dissolution and its models

Dissolution and dissolution model’s:

Dissolution and dissolution model’s By VIKAS DIXIT. Under supervision NEHETE MADAM. M.G.V College of pharmacy; Panchavati; Nashik. 7/26/2011 1 Dissolution and dissolution model's

Objectives::

Objectives: Dissolution science is not just a quality control tool. Apart from that in present era dissolution data act as surrogate marker for in-vivo bioavailability . Along with wide versatility of application to pharmaceutical scientist it also form basis for setting specification to allow the release of batch to market. Present seminar try’s to give a bird eye view of various dissolution apparatus along with the dissolution model’s which will be helpful in predicting the drug release kinetics ( dissolution kinetics.) In order to make this seminar effective and informative concept of Biorelavant media; Biowavier; Hydrodynamic induced variability in USP type –II apparatus is brought to light…..

HISTORY12:

HISTORY 12 1945,1950 Disintegration official in Brit. Pharmacopeia. and USP 1962, PMA Tablet Committee proposes 1% solubility invert threshold 1967,USP and NF Joint Panel on Physiological Availability choose Dissolution as a test, chooses an apparatus. 1970 Initial twelve monograph standards official 1971-74 Variables assessment; more laboratories, three Collaborative studies 7/26/2011 Dissolution and dissolution model's 3

HISTORY cont......:

HISTORY cont...... 1975,First calibrator tablets pressed; First Case default proposed to USP 1976 USP Policy—comprehensive need; calibrators (3) Collaboration Study 1977 USP Guidelines for setting Dissolution standards 1978 Apparatus. 2—Paddle adopted; two Calibrator Tablets adopted 1979 New decision rule and acceptance criteria 1980 Three case Policy proposed; USP Guidelines revised; 70 monographs now have standards 1981 New policy adopted January, includes the default First Case, monograph proposals published in June 7/26/2011 4 Dissolution and dissolution model's

HISTORY; cont.:

HISTORY; cont. 1982 USP Policy proposed for Modified-release dosage forms 1984 Revised policy adopted for Modified-release forms 1985 Standards now in nearly 400 monographs; field considered mature; Chapter <724> covers Extended-release and Enteric-coated 1990 Harmonization: Appar 4—Flow- through adopted; Appar 3 Appar 5, 6,7 for transdermal articles. 1991 USP chapter on in vivo/in vitro Correlations published 1995 Third Generation testing proposed—batch phenomenon; propose reduction in calibration test number 1997 FIP Guidelines for Dissolution Testing of Solid Oral Products; pooled analytical samples allowed 7/26/2011 5 Dissolution and dissolution model's

Dissolution apparatus(9):

Dissolution apparatus (9) USP dissolution apparatus Apparatus 1 (Basket) Apparatus 2 (paddle) Apparatus 3 ( Reciprocating cylinder) Apparatus 4 (Flow-through cell) Apparatus 5 ( paddle over disk ) Apparatus 6 (R otating cylinder) Apparatus 7 (R eciprocating holder ) IP DISSOLUTION APPARATUS Apparatus 1(paddle) Apparatus 2 (Basket) 7/26/2011 6 Dissolution and dissolution model's

Slide 7:

7/26/2011 Dissolution and dissolution model's 7 Fig . Flow through cell along with sample holder 5 Fig. Dissolution apparatus 5 Fig. Basket and Paddle 5 Fig. Rotating Cylinder 5

Apparatus uses(9):

Apparatus uses (9) Solid oral dosage forms (IR, MR products). Apparatus 1 (basket). Apparatus 2 (paddle). Bead-type MR products. Apparatus 3 (reciprocating cylinder) MR products, very limited solubility of active ingredient Apparatus 4 (flow-through cell) Soft gelatin capsules, bead products, suppositories, poorly soluble drug Apparatus 3 Apparatus 4 Transdermal dosage forms. Apparatus 5 (paddle over disk). Apparatus 6 (rotating cylinder). Non disintegrating oral MR products and transdermal products. Apparatus 7 (reciprocating holder) 7/26/2011 8 Dissolution and dissolution model's

Fundamentals of kinetics of drug release Noyes-Whitney Rule1:

Fundamentals of kinetics of drug release Noyes-Whitney Rule 1 The fundamental principle for evaluation of the kinetics of drug release was offered by Noyes and Whitney in 1897 as the equation dM/dt = KS (Cs - Ct) (1) Rate of dissolution “dM/dt” ,is the amount dissolved per unit area per unit time and can be expressed in units of g × cm-2 ×s- 1 . “ S” Solid particle of instantaneous surface . (Cs-Ct) Concentration driving force. “Cs” is the equilibrium solubility of the solute at the experimental temperature. “Ct” is the concentration at time t. 7/26/2011 9 Dissolution and dissolution model's

Slide 10:

7/26/2011 Dissolution and dissolution model's 10 Note When Ct is less than 15% of the saturated solubility Cs, Ct has a negligible influence on the dissolution rate of the solid. Under such circumstances, the dissolution of the solid is said to be occurring under “sink” conditions. In general, the surface area “S” is not constant except when the quantity of material present exceeds the saturation solubility, or initially, when only small quantities of drug have dissolved

Nernst and Brunner Film Theory(1):

Nernst and Brunner Film Theory (1) Brunner and Nernst used Fick’s law of diffusion to establish a relationship between the constant in the equation (1) and the diffusion coefficient of the solute, as the equation: K = DS/ h γ D is the diffusion coefficient S is the area of dissolving surface or area of the diffusion layer γ is the solution volume and h is the diffusion layer thickness . Note: Nernst and Brunner assumed that the process at the surface proceeds much faster than the transport process and that a linear concentration gradient is confined to the layer of solution adhering to solid surface. 7/26/2011 11 Dissolution and dissolution model's

Slide 12:

7/26/2011 Dissolution and dissolution model's 12 The ideal condition can never be achieved as the actual surface is changed permanently with the progress of dissolution processes during the usual determination of drug release. In the Noyes-Whitney equation, the dissolution process corresponds to a first order reaction.

Methods to investigate the kinetics of drug release from controlled release formulation can be classified into three categories:1:

Methods to investigate the kinetics of drug release from controlled release formulation can be classified into three categories: 1 Statistical methods : Exploratory data analysis method. Repeated measures design. Multivariate approach [MANOVA: multivariate analysis of variance.] Model dependent methods: Zero order. First order. Higuchi. Korsmeyer - Peppas model. Hixson Crowell. Baker-Lonsdale model. Weibull model. Gompertz model. Hopfenberg model. Model independent methods: Difference factor(f 1 ). Similarity factor (f 2 ). 7/26/2011 13 Dissolution and dissolution model's

Statistical method:1:

Statistical method: 1 Exploratory Data Analysis methods. Methods are not currently endorsed by the FDA, but it improved understanding of the dissolution data of controlled release formulation and therefore, its use is recommended. This method can be used in the first step to compare dissolution profile data in both graphical and numerical manner. Dissolution profile data are illustrated graphically by plotting the mean dissolution profile data for each formulation with error bars extending to two standard errors at each dissolution time point. Then, the data of the dissolution profiles are summarized numerically and 95% confidence intervals for the differences in the mean dissolution profiles at each dissolution time point are evaluated 7/26/2011 14 Dissolution and dissolution model's

Statistical method cont;:

Statistical method cont; Multivariate approach (MANOVA). These methods were based upon repeated measures designs where time is the repeated factor and percent dissolved is the dependent variable. The calculated statistics of this method were, Pillaiis Trace, Wilksi Lambda, Hotellingis Trace, Royis Largest Root. Since the data were collected as repeated measurements over time on the same experimental unit, a repeated measures design was applied. When compared to Student’s “t’’-test and paired “t’’- tests, the major advantage of this design is increased precision 7/26/2011 15 Dissolution and dissolution model's

Slide 16:

7/26/2011 Dissolution and dissolution model's 16 Repeated measures, ANOVA containing repeated measures factors with more than two levels, additional special assumptions are require these include viz: Compound symmetry assumption The assumption of spherocity.(Mauchlyis test of spherocity are used) MANOVA approach to repeated measures ANOVA ; the compound symmetry assumption requires that the variances and co-variances of the different repeated measures are homogeneous. This is a sufficient condition for the univariate “F”test for repeated measures to be valid. The spherocity assumption is a necessary and sufficient condition for the F test to be valid. When the compound symmetry or spherocity assumptions have been violated, the univariate ANOVA table will give erroneous results.

Slide 17:

7/26/2011 Dissolution and dissolution model's 17 Model dependent methods : 1 Model dependent methods are based on different mathematical functions, which describe the dissolution profile. Once a suitable function has been selected, the dissolution profiles are evaluated depending on the derived model parameters. The model dependent approaches included Zero order. First order. Higuchi. Hixson-Crowell. Korsmeyer-Peppas. Baker-Lonsdale. Weibull. Hopfenberg. Gompertz. Regression model.

Slide 18:

Zero-order model: ` Drug dissolution from dosage forms that do not disaggregate and release the drug slowly can be represented by the equation: Q 0 -Q t = K 0 t Rearrangement of equation yields: Q t = Q 0 + K 0 t where , Q t is the amount of drug dissolved in time t, Q 0 is the initial amount of drug in the solution (most times , Q 0 = 0 ) and K 0 is the zero order release constant expressed in units of concentration/time . To study the release kinetics, data obtained from in vitro drug release studies were plotted as cumulative amount of drug released versus time 7/26/2011 18 Dissolution and dissolution model's

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7/26/2011 Dissolution and dissolution model's 19 Application Zero-order model : This relationship can be used to describe the drug dissolution of several types of modified release pharmaceutical dosage forms, as in the case of some transdermal systems, as well as matrix tablets with low soluble drugs in coated forms, osmotic systems, etc.................

Slide 20:

7/26/2011 Dissolution and dissolution model's 20 First order model: This model has also been used to describe absorption and/or elimination of some drugs, although it is difficult to conceptualize this mechanism on a theoretical basis. The release of the drug which followed first order kinetics can be expressed by the equation: dC / dt = - Kc Where; K is first order rate constant expressed in units of time-1. Equation can be expressed as: log C = log C 0 n Kt / 2.303 Where; C 0 is the initial concentration of drug, k is the first order rate constant, and t is the time . Note: The data obtained are plotted as log cumulative percentage of drug remaining vs. time which would yield a straight line with a slope of -K/2.303.

Application: This relationship can be used to describe the drug dissolution in pharmaceutical dosage forms such as those containing water-soluble drugs in porous matrices. TYPICAL FIRST ORDER PLOT............................. :

Application: This relationship can be used to describe the drug dissolution in pharmaceutical dosage forms such as those containing water-soluble drugs in porous matrices. TYPICAL FIRST ORDER PLOT............................. 7/26/2011 21 Dissolution and dissolution model's

Slide 22:

7/26/2011 Dissolution and dissolution model's 22 Higuchi model : The first example of a mathematical model aimed to describe drug release from a matrix system was proposed by Huguchi in 1961. This model is based on the following hypotheses: Initial drug concentration in the matrix is much higher than drug solubility; Drug diffusion takes place only in one dimension (edge effect must be negligible); Drug particles are much smaller than system thickness; Matrix swelling and dissolution are negligible; Drug diffusivity is constant; Perfect sink conditions are always attained in the release environment

Slide 23:

7/26/2011 Dissolution and dissolution model's 23 Model expressions given by the equation: f t = Q = A √ D(2C-C s ) C s t where ; Q is the amount of drug released in time t per unit area A, C is the drug initial concentration , C s is the drug solubility in the matrix media D is the diffusivity of the drug molecules (diffusion coefficient)in the matrix substance. Note: This relation is valid during all the time, except when the total depletion of the drug in the therapeutic system is achieved.

Slide 24:

7/26/2011 Dissolution and dissolution model's 24 To study the dissolution from a planar heterogeneous matrix system, where the drug concentration in the matrix is lower than its solubility and the release occurs through pores in the matrix, the expression is given by equation. f t = Q = √ D δ / τ (2C - δ Cs) Cs t where D is the diffusion coefficient of the drug molecule in the solvent. δ is the porosity of the matrix. τ is the tortuisity of the matrix.

Slide 25:

7/26/2011 Dissolution and dissolution model's 25 Tortuisity is defined as the dimensions of radius and branching of the pores and canals in the matrix. In a general way it is possible to simplify the Higuchi model. f t = Q = K H t 1/2 where, K H is the Higuchi dissolution constant . Application: This relationship can be used to describe the drug dissolution from several types of modified release pharmaceutical dosage forms, as in the case of some transdermal systems and matrix tablets with water soluble drugs Note: The data obtained were plotted as cumulative percentage drug release versus square root of time.

Typical plot of higuchi model...:

Typical plot of higuchi model... 7/26/2011 26 Dissolution and dissolution model's

Slide 27:

7/26/2011 Dissolution and dissolution model's 27 Hixson-Crowell model: Hixson and Crowell (1931) recognized that the particles regular area is proportional to the cube root of its volume. They derived the equation: W 0 1/3 -W t 1/3 = κ t Where; W 0 is the initial amount of drug in the pharmaceutical dosage form, W t is the remaining amount of drug in the pharmaceutical dosage form at time t κ (kappa) is a constant incorporating the surface-volume relation. Note: The equation describes the release from systems where there is a change in surface area and diameter of particles or tablets. To study the release kinetics, data obtained from in vitro drug release studies were plotted as cube root of drug percentage remaining in matrix versus time .

Application Hixson-Crowell model: This expression applies to pharmaceutical dosage form such as tablets, where the dissolution occurs in planes that are parallel to the drug surface if the tablet dimensions diminish proportionally, in such a manner that the initial geometrical form keeps constant all the time. TYPICAL PLOT OF HIXON-CROWELL MODEL.... :

Application Hixson-Crowell model: This expression applies to pharmaceutical dosage form such as tablets, where the dissolution occurs in planes that are parallel to the drug surface if the tablet dimensions diminish proportionally, in such a manner that the initial geometrical form keeps constant all the time. TYPICAL PLOT OF HIXON-CROWELL MODEL.... 7/26/2011 28 Dissolution and dissolution model's

Slide 29:

7/26/2011 Dissolution and dissolution model's 29 Korsmeyer- Peppas model: Korsmeyer et al. (1983) derived a simple relationship which described drug release from a polymeric system equation. M t / M ∞ = Kt n where; M t / M ∞ is a fraction of drug released at time t, k is the release rate constant and n is the release exponent. n value is used to characterize different release for cylindrical shaped matrices; and it is describe in table 1. For the case of cylindrical tablets. 0.45 ≤ n corresponds to a Fickian diffusion mechanism. 0.45 < n <0.89 to non-Fickian transport. n = 0.89 to Case II (relaxational) transport . n > 0.89 to super case II transport.

Slide 30:

Application Korsmeyer-Peppas model: This equation has been used to the linearization of release data from several formulations of microcapsules or microspheres. Note: To study the release kinetics, data obtained from in vitro drug release studies were plotted as log cumulative percentage drug release versus log time . Release exponent (n) Drug transport mechanism Rate as a function of time 0.5 Fickian diffusion t - 0.5 0.45 < n = 0.89 Non - Fickian transport t n - 1 0.89 Case II transport Zero order release Higher than 0.89 Super case II transport t n - 1 7/26/2011 30 Dissolution and dissolution model's

Typical plot of Korsmeyer-Peppas model.............:

Typical plot of Korsmeyer-Peppas model............. 7/26/2011 31 Dissolution and dissolution model's

Slide 32:

7/26/2011 Dissolution and dissolution model's 32 Baker-Lonsdale model This model was developed by Baker and Lonsdale (1974) from the Higuchi model and described the drug release from spherical matrices according to the equation: f 1 = 3/2[1-(1-M t /M ∞ ) 2/3 ] M t /M ∞ = kt where the release rate constant, k, corresponds to the slope. Note: To study the release kinetics, data obtained from in vitro drug release studies were plotted [d (Mt / M ∞ )] / dt with respect to the root of time inverse. Application: This equation has been used to the linearization of release data from several formulations of microcapsules or microspheres

Slide 33:

7/26/2011 Dissolution and dissolution model's 33 Weibull model: This model has been described for different dissolution processes as the equation M = M 0 [1-e- (t-T/a) b ] Where; M is the amount of drug dissolved as a function of time t. M o is total amount of drug being released. T account for lag time measured as a result of the dissolution process. a denotes a scale parameter that describes the time dependence. b describes the shape of the dissolution curve progression Note: For b = 1 , the shape of the curve corresponds exactly to the shape of an exponential profile If b has a higher value than 1, the shape of the curve gets sigmoidal with a turning point, The shape of the curve with b lower than 1 would show a steeper increase than the one with b = 1

Slide 34:

7/26/2011 Dissolution and dissolution model's 34 The time, when 50% (w/w) and 90% (w/w) of drug being in each formulation was released, was calculated using the inverse function of the Weibull equation: t (50% resp. 90% dissolved) = (-a ln M 0 -M/M 0 ) 1/b + T Application: The Weibull model is more useful for comparing the release profiles of matrix type drug delivery

Slide 35:

7/26/2011 Dissolution and dissolution model's 35 Gompertz model: The in-vitro dissolution profile is often described by a simpler exponential model known as Gompertz model, expressed by the equation X(t) = Xmax exp [-α β log t ] where X(t) = percent dissolved at time t divided by 100 Xmax = maximum dissolution. α determines the undissolved proportion at time. t = 1 and described as location or scale parameter. β = dissolution rate per unit of time described as shape parameter. Note: This model has a steep increase in the beginning and converges slowly to the asymptotic maximal dissolution. Application: The Gompertz model is more useful for comparing the release profiles of drugs having good solubility and intermediate release rate.

Slide 36:

7/26/2011 Dissolution and dissolution model's 36 Hopfenberg model Hopfenberg developed a mathematical model to correlate the drug release from surface eroding polymers so long as the surface area remains constant during the degradation process . The cumulative fraction of drug released at time t is described as M t / M ∞ = 1- [1- k 0 t / C L a] n Where; k 0 is the zero order rate constant describing the polymer degradation (surface erosion) process. C L is the initial drug loading through out the system. a is the system’s half thickness (i.e. the radius for a sphere or cylinder). n is an exponent that varies with geometry. n = 1, 2 and 3 for slab (flat), cylindrical and spherical geometry, respectively. Application: This model is used to identify the mechanism of release from the optimized oilispheres using data derived from the composite profile, which essentially displayed site-specific biphasic release kinetics.

Slide 37:

7/26/2011 Dissolution and dissolution model's 37 Regression model: Statistical optimization designs have been previously documented for the formulation of many pharmaceutical dosage forms. Several types of regression analysis are used to optimize the formulation from in vitro release study. Linear or first order regression model. Quadratic model or second order regression model Non linear regression models .

Slide 38:

7/26/2011 Dissolution and dissolution model's 38 Model Independent Approach (11) For comparison of in vitro dissolution profiles, similarity and difference factors are emphasized by US FDA. Similarity Factor (f 2 ): It stresses on the comparison of closeness of two comparative formulations. Generally similarity factor in the range of 50-100 is acceptable according to US FDA . It can be computated using the formula. f 2 = 50×log {[1+ (1/n) Σ t=1 n (R t -T t ) 2 ] -0.5 ×100}. where, n is the number of dissolution sample times. R t and T t are the individual or mean percent dissolved at each time point, t, for the reference and test dissolution profiles, respectively. Note: The similarity factor should be between 0 and 100. It is 100 when two comparative groups of reference and test are identical and approaches 0 as the dissimilarity increases.

Slide 39:

7/26/2011 Dissolution and dissolution model's 39 Difference Factor (f 1 ): Difference factor focuses on the difference in percent dissolved between reference and test at various time intervals. It can be mathematically computed by using. f 1 = {[ Σ t=1 n |R t -T t |] / [ Σ t=1 n R t ]} ×100. The factors directly compare the difference between percent drug dissolved per unit time for a test and a reference product. Note: US FDA included the f 1 , f 2 factors in various guidance documents and stated different criteria's for dissolution profile comparison as. The dissolution profiles can be compared only when number of dissolution units used are equal to or greater than 12. The similarity factor should be computed from the average mean dissolution data of 12 units. The mean data for comparison can be used only if the coefficient of variation at the first time point is NMT 20%, and NLT 10% at the rest of time intervals. For accurate calculation of similarity factor, statistical approach of establishment of confidence intervals, to determine whether the reference and test are statistically significant or not may be used.

Slide 40:

7/26/2011 Dissolution and dissolution model's 40 The dissolution conditions should be identical for both reference and test products (example the strength of dosage form, test time intervals, temperature, rpm, total test time etc). The literature also states to consider only one time after 85% dissolution of product, since f2 values are sensitive to number of dissolution time points. For rapid dissolving products, that may dissolve 85% in 15 minutes, comparison of dissolution profiles is not mandatory. Similarity factor of 50-100 ensures sameness of two products. Difference factor of 0-15 ensures minor difference between two products. Prior to in vivo study, comparison of in vitro dissolution profiles using similarity and difference factors may be the promising surrogate.

Biorelevant Media(6):

Biorelevant Media (6) Need for biorelavant media: Aqueous buffers can be used to reflect typical pH conditions in the stomach or small intestine, but do not represent other key aspects of the composition of the GI contents (e.g., osmolality, ionic strength, viscosity, surface tension) that can be relevant to drug release from the dosage form to be tested. Aqueous buffers cannot be used to simulate the influence of food ingestion on drug release. In the case of poorly soluble compounds, it is often observed that the in vivo fraction absorbed increases when the drug is given with a meal. 7/26/2011 Dissolution and dissolution model's 41

Slide 42:

7/26/2011 Dissolution and dissolution model's 42 Uses of Biorelavant media. Dissolution testing is used to forecast the in vivo performance of a drug, it is critical that the in vitro test mimic the conditions in vivo as closely as possible; hence biorelevant gastrointestinal media that simulate the fasted and fed states. Media have been used to examine the solubility and dissolution characteristics of several classes of drugs including poorly soluble weak bases and lipophilic drugs to assist in predicting in vivo absorption behavior. Biorelevant in vitro dissolution testing is useful for qualitative forecasting of formulation and food effects on the dissolution and availability of orally administered drugs. It has been observed that biorelevant media can provide a more accurate simulation of pharmacokinetic profiles than simulated gastric fluid or simulated intestinal fluid. The use of biorelevant media can have a great impact on the pharmacokinetic studies performed to optimize dosing conditions and product formulation. In addition, biorelevant dissolution testing could be used to assess bioequivalence of post-approval formulation changes in certain kinds of drugs.

Slide 43:

7/26/2011 Dissolution and dissolution model's 43 Biorelavant media for gastric fluid……. FaSSGF pH 1.6 FeSSGF pH 5 sodium taurocholate 80 μ M NaCl 237.02 mM Lecithin 20 μ M Acetic acid 17.12 mM Pepsin 0.1 mg/ml Sodium acetate 29.75 mM NaCl 34.2 mM Milk / acetate buffer 1:1 HCl conc. qs ad pH 1.6 HCl conc. qs ad pH 5.0 Deionized water ad 1 l Deionized water ad 1 l pH 1.6 pH 5.0 Osmolality ( mOsmol /kg) 120.7 ± 2.5 Osmolality ( mOsmol /kg) 400 Buffer capacity ( mEq /pH/L) – Buffer capacity ( mEq /pH/L) 25 Surface tension ( mN /m) 42.6

Slide 44:

7/26/2011 Dissolution and dissolution model's 44 Composition and Physicochemical Properties of FaSSIF and FeSSIF. FeSSIF. FaSSIF. Sodium taurocholate 3 mM Sodium taurocholate 15 mM Lecithin 0.75 mM Lecithin 3 mM NaH 2 PO 4 3.438 g Acetic acid 8.65 g NaCl 6.186 g NaCl 11.874 g NaOH pellets qs ad pH 6.5 NaOH pellets 4.04 g Deionized water qs ad 1 litre Deionized water qs ad 1 litre pH 6.5 pH 5.0 Osmolality [mOsmol/kg] ~ 270 Osmolality [mOsmol/kg] ~ 670 Buffer capacity [mEq/pH/L] ~ 12 Buffer capacity [mEq/pH/L] ~ 72 Surface tension [mN/m] 54 Surface tension [mN/m] 48

Biowaiver(7,8 ):

Biowaiver (7,8 ) The regulatory acceptance of in vitro testing as a reliable surrogate for an in vivo BE study is commonly referred to as “biowaiver”. 7/26/2011 Dissolution and dissolution model's 45 scope Simplified approval for IR generic solid oral products. Advantage Demonstration of BE by in vitro instead of in vivo PK Studies.

Biowaiver criteria(8):

Biowaiver criteria (8) 7/26/2011 Dissolution and dissolution model's 46 Biowavier Dissolution Risk. Therapeutic index Indication Interactions with Food and Excipients BA/BE Studies BCS

The Biowaiver Monograph8 What is taken into consideration? :

The Biowaiver Monograph 8 What is taken into consideration? 7/26/2011 Dissolution and dissolution model's 47 Physicochemical properties, especially solubility at 37°C between pH 1.2 and 6.8, but also pKa, logP, polymorphism, solvates and salts If necessary, additionaly solubility and dissolution studies are run with the pure API Determinations of Permeability e.g. BA abs , urinary excretion, Caco-2 studies Literature studies on bioequivalence of existing products Interactions with food and excipients Literature and laboratory data comparing dissolution of existing products Therapeutic indications, therapeutic index, types and severity of toxic effects observed.

The Biopharmaceutics Classification System (8) :

The Biopharmaceutics Classification System (8) 7/26/2011 48 Dissolution and dissolution model's I II III IV Highly permeable Highly soluble Poorly soluble Poorly permeable

BCS Criteria according to WHO(8):

BCS Criteria according to WHO (8) Solubility Permeability. Dose/Solubility ratio ≤ 250 ml. In 3 aqueous media pH 1.2 – 6.8 . Temperature 37°C. Absorption ≥ 85 %. Human absolute BA or mass balance studies. Alternatives are intestinal perfusion and tissue permeation studies. 7/26/2011 Dissolution and dissolution model's 49

Hydrodynamic variability4:

Hydrodynamic variability 4 Hydrodynamics in the USP apparatus II shows that the device is highly vulnerable to mixing problems that can affect testing performance and consistency. Experimental and computational techniques reveal that the flow field within the device is not uniform, and dissolution results can vary dramatically with the position of the tablet within the vessel. Computations predict sharp variations in the shear along the bottom of the vessel where the tablet is most likely to settle. Fluctuations in the flow introduce variability in the evolution of processes that are affected by hydrodynamics, such as shearing of the tablet surfaces, de-agglomeration of particles, mass transfer from the solid to the liquid, suspension and mixing of tablet fragments. Shear represents an important factor for dissolution since the shear forces control the thickness of the boundary layer that limits mass transfer rates on tablet and particle surfaces. 7/26/2011 Dissolution and dissolution model's 50

Slide 51:

7/26/2011 Dissolution and dissolution model's 51 Fig. 1. Two-dimensional, time-averaged CFD velocity fields for (a) Re = 4688, and (b) Re = 9375. Fig. 2. Distribution of strain rates for Re = 4688 (a) in the fluid, (b) along the wall, depicted from a bottom view of the dish, (c) along the wall, depicted from a side viewof the entire vessel; and for Re = 9375, (d) in the fluid, (e) along the wall, depicted from a bottom view of the dish, (f) along the wall, depicted from a side view of the entire vessel.

Slide 52:

7/26/2011 Dissolution and dissolution model's 52 Fig. 3. Average rate of strain along the wall as a function of distance.

Application(13) :

Application (13) 7/26/2011 Dissolution and dissolution model's 53

Dissolution hyphenation(13):

Dissolution hyphenation (13) 7/26/2011 54 Dissolution and dissolution model's

Conclusion:

Conclusion It had been found that the application and evaluation of in-vitro data through model dependent approaches and ANOVA is more complicated and discriminant wherease on the other hand application of model independent approaches of f- Factor are more easier. Secondly; after several literature survey it is found that compendial dissolution media have several short coming because it doesn't take into account for fed state and fast state along with effect of food on dissolution characteristic .on the other hand use of the biorelavant media help in establishment of the better IVIVC. It has also been seen that biowavier are only given for the BCS- class I drug which had been the matter of discrimination. Because several author’s had given mathematical justification for class II & III drug and expect the biowavier extension for this class of drug. Finally, in the recent trend of the globalisation, the concept of the biowavier need to be harmonised since the compendial requirement are different in different countries..... 7/26/2011 Dissolution and dissolution model's 55

References::

References: Suvakanta Dash, P.N. Murthy, L. Nath, P. Chowdhury, Kinetic Modelling of Drug Release From controlled drug delivery systems, Polish Pharmaceutical society vol.67, page 217-223. Indira. Comparison of dissolution Profile using f 1 & f 2 factor , Pharmainfo.net 2010. E. jantratid, J. B. Dressman, V. Mattavelli Application of biorelevant dissolution tests to the prediction of in vivo performance of diclofenac sodium from an oral modified release pellet dosage Form. E.J pharmaceutical sciences 37 (2009) 434-441. E. Rinaki, A. Dokoumetzidis, Identification of biowaivers among class II drugs: Theoretical justification and practical examples. Pharmaceutical research, vol.21, no.9 September 2004 page no.1567-1571 J. L. Baxter, F. J.Muzzio Hydrodynamics induced variability in the USP Apparatus II dissolution test International journal of pharmaceutics,292 (2005) 17-28. Vinod P. Shah The role of dissolution testing in the regulation of pharmaceuticals: The FDA perspective, Taylor and Francis Group 2005 page no.81-95. Sandra Kein, The use of biorelevant dissolution media to forecast the in vivo performance of a drug , The AAS P Journal. Vol.12 no.3 september 2010. E. Gupta , V.P shah, J.B Dressman, Review of global regulations concerning biowaivers for immediate release solid forms, European Journal Of Pharmaceutical Sciences 29 (2006), 315-324. J.B Dressman, C. Beckar, Dissolution, Pharmaceutical Product Interchange ability and biopharmaceutic classification, WHO prequalification Programme 2007 ppt. USP 32/NF 27,chapter 711,724. N. Yuksel, A.E Kanik, Comparison of in-vitro dissolution profile by ANOVA, Model dependent and independent method, International Journal of pharmaceutics 209 (2000) 57-67. Lee Timothy Grady, Perspective of History of dissolution testing, USP. High Resolution images, www.google.com. 7/26/2011 Dissolution and dissolution model's 56

QUESTION...........:

QUESTION........... 7/26/2011 57 Dissolution and dissolution model's