Permeability and clearance views of drug absorption: A commentary

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/45051/1/10928_2006_Article_BF02354289.pd

Estimating the dissolution and absorption of water-insoluble drugs in the small intestine.

The intrinsic dissolution rate and solubility of carbamazepine, a water insoluble drug by working definition, were determined in water, sodium lauryl sulfate solutions, and a 20% soybean oil in water emulsion. Micelle facilitated dissolution of carbamazepine in 2% w/v sodium lauryl sulfate was over sixfold higher than in water. Two models, the reaction plane and film equilibrium model, were used to describe the flux enhancement and both models expressed the flux enhancement as a linear function of the surfactant concentration. No significant difference in dissolution was observed for different degrees of surfactant purity, but the solubility of carbamazepine in 99% sodium lauryl sulfate was significantly higher than in the 95% pure surfactant and 95% pure surfactant in 0.15M NaCl. This was attributed to the incorporation of lauryl alcohol impurities to form mixed micelles. Dissolution of carbamazepine in the emulsion system was approximately twofold higher than in water. Computer simulations were performed to determine the effect of particle size distribution and small intestinal transit time on the fraction of ordinary doses of carbamazepine and griseofulvin absorbed using a Macroscopic Mass Balance Approach (MMBA) model. At a constant mean particle diameter of 150 microns, varying the geometric standard deviation of the particle size distribution from 1.0 to 2.0 decreased the estimated fraction dose absorbed from 1.0 to 0.6 for carbamazepine and 0.28 to 0.02 for griseofulvin. Varying the small intestinal transit time $\pm$ two standard deviations from the mean (182.5 minutes) resulted in fraction dose absorbed values between 1.0 and 0.19 for carbamazepine (particle diameter range 50-200 microns) and 0.5 and 0.04 for griseofulvin (particle diameter range 40-100 microns). The results of the in vitro dissolution experiments and computer simulations are useful in interpreting the variability in absorption of slightly water soluble drugs observed in clinical usage. The MMBA model described can help identify the source of variability in oral drug absorption of these compounds. This information can be used to optimize formulations to increase bioavailability either by physical (particle size reduction, size distribution limitations) or chemical (increased solubility, prodrug approach) modification.Ph.D.Applied SciencesChemical engineeringHealth and Environmental SciencesPharmaceutical sciencesPharmacy sciencesPure SciencesUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/129058/2/9319511.pd

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 × 10 −7 cm 2 /s for the 99% SLS, 9.5 × 10 −7 cm 2 /s for the 95% SLS, and 1.2 × 10 −6 cm 2 /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.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/97288/1/18_ftp.pd

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. This classification scheme provides a basis for establishing in vitro-in vivo correlations and for estimating the absorption of drugs based on the fundamental dissolution and permeability properties of physiologic importance.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/41443/1/11095_2004_Article_306840.pd

Quality-by-Design: Are We There Yet?

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Meeting Report: Applied Biopharmaceutics and Quality by Design for Dissolution/Release Specification Setting: Product Quality for Patient Benefit

A biopharmaceutics and Quality by Design (QbD) conference was held on June 10–12, 2009 in Rockville, Maryland, USA to provide a forum and identify approaches for enhancing product quality for patient benefit. Presentations concerned the current biopharmaceutical toolbox (i.e., in vitro, in silico, pre-clinical, in vivo, and statistical approaches), as well as case studies, and reflections on new paradigms. Plenary and breakout session discussions evaluated the current state and envisioned a future state that more effectively integrates QbD and biopharmaceutics. Breakout groups discussed the following four topics: Integrating Biopharmaceutical Assessment into the QbD Paradigm, Predictive Statistical Tools, Predictive Mechanistic Tools, and Predictive Analytical Tools. Nine priority areas, further described in this report, were identified for advancing integration of biopharmaceutics and support a more fundamentally based, integrated approach to setting product dissolution/release acceptance criteria. Collaboration among a broad range of disciplines and fostering a knowledge sharing environment that places the patient's needs as the focus of drug development, consistent with science- and risk-based spirit of QbD, were identified as key components of the path forward

Mitigation of Adverse Clinical Events of a Narrow Target Therapeutic Index Compound through Modified Release Formulation Design: An in Vitro, in Vivo, in Silico, and Clinical Pharmacokinetic Analysis

BMS-914392 is a tricyclic pyranoquinoline BCS class 2 weak base that demonstrates high solubility in low pH environments. Initial clinical studies indicated that rapid release of high dose BMS-914392 led to transient adverse events associated with peak plasma concentrations. A modified release (MR) formulation strategy was proposed to suppress the peak blood concentration and maintain total exposure to overcome the adverse effects. Three modified release prototype formulations were developed and tested via a USP 3 dissolution method to verify that each formulation can effectively slow the release of BMS-914392. A pharmacokinetic (PK) absorption model was employed to guide the formulation development and selection. Simulations showed good agreement with plasma levels measured after oral dosing in dogs. Identification of key formulation factors to achieve release rates suitable for blunting peak blood levels without diminishing exposure were achieved through combined preclinical data and use of GastroPlus simulations. PK absorption model refinements based on phase 1 data, dog pharmacokinetic results, and in vitro data provided reliable predictions of human absorption profiles and variability in patients. All three prototype formulations demonstrated lower maximum plasma concentrations of BMS-914392 and maintained satisfactory relative bioavailability. Both the PK absorption model and subsequent clinical data indicated that an acidified hydrophilic matrix MR formulation had the greatest potential to reduce the incidence of adverse events and showed the best exposure profile in fasted state healthy subjects with and without famotidine coadministration. The risk based development process achieved successful screening and selection of a suitable modified release formulation to enable clinical efficacy trials