Optimization of the Ussing chamber setup with excised rat intestinal segments for dissolution/permeation experiments of poorly soluble drugs.

CONTEXT: Prediction of the in vivo absorption of poorly soluble drugs may require simultaneous dissolution/permeation experiments. In vivo predictive media have been modified for permeation experiments with Caco-2 cells, but not for excised rat intestinal segments. OBJECTIVE: The present study aimed at improving the setup of dissolution/permeation experiments with excised rat intestinal segments by assessing suitable donor and receiver media. METHODS: The regional compatibility of rat intestine in Ussing chambers with modified Fasted and Fed State Simulated Intestinal Fluids (Fa/FeSSIFmod) as donor media was evaluated via several parameters that reflect the viability of the excised intestinal segments. Receiver media that establish sink conditions were investigated for their foaming potential and toxicity. Dissolution/permeation experiments with the optimized conditions were then tested for two particle sizes of the BCS class II drug aprepitant. RESULTS: Fa/FeSSIFmod were toxic for excised rat ileal sheets but not duodenal sheets, the compatibility with jejunal segments depended on the bile salt concentration. A non-foaming receiver medium containing bovine serum albumin (BSA) and Antifoam B was nontoxic. With these conditions, the permeation of nanosized aprepitant was higher than of the unmilled drug formulations. DISCUSSION: The compatibility of Fa/FeSSIFmod depends on the excised intestinal region. The chosen conditions enable dissolution/permeation experiments with excised rat duodenal segments. The experiments correctly predicted the superior permeation of nanosized over unmilled aprepitant that is observed in vivo. CONCLUSION: The optimized setup uses FaSSIFmod as donor medium, excised rat duodenal sheets as permeation membrane and a receiver medium containing BSA and Antifoam B.

Advances in dissolution instrumentation and their practical applications.

The rising demands on discriminatory and prediction abilities of dissolution methods and the increasing complexity of new drug products are the main driving forces of the progress in this field. The research moves forward as imperfections and shortcomings of classical methods are being described, and where the capabilities of the contemporary methods are insufficient, new methods are being developed. The review discusses these advances with respect to the issues that currently draw the most attention, i.e. correct simulation of hydrodynamics and stress forces, maintenance of sink conditions, study of precipitation, use of biorelevant media and the employment of more physiologically relevant methods in general.

Detecting Crystallinity in Amorphous Solid Dispersions Using Dissolution Testing: Considerations on Properties of Drug Substance, Drug Product, and Selection of Dissolution Media.

Dissolution testing has long been used to monitor product quality. Its role in quality control of amorphous solid dispersion (ASD) formulations is relatively new. In the presence of the crystalline phase, the dissolution of ASDs is determined by the dynamics between the dissolution rate of the amorphous solids and the rate of crystal growth. The detection of crystalline phase by dissolution test has not been well understood in the context of drug properties, formulation characteristics and dissolution test variables. This study systematically evaluated the impact of key parameters such as intrinsic crystallization tendency of the API, drug loading, extent of dissolution sink conditions and level of crystallinity on the ASD dissolution behavior. The results indicated diverse dissolution behaviors due to the differences in the intrinsic crystallization propensity of the drug, the drug loading, the ASD polymers and the dissolution sink index. Each of the complex dissolution profiles were interpreted based on visual observations during dissolution, the appropriate sink index based on the amorphous solubility, and the competition between drug dissolution versus crystallization. The findings of this study provide insights towards the various considerations that should be taken into account towards rationally developing a discriminatory dissolution method.

Exploring bulk volume, particle size and particle motion definitions to increase the predictive ability of in vitro dissolution simulations.

The definition of the local dissolution environment is central to accurate particle dissolution simulation, and is determined by the apparatus and conditions used. In the flow-through apparatus dissolution occurs in the cell, often in a low velocity environment, with the reservoir considered the relevant volume for dissolution kinetics. Dissolution simulations were conducted using a reduced-order model based on the Ranz-Marshall correlation for mass transfer from spherical particles. Using ibuprofen as a model drug, the effect of defining a local volume to simulate dynamic bulk concentration conditions in the flow-through and paddle apparatus was assessed by comparing use of a near particle volume (NPV), extending a distance of one radius from the particle surface, with a flow-through apparatus cell volume or paddle apparatus vessel volume as the relevant instantaneous volume for dissolution. The instantaneous inlet concentration to NPV or cell volume is the reservoir/vessel concentration at that simulation time point, reflecting the continuous input to the cell of more dilute solution from the reservoir (closed system). Additionally, inputting particle size distribution (PSD) instead of a median particle size (MPS) and enabling or disabling particle motion were investigated, in two media (resulting in low and high solubility) and with two fluid velocity conditions in each apparatus. The NPV predicted effects of fluid velocity differences on dissolution in the high solubility medium in the flow-through apparatus, but had no effect on predictive ability in the paddle apparatus. In both apparatuses, simulations were reasonable for the high solubility environment but underpredicted dissolution in the low solubility environment. The PSD option and disabling particle motion increased the predictive ability of the simulations in low solubility media in the flow-through apparatus. The results highlight the necessity to incorporate the local dynamic dissolution conditions in the flow-through apparatus for accurate dissolution simulation, and the challenges of defining an effective particle size for dissolution simulation and of reflecting hydrodynamic complexity in simulating dissolution in the paddle apparatus.

Surfactant Mediated Accelerated and Discriminatory In Vitro Drug Release Method for PLGA Nanoparticles of Poorly Water-Soluble Drug.

In vitro drug release testing is an important quality control tool for formulation development. However, the literature has evidence that poly-lactide-co-glycolide (PLGA)-based formulations show a slower in vitro drug release than a real in vivo drug release. Much longer in vitro drug release profiles may not be reflective of real in vivo performances and may significantly affect the timeline for a formulation development. The objective of this study was to develop a surfactant mediated accelerated in vitro drug release method for the PLGA nanoparticles (NPs) of a novel chemotherapeutic agent AC1LPSZG, a model drug with a poor solubility. The Sotax USP apparatus 4 was used to test in vitro drug release in a phosphate buffer with a pH value of 6.8. The sink conditions were improved using surfactants in the order of sodium lauryl sulfate (SLS) < Tween 80 < cetyltrimethylammonium bromide (CTAB). The dissolution efficiency (DE) and area under the dissolution curve (AUC) were increased three-fold when increasing the CTAB concentration in the phosphate buffer (pH 6.8). Similar Weibull release kinetics and good linear correlations (R2~0.99) indicated a good correlation between the real-time in vitro release profile in the phosphate buffer (pH 6.8) and accelerated release profiles in the optimized medium. This newly developed accelerated and discriminatory in vitro test can be used as a quality control tool to identify critical formulation and process parameters to ensure a batch-to-batch uniformity. It may also serve as a surrogate for bioequivalence studies if a predictive in vitro in vivo correlation (IVIVC) is obtained. The results of this study are limited to AC1LPSZG NPs, but a similar consideration can be extended to other PLGA-based NPs of drugs with similar properties and solubility profiles.

Sink conditions do not guarantee the absence of saturation effects.

Limited drug solubility effects can play a major role for the control of drug release from a variety of drug delivery systems, e.g. tablets, pellets, implants and microparticles. Importantly, such saturation effects can occur inside and/or outside the dosage form. This is true for drug release occurring in vitro and in vivo. In vivo, released drug might be rapidly transported away from the site of administration, e.g. due to absorption into the blood stream. In vitro, many frequently used experimental set-ups are "closed systems" and eventually drug saturation effects in the surrounding release medium might artificially occur, "falsifying" the resulting release kinetics. To avoid such errors, often "sink conditions" are provided: Selecting appropriate release medium volumes, renewal rates and/or "open systems", it is assured that the maximum concentration in the release medium does not exceed about 20% of the drug solubility. However, this does not mean that drug saturation effects within the dosage form are also avoided. It should clearly be distinguished between potential limited drug solubility effects inside versus outside the drug delivery system. This articles aims at: (i) giving a brief overview on the underlying physico-chemical phenomena involved in drug dissolution and drug release, (ii) clarifying some key terms, and (iii) presenting several examples of dosage forms in which drug saturation effects within the system are of importance, even when providing sink conditions in the surrounding bulk fluid. Interestingly, this can also include highly hydrated delivery systems containing freely water-soluble drugs.

In vitro release testing methods for drug-releasing vaginal rings.

Drug-releasing vaginal rings are torus-shaped devices, generally fabricated from thermoplastic polymers or silicone elastomers, used to administer pharmaceutical drugs to the human vagina for periods typically ranging from three weeks to twelve months. One of the most important product performance tests for vaginal rings is the in vitro release test. Although it has been fifty years since a vaginal ring device was first described in the scientific literature, and despite seven drug-releasing vaginal rings having been approved for market, there is no universally accepted method for testing in vitro drug release, and only one non-compendial shaking incubator method (for the estradiol-releasing ring Estring®) is described in the US Food and Drug Administration's Dissolution Methods Database. Here, for the first time, we critically review the diverse range of test methods that have been described in the scientific literature for testing in vitro release of drug-releasing vaginal rings. Issues around in vitro-in vivo correlation and modelling of in vitro release data are also discussed.