MATHEMATICAL MODELS USED IN DRUG RELEASE STUDIES

(Assignment of Drug Delivery System)

Submitted To
Dr. Panna Thapa Department of Pharmacy Kathmandu University Dhulikhel, Nepal

Submitted By
Ruby Maharjan Master in Pharmacy (Industrial Pharmacy) 1st semester, 1st year Batch of 2011

Date of Submission
4th February 2012

Introduction Drug release is the process by which the drug leaves a drug product and is subjected to absorption, distribution, metabolism, and excretion (ADME), eventually becoming available for pharmacological action. The study of drug release is simple in the conventional dosage form and becomes more complex as the dosage form advances like controlled released dosage forms. Controlled release is a technique in which an active drug is made available to a specified target at a rate and period designed to achieve an intended effect. Such controlled release drug delivery devices offer definite advantages which include i) a reduced dosing frequency, ii) a decreased incidence and/or intensity of side effects, iii) a more constant and/or prolonged therapeutic effect, and iv) an increase in cost effectiveness. The release of drug from a delivery system involves factors of both dissolution and diffusion. Dissolution is defined as the rate of mass transfer from a solid surface into the dissolution medium or solvent under standardized conditions of liquid/solid interface, temperature and solvent composition. The basic step in drug dissolution is the reaction of the solid drug with the fluid and/or the components of the dissolution medium. Diffusion is defined as the process of mass transfer of the individual molecule of a substance brought about by the random molecular motion associated with a driving force such as concentration gradient. Describing mode or mechanism of drug release from developed polymeric system, meant to delivery drug conventionally or in controlled manner, is executed by applying various mathematical models nowadays. The major advantages of these models are: (i) the elucidation of the underlying mass transport mechanisms (ii) the possibility to predict the effect of the device design parameters (e.g., shape, size and composition) on the resulting drug release rate. (iii)Designing the new drug delivery system based on general release expression (iv)Optimization of the release kinetics (v) accurately predict the drug release profile and improve the overall therapeutic efficacy and safety of these drug carrier systems. Mathematicals models Various simple empirical or semi-empirical models such as zero order kinetics, Higuchi equation and power law, as well as more complex mechanistic theories that consider diffusion,

swelling and dissolution processes simultaneously are applied in dosage form research to understand the mechanism and actual behavior drug polymer matrix in dissolution testing. Some of the mathematical models used in drug release studies are described as following. 1. Diffusion model This model assumes that a layer of liquid, H cm thick, adjacent to the solid surface remains stagnant as the bulk liquid passes over the surface with a certain velocity.

Figure 1: Diffusion model The reaction at the solid/liquid interface is assumed to be instantaneous forming a saturated solution, Cs, of the solid in the static liquid film. The rate of dissolution is governed entirely by the diffusion of the solid molecules from the static liquid film to the bulk liquid according to Ficks first law: J = - D f dc / dx where J is the amount of substance passing perpendicularly through a unit surface area per time, D f ,is the diffusion coefficient and dc / dx, is the concentration gradient. After a time t, the concentration between the limit of the static liquid layer and the bulk liquid becomes Ct. Once the solid molecules pass into the bulk liquid, it is assumed that there is rapid mixing and the concentration gradient disappears. The theory predicts that if the concentration gradient is always constant i.e. Cs - Ct is constant because Cs>>Ct (sink conditions which usually mean Cs > 10 Ct) then a uniform rate of dissolution is obtained. 2. Zero order release model The ideal delivery of drugs would follow zero-order kinetics, wherein blood levels of drugs would remain constant throughout the delivery period. This ideal delivery is particularly important

in certain classes of medicines intended, for example, for antibiotic delivery, heart and blood pressure maintenance, pain control and antidepressants. Consequently, there has been substantial activity by scientists searching for improved methods of achieving both controlled and sustained delivery of drugs. Zero order release kinetics refers to the process of constant drug release from a drug delivery device such as oral osmotic tablets, transdermal systems, matrix tablets with low-soluble drugs and other delivery systems. Zero order release can be represented as Q = Q0 + K0 t where Q is the amount of drug released or dissolved (assuming that release occurs rapidly after the drug dissolves), Q0 is the initial amount of drug in solution (it is usually zero), and K0 is the zero order release constant. To study the release kinetics, data obtained from in vitro drug release studies were plotted as cumulative amount of drug released versus time.

Figure 2: Zero order release model of Ibuprofen sustained release formulation Application: 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. 3. First order release model The application of this model to drug release studies was first proposed by Gibald & Feldman (1967) later by Wagner (1969). This model can be expressed as:

where Qt is the amount of drug released in time t, Q0 is the initial amount of the drug in the solution and k1 is the first order release constant. This equation can also be expressed in decimal logarithms:

The graphical representation of the decimal logarithm of the released amount of drug versus time will be linear. The dosage forms that follow this dissolution profile release the drug in a way that is proportional to the amount remaining in the interior of the dosage form, in such a way that the amount of drug released by unit of time diminishes. 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.

Figure 3: First order release mode of Ibuprofen sustained release formulation 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. 4. Higuchi Model Higuchi (1961, 1963) developed several theoretical models to study the release of water soluble and low soluble drugs incorporated in semi-solid/ or solid matrixes. Mathematical expressions were obtained for drug particles dispersed in a uniform matrix behaving as the diffusion media. Initially it was used to study the dissolution from a plannar system having a homogeneous matrix and it was then extended to different geometrics and porous systems.

This model is based on the hypotheses that (i) initial drug concentration in the matrix is much higher than drug solubility; (ii) drug diffusion takes place only in one dimension (edge effect must be negligible); (iii) drug particles are much smaller than system thickness; (iv) matrix swelling and dissolution are negligible; (v) drug diffusivity is constant; and (vi) perfect sink conditions are always attained in the release environment.

where Q is the amount of drug released in time t per unit area A, C is the drug initial concentration, Cs is the drug solubility in the matrix media and D is the diffusivity of the drug molecules (diffusion coefficient) in the matrix substance. 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:

where D is the diffusion coefficient of the drug molecule in the solvent, is the porosity of the matrix and is the tortuisity of the matrix. Tortuisity is defined as the dimensions of radius and branching of the pores and canals in the matrix. The simplified Higuchi model, generally known as the simplified Higuchi model, is given below: f t = Q = KH * t1/2 where, K is the Higuchi dissolution constant The data obtained were plotted as cumulative percentage drug release versus square root of time.

Figure 4: Higuchi release model of Ibuprofen sustained release formulation

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. 5. Hixson-Crowell cube-root Model The Hixson-Crowell cube root law describes the release from systems where there is a change in surface area and diameter of particles or tablets. Hixson and Crowell (1931) recognized that the particles regular area is proportional to the cube root of its volume. They derived the equation: Q01/3 Qt1/3 = Ks t where Qt is the amount of drug released in time t, Q0 is the initial amount of the drug in the dosage form and Ks is the rate constant for Hixson-Crowell rate equation. 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.

Figure 5: Hixson-Crowell cube root plots of Ibuprofen sustained release formulation. Application: 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 6. Korsmeyer-Peppas Model

Korsmeyer et. al. (1983) derived a simple relationship which described drug release from a polymeric system equation. To find out the mechanism of drug release, first 60% drug release data were fitted in Korsmeyer-Peppas model.

where Mt/ M is a fraction of drug released at time t, k is the release rate constant and n is the release exponent. The n value is used to characterize different release for cylindrical shaped matrices. Key attributes of the model include: Tablet geometry is cylindrical Water and drug diffusion coefficients vary as functions of water concentration Polymer dissolution is incorporated Change in tablet volume is considered

In this model, the value of n characterizes the release mechanism of drug as described in table given below. 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, and n > 0.89 to super case II transport. To find out the exponent of n, the portion of the release curve where Mt/M < 0.6 should only be used.

Table 1: Interpretation of diffusional release mechanisms from polymeric films. To study the release kinetics, data obtained from in vitro drug release studies were plotted as log cumulative percentage drug release versus log time.

Figure 6: KorsmeyerPeppas Model for mechanism of drug release (first 60% drug release) Application: This model, also known as the Power Law, has been used frequently to describe the drug release from several different pharmaceutical modified release dosage forms. 7. Baker-Lonsdale model This model was developed by Baker and Lonsdale (1974) from the Higuchi model and described the drug release from spherical matrix. This model can be represented as the following equation:

Where Mt is the drug release amount at time t, M is the amount of drug released at an infinite time and the release constant k corresponds to the slope of the graph. To study the release kinetics, data obtained from in vitro drug release studies were plotted as [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. 8. Weibull model Weibull (1951) described a general empirical equation that was successfully applied to the dissolution and drug release from pharmaceutical dosage forms. This equation expresses the accumulated fraction of the drug m in a solution at time t.

where a (scale parameter) defines the time scale of the process and Ti (location parameter) represents the lag time before the onset of the dissolution or release process and in most cases will be zero. The shape parameter b characterizes the curve as either exponential (b = 1) (case 1), sigmoid, S-shaped, with upward curvature followed by a turning point (b>1) (case 2), or parabolic, with a higher initial slope and after that consistent with the exponential (b<1) (case 3). This equation may be rearranged into: Log [-In (1-m)] = log b (t Ti) log a From this equation a linear relation can be obtained for a log-log plot of In (1 m) versus time t. The shape parameter (b) is obtained from from the slope of line and scale parameter (a) is estimated from the ordinate value (1/a) at time t = 1. The parameter a can be replaced by the more informative dissolution time Td that is defined by a = (Td)b and is read from the graph as the time value corresponding to the ordinate In (1 m) = 1. Since In (1 m) =1 is equivalent to m = 0.632, Td represents the time interval necessary to dissolve or release 63.2% of the drug present in the pharmaceutical dosage form. In the pharmaceuticals systems following this model, the logarithm of the dissolved amount of drug versus the logarithm of time plot will be linear. Limitations: There is not any kinetic fundament and could only describe, but does not adequately characterize, the dissolution kinetic properties of the drug. There is not any single parameter related with the intrinsic dissolution rate of the drug. It is of limited use for establishing in vivo/in vitro correlation.

Application: The Weibull model is more useful for comparing the release profiles of matrix type drug delivery. 9. Hopfenberg model Hopfenberg developed a mathematical model to correlate the drug release from surface-eroding devices with several geometrices so long as the surface area remains constant during the degradation process. The cumulative fraction of drug released at time t was described as:

Where Mt is the amount of drug dissolved in time t, M is the total amount of drug dissolved when the pharmaceutical dosage form is exhausted, ko is the erosion rate constant, Co is the initial concentration of drug in the matrix and a is the initial radius for a sphere or cylinder or the halfthickness for a slab. The value of n is 1, 2 and 3 for a slab, cylinder and sphere respectively. A modified form of this model was developed (El-Arini and Leuenberger, 1998) to accommodate the lag time (l) in the beginning of the drug release from the pharmaceutical dosage form: Mt / M = 1 [1 kl t ( t l )]n Where, kl is equal to ko/Coa. This model assumes that the rate-limiting step of drug release is the erosion of the matrix itself. 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. 10. 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 [- e log t] where X(t) is percent dissolved at time t divided by 100; Xmax is maximum dissolution; determines the undissolved proportion at time t = 1 and described as location or scale parameter and is dissolution rate per unit of time described as shape parameter. 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. Conclusion The drug release study has become very important these days. With the advancement in the novel drug delivery systems, the study of drug release has become widely used. Whenever a new dosage form is developed, it is necessary to ensure that drug release or dissolution occur in an appropriate manner. The quantitative analysis of the values obtained in the dissolution or release test is easier

when mathematical formulas that express the dissolution results as a function of some of the dosage forms characteristics are used. The mathematical models used for drug release and dissolution are zero order release, first order release, Higuchi model, Weibull model etc. The different model is used in the different delivery systems like Higuchi model is used in matrix tablets with water soluble drugs, zero order model is used in matrix tablets with low soluble drugs etc. The release models with major application and best describing drug release phenomena are Higuchi model, zero order model, first order model and Korsemeyer-Peppas model. References 1. Coasta P. and Jose M.S.Lobo, Modelling and comparison of dissolution profiles, European Journal of Pharmaceutical Sciences, 2001, 13, 123-133. 2. Dash et. al., Kinetic modeling on drug release from controlled drug delivery systems, Acta Poloniae Pharmaceutica-Drug Research, 2010, 67 (3), 217-223 3. Singhvi G. and Singh M., Review: In-vitro drug release characterization models, International Journal of Pharmaceutical Studies and Research, 2011, II (I), 77-84 4. Khan M.A. and Shefeeq T., Role of Mathematical Modeling in Controlled Drug Delivery, Journal of Scientific Research, 2009, 1 (3), 539-550 5. Qin H. and Wang C.H., Mathematical Modeling and Simulation of Drug Release from Microparticles 6. Martin A., Swarbrick J. and Cammarata A., Physical Pharmacy , 3rd edition, Varghese Publishing House, Bombay, 1991 7. Gilhotra R.M. et. al., Mathematical Modeling of Drug Release From Polymeric DevicesAn Overview of Widely Used Models - Theory, Implementation and Rationale, The Pharma Review, 2009