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Eudragit E PO as a Complementary Material for Designing Oral Drug Delivery Systems with Controlled Release Properties: Comparative Evaluation of New Interpolyelectrolyte Complexes with Countercharged Eudragit L100 Copolymers R. I. Moustafine,*,† A. V. Bukhovets,† A. Y. Sitenkov,† V. A. Kemenova,§ P. Rombaut,‡ and G. Van den Mooter*,‡ †

Department of Pharmaceutical, Toxicological and Analytical Chemistry, Kazan State Medical University, 420012 Kazan, Russian Federation ‡ Drug Delivery and Disposition, University of Leuven (KULeuven), 3000 Leuven, Belgium § Scientific Center for Biomedical Technology, State Research Institute of Medicinal and Aromatic Plants (VILAR), 123056 Moscow, Russian Federation ABSTRACT: The design of new interpolyelectrolyte complexes (IPEC) between countercharged polymers (Eudragit EPO (EPO) and Eudragit L100 (L100)) was investigated. The formation and chemical composition of three new IPECs between EPO and L100 was established by elemental analysis. The structure and solid state properties of the synthesized IPEC were investigated using Fourier transform infrared (FTIR) spectroscopy and modulated temperatre differential scanning calorimetry (MTDSC). The binding ratio of a unit molecule of EPO with L100 was found to range between 1:0.98 (Z = 1.02) and 1:0.50 (Z = 2.00) while increasing the pH from 6.0 to 7.0. As a result of electrostatic interaction between the copolymer chains, the glass transition temperature of the IPEC increased significantly. Considerable pH-sensitive swelling in acidic and neutral media was observed for different type of IPECs. Through evaluation of diffusion-transportation properties of the IPECs, basic mechanisms controlling the delivery of chemically different drugs (diclofenac sodium and theophylline) were obtained. The results of swelling and release of the model drugs from the polycomplex matrices confirm that they have potential to be used in oral controlled drug delivery. KEYWORDS: interpolyelectrolyte complexes, Eudragit E PO, Eudragit L 100, Eudragit RL30D, pH-dependent swelling behavior, oral drug delivery, FTIR, MTDSC, glass transition, diclofenac sodium, theophylline modifying their properties.5 The structural feature of the polycomplexes is the alternating so-called “ladder” (ordered) chain fragments of macromolecules and oppositely charged groups interacting with each other. The sequence of hydrophobic units and “defective” regions consisting of disparate units is responsible for the overall hydrophilicity of the polymer−polymer complex. Hence, targeted regulation of both fragments in the overall structure of interpolyelectrolyte complex (IPEC) allows the creation of a system with desired

1. INTRODUCTION Methacrylate copolymers manufactured under the brand name Eudragit have been used in oral dosage form development for five decades.1,2 These excipients are used in the manufacturing of tablets, granules, micro- and nanosized particles as coatings, or as binders in the granulation stage to prepare matrix tablets. Due to their unique properties, coating of tablets with Eudragit is carried out using different methodswet and dry deposition. As a consequence of their plasticity due to the low glass transition temperatures of polymethacrylates, some Eudragits are used in hot melt extrusion.3,4 Evonik Röhm GmbH offers grades of synthesized Eudragit copolymers, which are oppositely charged. Thus, the interpolyelectrolyte interaction proved very successful in © XXXX American Chemical Society

Received: February 5, 2013 Revised: May 29, 2013 Accepted: June 3, 2013

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dx.doi.org/10.1021/mp4000635 | Mol. Pharmaceutics XXXX, XXX, XXX−XXX

Molecular Pharmaceutics

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properties.6−9 Tuning of the properties of the IPEC can be realized by varying some of the macromolecular components, the main ones being the degree of polymerization and charge density of reactive copolymers. The easiest way to control the reactivity of polyelectrolytes is to increase or decrease the charge density of reacting macromolecules by changing the pH of their solutions.6 The advantages of IPECs as polymeric carriers in controlled drug release have been reported elsewhere.5,10−14 Despite the fact that a comprehensive analysis of the physicochemical principles of the intermacromolecular interactions that elucidate the mechanism for regulating the drug release rate from oral DDS based on chemically complementary Eudragit grades was examined in recently published review,5 further discussion addresses ionogenic Eudragit types that forms IPECs with countercharged (co)polymers. Interpolymer combinations15−18 or polycomplexes based on a basic butylated methacrylic terpolymer (Eudragit E) and countercharged synthetic copolymers {Eudragit L100-55, L100, S100, FS;9,19−28 Carbomer 940;29−32 Carbopol 93433,34} and polymers of natural origin {(polysaccharides: sodium alginate,35−37 naturally sulfated polysaccharides of the seaweed Polysihhonia nigrescens38 and κ-carrageenan39,40), shellac,41 casein42} prepared in aqueous or organic solutions have been extensively investigated in recent years. Moreover, physicochemical characterization and controlled drug delivery applications of the IPECs based on Eudragit polyanions (L100-55, L100, S100) with countercharged chitosan have been reported.43−48 Recently, a novel self-organized nanoparticulate carrier, based on a drug−IPEC Eudragit E100/L100 (DIPEC) system, was successfully prepared using a simple aqueous dispersion method.49 In this study, the authors have reported that freeze-dried complexes were easily redispersed in water and the formulated DIPEC dispersions behave as zwitterionic macromolecular systems that may shift the sign of the zeta potential from negative to positive by appropriate changes in the composition. Moreover, the DIPEC systems exhibit interesting properties to design nanoparticulate DDS for oral and topical routes. Few publications have investigated structural and compositional microenvironment transformations during swelling and release studies of polycomplex matrix systems,18,25,26,31,34,36,46 although macromolecular distribution in polymer blends due to their interactions with fluorescent conjugated Eudragit RL/S50 and RS/FS51 polymer in microparticles using confocal laser scanning microscopy have been reported. Further to the published results on the characterization of oppositely charged Eudragit EPO/L100 and EPO/L100-55 copolymer pairs, it is still possible to modify the properties of the resulting polycomplexes by directed synthesis of new IPECs with variable charge density of the reacting macromolecules. The objective of this study was to investigate the fundamental physicochemical characteristics of new IPECs prepared from Eudragit type E PO (EPO) and Eudragit L 100 (L100) in aqueous solutions in order to monitor possible structural transformation and composition changes of polycomplex matrices during swelling and drug release in simulated gastrointestinal tract (GIT) conditions with respect to their potential application in oral drug delivery. Diclofenac sodium (DS) and theophylline (TEO) were used as a model drugs.

2. EXPERIMENTAL SECTION 2.1. Materials. The polycations used were: Eudragit E POa terpolymer of N,N-dimethylaminoethyl methacrylate (DMAEMA) with methylmethacrylate (MMA) and butylmethacrylate (BuMA), PDMAEMA-co-MMA/BMA (mole ratio 2:1:1, MW 150 000 g/mol); Eudragit RL POa terpolymer of ethylacrylate (EA) with methylmethacrylate (MMA) and N,Ntrimethyl ammonioethyl methacrylate chloride (TAMCl), PEAco-MMA-co-TAMCl (mole ratio 1:2:0.2, MW 150 000 g/mol). Eudragit L 100 was used as the polyanion. This is a copolymer of methacrylic acid (MAA) with methylmethacrylate (MMA), PMAA-co-MMA (mole ratio 1:1, MW 135 000 g/mol). The different types of Eudragit (EPO, L100, RLPO) were generously donated by Evonik Röhm GmbH (Darmstadt, Germany). The copolymers were used after vacuum drying at 40 °C for 2 days. DS and TEO were used as a model drugs and were purchased from Sigma (Bornem, Belgium). Molecular structures of the materials used are shown in Figure 1. 2.2. Methods. 2.2.1. Synthesis of Solid IPECs with Different Macromolecular Composition. EPO solutions were

Figure 1. Structural monomer unit fragments of copolymers: Eudragit L 100 (a), Eudragit E PO (b), and Eudragit RL PO (c) and molecular structures of model drugs: diclofenac sodium (d) and theophylline (e). B



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Table 1. Characteristics of IPEC EPO/L100 Systems IPEC composition polycomplex type

Z = [EPO]/[L100]

EPO:L100 (mol/mol)

EPO:L100 (w/w)

weight fraction of EPO

Tg value (°C)

IPEC-1 IPEC-2 IPEC-3

1.02 1.49 2.00

1:0.98 1:0.67 1:0.50

1:0.66 1:0.45 1:0.33

0.603 0.690 0.750

144.5 116.4 71.8

2.2.5. Preparation of Tablets. To determine the degree of swelling, flat-faced tablets of 100 mg of polymer carrier and 8 mm diameter were prepared by compressing the given amount of powder (RLPO, PMs, and IPECs) at 2.45 MPa using a hydraulic press (Rodac, Sittard, The Netherlands). For dissolution testing, flat-faced tablets of 150 mg weight (100 mg of DS or TEO, 50 mg polymer carrier) and 8 mm diameter were prepared by compressing the given amount of the polymer carriers at 2.45 MPa using a hydraulic press (Rodac, Sittard, The Netherlands). 2.2.6. Determination of the Degree of Swelling of Matrices. Swelling was investigated in conditions, mimicking the gastro-intestinal tract up to the colon:43 the first hour in simulated gastric medium (0.1 M HCl; pH 1.2), then the pH of the medium was gradually increased using phosphate buffers: pH 5.8 for the next two hours, pH 6.8 for a further two hours, and finally pH 7.4 was maintained until the end of the experiment (a further two hours). The polymeric matrix was placed in a tarred basket, which was immersed into a thermostatted bath (37.0 ± 0.5 °C). The volume of the medium was 40 mL. The basket was removed from the medium every 15 min, the tablet carefully dried using a filter paper and weighed. For determination of the equilibrium degree of swelling a final weighing was performed after incubation in the final medium for 24 h. The degree of swelling (H, %) was calculated as:

prepared by dissolving the polymer in 1 M CH3COOH. This solution was diluted with demineralized water to the desired volume and titrated with 1 M NaOH to the required pH. L100 solutions were prepared by dissolving the polymer in 1 M NaOH. This solution was diluted with demineralized water to the desired volume and titrated with 1 M CH3COOH to the required pH. EPO solutions (0.05 M, pH 6.0, 6.5, and 7.0) were mixed with L100-55 solutions (0.05 M, pH 6.0, 6.5, and 7.0) at constant temperature. After isolation of the precipitates from the solutions, they were washed with demineralized water and the solid IPECs were subsequently dried under vacuum for 2 days at 40 °C to constant weight. The dried complex was ground with a grinder A 11 basic (IKAWerke GmbH, Staufen, Germany) and ball milled by ULTRA-TURRAX Tube Drive with BMT-20-G tube (IKAWerke GmbH, Staufen, Germany). The powder was passed through a 200 μm sieve and used for further study. 2.2.2. Elemental Analysis. The composition of the dried IPEC samples before, during, and after swelling testing were investigated by elemental analysis using a EuroVector model EuroEA3028-HT-OM CHN/O Elemental analyzer (Milan, Italy) and calculated as Z = [EPO]/[L100]. 2.2.3. Fourier Transform Infrared (FTIR) Spectroscopy. FTIR spectra of the solid IPEC EPO/L100 systems and the vacuum-dried samples during and after swelling testing were measured by a Bruker FTIR model Vector 22 spectrophotometer (Bruker, Karlsruhe, Germany) using the KBr disk method. The dried IPEC were ground and ball-milled by ULTRA-TURRAX Tube Drive with BMT-20-G tube (IKA Werke GmbH, Staufen, Germany). The powder was passed through a 200 μm sieve before use. 2.2.4. MTDSC-Measurements (Modulated Temperature Differential Scanning Calorimetry). MTDSC measurements were carried out using a Q2000 modulated DSC (TA Instruments, Leatherhead, UK), equipped with a refrigerated cooling system (RCS). Data were treated mathematically using the Thermal Solutions software (TA Instruments, Leatherhead, UK). Dry nitrogen at a flow rate of 50 mL/min was used as the purge gas through the DSC cell, and 150 mL/min of dry nitrogen was used through the RCS unit. TA Instruments (Leatherhead, UK) pans were used for all calorimetric studies. The amplitude used was 0.212 °C, the period 40 s, and the underlying heating rate 2 °C/min. Octadecane, benzoic acid, cyclohexane, and indium standards were used to calibrate the DSC temperature scale; the enthalpic response was calibrated with indium. The heat capacity signal was calibrated using dry, powdered aluminum oxide. Validation of temperature, enthalpy, and heat capacity measurement using the same standard materials showed that deviation of the experimental from the reference value was less than 0.5 °C for temperature measurement, less than 0.1% for enthalpy measurement, and less than 1% for measurement of the heat capacity in the range between 0 and 250 °C. Measurements were performed in duplicate.

H% = (m2 − m1/m1)100

in which m1 is the weight of the dry sample and m2 the weight of the swollen sample. Swelling was also investigated in simulated gastric medium (0.1 M HCl; pH 1.2) alone using the procedure described above. For determination of the stability of the polycomplex matrices, a final weighing was performed after 24 h of incubation in this medium. 2.2.7. Release Testing of the Model Drugs. The release of diclofenac sodium (DS) and theophylline (TEO) from matrix tablets was performed at 37 ± 0.1 °C using a standard dissolution tester DT 626/1000 HH (Erweka, Heusenstamm, Germany) (basket method). The rotation speed was 100 rpm, and the volume of the medium was 900 mL. The release was investigated in GIT conditions. The pH of the release medium was gradually increased: pH 1.2 for the first hour, pH 5.8 for the next 2 h, then 6.8 for a further two hours, and finally pH 7.4 was maintained until the end of the experiment. Aliquots (3 mL) of solution were taken at specific time intervals, and the volume was made up to the original value by adding fresh dissolution medium. The amounts of DS and TEO released in the dissolution medium were determined by UV spectrophotometry at 276 and 271 nm, respectively (Lambda 25; Perkin-Elmer, Norwalk, CT, USA). Results are given as the mean values of three determinations. Preliminary experiments had shown that the polymers did not interfere with the quantitation of the model drugs. Release profiles were C



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modeled mathematically using Origin (Scientific Graphing & Analysis software, Version 7.5, Origin Lab Corp., USA).

3. RESULTS AND DISCUSSION 3.1. Composition Study. Compositional differences of the synthesized IPECs were observed using elemental analyses (Table 1). The fraction of polycation (EPO) incorporated in the polycomplex increases as the pH rises. Whereas the first, synthesized at pH 6.0 (denoted as IPEC-1), has a composition close to equimolar (Z = [EPO]/[L100] = 1.02), IPEC-3 (synthesized at pH 7.0) contains a 2-fold excess of EPO (Z = 2). IPEC-2, prepared at pH 6.5, has correspondingly an intermediate composition (Z = 1.49). Thus, the polycomplexes are enriched with the less ionized component (charge density on EPO chains > 0). On the other hand, incorporation of the polyanion (L100) decrease due to the progressive increase of the fraction of ionized carboxylic acids. This also increases its reactivity. 3.2. Structure of the Polycomplexes. 3.2.1. Infrared Spectroscopy. From the results, the IPECs have different compositions (1.02 < Z < 2.00). All of them have a band at 1570 cm−1, which can be assigned to the stretching vibration band of the carboxylate groups that form the ionic bonds with the protonated dimethylamino groups of EPO (Figure 2). It should be noted that the fraction of reactive groups involved in interpolymer ionic bonds decreases with increasing pH. Furthermore, bands corresponding to the presence of nonionized dimethylamino groups (2770 and 2820 cm−1) become stronger as the pH rises. This is understandable because the charge density of the EPO macromolecule chains decreases smoothly. All samples contain the bands of nonionized dimethylamino groups with increased intensity. These phenomena were in agreement with those observed in our previous studies with Eudragit E/Eudragit L100 (L100-55) systems and with reports from the literature.19−21,25,27 Therefore, if we compare our previously published data for the same system with the current, we can conclude that the presence or absence of nonionized dimethylamino groups is not only dependent on the IPEC composition, but mostly on the polycomplex structure, which depends on charge density of the interacting copolymers. The existence of nonionized dimethylamino groups in all polycomplex samples indicates that in these structures, they are localized mainly in “defects” fields together with ionized unbound groups of EPO which is largely dependent on the conditions of the IPEC synthesis procedure. Moreover, in all polycomplexes a new band appeared at 1640 cm−1 arising from the intermolecular hydrogen bonding between carboxylic groups52 and between acid hydroxyls (COOH) and the carbonyl stretching vibrations of all three monomer units (MMA, BMA, DMAEMA) from the acrylic groups.27,53 3.2.2. Thermal Analysis. Eudragit copolymers are amorphous substances and have a characteristic glass transition temperature. MTDSC was used to confirm the structural differences between the polycomplexes identified by FTIR spectroscopy, as well as to evaluate the chemical homogeneity of the polymer systems by the absence of microdomains of free copolymers, the thermal characteristics of the synthesized IPECs vary with their composition and are given in Table 1. All polycomplexes were characterized by the presence of only a single Tg, which was higher compared to that of pure EPO.54−56 However, increasing the amount of L100 led to an increase in the resulting Tg which is consistent with our studies on the

Figure 2. FTIR spectra of interpolyelectrolyte complexes (IPECs) with different composition: IPEC-1 (1), IPEC-2 (2), and IPEC-3 (3).

complementary pair of EPO/L100-55.9,23,25 As a result, IPEC-1 (Tg = 144.5 °C) is characterized by very high Tg, and IPEC-3 (Tg = 71.8 °C) has the lowest glass transition temperature of all the samples. Comparison of the experimentally obtained values with theoretically calculated values of glass transition temperatures was carried out according to the Gordon−Taylor equation,57 the most commonly used for the prediction of Tg in binary mixtures: Tgx =

Tg1w1 + Tg2Kw2 w1 + Kw2

in which Tg1 and Tg2 are the glass transition temperature of EPO (52.1 ± 1.3 °C) and L100 (193.3 ± 1.8 °C), respectively, w1 and w2 are the weight fractions of EPO and L100 in the D



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dispersions, respectively, and K is a constant which was estimated using the Simha−Boyer rule:58 K≅

ρ1Tg1 ρ2 Tg2

where ρ is the density of the copolymers; the densities are 0.815 and 0.840 g/cm3 for EPO and L100, respectively, and K is calculated to be 0.680. Significant deviations were found between the experimentally obtained and theoretically calculated values of glass transition temperatures of the IPEC and are presented in Figure 3. The

Figure 4. (a) Degree of swelling of physical mixtures (PM) of EPO/ L100 with different compositions and RLPO matrices in GIT conditions (n = 3; ± SD); (b) changes of external appearance of RLPO matrices during swelling test.

Figure 3. Comparison of the experimental (■) and theoretical (□) values of the glass transition temperature of the different IPEC calculated according to the Gordon−Taylor equation.

studies of the same countercharged system made up of equimolar combinations of E100/L100.19,21 To investigate the influence of polymer matrix structure on swelling properties, PMs were compared with Eudragit type RL PO (RLPO). This polymer is often used in controlled release systems and, thus, the most interesting for comparative evaluation. As can be clearly seen from Figure 4a, the swelling profiles had a different character in all pH regions yet disintegrated later due to surface erosion during immersion in the final medium (macroscopic changes were visible and shown in Figure 4b). According to the manufacturer’s specifications, this copolymer contains 10% of quaternary amino groups, which are responsible for its swelling properties, is recommended as pHindependent carrier for an erosion-controlled drug release.1,2 Thus, in spite of its rather hydrophilic properties, RL has a hydrophobic pH-independent structure, unlike IPECs, which is regulated by the hydrophilic−hydrophobic balance. Indeed, the swelling of the polycomplex pH-sensitive matrix is easily regulated by changing the hydrophobic (interacting chains) and hydrophilic (defects) sequences in the IPEC structure, which are may be further modified on immersion in media of different pH and/or ionic strength. This is in agreement with previous findings, concerning countercharged systems made up of Eudragit EPO/L100-55 and RLPO or RSPO matrices.9 3.3.2. Monitor of Structural Transformations Inside Polycomplex Matrices in GIT Conditions. It is known that the suitability of new polymeric compounds as drug carriers can be predicted beforehand using results from studying their swelling capability in media mimicking the movement through the GIT.9,20−26 Figure 5a shows swelling profiles of the polycomplexes that had been digitally photographed after residence in each of the test media and after spending 24 h in the final medium at pH 7.4 (Figure 5b). It can be seen that the nature of the swelling and the externally occurring processes of

calculated mass fractions of EPO needed to build this relationship are given in Table 1. It is clear that the increase in the proportion of EPO in the structure of the IPEC leads to a reduction in the resulting Tg. A decrease in mobility of the polymer chains confirms the existence of significant electrostatic interactions between the copolymer units and proves the compatibility of the components. However, comparing the results with those published previously by our group9,23,25 with respect to EPO/L100-55 systems, the discrepancy between the calculated and experimentally obtained values is less pronounced in this case. This is at least in part due to the greater plasticity of Eudragit L100-55 (Tg = 124.4 ± 1.6 °C) because of the presence of ethylacrylate (EA) units in its structure which favor interpolymer interaction.6 3.3. Pharmaceutical Evaluation of EPO/L100 Systems. 3.3.1. Monitor of Changes in External Appearance of the Matrices Made up from Physical Mixtures EPO/L100 and RLPO in GIT Conditions. Physical mixtures (PM) with equimolar composition (Z = 1.02 − PM-1) and an excess amount of EPO (Z = 1.49, 2.00, denoted as PM-2 and PM-3, respectively) were completely disintegrated and dissolved at the end of the first hour, due to immediate leaching of EPO, localized in external layers of the matrices in acidic medium (Figure 4a). Results were published showing that EPO/L10055 IPEC matrices were more stable under similar conditions. Moreover, in the case of two samples of PMs containing an excess amount of L100-55 (Z = 0.68 and Z = 0.36), stable swelling profiles were observed, relatively independent of the medium. The FTIR spectra of these PMs were characterized by changes indicating an interaction between chains of two oppositely charged copolymers (a new band at 1570 cm−1 appeared). Concurring results were observed in previous E



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Figure 5. (a) Degree of swelling of IPECs EPO/L100 with different composition in GIT conditions (n = 3; ± SD); (b) Changes of external appearance of polycomplex matrices during swelling test.

lecular ionic bonds is destroyed in IPEC-1 (lack of the characteristic band at 1570 cm−1) in strongly acidic, simulated gastric medium. However, the bonds are restored to the initial level already at pH 5.8 as the pH rises. The band becomes 2−3 times stronger with a further increase of pH. The interactivity of the macromolecule chains at pH 5.8 corresponds to the conditions under which this polycomplex was synthesized. Then, only the fraction of bound portions increases. IPEC-2 behaves slightly differently. The band for intermolecular ionic bonds weakens to a minimum at pH 1.2 and remains practically unchanged at pH 5.8 and 6.8; that is, the structure of this sample undergoes little change in the pH range 1.2−6.8. Only at pH 7.4 is the system of bonds restored to the initial state. The final sample IPEC-3 undergoes hardly any change during the course of the experiment after several structural changes in the first medium. Thus, both external and internal structural transformations were observed within each of the samples. 3.3.3. Macromolecular Compositional Changes Inside Polycomplex Matrices in GIT Conditions. However, despite the obviousness of the detected transformations, an evaluation of only structural changes would be incomplete. Potential compositional transformations in the polycomplex matrices were monitored using elemental analysis which were first proposed for analyzing systems containing alginate−Eudragit EPO36 and recently successfully applied for the Eudragit EPO− Eudragit L100-55 system.25

IPEC-1 and IPEC-2 are very similar. IPEC-3 differs considerably from them, giving a pH-dependent profile and having only 50% of the swelling (500% at pH 5.8 compared to 900−1000% for the other two IPECs). Furthermore, from visible observations, the matrix based on IPEC-3 changed much less and predominantly due to surface erosion. This is known to be characteristic only for pH-insensitive types of Eudragits (RL and RS). However, the matrices of the two other samples (IPEC-1 and IPEC-2) did swell significantly. They have a clearly discernible hydrogel layer and a friable core in acidic medium. This is more pronounced for IPEC-1. The bilayer persists as the pH increases. However, it is not as clearly discernible because of a sharp drop in the transparency of the matrix. Thus, hydrogelation processes prevail over erosion processes with a clear pH-sensitivity in samples IPEC-1 and IPEC-2. Nevertheless, a decrease in the composition of acidstable L100 produces a decrease in the degree of swelling in the order IPEC-1−IPEC-2−IPEC-3. FTIR spectroscopy was used to detect structural changes in the matrix microenvironments during swelling in media mimicking the GIT. This method was successfully applied for Eudragit EPO−Eudragit L100-55,25 chitosan−Eudragit L10055/L100,46 alginate−Eudragit EPO,36 and other polycomplex systems.59 Figure 6a shows FTIR spectra that demonstrate the occurring structural transformations. The system of intermoF



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Figure 6. Monitoring of structural (a) and compositional (b) changes during swelling of polycomplex matrices in GIT conditions (n = 3; ± SD): S (Sample) IR spectrum (a) or composition (b) of starting polycomplex samples.

Considering that the most significant changes are observed by FTIR spectroscopy in strongly differing media at pH 1.2 and 7.4, it was considered most appropriate to evaluate the structural transformations in these media. Figure 6b shows changes in the compositions of the polycomplex matrices as a function of pH compared to the compositions of the starting polycomplex samples. The composition of IPEC-1, the equimolar compound, practically does not change. However, the two other samples, which contain an excess of EPO (IPEC-2, IPEC-3), undergo significant compositional changes as a result of the gradual loss of EPO in the polycomplex up to the retention of only a slight excess, relative to L100 (in case of IPEC-3). Moreover, the composition of IPEC-2 becomes close to equimolar toward the end of the experiment. Apparently, compositional changes predominated over structural changes in this instance. By contrast, for example, with the equimolar composition (IPEC1), which exhibited a different behavior, the composition remained unchanged despite pronounced structural transformations.

Opposite results were observed with previously reported data for similar Eudragit EPO/L100-55 systems. Thus, the composition of the polycomplex sample synthesized at pH 7.0 (Z = 1.81) was relatively constant during passage through all tested solutions, and the unit molar ratio was found to be approximately the same (2:1). Such differences could be explained from the differences in physicochemical properties of the polyanions used. From their chemical structure, both Eudragit L types have the same ratio between charged and noncharged fragments in the copolymer (1:1), but differences in pH-solubility depending on the nature of the nonionized ether groups. For L100-55 contains the more hydrophilic ethyl acrylate (EA) units, while L100 consists of the more hydrophobic methyl methacrylate (MMA) monomer units.1,2 This means that, at the same pH they have the same charge density (same amount of carboxyl groups are able to interact with oppositely charged polycation sequences), but a different structure of IPEC is formed, in spite of their similar composition. It contains approximately a 2-fold excess of EPO. G



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3.3.4. Stability Testing: Monitoring of Structural and Compositional Transformations Inside Polycomplex Matrices in Simulated Gastric Conditions. Further evaluation of the matrices in 0.1 M HCl for 24 h was deemed necessary in the light of the obtained during swelling testing of the polycomplex matrices in GIT simulated conditions and to understand their gastroretentive release properties. FTIR analysis indicated that samples were not stable in acidic medium due to disappearance of the interpolymer ionic bonds. However, they were self-healing after a pH increase. The swelling profiles in gastric simulated conditions are presented in Figure 7a. It is interesting to note that the two

Figure 7. Comparison of swelling profiles (a) and monitoring of changes in external appearance (b) of IPEC matrices in simulated gastric conditions (n = 3; ± SD).

polycomplex matrices from IPEC-1 and IPEC-3 continuously dissolved, but IPEC-2 was still stable after 24 h (Figure 7b). Moreover, from the visible changes (transparent hydrogel layer around the less swollen matrix core) observed from the beginning (first hour), IPEC-1 and 3 matrices behave similarly up to 3 hthe front of the external layer appeared turbid. The IPEC-1 and 3 matrices dissolved completely most likely due to transformation of a water insoluble stoichiometric polycomplex into nonstoichiometric soluble IPECs. If this were not be the case, the IPECs would simply be converted back to individual copolymers which would form a precipitate in acidic media (L100), but this was never observed. To investigate the fate of polycomplex matrices during swelling in simulated gastric conditions, structural transformations of the most stable IPEC-2 (the only sample which was not dissolved after 24 h in acidic medium) were also investigated using FTIR and MTDSC methods. According to the FTIR spectra of the polycomplex sample presented in Figure 8a, the absence of the characteristic band at 1570 cm−1, responsible for the confirmation of intermacromo-

Figure 8. Monitoring of structural (panel a and b) and compositional (panel c) changes during swelling of polycomplex matrices made up from IPEC-2 at different hours following administration in acidic media (n = 3; ± SD).

lecular ionic bonds, points to their destruction in acidic environment. An excess content of carboxyl copolymer chains (L100) in the overall structure of the originally “defective” IPEC-2 obviously leads to a clustered segregation of hydrophobic regions of the polyanion. The carbonyl groups from MMA, BuMA, and DMAEMA of EPO act as proton acceptors and are capable of interacting with the proton-donating groups. Additionally, the nitrogen from DMAEMA has an average pKa of 8.4,27 and hence EPO can act as a proton acceptor which is capable of forming hydrogen bonds. Moreover, the carbonyl and dimethylamino groups in H



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EPO can form hydrogen bonds with acid hydroxyls in polyacids. Thus, the peak at 1630 cm−1 is due to the intermacromolecular hydrogen bonding between CO of DMAEMA and COOH of L100.59 On the other hand, significant peak broadening at approximately 2520−2478 cm−1 can be assigned to the interpolymer absorption band which resulted from hydrogen bonding interaction of the dimethylamino groups of DMAEMA or the carbonyl from MMA, BuMA, and DMAEMA of EPO with the hydroxyls from the carboxylic acid of L100, respectively. Moreover, the free hydroxyl groups in neat L100 show a band in the region 3500−3550 cm−1 with a shoulder at 3200 cm−1, which indicates hydrogen-bonded hydroxyls. The carbonyl bandwidth in IPEC (1725 cm−1) appears narrower than that in the L100 copolymer alone. The self-association between the carboxylic carbonyls and hydroxyls within L100 is overcome by the interaction with EPO and the carboxylic hydroxyls now participate in interpolymer association with EPO. This is reflected in the appearance of the band at 1725 cm−1. Another new wide band between 2350 and 2750 cm−1 in the polycation spectrum (Figure 8a) indicates the occurrence of different dimeric and monomeric forms of the ammonium cation, which, in turn, may be associated with water molecules. Our findings are in line with to those previously reported.27,59−67 We applied MTDSC to analyze the behavior of IPEC-2 in acidic medium in which it was stable (Figure 8b). It is interesting to note that immersion of the polycomplex matrices for more than 1 h leads to a sharp increase of the Tg from 116.4 to 170.9 °C followed by a continuous decrease in Tg to 162.7 °C at 24 h. Moreover, all DSC thermograms show only one Tg, which indicates that the IPEC-2 was not converted back to its individual copolymers. A composition change of the synthesized IPEC-2 was found using elemental analysis. Figure 8c illustrates that the sample containing an excess of EPO (IPEC-2, Z = 1.49) is subject to significant compositional changes as a result of the gradual loss of EPO in the polycomplex. Thus, during testing only one-third of the EPO is retained relative to L100 (Z = 0.5). Comparative analysis of the Tg values indicates that the process of EPO leaching during residence in acidic medium correlates well with the compositional changes of the tested polycomplex system (IPEC-2). 3.3.5. Drug Release from Poly(meth)acrylate Matrices in GIT Conditions. In a further set of experiments, we tested the potential of the IPECs to be used in matrix drug delivery systems to control the release of the model drugs DS and TEO. To determine the universal applicability of the polycomplex systems further evaluations of the diffusion-transport properties were carried out on the release of the model drugs, diclofenac sodium (pKa = 4.14) and theophylline (pKa = 11.4), from the polymer matrix (Figures 9a and 10a). An annalysis of the drug release profiles indicated a reasonable correlation with the swelling properties of the IPEC systems and with their glass transition temperatures. The greater the degree of swelling and the lower the Tg value of the IPEC, the faster the release of TEO (dissolution, less dependent on the pH) and, correspondingly, the slower the DS release (dissolution, increasing with increasing pH). Thus, the degree of swelling decreased in all media in the order IPEC1, IPEC-2, and IPEC-3, with the degree of release of DS and TEO decreasing and increasing, respectively, in the same order.

Figure 9. (a) Release profiles of DS from matrices made up of IPECs with different compositions and (b) DS apparent rate constants (k, %/hn) from IPECs in GIT conditions (n = 3; ± SD).

Comparative analysis of the drug release from polycomplex matrices (Z = 1.02− 2.00) in GIT conditions is presented in Figure 9a. The slowest DS release can be observed for the IPEC-3 matrix. Approximately 30% was released after 7 h. Moreover, the release process for IPEC-1 matrices is also comparatively slow in the first two hours but faster afterward. Drug molecules could simply diffuse through less swollen matrices. Moreover, molecules of the tested drug (DS), which could not compete in interpolyelectrolyte reaction, could not find free sequences of charged dimethylamino groups in the monolithic structure of the IPEC matrix, which could definitely sustain drug release. To understand the mechanisms underlying the release of the model drugs from polycomplex matrix systems, data were fitted according to the Korsmeyer−Peppas equation, which combines two independently occurring processes: Fickian diffusion and Case-II transport:68 M t /M∞ = kt n

(3)

where Mt is the amount of drug released by time t, M∞ is the total amount of drug, k is the apparent release rate constant, which includes structural and geometric characteristics of the matrix, and n is the exponent of release, showing the drug transport mechanism. Tables 2 and 3 present the relationship of the release exponent (n) to the proposed transport mechanism applicable to the studied DS and TEO samples, respectively. It can be seen that the transport mechanism depends on the physicochemical properties of the drug. The release of DS from the IPEC matrices corresponded to a Case-II transport I



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and IPEC-3) display a gradual decrease in DS release constants and an increase in those for the more soluble TEO. Thus, a comparative analysis of the synthesized IPEC as polymeric carriers revealed their differences in the mechanism of transport, depending on the physicochemical characteristics of the used drugs.

4. CONCLUSIONS The results of the present investigation confirm the formation of new interpolyelectrolyte complexes between EPO and L100 at a pH between 6.0 and 7.0. The structure of the synthesized IPECs, due to differences in starting charge density of interacting macromolecules, depends on the molar ratio of each component in the polyelectrolyte mixture and correlates with their glass transition temperatures. The assessment of possible structural and compositional differences in the formulation of polycomplexes during their stay in the tested media indicates that, except for IPEC-1, the analyzed samples are self-healing systems. The most pH-insensitive, and therefore sustainable, with respect to structural and compositional modifications, during swelling, was IPEC-3. In vitro swelling and release experiments for IPEC-3 showed the potential of this polycomplex to be used as a colon-specific carrier, due to comparable swelling properties in acidic as well as in neutral medium. IPEC-2 shows the potential as a controlled release material for gastroretentive delivery. IPEC-1 due to its highly hydrophilic properties could be suitable in controlled DDS for sustained drug delivery purposes. Overall, the formation of IPECs opens up new possibilities for oral controlled drug release. The design of new materials based on existing approved ones is therefore an option that can be readily applied.

Figure 10. (a) Release profiles of TEO from matrix tablets made up of IPECs with different compositions and (b) TEO apparent rate constants (k, %/hn) from IPECs in GIT conditions (n = 3; ± SD).

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Table 2. Mathematical Modeling of Diclofenac Sodium Release

Corresponding Author

*R.I.M.: Kazan State Medical University, Department of Pharmaceutical, Toxicological and Analytical Chemistry; Butlerov str., 49; 420012 Kazan; Tatarstan; Russian Federation. E-mail: [email protected]; tel.: +7 843 5213782; fax: +7 843 2360393. G.V.d.M.: University of Leuven, Department of Pharmaceutical and Pharmacological Sciences, Campus Gasthuisberg; O+N2; Herestraat 49, 3000 Leuven, Belgium. Email: [email protected]; tel.: +32 16 330304; fax: +32 16 330305.

matrix characteristics release exponent (n) release constant (k) R2 transport mechanism

IPEC-1

IPEC-2

IPEC-3

1.13 ± 0.05 3.91 ± 0.31 0.99051 Case-II

1.08 ± 0.03 3.04 ± 0.15 0.99524 Case-II

1.30 ± 0.05 1.51 ± 0.14 0.99117 Case-II

Table 3. Mathematical Modeling of Theophylline Release matrix characteristics release exponent (n) release constant (k) R2 transport mechanism

AUTHOR INFORMATION

Notes

IPEC-1

IPEC-2

IPEC-3

0.48 ± 0.02 22.99 ± 0.82 0.98246 Fickian diffusion



The authors declare no competing financial interest.

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