Suspensions PDF

Department of Pharmaceutics and Pharmaceutical Technology College of Clinical Pharmacy Al-Azhar University Pharmaceutics -1 Suspensions Instructor: Dr. Ahmed Elgendy 1  LE SuspensionsOUTLINE Contents Disperse system classification. De...

Department of Pharmaceutics and Pharmaceutical Technology College of Clinical Pharmacy Al-Azhar University Pharmaceutics -1 Suspensions Instructor: Dr. Ahmed Elgendy 1  LE SuspensionsOUTLINE Contents Disperse system classification. Definition of pharmaceutical suspension. Advantages / disadvantages, rationale & application. Theory of suspension: sedimentation, stability & Brownian motion. Properties of ideal / optimal Suspensions. Classification of suspensions. Formulation aspects. Difference between flocculated & deflocculated suspensions. Rheological characteristics. Preparation. Evaluation. Stability. Packaging and storage.  LE SuspensionsOUTLINE Suspensions: liquid preparations containing finely divided drug particles (dispersion phase) distributed uniformly throughout a suitable vehicle (dispersion medium). In suspensions, the drug exhibits a minimum degree of solubility in the dispersion medium. Range of solid particles in suspensions is from 0.5 - 5.0 micron.  LE SuspensionsOUTLINE Physical Properties of a well-Formulated Suspension 1. Ideally, particles in a suspension should not sediment on bottoms of the containers during storage. 2. Settled particles must not form a hard cake. 3. Settled particles should be easily re-dispersed by a gentle shaking. 4. Remains sufficiently homogenous for a period between shaking the container and dose removing. 5. Free from gritting particles. 6. Pleasant & palatable (orally). 7. Chemically & physically stable(temperature insensitive).  LE SuspensionsOUTLINE Pharmaceutical Applications of Suspensions 1. Suspensions as oral drug delivery systems Insoluble drug or poorly soluble drugs which required to be given orally in liquid dosage forms (in case of children, elderly, and patients have difficulty in swallowing solids dosage forms). To overcome the instability of certain drug in aqueous solution. A drug that degraded in the presence of water can be suspended in non- aqueous vehicles as phenoxymethypencillin/coconut oil and tetracycline HCL/oil.  LE SuspensionsOUTLINE 2. Suspensions for topical administration ▪ They can be fluid preparations, such as Calamine Lotion, which are designed to leave a light deposit of the active agent on the skin after quick evaporation of the dispersion medium. ▪ Some suspensions are semisolid in consistency, such as pastes, which contain high concentrations of powders dispersed. It may also be possible to suspend a powdered drug in an emulsion base, as in Zinc Cream. 3. Suspensions for parenteral use ▪ Suspensions are formulated for parenteral administration in order to control the rate of absorption of the drug. ▪ By varying the size of the dispersed particles (rate of dissolution) of active agent, the duration of activity can be controlled. In vaccines: e.g. Diphtheria and Tetanus vaccines. 4. Suspensions for ophthalmic use: various eye drops on the market. 5. Suspensions in aerosol Inhalation therapy: suspension of active agents in mixture of propellants.  LE SuspensionsOUTLINE Classifications of Suspensions 1. Based on General Classes Oral suspension Externally applied suspension Parenteral suspension 2. Based on Size of Solid Particles Colloidal suspension (< 1 micron) Coarse suspension (>1 micron) Nano suspension (10 nm) 3. Based on Proportion of Solid Particles Dilute suspension (2-10 % w/v solid) Concentrated suspension (50 % w/v solid) 4. Based on Electro-kinetic Nature of Solid Particles Flocculated suspension Deflocculated suspension  LE SuspensionsOUTLINE Formulation of Suspensions Particle Size Control Particles have to be suspended in suspensions. The rate of sedimentation of a suspended particle can be retarded by a reduction in its size. The velocity (v) at which particles in a suspension settle may be expressed by Stokes’ law: v = d2 (p-po) g 18 ηo d: diameter of the particle in cm  s: density of the dispersed phase (particles)  o: density of the dispersed medium g: acceleration due to gravity : viscosity of the dispersion medium in poise  LE SuspensionsOUTLINE Physical stability of suspensions is concerned with keeping particles uniformly distributed in the dispersion medium. Particle sizes of any suspension influence velocity of their sedimentation. Larger particles settle faster at the bottom of the container. Particle size can be reduced by using mortar and pastel. But very fine particles will easily form hard cake at the bottom of the container when they settle.  LE SuspensionsOUTLINE Particles having a diameter of 2-5 m, Brownian movement counteracts sedimentation to a measurable extent at room temp by keeping dispersed material in random motion.  LE SuspensionsOUTLINE Formulation Aspects of Suspensions (Ingredients of Suspensions) 1. Insoluble drug. 2. Vehicle (suspending medium). 3. Wetting agents. 4. Compounds to control stability and sedimentation (flocculating, suspending agent). 5. Additives to regulate the flow behavior. 6. pH regulators. 7. Other additives ( flavor, color, taste preservatives).  LE SuspensionsOUTLINE The Insoluble Drug: Parameters to be Considered Size of the particles Size distribution of the powder. Ease of wetting. Surface electric charge of the particles in suspension. Chemical stability of the drug, and possible interactions and incompatibilities with other constituents. Work must be done to reduce the solid to small particles and disperse them in a continuous medium. An increase in surface free energy (W) brought about by dividing the solid into smaller particles and consequently increasing the total surface area (A) is given by: W = SL. A Where: SL: interfacial tension between the liquid medium and the solid particles. In order to approach a stable state, the system tends to reduce the surface free energy by decreasing surface area (agglomeration).  LE SuspensionsOUTLINE The Suspending Medium or Vehicle 1. Distilled water or deionized water 2. Water- alcohol 3. Solution of glycerol 4. Non-aqueous vehicles (topical use) 5. Structured vehicles  LE SuspensionsOUTLINE Structured Vehicles Structured vehicles are vehicles containing thixotropic compounds/polymers like acacia which are pseudo-plastic or plastic in nature. Thixotropic compounds/polymers form a three-dimensional gel network structure which entrap the particles so that, ideally, no settling occurs. During shaking the gel network is completely destroyed (pseudoplastic and plastic in nature) so that administration is facilitated.  LE SuspensionsOUTLINE Structured Vehicles 1. These structured vehicles reduce, not completely eliminate, the sedimentation of particles. 2. Thus, deflocculated particles in a structured vehicle may form solid hard cake upon long storage. 3. Caking may be eliminated by forming flocculated particles in a structured vehicle.  LE SuspensionsOUTLINE Wetting Agents: a substance that reduces the surface tension of water or another liquid, causing the liquid to spread across or penetrate more easily surfaces of a solid. Explanation: 1. It is difficult to disperse solid particles in a liquid vehicle due to the layer of adsorbed air on the surface. 2. Thus, the particles, float on the surface of the liquid until the layer of air is displaced completely. 3. Wetting agent allows to remove this air from the surface and to easy penetration of the vehicle into the powders. 4. Powders not easily wetted by water as sulfur and magnesium stearate are called hydrophobic. 5. Powders readily wetted by water are called hydrophilic e.g. zinc oxide. 6. The wettability of a powder may be ascertained easily by observing the contact angle and spreading coefficient.  LE SuspensionsOUTLINE Wetting Agents and Contact Angle Contact angle: is the angle at which the liquid interface meets the surface of the solid. Contact angles indicate the degree of wetting when a solid and liquid interact. The lower the contact angle the greater the wetting.  LE SuspensionsOUTLINE Wetting Agents Sc = S - L - SL Sc: spreading coefficient S: surface tension of solid L: surface tension of liquid SL: surface tension of solid - liquid interface. For a convenient wetting, the value of spreading coefficient (Sc) should be positive. This is achieved by modification of the values of surface tension of several surfaces involved until a positive value of spreading coefficient is reached. By adding wetting agent (surfactant) such as non ionic surfactant polysorbates.  LE SuspensionsOUTLINE Types of Wetting Agents 1. Surfactants: are compounds that lower the surface tension (or interfacial tension) between two liquids, between a gas and a liquid, or between a liquid and a solid. Here they reduce interfacial tension between solid particles and the vehicle (SL). As a result Sc will be positive and the contact angle is lowered. Air is displaced from the surface of the particles, and wetting is promoted. Example: Polysorbate 80 is most widely used: ✓ It is non-ionic so no change in pH of medium ✓ No toxicity. ✓ Safe for internal use. ✓ Less foaming tendencies. ✓ Compatible with most of the adjuvant. ✓ Decreases zeta potential thus stabilizes the suspension  LE SuspensionsOUTLINE 2. Glycerin and similar hygroscopic substances: as alcohol, glycerin, polyethylene glycol and polypropylene glycol: Wetting Action: flows into the voids between the particles to displace the air and reduce liquid air interfacial tension so that water can penetrate and wet the individual particles. 3. Hydrophilic Colloids: as gum acacia, tragacanth, alginates, guar gum, pectin, gelatin, wool fat, egg yolk, bentonite, veegum and methylcellulose. Wetting action: they coat hydrophobic drug particles. This will provide hydrophilic properties to drug particles and facilitate wetting. Most hydrophilic colloids are negatively charged, they cause deflocculation of suspension because force of attraction is declined.  LE SuspensionsOUTLINE Compounds Controlling Stability and Sedimentation A. Suspending agents/Viscosity Modifier/Thickener: a substance that is added to fluids to promote particle suspension or dispersion and reduce sedimentation. Suspensions have least physical stability amongst all dosage forms due to sedimentation and cake formation. Developing a suitable suspension requires the following to be controlled: 1. Rate of settling 2. Ease of re-dispersion 3. Prevention of caking the particles as a dense mass. Mechanism of action of suspending agents:  LE SuspensionsOUTLINE Viscosity of suspensions is of great importance: for stability and pour ability of suspensions. When viscosity increases, settling velocity decreases thus the dispersed phase settle at a slower rate and remains dispersed for longer time yielding stable suspension. On the other hand if viscosity increases, it’s pour ability decreases and inconvenience of dosing increases. Solution: viscosity of suspensions should be maintained within an optimum range to yield stable and easily pourable suspensions.  LE SuspensionsOUTLINE Examples of Suspending Agents: Natural gums (acacia, tragacanth, Xanthan gum ) Sugars (glucose, fructose) Cellulose derivatives (sodium carboxymethyl cellulose (CMC) and methyl cellulose). Sodium alginates & gelatin Clays (bentonite, veegum) Poly acrylic acid (Carbomer) Colloidal silicon dioxide (Aerosil) Co-solvents: Some solvents of high viscosity are used as co-solvents to enhance viscosity of dispersion medium: For example glycerol, propylene glycol, sorbitol and glycerin. Glycerin as co-solvent: Viscosity is too high, so its hard to pour easily and spread on skins. It shows the undesirable property of stickiness. It is hygroscopic.  LE SuspensionsOUTLINE Ideal Suspending Agents 1. Should have a high viscosity at negligible shear, i.e., during storage. 2. Should have a low viscosity at high shearing rate, i.e., it should be free flowing during agitation, pouring, and spreading. Pseudo-plastic substances such as: tragacanth, sodium alginate, and sodium carboxymethyl cellulose show these desirable qualities. A suspending agent which is thixotropic as well as pseudo-plastic are useful since it forms a gel on standing and becomes fluid when disturbed. 3. Inert, non-toxic and compatible with other excipients. 4. Readily dissolved or dispersed in water without need of special technique. 5. No influence on absorption or dissolution rate of drugs.  LE SuspensionsOUTLINE B. Flocculating Agents: chemicals that promote flocculation by causing colloids and other suspended particles in liquids to aggregate, forming a floc. Flocculation: formation of light, fluffy groups of particles held together by weak Van der Waal's forces. Suspending agents entrapped the particle and reduces the sedimentation of particles. They may affect drug absorption since they adsorb on the surface of particle and suppress the dissolution rate.  Suspensions Flocculating agents are added to enhance particle re- dispersability: floc-1 cake floccules A controlled flocculation of the particles, where they appear as floccules or like tufts of wool with a loose fibrous structure. Controlled flocculation of particles is obtained by adding flocculating agents: 1. electrolytes (2)- surfactants (3)- polymers. In contrast to deflocculated particles, flocculated suspensions can always be re- suspended with gentle agitation.  LE SuspensionsOUTLINE Types of Flocculating Agents 1. Electrolytes 2. Surfactants 3. Polymers  LE SuspensionsOUTLINE Electrolytes as Flocculating Agent Dispersed solid particles in a suspension may have charge in relation to their surrounding vehicle, because of- Selective adsorption of a particular ionic species present in the vehicle. Ionization of functional group of the particle. The ions that gave the particle its charge, are called POTENTIAL- DETERMINING IONS that serve to repel the particles. Immediately adjacent to the surface of the particle is a layer of tightly bound solvent molecules, together with some ions oppositely charged to the potential-determining ions, called COUNTER IONS. Electrolytes acts as flocculating agents by reducing the electrical barrier between the particles, thus, decrease the zeta potential, this leads to decrease in repulsion potential and makes the particle come together to form loosely arranged structure (floccules).  LE SuspensionsOUTLINE Electrolytes as Flocculating Agent Zeta potential is the potential difference between the ions in the tightly bound layer and the electro neutral region. Zeta potential governs the degree of repulsion between adjacent, similar charged, solid dispersed particles.  LE SuspensionsOUTLINE Electrolytes as Flocculating Agent Sedimentation curve Zeta potential curve Caking diagram, showing the flocculation of suspension by means of the electrolyte  LE SuspensionsOUTLINE Flocculating Agents: Electrolytes ▪ If we disperse particles of bismuth subnitrate in water, we find that, they possess a large positive charge, or large zeta potential. ▪ Because of the strong forces of repulsion between adjacent particles, the system is deflocculated. ▪ The addition of monobasic potassium phosphate to the suspended bismuth subnitrate particles causes the positive zeta potential to decrease due to the adsorption of the negatively charged phosphate anion. ▪ With the continued addition of the electrolyte, the zeta potential falls to zero and then increases in a negative direction. ▪ The flocculating power increases with the valency of the ions. Calcium ions are more powerful than sodium ions because the valency of calcium is two whereas sodium has valency of one.  LE SuspensionsOUTLINE Surfactants as Flocculating Agents: Both ionic and non ionic surfactants could be used to control flocculation, e.g. Tween 80, Sodium lauryl sulfate. Conc. of surfactants necessary to achieve flocculation is critical. Optimum conc. bring downs the surface free energy by reducing the surface tension between liquid medium and solid particles. Particles possessing less surface free energy are attracted towards each other by van der-waals forces and forms loose agglomerates.  LE SuspensionsOUTLINE Polymers as Flocculating Agents Polymers like Starch, alginates, cellulose derivatives, carbomers, tragacanth are long chain, high molecular weight compounds containing active groups spaced along their length. These agents act as flocculating agents because part of the chain is adsorbed on the particle surface with the remaining parts projecting out in the dispersion medium. Bridging between these portions leads to the formation of floccules. Polymers exhibit pseudo-plastic flow in solution promoting the physical stability of suspension.  LE SuspensionsOUTLINE Difference between Flocculated and Deflocculated Suspensions  LE SuspensionsOUTLINE Other Additives  LE SuspensionsOUTLINE Rheological properties of pharmaceutical suspensions The flow of the acceptable suspension will be either pseudoplastic or plastic & it is desirable that thixotropy be associated with these two types of flow. Thixotropy is defined as the isothermal slow reversible conversion of gel to sol. Thixotropic substances on applying shear stress convert to sol(fluid) and on standing they slowly turn to gel(semisolid). At rest the solution is sufficient viscous to prevent sedimentation and thus aggregation or caking of the particles. When agitation is applied the viscosity is reduced and provide good flow characteristic from the mouth of bottle.  LE SuspensionsOUTLINE Rheological properties of suspensions are affected by: The degree of flocculation: floccules tends to reduce the amount of free continuous medium; since much of it is entrapped within the floccules. The viscosity of a flocculated suspension is therefore usually higher than that of a similar suspension in which the particles are deflocculated. Flocculated suspensions exhibit plastic or pseudo-plastic behavior. i.e. the viscosity of flocculated suspensions is relatively high when the applied shearing stress is low, but decreases as the applied stress increases. If plastic behavior is exhibited then the system behaves like a solid up to particular shearing stress (yield value), and no flow occurs in the system until the value is exceeded. Rheological properties o Suspensions f flocculated Plastic Flow Pseudoplastic Rate of Shear Rate of Shear Flow fB (yield value) Shear Stress Shear Stress ▪ The yield value is because the van der Waals forces between adjacent particles, which must be broken first before flow can occur. ▪ The more flocculated the suspension the higher will be the yield value. Rheological properties o Suspensions f flocculated Rate of Shear Dilatant Flow Shear Stress Deflocculated suspensions exhibit dilatant behavior. i.e. the viscosity of deflocculated suspensions is low at low shearing stresses and increases as the applied stress increases.  LE SuspensionsOUTLINE Preparation of Suspensions Steps 1. Wetting and Dispersion of the Active Ingredient. 2. Stabilization of Dispersed Solid. 3. Preparation of the Vehicle /structured vehicle. 4. Addition and Dispersion of Active Ingredient in Vehicle. 5. Addition of Remaining Ingredients and Final Mixing  LE SuspensionsOUTLINE Wetting and Dispersion of the Active Ingredient Dry mill the powders to achieve target particle size and particle size range. Powder should be added to a low viscosity portion of the product, preferably plain water. This allows for most efficient mixing and homogenization. Wetting agent is added to the water to aid in wetting and displacement of air. Drug powder may be treated with a water miscible material such as glycerin to aid in wetting. Stabilization of the Dispersed Solid Electrical (Controlled flocculation). Addition of electrolytes to produce charges around each particle and allow for electrical repulsion to prohibit particle interactions.  LE SuspensionsOUTLINE Preparation of the Vehicle Polymers such as sodium carboxymethylcellulose and gums such as xanthan gum and tragacanth will form lumps if added to water improperly. It is often practical to disperse them in a water miscible liquid in which they are insoluble. A common technique is to make a paste of the material in glycerin, then carefully add this paste to water. It is also usual to allow this mixture to stand for up to 24 hours to ensure complete hydration of the polymer. Addition and Dispersions in Vehicle The dispersion of the active ingredient is added to the vehicle with low intensity mixing. The mixture is then homogenized to ensure uniform dispersion of the ingredients.  LE SuspensionsOUTLINE Summary of Preparation of Suspensions Evaluation of Suspensions Two useful parameters for the evaluation physical stability. of suspensions are Sedimentation volume "F" & Degree of flocculation “B”. Sedimentation volume: (F): the ratio of the equilibrium volume of the sediment, Vu, to the total volume, Vo, of the suspension. F = Vu/Vo Value of F provides a qualitative knowledge about physical stability of suspensions. F= 1 No sedimentation, no clear supernatant F = 0.5 50% of the total volume is occupied by sediment F>1 Sediment volume is greater than the original volume due to formation of floccules which are fluffy and loose. LE SuspensionsOUTLINE LE SuspensionsOUTLINE  Suspensions Stability of Suspensions Physical Stability Chemical Stability Appearance, color, odor & taste pH change Specific gravity Viscosity change Sedimentation arte Degradation of active ingredient Sedimentation volume Antimicrobial activity: Zeta potential measurement 1. Incompatibility with Compatibility with container preservative Compatibility with cap liner 2. Degradation of preservative Microscopic examination 3. Adsorption of preservative Determination of crystal size onto drug particle Determination of uniform drug distribution  LE SuspensionsOUTLINE Packaging and Storage of Suspensions 1. Should be packaged in wide mouth containers having adequate air space above the liquid. 2. Should be stored in tight containers protected from: freezing, excessive heat & light. 3. Label: "Shake Before Use" to ensure uniform distribution of solid particles and thereby uniform and proper dosage. 4. Stored in room temperature if it is dry powder (25 0C). 5. Note: It should be stored in the refrigerator after opening or reconstitute (freezing should be avoided to prevent aggregation).