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In Vitro Dissolution Testing Methods:

I n Vitro Dissolution Testing Methods Submitted by D. Basker reddy 1 st yr M.Pharm Submitted to Mrs. Sujatha Asst.professor R.R. College of pharmacy

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Dissolution Dissolution is a process by which a solid substance enters in the solvent. Dissolution rate may be defined as the amount of drug substance that goes into solution per unit time under standardized condition of liquid /solid interface, temperature and solvent composition

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In vivo determination of bioavailability which is usually done whenever a new formulation is to be introduced into the market. However, monitoring batch-to-batch consistency through use of such in vivo tests is extremely costly, tedious and time consuming besides exposing the healthy subjects to hazard of drugs. The best available tool which can at least quantitatively assure about the biological availability of a drug from its formulation is its in vitro dissolution test. For an in vitro test to be useful, it must predict the in vivo behavior to such an extent that in vivo bioavailability test need not be performed. The Efforts are mainly aimed at mimicking the environment offered by the biological system.

Factors considered in designing a dissolution test:

Factors considered in designing a dissolution test Factors relating to Dissolution apparatus Factors relating to the dissolution fluid Process parameters

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Factors relating to the dissolution apparatus: Design, Size of the container(several ml to several liters), Shape of the container( round bottomed or flat), Nature of agitation (stirring, rotating or oscillating methods), Speed of agitation, Performance precision of the apparatus. Factors relating to the dissolution fluid: Composition (water, 0.1N HCl, phosphate buffer, simulated gastric fluid , simulated intestinal fluid) Viscosity, Volume, Temperature, Maintenance of sink or non-sink condition.

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Process parameters: Method of introduction of dosage form Sampling techniques Changing the dissolution fluid

Ideal characteristics :

Ideal characteristics Simple in design, easy to operate, and usable under a variety of conditions Fabrication dimensions and positioning of all components are precisely specified and reproducible, run-to-run Provide an easy way of introducing the dosage form into the dissolution medium Permit controlled variable intensity of mild, uniform, non-turbulent liquid agitation Maintains nearly perfect sink conditions

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Prevent/eliminate the evaporation of the dissolution medium and maintains it at a fixed temperature within a specified narrow range Ease of drawing samples for automatic or manual analysis without interrupting the flow characteristics of the liquid Facilitates good inter-laboratory agreement Permit evaluation of disintegrating, non-disintegrating, dense or floating tablets or capsules, and finely powdered drugs.

Dissolution Testing Methods:

Dissolution Testing Methods Official methods USP Methods B.P Methods I.P Methods Non-official methods Rotating bottle method Dialysis system

USP Methods:

USP Methods Rotating basket method(Apparatus I) Shaft(or)paddle rod Basket

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Rotating paddle method(Apparatus II)

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Reciprocating cylinder method (Apparatus III)

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Flow through cell method(Apparatus IV)

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Paddle over disc method(Apparatus V)

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Rotating cylinder method(Apparatus VI)

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Reciprocating disc method(Apparatus VII)

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B.P Methods Rotating Basket Method (Apparatus I) Rotating Paddle Method (Apparatus II) Flow through Method I.P Methods Rotating paddle method (Apparatus I) Rotating basket method (Apparatus II)

Non-Official Methods:

Non-Official Methods Rotating bottle method The system consists of 12 small bottle attached to a horizontal shaft that rotates at a slow rate of 6-50 rpm. The whole assembly is placed in a constant water bath. Each bottle consists of 60 ml of dissolution fluid that is decant through a 40-mesh screen after each sampling period and is replaced by fresh fluid.

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Dialysis method This method is useful for poorly soluble drugs which require huge volume of solvent for maintaining a perfect sink condition. This method is tried using dialysis membrane as a selective barrier between the reservoir compartment and donor compartment. This method has not been widely accepted as an alternative technique for solid dosage forms but it has been used with success in case of other dosage forms like ointments, creams and suspensions.

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ACCEPTANCE CRITERIA FOR DISSOLUTION TEST Q- percentage of dug content dissolved in a given time period The criteria for acceptance/passing of test results are based on Q values. STAGE NO. of dosage units Tested Acceptance criteria S1 6 No dosage unit is less than Q+5 S2 6 Average of the 12 dosage units (S1+S2) ≥ Q% and no dosage units is less than Q–15% S3 12 Average of the 24 dosage units (S1+S2+S3) ≥ Q% and not more than two dosage units are less than Q–15% and no dosage unit is less than Q–25%

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In vitro-In vivo correlation

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In vitro-in vivo correlation is defined as the predictive mathematical method that describes the relationship between an in vitro property (such as the rate and extent of dissolution) of a dosage form and an in vivo response (such as the plasma drug concentration or amount of drug absorbed). In vitro- in vivo correlation is a tool for predicting in vivo results based on in vitro data. Correlation between in vitro and in vivo data are often used during pharmaceutical development in order to reduce development time, optimize the formulation, to monitor drug product stability and manufacturing process control. The main objective of developing and evaluating an IVIVC is to enable the dissolution test is to serve as a surrogate (alternative) for in vivo bioavailability studies in human beings.

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Objectives The objective of developing such an IVIVC are:- To ensure batch-to-batch consistency in the physiological performance of a drug product by use of such in vitro values To serve as a tool in the development of a new dosage form with desired in vivo performance. To assist in validating or setting dissolution specifications

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Approaching a correlation There are two basic approaches by which a correlation between dissolution testing and bioavailability can be developed: By establishing a relationship, usually linear, between the in vitro dissolution and the in vivo bioavailability parameters. By using the data from previous bioavailability studies to modify the dissolution methodology in order to arrive at meaningful in vitro-in vivo correlation. Classification Correlation based on the plasma level data Correlation based on the urinary excretion data Correlation based on the pharmacological response

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Correlation based on the plasma level data Dissolution parameters are correlated to the plasma level data. Linear relationship can be established In vitro dissolution parameters In vivo plasma data parameters Time for specific amount of drug to dissolve ( Ex. 50% of the dose) AUC, C max Amount dissolved at a specific time point Fraction absorbed, absorption rate constant Ka Mean dissolution time Mean residence time, Mean dissolution time, Mean absorption time Parameter estimated after modeling the dissolution process Concentration at time t, amount absorbed at time t

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Correlation Based on the Urinary Excretion Data Dissolution parameters are correlated to the amount of drug excreted unchanged in the urine, cumulative amount of drug excreted as a function of time. Correlation Based on the Pharmacological Response An acute pharmacological effect such as LD 50 in animals is related to any of the dissolution parameters .

Levels Of Correlation:

Levels Of Correlation Level A Correlation This type of correlation is generally linear and represents a point-to-point relationship between in vitro dissolution and the in vivo input rate. In a linear correlation, the in vitro dissolution and in vivo input curves may be directly super imposable or may be made to be super imposable by the use of scaling factor. Whatever the method used to establish a level A IVIVC, the model should predict the entire in vivo time course from the in vitro data.

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Advantages: A point-to-point correlation is developed. The in vitro dissolution curves such as a surrogate for the in vivo performance. Any change in manufacturing procedure or modification in formula can be justified without the need for additional human studies. The in vitro dissolution serves as in vivo indicating quality control procedure for predicting dosage form’s performance.

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Level B correlation It utilizes the principles of statistical moment analysis. In this level of correlation, the mean in vitro dissolution time of the product is compared to either mean in vivo residence time or mean in vivo dissolution time It is not a point-to-point correlation since there are a number of in vivo curves that will produce similar mean residence time values. Disadvantage: Level B correlation does not uniquely reflect the actual in vivo plasma level curves. Therefore, one can not rely upon level B correlation to justify changes in manufacturing or modification in formula. The in vitro data can not be used for quality standards.

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Level C correlation It is a single point correlation. It relates one dissolution time point (t 50% , t 90% etc) to one pharmacokinetic parameter such as AUC, t max or C max . This is the weakest level of correlation as partial relation between absorption and dissolution is established. This level is generally useful only as a guide in formulation development or quality control owing to its obvious limitations. Multiple C correlation It relates one or several pharmacokinetic parameters of interest ( C max , AUC or any other suitable parameters) to the amount of drug dissolved at several time points of the dissolution profile. A multiple level C correlation should be based on at least three dissolution time points covering the early, middle, and late stages of the dissolution profile.

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BCS & IVIVC The biopharmaceutical classification system(BCS) is a fundamental guideline for determining the conditions under which in-vitro in-vivo correlations are expected Class Solubility Permeability IVIVC expectations Possibility of predicting IVIVC from dissolution data I High High IVIVC expected, if dissolution rate is slower than gastric emptying rate, other wise limited or no correlation Yes II Low High IVIVC expected, if in vitro dissolution rate is similar to in vivo dissolution rate, unless dose is very high Yes III High Low Absorption is rate determining and limited or no IVIVC with dissolution No IV Low low Limited or no IVIVC is expected No

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Class Solubility Permeability IVIVC Ia High & site independent High & site independent Level A expected Ib High & site independent Dependent on site and narrow absorption window Level C expected IIa Low and site independent High and site independent Level A expected IIb Low and site independent Dependent on site and narrow absorption window Little or no IVIVC Va : Acidic Variable Variable Little or no IVIVC Vb : Basic Variable Variable Level A expected

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References D.M. Brahmankar, Sunil B. Jaiswal. “A Textbook of Biopharmaceutics and pharmacokinetics”. Pg no. 325 – 336. H.P. Tippins , Amrita Bajat . “Principles and applications of Biopharmaceutics & Pharmacokinetics”. Pg no. 280 – 294. V.Venkateshwarlu . “Biopharmaceutics and pharmacokinetics”, s2: 294- 299 Dr.L.Prabakaran and Mr.purushotam . “Modern pharmacokinetics and biopharmaceutics”. 225- 231 Internet source