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  1. 1. DRUG DISSOLUTION 1 Mr:Roshan G Bodhe Research Scholar, M. Pharm. (Pharmaceutics) R. C Patel Institute of Pharmaceutical Education and Research, Shirpur
  2. 2. CONTENTS 2 • Definition • Theories of Drug Dissolution • Mechanism of dissolution • Factors affecting Drug Dissolution • Intrinsic dissolution rate and its factors • In-vitro dissolution testing models
  3. 3. Definition- 3 • 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.
  4. 4. 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. 4
  5. 5. The rate of dissolution depends on: • nature of the solvent and solute • temperature (and to a small degree pressure) • degree of under saturation • presence of mixing • interfacial surface area • presence of inhibitors (e.g., a substance adsorbed on the surface). 5
  6. 6. Theories of Drug Dissolution 6 I. Diffusion layer model/Film Theory II. Danckwert’s model/Penetration or surface renewal Theory III. Interfacial barrier model/Double barrier or Limited solvation theory.
  7. 7. I. Diffusion layer model/Film Theory :- 7 • It involves two steps :- a. Solution of the solid to form stagnant film or diffusive layer which is saturated with the drug b. Diffusion of the soluble solute from the stagnant layer to the bulk of the solution; this is r.d.s in drug dissolution.
  8. 8. 8
  9. 9. • The rate of dissolution is given by Noyes and Whitney: Where, dc/dt= dissolution rate of the drug K= dissolution rate constant Cs= concentration of drug in stagnant layer Cb= concentration of drug in the bulk of the solution at time t = k (Cs- Cb) dc dt 9
  10. 10. Modified Noyes-Whitney’s Equation - dC= DAKw/o (Cs – Cb ) dt Vh Where, D= diffusion coefficient of drug. A= surface area of dissolving solid. Kw/o= water/oil partition coefficient of drug. V= volume of dissolution medium. h= thickness of stagnant layer. (Cs – Cb )= conc. gradient for diffusion of drug. 10
  11. 11. • This is first order dissolution rate process, for which the driving force is concentration gradient. • This is true for in-vitro dissolution which is characterized by non-sink conditions. • The in-vivo dissolution is rapid as sink conditions are maintained by absorption of drug in systemic circulation i.e. Cb=0 and rate of dissolution is maximum. 11
  12. 12. • Under sink conditions, if the volume and surface area of the solid are kept constant, then dC dt • This represents that the dissolution rate is constant under sink conditions and follows zero order kinetics. = 12 K
  13. 13. Conc.ofdissolveddrug Time zero order dissolution under sink condition first order dissolution under non-sink condition 13 Dissolution rate under non-sink and sink conditions.
  14. 14. • Hixon-Crowell’s cubic root law of dissolution takes into account the particle size decrease and change in surface area, W0 1/3– W1/3= Kt Where, W0=original mass of the drug W=mass of drug remaining to dissolve at time t Kt=dissolution rate constant. 14
  15. 15. II. Danckwert’s model/Penetration or surface renewal Theory :- 15 • Dankwert takes into account the eddies or packets that are present in the agitated fluid which reach the solid-liquid interface, absorb the solute by diffusion and carry it into the bulk of solution. • These packets get continuously replaced by new ones and expose to new solid surface each time, thus the theory is called as surface renewal theory.
  16. 16. 16
  17. 17. • The Danckwert’s model is expressed by equation Where, m = mass of solid dissolved Gamma (γ) = rate of surface renewal dt dm = dt A (Cs-Cb). γDV dC = 17
  18. 18. III. 18 • • • This model can be extended to both the diffusion layer model and danckwert’s model Interfacial barrier model/Double barrier or Limited solvation theory Based on solvation mechanism, and it is function of solubility rather than diffusion When considering dissolution of the crystal have different interfacial barrier , given by the following equation G = Ki (Cs - Cb) Where, G = dissolution rate per unit area, Ki = effective interfacial transport constant.
  19. 19. Mechanism of dissolution Dissolution test determines the cumulative amount of drug that goes into solution as a function of time Steps involved liberation of the solute or drug from the formulation matrix (disintegration) dissolution of the drug (solubilization of the drug particles) in the liquid medium The overall rate of dissolution depends on the slower of these two steps
  20. 20. Mechanism of dissolution First Step Cohesive properties of the formulated solid dosage form drug play a key role disintegration and erosion semi- solid or liquid formulations, the dispersion of lipids or partitioning of the drug from the lipid phase is the key factor If the first step of dissolution is rate-limiting, then the rate of dissolution is considered to be disintegration controlled
  21. 21. Mechanism of dissolution Second Step Solubilization of the drug particles depends on the physicochemical properties of the drug such as its chemical form (e.g., salt, free acid, free base) and physical attributes
  22. 22. • Factors affecting Drug Dissolution :- 1. Factors related to apparatus and test parameters 2. Factors relating to the physicochemical properties of drug. 3. Factors relating to the dosage forms. 22
  23. 23. A.FACTORS RELATED TO APPARATUS AND TEST PARAMETERS 1.Temperature 2.Agitation 3.Dissolution medium,pH 23
  24. 24. B. Factors relating to the physicochemical properties of drug- 24 i. Solubility- • Solubility plays important role in controlling dissolution from dosage form. • From Noyes-Whitney equation it shows that aqueous solubility of drug which determines its dissolution rate.
  25. 25. 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. 25
  26. 26. • Effective surface area is directly related to the dissolution rate. • Greater the effective surface area, more intimate the contact between the solid surface and the aqueous solvent and faster the dissolution. 26
  27. 27. iii. Polymorphism and amorphism – 27 • 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.
  28. 28. • 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 28
  29. 29. IV. Salt form of the drug- 29 • 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.
  30. 30. iv. Hydrates/solvates – 30 • The stoichiometric type of adducts where the solvent molecules are incorporated in the crystal lattice of the solid are called as the solvates. • When the solvent in association with the drug is water, the solvate is known as hydrate. • • The organic solvates have greater aqueous solubility than the nonsolvates. E.g. – chloroform solvates of griseofulvin is more water soluble than their nonsolvated forms
  31. 31. B. Factors relating to the dosage forms – 31 i. Pharmaceutical excipients –       Vehicle Diluents Lubricants Binders Surfactants colorants
  32. 32. INTRINSIC DISSOLUTION RATE The intrinsic dissolution rate is defined as the dissolution rate of pure substances under the condition of constant surface area, agitation-stirring speed, pH and ionic-strength of the dissolution medium. 32
  33. 33. • Dissolution is dependent on many factors, both intrinsic and extrinsic. • The definition of intrinsic dissolution rate, IDR is the dissolution rate when extrinsic factors are held constant for a pure substance. • Intrinsic factors are defined by the solid state properties of the pure substance, such as; 33
  34. 34. • • • • • • 34 Crystal habit Crystallinity Amorphism Polymorphism Pseudo-polymorphism Particle size and surface area The above are predetermined factors which are different for each substance.
  35. 35. • • • • • • 35 IDR is the rate of dissolution of pure substances when extrinsic factors as the following are kept constant; Agitation Surface area of tablet or sample Temperature pH Buffer strength Viscosity of the dissolution medium • Ionic strength of the dissolution medium
  37. 37. NON SINK METHODS 37 • • 1) NATURAL CONVECTION NONSINK METHODS a) Klein solvmeter method b) Nelson Hanging Pellet Method c) Levy static Disk Method 2) FORCED CONVECTION NON SINK METHODS a) Tumbling method b) Levy Method Or Beaker Method c) Rotating Disk Method d) Particle Size Method e) Oscillating Tube Method f) USP Rotating Basket Apparatus
  38. 38. SINK METHODS 38 • • 3) FORCED CONVECTION SINK DEVICES a) Wurster Pollis adsorption method b) Partition method c) Dialysis method d) Rotating disk apparatus 4) CONTINUOUS FLOW/FLOWTHROUGH METHODS a) Pernarowski method b) Langenbucher method c) Baun and Walker d) Tingstad and Reigelman f) Modified column apparatus g) Cakiryildiz method h) Takenaka method
  39. 39. NATURAL CONVECTION NONSINK METHOD: 39 • In this method the density difference is utilized for replacing the surrounding dissolution medium.
  40. 40. Klein solvmeter method: • • • • • carrier device surrounded by float and is immersed in dissolution medium. measuring bar connects float to the to the calibration scale above. when dosage form is placed in the boat the bar moves down and as dosage form dissolves it moves upwards. Amount of the dosage from dissolved is revealed from the difference in the height of the bar movement. Dosage form disintegrated cannot be evaluated and concentration effects on dissolution rate and measuring system is not accountable. 40
  41. 41. Nelson Hanging Pellet Method: • • • aluminum strip having provision for holding dosage form which is in turn connected to a perfectly maintained balance arm of strip. the dosage form is mounted on the aluminum strip with the help of wax. since only one part of the dosage form is exposed to the dissolution, this method can be employed to know the intrinsic dissolution rate. To prevent the disintegration further high pressures can be applied and also constant surface area can be maintained by reducing permeability of the compact. 41
  42. 42. Levy static Disk Method: • • • • Acrylic holder containing dosage form is inserted into a known volume of medium (25ml) through rubber stopper. The vial is inverted and is placed in a incubator at 37 C. At specified time intervals the vial is removed from the incubator and the samples are analyzed. Intrinsic dissolution is possible if the dosage form is mounted on to the acrylic holder such that only one face of it is exposed. disadvantages - effect of concentration on the dissolution medium is ignored and the surface area of the dosage form while dissolving is assumed constant which is not impractical. 42
  43. 43. FORCED CONVECTION NON SINK METHODS: • As the name indicates the devices are agitated to induce relative motion between dissolution medium and the dissolved particles. Agitation is implemented by stirring, rotation or oscillation. 43
  44. 44. Tumbling method: • • dosage form with the dissolution medium is placed in test tube that is in turn clamped to the revolving drum which is rotated at a speed of 6 to 12 rpm in a water bath at 370C. The test tubes are removed and the medium is assayed at regular time points for the dissolved drug amount. Test tube dosage 44 Rotating drum
  45. 45. Levy Method Or Beaker Method: • • • 400ml beaker is placed in a constant temperature bath kept at 37 C. A 5 centimeter three blade polyethylene stirrer is centered and rotated at 59 rpm. The tablet is dropped at the side of the beaker and samples are taken at specified time points for analysis. This method is amenable to measure intrinsic dissolution rate. 45 stirrer Thermoregulated dissolution vessel Wing blade stirrer Dissolution medium Dosage form
  46. 46. Rotating Disk Method: • • • ideally suitable for measurement of the intrinsic dissolution rate with those which maintain a constant surface area. The dosage forms which are prepared by hydraulic press are mounted onto the Plexiglas holder that is in turn attached to metal shaft which is stirred at a constant speed. This holder is immersed at a depth of 1 inch in a 500ml dissolution medium that is maintained at 370C and rotated at 555rpm. Rotating disk Dissolution medium 46 Thermoregulated dissolution vessel
  47. 47. Particle Size Method: • • • primary purpose is to incorporate vigorous agitation so as to suspend the dissolved particles. The changes in the particles size is measured with the help of coulter counter. The particle size and the surface area data together will enable to know the dissolution kinetics. but, practically chemical analysis outweigh the particle size analysis and this method is not suitable for dosage forms. 47
  48. 48. Oscillating Tube Method: • • • • Broadbent have employed BP (British pharmacopoeia) disintegration apparatus for dissolution. The difference is that only one tablet is placed instead of five and immersed in 200 ml of dissolution medium. advantage- both disintegration as well as dissolution can be observed simultaneously. With the help of this device only total dissolution rate can be determined because constant surface area cannot be maintained due to the extreme agitation and abrasion caused by the mesh. Other limitations. •Increasing solute concentration •lack of reproducibility • intensity of agitation • constancy of agitation 48
  49. 49. USP Rotating Basket Apparatus: 49 • The rotating basket of 10 mesh is placed at a distance of 2.5 cm from the bottom of the vessel, is centered within 2 mm of the centerline of the vessel. • The shaft is rotated at 100 rpm and temperature of the medium is maintained at 37 C. • Aliquots should preferably be withdrawn midway between the surface of the medium and the bottom of the vessel and midway the cylindrical edge of the basket and wall of the vessel.
  50. 50. Speed (25-150rpm) Shaft Centering or tilt eccentricity Sampling point flask 50 basket basket position
  51. 51. Magnetic basket dissolution apparatus: 51 • • • • • • it enables reproducible and precise placement of the dosage form. It consists of a beaker (800 ml)and a magnetic basket of 50 mm long and 11 mm inner diameter whose exact placement is ensured by a magnetic bar placed outside the beaker at the bottom. The additional modifications include the basket is constructed of epoxy resin that inert in both acidic and basic environment. the agitation is provided by a three bladed, blades of 18 mm diameter set at an angle of 60 angle and 45 0from the vertical shaft of 7 mm, propeller with a diameter of 51mm. The dissolution container, of 600 ml of medium is in turn immersed in a water bath so as to maintain the desired 37 c. propeller is immersed at a depth of 41 mm of the beaker For the adjustment of the pH electrodes are placed at a depth of 27 mm from the vertical top and 7 mm from the horizontal beaker walls. With all these the device can be used to characterize inter product variation of products.
  52. 52. stirrer Magnetic basket magnet 52 Sampling port
  53. 53. Modified USP Basket apparatus: 53 • • • • • It is known fact that the flow of the medium should be sufficient for the dosage form such that the disintegrated particles during the dissolution should be swept by the medium from the basket screen. in order to fulfill this, the effort done was to change the direction of the basket by the angle of 90 0by bending the stirring rod so as to get L- shaped configuration. a cylindrical SS screen of 24-mesh was seam welded and fitted over the Teflon holder so as to hold the tablet firmly. This device facilitates the increase in the dissolution rate because of the enhanced flow of the medium. wandering of the dosage form within the basket is the major disadvantage while the advantages include economically feasible and simple construction, dual functionality i.e. both holding the dosage form as well as stirring of the holder.
  54. 54. Dissolution vessel 54 USP basket
  55. 55. Rotating Filter-Stationary Basket Apparatus: 55 • • • • This device consists of stationary basket, a fluid container and filter assembly with an external magnetic stirrer. the dissolution medium is contained in a fluid container of 1.5 l volume capacity. There are a total of 4 ports: For sample, for glass tube to favor the withdrawal of the aliquots, another for replacement of the fresh medium and other for thermometer to check the temperature. the basket is of 12 mesh which is kept stationary held at 2 to 5 cm from the bottom of the fluid container. the dosage form is placed in the filter providing different intensities of agitation.
  56. 56. Sampling port thermometer 56 Rotating filterStationary basket
  57. 57. USP Paddle method: It is also called USP apparatus-2, the paddle should be centered within 0.2 cm of the centerline of the vessel, 2.5 + 0.2 cm from the bottom of the vessel. 57 • • • • the shaft should rotate at a speed of 100 rpm with a temperature of about 37 0C. the dosage form should experience some movement under the paddle till disintegration progresses. once disintegration occurs, aliquots should be drawn preferably from midway upper edge of the paddle and the surface of the medium between the wall of the vessel and stirrer shaft. the lower portion of vessel should be hemispherical and uniform in all aspects of weight, inside diameter and curvature. In case of floating dosage forms stainless steel or glass helix is attached to the dosage form. in this case excess abrasion and wear of the dosage forms due to the friction from the inner surfaces is observed, affecting the micro environment adversely.
  58. 58. 58 Speed 25-150rpm shaft Centering or tilt eccentricity Sampling point flask paddle Paddle position Stainless or glass helix
  59. 59. • 59 • Forced Convection Sink Devices: An ideal dissolution process is one which will mimic the invivo conditions by maintaining perfect sink conditions. these perfect sink conditions can be maintained by either of the following systems: a) Fixed fluid volume. b) Multiple phase c) Continuous fluid flow d)Fixed fluid volume: in this system the fluid volume is kept fixed such that the volume is sufficient to maintain the drug concentration below 10-20% of its solubility. fro example USP apparatus I and II. e)Multiple phase: upon dissolution, the drug is either partitioned into water immiscible phase or adsorbed onto the solid interface. f)Continuous fluid flow: this system helps to know the solubility irrespective of its solubility or dosage strength. the dissolved drug along with the medium is removed constantly and is replaced by fresh medium.
  60. 60. Wurster-Polli Adsorption Method: • in this method the dissolved drug is adsorbed by charcoal or bentonite. • care should be taken regarding the adsorbent, adsorbent should not alter the viscosity of the medium 60
  61. 61. Partition Method: • In this device organic phase is employed to remove the dissolved drug such that the drug would partition between the lipophilic and hydrophilic phases. • selection of organic phase plays a critical role. 61
  62. 62. Dialysis Method: • In this method dialysis membrane having minimal equilibrium time, adequate physical strength and solid particle retention is employed. • in this device dissolution medium is placed on one side of the membrane and the next side is dosage form and the assembly is rotated at 15 rpm speed. • aliquots are withdrawn at the distal end. • the advanced method included baffled rotating round bottomed flask at 37 0Csuch that sloshing action is provided. 62
  63. 63. 63
  64. 64. Rotating Flask apparatus: • • • In this method a flask containing dissolution medium is rotated around its horizontal axis in a water bath kept at a temperature of 37 C. The flask has a provision of sampling such that aliquots can be withdrawn and the fresh medium can be replaced back. This apparatus is best suited for oral solid dosage forms like tablets and capsules since they do not require much agitation. 64
  65. 65. Flow Through Devices: • For the drugs which saturate rapidly in large volumes of medium, USP apparatus will not serve the purpose. • For this the suitable device is flow through device. In this device unlimited quantity of fresh dissolution is available. • A dosage form is placed in a small cell and is subjected to a stream of fresh dissolution media. 65
  66. 66. Continuous Flow Apparatus by Pernarowski • • • It consists of 10 mesh stainless steel basket stirrer assembly with an adjustable stirrer. the chamber is 3 necked flask of 33 mm and the rest two of 20 mm diameter. 1L of medium is employed within the flask. the dissolution characteristics are dependent upon the amount of medium pumped through the Type 1 fluid 66 Type 2 fluid Two way stopper Glass tube dissolution chamber. Stirring shaft Suction to sampling basket
  67. 67. Langenbucher Column-type flow through Method: 67 • • • This device is according to the dissolution basic design . The screen is constructed such that the medium flows equally through the entire cross section in a laminar pattern. This is again closed by a secondary screen, filter which prevents the undissolved drug from being eluted.
  68. 68. (a) B-particle bed, C-cell, F1&F2-screens, H-heat exchanger, h-height of 68 x-circulatory factor,the cell, P1,P2-volumetric pumps, R-liquid reservoir, Q,xQ,(1-x)Q=volumetric flow rates, (b) And (c) =designs of flow through cells (b) (c)
  69. 69. Continuous Flow apparatus by Baun and walker: • • • Also called as constant- circulation apparatus. This consists of a cell, holding dosage form, a reservoir with dissolution medium, a pump and water bath. there is a constant circulation apparatus that can be altered depending upon the dosage form. Oscillating pump 69 reservoirDissolution cell Water bath
  70. 70. Continuous flow apparatus by Tingstad and Riegelman: • • • • a cylindrical glass cell of 6.1 cm long and 1.9 cm in diameter constructed with two glass filter funnels is used. The dissolution cell has filter membranes which prevents the solid particles from being analyzed. There are also external valves to control the excess flow of solvent into the system. the air trap averts air bubbles. The complete assembly is immersed in a temperature bath kept at 37 C. 70
  71. 71. Flow-Through Modified Column apparatus: • • • • The device consists of filter of 14 M -size made of nylon. the tubing from the pump is connected to the dissolution cell. the Teflon faced stainless steel supports the screen resting on the bottom half of the filter holder. The direction of the flow is such that the particles do not fall through the screen. the rest of the process is the same. 71
  72. 72. Continuous flow apparatus by Takenaka 72 • • • • The release of drug is measured with the aid of in vitro simulator device consisting of flow type dissolution container. The dosage form is placed in the basket rotating at 94 rpm with 300 ml of medium. then the medium is removed by collecting reservior using peristaltic pump. aliquots are withdrawn using syringe and then filtered using Whatman filter paper and the same volume is replaced immediately with fresh medium.
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