pharmaceutical SUSPENSIONS

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overview on pharmaceutical suspensions

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PHARMACEUTICAL SUSPENSIONS : 

By R.NAVEEN KUMAR. Roll No: 04, Shift - I (M.PHARMACY). PHARMACEUTICAL TECHNOLOGY. SRINIVASA RAO COLLEGE OF PHARMACY. SUSPENSIONS PHARMACEUTICAL SUSPENSIONS

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SUSPENSIONS Definition. Classification. Advantages & disadvantages. Applications. Theoretic consideration of suspensions. Sedimentation Brownian movement Electrokinetic properties CONTENTS

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SUSPENSIONS Formulation of suspensions Packing of suspensions Storage requirement & labelling Evaluation of suspension Dissolution study of suspensions Innovation of suspensions 3

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SUSPENSIONS WHAT ARE SUSPENSIONS? WHY WE ARE USING SUSPENSIONS? 4

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SUSPENSIONS 5 The term " Disperse System " refers to a system in which one substance ( The Dispersed Phase ) is distributed, in discrete units, throughout a second substance ( the continuous Phase ). Each phase can exist in solid, liquid , or gaseous state . Suspensions are heterogenous system consisting of 2 phases. DISPERSE SYSTEM

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SUSPENSIONS 6 A solid in liquid dispersion in which the particles are of colloidal size. DISPERSE SYSTEM DISPERSED MEDIUM DISPERSED PHASE Aqueous oily liquid Insoluble solid

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SUSPENSIONS Definition A Pharmaceutical suspension is a coarse dispersion in which internal phase ( therapeutically active ingredient )is dispersed uniformly throughout the external phase. 7

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SUSPENSIONS The internal phase consisting of insoluble solid particles having a range of size( 0.5 to 5 microns ) which is maintained uniformly through out the suspending vehicle with aid of single or combination of suspending agent. The external phase ( suspending medium ) is generally aqueous in some instance, may be an organic or oily liquid for non oral use. 8

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SUSPENSIONS The reasons for the formulation of a pharmaceutical suspension: -- when the drug is insoluble in the delivery vehicle. –To mask the bitter taste of the drug. –To increase drug stability. –To achieve controlled/sustained drug release. 9

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SUSPENSIONS 1. Antacid oral suspensions 2. Antibacterial oral suspension 3. Dry powders for oral suspension (antibiotic) 4. Analgesic oral suspension 5. Anthelmentic oral suspension 6. Anticonvulsant oral suspension 7. Antifungal oral suspension SOME MARKETED SUSPENSIONS SOME PHARMACEUTICAL SUSPENSIONS 10

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SUSPENSIONS Oral suspension eg: Paracetamol suspension antacids, Tetracycline HCl. Externally applied suspension eg :Calamine lotion. Parenteral suspension eg: Procaine penicillin G Insulin Zinc Suspension Classification Based On General Classes 11

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SUSPENSIONS Based on Proportion of Solid Particles Dilute suspension (2 to10%w/v solid) Eg: cortisone acetate, predinisolone acetate Concentrated suspension (50%w/v solid) Eg: zinc oxide suspension 12

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SUSPENSIONS Based on Electrokinetic Nature of Solid Particles Flocculated suspension Deflocculated suspension 13

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SUSPENSIONS Based on Size of Solid Particles Colloidal suspensions (< 1 micron) Suspensions having particle sizes of suspended solid less than about 1micron in size are called as colloidal suspensions. 14

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SUSPENSIONS Coarse suspensions (>1 micron) Suspensions having particle sizes of greater than about 1micron in diameter are called as coarse suspensions. Suspensions are the biphasic colloidal dispersions of nanosized drug particles stabilized by surfactants. Size of the drug particles is less than 1mm. Nano suspensions (10 ng) Coarse dispersion Barium sulphate 15

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SUSPENSIONS Advantages And Disadvantages . Suspension can improve chemical stability of certain drug. E.g. Procaine penicillin G. Drug in suspension exhibits higher rate of bioavailability than other dosage forms. Solution > Suspension > Capsule > Compressed Tablet > Coated tablet Duration and onset of action can be controlled. E.g. Protamine Zinc-Insulin suspension. Suspension can mask the unpleasant/ bitter taste of drug. E.g. Chloramphenicol 16 Advantages

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SUSPENSIONS Physical stability , sedimentation and compaction can causes problems. It is bulky sufficient care must be taken during handling and transport. It is difficult to formulate. Uniform and accurate dose can not be achieved unless suspension are packed in unit dosage form. 17 Disadvantages

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SUSPENSIONS Applications Suspension is usually applicable for drug which is insoluble (or ) poorly soluble. E.g. Prednisolone suspension To prevent degradation of drug or to improve stability of drug. E.g. Oxy tetracycline suspension To mask the taste of bitter of unpleasant drug . E.g. Chloramphenicol palmitate suspension Suspension of drug can be formulated for topical application e.g. Calamine lotion 18

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SUSPENSIONS Suspension can be formulated for parentral application in order to control rate of drug absorption . E.g. penicillin procaine Vaccines as a immunizing agent are often formulated as suspension. E.g. Cholera vaccine X-ray contrast agent are also formulated as suspension . eg: Barium sulphate for examination of alimentary tract. 19

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SUSPENSIONS The suspended particles should not settle rapidly and sediment produced, must be easily re-suspended by the use of moderate amount of shaking . It should be easy to pour yet not watery and no grittiness. It should have pleasing odour , colour and palatability . Good syringeability . It should be physically,chemically and microbiologically stable . Parenteral /Ophthalmic suspension should be sterilizable . Features Desired In Pharmaceutical Suspensions 20

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SUSPENSIONS THEORITIC CONSIDERATION OF SUSPENSIONS A knowledge of the theoretic considerations pertaining to suspension s technology ultimately help formulator to select ingredients that are Appropriate for suspension preparation That available for milling Mixing equipment 21

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SUSPENSIONS Some theoretic considerations are : Particle size control. Wetting Sedimentation Brownian movement Electokinetic Aggregation 22

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SUSPENSIONS 23 Particle size control : - Particle size of any suspension is critical and must be reduced within the range . -Too large or too small particles should be avoided. Larger particles will: settle faster at the bottom of the container particles > 5 um impart a gritty texture to the product and also cause irritation if injected or instilled to the eye particles > 25 um may block the needle - Too fine particles will easily form hard cake at the bottom of the container .

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SUSPENSIONS 24 Wetting of the particles Hydrophilic materials (talc, ZnO, Mg 2 CO 3 ) are easily wetted by water while hydrophobic materials (sulphur , charcoal) are not due to the layer of adsorbed air on the surface. Thus, the particles, even high density, float on the surface of the liquid until the layer of air is displaced completely. The use of wetting agent allows removing this air from the surface and to easy penetration of the vehicle into the pores. However hydrophobic materials are easily wetted by non-polar liquids.

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SUSPENSIONS THEORY OF SEDIMENTATION SEDIMENTATION : Sedimentation means settling of particle (or) floccules occur under gravitational force in liquid dosage form. 25

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SUSPENSIONS 2.1. Velocity of sedimentation expressed by Stoke’s equation Where, d = Diameterof particle r = radius of particle v sed. = sedimentation velocity in cm / sec ρ s = density of disperse phase ρ o = density of disperse media g = acceleration due to gravity η o = viscosity of disperse medium in poise 26

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SUSPENSIONS Limitation Of Stoke’s Equation . Stoke's equation applies only to: Spherical particles in a very dilute suspension (0.5 to 2 gm per 100 ml) Particles which freely settle without collision . Particles with no physical or chemical attraction. 27

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SUSPENSIONS Sedimentation Parameters 28 Sedimentation volume (F) or height (H) for flocculated suspensions: Definition: Sedimentation volume is a ratio of the ultimate volume of sediment (Vu) to the original volume of sediment (VO) before settling. F = V u / VO Where, Vu = final or ultimate volume of sediment VO = original volume of suspension before settling

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SUSPENSIONS 29 F has values ranging from less than one to greater than one. When F < 1 Vu < Vo When F =1 Vu = Vo The system is in flocculated equilibrium and show no clear supernatant on standing. When F > 1 Vu > Vo Sediment volume is greater than the original volume due to the network of flocs formed in the suspension and so loose and fluffy sediment

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SUSPENSIONS The sedimentation volume gives only a qualitative account of flocculation . Fig : Suspensions quantified by sedimentation volume (f) 30

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SUSPENSIONS 31 Degree of flocculation ( β) It is the ratio of the sedimentation volume of the flocculated suspension ,F , to the sedimentation volume of the deflocculated suspension, F∞ ß = F / F∞ (Vu/Vo) flocculated ß = -------------------- (Vu/Vo) deflocculated The minimum value of ß is 1,when flocculated suspension sedimentation volume is equal to the sedimentation volume of deflocculated suspension.

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SUSPENSIONS . 2.Brownian Movement (Drunken walk) Brownian movement of particle prevents sedimentation by keeping the dispersed material in random motion. Brownian movement depends on the density of dispersed phase and the density and viscosity of the disperse medium . 32 The kinetic bombardment of the particles by the molecules of the suspending medium will keep the particles suspending, provided that their size is below critical radius (r).

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SUSPENSIONS Brownian movement can be observed , If particle size is about 2 to 5mm, When the density of particle & viscosity of medium are favorable. 33

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SUSPENSIONS Brownian motion is given by equation : Where, R = gas constant T = temp. in degree Kelvin N = Avogadro’s number η = viscosity of medium t = time r = radius of the particle 34

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SUSPENSIONS 3.Electro kinetic Properties Zeta Potential The zeta potential is defined as the difference in potential between the surface of the tightly bound layer (shear plane) and electro-neutral region of the solution. 35

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SUSPENSIONS b As the potential drops off rapidly at first, followed more gradual decrease as the distance from the surface increases. This is because the counter ions close to the surface acts as a screen that reduce the electrostatic attraction between the charged surface and those counter ions further away from the surface. 36

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SUSPENSIONS Zeta potential has practical application in stability of systems containing dispersed particles . Since this potential, rather than the Nernst potential, governs the degree of repulsion between the adjacent, similarly charged, dispersed particles. If the zeta potential is reduced below a certain value , the attractive forces exceed the repulsive forces, and the particles come together. This phenomenon is known as flocculation. 37

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SUSPENSIONS The flocculated suspension is one in which zeta potential of particle is -20 to +20 mV. Thus the phenomenon of flocculation and de flocculation depends on zeta potential carried by particles . 38

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SUSPENSIONS 39 Deflocculation and flocculation Flocculated Suspensions In flocculated suspension, formed flocs (loose aggregates ) will cause increase in sedimentation rate due to increase in size of sedimenting particles. Hence, flocculated suspensions sediment more rapidly. Here, the sedimentation depends not only on the size of the flocs but also on the porosity of flocs.

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SUSPENSIONS 40 Deflocculated suspensions In deflocculated suspension, individual particles are settling. Rate of sedimentation is slow , which prevents entrapping of liquid medium which makes it difficult to re-disperse by agitation. This phenomenon called ‘caking’ or ‘claying’. In deflocculated suspension larger particles settle fast and smaller remain in supernatant liquid so supernatant appears cloudy.

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SUSPENSIONS The formulation of a suspension depends on whether the suspension is flocculated or deflocculated. Three approaches are commonly involved Use of structured vehicle Use of controlled flocculation Combination of both of the methods : FORMULATION OF SUSPENSIONS 41

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SUSPENSIONS 42 Flow chart of formulation of suspension

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SUSPENSIONS Structured vehicles called also thickening or suspending agents. They are aqueous solutions of natural and synthetic gums. These are used to increase the viscosity of the suspension. It is applicable only to deflocculated suspensions. E.g. methyl cellulose, sodium carboxy methyl cellulose, acacia, gelatin and tragacanth. 43 Structured vehicle

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SUSPENSIONS These structured vehicles entrapped the particle and reduces the sedimentation of particles. Thus, the use of deflocculated particles in a structure vehicle may form solid hard cake upon long storage. 44

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SUSPENSIONS Too high viscosity is not desirable as: a) It causes difficulty in pouring and administration. b) It may affect drug absorption since they adsorb on the surface of particle and suppress the dissolution rate. Structured vehicle is not useful for Parenteral suspension because they may create problem in syringeability due to high viscosity. 45

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SUSPENSIONS ° Controlled flocculation of particles is obtained by adding flocculating agents, which are: (1) electrolytes (2) surfactants (3) polymers 46 Controlled flocculation

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SUSPENSIONS Sometimes suspending agents can be added to flocculated suspension to retard sedimentation ° Examples of these agents are: Carboxymethylcellulose (CMC), Carbopol 934, Veegum, and bentonite 47 Flocculation in structured vehicles

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SUSPENSIONS FORMULATION OF SUSPENSIONS INGREDIENTS FOR 48

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SUSPENSIONS . Wetting agents They are added to disperse solids in continuous liquid phase. Flocculating agents They are added to floc the drug particles Thickeners They are added to increase the viscosity of suspension. Buffers and pH adjusting agents They are added to stabilize the suspension to a desired pH range. Osmotic agents They are added to adjust osmotic pressure comparable to biological fluid. Coloring agents They are added to impart desired color to suspension and improve elegance. Preservatives They are added to prevent microbial growth. External liquid vehicle They are added to construct structure of the final suspension. 49

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SUSPENSIONS Suspending agent are also known as hydrophilic colloids which form colloidal dispersion with Water and increase the viscosity of the continous phase. Suspending agent form film around particle and decrease interparticle attraction. 50 Most suspending agents perform two functions i.e. besides acting as a suspending agent they also imparts viscosity to the solution. Suspending agents

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SUSPENSIONS Preferred suspending agents are those that give thixotropy to the media such as 51 Xanthan gum, Carageenan, Na CMC/MC mixers, Avicel RC 591 Avicel RC 581 and Avicel CL 611. .

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SUSPENSIONS Suspending agents Stability pH range Concentrations used as suspending agent Sodium alginate 4-10 1– 5 % Methylcellulose 3-11 1– 2 % Hydroxyethyl cellulose 2-12 1-2% Hydroxypropyl cellulose 6-8 1-2% Hydroxypropyl methylcellulose 3-11 1-2% CMC 7-9 1-2% Colloidal silicon dioxide 0-7.5 2 - 4 % Stability pH range and concentrations of most commonly used suspending agents. 52

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SUSPENSIONS List of Suspending Agents Alginates Methylcellulose Hydroxyethylcellulose Carboxymethylcellulose Sodium Carboxymethylcellulose Microcrystalline cellulose Acacia Tragacanth Xantham gum Bentonite Carbomer Carrageen Powdered cellulose Gelatin 53

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SUSPENSIONS Alginates Alginate salts have about same suspending action to that of Tragacanth. Alginate solution looses its viscosity when heated above 60ºC. due to polymerization. Alginate granules 54

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SUSPENSIONS Maximum viscosity is observed at a pH range of 5-9 of alginate. Chemically alginates are polymers composed of mannuronic acid and glucuronic acid monomers . In practice, alginate is used at concentration less than 10 % w/w, particularly at 5 % w/w. 55

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SUSPENSIONS Methylcellulose Methylcellulose is available in several viscosity grades. The difference in viscosity is due to difference in methylation and polymer chain length. Methylcellulose is more soluble in cold water than hot water. Methylcellulose is stable at pH range of 3-11. Methyl cellulose powder 56 Methyl cellulose on heating Gel form on cooling Solution form

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SUSPENSIONS Hydroxy ethylcellulose : Hydroxyethylcellulose (HEC) is another good suspending agent having somewhat similar characteristics to methylcellulose. In HEC hydroxyethyl group is attached to cellulose chain . Unlike methylcellulose, HEC is soluble in both hot and cold water and do not form gel on heating . 57

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SUSPENSIONS Carboxy methylcellulose (CMC) Carboxy methylcellulose is available at different viscosity grades. Low, medium and high viscosity grades are commercially available. In case of HV-CMC, the viscosity significantly decreases when temperature rises to 40 ºC from 25 ºC . Therefore, to improve viscosity and stability of suspension MV-CMC is widely accepted. 58

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SUSPENSIONS Microcrystalline Cellulose (MCC; Tradename-Avicel) It is not soluble in water , but it readily disperses in water to give thixotropic gels. It is used in combination with Na-CMC, MC or HPMC, because they facilitate dispersion of MCC. 59

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SUSPENSIONS The advantages of MCC: Alginate complex compositions are that they provide excellent stability. Formulation of dry powder suspensions with MCC; Alginate complexes produce an excellent dry readily hydratable and dispersible formulation for reconstitution. 60

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SUSPENSIONS Hydrophilic materials are easily wetted by water while hydrophobic materials are not. However hydrophobic materials are easily wetted by non-polar liquids. The extent of wetting by water is dependent on the hydrophillicity of the materials. If the material is more hydrophilic less difficulty in wetting by water. The concentration used is less than 0.5 %. 61 Wetting Agents

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SUSPENSIONS . Surfactants decrease the interfacial tension between drug particles and liquid thus liquid is penetrated in the pores of drug particle displacing air from them and thus ensures wetting. Generally, we use non-ionic surfactants but ionic surfactants can also be used depending upon certain conditions. Polysorbate 80 is most widely used due to its following advantages It is non-ionic so no change in pH of medium No toxicity. Safe for internal use. 62 Surfactants

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SUSPENSIONS Hydrophilic colloids coat hydrophobic drug particles in one or more than one layer. This will provide hydrophillicity to drug particles and facilitate wetting. They cause deflocculation of suspension because force of attraction is declined. e.g . acacia, tragacanth, alginates, guar gum. 63 Hydrophilic Colloids

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SUSPENSIONS The most commonly used solvents used are alcohol, glycerin, polyethylene glycol and polypropylene glycol. The mechanism by which they provide wetting is that they are miscible with water and reduce liquid air interfacial tension. Liquid penetrates in individual particle and facilitates wetting. 64 Solvents

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SUSPENSIONS n. Buffers are the materials which when dissolved in a solvent will resist any change in pH when an acid or base is added. To encounter stability problems all liquid formulation should be formulated to an optimum pH. Rheology, viscosity and other property are also dependent on the pH of the system. 65 Buffers

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SUSPENSIONS . Generally pH of suspension preferably at 7.4-8.4. Most commonly used buffers are salts of weak acids such as carbonates, citrates, gluconates, phosphate and tartrates. 66

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SUSPENSIONS They are added to produce osmotic pressure comparable to biological fluids when suspension is to be intended for ophthalmic or injectable preparation. Most commonly used osmotic agents are dextrose, mannitol sorbitol. sodium chloride, sodium sulfate glycerol. 67 Osmotic Agents

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SUSPENSIONS Naturally occurring suspending agents such as tragacanth, acacia, xanthan gum are susceptible to microbial contamination. This leads to: loss in suspending activity of suspending agents, loss of color, flavor and odor, change in elegance etc. 68 Preservatives

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SUSPENSIONS Name of preservatives Concentration range Propylene glycol 5-10% Disodium EDTA 0.1% Benzalkonium chloride 0.01-0.02% Benzoic acid 0.1% Butyl paraben 0.006-0.05% oral suspension 0.02-0.4% topical formulation Disodium EDTA benzalkanonium 69

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SUSPENSIONS They are added to increase patient acceptance. Only sweetening agent are not capable of complete taste masking of unpleasant drugs therefore, a flavoring agents are incorporated . 70 Flavoring And Coloring Agents

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SUSPENSIONS Acacia Ginger Sarsaparilla syrup Anise oil Glucose Spearmint oil Benzaldehyde Glycerin Thyme oil Eg: 71

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SUSPENSIONS Colors are obtained from natural or synthetic sources. Plant colors are most widely used for oral suspension. The synthetic dyes should be used within range of( 0.0005 % to 0.001%) 72 Coloring agents Color aids in identification of the product. The color used should be acceptable by the particular country.

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SUSPENSIONS Most widely used colors are as follows . · Titanium dioxide (white) · Brilliant blue (blue) · Indigo carmine(blue ) · Amaranth (red) · Tartarazine (yellow ) 73 Annatto seeds(yellow to orange) Annatto seeds

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SUSPENSIONS They are used for taste masking of bitter drug particles. Bulk sweeteners Sugars such as xylose, ribose, glucose, mannose. Sugar alcohols such as sorbitol, xylitol, mannitol A bulk sweeteners is used at concentration of 15-70 % 74 Sweetening Agents

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SUSPENSIONS Artificial sweetening agents Sodium cyclamate Sodium saccharin Aspartame 75

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SUSPENSIONS Humectants absorb moisture and prevent degradation of API by moisture. Examples of humectants most commonly used in suspensions are propylene glycol glycerol. Total quantity of humectants should be between 0-10 % w/w. 76 Humectants

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SUSPENSIONS Ascorbic acid derivatives such as ascorbic acid, erythorbic acid, Thiol derivatives such as thio glycerol, cytosine, acetylcysteine , Tocopherols Butylated hydroxy anisole(BHA) Butylated hydroxytoluene (BHT) Sodium bi sulfite, Sodium sulfateacetone 77 Antioxidant

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SUSPENSIONS Following consideration are important for manufacturing pharmacist Selection of right material that go into the manufacture. The step involved and their sequence in the manufacture. Preservation and storage of the product. 78 PREPARATION OF SUSPENSIONS

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SUSPENSIONS Small scale preparation of suspensions: Step 1: Suspensions are prepared by grinding (or) levigating the insoluble materials in the mortar to a smooth paste with a vehicle containing the wetting agent. 79

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SUSPENSIONS Step 2: All soluble ingredients are dissolved in same portion of the vehicle and added to the smooth paste to step1 to get slurry. Step 3: The slurry is transformed to a graduated cylinder, the mortar is rinsed with successive portion of the vehicle. 80

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SUSPENSIONS Step 4: Decide whether the solids are Suspended in a structured vehicle Flocculated Flocculated and then suspended Add the vehicle containing the suspending agent (or) flocculating agent 81 Make up the dispersion to the final volume . Thus suspension is prepared. Step-5

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SUSPENSIONS Introduction Pharmaceutical suspensions for oral use are generally packed in wide mouth container having adequate space above the liquid to ensure proper mixing. Parenteral suspensions are packed in either glass ampoules or vials. 82 Packaging of Suspensions

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SUSPENSIONS Ideal Requirements of Packaging Material It should be inert. It should effectively preserve the product from light, air, and other contamination through shelf life. It should be cheap. It should effectively deliver the product without any difficulty. 83

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SUSPENSIONS Materials Used For Packaging Generally glass and various grades of plastics are used in packaging of suspension. Glass Generally soda lime and borosilicate glass are used in preparation of non sterile suspensions. 84

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SUSPENSIONS Amber glass doesn’t allow U.V light to pass through. Amber characteristics can be developed in the glass by addition of various types of additives. Type of glass Additive giving amber color Soda lime FeO + sulfur (in presence of reducing agent) Borosilicate FeO+TiO 2 85

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SUSPENSIONS Disadvantages of Glass Materials: They are fragile . They are very heavy as compared to plastic so handling and transport is difficult. Most important disadvantage of glass that glass constituents get extracted into the product . 86

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SUSPENSIONS Plastic Due to the negative aspects of glass, plastic material significantly use of plastic as packaging material for sterile as well as non-sterile pharmaceutical suspension increased. 87

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SUSPENSIONS Advantages Of Plastic Material: Non breakability. Light weight. Flexibility. Materials used: - Polyethylene, PVC, polystyrene, polycarbonate etc 88

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SUSPENSIONS Closure And Liners With an exception of ampoules all containers required elastomeric closure. . closures liners 89

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SUSPENSIONS Factors affecting in selecting closure: Compatibility with product. Seal integrity. It should be stable throughout the shelf life. 90 Factors affecting in selecting liner : Chemical resistance. Appearance Gas and vapor transmission. Removal torque. Heat resistance. Shelf life. Economical factors

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SUSPENSIONS STORAGE REQUIREMENTS & LABELLING Labelling: Shake well before use Do not freeze Protect from direct light(for light sensitive drugs) In case of dry suspensions powder the specified amount of vehicle to be mixed may indicated clearly on label. 91

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SUSPENSIONS Label: 92

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SUSPENSIONS STORAGE : Suspensions should be stored in cool place but should not be kept in a refrigerator Freezing at very low temperatures should be avoided which may lead to aggregation Of suspended particles 93 Stored at controlled temperature from 20-25 c 0

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SUSPENSIONS 94 Evaluation of Suspensions

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SUSPENSIONS Sedimentation method Rheological method Electro kinetic method Micromeritic method Evaluation of Suspensions 95

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SUSPENSIONS Sedimentation method : Two parameters are studied for determination of sedimentation. Sedimentation volume, Degree of flocculation. , 96

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SUSPENSIONS 97 Sedimentation volume The suspension formulation (50 mL) was poured separately into 100 mL measuring cylinders and sedimentation volume was read after 1, 2, 3 and 7 days, and thereafter at weekly intervals for 12 weeks. Triplicate  results  were  obtained  for  each  formulation. Sedimentation volume was calculated according to the equation: Where, F = sedimentation volume, V u = ultimate height of sediment and V o = initial height of total suspension F = V u /V o

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SUSPENSIONS Rheological method It provide information about Settling behaviour . The arrangement of the vehicle and the particle structural features. Brookfield viscometer is used to study the viscosity of the suspension . It is mounted on heli path stand and using T-bar spindle. T-bar spindle is made to descend slowly into the suspension and the dial reading on the viscometer is then a measure of the resistance the spindle meets at various level. 98

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SUSPENSIONS This technique also indicates at which level of the suspension the structure is greater owing to particle agglomeration. The dial reading is plotted against the number of turns of the spindle. The better suspension show a lesser rate of increase of dial reading with spindle turns, i.e. the curve is horizontal for long period. 99

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SUSPENSIONS Electro kinetic method Measurement of Zeta-potential using Micro electrophoresis apparatus & ZetaPlus (Brookhaven  Instruments  Corporation,  USA). It shows the stability of a disperse system. Micro-Electrophoresis Apparatus Mk I 100 ZetaPlus

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SUSPENSIONS 101 Zeta potential The  zeta  potential  of  the  formulated  suspensions  was  determined using  a  ZetaPlus  (Brookhaven  Instruments  Corporation,  USA). Approximately  1  mL  of  suspension  was  transferred  into  a  plastic cuvette  using  a  pipette  and  diluted  with  distilled  water. The Brookhaven  zeta  potential  software  was  used for the measurement . Parameters  set  to  a  temperature  of 25 0 C and refractive index (1.33) The zeta potential of the formulations was determined  on day  0,  7, 14, 21 and day 28 post formulation.

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SUSPENSIONS Micromeritic method : The stability of suspension depends on the particle size of the dispersed phase. Change in the particle size with reference to time will provide useful information regarding the stability of a suspension. A change in particle size distribution and crystal habit studied by microscopy coulter counter method 102

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SUSPENSIONS 103 PHOTOMICROSCOPIC TECHNIQUE The microscope can be used estimate and detect changes in particle size distribution and crystal form. Rapid processing of photo micrographs is enhanced by attaching Polaroid camera to the piece of monomolecular microscope By using this photo micrographs we can determine the changes in physical properties and stability of suspensions .

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SUSPENSIONS Freeze-Thaw test conducted by placing the sample in a freezer for 18 hours followed by thawing at room temperature for 4 to 6 hours. Repeat the Freeze-Thaw cycle for up to 10 times. FREEZE- THAW TEST Freeze-thaw testing freezer INNER CHAMBER 104 This test is conducted to determine the tendency to crystallize or cloud)

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SUSPENSIONS pH MEASUREMENT The measurement and maintenance pH is also very important step in the Quality control testing . Generally there are 2 different types of methods used in the measurement of pH. 105

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SUSPENSIONS METHODS FOR pH MEASUREMENT: The simplest and cheapest is to dip a piece of pH paper into the sample. The paper is impregnated with chemicals that change color and the color may be compared to a chart supplied with the paper to give the pH of the sample. 106

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SUSPENSIONS If greater accuracy is required a pH meter should be used. A typical pH meter consists of a special measuring  glass electrode connected to an electronic meter that measures and displays the pH reading. 107

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SUSPENSIONS VISUAL INSPECTION : With visual inspection, the ingredients and the final products are carefully examined for purity and for appearance . Physical appearance of products for patient adherence and compliance is critical so it should be: Good looking Elegance in appearance . 108

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SUSPENSIONS DISSOLUTION STUDY OF SUSPENSIONS Introduction: The drug release from suspensions is mainly through dissolution. Suspensions share many physico-chemical characteristics of tablet & capsules with respect to the process of dissolution. As tablets & capsules disintegrate into powder and form suspensions in the biological fluids. So dissolution is carried as follows 109

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SUSPENSIONS Dissolution Testing Official Method (Conventional Method): It is known as paddle method. 110

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SUSPENSIONS Dissolution profile of the 500 mg sample suspension is determined at 37°C in 900 ml of pH 7.2 phosphate buffer using the FDA paddle method at 25 RPM. 111 The apparatus consists of a cylindrical 1000- ml round bottom flask in a multiple – spindle dissolution drive apparatus and immersed in a controlled temp bath maintained

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SUSPENSIONS The paddle should position to extend to exactly 2.5 cm above the flask bottom. The suspension is to be introduced carefully into the flask at the bottom using a 10- ml glass syringe with an attachment 19-cm needle . Withdraw 5 ml of dissolution medium (and replace with an equal volume of drug –free buffer) in a 5 ml glass syringe. Immediately filter through a 0.2 µm membrane and analyze. 112

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SUSPENSIONS 113 Innovations of suspensions

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SUSPENSIONS Innovations of suspensions Nano suspensions Taste masked pharmaceutical suspensions Sustained release suspensions 114

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SUSPENSIONS Nano suspensions are the biphasic colloidal dispersions of nano sized drug particles stabilised by surfactants without the matrix materials. They can also be defined as a biphasic system consisting of pure drug particles dispersed in an aqueous vehicle in which the diameter of the suspended particle is less than 1 μm in size. 115 Nano suspensions:

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SUSPENSIONS 116

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SUSPENSIONS Un-palatability due to bad taste is a major concern in most of the dosage forms containing bitter drugs. In case of suspensions also taste masking is being applied to mask bitterness of drugs formulated. 117 2.Taste Masked Pharmaceutical Suspensions .

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SUSPENSIONS The taste masking approaches for suspensions are : Polymer coating of drugs. Encapsulation with basic drugs. Polymer coating with basic substances. Coating and pH control . 118

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SUSPENSIONS Polymer Coating of Drugs The polymer coat allows the time for all of the particles to be swallowed before the threshold concentration is reached in the mouth and the taste is perceived. The polymers used for coating are Ethyl cellulose Eudragit RS 100 Eudragit RL 100 Eudragit RS 30 D Eudragit RL 30 D 119

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SUSPENSIONS b. Encapsulation with a Basic Substance Here a basic substance is mixed with a bitter tasting drug which is insoluble at high pH. The mixer is then encapsulated with a polymer (cellulose derivative, vinyl derivative or an acid soluble polymer Eg: copolymer of dimethyl ammonium methyl methacrylate). The drug after encapsulation are suspended, dispersed or emulsified in suspending medium to give the final dosage form . 120

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SUSPENSIONS c. Coating and pH Control Those drugs which are soluble at high pH are preferably be maintained in a suspension at a low pH where the drug exhibit maximum insolubility. Similarly drugs which are soluble at low pH are preferably maintained in suspension at a high pH where the drug is insoluble. Also applying polymeric coating to the drug substance avoids solubilization of drug when administered providing taste masking. 121

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SUSPENSIONS Some Examples of Taste Masked Suspensions Sr.No Name of the drug Taste masking approach 1 RISPERIDONE pH control and polymer coating (with Eudragit RS ) 2 DICLOFENAC Polymer coating with Eudragit RS 100 3 LEVOFLOXACIN Polymer coating ( Eudragit &cellulose acetate ,) 122

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SUSPENSIONS Sustained release is a method to increase only the duration of action of drug being formulated without affecting onset of action . In suspension sustained release affected by coating the drug to be formulated as suspension by insoluble polymer coating . The polymer coating provides sustained release and also masks the taste of the bitter drug. 123 Sustained Release Suspensions

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SUSPENSIONS The polymer used for sustained release in suspension is as follows as Ethyl cellulose, Eudragit, Cellulose acetate, etc. The main advantage of sustained release suspension is decrease in dosing frequency . 124

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SUSPENSIONS Approaches used in formulation of sustained release oral suspensions Ion exchange resin. Microencapsulation technique Saturated drug suspension as a suspending medium. Using non aqueous vehicle. Reconstitution. Protective coating. 125

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SUSPENSIONS Subramanyam C.V.S., Second edition, “Suspensions” Text Book of Physical Pharamaceutics, PageNo. 374-387. Ansel C., Allen L.V., Popovich N.G. Eighth edition “Disperse systems” Pharmaceutical Dosage Forms & Drug Delivery Systems, Lippincott Williams and Wilkins, Philadelphia 2005, Page No. Page No. 387-389, 398. 126 REFERENCES

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SUSPENSIONS Cooper & Gun, Sixth edition, “Dispersed system” Tutorial Pharmacy, Page No. 75-78. Aulton M.E. Second edition, “Suspension” Pharmaceutics- The Science of Dosage Form Design, Churchill Livingstone, Edinburgh 2002, PageNo. 84-86, 273. 127

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SUSPENSIONS Remington, Twentieth edition, “Colloidal Dispersions” The Science and Practice of Pharmacy, Lippincott Williams and Wilkins, Philadelphia 2000, Page No. 298-307. Martin A. Fourth edition, “Coarse dispersion” Physical Pharmacy, Lippincott Williams and Wilkins, Philadelphia 2001, Page No. 479-481. 128

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Heartly thanks to Prof .Dr. M.B.Venkatapathi Raju Sir,Principal,SRCP. Prof : G.Sudhakar sir , Vice principal,SRCP. Prof .Dr. R. Santosh Kumar sir , H.O.D,SRCP. My Teachers and other faculty members and non teaching staff,SRCP. Finally special thanks to Srinivasa Rao College of Pharmacy Management. 129

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SUSPENSIONS 130