The release behavior and kinetic evaluation of tramadol HCl from chemically cross linked Ter polymeric hydrogels
© Malana and Zohra; licensee BioMed Central Ltd. 2013
Received: 18 September 2012
Accepted: 13 December 2012
Published: 18 January 2013
Background and the purpose of the study
Hydrogels, being stimuli responsive are considered to be effective for targeted and sustained drug delivery. The main purpose for this work was to study the release behavior and kinetic evaluation of Tramadol HCl from chemically cross linked ter polymeric hydrogels.
Ter-polymers of methacrylate, vinyl acetate and acrylic acid cross linked with ethylene glycol dimethacrylate (EGDMA) were prepared by free radical polymerization. The drug release rates, dynamic swelling behavior and pH sensitivity of hydrogels ranging in composition from 1-10 mol% EGDMA were studied. Tramadol HCl was used as model drug substance. The release behavior was investigated at pH 8 where all formulations exhibited non-Fickian diffusion mechanism.
Results and major conclusion
Absorbency was found to be more than 99% indicating good drug loading capability of these hydrogels towards the selected drug substance. Formulations designed with increasing amounts of EGDMA had a decreased equilibrium media content as well as media penetrating velocity and thus exhibited a slower drug release rate. Fitting of release data to different kinetic models indicate that the kinetic order shifts from the first to zero order as the concentration of drug was increased in the medium, showing gradual independency of drug release towards its concentration. Formulations with low drug content showed best fitness with Higuchi model whereas those with higher concentration of drug followed Hixson-Crowell model with better correlation values indicating that the drug release from these formulations depends more on change in surface area and diameter of tablets than that on concentration of the drug. Release exponent (n) derived from Korse-Meyer Peppas equation implied that the release of Tramadol HCl from these formulations was generally non-Fickian (n > 0.5 > 1) showing swelling controlled mechanism. The mechanical strength and controlled release capability of the systems indicate that these co-polymeric hydrogels have a great potential to be used as colon drug delivery device through oral administration.
Tramadol, a synthetic opioid of the amino-cyclohexanol group, exhibiting weak opioid agonist properties, is a centrally acting analgesic and has been observed to be effective in both experimental and clinical pain and additionally causes no serious cardiovascular or respiratory side effects. The usual oral dosage requirement of the drug is 50 to 100 mg every 4 to 6 hours with a maximum dosage of 400 mg per day. A sustained-release formulation of tramadol is required to improve patient compliance and to reduce the administration frequency. To modulate the drug release, the most commonly used method is to include it in a matrix system. As hydrophilic polymer matrix systems are proved to be flexible to obtain a desirable drug release profile, these are widely used in oral controlled drug delivery. Using a hydrophilic matrix system to release the drug for extended duration, especially, for highly water-soluble drugs, is restricted to rapid diffusion of the dissolved drug through the hydrophilic gel structures. For such highly soluble drug substances, chemically cross linked hydrogels are considered suitable as matrixing agents for developing sustained-release dosage forms. This extensive use corresponds to the non-toxicity, high drug loading capacity and pH-sensitivity of the network structure. Moreover, a problem, frequently, encountered with the oral administration of these formulations, is inability to increase the resistance time in stomach and proximal portion of small intestine. To overcome this problem, it becomes necessary to prolong the dosage form either in the stomach or somewhere in the upper small intestine until all the drug is released over the desired period of time[6, 7].
These polymer matrices can be either chemically cross linked having covalent bonding or physically cross linked through hydrogen bonds depending on the monomers, polymerization methods and the mode of application. Advance research has flashed over synthesizing and characterizing hydrogels having particular mechanical properties such as strength and modulus, environmental sensitivity to temperature, electric field, pH or ionic strength and mass transport control that can be “tuned” to get special pharmacological application including reduced toxic “burst” effects of a drug, protections of fragile drugs in their dosage environment and location specific dosage etc..
In the present work, the main objective was to study the release behavior and kinetic evaluation of a model drug tramadol HCl from chemically cross linked (Vinylacetate-co-methacrylate-co-acrylic acid) (VA-co-MA-co-AA) co-polymeric ternary systems. The preliminary swelling studies are indicative of the fact that these hydrogels may be able to face the problems related to sustained drug delivery. For this purpose chemically cross linked co-polymeric hydrogels were prepared with a range of cross linker concentration. Effect of the concentration of the cross linker on various swelling parameters and the drug release profiles was estimated. Influence of amount of drug loaded on drug release rate was also studied in detail. Different release models were applied to evaluate the release kinetics of the drug from the optimized formulation.
Materials and polymer preparation
Two hydrophobic monomers, methacrylate (MA) (MERCK, 99%) and vinylacetate (VA) 9Fluka, 99%) were mixed with a hydrophilic monomer, acrylic acid (AA) (fluka, 99%) to prepare the polymer for this study. Copolymers of MA, VA and AA were prepared according to the previously reported method by free radical polymerization using Benzoylperoxide (BPO) (MERCK, 100%) as the initiator and ethanol as solvent. Different grades (E1, E2, E3, E4 having 1, 3.5, 6.5, 10 mol% respectively) of the cross linker Ethylene glycoldimethacrylate (EGDMA) (Fluka, 100%) were added to prepare chemically cross linked co-polymeric networks.
Where Wt is the dynamic media content at time t and We is the equilibrium media content, n stands for diffusion exponent and k is the rate constant.
Where Q (mg/g) is the absorbency of tramadol by the xerogel; C1 (mg/ml) is the initial concentration of tramadol solution; V1 (ml) represents the initial volume of tramadol solution; C2 (mg/ml) is the concentration of tramdol after absorption by the xerogel; V2 (ml) is the volume of tramadol solution after absorption by the polymer; and mo is the mass of the polymer in dry state.
In vitro drug release studies
In vitro drug release of Tramadol HCl from co-polymeric hydrogels was evaluated in triplicate using UV-Visible spectrophotometry. The dried drug loaded disks were transferred into the fixed volume of buffer solution of pH 8 at 37°C. At specified time intervals, 3 ml of aliquots were removed from every buffer solution and the absorbance was noted using UV-visible spectrophotometer at the maximum absorption wave length (240nm) already measured using a stock solution of Tramadol HCl in phosphate buffer of pH 8. Three aliquots of various solutions were studied for any single point of release curve. After absorbance measurements, aliquots were returned to the original solution, so that the volume may be kept constant. To transform absorbance determinations into concentrations, calibration curve was used.
To study the release kinetics of Tramadol HCl from the matrix tablets, the release data were fitted to the following equations:
Where Qt stands for the percentage of drug released at time t and ko is the release rate constant;
Where k1 stands for release rate constant for the first order kinetics;
Where kH represents the Higuchi release rate constant;
Where, kHC stands for Hixson-Crowell rate constant.
Where Qt/Qe is the fraction of the drug released at time t, kKP is a constant corresponding to the structural and geometric characteristics of the device and n is the release exponent which is indicative of the mechanism of the drug release. In case of cylindrical geometries such as tablets, for fitting the data to the equations, only the points within the interval 10-70% were used. In case of Hixson-Crowell and korsmeyer-Peppas models, the data taken was within 10-60% drug release.
Thermal degradation of the hydrogel systems was studied using a thermo-gravimetric analyzer [TA Instruments SDT Q. 600 V20 .9 Build 20 simultaneous TGA-DSC], by heating them from room temperature to 600°C at a heating rate of 10°C/min under a nitrogen flow.
Media penetration velocity and equilibrium media content
The change in media penetration velocity with increasing EGDMA content may be due to two possible mechanisms: first if the media travelled primarily through the hydrophilic AA regions of these copolymers, the increasing number of cross link domains might keep AA content busy in building the cross links that could obstruct the media diffusive path way for diffusion; secondly, the increased cross linker’s concentration may also inhibit polymer chain relaxation, thus reducing the free volume through which the media can travel.
Media diffusion mechanism
Summary of media penetration velocities, equilibrium media contents, mechanical strength and power law parameters for the polymers
Media penetration velocity
Equilibrium media sorbed
(mg media/mg polymer)
In vitro release of tramadol HCl from the copolymer
Kinetic parameters of tramadol HCl release from the matrix tablets
To analyze the effect of the concentration of the cross linker on the release behavior of the drug, only three samples E1, E2 and E3 were used for experiment as the sample E4 was collapsed during the loading process (Figure6). The most probable explanation for the behavior of E4 may be that there is some type of repulsive interaction between the material of the drug loaded and the highly cross linked dense polymeric matrix. Figure6 is showing the release profile for influence of the cross linking agent concentration. As predicted from swelling studies, the drug release rate decreased with increase in the cross link density. Same effect of the cross linker’s concentration on the drug release rate has also been reported by other authors. On the other hand, the release rate was enhanced by the amount of the drug loaded in the polymer networks. The optimized formulation (E2) was used to study the effect of amount of the drug loaded in the system as shown in the Figure7.
In initial stages the effect was not pronounced. The difference was negligible up to 1.6 mg/ml initially prepared drug concentration solution. However, for higher drug loading concentrations, the amount of the drug release as well as the drug release rate were increased significantly. The root cause for the observed effect might be the higher concentration gradient which is responsible for a more efficient diffusion of the drug substance through the polymer network, keeping all other conditions the same. Hence, variation in drug loading concentration offers a real probability of controlling the drug release.
Various mathematical equations have been proposed to describe the kinetics of the drug release from the controlled release formulations. The zero order model equation (Eq. 4) describes the systems, where the drug release does not depend on its concentration. The first order release kinetics describes the dependency on the drug concentration in the polymeric networks. Higuchi model proposes a direct relation of the drug release from the matrix to a square root of time and is based on the Fickian diffusion. The Hixson-Crowell cube root law describes the release rate from the systems depending on the change in surface area and diameter of the particles or tablets and specifically is applied for the systems which erode over time.
The values of “n” determined for chemically cross linked hydrogels studied, ranged from 0.688 to 0.982 as tabulated in the Table2. The results indicated that all the formulations exhibited anomalous transport (i.e non-Fickian diffusion mechanism), so the drug release was governed by both diffusion of the drug and dissolution of the polymeric network. In fact all the tablets started to erode during the first two hours of their introduction into a fixed volume of phosphate buffer solutions. Even the samples with higher drug concentrations were collapsed during the first hour of exposure of the formulations to the dissolution medium.
The mechanical strength of the xerogels was determined, applying a maximum weight on them. Surprisingly, not a single disk was broken down even the maximum force was applied on them. However, the polymers with low concentration of the cross linker showed a little strain in them by equal increase in their diameter, thus decreasing their thickness; but the observed strain was vanished away within a few minutes after the applied stress was released. The fully swollen hydrogels up to their equilibrium point, exhibited a regular increase in the mechanical strength with the concentration of the cross linker (Table1). Similar effect of the cross linker on the mechanical strength was also observed by other authors.
DSC and TGA
The chemically cross linked hydrogel copolymer comprised of VA-co-MA-co-AA and EGDMA has proven to be effective controlling the desorption rate of the drug substance from its matrix. The introduction of the higher cross link density decreased (1) the media penetration velocity through the hydrogels in basic media (2) the equilibrium media content in the hydrogels (3) the absorbency of the drug into the polymeric material and (4) the drug release rate from the hydrogels. The shift of the mechanism from diffusion controlled to an anomalous transport changing the pH of the medium from acidic to basic conditions and the mechanical strength indicate that the polymer matrix not only can maintain its structure in the acidic medium of the stomach but also can resist peristaltic movements of the digestive tract, thus preventing the drug release until the target has been achieved. The ability of these ter-polymeric hydrogels systems to load and deliver a drug substance at a controlled rate suggests that these hydrogels show a great promise as a drug delivery system.
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