prepare by mixing zinc sulfite and sulfurated potash solution.

32. 2) Dispersion Methods: • A suspension is prepared on the small scale by grinding or levigating the insoluble material in the mortar to a smooth paste with a vehicle containing the dispersion stabilizer and gradually adding the remainder of the liquid phase in which any soluble drugs may be dissolved. • The slurry is transferred to a graduate, the mortar is rinsed with successive portions of the vehicle, and the dispersion is finally brought to the final volume. • On a large scale, dispersion of solids in liquids is accomplished by the use of colloid mills. Dough mixers, pony mixers, and similar apparatus are also employed.

33. Flocculating Agents: 1) Electrolytes: Addition of an inorganic electrolyte to an aqueous suspension will alter the zeta potential of the dispersed particles. If this value is lowered sufficiently then flocculation will occur. The ability of an electrolyte to flocculate hydrophobic particles depends on the valency of its counter ions (monovalent, divalent or trivalent ions). • The most widely used electrolytes as flocculating agents include: The sodium salts of acetates, phosphates and citrates

34. 2) Surfactants: Ionic surfactants may cause flocculation by neutralization of the charge on each particle, Non-ionic surfactants will have little effect on the charge density of a particle but may, because of their linear configurations, adsorb on to more than one particle thus forming a loose flocculated structure.

35. 3) Polymeric flocculating agents: The linear branched chain molecules will form a gel-like network within the system and become adsorbed on to the surfaces of the dispersed particles thus holding them in a flocculated state. The most widely used polymers as flocculating agents include: Starch, alginates, cellulose derivatives, tragacanth, carbomers and silicates

36. Viscosity modifiers of suspensions: 1) Acacia gum (gum Arabic) • This natural gum is used as a thickening agent • Its value as a suspending agent is largely due to its action as a protective colloid • It is not very satisfactory as a suspending agent for dense powders ( It is often combined with tragacanth, starch and sucrose)

37. Disadvantages of Acacia: • Acacia mucilage becomes acidic on storage due to enzyme activity • Acacia mucilage contains an oxidize enzyme which may cause deterioration of active agents which are susceptible to oxidation • Because of its stickiness it is rarely used in preparations for external use.

38. 2) Tragacanth • Its thixotropic and pseudo plastic properties make it better thickening agent than acacia • It will form viscous aqueous solution • It can be used for internal and external products • It is stable over a pH range of 4-7.5

39. Disadvantages of tragacanth: • It takes several days to hydrate fully after disperssion in water, so the maximum viscosity will achieved after this time • Its viscosity is also affected by heat

40. 3) Alginates • They are most viscous immediately after preparation • They exhibit a maximum viscosity over a pH range of 5-9 • Sodium alginate (Manucol) is the most widely used material in this class

41. Disadvantages of Alginates: • Alginate mucilage must not be heated above 60 °C as depolymerization occurs with a consequent loose in viscosity • At low pH they will precipitate • incompatible with cationic materials and heavy metals

42. 4) Starch * Rarely used on its own as a suspending agent * It is one of the constituents of Compound Tragacanth Powder BP * It can be used with sodium carboxymethylcellulose * Sodium starch glycollate (Explotab, Primojel) is used in the preparation of suspensions

43. 5) Methylcellulose (Celacol): • This is a semisynthetic polysaccharide and is produced by the methylation of cellulose • Several grades are available depending on their degree of methylation and on the chain length • The longer the chain the more viscous is its solution • It is more soluble in cold water than in hot water

44. It is stable over a wide range of pH, from 3 to 11 • It is non-ionic and are compatible with many ionic derivatives • On heating become progressively hydrated an eventually gel at about 50 C and on cooling the original form is regained

45. 6) Hydroxyethylcellulose (Natrosol 250) • It exhibits the same properties as methylcellulose • It is soluble in both hot and cold water • It will not form gel on heating

46. 7) Sodium carboxymethylcellulose (SCMC) (Edifas, Cellosize) • It is widely used at concentrations up to 1% in products for oral, parenteral or external use. • Produces clear solutions in both hot and cold water • It is stable over a pH range of about 5-10

47. Disadvantages of SCMC • It is incompatible with polyvalent cations • Will precipitate at low pH • Heat will reduce the viscosity

48. 8) Microcrystalline cellulose (Avicel) • It is a widely used suspending agent often with 8 to 11% SCMCadded to aid its dispersion and to act as a protective colloid • It will disperse readily in water (but are not soluble) to produce thixotropic gels

49. 9) Bentonite • It hydrate rapidly, absorbing up to 12 times its weight of water particularly at elevated temperatures • The gel formed is thixotropic and therefore has useful suspending properties • It is used at concentration of up to 2 or 3% in preparations for external use • It may contain pathogenic spores (sterilization needed)

50. 10) Magnesium aluminium silicate (Veegum) • It exhibits the same properties as Bentonite • It can be used both internally and externally at concentration of up to 5% • It is stable over a pH range of 3.5-11%