Dissolution testing
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  • 1. DISSOLUTION TESTING12/08/12
  • 2. CONTENTS Definition Factors affecting Drug Dissolution Study of various approaches to improve dissolution of poorly soluble drug In-vitro dissolution testing models References 12/08/12 2
  • 3. Definition- Dissolution is a process in which a solid substance solubilizes in a given solvent i.e. mass transfer from the solid surface to the liquid phase. Rate of dissolution is the amount of drug substance that goes in solution per unit time under standardized conditions of liquid/solid interface, temperature and solvent composition. 12/08/12 3
  • 4. DISSOLUTION PROCESS OF SOLID DOSAGEFORMS 12/08/12 4
  • 5.  Factors affecting Drug Dissolution :-A. Factors relating to the physicochemical properties of drug.B. Factors relating to the dosage forms. 12/08/12 5
  • 6. A. Factors relating to the physicochemical properties of drug-i. Solubility- Solubility plays important role in controlling dissolution from dosage form. Aqueous solubility of drug is a major factor for determines dissolution rates. 12/08/12 6
  • 7. ii. Particle size and effective surface area of the drug – Particle size and surface area are inversely related to each other. Two types of surface area – Absolute surface area which is the total surface area of any particle. Effective surface area which is the area of solid surface exposed to the dissolution medium. 12/08/12 7
  • 8.  Effectivesurface area is directly related to the dissolution rate. Greaterthe effective surface area, more intimate the contact between the solid surface and the aqueous solvent and faster the dissolution. 12/08/12 8
  • 9. iii. Polymorphism and amorphism – When a substance exists in more than one crystalline form, the different forms are designated as polymorphs and the phenomenon as Polymorphism. Stable polymorphs has lower energy state, higher M.P. and least aqueous solubility. Metastable polymorphs has higher energy state, lower M.P. and higher aqueous solubility. 12/08/12 9
  • 10.  Amorphous form of drug which has no internal crystal structure represents higher energy state and greater aqueous solubility than crystalline forms. E.g.- amorphous form of novobiocin is 10 times more soluble than the crystalline form. Thus,the order for dissolution of different solid forms of drug is – amorphous > metastable > stable 12/08/12 10
  • 11. IV. Salt form of the drug- Dissolution rate of weak acids and weak bases can be enhance by converting them into their salt form. With weakly acidic drugs, a strong base salt is prepared like sodium and potassium salts of barbiturates and sulfonamides. With weakly basic drugs, a strong acid salt is prepared like the hydrochloride or sulfate salts of alkaloidal drugs. 12/08/12 11
  • 12. B. Factors relating to the dosage forms –i. Pharmaceutical excipients – Diluents Lubricants Binders Surfactants Colorants Disintegranting Agents 12/08/12 12
  • 13. ii. Manufacturing processes -Method of granulation –Wet granulationDirect compressionAgglomerative phase of communication (APOC) 12/08/12 13
  • 14.  Compression Force :-Rate of drug dissolution A B C D Compression force Influence of compression force on dissolution rate of tablet 12/08/12 14
  • 15.  Factors contributing to the faster dissolution rate of a drug dispersed in eutectic are :-a. Reduction of particle size.b. An increase in drug solubilityc. Absence of aggregation and agglomeration between the fine crystallites of pure drug.d. Excellent wettability and dispersibility of a drug as the encircling soluble carrier readily dissolves and causes the water to contact and wet the particles.e. Crystallization of the drug in metastable form after solidification from the fused solution which has high solubility 12/08/12 15
  • 16. IN-VITRODISSOLUTIONTESTING MODELS 12/08/12 16
  • 17. FACTORS TO BECONSIDERED WHILEDESIGNING OF ADISSOLUTION TEST 12/08/12 17
  • 18. FACTORS RELATING TO THEDISSOLUTION APPARATUS Design of the container Size of the container Shape of the container Nature of agitation Speed of agitation Performance precision of the apparatus 12/08/12 18
  • 19. FACTORS RELATING TO THEDISSOLUTION FLUID Volume Temperature Deaeration of dissolution medium PH 12/08/12 19
  • 20. 12/08/12 20
  • 21. CLASSIFICATION There are basically three general categories of dissolution apparatus :1. Beaker methods2. Open flow-through compartment system3. Dialysis concept 12/08/12 21
  • 22. 1. BEAKER METHODS 12/08/12 22
  • 23. ROTATING BASKETAPPARATUS(APPARATUS 1) It is basically a closed-compartment, beaker type apparatus. It comprising of a cylindrical glass vessel with hemispherical bottom of one litre capacity partially immersed in a water bath. A cylindrical basket made of #22 mesh is located centrally in the vessel at a distance of 2 cm from the bottom and rotated by a variable speed motor through a shaft. 12/08/12 23
  • 24. CONTD….. All metal parts like basket and shaft are made of stainless steel 316. 12/08/12 24
  • 25. ROTATING PADDLEAPPARATUS(APPARATUS 2) Here, basket is replaced with a stirrer. A small, loose, wire helix may be attached to the dosage form that would otherwise float. The position and alignment of the paddle are specified in the official books. 12/08/12 25
  • 26. THE RECIPROCATINGCYLINDER METHOD(APPARATUS 3) This method adopts the USP disintegration “basket and rack” assembly for the dissolution test. The disks are not used. This method is less suitable for precise dissolution testing due to the amount of agitation and vibration involved. E.g. Chlorpheniramine ER tablets, Carbamazepine chewable tablet 12/08/12 26
  • 27. 12/08/12 27
  • 28. PADDLE OVER DISK METHOD(APPARATUS 5)  Modification of Apparatus 2.  Here, stainless steel disk designed for holding transdermal system at the bottom of the vessel.  The disk/device should not , react with, or interfere with the specimen being tested.  The disk holds the system flat and is positioned such that the release surface is parallel with the bottom of the paddle blade. 12/08/12 28
  • 29. 12/08/12 29
  • 30. CYLINDER METHOD(APPARATUS 6) Same as apparatus 1,except to replace the basket and shaft with a S.S. cylinder stirring element. Temperature - 32 ± 0.5° The dosage unit is placed on the cylinder. Distance between the inside bottom of the vessel and cylinder is maintained at 25 ± 2 mm. 12/08/12 30
  • 31. RECIPROCATING HOLDERMETHOD (APPARATUS 7) The assembly consists of a set of calibrated solution containers, a motor and drive assembly to reciprocate the system vertically. Various type of sample holder are used. 12/08/12 31
  • 32. 2. OPEN FLOW-THROUGH COMPARTMENT SYSTEM The dosage form is contained in a small vertical glass column with built in filter through which a continuous flow of the dissolution medium is circulated upward at a specific rate from an outside reservoir using a peristaltic or centrifugal pump. Dissolution fluid is collected in a separate reservoir. E.g. lipid filled soft Gelatin capsule 12/08/12 32
  • 33. 12/08/12 33
  • 34. 12/08/12 34
  • 35. ADVANTAGES No stirring and drug particles are exposed to homogeneous, laminar flow that can be precisely controlled. All the problems of wobbling, shaft eccentricity, vibration, stirrer position don’t exist. There is no physical abrasion of solids. Perfect sink conditions can be maintained. 12/08/12 35
  • 36. DISADVANTAGES Tendency of the filter to clog because of the unidirectional flow. Different types of pumps, such as peristaltic and centrifugal, have been shown to give different dissolution results. Temperature control is also much more difficult to achieve in column type flow through system than in the conventional stirred vessel type. 12/08/12 36
  • 37. 3. DIALYSIS SYSTEM Here, dialysis membrane used as a selective barrier between fresh solvent compartment and the cell compartment containing dosage form. It can be used in case of very poorly soluble drugs and dosage form such as ointments, creams and suspensions. 12/08/12 37
  • 38. 12/08/12 38
  • 39. 12/08/12 39
  • 40. DISSOLUTION TESTING FOR NDDS OCULAR DRUG DELIVERY 12/08/12 SYSTEMS A number of methods are used to conduct in-vitro evaluation of controlled ocular drug delivery systems. (a) Bottle method In this method, dosage forms are placed in the culture bottles containing phosphate buffer at pH 7.4. The culture bottles are shaken in a thermostatic water bath at 37°C. A sample of medium is taken out at appropriate 40 intervals and analyzed for drug contents.
  • 41. 12/08/12 b) Modified rotating basket method In this method, dosage form is placed in a basket assembly connected to a stirrer. The assembly is lowered into a jacketed beaker containing buffer medium. The temperature of system is maintained at 41 37°C. A sample of medium is taken out at
  • 42. MICROSPHERES Beaker method The dosage form in this method is made to adhere at the bottom of the beaker 12/08/12 containing the medium and stirred uniformly using over head stirrer. Volume of the medium used for the studies varies from 50-500 ml and the stirrer speed form 60-300 rpm. Modified Keshary Chien Cell A specialized apparatus was designed in the laboratory. It comprised of a Keshary Chien cell containing distilled water (50ml) at 37 0 c as dissolution medium. TMDDS (Trans Membrane Drug Delivery System) was placed in a glass tube fitted with a 10# sieve at the bottom which reciprocated in the medium at 30 strokes per min. Samples are removed at appropriate time intervals and analyzed for drug content. 42
  • 43. DISSOLUTION STUDY OFCHEWING GUM AS ADOSAGE FORM 12/08/12 43
  • 44. 12/08/12 TEMP-37.c Chew Rate-60 chew/min. Unspecified buffer (ph close to 6)-20 ml 44
  • 45. DISSOLUTION ACCEPTANCECRITRIA 12/08/12 Q –Value – Define as a percentage of drug conten dissolved in a given time period. 45
  • 46. DISSOLUTION ACCEPTANCECRITRIASTAGE No. of Dosage units Acceptance criteria 12/08/12 testedS1 6 No Dosage unit is less then Q+5%S2 6 Average Of 12 dosage units (S1+S2) and no dosage unit is less then Q-15%S3 12(6+6+12=24) Average of 24 dosage units >- And not more than two dosage units are less than Q-15% and No dosage unit is less 46 than Q-25%
  • 47. METHOD FOR COMPARISONOF DISSOLUTION PROFILE 12/08/12 Difference factor (F1 Value)- Define as calculate the % Difference between 2 curves at each time point and is a measurement of the relative error between 2 curves. f1= {[Σ t=1n |Rt-Tt|] / [Σ t=1n Rt]} ×100. Values range from 0 to 15 47
  • 48.  Similarity Factor (F 2 value)-define as measurement of similarity in % Dissolution between two curve. Where Rt and Tt = cumulative % dissolved for reference and test Values range from 50 to 100 12/08/12 48
  • 49. REFERENCES D.M.Brahmankar, Biopharmaceutics and pharmacokinetics- A Treatise; Vallabh Prakashan, page no. 20–31. Leon Shargel, Applied Biopharmaceutics & Pharmacokinetics; 4th edition, page no. 132-136. TheIndian Pharmacist, February 2008, page no.10-12 12/08/12 49
  • 50. REFERENCES United States Pharmacopoeia – 24, page no.: 1942 – 1951. “Current perspectives in dissolution testing of conventional and novel dosage forms”, by Shirazad Azarmi, Wilson Roa, Raimar Lobenberg, Int. jou. Of pharmaceutics 328(2007)12 – 21. Alton’s pharmaceutics “ The design and manufacturing of medicines”, by Michael E. Alton, page no.: 21 – 22. 12/08/12 50
  • 51. 12/08/12Thankyou 51