A different diffusion mechanism for drug molecules in amorphous polymers

Polymer materials are widely used in controlled drug release, and the diffusion property of drug molecules in these materials is of great importance. In this work, the diffusion behavior of a model drug (aspirin) in different ratios of poly(lactic acid-co-ethylene glycol) (PLA-PEG) was investigated by molecular dynamics simulations. Two major factors, which influence the diffusion of aspirin in polymer matrix: the wriggling of the polymer chain and the free volume of the polymer matrix, are discussed. The wriggling of the polymer chain mainly controls the diffusion of aspirin molecules. Free volume becomes the secondary effect. For two different polymers having a similar degree of wriggling, the free volume controls the diffusion of the aspirin molecules. Comparing with the diffusion behavior of small gas molecules in polymer matrix, a different mechanism was proposed for the drug molecules. The drug molecules can only diffuse along with the wriggling of the polymer matrix.     

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

When 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.     

The role of polymer/drug interactions on the sustained release from poly(dl-lactic acid) tablets

The release profiles of model drugs (propranolol HCl, diclofenac sodium, salicylic acid and sulfasalazine) from low molecular weight poly(d,l-lactic acid) [d,l-PLA] tablets immersed in buffer solutions were investigated in an attempt to explore the mechanism of the related phenomena. It was confirmed that drug release is controlled by diffusion through the polymer matrix and by the erosion of the polymer. The pH of the surrounding medium influences the drug solubility as well as swelling and degradation rate of the polymer and therefore the overall drug release process. Physicochemical interaction between d,l-PLA and drug is an additional factor which influences the degree of matrix swelling and therefore its porosity and diffusion release process. Propranolol HCl shows extended delivery time at both examined pH values (5.4 and 7.4) and especially at pH 7.4 where release was accomplished in 190 days, most probably due to its decreased solubility at higher pH values. The acidic drugs gave shorter delivery times especially at pH 7.4. A slower drug release rate and more extended delivery time at pH 7.4 in comparison with that at pH 5.4 was recorded for tablets loaded with diclofenac sodium and salicylic acid. The opposite effect was observed with samples loaded with propranolol HCl.     

渗透物在致密聚合物膜中扩散的分形介质模型

利用自由体积理论讨论了渗透物分子在致密聚合物膜内的扩散机理, 提出了“扩散通道”的概念, 建立了渗透物在致密聚合物膜中扩散的分形介质模型, 考虑了自由体积分布对扩散过程的影响. 根据建立的模型, 渗透物在膜内的扩散是由在“扩散通道”上的一系列跳跃构成的. 根据致密膜内扩散通道的关联长度ξ(p)与膜厚L的关系, 可以把扩散分为正常扩散、 过渡扩散和分形扩散三部分, 给出了扩散相图, 提出并解释了分形渡越现象.     

Disentanglement and reptation during dissolution of rubbery polymers

The dissolution mechanism of rubbery polymers was analyzed by dividing the penetrant concentration field into three regimes that delineate three distinctly different transport processes. The solvent penetration into the rubbery polymer was assumed to be Fickian. The mode of mobility of the polymer chains was shown to undergo a change at a critical penetrant concentration expressed as a change in the diffusion coefficient of the polymer. It was assumed that beyond the critical penetrant concentration, reptation was the dominant mode of diffusion. Molecular arguments were invoked to derive expressions for the radius of gyration, the plateau modulus, and the reptation time, thus leading to an expression for the reptation diffusivity. The disentanglement rate was defined as the ratio between the radius of gyration of the polymer and the reptation time. Transport in the second penetrant concentration regime was modeled to occur in a diffusion boundary layer adjacent to the polymer-solvent interface, where a Smoluchowski type diffusion equation was obtained. The model equations were numerically solved using a fully implicit finite difference technique. The results of the simulation were analyzed to ascertain the effect of the polymer molecular weight and its diffusivity on the dissolution process. The results show that the dissolution can be either disentanglement or diffusion controlled depending on the polymer molecular weight and the thickness of the diffusion boundary layer. © 1996 John Wiley & Sons, Inc.     

Investigation of swelling,drug release and diffusion behaviors of poly(N‐isopropylacrylamide)/poly (N‐vinylpyrrolidone) full‐IPN hydrogels

The synthesis of sequential full interpenetrating polymer networks (IPNs) based on poly (N‐isopropylacrylamide) (PNIPAAm) and negatively charged poly(N‐vinyl‐2‐pyrrolidone) (PNVP) was described and their swelling, drug release, and diffusion studies were investigated. PNIPAAm was used as a host network. According to swelling experiments, IPNs gave relatively lower swelling ratios compared to PNIPAAm hydrogel due to the higher cross‐linking density. Lidocaine (LD) was used as a model drug for the investigation of drug release behavior of IPNs. LD uptake of the IPNs were found to increase from 24 to 166 (mg LD / g dry gel) with increasing amount of PNIPAAm and AMPS contents in the IPN structure. It was observed that the specific interaction between drug and AMPS co‐monomer influenced the drug release profile. In the diffusion transport mechanism study in water, the results indicated that the swelling exponents n for all IPNs are in the range from 0.50 to 0.72. This implies that the swelling transport mechanism was transferred from Fickian to non‐Fickian transport, with increasing AMPS content and NIPAAm character in the IPN structure. In addition, diffusion of LD within the IPNs showed similar trend. The incorporation of AMPS leads to an increase in electrostatic interaction between charge sites on carboxylate ions and cationic LD molecules. Therefore, the highest diffusion coefficient (D) of drug was found for IPN2 sample. Copyright © 2007 John Wiley & Sons, Ltd.     

Mechanism of pellet coat rupture and its effect on drug release.

In the formation of a coated controlled release preparation with functional coat layers, hydroxypropyl-methylcellulose was used to form a diffusion layer which swelled immediately upon wetting. Eudragit RS30D was used to form the outer retention layer. The rupture of pellet coat occurred when the Eudragit RS30D was unable to withstand the expansion in volume due to the influx of water and swelling of the hydroxypropylmethylcellulose diffusion layer. The sucrose core was able to contribute an osmotic effect. The hydrostatic pressure built up within the pellet can cause the pellet coat to rupture. Sodium chloride deposited in the diffusion coat was able to delay the bursting of the pellet coat. This was due to the competition for the imbibed water between sodium chloride and hydroxypropylmethylcellulose. The rupture of the pellet coat did not result in a total failure of the controlled drug delivery mechanism. Similar drug release rates were obtained irrespective whether there was a puncture in the pellet coat or not. Pressure built-up in the region away from the puncture pushed the core material towards the point of puncture and sealed the puncture point. In addition, the swelling of polymer around the point of rupture ensured continuity in the drug diffusion barrier.     

Formation of polymeric toroidal-spiral particles

Compared to spherical matrices, particles with well-defined internal structure provide large surface to volume ratio and predictable release kinetics for the encapsulated payloads. We describe self-assembly of polymeric particles, whereby competitive kinetics of viscous sedimentation, diffusion, and cross-linking yield a controllable toroidal-spiral (T-S) structure. Precursor polymeric droplets are splashed through the surface of a less dense, miscible solution, after which viscous forces entrain the surrounding bulk solution into the sedimenting polymer drop to form T-S channels. The intricate structure forms because low interfacial tension between the two miscible solutions is dominated by viscous forces. The biocompatible polymer, poly(ethylene glycol) diacrylate (PEG-DA), is used to demonstrate the solidification of the T-S shapes at various configurational stages by UV-triggered cross-linking. The dimensions of the channels are controlled by Weber number during impact on the surface, and Reynolds number and viscosity ratio during subsequent sedimentation. We anticipate applications of the T-S particle in drug delivery, wherein diffusion through these T-S channels and the polymer matrix would offer parallel release pathways for molecules of different sizes. Polyphosphate, as a model macromolecule, is entrained in T-S particles during their formation. The in vitro release kinetics of polyphosphate from the T-S particles with various channel length and width is reported. In addition, self-assembly of T-S particles occurs in a single step under benign conditions for delicate macromolecules, and appears conducive to scaleup.     

Determination of penetrant solubility from transient permeation measurements

The permeability coefficient for the transport of a gas, vapor, or liquid through a polymer film is the product of the penetrant solubility and a diffusion coefficient. A transient permeation experiment known as the time-lag technique can be used to separate this product, provided the diffusion coefficient is independent of penetrant concentration. In this well-known experiment the polymer is initially free of penetrant. A new transient permeation experiment where the polymer is initially saturated with penetrant is suggested here. A general mathematical proof is given to show that by using the results form these two transient experiments which have different initial conditions one can determine the penetrant solubility no matter how the diffusion coefficient depends on penetrant concentration. Also one can determine two different concentration averaged diffusion coefficients from the results.     

Microspheres based on poly(3-hydroxy)butyrate for prolonged drug release

The kinetics of the controlled release of the antiproliferative drug dipyridamole from microspheres based on the biocompatible and biodegradable polymer poly(3-hydroxy)butyrate is studied. As carriers for dipyridamole, microspheres prepared from a solution of poly(3-hydroxy)butyrate by single emulsion method are used. Under in vitro conditions, the kinetic curves describing the release of dipyridamole from microspheres with diameters of 19, 63, and 92 μm show two characteristic regions: the region of fast drug release within a short time period and a well-pronounced continuous linear region. For microspheres with a diameter of 4 μm, the linear region is missing. Analysis of the kinetic curves illustrating controlled drug release together with the measurements on polymer degradation shows that their kinetic profiles depend on the diffusion-controlled process and hydrolytic degradation of poly(3-hydroxy)butyrate. The diffusion kinetic equation describing both linear and nonlinear regions of dipyridamole released from the microspheres involves the sum of two terms: desorption from the sphere via the diffusion-controlled mechanism and drug release via the zero-order reaction. The linear region of the drug release curve is explained by the zero-order hydrolysis of poly(3-hydroxy)butyrate. The diffusion coefficients and kinetic constants are calculated. For bigger microspheres, the existence of the continuous linear region in the corresponding kinetic curves makes it possible to use microsystems based on poly(3-hydroxy)butyrate and dipyridamole as novel systems for local prolonged drug delivery.     

Simultaneous nonlinear diffusion of a solvent and organic penetrant in a polymer

We obtain the exact solution of a fairly large class of somewhat simplified problems involving the simultaneous nonlinear Fickian diffusion of a poor solvent and a dilute organic penetrant, such as a plasticizer, in a semi-infinite polymer slab immersed in the solvent bath. Such problems can also provide useful estimates during certain time regimes of release of drugs from implants, and pesticides and pheromones from certain slow or controlled-release polymeric devices, insofar as these are affected by an environmental solvent bath. We assess the effect of various simplifications made (e.g., neglect of the penetrant concentration dependence in the diffusion coefficient, cross diffusion of solvent and penetrant, and a variety of boundary conditions) by solving exactly some additional specialized cases.     

Preparation of Losartan Potassium Controlled Release Matrices and In-Vitro Investigation Using Rate Controlling Agents

Controlled release matrices have predictable drug release kinetics, provide drugs for an extended period of time, and reduce dosing frequency with improved patient compliance as compared with conventional tablet dosage forms. In the current research work, losartan potassium controlled release matrix tablets were fabricated and prepared with rate altering agents; that is, Ethocel grade 100 combined with Carbopol 934PNF. Various drug to polymer ratios were used. HPMC, CMC, and starch were incorporated in some of the matrices by replacing some amount of filler (5%). The direct compression method was adopted for the preparation of matrices. In phosphate buffer (pH 6.8), the dissolution study was conducted by adopting the USP method-I as the specified method. Drug release kinetics was determined and dissolution profiles were also compared with the reference standard. Prolonged release was observed for all matrices, but those with Ethocel 100FP Premium showed more extended release. The co-excipient (HPMC, CMC, and starch) exhibited enhancement in the drug release rates, while all controlled release matrices released the drug by anamolous non-Fickian diffusion mechanism. This combination of polymers (Ethocel grade 100 with Carbopol 934PNF) efficiently extended the drug release rates up to 24 h. It is suggested that these matrix tablets can be given in once a day dosage, which might improve patient compliance, and the polymeric blend of Ethocel grade 100 with Carbopol 934PNF might be used in the development of prolonged release matrices of other water-soluble drugs.     

Modeling of penetrant diffusion in glassy polymers with an integral sorption deborah number

A mathematical model was developed to explain the anomalous penetrant diffusion behavior in glassy polymers. The model equations were derived by using the linear irreversible thermodynamics theory and the kinematic relations in continuum mechanics, showing the coupling between the polymer mechanical behavior and penetrant transport. The Maxwell model was used as the stress–strain constitutive equation, from which the polymer relaxation time was defined. An integral sorption Deborah number was proposed as the ratio of the characteristic relaxation time in the glassy region to the characteristic diffusion time in the swollen region. With this definition, an integral sorption process was characterized by a single Deborah number and the controlling mechanism was identified in terms of the value of the Deborah number. The model equations were two coupled nonlinear differential equations. A finite difference method was developed for solving the model equations. Numerical simulation of integral sorption of penetrants in glassy polymers was performed. The simulation results show that (1) the present model can predict Case II transport behavior as well as the transition from Case II to Fickian diffusion and (2) the integral sorption Deborah number is a major parameter affecting the transition. © 1993 John Wiley & Sons, Inc.     

Sponge-like nanostructured conducting polymers for electrically controlled drug release

An electrically controlled drug release (ECDR) system based on sponge-like nanostructured conducting polymer (CP) polypyrrole (PPy) film was developed. The nanostructured PPy film was composed of template-synthesized nanoporous PPy covered with a thin protective PPy layer. The proposed controlled release system can load drug molecules in the polymer backbones and inside the nanoholes respectively. Electrical stimulation can release drugs from both the polymer backbones and the nanoholes, which significantly improves the drug load and release efficiency. Furthermore, with one drug incorporated in the polymer backbone during electrochemical polymerization, the nanoholes inside the polymer can act as containers to store a different drug, and simultaneous electrically triggered release of different drugs can be realized with this system.     

Controlled release of antibiotics from poly‐ε‐caprolactone/polyethylene glycol wound dressing fabricated by direct‐writing melt electrospinning

Wound dressing, which can release anti‐infectives in a controlled way, is taking an important role in the treatment and recovery of the open wound. An adequate release of antibiotics can prevent infections from microorganisms effectively. Among the new candidates of fabricating base materials for wound dressing, electrospinning fiber mats are attracting numerous attentions for their excellent performance in controlled drug delivery. The drug release behavior of electrospinning fiber mats can be tuned by changing the chemical components and the geometric structures of the mats. In this study, fiber mats with different geometric structures, which composed of poly‐ε‐caprolactone (PCL), polyethylene glycol (PEG), and ciprofloxacin (Cip) with different blending ratios, were successfully fabricated by direct‐writing melt electrospinning, and the release behavior of Cip were subsequently investigated in vitro. The results showed that the addition of PEG improved the hydrophilicity of the mats, which in turn affected the manner of drug release. The presence of PEG changed the releasing mechanism from a non‐Fickian diffusion into Fickian diffusion, which indicated that the diffusion of Cip from the composite fiber mats became the main factor of drug release instead of polymer degradation. Besides, with the same composition but different geometric structures, the drug release behavior is of significant difference. Therefore, all the Cip‐loaded composite fiber mats showed antibacterial activities but with different efficiency. In summary, the release of the drug could be controlled by adding PEG and changing the geometric structures according to the different requirement of wound dressings.     

Investigation of drug release and 1H‐NMR analysis of the in situ forming systems based on poly(lactide‐co‐glycolide)

In situ forming biodegradable polymeric systems loaded with betamethasone (BTM) and betamethasone acetate (BTMA) were prepared using poly(DL ‐lactide‐co‐glycolide) (PLGA), ethyl heptanoate (EH), and N‐methyl‐2‐pyrrolidone (NMP) as the biodegradable polymer, additive, and solvent, respectively. The drug release studies were carried out in buffer (pH = 7.4, 37°C) using high performance liquid chromatography (HPLC). ¹H‐NMR was used to determine the polymer degradation behavior, release mechanism, and interactions between the polymer and drug. The ¹H‐NMR spectra showed that all interactions between the polymer and drug were hydrogen bonding. Hydroxyl groups and fluorine in drugs were involved in hydrogen bonding with PLGA polymer. In ¹H‐NMR studies, we found that the degradation rate in the systems loaded with BTMA was higher than the systems loaded with BTM because BTMA is only slightly soluble and accelerates the hydrolysis of PLGA chains. The formulations loaded with BTM had obviously lower burst release compared with BTMA loaded samples. With respect to ¹H‐NMR spectra, the mechanism of BTM release is controlled by two effective factors: solvent removal and polymer degradation. Copyright © 2008 John Wiley & Sons, Ltd.     

Solute and penetrant diffusion in swellable polymers. I. Mathematical modeling

A mathematical model was developed to describe diffusion of a penetrant and a solute in a swellable polymer slab. The model was applied to the case of a hydrophilic polymer loaded with a soluble bioactive agent, in which the penetrant (water) is sorbed and solute is desorbed. The model allows the incorporation of any appropriate form of the diffusion coefficients. A Fujita-type exponential dependence on penetrant concentration was chosen and shown to be adequate for prediction of a range of transport behavior. Dimensional changes in the sample were predicted by allowing each spatial increment to expand according to the amount of penetrant sorbed. During the initial period of release, the swelling was restricted to one dimension by the glassy core of the sample. At a later point in the process, the center of the sample had sorbed enough penetrant to plasticize it, and the sample relaxed to an isotropically swollen state; thereafter swelling was three-dimensional.     

Diffusion of organic vapors at low concentrations in glassy PVC, polystyrene, and PMMA

Diffusion coefficients of various C₁ to C₆ organic vapors, at concentrations 0.5 wt. percent, have been determined by gravimetric sorption rate measurements on emulsion and suspension-polymerized powder samples of PVC, polystyrene, and PMMA. Fickian diffusion kinetics were observed at the lowest concentrations, with a second-stage, relaxation-controlled sorption appearing at higher concentrations. In conjunction with published data for diffusivities of fixed gases in these polymers, the results indicate that diffusivity decreases exponentially, and that diffusion activation energy (E_D) increases linearly, with increasing diameter of “spherical” penetrant molecules (e.g., the noble gases, CH₄, SF₆, CCl₄, and neopentane). Much of the observed scatter in these correlations is attributable to uncertainty in the molecular diameters. For C₄ and larger n-alkanes and other elongated or flattened molecules, diffusivities are higher, and E_D lower, than for spherical molecules of similar molar volume. This finding suggests that anisometric molecules are oriented and move along their long axes during diffusion through the glassy polymer matrix. Correlations of diffusivities with molecular dimensions suggests that transport of anisometric molecules is governed by a diameter smaller than the mean (equivalent sphere) diameter but larger than the minimum dimension of their extended-chain conformation. Among the three polymers studied, diffusivity of each penetrant, at a given temperature, decreases in the order polystyrene> PVC ≥ PMMA.     

The development of a novel smart mid-infrared sensing methodology for residual solvents

The potential of a novel polymer modified mid-infrared technique as a ‘smart’ sensing methodology is demonstrated. Diffusion of a penetrant (analyte molecule) was monitored into a Teflon® AF2400 membrane through observation of one of its infrared absorption bands. During the diffusion of select analytes, mid-IR polymer bands were observed to experience a red shift (reduction in absorption frequency). The rate of appearance of these bands matched that of analyte diffusion. As these bands are specific to certain analytes, and their intensity is analyte-dependent, monitoring of these shifted bands forms the basis of a ‘smart’ sensing regime. The suitability of this smart sensing methodology for the enhanced detection of several residual solvents is presented. A fivefold increase in sensitivity through the monitoring of these bands was realized for the detection of ethylbenzene. One of the aims of this work was to determine whether the cause of the polymer band shifting is chemical or optical in nature. Result data presented support the hypothesis that polymer/diffusant interactions cause this band shifting. This is demonstrated by the fact that a penetrant (tetrahydrofuran), which affected a band shift in the polymer, displayed a blue shift (increase in absorption frequency) in its own spectrum. Ethanol did not cause a polymer band shift and displayed no band shifts in its absorbance spectrum. The relative absorbance of the shifted polymer bands is compared between analytes and does not demonstrate a correlation to analyte refractive indices supporting a polymer/diffusant interaction hypothesis.