IN-VITRO-IN VIVO CORRELATION (IVIVC).pptx

An in vitro – in vivo correlation (IVIVC) is defined by the U.S Food and Drug Administration (FDA) as a predictive mathematical model describing the relationship between the in vitro property of an oral dosage form and relevant in vivo response.

1. IN-VITRO-IN VIVO CORRELATION (IVIVC) Submitted By: Rahul Pal , Prachi Pandey Submitted to: Dr. Tejpal Yadav M. PHARM (PHARMACEUTICS), II ND SEM Subject: “Advanced Biopharmaceutics & Pharmacokinetics” Department of Pharmacy, NIMS Institute of Pharmacy, NIMS University Jaipur, Rajasthan India.

2. Introduction IVIVC plays an critical role in drug development and in optimization of formulation which is certainly a time consuming and expensive process. In IVIVC, “C” denotes “Correlation” which means “The degree of relationship” between Two variables. “The term IVIVC, could also be employed to establish dissolution specification and to support and/ or validate the use of dissolution methods.”

3. Ivivc: DEFINITION USP (United State Pharmacopoeia) Definition: “The establishment of rational relationship between a biological property or a parameter derived from a biological property produced by a dosage from and physicochemical property of same dosage form”. Conceptually, IVIVC describes a relationship between the in-vitro dissolution/release versus the in-vivo absorption. FDA (Food and Drug Administration) Definition: “A predictive mathematical model describing relationship between in-vitro property of a dosage form and in-vivo response.”

4. In vitro-in vivo correlation (ivivc) It is defined as “The predictive mathematical model that describes the relationship between in vitro property (such as rate & extent of dissolution ) of a dosage form and in-vivo response (such as plasma drug concentration or amount of drug absorbed) ”. The main objectives of developing and evaluating IVIVC is to use dissolution test to serve as alternate for In-vivo study in human beings. Assuring the bioavailability of active ingredients from a dosage form. Support and or validates the use of dissolution methods and specification.

5. APPROACHES There are mainly of two approaches: By establishing a relationship between the in-vitro dissolution and the in-vivo bioavailability parameters. By using the data obtained from previous bioavailability studies to modify the dissolution methodology in order to arrive at meaningful in-vitro in vivo correlation

6. PARAMETERS FOR related CORRELATION IN-VITRO Dissolution rate. Percentage (%) drug dissolved. Percent drug dissolved. IN-VIVO Absorption rate (or absorption time) Percent of drug absorbed. Maximum plasma concentration, Cmax. Serum drug concentration, Cp

7. LEVELS OF CORRELATION IN IVIVC

8. Different level of correlation Highest category of correlation. Linear correlation. Superimposable in-vitro and in-vivo input curve or can be made superimposable by user of constant offset value. Most informative and useful from a regulatory perspective. Uses the principle of statistical moment analysis. The mean in-vitro dissolution time is compared either to the mean residence time (MRT) or to the mean in-vivo dissolution time. Is not a point-to-point correlation. Level B correlation are rarely seen in the NDAs. Level C correlation represents a single point correlation. One dissolution time point (t50%, t90%) is compared to one mean pharmacokinetics parameter such as AUC, tmax and Cmax. Weakest level of correlation as partial relationship between absorption and dissolution is established. LEVEL A LEVEL B LEVEL C

9. Multiple Level C Multiple Level C correlation relates one or several pharmacokinetics 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 the level C as several time points are considered.

10. DISSOLUTION PROFILE COMPARISON Definition: “It is a graphically representation in terms of ( concentration vs. time ) of complete release of API from a dosage from in a appropriate selected dissolution medium”. Objectives: Development of bioequivalent product. To develop in-vitro-in-vivo (IVIVC) correlation which can help to reduce the costs, speed-up product development and reduced the need of perform costly bioavailability human volunteer studies. To stabilize final dissolution specification for the pharmacological. For optimizing the dosage formula by comparing the dissolution profiles of various formulas of the same API.

11. IMPORTANCE OF DISSOLUTION PROFILE COMPARISON Dissolution profile of an API reflects its release pattern under the selected condition sets, i.e. either sustained release or immediate release of the formulated formulas. For optimization the dosage form formula by comparing the dissolution profile of various formulas of the same API. FDA has placed more emphasis on dissolution profile comparison in the field of post approval changes. By knowing the dissolution profile of particular of the BRAND ® .

12. METHODS TO COMPARE DISSOLUTION PROFILE

13. GRAPHICAL METHOD Graphical method is first step in comparing dissolution profile and it is easy to implement but it is difficult to make definitive conclusions from the it. In this method, plot graph of time vs. concentration of solute (drug) in the dissolution medium or biological fluids. The shape of two curves is compared from comparison of dissolution patterns and the concentration of drug at each point is compared for extent of dissolution. If two or more curves are overlapping then the dissolution profile is comparable. If difference is small then it is acceptable but higher differences indicate that the dissolution profile is not comparable.

14. DISTINGUISH BETWEEN STUDENT T-TEST AND ANOVA It is a statistical test used to compare the means of two samples. The common types of t-test, are one-sample, two-sample and paired t-test. The test statistical value if t. If the t-sore or t-value is small, the group or samples are similar, whereas if the t-value is large, the group or samples are different. It is a statistical method that compares the means of more than two samples. It having two types such as one-way and two-way ANOVA. The test statistical value if F. The higher the F value, there exist significant variation between sample or groups means, and a low F value indicates low variability. ANOVA Test Student t-test

15. METHODS OF DEPENDENT METHOD Zero-order kinetics First -order kinetics Korsmeyer -Peppas Model Higuchi Model Hixon-Crowell Model Osmotic/ transdermal system Water-soluble drug in polymer matrix Erodible matrix formulation Diffusion matrix formulation The various dependent methods can be used to compare the dissolution profile but selecting the model, interpretation of model parameters and setting similarity limit is difficult.

16. Model dependent methods: zero order KINETICS Zero order API contributes drug release from dosage form that is independent of amount of drug in delivery system (constant drug release): Qt = Q o + K o t Where, Qt is the amount of drug dissolution in time t, Qo is the amount of drug in the solution and Ko is the zero order kinetics constant expressed in units of concentration/time. Plot: The graph plotted between cumulative amount of drug released versus time. Application: Transdermal system, as well as matrix tablets with low solubility drugs in coated forms, osmotic systems etc. This release is achieved by making: Reservoir diffusion systems. Osmotically controlled devices.

17. First order model (Water soluble drugs in matrix) log C = log C –Kt/2.303 Where C o is the initial concentration of drug, K is the first order rate constant and t is the time. Plot: log cumulative percentage of drug remaining vs. time which would yield a straight line with a slope of –K/2.303. Application: The relation describing the drug dissolution in dosage form such as those containing water soluble drugs in porous matrix.

18. Hixon- crowell model (Erodible matrix formulation) It model used to evaluate the drug release with the changes in the surface area and the diameter of the particles/tablets. This model is also known as “ Root Law”. Hixon and Crowell describing this; W o 1/3 –W t 1/3 = kt Where wo is the initial amount of drug, w t is the remaining amount of drug at time t. Plot: Data is to be plotted cube root of drug percentage remaining in the matrix versus time. Application: Applied to dosage forms such as tablet, where the dissolution occurs in planes that are parallel to the drug surface if the tablet dimension diminish proportionally.

19. Higuchi model (diffusion matrix formulation) This method/model used to study the release of water soluble and low soluble drugs incorporated in semisolid and solid matrix. This is given by Higuchi; Q = Where, Q is the amount of drug released in time ‘t’ per unit area, k is Higuchi constant and T is time in hr. Plot: The data is obtained is to be plotted as cumulative percentage drug release versus square root of time. Application: Modified release of dosage forms, transdermal system and matrix tablet with water soluble drugs.  

20. Korsmeyer-peppas model (swellable polymeric devices) This is empirical expression relates the functions of time for diffusion controlled mechanism. It is given by the equation; Mt/Ma = Kt n Where Mt/Ma is functions of drug released, t is time and k is the constant structural and geomatical characteristics of the dosage form. n is the release components which is indicative of drug release mechanism. If n= 1, the release is zero order. N = 0.5 the release is best described by the Fickian diffusion. 0.6 <n<1 then release is though amnomalus diffusion or case two diffusion. This model a plot of present drug release versus time is liner.

21. Graphical Representation of models Higuchi-Model Korsemeyar Peppas- Model Higuchi-Model

22. SIMILARITY FACTORs f1 Factors It calculates the percent (%) differences between the two curves at each point and is a measurement of the relative error between the two curves. f2 Factors It is logarithmic reciprocal square root transformation of the sum of error and is a measurement of the similarity in the percent (%) dissolution between the two curves. The valuers of f1 and f2 are sensitive to the number of dissolution time point used.