Initial Drug Concentration Research Articles

Assessment of the stability of 30 antipsychotic drugs in stored blood specimens

The stability of 30 common antipsychotics (APs) in spiked whole blood was investigated over ten weeks in a preliminary experiment (designated "P experiment"). Pools of blank blood spiked with drugs at two different therapeutic levels were stored at four different temperatures: 20 °C, 4 °C, -20 °C, and -60 °C and extracted once weekly in duplicate, using a previously published method. A loss of >15% of the initial drug concentration was considered to indicate possible instability and the respective drugs were selected for further investigation in a final experiment (designated "F experiment"). Eight APs (chlorpromazine, chlorprothixene, fluspirilene, droperidol, olanzapine, thioridazine, triflupromazine, and ziprasidone) were incorporated into the F experiment. The same conditions were used in both experiments, however only a high therapeutic drug concentration was chosen for the F experiment and the storage time was extended to 20 weeks. All drugs of interest in the F experiment showed significant losses after 20 weeks of storage under at least one storage condition. The most notable results involved olanzapine, where losses of almost 100% in all storage temperatures were observed. Drug degradation in fluspirilene samples was significant after 20 weeks under all storage conditions. Overall, extensive degradation was seen with approximately 80% drug loss when stored at 20 °C and 4 °C with samples also seriously affected by degradation of up to 50% when stored at -20 °C and -60 °C, respectively. Ziprasidone remained stable when stored at 4 °C, -20 °C, and -60 °C over 9 weeks, however significant degradation was observed when stored at 20 °C, with a loss of almost 100% after 20 weeks of storage. The time period and temperature of storage of biological samples can have a significant influence on the stability of several APs. It is therefore important to be aware of potential changes in drug concentrations during storage when interpreting analytical results.

Graphical process design tools for iontophoretic transdermal drug-delivery devices

A graphical procedure was proposed for the optimum design of transdermal drug-delivery systems enhanced by iontophoresis. Contour plots displayed the relationships among steady-state plasma level, current density and initial drug concentration in a vehicle. This information was combined with a closed-form expression of the process time constant, estimated as the medicament in the blood reaches a plateau after application of the electric field. Analysis was conducted using Laplace-transformed variables and did not require time-domain solutions. Simulation results show that a current density of 0.044mA/cm2 and a loading of 3500μg/ml of dexamethasone sodium m-sulfobenzoate were necessary to achieve an equilibrium plasma concentration of 1.254ng/cm3 with a time constant of 8.34h.

Integrating micromixer precipitation and electrospray drying toward continuous production of drug nanoparticles

We propose an integrated device combining micromixer precipitation and electrospray drying to directly produce dry drug nanoparticles. Drug nanoparticles were formed via non-solvent precipitation in the micromixer part of the device, and the resulted nanosuspension was subsequently dried by the electrospraying. The effects of the liquid flow rate, the applied voltage, the initial drug concentration, and the mixing/precipitation duration on the size and morphology of the products were experimentally investigated. By tuning the process conditions, nanoparticles with controllable shape and size could be achieved. In addition, the possibility of using this integrated device for a continuous production process of drug nanoparticles was explored.

Pharmacokinetic interaction between efavirenz and rifampicin in healthy volunteers

Rifampicin induces the metabolism of efavirenz in humans. This study evaluated efavirenz bioavailability after rifampicin administration to healthy volunteers. A 3-week, before-and-after trial was performed on 8 healthy volunteers. The pharmacokinetic parameters were: plasma drug concentration-time profile from 0 to 72 h (AUC0-72), plasma drug concentration-time profile from 0 h to infinity (AUC0-inf), maximal drug concentration (Cmax), time to reach maximal drug concentration (tmax), and time to reach half the initial drug concentration in elimination phase (t1/2). After an overnight fast, the volunteers ingested one efavirenz 600 mg tablet, then blood samples were drawn to evaluate plasma efavirenz levels at 0, 2, 3, 4, 5, 6, 24, 72, 120, and 168 h. The procedure was repeated after a 1-week induction period of 450 mg/day. Paired-t test and Wilcoxon matched-pairs test were used for differences between mean concentrations. Baseline mean AUC0-72 was 46.80 ± 9.27 µg/ml.h, AUC0-inf was 96.38 ± 38.10 µg/ml.h, Cmax 2.19 ± 0.68 µg/ml.h, tmax 4.50 ± 0.93 h, and t1/2 96.60 ± 42.38 h. Post-induction values were significantly increased: AUC0-72 9.53 ± 11.26 µg/ml.h (p < 0.05; CI95% = 0.112 - 18.940), AUC0-inf 37.24 ± 42.43 (p < 0.05; CI95% = 0.021 - 0.406) µg/ml.h, and tmax 1.13 ± 0.99 h (p < 0.05; CI95% = 0.296 - 1.953). No significant reduction occurred in post-rifampicin induction means of Cmax and t1/2. Co-administration of a single dose of efavirenz 600 mg/day with 1-week rifampicin 450 mg/day significantly reduced efavirenz bioavailability in healthy volunteers.

Pharmacokinetics and Pharmacodynamics of a Sustained-Release Dexamethasone Intravitreal Implant

To determine the pharmacokinetics and pharmacodynamics of a sustained-release dexamethasone (DEX) intravitreal implant (Ozurdex; Allergan, Inc.). Thirty-four male monkeys (Macaca fascicularis) received bilateral 0.7-mg DEX implants. Blood, vitreous humor, and retina samples were collected at predetermined intervals up to 270 days after administration. DEX was quantified by liquid chromatography-tandem mass spectrometry, and cytochrome P450 3A8 (CYP3A8) gene expression was analyzed by real-time reverse transcription-polymerase chain reaction. DEX was detected in the retina and vitreous humor for 6 months, with peak concentrations during the first 2 months. After 6 months, DEX was below the limit of quantitation. The C(max) (T(max)) and AUC for the retina were 1110 ng/g (day 60) and 47,200 ng · d/g, and for the vitreous humor were 213 ng/mL (day 60) and 11,300 ng · d/mL, respectively. The C(max) (T(max)) of DEX in plasma was 1.11 ng/mL (day 60). Compared with the level in the control eyes (no DEX implant), CYP3A8 expression in the retina was upregulated threefold up to 6 months after injection of the implant (0.969 ± 0.0565 vs. 3.07 ± 0.438; P < 0.05 up to 2-month samples). The in vivo release profile of the DEX implant in an animal eye was similar to the pharmacokinetics achieved with pulse administration of corticosteroids (high initial drug concentration, followed by a prolonged period of low concentration). These results are consistent with those in clinical studies supporting the use of the DEX implant for the extended management of posterior segment diseases.

Therapeutic Drug Monitoring in the Treatment of Active Tuberculosis

Therapeutic drug monitoring (TDM) is used to optimize dosing that maximizes therapeutic benefit while minimizing toxicity. In the treatment of active tuberculosis (TB), TDM is not routine, yet low levels of anti-TB drugs can be associated with poorer treatment outcomes. In a retrospective case control study, patients with active TB in whom TDM was performed were considered cases and compared with controls who did not undergo TDM, and matched according to year of diagnosis and the results of direct smear microscopy. Medical records were reviewed to abstract demographic, clinical, radiographic and microbiological data including time until smear and culture conversion. In total, 20 patients were identified in whom TDM was performed, of whom 17 (87%) had at least one low drug concentration. Overall, 27 of 45 (60%) initial drug concentrations were low and resulted in an increased drug dosage. Low drug levels were found in 13 of 15 (87%) isoniazid, four of five (80%) rifabutin and eight of 12 (67%) rifampin measurements, but in only two of 13 (15%) pyrazinamide measurements. Within cases only, the 17 patients with low serum drug levels were significantly more likely to have comorbid illnesses, be smear positive, have lower serum albumin levels and had nonsignificantly longer time to culture conversion, compared with the three cases in whom all drug levels were within therapeutic ranges. TB drug levels were frequently below clinically acceptable levels in patients with active TB, particularly in those with HIV infection or other comorbidities. TDM is potentially useful for the treatment of active TB, but is currently underused.

Randomized, Controlled, Single‐Masked, Clinical Study to Compare and Evaluate the Efficacy of Microspheres and Gel in Periodontal Pocket Therapy

The aim of this randomized, split-mouth, single-masked study is to compare the efficacy of a gel and microspheres as drug-delivery systems in the treatment of periodontal disease. Microspheres were prepared, the release patterns of the microspheres and gel formulations were analyzed using an ultraviolet spectrophotometer, and particle shapes were studied under a scanning electron microscope. A split-mouth design was followed in which 30 potential sites were identified and divided into three groups: one control group and two groups in which microspheres or a gel was placed. Patients were recalled at 1, 3, 6, and 9 months. Clinical recordings included plaque index (PI), gingival index (GI), probing depth (PD), and relative attachment level (RAL) measurements; subgingival plaque was also obtained for microbiologic examination prior to and after therapy. Microspheres had a more sustained release and a high initial drug concentration. There was a significant improvement in the PI and GI in the initial 3 months. The results were statistically significant at P = 0.01. The mean PD scores among scores for the three groups at baseline and follow-up visits showed a reduction of 0.4 to 1 mm. The microbiologic parameters were also statistically significant. These data suggest that the type of delivery system could significantly influence the outcome of therapy.

PH-Sensitive Micelles Self-Assembled from Amphiphilic Copolymer Brush for Delivery of Poorly Water-Soluble Drugs

A novel pH-sensitive amphiphilic copolymer brush poly(methyl methacrylate-co-methacrylic acid)-b-poly(poly(ethylene glycol) methyl ether monomethacrylate) [P(MMA-co-MAA)-b-PPEGMA] was defined and synthesized by atom transfer radical polymerization (ATRP) technique. The molecular structures and characteristics of this copolymer and its precursors were confirmed by (1)H NMR, FT-IR, and GPC. The CMC of P(MMA-co-MAA)-b-PPEGMA in aqueous medium was determined to be 1-4 mg/L. This copolymer could self-assemble into micelles in aqueous solution with an average size of 120-250 nm determined by DLS. The morphologies of the micelles were found to be spherical by SEM and TEM. Ibuprofen (IBU), a poorly water-soluble drug, was selected as the model drug and wrapped into the core of micelles via dialysis method. Drug entrapment efficiency reached to 90%. The in vitro release behavior of IBU from these micelles was pH-dependent. The cumulative release percent of IBU was less than 20% of the initial drug content in simulated gastric fluid (SGF, pH 1.2) over 12 h, but 90% was released in simulated intestinal fluid (SIF, pH 7.4) within 6 h. The release profiles showed that the P(MMA-co-MAA)-b-PPEGMA micelles could inhibit the premature burst drug release under the intestinal conditions. All the results indicate that the P(MMA-co-MAA)-b-PPEGMA micelle may be a potential oral drug delivery carrier for poorly water-soluble drugs.

Polyelectrolyte microcapsules for sustained delivery of water-soluble drugs

Polyelectrolyte capsules composed of weak polyelectrolytes are introduced as a simple and efficient system for spontaneous encapsulation of low molecular weight water-soluble drugs. Polyelectrolyte capsules were prepared by layer-by-layer (LbL) assembling of weak polyelectrolytes, poly(allylamine hydrochloride) (PAH) and poly(methacrylic acid) (PMA) on polystyrene sulfonate (PSS) doped CaCO3 particles followed by core removal with ethylene-diaminetetraacetic acid (EDTA). The loading process was observed by confocal laser scanning microscopy (CLSM) using tetramethylrhodamineisothiocyanate labeled dextran (TRITC-dextran) as a fluorescent probe. The intensity of fluorescent probe inside the capsule decreased with increase in cross-linking time. Ciprofloxacin hydrochloride (a model water-soluble drug) was spontaneously deposited into PAH/PMA capsules and their morphological changes were investigated by scanning electron microscopy (SEM) and atomic force microscopy (AFM). The quantitative study of drug loading was also elucidated which showed that drug loading increased with initial drug concentration, but decreased with increase in pH. The loaded drug was released in a sustained manner for 6h, which could be further extended by cross-linking the capsule wall. The released drug showed significant antibacterial activity against E. coli. These findings indicate that such capsules can be potential carriers for water-soluble drugs in sustained/controlled drug delivery applications.

Mechanism analysis of poly(lactic acid) particles formation by mesoscale simulation

AbstractIn this work, the mechanism analysis of Poly(DL‐lactic acid) (PLA) particles formation is investigated by dissipative particle dynamics (DPD) simulations. The polymer PLA is usually as a carrier at the drug deliver system (DDS), first, the mechanism analysis of PLA particles formation was preceded on the basis of the blank PLA particles. At the same time, the formation of PLA particles for drug delivery systems has been investigated. The results of DPD simulations indicate that the formation of PLA particles with drug or not, consists of three steps: (1) aggregation‐individual PLA chains got aggregated with each other in solution; (2) formation and disruption of PLA particles; (3) solidification of PLA particles. At the same time, the effects of PLA, drug content on the aggregation morphology are investigated, which indicates the PLA particles with drug or not aggregated and formed is spherical particles, drug molecules are amorphously and homogeneously distributed inside the PLA matrix, the size of PLA particles increases with increasing the initial PLA content and drug content in the solution. The content of DMF is gotten when PLA chains and drug molecules begin to aggregate and form the particles. These could be used to guide the experimental preparation of PLA blank particles and DDS with desired properties. © 2010 Wiley Periodicals, Inc. J Appl Polym Sci, 2011

Effect of Drug Loading Method on Drug Content and Drug Release from Calcium Pectinate Gel Beads

Drug-loaded calcium pectinate gel (CaPG) beads were prepared by either mixing, absorption, or swelling method. The effects of drug loading method as well as the drug loading factors (i.e., drug concentration, soaking time in drug solution, type of solvent) on drug content and drug release were investigated. The amount of drug uptake (i.e., drug content) into CaPG beads increased as the initial drug concentration increased and varied depending on the loading method. The in vitro release studies in 0.1 N hydrochloric acid (HCl) and pH 6.8 buffer indicated that the drug loading method affected drug release and release parameter, time for 50% of drug release (T(50)). The mixing method provided a faster drug release and lower T(50) than the absorption method and swelling method, respectively. This is probably due to higher drug content in CaPG beads. The increased concentration of drug in soaking solution and soaking time resulted in higher drug content and thus faster drug release (lower in T(50) values). When using 0.1 N HCl as solvent for soaking instead of water, the drug release was slower owing to the increase in molecular tortuosity of CaPG beads. The drug release was also affected by pH of the release medium in which drug release in 0.1 N HCl was faster than in pH 6.8 buffer.

Multitemperature Stability and Degradation Characteristics of Pergolide Mesylate Oral Liquid

The stability of pergolide mesylate in an oral aqueous liquid was studied. Stability and solubility data were used to determine the degradation characteristics of the drug in this formulation. Samples were stored in the dark at 35°C, 45°C, and 60°C. At 1, 2, 4, 8, 12, and 16 weeks, samples were removed and stored in a −80°C freezer for high performance liquid chromatography (HPLC) assay at a later date. The initial drug concentration of 0.30 mg/mL was determined by assay after storage at −80°C. A solubility of 6.9 mg/mL was found for pergolide mesylate in the oral liquid at room temperature with a relative standard deviation (RSD) of 4.0%. The degradation process is considered first-order at 25°C and 35°C. At higher temperatures (45°C and 60°C), a color change and curvature at the latter time points in degradation profiles are ascribed to the presence of methylcellulose. The activation energy calculated for degradation of pergolide mesylate in the oral liquid was 21.3 kcal/mol. The time to reach 90% potency (t90) values were calculated to be 43 days and 3 days, respectively, for storage at 25°C and 35°C. Drug concentrations up to ~6 mg/mL can be maintained as a solution at room temperature with this formulation.

Alginate‐based biodegradable superabsorbents as candidates for diclofenac sodium delivery systems

AbstractNovel types of highly swelling hydrogels were prepared by grafting crosslinked polyacrylamide‐co‐poly‐2‐acrylamido‐2‐methylpropane sulfonic acid (PAAm‐co‐PAMPS) chains onto sodium alginate (Na‐Alg) through a free radical polymerization method. The superabsorbent formation was confirmed by Fourier transform infrared spectroscopic (FTIR). The controlled release behavior of diclofenac sodium (DS) from superabsorbent polymer was factinvestigated, and shown that the release profiles of DS from superabsorbent polymer were slow in simulated gastric fluid (SGF, pH 1.2) over 3 h, but nearly all of the initial drug content was released in simulated intestinal fluid (SIF, pH 7.4) within 21 h after changing media. Overall the results demonstrated that biodegradable superabsorbent could successfully deliver a drug to the intestine without losing the drug in the stomach, and could be potential candidates as an orally administrated drug delivery system. © 2010 Wiley Periodicals, Inc. J Appl Polym Sci, 2010

UV-A and Solar Photodegradation of Ibuprofen and Carbamazepine Catalyzed by TiO2

The objective of this study was to investigate the efficiency of solar and UV-A photocatalysis with suspended TiO2 to degrade ibuprofen and carbamazepine in aqueous matrices. Emphasis was given on the effect of various operating conditions such as catalyst type (six commercially available titanium oxide samples were tested) and concentration (50–3000 mg/L), initial drug concentration (5–20 mg/L), solution pH (3–10), the addition of hydrogen peroxide (0.07–1.4 mM), and the matrix (pure water and treated domestic wastewater) on degradation and mineralization. The former was assessed monitoring sample absorbance at each drug's characteristic wavelength, while the latter measuring dissolved organic carbon. The best performance was achieved at lower drug concentrations irradiated by UV-A in the presence of Degussa P25 catalyst and hydrogen peroxide in pure water.

Interactions of terbinafine with β-cyclodextrin polymers: sorption and release studies

β-cyclodextrin insoluble polymers (βCDP), a type of hydrogels with a high swelling capacity, can be obtained by crosslinking β-cyclodextrin (βCD) with epichlorohydrin. Terbinafine (TB) is an oral and topical antifungal drug that can be housed into the cavity of β-cyclodextrin, so it seems probable that the drug could interact with the insoluble βCDP. Different organic molecules can be sorbed on the polymer network and also included within the βCD cavities, so these hydrogels have potential applications in the pharmaceutical field as drug carriers. In this work, the sorption of TB on βCDP and the optimal conditions to load the polymer with the drug were studied. Sorption kinetics and Freundlich isotherms of TB on βCDP at 25°C were obtained and the influence of several parameters on the sorption process of TB was investigated. It was found that a high initial concentration of drug, high TB:β-CD molar ratios and low ionic strengths were the most favourable conditions. No significant influence of temperature was observed. Moreover, the sorption kinetic profile obtained for terbinafine was compared to that of naftifine, another antifungal agent of similar structure. Terbinafine presented higher affinity for the polymer, according to the higher stability constant of the drug-βCD inclusion complex. In relation to the release studies from the loaded polymer, 0.1 M HCl was the most favourable medium to allow the release of the drug. The maximum amount of drug released in 24 h was up to 50% of TB loaded. The predominant mechanism of drug release was Fickian diffusion.

Sonochemical degradation of ofloxacin in aqueous solutions

The use of low frequency (20 kHz), high energy ultrasound for the degradation of the antibiotic ofloxacin in water was investigated. Experiments were performed with a horn-type ultrasound generator at varying applied power densities (130-640 W/L), drug concentrations (5-20 mg/L), hydrogen peroxide concentrations (0-100 mM) and sparging gases (air, oxygen, nitrogen and argon). In general, conversion (which was assessed following sample absorbance at 288 nm) increased with increasing ultrasound energy and peroxide concentration and decreasing initial drug concentration. Moreover, reactions under an argon atmosphere were faster than with diatomic gases, possibly due to argon's physical properties (e.g. solubility, thermal conductivity and specific heat ratio) favoring sonochemical activity. Overall, low to moderate levels of ofloxacin degradation were achieved (i.e. it never exceeded 50%), thus indicating that radical reactions in the liquid bulk rather than thermal reactions in the vicinity of the cavitation bubble are responsible for ofloxacin degradation.

Effect of unilateral nephrectomy on the pharmacokinetics of amikacin in humans.

As unilateral nephrectomy is not a rare surgical procedure, it gives rise to the question whether drugs predominantly eliminated through the urinary tract can be handled effectively by the remaining kidney. Amikacin is predominantly excreted via glomerular filtration with only a small fraction undergoing tubular reabsorption, and can be used as a model drug of glomerular elimination. The study was carried out in 28 subjects, 10 one month and 10 one year after unilateral nephrectomy, as well as in 8 healthy subjects. The pharmacokinetics of amikacin was investigated after a 1-h infusion of 5 mg kg(-1) amikacin. Blood samples were collected for 24 h after the end of infusion. Pharmacokinetic parameters of amikacin were calculated using a one-compartment open model for intravenous administration. Amikacin concentrations were significantly elevated in nephrectomized patients as compared with control subjects, both 1 month and 1 year after the surgery, and were similar at these two time-points following unilateral nephrectomy. Pharmacokinetic parameters of amikacin in patients subjected to unilateral nephrectomy were significantly different from those observed in the control subjects. As compared with the controls, an increase in AUC (area under the serum concentration-time curve) by 81% (P < 0.001) and 63% (P < 0.01) 1 month and 1 year after nephrectomy was observed, respectively. The lambda(z) (elimination rate constant) was reduced by 39% (P < 0.001) after 1 month and by 38% (P < 0.001) 1 year after the operation and t 1/2 was prolonged by 70% (P < 0.001) and by 43% (P < 0.01) at the respective time-points following unilateral nephrectomy. CLT (total body clearance of the drug from plasma) and CL(BW) (clearance per kg body weight) were both significantly decreased in unilaterally nephrectomized subjects in comparison with the controls. CLT and CL(BW) were reduced by 53% (P < 0.001) and 42% (P < 0.01) 1 month after nephrectomy, and by 45% (P<0.001) and 42% (P<0.01) 1 year after the surgery, respectively. No significant differences among studied groups were found in C0 (initial serum drug concentration) and Vd (apparent volume of distribution). The results suggest that unilateral nephrectomy impairs elimination of amikacin, and possibly other drugs predominantly eliminated via glomerular filtration.

Inert gas sparge leads to alternate reaction pathway.

The effect of sparging with an inert gas (argon) was evaluated during the investigation of the solution kinetics of an oxidation-prone amphiphilic drug containing a sulphide moiety. Samples stored with an air headspace in pH7 and 8 phosphate buffers at elevated temperatures and in the absence of light degraded to two main products, a sulphoxide and a cinnamic acid analogue. Initially, this appeared to be a sequential mechanism which could be blocked by removing oxygen. Instead, argon-sparge forced the direct degradation to the cinnamate, which was evidenced by the formation of a strong odour of sulphide. In addition, argon-sparged samples remained colourless, while those sparged with oxygen or stored with an air headspace turned yellow and had negligible odour. The half-lives for samples stored in pH 8 buffers at 93 degrees C at an initial drug concentration of 25 mg mL(-1) were 128 days (argon sparged), 86 days (air headspace), and 65 days (oxygen sparged). The results indicated that for the drug under study, sparging with an inert gas affected the mechanism as well as the rate of the reaction at elevated temperatures.

Meloxicam formulations for transdermal delivery: hydrogels versus organogels

The objective of this work was to evaluate the efficacy and suitability of different organogel formulations as transdermal delivery systems of meloxicam (MX) compared to hydrogel formulations. Hydrogels and hydroalcoholic gels were prepared using either carbopol 940 or pluronic F-127 as gelling agents. The organogels used glyceryl monostrearate (GMS), a glyceryl fatty acid ester as organogelator in view of the good skin tolerability of this group of organogelators. The liquid phase was oleic acid, Mygliol 812 or Labrasol. In vitro drug release through cellophane membrane was studied. The effect of some formulation variables (organogelator concentration, type of liquid phase, drug concentration and method of drug incorporation) on the release patterns of meloxicam (MX) from different organogels was investigated. In vitro skin permeation through excised rat skin in phosphate buffer (pH 7.4) was carried out. The in vivo skin penetration was evaluated by measuring the anti-inflammatory effect in rats by the paw edema test. The highest drug release was obtained from Mygliol 812 organogel, Labrasol organogel and hydroalcoholic pluronic gel. The results revealed an inverse correlation between the drug release rate and organogelator concentration and direct correlation between the drug release rate and the initial drug concentration. The release rate of the drug was dependent on the nature of the gel's liquid component (which influences drug solubility), but not on the method of drug incorporation. Permeation across rat skin showed that Mygliol 812 and Labrasol organogels were superior to hydrogels and hydroalcoholic gels. The anti-inflammatory activity of the drug in different formulations was studied using carragenan-induced rat paw edema method. The results showed an excellent anti-inflammatory activity for the tested formulations, but the anti-inflammatory activity of organogels was significantly higher than that of hydroalcoholic gel. Histopathological examination of rat skin treated with the selected formulations showed normal skin histology. These findings suggest that these organogels could be effective vehicles for transdermal delivery of meloxicam.

Mathematical modeling of drug release from Eudragit RS-based delivery systems

Various types of tartaric acid, Metoprolol free base and Metoprolol tartrate containing Eudragit RS-based films were prepared and physicochemically characterized. In particular, the water uptake and compound release kinetics were monitored upon exposure to 0.1 M HCl, phosphate buffer pH 7.4 and distilled water. Appropriate analytical solutions of Fick’s second law of diffusion, considering the given initial and boundary conditions, were used to elucidate the underlying mass transport mechanisms. Furthermore, the apparent diffusion coefficients of water, tartaric acid, metoprolol free base and metoprolol tartrate in the different Eudragit RS-based networks were determined. Importantly, the diffusivity of metoprolol tartrate and metoprolol free base significantly increased with increasing initial drug content, illustrating the strong plasticizing capacity of these compounds for the polymer. In contrast to Eudragit RL-based films, metoprolol free base precipitation occurred only at higher initial drug loadings, due to the lower water uptake resulting from the lower contents of quaternary ammonium groups. Interestingly, negatively charged tartrate ions diffused out more rapidly from metoprolol tartrate containing films than positively charged metoprolol ions, indicating that the lower molecular weight over-compensates the attractive ionic interactions with the positively charged macromolecules.