Georgia Valsami

Quantitative Biopharmaceutics Classification System: The Central Role of Dose/Solubility Ratio

AbstractPurpose. To develop a quantitative biopharmaceutics drug classification system (QBCS) based on fundamental parameters controlling rate and extent of absorption. Methods. A simple absorption model that considers transit flow, dissolution, and permeation processes stochastically was used to illustrate the primary importance of dose/solubility ratio and permeability on drug absorption. Simple mean time considerations for dissolution, uptake, and transit were used to identify relationships between the extent of absorption and a drugs dissolution and permeability characteristics. Results. The QBCS developed relies on a (permeability, dose/solubility ratio) plane with cutoff points 2 × 10−6-10−5cm/s for the permeability and 0.5-1 (unitless) for the dose/solubility ratio axes. Permeability estimates, Papp are derived from Caco-2 studies, and a constant intestinal volume content of 250 ml is used to express the dose/solubility ratio as a dimensionless quantity, q. A physiologic range of 250-500 ml was used to account for variability in the intestinal volume. Drugs are classified into the four quadrants of the plane around the cutoff points according to their Papp, q values, establishing four drug categories, i.e., I (Papp> 10−5cm/s, q ≤ 0.5), II (Papp> 10−5cm/s, q >1), III (Papp< 2 × 10−6cm/s, q ≤0.5), and IV (Papp< 2 × 10−6cm/s, q >1). A region for borderline drugs (2 × 10−6< Papp< 10−5cm/s, 0.5 < q< 1) was defined too. For category I, complete absorption is anticipated, whereas categories II and III exhibit dose/solubility ratio-limited and permeability-limited absorption, respectively. For category IV, both permeability and dose/solubility ratio are controlling drug absorption. Semiquantitative predictions of the extent of absorption were pointed out on the basis of mean time considerations for dissolution, uptake, and transit in conjunction with drugs dose/solubility ratio and permeability characteristics. A set of 42 drugs were classified into the four categories, and the predictions of intestinal drug absorption were in accord with the experimental observations. Conclusions. The QBCS provides a basis for compound classification into four explicitly defined drug categories using the fundamental biopharmaceutical properties, permeability, and dose/solubility ratio. Semiquantitative predictions for the extent of absorption are essentially based on these drug properties, which either determine or are strongly related to the in vivo kinetics of drug dissolution and intestinal wall permeation.

The power law can describe the 'entire' drug release curve from HPMC-based matrix tablets: a hypothesis.

The purposes of this study were to (i) re-examine the relevance of Higuchi equation and the power law using both simulated and experimental release data in conjunction with the linearized, in terms of t(1/2), percent of drug release plots, (ii) demonstrate that the power law describes the entire drug release profile of several experimental data, and (iii) point out a physically based hypothesis for the successful use of power law in describing the entire drug release profile. Simulated data generated from the equation of power law were further analyzed using linear regression analysis in accord with the Higuchi equation. The analysis revealed that data generated from the equation of power law can be misinterpreted as obeying the Higuchi equation. The use of power law in describing the entire drug release curve from HPMC-based matrix tablets is validated by direct fit of power law equation to published data of other authors. A hypothesis based on the nonclassical diffusion of the solutes in the HPMC matrices is used to interpret the successful use of the power law in describing the entire release profile.

Identification of biowaivers among Class II drugs: Theoretical justification and practical examples

AbstractPurpose. To set up a theoretical basis for identifying biowaivers among Class II drugs and apply the methodology developed to nonsteroidal anti-inflammatory drugs (NSAIDs). Methods. The dynamics of the two consecutive drug processes dissolution and wall permeation are considered in the time domain of the physiologic transit time using a tube model of the intestinal lumen. The model considers constant permeability along the intestines, a plug flow fluid with the suspended particles moving with the fluid, and dissolution in the small particle limit. The fundamental differential equation of drug dissolution-uptake in the intestines is expressed in terms of the fraction of dose dissolved. Results. The fundamental parameters, which define oral drug absorption in humans resulting from this analysis, are i) the formulation-related factors, dose, particle radius size, and ii) the drug-related properties, dimensionless solubility/dose ratio (1/q), and effective permeability. Plots of dose as a function of (1/q) for various particle sizes unveil the specific values of these meaningful parameters, which ensure complete absorption for Class II drugs [(1/q) < 1]. A set of NSAIDs were used to illustrate the application of the approach in identifying biowaivers among the NSAIDs. Conclusions. The underlying reason for a region of fully absorbed drugs in Class II originates from the dynamic character of the dissolution-uptake processes. The dynamic character of the approach developed allows identification of biowaivers among Class II drugs. Several biowaivers among the NSAIDs were identified using solubility data at pH 5.0 and in fed-state-simulated intestinal fluid at pH 5.0. The relationships of formulation parameters, dose, particle radius, and the drug properties, dimensionless solubility/dose ratio (1/q), and permeability with the fraction of dose absorbed for drugs with low 1/q values [(1/q) < 1] can be used as guidance for the formulation scientist in the development phase.

Saffron: a natural product with potential pharmaceutical applications

Recently, a great deal of interest has been developed to isolate and investigate novel bioactive components from natural resources with health beneficial effects. Saffron is the dried stigma of Crocus sativus L. and has been used for centuries in traditional medicine mainly for its healing properties, as well as for the treatment of various pathological conditions. Objectives of the present review are to unravel its therapeutic properties and investigate the potential applications of saffron in contemporary therapy of a wide spectrum of diseases and summarize previous and current evidence regarding the biological/pharmacological activities of saffron and its active ingredients and their possible therapeutic uses.

Development of a reaction-limited model of dissolution: application to official dissolution tests experiments.

A reaction-limited model for drug dissolution is developed assuming that the reaction at the solid-liquid interface is controlling the rate of dissolution. The dissolution process is considered as a bidirectional chemical reaction of the undissolved drug species with the free solvent molecules, yielding the dissolved species of drug complex with solvent. This reaction was considered in either sink conditions, where it corresponds to the unidirectional case and the entire amount of the drug is dissolved, or reaching chemical equilibrium, which corresponds to saturation of the solution. The model equation was fitted successfully to dissolution data sets of naproxen and nitrofurantoin formulations measured in the paddle and basket apparatuses, respectively, under various experimental conditions. For comparative purposes these data were also analyzed using three functions based on the diffusion layer model. All functions failed to reveal the governing role of saturation solubility in the dissolution process associated with the diffusion layer model when the conditions for the valid estimation of saturation solubility, established theoretically in this study, were met by the experimental set up employed. Overall, the model developed provides an interesting alternative to the classic approaches of drug dissolution modeling, quantifying the case of reaction-limited dissolution of drugs.

Determination of Association Constants in Cyclodextrin/Drug Complexation Using the Scatchard Plot: Application to β-Cyclodextrin-Anilinonaphthalenesulfonates

The appropriate Scatchard equation was developed for a system involving the formation of 1:1 and 1:2 substrate: cyclodextrin complexes. Simulation of this system was performed under the most common experimental conditions encountered in this type of study. The use of the equation allows for nonlinear least-squares estimation of the association constants. The interaction of the model compounds 1-anilino-8-naphthalenesulfonate (1,8-ANS) and 2(p-toluidinyl)-6-naphthalenesulfonate (2,6-TNS) with β-cyclodextrin (β-CD) was used to evaluate the theoretical model. Binding experiments were performed using either potentiometric titration or fluorimetric detection. The experimental data for 1,8-ANS/β-CD fit well to the 1:1 binding model, with an association constant of 87 ± 1 M−1. The association constants of the 1:1 and 1:2 2,6-TNS/β-CD complexes utilizing direct potentiometry were 3737 ± 6 and 149 ± 2 M−l. It is shown that fluorimetry can give biased estimates for the association constants of the complexation 2,6-TNS/β-CD, since the assumption of an equivalent quantum yield of bound species is not valid.

Construction of a naproxen ion-selective electrode and its application to pharmaceutical analysis

A naproxenate-selective electrode with a liquid membrane consisting of a tetraheptylammonium-naproxenate ion pair dissolved in p-nitrocumene is described. The electrode exhibits a rapid and near-Nernstian response to naproxenate activity from 10(-1) to 10(-4) M at pH 9.0 (borate buffer). No serious interference from common ions and tablet excipients was found and the electrode was used for the direct assay of naproxen tablets by means of the calibration graph technique and of suppositories using the standard additions technique. A dissolution study of naproxen tablets was also carried out and the results compared favourably with those given by the USP XXI methods.

Biopharmaceutics classification systems for new molecular entities (BCS-NMEs) and marketed drugs (BCS-MD): Theoretical basis and practical examples.

The aim of this work is to develop biopharmaceutics classification systems for new molecular entities (BCS-NMEs) and marketed drugs (BCS-MD). The kinetics of gastrointestinal (GI) wall permeation and dissolution were re-considered theoretically. The relationships between the solubility/dose ratio and the fractions of dose dissolved and absorbed, were also examined. Mean time calculations for drug dissolution (MDT) and permeation (MPT) of the GI wall were analyzed in respect to the mean intestinal transit time (MITT) to identify a cutoff point for drug dissolution and GI wall permeation. Dissolution experiments for marketed drugs were carried out. NMEs were classified into four classes of BCS-NMEs, based on solubility/dose ratio and apparent permeability estimates. A physiologically based cutoff time point for dissolution and permeation was used to differentiate rapidly from slowly dissolving-permeating marketed drugs, which were classified into four classes of BCS-MD using their dissolution index (DI=MITT/MDT) and permeation index (PI=MITT/MPT) values as follows: I (DI>or=3, PI>or=3), II (DI<3, PI>or=3), III (DI>or=3, PI<3) and IV (DI<3, PI<3). In conclusion, two classification systems were developed, one for NMEs based on solubility/dose ratio and permeability estimates and one for marketed drugs based on MDT and MPT estimates.

Determination of fractal reaction dimension in dissolution studies

Abstract The paper presents a method for the calculation of fractal reaction dimension, DR, in dissolution studies of powdered substances with a given particle size distribution. An estimate for DR can be directly obtained from dissolution experiments using the well known Hixson-Crowell equations in a modified form. The estimation is accomplished with a special computer program in BASIC which was developed and applied to simulated errorless and contaminated data with very good results. A practical demonstration of the methods usefulness was shown on experimental data taken from the literature.

Binding Study of the Fluorescence Probe l-Anilino-8-naphthalenesulfonate to Human Plasma and Human and Bovine Serum Albumin Using Potentiometric Titration

The binding of l-anilino-8-naphthalenesulfonate (ANS) to bovine serum albumin (BSA), human serum albumin (HSA), and human plasma has been studied by potentiometric titration utilizing a laboratory constructed ion selective electrode (ISE) of ANS. Three classes of ANS binding sites were found on BSA, HSA, and plasma at 25 and 37°C. Computer analysis of the data resulted in estimates for the association constants, number of binding sites (HSA, BSA), and binding capacity of each class. The association constants for the first class of binding sites at 25°C were found to be 7.53 (±0.59) × 105, 2.70 (±0.20) × 105, and 2.64 (±0.26) × 105M−l for BSA, HSA, and plasma, respectively. Lower values for the association constants of all binding classes were estimated at the higher temperature (37°C). The binding capacity for ANS decreased in the order BSA, plasma, HSA.