Swelling Interface Number Research Articles

Smart Hydrogels Co‐switched by Hydrogen Bonds and π–π Stacking for Continuously Regulated Controlled‐Release System

AbstractA series of hydrogels with continuously regulatable release behavior can be achieved by incorporating hydrogen bonding and π–π stacking co‐switches in polymers. A poly(nitrophenyl methacrylate‐co‐methacrylic acid) hydrogel (NPMAAHG) for control over drug release is fabricated by copolymerizing 4‐nitrophenyl methacrylate and methacrylic acid using ethylene glycol dimethacrylate as a crosslinker. The carboxylic acid groups and nitrylphenyl groups form hydrogen bonds and π–π stacking interactions, respectively, which act as switches to control the release of guest molecules from the polymers. As revealed by the simulated gastrointestinal tract drug release experiments, the as‐synthesized NPMAAHG hydrogels can be regulated to release only 4.7% of drugs after 3 h in a simulated stomach and nearly 92.6% within 43 h in the whole digestive tract. The relation between the release kinetics and structures and the mechanism of the smart release control are analyzed in terms of diffusion exponent, swelling interface number, drug diffusion coefficient, and velocity of the swelling interface in detail. The results reveal that the release of guest molecules from the hydrogels can be continuously regulated for systemic administration by controlling the ratio of the hydrophilic hydrogen bonds and the hydrophobic π–π stacking switches.

Towards elucidation of the drug release mechanism from compressed hydrophilic matrices made of cellulose ethers. II. Evaluation of a possible swelling-controlled drug release mechanism using dimensionless analysis

A swelling-controlled mechanism, based on the simple fitting of drug release data to a power law, is frequently invoked to explain deviations from Fickian diffusion. Therefore, the purpose of this work was to evaluate whether such a mechanism is possible in the case of compressed hydrophilic matrices made of cellulose ethers, using parameters that were independently obtained, either in Part I (Ferrero et al., [1]) or in the present study. The derivatives used were hydroxypropyl methyl celluloses, hydroxyethyl celluloses and hydroxypropyl celluloses of varying molecular mass. We investigated polymer chain relaxation (by mechanical testing and oscillatory rheology), the release characteristics of the model drug sodium salicylate, as well as the swelling behavior of the compressed tablets (front movements and water uptake). Assessment of a possible swelling-controlled release (relaxation-controlled, penetrant-activated) mechanism was based on the use of the Deborah number, De, and that of the swelling interface number, Sw. Two extreme polymer fractions were considered for the evaluation of De and Sw, namely those fractions that were assumed to be present at the swelling front and at the eroding front. Analysis of drug release data using the Korsmeyer–Peppas model resulted in diffusional exponent n values that were consistently greater than 0.44 (for the cylindrical geometry used here), which could thus indicate anomalous (coupled diffusion–relaxation) drug transport behavior. However, from the observed De values ≪ 1 (at both fronts), which are indicative of water Fickian diffusion in the rubbery polymer matrix, and the Sw values ≫ 1 (at the swelling front), which correspond to drug Fickian diffusion, we infer that a swelling-controlled drug release mechanism should be dismissed for such water-soluble hydrophilic cellulose ethers, i.e. polymer chain relaxation is not the rate-limiting step in the drug release process from this type of hydrophilic polymer. In fact, Sw values close to unity were calculated for the erosion front, but this is not a sufficient criterion for a swelling-controlled release mechanism. In addition, the dimensionless numbers calculated for the erosion front should be considered cautiously and conservatively since relaxation of the macromolecules is very unlikely to still occur when the latter are in the process of detaching from the polymer matrix. In addition, it was experimentally confirmed from the front positions that erosion is the phenomenon operating with this type of swellable polymer, concomitantly with Fickian diffusion. As surface erosion follows the same kinetics as the relaxational process, the coupled diffusion/erosion mechanism accounts for diffusional exponent n values greater than 0.50, 0.45 and 0.43 for the slab (film), the cylindrical (disk) and the spherical geometry, respectively, as calculated from drug release data using the power law equation.

Drug diffusion in hydrophobically modified N,N-dimethylacrylamide hydrogels

The use of hydrophobically modified hydrogels for drug release was investigated. Copolymers of N,N-dimethylacrylamide and 2-(N-ethyl-perfluorooctanesulfonamido) ethyl acrylate (FOSA) were prepared by free-radical polymerization. The drug release rates, dynamic swelling behavior, and pH sensitivities of copolymers ranging in composition from 0 to 30mol% FOSA were studied. Pheniramine maleate, an ocular antihistamine, was used as the model drug substance. Hydrogels of DMA produced with increasing amounts of FOSA had a decreased equilibrium media content and exhibited a slower drug release rate. Early-time, late-time and Etters approximation drug diffusion coefficients ranged from 0.4×10−3 to 12.3×10−3mm2/min. The diffusion of the drug model was less sensitive to pH of the buffered media over the range of pH 4–8, but increasing the media pH slowed the permeability slightly by decreasing the swellability of the hydrogel. The power law exponent (n≈0.5) and the swelling interface number (Sw≫1) suggested that the drug release mechanism from these hydrogels was Fickian and not swelling controlled. These novel thermoprocessible hydrogels have potential to be used as controlled ocular drug delivery devices (e.g. contact lenses or ocular inserts).

Characterization of Drug Release and Diffusion Mechanism Through Hydroxyethylmethacrylate/Methacrylic Acid pH-Sensitive Hydrogel

Hydroxyethylmethacrylate/methacrylic acid copolymer cross-linked with ethylenglycol dimethacrylate was prepared by a bulk free radical polymerization method. The permeability studies of this pH-sensitive hydrogel to drugs with different water solubilities showed a water-content dependent diffusion or pore mechanism for ephedrine HCl (water-soluble model drug), whereas, a partition or solute-diffusion mechanism for indomethacin (a water-insoluble drug) was seen. Data analysis of release tests, according to the swelling interface number and Peppas equation for ephedrine HCl in pH 7.4, showed a biexponential model kinetic, whereas in pH 1.2 a swelling-controlled mechanism was seen. Indomethacin was released by an anomalous or non-Fickian release kinetics.

Drug diffusion mechanism through pH-sensitive hydrophobic/polyelectrolyte hydrogel membranes

Methylmethacrylate/dimethylaminoethyl methacrylate cross-linked with divinylbenzene is a pH-sensitive hydrogel. We have studied the diffusion mechanisms of drugs with different water solubilities through this hydrogel. A water-soluble model drug (aminopyrine) was used to study the diffusion coefficient changes in different pHs. The results showed a water-content dependent diffusion for this pH-sensitive polycationic hydrogel. However, decreasing the solubility of the drug and increasing the hydrophobic character of the polymer by changing the pH caused a greater affinity (or partition coefficient) between the hydrogel and the drug. Aminopyrine diffusion was shown to follow the free-volume theory, suggesting the ‘pore’ type mechanism for water soluble drugs, while the ‘partition’ or ‘solution-diffusion’ mechanism better described the slow diffusion of water insoluble solutes through this pH-sensitive hydrogel. Comparing the swelling interface number for aminopyrine release through this pH-sensitive hydrogel showed a non-Fickian mechanism in the hydrated form of the hydrogel (pH 1.2), while Fickian in the dehydrated form (pH 7.4).

The pH-dependent biphasic release of azidothymidine from a layered composite of PVA disks and P(MMA/MAA) spheres

A composite device was developed to provide a biphasic drug release using poly(vinyl alcohol) (PVA) and poly(methylmethacrylate-co-methacrylic acid) (P(MMA/MAA)) spheres. Azidothymidine (AZT), an anti-HIV agent with a short biological half-life, was used as the model drug. Dynamic and equilibrium swelling of the polymers, and kinetics of AZT release from these polymers were determined in pH 1.2 and 6.8 buffer solutions. The swelling of PVA and release of AZT from PVA disks were fast and nearly pH-independent, whereas the swelling behavior and drug release kinetics of P(MMA/MAA) spheres were strongly pH-dependent. A swelling interface number for the spheres at pH 6.8 was determined to be Sw≪1 and time dependent. Nevertheless, Fickian diffusion might also contribute to the drug release in this system. The composite disks consisting of PVA matrix and P(MMA/MAA) spheres provided prolonged (over 20 h) and more steady release profiles, differing profoundly from individual components. Such release profiles resulted from the second phase release at pH 6.8 and the presence of PVA layer. The relative drug loading in the matrix could be tailored to produce release profiles varying from a distinct bimodal release to a pseudo zero-order release with an initial burst.

Dimensionless analysis of swelling of hydrophilic glassy polymers with subsequent drug release from relaxing structures

Two dimensionless parameters, the diffusional Deborah number, De, and the swelling interface number, Sw, were used as indicators of solvent and solute transport behavior in swellable hydrogel systems. Polymer relaxation and concentration-dependent diffusion led to dynamically swelling polymers which displayed Fickian, Case II, or anomalous transport behavior. Experimental systems studied included crosslinked samples of poly(vinyl alcohol), designated PVA, and poly(2-hydroxyethyl methacrylate-co-methyl methacrylate), designated P(HEMA-co-MMA). Model solutes with molecular weights ranging from 200 to 17 000 were used to investigate release properties from these networks. Characteristic polymer relaxation times and swelling front velocities were determined experimentally. To gain an understanding of how polymer morphology and solute properties affected transport behavior, the calculated values of De and Sw were correlated to the diffusional exponent, n, used commonly to indicate the time dependence of sorption and release. The swelling interface number was found to correlate particularly with the transport kinetics, indicating anomalous and Case II solute transport when the Sw values were near 1.0.

Mechanisms of solute and drug transport in relaxing, swellable, hydrophilic glassy polymers

Water and solute or drug transport in crosslinked polymeric materials was investigated to determine the effects of polymer morphology, composition and solute properties on transport behavior. Two crosslinked polymer systems, poly(2-hydroxyethyl methacrylate- co-methyl methacrylate) (P(HEMA- co-MMA)) and poly(vinyl alcohol) (PVA), were used in water transport and solute release experiments. Structural parameters of the polymers investigated in this work included the initial polymer molecular weight, the nominal crosslinking ratio, and the copolymer composition. Swelling rates, water diffusion coefficients and the diffusional Deborah number, De, were used to characterize the water uptake process. Swelling rates correlated well with the polymer network mesh sizes; the slowest rate of water uptake was observed in P(HEMA- co-MMA) samples containing large quantities of methyl methacrylate. Initial crosslinking ratios had a sizable effect on water uptake in crosslinked PVA samples but not in the P(HEMA- co-MMA) polymers. Drug release rates, drug diffusion coefficients and the swelling interface number, Sw, were used to characterize solute transport. Release experiments were conducted using eight solutes: theophylline, triamterene, oxprenolol HCl, buflomedil HCl, vitamin B 12, dextran, inulin and myoglobin. Release rates decreased with increasing solute molecular weight. A molecular weight cut-off, beyond which drug release was greatly hindered by the hydrogel mesh size, was established for each polymer tested.

Modelling of water transport and solute release in physiologically sensitive gels

Water transport into and solute release from ionic, hydrophilic, initially glassy polymeric networks were investigated by deriving a model which takes in consideration the strong concentration dependence of the penetrant and solute diffusion coefficients. The model was solved with appropriate boundary conditions in an ionic buffered solution exhibiting simultaneous ionization of its components. Water uptake and solute release were described in terms of the Swelling Interface number and other parameters of the polymer/buffer system.

Zero-order release from glassy hydrogels. I. Enigma of the swelling interface number

In vitro release kinetics of structurally related benzoic acids and other active ingredients from glassy hydrogels are reported. It is shown that a zero-order release from swellable glassy poly(2-hydroxyethyl methacrylate) (PHEMA) hydrogels can be achieved by a judicious choice of the active ingredient. The criteria for the swelling controlled zero-order release proposed in the past have been examined. The equilibrium swelling interface number ( Sw e) is a rather conservative criterion. It is shown that swelling controlled zero-order release can be realized for values of the swelling interface number up to 0.6. The Deborah numbers for release ( De R) for the systems which follow zero-order kinetics are in good agreement with the predictions based on the time dependent diffusion coefficient to account for the role of the molecular relaxation processes.

Solute and penetrant diffusion in swellable polymers: VIII. Influence of the swelling interface number on solute concentration profiles and release

Penetrant-activated solute release was modeled in polymers undergoing Case-II penetrant uptake. The rate of solute release can be nearly constant for systems with Case-II penetrant uptake behavior, depending on the values of solute diffusion coefficients and the functional form of concentration dependence. It is shown that swelling of a polymer slab can have a significant effect on solute release behavior.

Solute and penetrant diffusion in swellable polymers. VII. A free volume-based model with mechanical relaxation

Penetrant transport through and solute release from continuously swelling polymers is viewed as a process associated with major structural changes in the polymer morphology. Changes in the diffusivities of penetrant and solute reflect a free volume mechanism for transport. The polymer is initially glassy with a uniform dispersion of solute. After the system is placed in contact with a thermodynamically good penetrant, a glassy/rubbery phase transition occurs at a well defined swelling interface. The Fickian equations with concentration-dependent diffusivities and moving boundaries are solved simultaneously in polymer-fixed coordinates. A constitutive relation is used to describe the effect of macromolecular relaxations on the rate of volume expansion as the polymer swells. The penetrant fractional uptake, solute fractional release, sample dimensions, swelling front position, and instantaneous swelling interface number are determined and related to the nature of the swelling process.

Solute and penetrant diffusion in swellable polymers: VI. The Deborah and swelling interface numbers as indicators of the order of biomolecular release

A theoretical framework based on the dimensionless analysis of the penetrant swelling and solute release phenomena in a swelling-controlled system was developed for use in the prediction of the release behavior of solutes from swellable polymers. Prediction is based on the values of the diffusional Deborah number, De, and the swelling interface number, Sw. The Deborah number takes into account the relative importance of polymer relaxation and penetrant diffusion in the penetrant uptake mechanism. The swelling interface number relates the rate of penetrant uptake to the rate of solute diffusion. It was concluded that zero-order (time-independent) release would be observed in cases for which De is of the order of unity and Sw is very small. In all other cases the release is either Fickian or non-Fickian but time-dependent. Experimental verification of the theory was conducted using poly(2-hydroxy-ethyl methacrylate-co-methyl methacrylate) copolymers containing 0.5 wt% theophylline and studying their swelling and release behavior.

The swelling interface number as a criterion for prediction of diffusional solute release mechanisms in swellable polymers

AbstractWhen a glassy polymer containing a uniformly dispersed solute is brought in contact with a penetrant, solute diffusion will be associated with the transport mechanism and penetration velocity of the penetrant in the polymer. Analysis and prediction of mechanisms of diffusional solute release may be obtained through a new dimensionless number, the swelling interface number, Sw, which compares the relative mobilities of the penetrant and the solute in the presence of macromolecular relaxations in the polymer. It is shown that a sufficient and necessary criterion for time‐independent diffusional solute release rates from these swellable systems is that the Sw be smaller than 10−2. The swelling interface number Sw may be related to easily determined structural and thermodynamic parameters of the solute/polymer/penetrant system. Preliminary experimental results of dynamic water swelling of poly(2‐hydroxyethyl methacrylate‐co‐methyl methacrylate) and diffusional release of theophylline from initially glassy copolymers show that decreasing values of Sw are related to increased pseudo‐case‐II transport kinetics of the solute.