KINETIC MODELING ON DRUG RELEASE FROM …

1 Acta Poloniae Pharmaceutica drug Research, Vol. 67 No. 3 pp. 217 223, 2010 ISSN 0001-6837 Polish Pharmaceutical SocietyOver the past few decades, significant medicaladvances have been made in the area of drug deliv-ery with the development of controlled releasedosage forms. There are large variety of formula-tions devoted to oral controlled drug RELEASE , andalso the varied physical properties that influencedrug RELEASE from these formulations. The releasepatterns can be divided into those that RELEASE drugat a slow zero or first order rate and those that pro-vide an initial rapid dose, followed by slow zero orfirst order RELEASE of sustained component (1).

2 Thepurpose of the controlled RELEASE systems is to main-tain drug concentration in the blood or in target tis-sues at a desired value as long as possible (2). Inother words, they are able to exert a control on thedrug RELEASE rate and duration (3). For this purpose,generally, controlled RELEASE system initially releasepart of the dose contained in order to attain rapidlythe effective therapeutic concentration of the , drug RELEASE kinetics follows a well definedbehavior in order to supply the maintenance doseenabling the attainment of the desired drug concen-tration. In the light of wide versatility of application ofcontrolled RELEASE formulations, in the field of med-ical sciences, they are unavoidable tools for theexploitation of the modern concept of therapeutictreatment whose aim is to increase drug effective-ness and patient compliance, to reduce the adminis-tration frequency and side effects connected to dos-ing.

3 As a matter of fact, controlled RELEASE formula-tions bring engineers and pharmacists to worktogether with the common aim of realizing more andmore effective products. For this purpose, the use ofmathematical MODELING turns out to be very usefulas this approach enables, in the best case, the pre-diction of RELEASE kinetics before the RELEASE systemsare realized. More often, it allows the measurementof some important physical parameters, such as thedrug diffusion coefficient and resorting to model fit-ting on experimental RELEASE data. Thus, mathemati-cal MODELING , whose development requires the com-prehension of all the phenomena affecting drugrelease kinetics (4), has a very important value in theprocess optimization of such formulation.

4 Themodel can be simply thought as a mathematicalmetaphor of some aspects of reality that, in thiscase, identifies with the ensemble of phenomena rul-ing RELEASE kinetics (5-9). For this generality, math-ematical MODELING is widely employed in differentdisciplines such as genetics, medicine, psychology,biology, economy and obviously engineering MODELING ON drug RELEASE FROM controlled drug DELIVERY SYSTEMSSUVAKANTA DASH1*, PADALA NARASIMHA MURTHY2, LILAKANTA NATH3and PRASANTA CHOWDHURY21 Girijananda Chowdhury Institute of Pharmaceutical Science, Azara, Hathkhowapara, NH-37, Guwahati, Assam, 781 017 India2 Royal College of Pharmacy and Health Sciences, Berhamur, Orissa, India3 Department of Pharmacy, Dibrugarh University, Assam, IndiaAbstract.

5 In this paper we review the mathematical models used to determine the kinetics of drug RELEASE fromdrug delivery systems. The quantitative analysis of the values obtained in dissolution/ RELEASE rates is easierwhen mathematical formulae are used to describe the process. The mathematical MODELING can ultimately helpto optimize the design of a therapeutic device to yield information on the efficacy of various RELEASE :dissolution, drug RELEASE KINETIC models, model dependent method, model independent method217* Corresponding author: e-mail: DASH et of kinetics of drug releaseNoyes-Whitney RuleThe fundamental principle for evaluation of thekinetics of drug RELEASE was offered by Noyes andWhitney in 1897 as the equation (10).

6 DM/dt = KS (Cs Ct) (1)where M, is the mass transferred with respect to time,t,by dissolution from the solid particle of instanta-neous surface, S,under the effect of the prevailingconcentration driving force (Cs Ct), where Ctis theconcentration at time t and Csis the equilibrium sol-ubility of the solute at the experimental rate of dissolution dM/dt is the amount dissolvedper unit area per unit time and for most solids can beexpressed in units of g cm-2 Ctis less than 15% of the saturated sol-ubility Cs, Cthas a negligible influence on the disso-lution rate of the solid. Under such circumstances,the dissolution of the solid is said to be occurringunder sink conditions.

7 In general, the surface area,S is not constant except when the quantity of mate-rial present exceeds the saturation solubility, or ini-tially, when only small quantities of drug have and Brunner Film Theory Brunner and Nernst (11, 12) used Fick s law ofdiffusion to establish a relationship between the con-stant in the equation (1) and the diffusion coefficientof the solute, as the equation:K = DS/ h (2)where D is the diffusion coefficient, S is the area ofdissolving surface or area of the diffusion layer, isthe solution volume and h is the diffusion layerthickness. In formulating their theories, Nernst andBrunner assumed that the process at the surface pro-ceeds much faster than the transport process and thata linear concentration gradient is confined to thelayer of solution adhering to solid ideal condition can never be achieved asthe actual surface is changed permanently with theprogress of dissolution processes during the usualdetermination of drug RELEASE .

8 In the Noyes-Whitney equation, the dissolution process corre-sponds to a first order reaction. RELEASE KINETIC modelingThere are number of KINETIC models, whichdescribed the overall RELEASE of drug from the dosageforms. Because qualitative and quantitative changesin a formulation may alter drug RELEASE and in vivoperformance, developing tools that facilitate productdevelopment by reducing the necessity of bio-studiesis always desirable. In this regard, the use of in vitrodrug dissolution data to predict in vivo bio-perform-ance can be considered as the rational developmentof controlled RELEASE formulations (7-9).

9 The methods of approach to investigate thekinetics of drug RELEASE from controlled RELEASE for-mulation can be classified into three categories: Statistical methods (exploratory data analy-sis method, repeated measures design, multivariateapproach [MANOVA: multivariate analysis of vari-ance] (13, 14). Model dependent methods (zero order, firstorder, Higuchi, Korsmeyer-Peppas model, HixsonCrowell, Baker-Lonsdale model,Weibull model,etc.) (15, 16). Model independent methods [difference fac-tor (f1), similarity factor (f2) (17-19)]. Statistical methodsExploratory Data Analysis methodsAlthough exploratory data analysis methodsare not currently endorsed by the FDA, the methodis useful in obtaining an improved understanding ofthe dissolution data of controlled RELEASE formula-tion and therefore, its use is recommended.)

10 Thismethod can be used in the first step to compare dis-solution profile data in both graphical and numericalmanner. The dissolution profile data are illustratedgraphically by plotting the mean dissolution profiledata for each formulation with error bars extendingto two standard errors at each dissolution time , the data of the dissolution profiles are sum-marized numerically and 95% confidence intervalsfor the differences in the mean dissolution profiles ateach dissolution time point are evaluated (20).Multivariate approach (MANOVA)These methods were based upon repeatedmeasures designs where time is the repeated factorand percent dissolved is the dependent variable.