Application of the Quality by Design Concept (QbD) in the Development of Hydrogel-Based Drug Delivery Systems.

Hydrogel-based drug delivery systems are of interest to researchers for many reasons, such as biocompatibility, high diversity, and the possibility of administration from different routes. Despite these advantages, there are challenges, such as controlling the drug release rate and their mechanical properties during the manufacturing of these systems. For this reason, there is a need for the production and development of such drug delivery systems with a scientific strategy. For this reason, the quality by design (QbD) approach is used for the development of drug delivery systems. This approach, by identifying the most effective factors in the manufacturing of pharmaceutical products and controlling them, results in a product with the desired quality with the least number of errors. In this review article, an attempt is made to discuss the application and method of applying this approach in the development of hydrogel-based drug delivery systems. So that for the development and production of these systems, according to the type of drug delivery system, what target characteristics should be considered (QTPP) and what factors, such as material properties (CMA) or process parameters (CPP), should be taken into account to reach the critical quality attributes of the product (CQA).

Tablet Geometry Effect on the Drug Release Profile from a Hydrogel-Based Drug Delivery System.

In order to achieve the optimal level of effectiveness and safety of drugs, it is necessary to control the drug release rate. Therefore, it is important to discover the factors affecting release profile from a drug delivery system. Geometry is one of these effective factors for a tablet-shaped drug delivery system. In this study, an attempt has been made to answer a general question of how the geometry of a tablet can affect the drug release profile. For this purpose, the drug release process of theophylline from two hundred HPMC-based tablets, which are categorized into eight groups of common geometries in the production of oral tablets, was simulated using finite element analysis. The analysis of the results of these simulations was carried out using statistical methods including partial least squares regression and ANOVA tests. The results showed that it is possible to predict the drug release profile by knowing the geometry type and dimensions of a tablet without performing numerous dissolution tests. Another result was that, although in many previous studies the difference in the drug release profile from several tablets with different geometries was interpreted only by variables related to the surface, the results showed that regardless of the type of geometry and its dimensions, it is not possible to have an accurate prediction of the drug release profile. Also, the results showed that without any change in the dose of the drug and the ingredients of the tablet and only because of the difference in geometry type, the tablets significantly differ in release profile. This occurred in such a way that, for example, the release time of the entire drug mass from two tablets with the same mass and materials but different geometries can be different by about seven times.

A novel three-dimensional printed device with conductive elements for electromembrane extraction combined with high-performance liquid chromatography and ultraviolet detector.

This study is focused on proposing a new design and setup for electromembrane extraction. A new cap was designed and conductive vials of different shapes were fabricated using three-dimensional printing. The new cap holds three fibers to enhance electromembrane extraction recovery. Conductive vials can simultaneously perform as electrodes therefore, there is no need to include an electrode in sample solutions. Phenobarbital and phenytoin were used as model compounds to assess the setup performance. Under optimal conditions, these analytes were extracted from the sample solution at pH = 9 to the acceptor solution at pH = 13 with a voltage of 40 V for 20 min, while 1-octanol was employed as the supported-liquid-membrane. The influence of conductive vials geometry on the recovery was examined and the effects of different shapes were studied by performing numerical simulation to establish electric potential distribution. Of the vials tested with circular, triangular, and floral-like cross-sections the latter exhibited the best voltage distribution. The circular vial had the highest recovery attributed to its better hydrodynamic shape, which allows rapid fluid sample transport and therefore enhanced system recovery. The extraction recovery and relative standard deviation of the circular vial with three fibers were 33.0 and 7.6 for phenobarbital and 42.2 and 10.4 for phenytoin.

Multiphysics modeling and experiments on ultrasound-triggered drug delivery from silk fibroin hydrogel for Wilms tumor.

In this study, silk fibroin hydrogel is employed as a carrier for vincristine and ultrasound as a method to accelerate the drug release. The Acoustic, deformation, swelling, and diffusion fields are coupled in a multi-physics model to optimize the drug delivery. A transient acoustic structure model and a chemically controlled mechanism are implemented, while a coupled model of deformation and diffusion takes the impact of mechanical forces into account. An evaluation of the model is made through experiments. To monitor the drug release rate over 40 days following injection of silk hydrogel syringes containing vincristine, they were triggered by ultrasound in some selected time intervals. Drug release rates were determined using different power intensities and induction times. Computed simulation results and laboratory experiments revealed that ultrasound could cause a significant improvement in drug release rate, with an increase of up to 10 times over a release without ultrasound stimulation. By increasing the ultrasound power and induction time up to their peak value, the drug release rate rises and drops then. Predictions of the drug release rate by the model were in good agreement with those observed in experiments. This makes the model a valuable tool for potential predictions. Results showed that the ultrasound triggers the increased cell death rates, but the Wilms tumor cells were resistant to higher concentrations of released drugs.

Computational analysis of vincristine loaded silk fibroin hydrogel for sustained drug delivery applications: Multiphysics modeling and experiments.

In this paper, silk fibroin hydrogel is used as a drug carrier for vincristine. To optimize drug delivery, a multi-physics model is proposed that couples the deformation and diffusion fields. We applied inverse analysis and general continuum mechanics to define material parameters and mechanical properties. To examine the mass transport and chemical behavior, an affinity-based diffusion and degradation of a drug-loaded polymer matrix is employed. Some experiments are carried out to examine the capability of the presented model. After preparing the vincristine loaded silk hydrogel syringes, they were injected into PBS and enzyme solutions to monitor the drug release rate for 40 days. Obtained results from the computational simulation and laboratory tests showed that the silk fibroin hydrogel was deswelled after about 40 days in enzyme solution. Degradation led to faster and higher doses of vincristine drug release in comparison to the case of PBS solution. Results revealed that more than 80% of the drug was released in the first 5 days in the enzyme solution, but in PBS solution only 10% of the drug was released during 40 days. The model predictions of deswelling behavior and drug release rate were in good agreement with those of experimental results. Therefore, it can be employed as a reliable tool for further predictions.

A computational simulation of electromembrane extraction based on Poisson - Nernst - Planck equations.

Electromembrane extraction (EME) has attracted a great deal of interest in researchers because of its advantages. For analysis, design and optimization purposes, understanding the ion transport mechanisms in the organic supported liquid membrane (SLM) is of prominent importance, where the interplay between the passive diffusion and electric-driven mass transport across SLM affects the mass transfer. In present work, a 2D numerical simulation is developed to examine the mass transfer behavior and the analyte recovery in EME devices. The presented model is capable of describing the effect of different parameters on the recovery of the EME setup. Initial analyte concentration in the sample solution, SLM thickness, applied potential, permittivity, diffusion coefficient, and the reservoir pH within both the sample and acceptor, can be considered as process variables. Predicted results revealed that the most important factors playing key role in EME, are the analyte diffusivity, distribution coefficient of the analyte as well as the level of protonation in both the donor and acceptor solutions. The proposed model is helpful in predicting the mass transfer behavior of the EME process in practical applications.

Transient swelling response of pH-sensitive hydrogels: A monophasic constitutive model and numerical implementation.

Due to their ability to swell/deswell under alternating pH conditions, pH-sensitive hydrogels present themselves as a potential candidate for controlled drug delivery. In this paper, a coupled electro-chemo-mechanical transient large deformation homogeneous and inhomogeneous swelling theory is developed for pH-sensitive hydrogels. The hydrogel is treated as a single-phase compressible isotropic hyperelastic material. The Nernst-Planck equation is used for the flux of the ionic species inside the hydrogel through its boundaries. The main reason which causes the hydrogel to swell is the osmotic pressure. The osmotic pressure is treated as external stress to the hydrogel. As soon as the concentration of the ions inside the hydrogel is known one may compute the osmotic pressure. Finally, the mechanical equilibrium equations give the deformation of the hydrogel. After presenting the swelling theory, the theory is implemented into the finite element method, and the experimental data is used in order to validate the theory. The simulation matches closely the experimental data which shows the accuracy of the proposed theory. The free swelling and constrained swelling of the pH-sensitive hydrogel are also simulated to show the capabilities of the proposed formulation and well as its numerical counterpart.

Evaluation of ethylcellulose and its pseudolatex (Surelease) in preparation of matrix pellets of theophylline using extrusion-spheronization.

OBJECTIVES: This study evaluates the effect of substitution of microcrystalline cellulose (MCC) with ethylcellulose (EC) on mechanical and release characteristics of theophylline pellets. MATERIALS AND METHODS: The effect of addition of EC was investigated on characteristics of pellets with varying drug content prepared by extrusion-spheronization. Also the effect of type of granulating liquid (water or Surelease) was investigated on characteristics of selected pellets. The pellets were characterized for particle size (sieve analysis), mechanical strength, morphology (microscopy), thermal (DSC) and dissolution behaviors. RESULTS: The exrtudability of the wet mass was reduced upon inclusion of EC so that complete replacement of MCC was not possible. Increase in EC percentage led to lower production yield and formation of pellets with larger diameter and slightly rough surfaces. Inclusion of EC also affected the mechanical properties of pellets but had negligible effect on drug release profile. The surface of selected pellets became smoother and their production yield increased upon the use of Surelease as granulating liquid. In addition the rate of drug release decreased to some extent when Surelease was used. CONCLUSION: Preparation of theophylline pellets with EC alone was not possible in process of extrusion-spheronization. Partial replacement of MCC with EC changed physicomechanical properties of pellets but hardly affected drug release. Although the use of Surelease as granulation liquid slightly decreased the rate of drug release, desirable matrix pellets with sustained drug release could not be produced. Despite this outcome however, these pellets could benefit from reduced coating thickness for drug release control.