Dissolution of ionizable water-insoluble drugs: the combined effect of pH and surfactant.

This study reports the results of the combined effect of pH and surfactant on the dissolution of piroxicam (PX), an ionizable water-insoluble drug in physiological pH. The intrinsic dissolution rate (J(total)) of PX was measured in the pH range from 4.0 to 7.8 with 0%, 0.5%, and 2.0% sodium lauryl sulfate (SLS) using the rotating disk apparatus. Solubility (c(total)) was also measured in the same pH and SLS concentration ranges. A simple additive model including an ionization (PX <--> H(+) + PX(-)) and two micellar solubilization equilibria (PX + micelle <--> [PX](micelle), PX(-) + micelle <--> [PX(-)](micelle)) were considered in the convective diffusion reaction model. J(total) and c(total) of PX increased with increasing pH and SLS concentration in an approximately additive manner. Nonlinear regression analysis showed that observed experimental data were well described with the proposed model (r(2) = 0.86, P < 0.001 for J(total) and r(2) = 0.98, P < 0.001 for c(total)). The pK(a) value of 5.63 +/- 0.02 estimated from c(total) agreed well with the reported value. The micellar solubilization equilibrium coefficient for the unionized drug was estimated to be 348 +/- 77 L/mol, while the value for the ionized drug was nearly equal to zero. The diffusion coefficients of the species PX, PX(-), and [PX](micelle) were estimated from the experimental results as (0. 93 +/- 0.35) x 10(-5), (1.4 +/- 0.30) x 10(-5), and (0.59 +/- 0.21) x 10(-5) cm(2)/s, respectively. The total flux enhancement is less than the total solubility enhancement due to the smaller diffusion coefficients of the micellar species. This model may be useful in predicting the dissolution of an ionizable water insoluble drug as a function of pH and surfactant and for establishing in vitro-in vivo correlations, IVIVC, for maintaining bioequivalence of drug products.

Dissolution media for in vitro testing of water-insoluble drugs: effect of surfactant purity and electrolyte on in vitro dissolution of carbamazepine in aqueous solutions of sodium lauryl sulfate.

The intrinsic dissolution rate and solubility of carbamazepine was measured in aqueous solutions of sodium lauryl sulfate (SLS) prepared with two different grades of purity, 95 and 99%, and 95% SLS in 0.15 M NaCl to determine the effect of surface-active impurities and electrolytes. Four significant observations resulted from this work: (1) the equilibrium coefficients calculated from the solubility experiments in the 99% SLS, 95% SLS, and 95% with 0.15 M NaCl SLS solutions were 295, 265, and 233 L/mol, respectively; (2) the dissolution rate enhancement in the 99% SLS was 10% greater than that in the 95% SLS and 95% with 0.15 M NaCl solutions, which were not significantly different; (3) the diffusion coefficients of the drug-loaded micelles estimated from the dissolution experiments were 8.4 x 10(-7) cm2/s for the 99% SLS, 9.5 x 10(-7) cm2/s for the 95% SLS, and 1.2 x 10(-6) cm2/s for the 95% with 0.15 M NaCl; and (4) the critical micelle concentrations for the 99% SLS, 95% SLS, and 95% SLS with 0.15M NaCl were 6.8, 4.2, and 0.35 mM, respectively. The results of this study clearly illustrate the sensitivity of the micelle to impurities and electrolytes with regard to size and loading capacity and the effect these changes have on the solubility and dissolution rate. Therefore, when using surfactants in dissolution media for in vitro testing of dosage forms, consideration must be given to the level of impurities present so that the results are consistent and reliable. Intrinsic dissolution rate, surface tension, or solubility measurements may be useful, convenient methods for identifying changes in the surfactant due to either degradation or lot-to-lot variability.

Drug dissolution into micellar solutions: development of a convective diffusion model and comparison to the film equilibrium model with application to surfactant-facilitated dissolution of carbamazepine.

The intrinsic dissolution rate of carbamazepine in solutions of sodium lauryl sulfate was measured to study the convective diffusion transport of drug-loaded micelles from a rotating disk. Alternative definitions for effective diffusivity and reaction factor are presented and compared with those commonly used for this type of transport problem. The conventional and alternative approaches are based on the same fundamental assumptions differing only in their interpretation of the diffusional boundary layer. For example, in this study it was observed that, above the cmc, a 2% w/v solution of sodium lauryl sulfate increased the dissolution rate approximately 6-fold and the solubility approximately 20-fold. This difference between the solubility and dissolution enhancement was attributed to the contribution to the total transport of both the enhanced solubility, a 20-fold increase, and the effective diffusivity of the drug-micelle complex, a 3-fold decrease, hence a net 6-fold increase in dissolution. The diffusivity of the drug-loaded micelle estimated from the dissolution data using the new definitions compared well with values determined by other methods (Dsm = 8.4 x 10(-7) cm2/s). On the basis of these results, the new definitions for the effective diffusivity and reaction factor offer a practical method for estimating micellar diffusion coefficients and predicting drug dissolution under the well-defined hydrodynamics of the rotating disk. It may also be possible to extend the application of these definitions to study the dissolution of water-insoluble drugs in other media, such as emulsions, to better understand drug dissolution under fed conditions in vivo.

Novel approach to the analysis of in vitro-in vivo relationships.

The objective of this study was to quantify the dependence of degree of in vitro-in vivo correlation on the relative rates of dissolution and intestinal permeation and on the fraction of dose absorbed. The following equation was derived assuming first-order dissolution and permeation after oral drug administration: Fa = fa-1(1 - alpha(alpha - 1)-1 (1 - Fd) + (alpha - 1)-1(1 - Fd)alpha), where Fa is the fraction of the total amount of drug absorbed at time t, fa the fraction of the dose absorbed at t = infinitive, alpha is the ratio of the first-order permeation rate constant to the first-order dissolution rate constant, and Fd is the fraction of dose dissolved in vitro at time t. This equation was examined in order to pursue a theoretical treatment of in vitro-in vivo correlation. The degree of in vitro-in vivo correlation between Fa and Fd was measured by r2. alpha was varied between 1000 and 0.001. fa was varied between 0.1 and 1.0. Points employed in the linear regression were geometrically balanced about the derived equation. r2 values decreased as alpha decreased for all values of fa. r2 values were virtually independent of fa for all values of alpha, except for 0.01 < alpha < 1.0. The slope of the regression was modulated by both alpha and fa; larger alpha and smaller fa each increased slope. Application of the equation to a piroxicam data set demonstrated the equation's utility relative to the USP Level A correlation approach. It is concluded that the degree of in vitro-in vivo correlation depends on the relative rates of dissolution and intestinal permeation and on the fraction of dose absorbed and that the derived model merits further study.

Transport approaches to the biopharmaceutical design of oral drug delivery systems: prediction of intestinal absorption.

For almost a half century scientists have striven to develop a theoretical model capable of predicting oral drug absorption in humans. From the pH-partition hypothesis to the compartmental absorption and transit (CAT) model, various qualitative/quantitative approaches have been proposed, revised and extended. In this review, these models are classified into three categories; quasi-equilibrium models, steady-state models and dynamic models. The quasi-equilibrium models include the pH-partition hypothesis and the absorption potential concept, the steady-state models include the film model and the mass balance approaches, and the dynamic models include the dispersion, mixing tank and CAT models. The quasi-equilibrium models generally provide a basic guideline for understanding drug absorption trends. The steady-state models can be used to estimate the fraction of dose absorbed. The dynamic models predict both the fraction of dose absorbed and the rate of drug absorption and can be related to pharmacokinetic models to evaluate plasma concentration profiles.

A theoretical basis for a biopharmaceutic drug classification: the correlation of in vitro drug product dissolution and in vivo bioavailability.

A biopharmaceutics drug classification scheme for correlating in vitro drug product dissolution and in vivo bioavailability is proposed based on recognizing that drug dissolution and gastrointestinal permeability are the fundamental parameters controlling rate and extent of drug absorption. This analysis uses a transport model and human permeability results for estimating in vivo drug absorption to illustrate the primary importance of solubility and permeability on drug absorption. The fundamental parameters which define oral drug absorption in humans resulting from this analysis are discussed and used as a basis for this classification scheme. These Biopharmaceutic Drug Classes are defined as: Case 1. High solubility-high permeability drugs, Case 2. Low solubility-high permeability drugs, Case 3. High solubility-low permeability drugs, and Case 4. Low solubility-low permeability drugs. Based on this classification scheme, suggestions are made for setting standards for in vitro drug dissolution testing methodology which will correlate with the in vivo process. This methodology must be based on the physiological and physical chemical properties controlling drug absorption. This analysis points out conditions under which no in vitro-in vivo correlation may be expected e.g. rapidly dissolving low permeability drugs. Furthermore, it is suggested for example that for very rapidly dissolving high solubility drugs, e.g. 85% dissolution in less than 15 minutes, a simple one point dissolution test, is all that may be needed to insure bioavailability. For slowly dissolving drugs a dissolution profile is required with multiple time points in systems which would include low pH, physiological pH, and surfactants and the in vitro conditions should mimic the in vivo processes.(ABSTRACT TRUNCATED AT 250 WORDS)