Suspension

Vikash Dahiya

1. Suspension Hindu College of Pharmacy Sonipat(131001) Guided by Dr. Dinesh Kaushik Associate professor Hindu College of Pharmacy Sonipat Presented by Vikash M-Pharmacy(1 st Sem) Modern Pharmaceutics Roll no. 8-M/2019

2. Definition Classification Formulation Packing Evaluation Storage Content

3. Definition Suspension may be defined as preparation containing finely divided drug particles distributed uniformly throughout a vehicle in which the drug exhibits a minimum degree of solubility. or

4. Suspension are the biphasic liquid dosage form of medicaments in which the finely divided solid particles. The range of solid particles in suspension from 0.5 to 5.0 micron. Suspensions are used in orally, parentally and also externally. They are chemically stable than solution.

5. Properties of good Suspension: Suspension should settle slowly & should be readily re-dispersed upon shaking of the container. The suspension is pourable. Particle in suspension are small and relatively uniform in size. So that the product is free from a gritty texture.

6. Advantages of suspensions: Suspension can improve chemical stability of certain drug. Ex. Procaine penicillin G Drug in suspension exhibits higher rate of bioavailability than other dosage forms. Bioavailability is in following order: Emulsion>Suspension>Capsule>Compressed tablet>Coated tablet Duration and onset of action can be controlled. Ex. Protamine Zinc-insulin suspension. Suspension can mask the unpleasant/bitter taste of drug. Ex. Chloramphenicol palmitate.

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

8. Pharmaceutical Application of Suspension 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. Oxytetracycline suspension. Suspension of drug can be formulated for topical application. E.g. Calamine lotion. To mask the taste of bitter or unpleasant drug when formulated in solution form. Bulky, insoluble powders can be formulated as a suspension so that they are easier to take. E.g. Kaolin or chalk.

9. Internal phase: The internal phase consisting of insoluble solid particles having 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. External phase: The external phase (suspending medium) is generally aqueous in some instance, may be an organic or oily liquid for non oral use.

10. Classification: Based on General class I. Oral suspension e.g. Paracetamol suspension, antibiotic II. Externally applied suspension e.g. calamine lotion III. Parenteral suspension e.g. Insulin zinc suspension

11. Based on nature of solid particle : Flocculated suspension Deflocculated suspension Based on proportion of Solid Particles : Dilute Suspension (2 to 10% w/v solid e.g. cortisone acetate. Concentrated Suspension (50% w/v solid) e.g. Zinc oxide suspension

12. According to particle size of the dispersed phase, suspensions are divided into: Coarse suspension: Which is a dispersion of particles with a mean diameter greater than 1 µm . Colloidal suspension: Which is a dispersion of particles with a mean diameter less than 1 µm.

13. Flocculated system In flocculated system the individual particle are contact with each other to form loose aggregate & create network like structure. Rate of sedimentation is high. Sediment is loosely packed. When shaking it can be re-disperse easily & reform the original suspension. Flocculated suspensions not be elegant because they are difficult to remove from bottles & on transferring from the bottle the floccules remaining sticking to the side of the bottle.

14. De-flocculated or Non-flocculated system In deflocculated system the individual particle are exist as separate entities. Rate of sedimentation is low. Sediment is tightly packed. When shaking it can not be re-disperse easily & form the cake. Deflocculated suspensions be elegant. They have pleasing appearance because the substance remain suspended for sufficient long time.

15. Difference between flocculated and deflocculated suspension Flocculated Deflocculated 1. Particles forms loose aggregates and form a network like structure. 1. Particle exists as separate entities. 2. Rate of sedimentation is high. 2. Rate of sedimentation is low. 3. Sediment is rapidly formed. 3. Sediment is slowly formed. 4. Sediment is loosely packed and doesn’t form a hard cake. 4. Sediment is very closely packed and a hard cake is form. 5. Sediment is easy to re-disperse. 5. Sediment is difficult to re-disperse. 6. Suspension is not pleasing in appearance. 6. Suspension is pleasing in appearance. 7. The floccules stick to the sides of the bottle. 7. They don’t stick to the sides of the bottle.

16. Theory of sedimentation SEDIMENTATION: Sedimentation means settling of particle (or) floccules occur under gravitational force in liquid dosage form.

17. DLVO Theory The scientists Deryaguin , Landau , Vervey and Overbeek developed a theory in the 1940s which dealt with the stability of colloidal systems. DLVO theory suggests that, the stability of a colloidal system is determined by the sum of the Vander Waals attractive (VA) and electrical double layer repulsive (VR) forces that exist between particles as they approach each other due to the Brownian motion they are undergoing. The Vander waal forces depend on chemical nature and size of particle. The electrostatic repulsive forces depend on density, surface charge and thickness of double layer.

18. Methods for stabilizing suspension Physical Stability can be achieved by maintaining the particle in Brownian motion Provide Electric charge on surface of dispersed particle: The like charge on the particles will prevent these coming closer together and thus maintaining a Brownian motion. Maintain solvent sheath around the particle: The solvent layer prevent the particle coming closer and also maintain Brownian motion.

19. Stoke ’s equation W here V sed. =sedimentation velocity in cm/sec d=diameter of particle r s =density of disperse phase r o =density of disperse media g= acceleration due to gravity h= viscosity of disperse medium in poise

20. 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.

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

22. Formulation of suspensions: Wetting agents: They are added to disperse solids in continuous phase. Ex: polysorbate 80,20, span etc. Suspending agents: They are added to flocs the drug particles. Thickeners: They are added to increase the viscosity of suspension. Ex: gaur gum, xanthan gum. Buffers and pH adjusting agents: They are added to stabilize the suspension to a desired pH range. Coloring agents: They are added to impart desired color to suspension and improve elegance. Preservative: They are added to prevent microbial growth. e.g. benzoic acid, sodium benzoate, methyl & propyl paraben.

23. Preparation of suspension Step 1: Suspensions are prepared by grinding the insoluble materials in the mortar. To a smooth paste with a vehicle containing the wetting agent. 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.

24. Step 5 : Make up the dispersion to the final volume . Thus suspension is prepared. 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) flocculated agent

25. Packing of Suspension: Pharmaceutical suspension for ideal 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.

26. Ideal requirements of Packaging material It should be inert. It should effectively preserve the product from light, air, and other contamination. It should effectively deliver the product without any difficulty. It should be cheap.

27. Evaluation of suspension Sedimentation method Rheological method Electrokinetic method

28. Sedimentation method: Two parameters are studied for determination of sedimentation. Sedimentation volume. Degree of flocculation.

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

30. It is the ratio of the sedimentation volume of the flocculated suspension , F, to the sedimentation volume of the deflocculated suspension, F’ b= F/F’ The minimum value of b is 1, when flocculated suspension sedimentation volume is equal to the sedimentation volume of deflocculated suspension. Degree of flocculation ( b) b= (Vu/Vo) flocculated (Vu/Vo) deflocculated

31. Rheological method: I t provide information about Settling behaviours. Brookfield viscometer is used study the viscosity of the suspension. It is mounted on Heli-path stand 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. This technique also indicates at which level of the suspension the structure is greater owing to particle agglomeration.

32. B rookfield viscometer Apparatus In the screening study, good suspension show a lesser rate of increase of dial reading as the spindle turns, that is , the curve is horizontal for a longer period.

33. Electrokinetic method Measurement of Zeta-potential using Micro electrophoresis apparatus & Zeta Plus (Brook haven Instruments Corporation , USA) It shows the stability of a disperse system. Zeta Plus Micro electrophoresis apparatus

34. Electrokinetic method Zeta Potential: The zeta potential defined as the difference between the surface of the tightly bound layer (shear plane) & the electroneutral region of the solution. Zeta potential has practical application in stability of systems containing dispersed particles. If the zeta potential is reduced below a certain value , the attractive forces exceed the repulsive forces, and the particles come together.

35. Factors that contribute to appreciable stability of a suspension include: Small particle size: reduce the size of the dispersed particle increases the total surface area of the solid. Greater the degree of subdivision of a given solid the larger the surface area. Increase in surface area means also an increase in interface between the solids and liquids leading to an increase in viscosity of a system. Stability of suspension

36. Increasing the viscosity- increasing the viscosity of the continuous phase can lead to the stability of suspensions. Rate of sedimentation can be reduced by increase in viscosity. Viscosity increase by addition of thickening agents to the external phase Rate of release of a drug from a suspension is also dependent on viscosity. Temperature- Another factor which negatively affects the stability of suspension is fluctuation of temperature. Temperature fluctuation can lead to caking and claying

37. Storage requirements & labelling Label: Shake well before use. Do not freeze. Protect from direct sunlight (for light sensitive drugs). In case of dry suspensions powder the specified amount of vehicle to be mixed may be indicated clearly on label. Storage: Suspension should be stored in cool place but should not kept in a refrigerator. Freezing at very low temperatures should be avoided which may lead to aggregation of suspended particles. Stored at controlled temperature from 20-25 o C .

38. Nano suspensions. Taste masked pharmaceutical suspensions. Sustained release suspensions. Recent advances in suspension

39. Nano suspension Nano suspensions are the biphasic colloidal dispersions of nanosized drug particles stabilized 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. They have average diameter of particle 200-600nm.

40. Taste masked pharmaceutical suspension 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. The taste masking approaches for suspensions are: Polymer coating of drugs. Encapsulation with basic drugs. Coating and pH control.

41. 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

42. 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 Example: copolymer of dimethyl ammonium methyl methacrylate). The drug after encapsulation are suspended, dispersed or emulsified in suspending medium to give the final dosage form.

43. 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.

44. 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,)

45. Sustained release suspension 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. 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