1. IN VITRO IN VIVO CORRELATIONS

2. Question What is meaning of Level A IVIVC?
What is meaning of Level B IVIVC?
What is meaning of Level C IVIVC?
What is meaning of Level Multiple C IVIVC?
What is meaning of Level D IVIVC?

3. Comment
In vitro in vivo correlations (IVIVC) play a key role in the drug development and optimization of formulation.
IVIVC as surrogate for in vitro dissolution study and to support biowaivers (Time and cost saving).
IVIVC is a mathematical relationship between in vitro properties of a dosage form with its in vivo performance.
IVIVC produce regulatory burden.
IVIVC can be used in the development of new pharmaceuticals to reduce the number of human studies during the formulation development.

4. Identify Level of IVIVC

6. Identify Level of IVIVC

7. Describe This Figure

8. Case Studies
In Vitro-in Vivo Correlation (IVIVC) Study Of Leflunomide Loaded Microspheres.
The parameters correlated were amount of drug dissolved to the respective fraction of dose absorbed.
The in vitro release from leflunomide microspheres B1,B2,B3,B4 show good sustained release property
The selected formulations were examined in In vivo rabbit model, the Tmax of all microspheres were increased from 1 to 4hr confirming its sustaining property.

10. Definitions
In vitro dissolution: It’s a process of release of drug from dosage form as measured in an in vitro dissolution apparatus
In vivo dissolution: process of dissolution of drug in the GI tract.
Correlation: relationship between in vitro dissolution rate and in vivo absorption rate as used in bio-equivalence guidance
IVIVC has been defined as “a predictive mathematical model describing the relationship between an in-vitro property of a dosage form and an in-vivo response”

11. United state pharmacopoeia (USP) definition of IVIVC
The establishment of a rational relationship between a biological property, or a parameter derived from a biological property produced by a dosage form, and a physicochemical property or characteristic of the same dosage form.

12. Significance of ivivc
The main objective of developing and evaluating an IVIVC is to enable the dissolution test to serve as a surrogate. It reduces the number of bio-equivalence required for approval as well as during scale up and post approval changes (SUPAC).
IVIVC shortens the drug development period, economizes the resources and leads to improved product quality.
A means of assuring the bioavailability of active ingredients from a dosage form.
Supports and or validates the use of dissolution methods and specifications
IVIVC assists in supporting biowaivers.

13. Parameters for correlations
SL. No.
IN VITRO
INVIVO 1.
Dissolution rate
Absorption rate (or absorption time) 2.
Percent drug dissolved
Percent of drug absorbed 3.
Maximum plasma concentration, Cmax 4.
Serum drug concentration, Cp

14. Dissolution rate versus absorption rate
If dissolution of drug is rate limiting step, the faster the dissolution rate, the faster is the rate of appearance of drug in the plasma. Therefore, absorption time and dissolution time may be considered for correlation
Figure 1: In vitro-in vivo correlations-Dissolution time Vs absorption time of three sustained release products

15. Percent of drug dissolved versus percent of drug absorbed:
. Appropriate dissolution medium and a slow stirring rate during dissolution should be considered to mimic in vivo dissolution.
. If the drug is absorbed completely after dissolution, a linear correlation may be obtained by comparing the percent drug absorbed to the percent drug dissolved.
Figure 2: In vitro-in vivo correlations- Percent of drug dissolved Vs percent of drug absorbed of three sustained release aspirin products

16. Percent of drug dissolved versus maximum plasma concentration:
A poorly formulated drug may not be completely dissolved and released, resulting in lower plasma drug concentration.
The percentage of drug released at any time interval will be greater for more bioavailable drug product, the peak serum concentration will be higher for the drug that shows highest percent of drug dissolved.
Figure 3: percent drug dissolved in 30 minutes Vs Cmax of drug for nine products of phenytoin (100 mg).

17. Serum drug concentration versus percent of drug dissolved
In a study on aspirin absorption, serum concentration of aspirin was correlated to percent of drug dissolved using an in vitro dissolution method
Dissolution of drug is rate limiting step, and various formulations with different dissolution rates has difference in serum concentration of aspirin
Figure 4:In vitro-In vivo correlations-serum drug concentration Vs percent of drug dissolved of aspirin

18. Levels of correlation Level A Correlation Level B Correlation
Level C Correlation
Multiple Level C Correlation

19. Level A correlation
It is estimated by two step method, deconvolution followed by comparison of fraction of drug absorbed to the fraction of drug dissolved.
Defines a direct relationship between in vivo data such that measurement of in vitro dissolution rate alone is sufficient to determine the biopharmaceutical rate of the dosage form.
An in vitro dissolution curve can serve as a surrogate for in vivo performance
Figure 5: Correlation between percent theophylline dissolved in vitro and percent theophylline absorbed after administration of extended release product

20. Level B correlation:
Level B correlation utilizes the principles of statistical moment analysis.
Mean in vitro dissolution time (MDTvitro) of the product is compared to mean in vivo residence time (MRT).
MRT may be calculated as the ratio of the area under the first moment curve (AUMC) to the AUC, where AUMC is the area under the curve observed for the product of time and concentration versus time.
Figure 6: Correlation of mean in vitro dissolution time (MDT) and mean in vivo absorption time (MAT)

21. Level C correlation
Level C correlation represents a single point correlation.
One dissolution time point (t50%, t90%, etc.) is compared to one mean pharmacokinetic parameter such as AUC, tmax or Cmax.
Weakest level of correlation as partial relationship between absorption and dissolution is established.
Figure 7: Correlation between percent drug dissolved in 45 minutes and AUC of plasma drug-time curve .

22. Multiple level C correlations
Multiple Level C correlation relates one or several pharmacokinetic parameters of interest (Cmax, AUC, or any other suitable parameters) to the amount of drug dissolved at several time points of the dissolution profile.
Its correlation is more meaningful than that of Level C as several time points are considered.

23. Development of in vivo/ in vitro correlation

24. Case Studies
In Vitro-in Vivo Correlation (IVIVC) Study Of Leflunomide Loaded Microspheres.
The parameters correlated were amount of drug dissolved to the respective fraction of dose absorbed.
The in vitro release from leflunomide microspheres B1,B2,B3,B4 show good sustained release property
The selected formulations were examined in In vivo rabbit model, the Tmax of all microspheres were increased from 1 to 4hr confirming its sustaining property
Degree A level of correlation was established from the results

26. Factor Affecting IVIVC

27. Factor related to physicochemical property
Solid phase characteristics
Amorphicity & crystallinity
Amorphous form of drug usually greater solubility &higher dissolution rate as compared to crystalline form.

28. Co precipitation &/or Complexation
Polymorphism
Co precipitation &/or Complexation
Co precipitation as well as complexation are use for enhancing the dissolution rate of drug due to,
Formation energetic amorphous drug phase or
Drug being molecularly dispersed or
Formation of co accervates
e.g. Hydroflumethiazide – PVP co precipitate has four times more solubility than crystalline drug.

29. Particle size
If the drug hydrophobic reduction in particle size may lead to decrease in effective surface area and hence slower the rate of dissolution.

30. Salt formation
by salt formation to increase the solubility

31. Factor Related To Drug Product Formulation (Solid Dosage Form)
Diluent & Disintegrant
Studies of starch on dissolution rate of salicylic acid tablet
excipient dilution (drug/excipient ratio).

32. Granulating agent and Binder
e.g. Phenobarbital tablet granulated with gelatin solution, Na – carboxymethyl cellulose or polyethylene glycol 6000 as binder.
Also depend on conc. of binder.
Water soluble granulating agent Plasdone give faster dissolution rate than with gelatin. .
J. pharm Sci.,59,49,(1970)

33. Disintegrating agent Lubricants
Studies of various disintegrating agents on Phenobarbital tablet
Lubricants

34. Effect of certified water – soluble dyes on the dissolution rate
Surfactant
e.g. treated cassava starch with SLS/polysorbate – 80 in sulfadiazine tablet
Effect of certified water – soluble dyes on the dissolution rate
Effect of coating component on tablet dissolution

35. Factor Related To Dosage Form
Manufacturing procedure (granulation)
Granule size

36. Drug excipient interaction
The dissolution of prednisolone found to depend on the length of mixing time with Mg-stearate
Compression force
The compression process influence density, porosity, hardness, disintegration time & dissolution of tablet
1. tighter bonding
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

37. Deaggregation Storage of dosage form
Deaggregation is prerequisite for dissolution
Deaggregation controls the rate of dissolution
Storage of dosage form

38. Factor Related To The Dissolution Testing Device
Agitation
Agitation changes hydrodynamic condition & flow pattern
Relation ship between intensity of agitation & rate of dissolution.
K = a (N) b
Where N = speed of agitation
K = dissolution rate
a & b are constant

39. Stirring element alignment
Vibration
The speed of rotation device officially 100 rpm.
Periodical variation in rpm might result in possible disturbance in rotational acceleration this phenomenon is known as torsional vibration.
Stirring element alignment
The USP / NF XV states that the axis of the stirring element must not deviate more than 2 mm from the axis of the dissolution vessel
Tilt in excess of may increase dissolution rate from 2 to 25%.

40. Flow pattern disturbance
The geometry and alignment of stirring device, external vibration rotational speed, thermometer, distance of basket or paddle from the lowest point of the bottom of the round bottom flask are affecting on the flow pattern.
Sampling Probe, Position & Filter
Sampling probe can affect the hydrodynamic of the system
Position of sampling, USP / NF state that sample should be removed at approximately half the distance from the basket or paddle to the dissolution medium and not closer than 1 cm to the side of the flask
Filter material must be saturated with the drug by repeated passage to avoid losses that might go undetected during the test sampling.

41. Factor Related To Dissolution Test Parameter
Temperature
USP /NF specifies that the dissolution medium must be held at 370C (±0.5) & for topical (320±0.5).
Dissolution medium
Effect of dissolution air on dissolution medium
Altering PH
Dissolved air tends to release slowly in form of tiny air bubble that circulate randomly and affect hydrodynamic flow pattern
Specific gravity decrease thus floating of powder thus wetting and penetration problem.
Dissolution media composition & PH
Addition of Na – sulfate decrease the dissolution rate.
Addition of urea increase dissolution rate.
J. pharm. Sci.,74,148,(1985)