IVIVC.pptx

In vitro In vivo Correlation

1. IN-VITRO DISSOLUTION AND IN VITRO-IN VIVO CORRELATION Dr. Rajan Swami

2. IN VITRO DISSOLUTION

3. DISSOLUTION Dissolution is defined as the process by which solid substances enters in solvent to yield a solution. Stated simply, dissolution is the process by which a solid substance dissolves. Processes involved in the dissolution of solid dosage forms : Initial mechanical lag Wetting of the dosage form Penetration of the dissolution medium into the dosage form Disintegration Deaggregation of the dosage form and dislodgement of the granules Dissolution Occlusion of some particles of the drug

4. Intrinsic Dissolution The rate of dissolution of a pure pharmaceutical active ingredient when conditions such as surface area, temperature, agitation or stirring speed, pH, ionic strength of the dissolution medium is kept constant is known as intrinsic dissolution rate. Mathematically, dissolution process can be simply described as follows: = KA(Cs - C) where, M is the mass of the substance remaining to be dissolved, A is the surface area exposed to the dissolution medium, Cs is the saturation concentration referred to as solubility in the dissolution medium, C is the amount dissolved or the concentration of the drug in solution at time t, K is the intrinsic dissolution rate constant or simply the dissolution rate constant.  

5. When C is small, C < 0.15Cs, then dM / dT is proportional to Cs, since (Cs - C) is large. If this applies, then to a good approximation we may write = KACs This equation is commonly referred to as a sink-condition equation, Under sink conditions, a stagnant film of liquid (dissolution medium) is adsorbed onto the solid, the thickness of this film being l cm. The liquid in the film that is in direct contact with the solid is saturated with drug in solution. The concentration of the drug in solution then drops as the distance from the dissolving solid surface increases. At the end of the film, l cm from the surface, the concentration in the film is the same as that in the bulk solution, Cb . The driving force behind the movement of solute molecules through the stagnant film is the concentration gradient that exists between the saturation concentration of the solute, Cs, in the stagnant layer at the surface of the solid and its concentration on the farthest side of the stagnant film, Cb .  

6. Compendial methods : When selecting apparatus for dissolution testing, routine quality control, new drug development, or complying with regulatory requirements, the analyst must follow the latest issue of compendia, including revisions.

7. Classification of dissolution apparatus in different pharmacopoeias

8. USP TABLET CALIBRATORS USP Prednisone Tablets RS(Dissolution Calibrator; Disintegrating ) USP Salicylic Acid Tablets RS(Dissolution Calibrator; Nondisintegrating ) USP Chlorpheniramine Maleate Extended-Release Tablets RS (Drug Release Calibrator; Single Unit)

9. USP/NF Method 1 (Rotating Basket Method) : The USP/NF rotating basket method of dissolution testing essentially consists of a 1-in diameter 13/ 8-in-high stainless-steel 40-mesh wire basket rotated at a constant speed ranging between 25 and 150 rpm . It is immersed in 900 ml of dissolution medium in a vessel of 1000 ml capacity. The medium in the vessel is maintained at a constant temperature of 37 ±0.5°C by means of a suitable water bath. The dosage unit is placed in a dry basket at the beginning of each test. Distance between inside bottom of the vessel and the basket is maintained at 25±2 mm during the test. In case of non-disintegrating dosage forms this apparatus is superior to Apparatus 2 since it constrains the dosage form in steady state fluid flow.

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11. USP/NF Method 2 (Rotating Paddle Method): For all practical purposes the compendial specifications outlined for this method are identical to method 1 except that the paddle is substituted for the rotating basket. The metallic or suitably inert, rigid blade and shaft comprise a single entity. The paddle and blade shaft may be coated with suitable inert coating. The dosage form is allowed to sink to the bottom of the vessel before rotation of the blade is started. This apparatus is frequently used for both disintegrating and non-disintegrating dosage form at 50 rpm. Other agitation speeds are acceptable with proper justification

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13. USP/ NF Method 3 (Reciprocating Cylinder) : The assembly consists of a set of cylindrical, flat bottomed glass vessels; a set of glass reciprocating cylinders; stainless steel fittings (type 316 or equivalent) and screens and a motor and drive assembly to reciprocate the cylinders vertically inside the vessels and, if desired, index the reciprocating cylinders horizontally to a different row of vessels. The vessels are immersed in suitable water bath of any size that permits holding the temperature at 37 ±0.5°C during the test. One advantage of reciprocating cylinder is that gastrointestinal tract conditions can be easily simulated, as it is easy to make time dependent pH changes. This apparatus is most suitable for nondisintegrating (extended release) or delayed-release dosage (enteric coated) dosage forms. 15

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15. USP Apparatus 4 (Flow-Through Cell) : The assembly consists of a reservoir and a pump for dissolution medium; a flow-through cell; a water bath that maintains dissolution medium at 37 ±0.5°C. The pump forces the dissolution medium upwards through the flow-through cell. The pump has a delivery range between 240 and 960 ml/ hr, with the standard flow rates of 4, 8, and 16 ml/min. the flow profile is sinusoidal with a pulsation of 120±10 pulses per minute. The advantages of flow through cell apparatus most often cited are the ability to test drugs of very low aqueous solubility in the open loop mode and the ability to change the pH conveniently during the test. The disadvantage associated with it might be the operational difficulties of preparing large volumes of medium for operation in the open loop mode and the added time in the system set up and cleaning.

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17. USP Apparatus 5 (Paddle Over Disk) : The Apparatus 2 is used, with the addition of a stainless steel disk assembly designed for holding the transdermal system at the bottom of the vessel. Temperature is maintained at 32 ± 0.5°C. A distance of 25 ± 2 mm between the paddle and blade and the surface of the disk assembly is maintained during the test. The vessel may be covered during the test to minimize evaporation. Disk assembly for holding the transdermal system is designed to minimize any ‘dead’ volume between the disk assembly and the bottom of the vessel. Disk assembly holds the system flat and is positioned such that the release surface is parallel with the bottom of the paddle blade.

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19. USP Apparatus 6 (Cylinder) : The vessel assembly used is same as Apparatus 1, except the basket and the shaft is replaced with a stainless steel cylinder stirring element and to maintain the temperature at 32 ± 0.5°C during the test. The shaft and cylinder components of the stirring element are fabricated of stainless steel to the specifications . The dosage units are placed on the cylinder at the beginning of each test. The distance between the inside of the vessel and the cylinder is maintained at 25 ± 2 mm during the test.

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21. USP Apparatus 7 (Reciprocating holder) : The assembly consists of a set of volumetrically calibrated or tared solution containers made of glass or other suitable inert material, a motor and drive assembly to reciprocate the system vertically and to index the system horizontally to a different row of vessels automatically if desired, and a set of suitable sample holders . 23

22. ALTERNATIVE METHODS OF DISSOLUTION TESTING

23. ROTATING BOTTLE METHOD ROTATING BOTTLE METHOD Mainly used for controlled release beads. Equipment consist of a rotating rack that holds the sample drug products in bottles. The bottles are capped tightly and rotated in a 37⁰ C temperature bath. At various times samples are removed from the bottle, decanted through a 40 mesh screen and the residues are assayed. Equal volume of fresh medium is added to the remaining drug residues within the bottles and dissolution test is continued. Disadvantage- manual and tedious .

24. PERISTALSIS METHOD To stimulate hydrodynamic condition of GIT tract in an in-vitro dissolution device. It consists of rigid plastic cylindrical tubing fitted with septum and rubber stopper at both ends. Dissolution chamber consists of a space between septum and lower stopper. The apparatus is placed in beaker containing the dissolution medium. Dissolution medium is pumped with peristaltic action through the dosage form

25. FRANZ DIFFUSION CELL Static or flow through diffusion cells are used to characterize invitro drug release and drug permeation kinetics from a topical drug product eg : Ointment, cream or transdermal drug product. The Franz diffusion cell is static diffusion system used to characterize drug permeation through skin model. The skin is mounted on the Franz diffusion cell and the drug product is placed on the skin surface. The drug permeates across the skin into a receptor fluid compartment that may be sampled at various times. This system is used for selection of appropriate formulation that has optimum drug delivery.

26. FRANZ DIFFUSION CELL

27. PROBLEMS OF VARIABLE CONTROL IN DISSOLUTION TESTING

28. PROBLEMS OF VARIABLE CONTROL IN DISSOLUTION TESTING

29. PROBLEMS OF VARIABLE CONTROL IN DISSOLUTION TESTING

30. Dissolution test for evaluation of tablets This test is done to show the release of drug to as close as 100% and uniform from batch to batch Interpretation of results : Stage 1 : 6 tablets tested and accepted if all the tablets are not less than the monograph tolerance limit (Q) plus 5% Stage 2 : additional 6 tablets tested and accepted of the average of 12 is greater than of equal to Q and no unit less than Q-15%. If fail then next stage. Stage 3 : Additional 12 tablets tested and accepted if average of 24 is greater than of equal to Q and nmt 2 tablets are less than Q-15%

31. CORRELATION

32. IN VITRO IN VIVO CORELATION (IVIVC) An  in vitro in vivo  correlation (IVIVC) is a predictive mathematical model that describes the relationship between an  in vitro  property of a dosage form (primarily dissolution or drug release) and a relevant  in vivo  response ( primarily a drug’s plasma concentration or the amount of drug absorbed). In other terms, IVIVC expresses the relationship between drug release in a dissolution apparatus and how that translates to the amount of drug that enters the bloodstream following administration.

33. Why Conduct IVIVC? An IVIVC model is recommended by regulatory authorities for most modified release dosage forms. Once a validated IVIVC model has been established, it can be used to predict (BA/BE) based on  in vitro  data that are already available.

34. ADVANTAGES OF IVIVC The main advantage of IVIVC is that it provides a mechanism for evaluating the change in  in vivo  absorption based on  in vitro  dissolution changes when there are small changes in a formulation. Another advantage of IVIVC is that it conveys a better understanding of the drug product itself.

35. Establishing an IVIVC model can be even more helpful after the product has been approved by determining the impact of post-approval manufacturing changes, changes in the site of manufacture, and issues with individual lots of manufactured products all without having to repeat costly  in vivo  BE studies. CONTD..

36. FDA Guidance The FDA Guidance, “Extended Release Oral Dosage Forms” is more than 20 years old. At the time of its release, the ability to precisely predict expected BA characteristics for a product from its dissolution profile had been a goal. The guidance outlines IVIVC development and how to evaluate predictability, use an IVIVC to establish specifications for dissolution, and apply an IVIVC as a surrogate for  in vivo  BE studies.

37. IVIVC

38. IVIVC METHODOLOGY 1. Finding in vitro product parameters 2. Developing and validating suitable dissolution method to predict in vitro drug product performance to establish best IVIVC sensitive enough to detect subtle changes in in vivo performance due to changes in one or more of: • Formulation • Process parameters • Drug release patterns • Fluctuations in environmental conditions

39. 3. Establishing robustness of dissolution method 4. Identifying various factors affecting in vivo drug release 5. Using the acquired information to develop better prototype formulations 6. Optimizing the best prototype formulation using validated dissolution methods and establishing IVIVC during: • Post-approval use • Post scale-up • Post-approval change(s) in formulation CONTD..

40. IVIVC MODEL DEVELOPMENT There are five different types of correlation accepted in as per the FDA guidance: Level A, Level B Level C, Multiple level C correlation Level D , (a rank order correlation is not Federal acceptable, therefore have limited significance).

41. LEVEL A CORRELATION It is highest level; point to point relationship between in-vitro dissolution rate and in-vivo rate of the drug from the dosage form. Figure1: Correlation between percent theophylline dissolved in vitro and percent theophylline absorbed after administration of extended release product

42. Using ACAT modelling

43. Transporter role, fraction of drug absorbed, fraction of drug permeated etc.

44. Mean in vitro dissolution time (MDT vitro ) of the product is compared to mean in vivo residence time (MRT). Least used as MDT and MRT varies. It utilizes principle of Statistical moment analysis Drawback: Does not reflect actual in vivo plasma level curves. Figure 2: Correlation of mean in vitro dissolution time (MDT) and mean in vivo absorption time (MAT) LEVEL B CORRELATION

45. Level C correlation Level C correlation represents a single point correlation. One dissolution time point (t 50% , t 90% , etc.) is compared to one mean pharmacokinetic parameter such as AUC, t max or C max Figure 3: Correlation between percent drug dissolved in 45 minutes and AUC of plasma drug-time curve

46. LIMITATION Does not reflect entire plasma drug concentration curve. It is the weakest level as partial relationship between absorption and dissolution is established. So,limited in predicting in vivo drug performance in early stages of formulation development when pilot formulations are being selected.

47. MULTIPLE LEVEL C CORRELATION Relates one or several pharmacokinetic parameters of interest (Cmax, AUC etc.) to the amount of drug dissolved at several time points of the dissolution profile. It should be based on at least 3 dissolution time points covering early, middle and late stages of dissolution profile. Used to justify bio-waivers, provided that the correlation has been established over the entire dissolution profile and one or more pharmacokinetic parameters.

48. LEVEL D CORRELATION Level D correlation is a rank order and qualitative analysis and is not considered useful for regulatory purposes. It is not a formal correlation but serves as an aid in the development of a formulation or processing procedure.

49. BENEFITS OF IVIVC Reduces the costs associated with expensive bioavailability/ bioequivalence studies in human subjects. Serve as a surrogate for more number of human studies Speeds up the product development process with meaningful

50. Understanding of the product behaviour under in vitro and in Vivo conditions Demonstrates bioequivalence when certain pre-approval changes are made in formulation, equipment, manufacturing process or in manufacturing site. Improves product quality using more meaningful dissolution specifications. CONTD..

51. IVIVC IN THE LIGHT OF BCS

52. For BCS Class I compounds formulated as immediate release (IR) drug products, usually good IVIVC is not observed, as drug absorption depends on the rate of gastric emptying. FOR BCS CLASS I DRUGS

53. FOR BCS CLASS II DRUGS When a class II drug is formulated as an ER product, where solubility and permeability of the drug is site-independent, a good level A IVIVC is observed. However, once the permeability is site-dependent, little or no IVIVC is expected.

54. FOR BCS CLASS III DRUGS As drug permeation is rate controlling, limited or no IVIVC is expected. Class III drugs, such as proteins and peptides; require the technologies that address to fundamental limitations of permeability.

55. FOR BCS CLASS IV DRUGS Class IV drugs exhibit significant problems for effective oral delivery and no IVIVC is expected in this class. This class of drugs presents a major challenge for development of DDS and the route of choice for administering such drugs is parenteral with the formulation containing solubility enhancers

56. IVIVC MODEL VALIDATION The objective of IVIVC is to successfully predict the outcome (in vivo profile ) using a given model and test condition (in vitro profile). The focus is on predictive performance of the model and therefore, the prediction error is evaluated. Depending on the intended application of an IVIVC and the therapeutic index (TI) of the drug, evaluation of internal and/or external predictability may be appropriate.

57. INTERNAL VALIDATION Evaluation of internal predictability is based upon the initial data used to define the IVIVC model. Internal predictability is applied to IVIVC established using formulations with three or more release rates for wide therapeutic index drug exhibiting conclusive prediction error. Average percent prediction error (%PE) of 10% or less, with none greater than 15% is acceptable. If criteria are not met, proceed to evaluation of external predictability.

58. EXTERNAL VALIDATION Evaluation of external predictability is based on additional test data sets. The formulations with different release rates provide the optimal test of an IVIVC’s predictability. Average percent prediction error (%PE) of 10% or less, with none greater than 20% is acceptable.

59. reference WHO http://www.who.int/medicines/areas/quality_safety/quality_assurance/BE-invivo-studies-guidance-QAS15-622_21052015.pdf?ua=1 From Biostudies to Biowaivers using IVIVC:A Favorable but Fastidious Sojourn. Essentials of Pharmaceutics; Remington;Dissolution;21 st Edition;Volume 1; Page 63-80.