CHEMICAL INSTABILITY

Chapter 27suspensions & emulsionsSubgroup 9 3APharmacyCaringal, Ebuengan, Montenegro, & Uy

1INTRODUCTIONSuspensiondispersion of finely divided, insoluble solid particles (dispersed phase) in a fluid (dispersion medium or continuous phase); solid in liquid suspension in which particles are above the colloidal size (1um)

Emulsionmixture of two immiscible liquids, one of which is finely subdivided and uniformly distributed as droplets throughout the otherdispersed liquid (internal phase) usually consists of globules of diameters down to 0.1 um which are distributed within the external or continuous phase

2PHYSICAL PROPERTIES OF WELL-FORMULATED SUSPENSIONS AND EMULSIONSProduct must remain sufficiently homogenous for at least the period between shaking the container and removing the required amountSediment or creaming produced on storage (if any) must easily be resuspended by moderate agitation of the containerProduct may need to be thickened in order to reduce rate of the particles or the creaming rate of oil globulesResulting viscosity must not be so high that removal of the product from the container and transfer to the site of application are difficultAny suspended particles should be small and uniformly sized in order to give a smooth, elegant product, free from gritty texture

3PHARMACEUTICAL APPLICATIONS OF SUSPENSIONSAs oral drug delivery systemsIntended for those having difficulty swallowing solid dosage formsTaste of most drugs is less noticeable in insoluble form rather than in solution form

For topical administrationCan be in the form of lotion, pastes, and creams

For parenteral use and inhalationParenteral: Employed to control rate of absorption of drug and its duration of activity Ex: cholera vaccine, adsorbed diphtheria and tetanus vaccine, barium sulfate, and propyliodoneInhalation:Since volatile component is lost very rapidly from solution, a more prolonged release of volatile components can be obtained prior to the preparation of suspension

4SOLUBILITY AND STABILITY CONSIDERATIONSIf drug is poorly soluble in a suitable solvent, then formulation as suspension is usually required It may be possible to synthesize an insoluble derivative that can be formulated as suspensionProlonged contact between the solid drug particles and the dispersion medium can be considerably reduced by preparing the suspension immediately prior to issue to the patient

5FORMULATION OF SUSPENSIONS6PARTICLE SIZE CONTROLDrug must be of fine particle size prior to formulation to ensure slow rate of sedimentation of suspended particles because larger particles (> 5um diameter) will impart gritty texture and may cause irritation if injected or instilled into the eyesSolubility of drug may increase as the temperature rises but on cooling, the drug will crystallize out which is a particular problem with slightly soluble drugs (ex: paracetamol)Inclusion of surface active agents or polymeric colloids which adsorb on to the surface of each particle, may help to prevent crystal growth

7WETTING AGENTSCommonly Used Wetting AgentsSURFACE-ACTIVE AGENTSHLB value between 7 and 9 with concentrations up to 0.1% Main surfactants used: polysorbates, some poloxamers (polyoxyethylene or polyoxypropylene copolymers), and lecithinEx: polysorbates (Tweens) and sorbitan esters (Spans) for oral use; sodium lauryl sulfate and sodium dioctylsulfosuccinate for external applicationDisadvantages: excessive foaming and possible formation of a deflocculated system

HYDROPHILIC COLLOIDSBehave as protective colloids Ex: acacia, bentonite, tragacanth, alginates, xanthan gum, and cellulose derivativesDisadvantage: may produce a deflocculated system if used at low concentrations

SOLVENTSWater miscible and reduce liquid/air interfacial tensionPenetrate the loose agglomerates of powder, displacing air from the pores of individual particlesEx: alcohol, glycerol, and glycols

8FLOCCULATED VS DEFLOCCULATED SYSTEMSDEFLOCCULATED SYSTEMSHave the advantage of a slow sedimentation rate thereby enabling a uniform dose to be taken from the containerHowever, when settling occurs, the sediment is compacted and is difficult to redisperse; this phenomenon is referred to as caking or claying

FLOCCULATED SYSTEMSForm loose sediments which are easily redispersible However, the sedimentation rate is fast and posts a danger of inaccurate dose being administeredProduct looks inelegant

9CONTROLLED FLOCCULATIONusually achieved by a combination of particle size control, the use of electrolytes to control zeta potential, and the addition of polymers to enable crosslinking to occur between particlesflocculating agents are used to convert a deflocculated to a partially flocculated state by addition of flocculating agents

10FLOCCULATING AGENTSCommonly Used Flocculating AgentsELECTROLYTESAlter zeta potential of the dispersed particles; represented by Schultz-HardyMost widely used: sodium salts of acetates, phosphates, and citrates

SURFACTANTSIon surfactants cause flocculation by neutralizing the charge on each particle thus resulting in a deflocculated systemNon-ionic surfactants have negligible effect on charge density but may adsorb onto more than one particle thereby forming a loose flocculated structure

POLYMERIC FLOCCULATING AGENTSHas linear branched-chain molecules that 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 stateEx: starch, alginates, cellulose derivatives, tragacanth, carbomers, and silicates

11RHEOLOGY OF SUSPENSIONSExhibit a high apparent viscosity at low rates of shear so that on storage, the suspended particles would either settle slowly or preferably remain permanently suspendedAt higher rates of shear, the apparent viscosity should fall sufficiently for the product to be poured easily from its containerIf used externally, the product must spread easily without excessive dragging but must not be so fluid that it runs off the skin surfaceIf intended for injection, the product should pass easily through a hypodermic needle with only moderate pressure applied to the syringe plunger

A flocculated system partially fulfills these criteria since it exhibits a pseudoplastic or plastic behavior whereas, a deflocculated system exhibit Newtonian behavior and even dilatancy12Viscosity modifiers13POLYSACCHARIDESExamples of Polysaccharides UsedACACIAOften used as suspending agent for extemporaneously prepared suspensions due to its action as a protective colloid; not a good thickening agentUseful for preparations containing tinctures of resinous materials that precipitate on addition to water; not very effective for dense powders and is often combined with other thickeners

TRAGACANTHThixotropic and pseudoplastic properties make it better thickening agent and can be used for both internal and external products; used for extemporaneous preparation of suspensions with short shelf life; stable over pH 4-7.5

ALGINATESPolymer of D-mannuronic acid and is prepared from kelp; suspending properties similar to tragacanth; not be heated above 60C; exhibit maximum viscosity over pH 5-9 and at low pH the acid is precipitatedSodium alginate (Manucol) is most widely used but is incompatible with cationic materials

STARCH Rarely used on its own suspending agent but is one of the constituents of compound tragacanth powder; can be used with carmellose sodium

XANTHAN GUMAnionic heteroplysaccharide produced by Xanthomonas campestris on corn sugars; very soluble in cold water; one of the most widely used thickening agents for extemporaneous preparation of suspension for oral use; used in concentrations up to 2% and stable over a wide pH range

14WATER-SOLUBLE CELLULOSESExamples of Water-soluble Celluloses UsedMETHYLCELLULOSE (Celacol, Methocel)Semi-synthetic polysaccharide of general formula : (C6H7O2(OH2)OCH3)nMore soluble in cold water; often dispersed in warm water and on cooling with constant stirring, a clear or opalescent viscous solution is producedNon-ionic, stable over a wide pH range and compatible with many ionic additives

HYDROXYETHYL- CELLULOSE (Natrasol)Has hydroxyethyl instead of methyl groups attached to the cellulose chain; soluble both on hot and cold water and do not gel on heating15CHEMICAL INSTABILITY OF EMULSIONS16Ionic emulsifying agents are usually incompatible with materials of opposite charge. Anionic and cationic emulgents are mutually incompatible.Electrolyte influence the stability of an emulsion by reducing the energy of interaction between adjacent globules and salting-out effectPhase inversion may occur rather than demulsification.Emulgents may be precipitated by the addition of materials in which they are insoluble. Changes in pH may also lead to the breaking of emulsions

17OXIDATIONOils and fats is susceptible to oxidation by atmospheric oxygen or by the action of microorganisms. Manifested by the formation of degradation products of unpleasant odour and taste. Occur with certain emulsifying agents such as wool fat or wool alcohols.To control oxidation of:Microbiological origin- use of antimicrobial preservatives Atmospheric oxidation- use of reducing agents/antioxidants 18MICROBIAL CONTAMINATIONContamination of emulsions by microorganisms can adversely affect the physicochemical properties of the product which causes:Gas productionColour and odour changesHydrolysis of fats and oilspH changes in the aqueous phasebreaking of the emulsion19MICROBIAL CONTAMINATIONFungi and bacteria multiply readily in the aqueous phase of an emulsion at room temp.Moulds tolerate a wide pH range.Hydrophilic colloids provide a suitable nutritive mediumEmulgents from natural sources may introduce heave contamination into products.Bacteria can reproduce in resin beds.Oil-in-water emulsions are more susceptible to microbial spoilage.Antimicrobial agent is included to prevent growth of any microorganisms that may contaminate the product.20ADVERSE STORAGE CONDITIONSCause emulsion instability.Increase in temperature cause:Increase in rate of creaming, owing to a fall in apparent viscosity of the continuous phase.Increase kinetic motion. Disperse phase will enable the energy barrier to be easily surmounted and increase number of collisions between globules.Emulgent will result in a more expanded monolayer leading to coalescence.Certain macromolecular emulsifying agents may be coagulated.21ADVERSE STORAGE CONDITIONSFreezing of the aqueous phase will:Produce ice crystals that may exert unusual pressures Dissolved electrolyte may concentrate in the unfrozen water affecting charge density on globules.Certain emulgents may also precipitate at low temperatures.Must be protected from the ingress of microorganisms during manufacture, storage and use, and contain adequate preservatives.22CLASSIFICATION OF EMULSIFYING AGENTS Synthetic/ Semi-synthetic surface-active agents Naturally occurring materials and their derivatives

SYNTHETIC and SEMI-SYNTHETIC SURFACE ACTIVE AGENTS-depend on their ionization in aqueous solutions:

1.) AnionicAlkali metal and Ammonium groupsSoaps of Divalent and Trivalent MetalsAmine soapsSulfated and Sulfonated Compounds

2.) CationicQuaternary ammonium compounds

3.) Non-IonicGlycol and Glycerol EstersSorbitan EstersFatty alcohol polyglycol estersFatty acid polyglycol estersPoloxalkolsHigher Fatty alchols

4.) AmpothericNATURALLY OCCURING MATERIALS AND DERIVATIVES

Natural Polysaccharides1.) AcaciaSemi-synthetic Polysaccharides 1.) Methylcellulose2.) Carmellose SodiumSterol-containing substances 1.) Beeswax2.) Wool fat3.) Wool alcohols

PHYSICAL STABILITY OF SUSPENSIONS PHYSICAL STABILITY OF SUSPENSIONS are normally assessed by:

- Measurement of its rate of sedimentation- Final volume or height of sediment- Ease of dispersionSTABILITY TESTING OF EMULSIONS30METHODS OF ASSESSING STABILITYMacroscopic examinationExamination of the degree of creaming or coalescenceRatio of the volume of the creamed part and the total volume

Globule size analysisCoalescence causes increase is mean globule size (decrease in globule numbers)Rates of coalescence by measuring changing in globule size and number.Microscopic examination, electronic particle counting devices (ex. Coulter counter) and laser diffraction sizing are most widely used.

31METHODS OF ASSESSING STABILITYViscosity changesVariation in globule size or number, or in the orientation or migration of emulsifier.To compare the relative stabilities of similar products, it is necessary to speed up the processes of creaming and coalescence.

Accelerated stability testTo assess physical stability, macroscopic examination and measurement of apparent viscosity are of value.32ACCELERATED STABILITY TESTSStorage at adverse temperaturesExaggerating temperature fluctuations enable to compare physical stabilities.Temperature cycles of storage for several hours followed by refrigeration or freezing until instability becomes evident.Useful for the assessment of crystal growth in suspensions.Measurement of particle size- laser diffraction or Coulter counter.Suspension must be deflocculated so that individual particle is measured rather than each floccule.

33ACCELERATED STABILITY TESTSCentrifugationSuitable method for artificially increasing the rate of sedimentation.Destroy the structure of a flocculated system that remains intact under normal storage conditions.Products particularly if used at speeds no faster than 200-300rpm.34ACCELERATED STABILITY TESTSRheological assessmentHigh shear rates involved destroy the structure of a suspension or emulsion.Very low shear rates (Ex. Brookfield viscometer with Helipath stand) can give change in the structure of the system after various storage times.Measurement of the residual apparent viscosity after breaking down the structure of the suspension can be used as a routine quality control procedure after manufacture.

35MANUFACTURE OF SUSPENSIONS36MANUFACTURE OF SUSPENSIONSPowder to be suspended must initially be in a suitably fine degree of subdivision in order to ensure adequate bioavailability, minimum sedimentation rate and impalpability.For extemporaneous preparation on small scale:The powdered drug can be mixed with the suspending agent and some of the vehicle using a pestle and mortar. May also include a wetting agent to aid dispersion. Other soluble ingredients should be dissolved in another portion of the vehicle, mixed with the concentrated suspension and then made up to volume.

37MANUFACTURE OF SUSPENSIONSFor larger scale:Adding material slowly to the vehicle while mixing.Mixers can either be an impeller type of blender or a turbine mixer.Drug to be suspended is then added along with the wetting agent.Other ingredients dissolved in a portion of the vehicle are added and the whole made up to volume.Homogenization ensures complete dispersion and produce smooth and elegant preparation.38MANUFACTURE OF SUSPENSIONSIt is also possible to suspend an insoluble drug by precipitating it from a solution. used if the drug is required to be sterile but is degraded by heat or irradiation.By double decomposition or by altering the pH of solution, or by precipitating the drug from a water-miscible solvent on the addition of waterUsed if the drug is required to be sterile but is degraded by heat or irradiation.sterilized by filtration and then precipitated to form a suspension.39MANUFACTURE OF EMULSIONS40MANUFACTURE OF EMULSIONSSmaller the globules, slower rate of creaming.A mean globule diameter of between 0.5 and 2.5um.Choice of equipment depends on the intensity of shearing required, volume and viscosity and interfacial tensionSurfactants, reduce interfacial tension, aid the process of emulsification and promote emulsion stability.Homogenizer can reduce globule size still further.More intense rate of shearing can be achieved using a turbine mixer (ex. Silverson mixer-homogenizer) 41MANUFACTURE OF EMULSIONS2 immiscible liquids in ultrasonic vibrations produce alternate regions of compression and rarefactionCavities formed in rarefaction cause emulsification.Frequency of vibration is usually produced electronically.Mechanical methods are limited to small-scale production.Colloid mills are for preparation on a continuous basis.Intense shearing between rotor and stator= small globuleOther ingredients are dissolved prior to mixing particularly when making w/o emulsions.42MANUFACTURE OF EMULSIONSOily ingredients must be melted before mixing.Heating of aqueous phase to same temperature avoid premature solidification of the oil phase.Stirring during the cooling process to avoid demulsification.Volatile ingredients (flavours, perfumes) must be fluid and are added after emulsion has cooled Alcoholic solutions or electrolytes are diluted before adding slowly and with constant mixing.

43RELEASE OF DRUGS FROM SUSPENSION AND EMULSION FORMULATIONS44Drug release from SUSPENSIONSDrug is presented to the gastrointestinal fluids in a finely divided form. Dissolution begins immediately. The rate of absorption of drug into blood stream is faster than solid dosageThe more viscous, the slower the release of drug.

45Drug release from SUSPENSIONSDrugs are often formulated as suspensions for intramuscular, intraarticular or subcutaneous injection in order to prolong drug release which is often termed as depot therapy.Drug release occur more slowly if drug is suspended in an oil that, after injection, remain as a globule, providing a minimal area of contact with tissue fluid.Sustained-release suspensions are less common but example is the use of pennkinetic system.

46Drug release from EMULSIONSOral, rectal and topical administration of oils and oil-soluble drugs.Lipid emulsions are widely used for intravenous feeding, choice of emulgent is very limited and globule size must be kept below 4 micrometre diameter to avoid formation of emboli.Can also be used as a sustained-release dosage form.Intramuscular injection of certain water-soluble vaccines as w/o emulsions provide a slow release of the antigen and result in greater antibody response (longer-lasting immunity)

47Drug release from EMULSIONSRate or release depend on o/w partition coefficient of drug and rate of diffusion across oil phase.w/o/w emulsion is used for prolonged release of drugs that are incorporated into the internal aqueous phase.o/w/o emulsions are potential sustained-release bases.Multiple emulsions tend to be stable only for a relatively short time but polymers are use as alternatives to improve their physical stability.

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