Dissolution study-Dissolution studies Factor affecting dissolution and Invitro- Invivo Correlation

Dissolution studies Factor affecting dissolution and Invitro- Invivo Correlation

1. Dissolution 1 Dissolution studies Factor affecting dissolution and Invitro - Invivo Correlation By Yogesh K. Chaudhari M Pharm 1 st Yr ) Mumbai University

2. What is dissolution? Dissolution is a process in which a solid substance solubilizes in a given solvent to yield a solution i.e . mass transfer from the solid surface to the liquid phase . It depends on the affinity between the solid substance and solvent . Dissolution 2

3. It quantifies the speed of the dissolution process. It depends on chemical natures of the solvent and solute , temperature (and possibly to a small degree, the pressure ), degree of undersaturation , presence of a means of mixing , interfacial surface area , and the presence of " inhibitors " (e.g., substances adsorbed on the surface ). It is defined as the amount of drug substance that goes in solution per unit time under standardized conditions of temperature, pH and solvent composition and constant surface area. Rate of dissolution Dissolution 3

4. Need of dissolution Drug in the blood and the body Dissolution 4

5. Initial mechanical lag . Wetting of dosage form . Penetration of dissolution medium . Disintegration . De-aggregation. Dissolution . Occlusion of some particles. Mechanism of dissolution The S-Shaped dissolution curve of solid dosage form Dissolution 5

6. For optimization of formulation and quality control . To identify the manufacturing variable , like the binding agent effect, mixing effects , granulation procedure, coating parameters and comparative profile studies. To show that the release of drug from the tablet is close to 100%. To show that the rate of drug release is uniform batch to batch. And to show that release is equivalent to those batches proven to be bioavailable and clinically effective . Application of dissolution studies Dissolution 6

7. Theories of dissolution Diffusion layer model Danckwert’s model Interfacial barrier model Dissolution 7

8. Also called ‘ film theory ’. 2 steps are involved: Interaction of solvent with drug surface to form a saturated drug layer , called stagnant layer . Diffusion of drug molecules from stagnant layer into bulk of the system. 1. Diffusion layer model Dissolution 8

9. Noyes- Whitney’s equation: where , dC/ dt = dissolution rate of the drug, k = dissolution rate constant, C s = concentration of drug in the stagnant layer, and C b = concentration of drug in the bulk of the solution at time t. Diffusion layer Model Dissolution 9

10. Modified Noyes-Whitney’s equation : Where, D = diffusion coefficient ( diffusivity ) of the drug A = surface area of the dissolving solid K w/o = water/oil partition coefficient of the drug. V = volume of dissolution medium h = thickness of the stagnant layer (C s – C b )= concentration gradient for diffusion of drug. Dissolution 10

11. - Noyes- Whitney’s equation represents first order kinetics , for which the driving force is concentration gradient. - This is true for in- vitro dissolution which is characterized by non sink condition . - The in- vivo dissolution is rapid as sink conditions are maintained by absorption of drug in systemic circulation I.e. C b = 0 . - Under sink condition, dissolution rate follows zero order kinetics . Dissolution rate under sink and non- sink conditions Dissolution 11

12. The Hixson-Crowell Cube Root Law Major assumptions in Noyes-Whitney relationship is that the surface area remains constant throughout dissolution process . However , size of drug particles will decrease as drug dissolves . and thus changes the effective surface area. Thus , Hixson & Crowell modified the equation to represent rate of appearance of solute by weight in solution . where , M = initial mass of powder M = mass of powder dissolved in time, t k = cube root dissolution rate constant Dissolution 12

13. 2. Danckwert’s Model Also called “ Penetration or Surface Renewal Theory ”. Danckwert’s 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.   Dissolution 13

14. Where, m = mass of solid dissolved, and γ = rate of surface renewal (or the interfacial tension) Danckwert’s Model Dissolution 14

15. 3. Interfacial Barrier Model Drug dissolution is a function of solubility rather than diffusion . Intermediate concentration exist at the interface as a result of solvation. Dissolution rate per unit area, G is given by, w here, Ki = effective interfacial transport constant. Dissolution 15

16. Factors affecting dissolution rate Factors related to Physicochemical Properties of Drug Factors related to Drug Product Formulation Processing Factor Factors Relating Dissolution Apparatus Factors Relating Dissolution Test Parameters Dissolution 16

17. Factor related to physicochemical properties of drug Particle size of drug There is a direct relationship between surface area of drug and its dissolution rate . Since, surface area increases with decrease in particle size , higher dissolution rates may be achieved through reduction of particle size. E.g. Micronisation of non-hydrophobic drug like griseofulvin leads to increase in dissolution rate. Micronisation of hydrophobic powders can lead to aggregation and floatation, when powder is dispersed into dissolution medium. E.g. hydrophobic drugs like aspirin, phenacetin and phenobarbital shows decrease in dissolution rate, as they tend to adsorb air at the surface and inhibit their wettability . Dissolution 17

18. 2. DRUG SOLUBILITY - Solubility of drug plays a prime role in controlling its dissolution from dosage form. Aqueous solubility of drug is a major factor that determines its dissolution rate . - E.g. Poorly soluble drug : griseofulvin, spironolactone H ydrophilic drug : neomycin Solubility Dissolution 18

19. 3. Solid state characteristics - Solid phase characteristics of drug, such as amorphicity, crystallinity , state of hydration and polymorphic structures have significant influence on dissolution rate. - Anhydrous forms dissolve faster than hydrated form because they are thermodynamically more active than hydrates. E.g . Ampicillin anhydrate faster dissolution rate than trihydrate . - Amorphous forms of drug tend to dissolve faster than crystalline materials. E.g . Novobiocin suspension, Griseofulvin . - Metastable(high activation energy ) polymorphic form have better dissolution than stable form. Dissolution 19

20. 4. Salt formation - It is one of the common approaches used to increase drug solubility and dissolution rate. E.g. sodium and potassium salts of Penicillin G, phenytoin, barbiturates etc . - While in case of Phenobarbital, dissolution of sodium salt was slower than that of weak acid. Dissolution and absorption of an acidic drug administered in salt form Dissolution 20

21. Factors related to drug product formulation Binders and granulating agents: In general, the hydrophilic ( aqueous) binders show better dissolution profile with poorly wettable drugs like phenacetin by imparting hydrophilic properties to the granule surface. Large amounts of such binders increase hardness and decrease disintegration / dissolution rates of tablets. Dissolution 21

22. . Rate of dissolution of phenacetin from ▲powder, ● granules, and ○ tablet in diluted gastric juice. Dissolution 22

23. 2. Disintegrants - Disintegrating agent added before & after the granulation affects the dissolution rate. - E.g. Phenobarbital tablet showed that when copagel (low viscosity grade of Na CMC) added before granulation decreased dissolution rate but if added after did not had any effect on dissolution rate. - Microcrystalline cellulose is a very good disintegrating agent but at high compression force, it may retard drug dissolution. - Starch is not only an excellent diluent but also superior disintegrant due to its hydrophilicity and swelling property. Dissolution 23

24. Effect of starch content on dissolution rate of salicylic acid tablet, ○ 5 %, ● 10 % and × 20 % starch in granules. Dissolution 24

25. 3. Effect of lubricants / anti-frictional agents - The nature , quantity , and quality of lubricants added can affect the dissolution rate . - Lubricants are hydrophobic in nature (several metallic stearate & waxes) which inhibit wettability, penetration of water into tablet so decrease in disintegration and dissolution. - The use of soluble lubricants like SLS and Carbowaxes promote drug dissolution. - E.g. Magnesium stearate , a hydrophobic lubricant, tend to retard the dissolution rate of salicylic acid tablet , whereas sodium lauryl sulfate enhances its dissolution , due to its hydrophobic but surface activity, which increases wetting and better solvent penetration into tablet. Dissolution 25

26. (A) Effect of magnesium stearate on dissolution rate of salicylic acid from rotating disc made from fine salicylic acid powder, ○ 3 % Mg. Stearate, ● no lubricant added. (B) Effect of lubricant on dissolution rate of salicylic acid contained in compressed tablet, × 3 % Mg. Stearate , ● no lubricant, and ○ 3 % Sodium lauryl sulphate. Dissolution 26

27. 4. Coatings - In general, the deleterious effect of various coatings on drug dissolution from a tablet dosage form is in the following order: Enteric coat > Sugar coat > Non- enteric film coat . 5. Buffers - Buffers are sometimes useful in creating the right atmosphere for drug dissolution , e.g . buffered aspirin tablets . 6. Complexing agents - A complexed drug may have altered stability, solubility, molecular size, partition coefficient and diffusion coefficient. - E.g . Enhanced dissolution through formation of a soluble complex of ergotamine tartarate-caffeine complex and hydroquinone-digoxin complex. Dissolution 27

28. Processing factors Method of granulation Wet granulation has been shown to improve the dissolution rate of poorly soluble drugs by imparting hydrophilic properties to the surface of granules . A newer technology called as APOC “Agglomerative Phase of Comminution” was found to produce mechanically stronger tablets with higher dissolution rates than those made by wet granulation. A possible mechanism is increased internal surface area of granules produced by APOC method. Dissolution 28

29. 2. Compression force - The compression process influence density, porosity, hardness, disintegration time & dissolution of tablet . - The curve obtained by plotting compression force versus rate of dissolution can take one of the 4 possible shapes tighter bonding increases hardness 2 . higher compression force cause deformation crushing or fracture of drug particle or convert a spherical granules into disc Shaped particle 3.& 4. both condition Dissolution 29 1 2 3 4

30. Factors related to dissolution apparatus 1. AGITATION R ate of dissolution depends on t ype of agitation used, the degree of laminar and turbulent flow in system, the shape and design of stirrer . Speed of agitation should be such that it prevent turbulence and sustain a reproducible laminar flow , which is essential for obtaining reliable results. So, agitation should be maintained at a relatively low rate . Dissolution 30

31. 2. SAMPLING PROBE POSITION & FILTER - Sampling probe can affect the hydrodynamic of the system. - USP states that sample should be removed at approximately half the distance from the upper surface of basket or paddle and surface of dissolution medium and not closer than 1 cm to the side of the flask . 3. STIRRING ELEMENT ALIGNMENT - The USP / NF states that the axis of the stirring element must not deviate more than 0.2 mm from the axis of the dissolution vessel. Dissolution 31

32. Factors related to dissolution test parameters 1. Vibration - The excessive vibration of dissolution apparatus increases dissolution rates. 2. Vessel design and construction Plastic vessels provide more perfect hemisphere than glass vessels. 3. Temperature control Should be maintained at 37 ± 0.5 º C 4. Dissolution medium parameters Surface tension, pH , Viscosity, De-aeration Dissolution 32

33. Dissolution apparatus Based on the absence or presence of sink conditions, there are two principal types of apparatus: 1 . Closed- compartment apparatus: It is basically a limited volume apparatus operating under non-sink conditions. e.g . beaker type apparatuses such as the rotating basket and the rotating paddle apparatus . 2 . Open- compartment ( continuous flow- through ) apparatus : It is the one in which the dosage form is contained in a column which is brought in continuous contact with fresh , flowing dissolution medium ( perfect sink condition ). 3 . A third type called as dialysis systems are used for very poorly aqueous soluble drugs for which maintenance of sink conditions would otherwise require large volume of dissolution fluid. Dissolution 33

34. USP compendial apparatus Basket type (USP apparatus 1) Paddle type (USP apparatus 2) Reciprocating cylinder type (USP apparatus 3) Flow - through cell type (USP apparatus 4) Paddle over disc type (USP apparatus 5) Cylinder type (USP apparatus 6) Reciprocating holder type (USP apparatus 7) Dissolution 34

35. Basket type (USP apparatus 1 ) Design: Vessel:- Made up of transparent, inert material ( borosilicate glass) Semi hemispherical bottom Capacity : 1000ml Shaft:- Stainless steel 316 Rotates smoothly without significance wobble Basket:- Stainless steel 316 Gold coatings up to 0.0001 inch (2.5 µm) Water bath:- Maintained at 37± 0.5˚c Dissolution 35

36. - Dosage form contained within basket - Dissolution should occur within Basket - pH change by media exchange Uses:- Capsules, tablets, delayed release dosage form, suppositories, floating dosage forms . Agitation:- Rotating stirrer Usual speed: 50 to 100 rpm Disadvantage:- Formulation may clog to 40 mesh screen Dissolution 36 Fig. Basket stirring element

37. Paddle type ( USP apparatus 2 ) Design: V essel :- Made up of transparent, inert material (borosilicate glass) Semi hemispherical bottom Capacity : 1000ml Shaft:- The blade passes through shaft so that bottom of blade fuses with bottom of shaft. Stirring elements :- Made of Teflon for laboratory purpose Stainless steel 316 Water bath:- Maintain at 37± 0.5˚c. Sinkers:- Small loose wire helix used to prevent capsule/tablet from floating. Dissolution 37

38. Dosage form should remain at the bottom center of the vessel. - pH change by media change. Useful for:- Tablets Capsules Agitation:- Rotating stirrer Usual speed: 25 to 100 rpm Advantages:- Easy to use and robust pH change possible Can be easily adapted to apparatus 5 Disadvantages:- Floating dosage forms require sinker Positioning of tablet. Dissolution 38 Fig. Paddle stirring element

39. Dissolution 39

40. Reciprocating cylinder type (USP apparatus 3 ) Design: V essel:- C ylindrical flat bottom glass vessel. Agitation:- R eciprocating G enerally 6-35 cycles/min Volume of dissolution fluids:- 200-250 ml Water bath :- M aintain at 37 ± 0.5˚C Use:- E xtended release Dissolution 40

41. - The apparatus consist of a set of cylindrical flat– bottomed glass vessel equipped with reciprocating cylinders . - The vessels are partially immersed in a suitable water bath of any convenient size that permits holding the temperature at 37 º C ± 0.5 º C during the test. - The dosage unit is placed in reciprocating cylinder & the cylinder is allowed to move in upward and downward direction constantly. Total distance it travels during stroke is 9.9- 10.1 cm. Useful for :- Tablets , Beads , controlled release Formulations. Advantages :- Easy to change the pH-profiles Hydrodynamics can be directly influenced by varying the dip rate. Disadvantages :- S mall volume (max. 250 ml ) Dissolution 41 Fig. Reciprocating cylinder

42. Flow-through cell type ( USP apparatus 4) The apparatus consist of a reservoir for the dissolution medium and a pump that forces medium through the cell holding the test sample . Dissolution fluid is collected in separate reservoir. Temperature is maintained at 37 º C ± 0.5 º C. Useful for:- Low solubility drugs , powders and granules , micro particles, implants . Advantages:- Easy to maintain sink condition. Easy to change media pH Disadvantages:- De-aeration necessary High volumes of media Labor intensive Dissolution 42 Fig. Flow through cell

43. Tablets 12mm Tablets 22.6mm Powder/ Implants Suppository/ Granule soft gelatin capsule Cell types Dissolution 43

44. Paddle over disc type (USP apparatus 5 ) This uses the paddle apparatus 2 with a stainless steel disk designed for holding transdermal system at the bottom of the vessel. The disk holds the system flat and is positioned such that the release surface is parallel with the bottom of the paddle blade. Media volume used is 900 ml which is maintained at 37 º C ± 0.5 º C. Useful for transdermal patches. Disadvantages:- Disk assembly restrict the size of patch . Transdermal patch retainer ( Hanson style) Dissolution 44 Fig. Paddle over disc

45. Cylinder type ( USP apparatus 6 ) This is a modification of Basket apparatus 1 , in which the basket is replaced with a stainless steel cylinder as a stirring element. Sample is mounted to cuprophan ( inner porous cellulosic material) and entire system is adhere to cylinder . The dosage unit is placed on the cylinder with release side out . Useful for testing of transdermal patches. Dissolution 45 Fig. Cylinder type Cylinder stirring element

46. Reciprocating holder type ( USP apparatus 7) The assembly consist of a set of calibrated solution containers , a motor and drive assembly to reciprocate the system vertically. The sample holder may take the form of disc, cylinder or a spring or acrylic rod , or it may simply be the rod alone. Capacity is 50– 200 ml. Reciprocating frequency is 30 cycles/ min. Useful for transdermal patches and solid dosage forms. Dissolution 46

47. Holder types Dissolution 47

48. IVIVC (In vitro- in vivo correlation) IVIVC is an approach to describe the relationship between an in-vitro property of dosage form ( rate and extent of drug release) and a relevant in- vivo response ( plasma drug conc. or amount of drug absorbed ) Dissolution 48

49. Purpose of IVIVC Serves as a surrogate for in- vivo bioavailability and to support biowaiver. Used in optimization of formulation. To reduce the number of human studies during formulation development. Dissolution 49

50. Levels of correlation Dissolution 50

51. Level A correlation The % of drug dissolved at a given time is correlated to % absorbed. Highest category of correlation. Represents point to point correlation between in vitro dissolution time course and in vivo response time course. Utilizes all the dissolution and plasma level data available to develop correlation. Dissolution 51

52. Level B correlation - The mean in vitro dissolution time (MDT) is compared either to the mean residence time (MRT) or to the mean in vivo dissolution time . Is not a point-to-point correlation . Does not reflects the actual shape of in- vivo plasma level curve. Level B correlations are rarely seen in NDAs. Dissolution 52

53. Level C correlation One dissolution time point (t 50% t 90% etc.) is compared to one mean pharmacokinetic parameter such as AUC, T max , C max . A single point estimation and does not reflect the entire shape of plasma drug concentration curve. Weakest level of correlation . Can be useful in early stages of formulation development when pilot formulations are being selected. Dissolution 53

54. References D.M. Brahmankar, Sunil B. Jaiswal. pg. no. 29- 59 and 328- 335. The science and practice of of pharmacy by Remington 21 st edition Pg. no. 673- 688. United states of pharmacopoeia, 2009. pg. no. 263- 276 Principles and Application of Biopharmaceutics and Pharmacokinetics by H.P. Tipnis and Amrita Bajaj. Pg. no. 332- 350. The theory and the practice of Industrial pharmacy by Lachman L, Liberman HA, Indian edition 2009. Pg. no. 302- 303. Article on Dissolution testing of various dosage forms by TK Indira . (http:// www.pharmainfo.net/Dissolution/dissolution-testing-various-dosage-forms) http://apps.who.int/phint/en/p/docf/ www.wikipedia.com www.ei-instrument.com for images https:// www.google.co.in/search?q=theory+of+dissolution&espv=2&biw=1600&bih=799&site=webhp&source=lnms&tbm=isch&sa=X&sqi=2&ved=0CAgQ_AUoA2oVChMIjf-ckKuXyAIVUEiOCh2mUQ5i#imgrc=_ http://www.pharmainfo.net/dissolution-test https://www.youtube.com/watch?v=CTxc9CCXurk https://www.youtube.com/watch?v=cG2IHw7S3nw https://www.youtube.com/watch?v=vmohYJn89NA https://www.youtube.com/watch?v=b40PbkbLP_M https://www.youtube.com/watch?v=nFShFBlzT5k Dissolution 54

55. Dissolution 55