Model Basic Drugs Research Articles

Application of polyacrylamide gel as a new membrane in electromembrane extraction for the quantification of basic drugs in breast milk and wastewater samples

Introducing new membranes with green chemistry approach seems to be a great challenge for the development of a practical method in separation science. In this regard, for the first time, polyacrylamide gel as a new membrane in electromembrane extraction (EME) was used for the extraction of three model basic drugs (pseudoephedrine (PSE), lidocaine (LID), and propranolol (PRO)), followed by HPLC-UV. In comparison with conventional EME, in this method neither organic solvent nor carrier agents were used for extraction of mentioned drugs. Different variables for fabrication of polyacrylamide gel and extraction process were evaluated. Polyacrylamide gel (containing 12% (w/v) acrylamide, and 3.0% (w/w) bisacrylamide) with 2 mm thickness at pH = 1.5 was fabricated as membrane. The drugs were extracted from aqueous samples, through a polyacrylamide gel membrane, to an aqueous acceptor phase on membrane. Under the optimized extraction conditions (Voltage: 85 V, extraction time: 28 min, acceptor phase's pH: 4.0, and donor phase’s pH: 7.0) limits of quantification and detection were in the ranges of 1.0–20.0 ng mL−1 and 0.3–6.0 ng mL−1, respectively. Applying the proposed method to determine and quantify intended drugs in breast milk, and wastewater samples have revealed acceptable results.

Direct Analysis of Free Aqueous and Organic Operational Solutions as a Tool for Understanding Fundamental Principles of Electromembrane Extraction.

Aqueous and organic phases in microelectromembrane extraction (μ-EME) were formed as adjacent plugs of free immiscible solutions in narrow-bore polymeric tubing, and each single phase was recovered and analyzed after μ-EME. A three-phase μ-EME setup was employed for investigation of time-dependent distribution of model basic drugs among aqueous and organic phases. Exact concentrations of nortriptyline and papaverine in donor solution, acceptor solution, and free liquid membrane (FLM) were determined by capillary electrophoresis with ultraviolet detection (CE-UV). At typical μ-EME conditions (acceptor, 1 μL of 25 mM HCl; FLM, 1 μL of 4-nitrocumene; donor, 1 μL of basic drugs in 10 mM HCl; and extraction potential, 250 V), experimentally determined distribution of the drugs confirmed the kinetic model for electrically mediated transfer of charged analytes. Rapid depletion of the drugs from donor solution (0-180 s) and rapid saturation of FLM with the drugs (15-60 s) were followed by gradual transfer of the drugs across FLM and gradual liberation into acceptor solution (30-240 s). Exhaustive transfer of the drugs from donor to acceptor solution was obtained in 15 min. A good correlation between the analytes' distribution and μ-EME electric currents was observed; the currents increased during drugs' transfer across FLM, were concentration dependent, and demonstrated transfer of the drugs across FLM in their ionized forms. Proper understanding of the fundamental principles of μ-EME transfer enabled further fine-tuning of the μ-EME process. Transfer of the drugs across FLM was controlled by optimizing the composition and pH of acceptor solution, and quantitative fractionation of nortriptyline into aqueous acceptor (96%) and of papaverine into organic FLM (95%) was achieved based on their different pKa values. μ-EME fractionation of the two drugs was compatible with raw human urine and excellent repeatability (RSD ≤ 3.9%), linearity (r2 ≥ 0.9989), and limits of detection (≤ 0.15 μg/mL) were achieved for μ-EME-CE-UV of the drugs in standard solutions and urine samples.

Absorptive Dissolution Testing of Supersaturating Systems: Impact of Absorptive Sink Conditions on Solution Phase Behavior and Mass Transport.

One of the most commonly used formulation development tools is dissolution testing. However, for solubility enhancing formulations, a simple closed compartment conventional dissolution apparatus operating under sink conditions often fails to predict oral bioavailability and differentiate between formulations. Hence, increasing attention is being paid to combined dissolution-absorption testing. The currently available mass transport apparatuses, however, have certain limitations, the most important being the small membrane surface area, which results in slow mass transfer. In this study, a novel high surface area, flow-through absorptive dissolution testing apparatus was developed and tested on a weakly basic model drug, nevirapine. Following optimization of the experimental parameters, the mass transfer attained for a nevirapine solution was 30 times higher in 60 min as compared to a side-by-side diffusion cell. To further evaluate the system, nevirapine powder and commercial tablets were first dissolved at an acidic pH, followed by pH increase, creating a supersaturated solution. Detailed information related to the extent of supersaturation achieved in crystallizing and noncrystallizing systems could be obtained from the combined dissolution-mass transport measurements. Differences in donor cell compartment concentration-time profiles were noted for absorptive versus closed compartment conditions. It is anticipated that this approach could be a promising tool to identify solubility enabling formulations that perform optimally in vivo.

Introduction of agarose gel as a green membrane in electromembrane extraction: An efficient procedure for the extraction of basic drugs with a wide range of polarities

Developing green methods for analyte extraction is one of the most important topics in the field of sample preparation. In this study, for the first time, agarose gel was used as membrane in electromembrane extraction (EME) without using any organic solvent, for the extraction of four model basic drugs (rivastigmine (RIV), verapamil (VER), amlodipine (AML), and morphine (MOR)) with a wide polarity window (log P from 0.43 to 3.7). Different variables playing vital roles in the proposed method were evaluated and optimized. As a driving force, a 25V electrical field was applied to make the analyte migrate from sample solution with pH 7.0, through the agarose gel 3% (w/v) with 5mm thickness, into an acceptor phase (AP) with pH 2.0. The best extraction efficiency was obtained with an extraction duration of 25min. With this new methodology, MOR with high polarity (log P=0.43) was efficiently extracted without using any carrier or ion pair reagents. Limits of detection (LODs) and quantification (LOQs) were in the ranges of 1.5–1.8ngmL−1 and 5.0–6.0ngmL−1, respectively. Finally, the proposed method was successfully applied to determine concentrations of the model drugs in the wastewater sample.

Injections from sub-μL sample volumes in commercial capillary electrophoresis

A simple sample injection procedure compatible with commercial capillary electrophoresis (CE) instrumentation was developed, which enables handling sample volumes as little as 250nL for analytical applications where sample volume availability is of concern. Single-use micro-sampling inserts were prepared by thermal modification of polypropylene micropipette tips and the inserts were accommodated in standard CE vials in CE autosampler carousel. To ensure direct contact of separation capillary injection end with sample solution and to avoid possible damage to the capillary, a soft compression spring was placed at the bottom of the vial underneath the micro-sampling insert. Injections from sub-μL samples were carried out in conventional as well as in short-end injection mode, were compatible with standard i.d./o.d. (25–100μm/365μm) fused silica capillaries and with various background electrolyte solutions and detection modes. Excellent repeatability of replicate injections from 250nL to 3μL was achieved based on RSD values of quantitative analytical measures (peak heights ≤2.4% and peak areas ≤3.7%) for CE-UV–vis, CE-ESI–MS and CE-contactless conductivity detection of model basic drugs. The achieved RSD values were comparable with those for replicate injections of the drugs from standard CE vials. The reported concept of injections from micro-sampling inserts was further demonstrated useful in evaluation of micro-electromembrane extraction (μ-EME) of model basic drugs. Sub-μL volumes of operational solutions resulted in reduced lengths of μ-EME phases and improved extraction recoveries (66–91%) were achieved.

Novel Salted Anionic-Cationic Polymethacrylate Polymer Blends for Sustained Release of Acidic and Basic Drugs.

Since a unique matrix tablet formulation that independently controls the release of various drug types is in a great demand, the objective of this research was to develop a sustained release matrix tablet as a universal dosage form using a binary mixture of the salt forms of Eudragit polymers rather than their interpolyelectrolyte complexes. Tablets were prepared by wet granulation and compressed at different compression forces, depending on drug type. Dissolution tests were conducted using USP XXII rotating paddle apparatus at 50 rpm at 37°C in consecutive pH stages. Tablets containing Ibuprofen (IB) as a model acidic drug and Metronidazole (MD) as a model basic drug showed controlled/sustained release behavior. For IB tablets containing 80% Ibuprofen and 5% (w/w) polymeric combination; the time for 50% of the drug release was about 24 hours compared to 8.5 hours for plain tablets containing 80% IB. In case of MD, the drug release extended to about 7 hours for tablets containing 80% MD and 5% (w/w) polymeric combination, compared to about 1 hour for plain tablets containing 80% MD. In terms of extending the release of medications, the dissolution profiles of the tablets containing polymeric salts forms were found to be statistically superior to tablets prepared by direct compression of the polymers in their powdered base forms, and superior to tablets containing the same polymers granulated using isopropyl alcohol. The findings indicated the significance of combining the polymers in their salt forms in controlling the release of various drug types from matrices.

Functional magnetic porous silica for T1–T2 dual-modal magnetic resonance imaging and pH-responsive drug delivery of basic drugs

A smart magnetic-targeting drug carrier γ-Fe2O3@p-silica comprising a γ-Fe2O3 core and porous shell has been prepared and characterized. The particles have a uniform size of about 60 nm, and a porous shell of thickness 3 nm. Abundant hydroxyl groups and a large surface area enabled the γ-Fe2O3@p-silica to be readily loaded with a large payload of the basic model drug rhodamine B (RB) (up to 73 mg g−1). Cytotoxicity assays of the γ-Fe2O3@p-silica particles indicated that the particles were biocompatible and suitable for carrying drugs. It was found that the RB was released rapidly at pH 5.5 but at pH 7.4 the rate and extent of release was greatly attenuated. The particles therefore demonstrate an excellent pH-triggered drug release. In addition, the γ-Fe2O3@p-silica particles could be tracked by magnetic resonance imaging (MRI). A clear dose-dependent contrast enhancement in both T1-weighted and T2-weighted MR images indicated the potential of the γ-Fe2O3@p-silica particles to act as dual-mode T1 and T2 MRI contrast agents.

Preparation of a β-Cyclodextrin-Based Open-Tubular Capillary Electrochromatography Column and Application for Enantioseparations of Ten Basic Drugs.

An open-tubular capillary electrochromatography column was prepared by chemically immobilized β-cyclodextrin modified gold nanoparticles onto new surface with the prederivatization of (3-mercaptopropyl)-trimethoxysilane. The synthesized nanoparticles and the prepared column were characterized by transmission electron microscopy, scanning electron microscopy, infrared spectroscopy and ultraviolet visible spectroscopy. When the column was employed as the chiral stationary phase, no enantioselectivity was observed for ten model basic drugs. So β-cyclodextrin was added to the background electrolyte as chiral additive to expect a possible synergistic effect occurring and resulting in a better separation. Fortunately, significant improvement in enantioselectivity was obtained for ten pairs of drug enantiomers. Then, the effects of β-cyclodextrin concentration and background electrolyte pH on the chiral separation were investigated. With the developed separation mode, all the enantiomers (except for venlafaxine) were baseline separated in resolutions of 4.49, 1.68, 1.88, 1.57, 2.52, 2.33, 3.24, 1.63 and 3.90 for zopiclone, chlorphenamine maleate, brompheniramine maleate, dioxopromethazine hydrochloride, carvedilol, homatropine hydrobromide, homatropine methylbromide, venlafaxine, sibutramine hydrochloride and terbutaline sulfate, respectively. Further, the possible separation mechanism involved was discussed.

Acid-Base Interactions of Polystyrene Sulfonic Acid in Amorphous Solid Dispersions Using a Combined UV/FTIR/XPS/ssNMR Study.

This study investigates the potential drug-excipient interactions of polystyrene sulfonic acid (PSSA) and two weakly basic anticancer drugs, lapatinib (LB) and gefitinib (GB), in amorphous solid dispersions. Based on the strong acidity of the sulfonic acid functional group, PSSA was hypothesized to exhibit specific intermolecular acid-base interactions with both model basic drugs. Ultraviolet (UV) spectroscopy identified red shifts, which correlated well with the color change observed in lapatinib-PSSA solutions. Fourier transform infrared (FTIR) spectra suggest the protonation of the quinazoline nitrogen atom in both model compounds, which agrees well with data from the crystalline ditosylate salt of lapatinib. X-ray photoelectron spectroscopy (XPS) detected increases in binding energy of the basic nitrogen atoms in both lapatinib and gefitinib, strongly indicating protonation of these nitrogen atoms. (15)N solid-state NMR spectroscopy provided direct spectroscopic evidence for protonation of the quinazoline nitrogen atoms in both LB and GB, as well as the secondary amine nitrogen atom in LB and the tertiary amine nitrogen atom in GB. The observed chemical shifts in the LB-PSSA (15)N spectrum also agree very well with the lapatinib ditosylate salt where proton transfer is known. Additionally, the dissolution and physical stability behaviors of both amorphous solid dispersions were examined. PSSA was found to significantly improve the dissolution of LB and GB and effectively inhibit the crystallization of LB and GB under accelerated storage conditions due to the beneficial strong intermolecular acid-base interaction between the sulfonic acid groups and basic nitrogen centers.

Conversion of solid dispersion prepared by acid–base interaction into free-flowing and tabletable powder by using Neusilin® US2

A novel method of greatly increasing solubility and dissolution rate of a model basic drug, haloperidol, by interacting it with water-soluble weak organic acids in aqueous media was previously reported in the literature. Amorphous solid dispersion (SD) was formed when solutions containing haloperidol and various acids were dried. However, the SDs were semisolid, viscous and sticky, especially when the drug load was high, and could not be processed into tablets. The drug release from SD was also incomplete since the viscous material did not readily mix with aqueous media. In the present study, a mesoporous metalosilicate, Neusilin® US2, was incorporated in SDs prepared by using malic, tartaric and citric acids. The silicate constituted 40% w/w of the total solid mass. The addition of silicate converted SDs into powders, which were then characterized for flow properties, bulk and tap density, and tabletability. Their physical properties were found to be acceptable for the development of tablets. DSC and powder XRD showed that haloperidol and acids converted completely to amorphous forms, and they did not show any sign of crystallization during accelerated stability study at 40°C/75% RH and 25°C/60% RH for 9 months. Complete drug release under gastrointestinal pH conditions could be obtained from tablets prepared.

An all-in-one electro-membrane extraction: Development of an electro-membrane extraction method for the simultaneous extraction of acidic and basic drugs with a wide range of polarities

Efficient and simultaneous extraction of a series of basic and acidic compounds with a large polarity range using only a single run of electro-membrane extraction (EME) has been a challenge. To overcome this difficulty, in this work, a new EME setup was developed for the determination of basic and acidic model drugs with different polarities using two auxiliary electrodes (one as the cathode and the other as the anode) and their circumferential hollow fibers impregnated with organic solvent compositions different from those of main hollow fibers, coupled with capillary electrophoresis (CE). Satisfactory analytical figures of merit including limits of quantification (15–45ngmL−1), good preconcentration factors (66–132) and recoveries (33–66%) were obtained by the proposed EME-CE/UV (detection at 214nm) procedure. Finally, the applicability of this method was evaluated by the extraction and determination of the drugs in urine samples from drug-using suspects.

Site specific solubility improvement using solid dispersions of HPMC-AS/HPC SSL – Mixtures

Many upcoming drug candidates are pH-dependent poorly soluble weak bases in the pH range of the gastrointestinal tract. This often leads to a high in vivo variability and bioavailability issues. Aiming to overcome these limitations, the design of solid dispersions for site specific dissolution improvement or maintenance of a potent supersaturation over the entire gastro-intestinal pH-range, is proposed to assure a reliable drug therapy. Solid dispersions containing different ratios of Dipyridamole (DPD) or Griseofulvin (GRI) and the enteric polymer hydroxypropylmethylcellulose-acetate succinate (HPMC-AS) and the water soluble low-viscosity hydroxypropylcellulose (HPC-SSL) were prepared by hot melt extrusion (HME). The solid dispersions were evaluated for their solid state, dissolution characteristics applying a three pH-step dissolution method following an acidic to neutral pH transition and stability. The use of HPMC-AS in binary mixtures with DPD and GRI facilitated increased solubility and supersaturation at pH-controlled release of the preserved amorphous state of the dispersed drug, which even inverted the pH-dependent solubility profile of the weakly basic model drug (Dipyridamole). I.e. a potent site specific delivery system was created. With ternary solid dispersions of API, HPMC-AS and HPC-SSL, tailored release profiles with superior supersaturation over the applied pH-range could be obtained. At the same time, binary and ternary mixtures showed favorable stability properties at a temperature difference between glass transition temperature and the applied storage temperature of down to 16°C.

Silicone Adhesive Matrix of Verapamil Hydrochloride to Provide pH-Independent Sustained Release

Providing pH-independent oral release of weakly basic drugs with conventional matrix tablets can be challenging because of the pH-dependent solubility characteristics of the drugs and the changing pH environment along the gastrointestinal tract. The aim of the present study was to use a hydrophobic polymer to overcome the issue of pH-dependent release of weakly basic model drug verapamil hydrochloride from matrix tablets without the use of organic buffers in the matrix formulations. Silicone pressure-sensitive adhesive (PSA) polymer was evaluated because of its unique properties of low surface energy, hydrophobicity, low glass transition temperature, high electrical resistance, and barrier to hydrogen ion diffusion. Drug release, hydrogen ion diffusion, tablet contact angle, and internal tablet microenvironment pH with matrix tablets prepared using PSA were compared with those using water-insoluble ethyl cellulose (EC). Silicone PSA films showed higher resistance to hydrogen ion diffusion compared with EC films. Verapamil hydrochloride tablets prepared using silicone PSA showed higher hydrophobicity and lower water uptake than EC tablets. Silicone PSA tablets also showed pH-independent release of verapamil and decreased in dimensions during drug dissolution. By contrast, verapamil hydrochloride tablets prepared using EC did not achieve pH-independent release.

Supersolubilization and Amorphization of a Model Basic Drug, Haloperidol, by Interaction with Weak Acids

To present a novel approach of greatly enhancing aqueous solubility of a model weakly basic drug, haloperidol, by using weak acids that would not form salts with the drug and to attain physically stable form of amorphous drug by drying such aqueous solutions. Aqueous solubility of haloperidol in presence of increasing concentrations of four different weak organic acids (malic, tartaric, citric, fumaric) were determined. Several concentrated aqueous solutions with differing drug-to-acid molar ratios were dried in vacuum oven, and dried materials were characterized by DSC, powder XRD, dissolution testing, and stability study. Acids were selected such that they would not form salts with haloperidol. Haloperidol solubility increased greatly with increased concentrations of malic, tartaric and citric acids, reaching >300mg/g of solution. In contrast to the haloperidol HCl aqueous solubility of 4mg/g, this may be called supersolubilization. Fumaric acid did not cause such solubilization as it had low water solubility. Dried solids formed dispersions of amorphous haloperidol in acids that were either amorphous or partially crystalline. Amorphous haloperidol was physically stable and had better dissolution rate than HCl salt. A novel method of drug solubilization in aqueous media by acid-base interaction is presented. Physically stable amorphous systems of drugs may also be prepared by using this organic solvent-free approach.

Improvement of capillary electrophoretic enantioseparation of fluoxetine by a cationic additive.

One of the problems encountered in CE separations of basic compounds is the adsorption of analytes onto the negatively charged capillary wall which could lead to poor repeatability of migration time and peak area. Additionally, separation of enantiomers of chiral of basic drugs is commonly carried out in low pH buffer which contributes to strong ionic interaction of the cationic drug ions with negatively charged chiral selectors. The two phenomena results in poor enantioseparations. To overcome the problems associated with chiral separations of basic drugs by CE, the effect of guanidine (GU) on the improvement of chiral separation of a model basic drug, fluoxetine (FLX), was investigated. In the present study, GU was used as a cationic additive to the running buffer containing a chiral selector, sulfated beta cyclodextrine. Better results obtained with GU as the buffer additive in enantioseparation of FLX.

Drug screening in human plasma by cloud-point extraction and HPLC

Abstract Cloud-point extraction (CPE) with RP-HPLC/DAD detection was used to develop a screen for six model basic drugs (paracetamol, promazine, amitriptyline, nortriptyline, clomipramine and chlorpromazine) in human plasma. These drugs’ varied hydrophobicities entail different affinities for the micelle-rich phase and CPE extraction efficiencies. Extraction recovery (except paracetamol) was above 80% and reproducibility (RSD%) ranged from 2.88 to 10.26 intraday and from 3.12 to 12.33 interday. The limits of detection were: 0.125 µg mL−1 (promazine and chlorpromazine), 0.25 µg mL−1 (amitriptyline and nortriptyline) and 0.5 µg mL−1 (paracetamol and clomipramine). The method was linear over the ranges: 0.125–1.0 µg mL−1 (promazine and chlorpromazine), 0.25–1.0 µg mL−1 (amitriptyline and nortriptyline), 0.5–1.0 µg mL−1 (clomipramine) and 0.5–10 µg mL−1 (paracetamol). The procedure is a good alternative to the SPE or LLE sample preparation usually used.

Alteration in plasma protein binding properties of propranolol and flurbiprofen during development of adjuvant-induced arthritis in rats

Adjuvant-induced arthritis (AA) in the rat is used as a model for rheumatoid arthritis. In AA rats, the pharmacokinetics of various drugs is affected due to the alterations of plasma protein binding of drugs. We choose propranolol (PL) and flurbiprofen (FP) as model basic and acidic drugs, respectively, and investigated the effect of AA induction on their plasma protein binding at each developing stage of inflammation. The plasma protein binding of PL and FP was dramatically changed due to reduced albumin and increased α1-acid glycoprotein levels for at least 21 days after adjuvant treatment. Moreover, we illustrated the differences in protein binding in AA between both the drugs in each developing stage of inflammation. These results suggest that the changed plasma protein levels in AA rats accompanying the altered protein binding of drugs affect the pharmacokinetics of drugs which extensively bind to plasma protein under inflammatory condition.

Selective electromembrane extraction at low voltages based on analyte polarity and charge

Electromembrane extraction (EME) at low voltage (0–15V) of 29 different basic model drug substances was investigated. The drug substances with logP<2.3 were not extracted at voltages less than 15V. Extraction of drug substances with logP≥2.3 and with two basic groups were also effectively suppressed by the SLM at voltages less than 15V. Drug substances with logP≥2.3 and with one basic group were all extracted at low voltages and with a strong compound selectivity which appeared to have some influence from the polar surface area of the compound. For this group of substances, recoveries varied between 0 and 23% at 5V, whereas, recoveries varied between 5.5 and 51% at 15V. Based on mass transfer differences related to charge, polarity, and polar surface, highly selective extractions of drug substances were demonstrated from human plasma, urine, and breast milk. An initial evaluation at low voltage (5V) was compared with similar extractions at a more normal voltage level (50V), and this supported that reliable data can be obtained under these low-voltage (mild) conditions by EME.

Self-organized nanoparticles based on drug-interpolyelectrolyte complexes as drug carriers

Potential applications in drug delivery from nanostructures composed of two oppositely charged polymethacrylates, eudragit L100 (EL) and eudragit EPO (EE), loaded with three model basic drugs (D), atenolol, propranolol, and metroclopramide were evaluated. The self-organized nanoparticles based on drug-interpolyelectrolyte complexes (DIPEC), (EL-D50)-EEX, were obtained by mixing the aqueous dispersions of both polyelectrolytes at room temper- ature in an ultrasound bath. Dispersions of (EL-D50) neutralized with increasing proportions of EE exhib- ited a rise of turbidity, particle sizes in the range of 150-400 nm, and high negative zeta potential. The sign of zeta potential was shifted from negative to positive by changes in composition of DIPEC. Freeze dried DIPEC were easily redispersed in water yielding nearly the same parameters of fresh dispersions. In vitro release experiments using Franz cells showed that DIPEC systems behave as a drug reservoir that slowly releases the drug as water is placed in the receptor compartment. The release rate was raised by ionic exchange with counterions present in simulated physiological fluids placed in the receptor media. Delivery of D from DIPEC exhibited a remarkable robustness toward simulated physiological media of different pH. The DIPEC systems exhibit interesting properties to design nanoparticulate drug delivery systems for oral and/or topical routes.

PH応答性を有するポリビニルアルコール系ヒドロゲルの調製とその薬物放出挙動

For the purpose of drug-carrying in oral administration, pH-responsive polyvinyl alcohol (PVA) hydrogels were prepared by the gelation of PVA with tetracarboxylic acid dianhydride as crosslinking part and pH-sensitive part. The resulting hydrogels were estimated on the swelling behavior and the releasing behavior of loaded drug in pH 1.6 buffer solution as imitation of gastric condition and pH 7.4 buffer solution as imitation of intestinal condition at 37°C. The swelling degree was drastically decreased in pH 1.6 buffer solution, but high swelling degree was observed in pH 7.4 buffer solution at 37°C. The equilibrium swelling degree in pH 7.4 buffer solution at 37°C was dependent on the amount of carboxylic acid groups introduced in hydrogels. The releasing behavior of diclofenac sodium (DFNa) as acidic model drug was analogous to the swelling behavior of hydrogels. The releasing rate of DFNa was also dependent on the amount of carboxylic acid groups introduced in hydrogels. However, the release of imipramine hydrochloride as basic model drug was not controlled with pH.