Release from or through a wax matrix system. VI. Analysis and prediction of the entire release process of the wax matrix tablet

Analysis of the entire release process of the wax matrix tablet was examined. Wax matrix tablet was prepared from a physical mixture of drug and wax powder to obtain basic or clear release properties. The release process began to deviate from Higuchi equation when the released amount reached at around the half of the initial drug amount. Simulated release amount increase infinitely when the Higuchi equation was applied. Then, the Higuchi equation was modified to estimate the release process of the wax matrix tablet. The modified Higuchi equation was named as the H-my equation. Release process was well treated by the H-my equation. Release process simulated by the H-my equation fitted well with the measured entire release process. Also, release properties from and through wax matrix well coincident each other. Furthermore, it is possible to predict an optional release process when the amount of matrix and composition of matrix system were defined.     

Release from or through a wax matrix system. II. Basic properties of release from or through the wax matrix layer

In order to examine basic properties of release from and through wax matrix layer, reservoir device matrix tablet was prepared from a physical mixture of hydrogenated caster oil and drug that was the same one in the reservoir. Release process could be divided into two stages. The first stage was the formation process of water channel by dissolving the drug in the wax matrix layer, and dissolved drug was released from the matrix layer following the square-root-of-time law equation. Hence, the drug penetration coefficient and tortuosity in the matrix layer were estimated. The second stage was the zero order release process of drug in the reservoir through the wax matrix layer. The release rate constant was calculated from the slope of line. Hence, the drug permeability coefficient and tortuosity were estimated. Fundamentally, tortuosity can not be expressed by some meaningful factors, and is obtained as an experimental result. By preparing wax matrix system from a physical mixture other than melted granule method, it was suggested that the matrix structure was uniform three-dimensionally. As a result, tortuosity could be expressed by a function of porosity, because unrecognized factors such as the surface coverage and thickness of melted wax on the soluble component should not be involved.     

Release from or through a wax matrix system. I. Basic release properties of the wax matrix system.

Release properties from a wax matrix tablet was examined. To obtain basic release properties, the wax matrix tablet was prepared from a physical mixture of drug and wax powder (hydrogenated caster oil) at a fixed mixing ratio. Properties of release from the single flat-faced surface or curved side surface of the wax matrix tablet were examined. The applicability of the square-root time law and of Higuchi equations was confirmed. The release rate constant obtained as g/min(1/2) changed with the release direction. However, the release rate constant obtained as g/cm2 x min(1/2) was almost the same. Hence it was suggested that the release property was almost the same and the wax matrix structure was uniform independent of release surface or direction at a fixed mixing ratio. However, these equations could not explain the entire release process. The applicability of a semilogarithmic equation was not as good compared with the square-root time law or Higuchi equation. However, it was revealed that the semilogarithmic equation was available to simulate the entire release process, even though the fit was somewhat poor. Hence it was suggested that the semilogarithmic equation was sufficient to describe the release process. The release rate constant was varied with release direction. However, these release rate constants were expressed by a function of the effective surface area and initial amount, independent of the release direction.     

Release from or through a wax matrix system. III. Basic properties of release through the wax matrix layer

Release property of reservoir device matrix tablet was examined. Wax matrix layer was prepared from physical mixture of lactose and hydrogenated castor oil to obtain basic release properties. Release process showed zero order kinetics in a steady state after a given lag times, and could be divided into two stages. The first stage was the formation process of water channel by dissolving the soluble component in the wax matrix layer. The lag time was considered to be the time required forming water channel and the time begun to release drug through the wax matrix layer at the same time. The lag time obtained by applying the square root law equation was well connected with the amount of matrix layer and mixed weight fraction of component in matrix layer. The second stage was the zero order release process of drug in the reservoir through the wax matrix layer. The release rate constants were calculated by taking into accounts of the thickness of matrix layer and permeability coefficient, and were well connected with the amount of matrix layer and mixed weight fraction of component. Also it was suggested that the tortuosity of matrix layer could be expressed by a function of the porosity defined by the mixed weight fraction.     

Release from or through a wax matrix system. IV. Generalized expression of the release process for a reservoir device tablet

Generalization of the release process through the wax matrix layer was examined by use of a reservoir device tablet. The wax matrix layer of the reservoir device tablet was prepared from a physical mixture of lactose and hydrogenated castor oil to simplify the release properties. Release through the wax matrix layer showed zero-order kinetics in a steady state after a given lag time, and could be divided into two stages. The first stage was the formation process of water channel by dissolving the soluble component in the wax matrix layer. The lag time obtained by applying the square root law equation was well connected with the amount of the matrix layer and mixed weight ratio of components in this layer. The second stage was the zero-order release process of drug in the reservoir through the wax matrix layer, because the effective surface area was fixed. The release rate constants were connected with thickness of the matrix layer and permeability coefficient, and the permeability coefficients were connected with the diffusion coefficient of drug and porosity. Hence the release rate constant could be connected with the amount of matrix layer and the mixed weight ratio of components in the matrix layer. It was therefore suggested that the release process could be generalized using the amount of matrix layer and the mixed weight ratio of components in the matrix layer.     

Analysis of the release process of phenylpropanolamine hydrochloride from ethylcellulose matrix granules V. Release properties of ethylcellulose layered matrix granules

In the pharmaceutical preparation of a controlled release drug, it is very important and necessary to understand the release properties. In previous papers, a combination of the square-root time law and cube-root law equations was confirmed to be a useful equation for qualitative treatment. It was also confirmed that the combination equation could analyze the release properties of layered granules as well as matrix granules. The drug release property from layered granules is different from that of matrix granules. A time lag occurs before release, and the entire release property of layered granules was analyzed using the combination of the square-root time law and cube-root law equations. It is considered that the analysis method is very useful and efficient for both matrix and layered granules. Comparing the granulation methods, it is easier to control the manufacturing process by tumbling granulation (method B) than by tumbling-fluidized bed granulation (method C). Ethylcellulose (EC) layered granulation by a fluidized bed granulator might be convenient for the preparation of controlled release dosage forms as compared with a tumbling granulator, because the layered granules prepared by the fluidized bed granulator can granulate and dry at the same time. The time required for drying by the fluidized bed granulator is shorter than that by the tumbling granulator, so the fluidized bed granulator is convenient for preparation of granules in handling and shorter processing time than the tumbling granulator. It was also suggested that the EC layered granules prepared by the fluidized bed granulator were suitable for a controlled release system as well as the EC matrix granules.     

Design and preparation of pulsatile release tablet as a new oral drug delivery system.

To achieve time-controlled or site specific delivery of a drug in the gastrointestinal tract, an orally applicable pulsatile drug release system with the dry-coated tablet form was developed. The system consisted of a less water permeable outer shell and a swellable core tablet; from such a system, the drug was expected to be rapidly released after a certain period of time on the basis of time-controlled disintegration mechanism. Various model disks of outer shell, consisting of hydrogenated castor oil and polyethyleneglycol 6000, were tested for their water penetration rate. The experimental results showed that water penetration proceeded obeying the boundary retreating mechanism, so that the lag time of the system could be controlled by changing either the thickness or the composition of the outer shell. The swelling force of various commercially available disintegrants was quantitatively compared, and it was found that carboxymethylcellulose calcium was the preferable disintegrant to be used for the core tablet. On the basis of the results of a series of fundamental studies, various pulsatile release tablets of isoniazide with different lag times were designed. In the in vitro dissolution test, typical pulsatile release was achieved for all the tablets prepared, and a good correlation was found between the observed lag time and the estimated lag time calculated from an empirical equation deduced from the thickness and polyethyleneglycol 6000 content of the outer shell.     

Development of a detection tablet for a portable NO2 monitoring system.

We have already developed a HCHO monitoring system which is called FP-30. In this experiment, we have developed a NO(2) detection tablet which can be used by the monitoring system. The detection tablet for the NO(2) was constructed with the sensing paper: porous cellulose paper that contains silica gel as an adsorbent, N-1-naphthylethylenediamine dihydrochloride (NED), and glycerin. The NO(2) in sample gas was blown over and adsorbed on the surface of the sensing paper. Then the NO(2) reacted with NED, producing a yellow compound. The coloring reaction took place on the surface of the sensing paper. The degree of color change of paper from white to yellow was monitored as a function of the intensity of the reflected light (lambda = 475 nm) of an LED. The detection limit was 0.01 ppm when the sampling time was 30 min, and the flow rate of sample gas was 250 ml/min. This sensing paper process was not interfered with by acetaldehyde, acetone, alcohols, hydrocarbons, carbon monoxide or carbon dioxide. The NO(2) concentrations in the rooms of a house or school were monitored using this monitoring system and the standard chemiluminescence method. The concentrations of NO(2) monitored by both methods were within 18% of the average. This highly sensitive, selective, and handy NO(2) gas monitoring system will be widely applicable and convenient for users who are not specialists in this field.     

Development and validation of a mechanistic model for the release of embelin from a polycaprolactone matrix

Embelin is a natural agent with antimicrobial, antifungal and analgesic activities. This work presents a mechanistic model for the release of embelin from a polycaprolactone matrix. Based on the results of embelin release experiments and Raman microscopy measurements, the model assumes a dual dispersion of the embelin: agglomerated and dispersed. Embelin release mechanism combines the effects of the liquid migration into the matrix, the drug diffusion, and the drug dissolution within the wetted matrix. The model is formulated in terms of four partial differential equations that account for the mass balances of dispersed, agglomerated, and dissolved embelin, and aqueous solution. Model predictions show that the release mechanism involves three stages: a burst stage, in which dispersed embelin is rapidly released; a transition stage, in which dispersed and agglomerated embelin are simultaneously released; and, once the dispersed embelin depletion, a stable release stage until the agglomerated embelin exhausts.     

External control of drug release. IV. Controlled release of 5-fluorouracil from a hydrophilic polymer matrix by microwave irradiation

A polymeric system capable of delivering 5-fluorouracil (5-FU) at increased rates on demand by external microwave irradiation was developed. Sustained-release systems were made by incorporating 5-FU into an ethylene-vinyl alcohol copolymer. When exposed to release medium, the delivery systems released the drug slowly and continuously. Upon exposure to microwave irradiation, the drug was released at a much higher rate. Release rates returned to base line levels when the microwave irradiation was discontinued. This study demonstrated that release rates of 5-FU from a polymer matrix can be increased at desired times by external microwave irradiation.     

Pure component vapour pressure from a Carnahan-Starling equation of state: theoretically based temperature law for the attractive parameter

The proposed equation of state associates the Carnahan-Starling hard-sphere repulsion term with an attraction term of the Redlich-Kwong type containing a temperature function α(T_r). It is applied for calculating the vapour pressures of 14 pure hydrocarbon and non-hydrocarbon components. For α(T_r), three empirical laws and one law deduced from the Clausius-Clapeyron equation are investigated. This last one gives the best results, and its two adjustable parameters may be generalized as a function of the acentric factor.     

Analysis of the release process of phenylpropanolamine hydrochloride from ethylcellulose matrix granules II. effects of the binder solution on the release process

The release properties of phenylpropanolamine hydrochloride (PPA) from ethylcellulose (EC) matrix granules prepared by an extrusion granulation method were examined. The release process could be divided into two parts; the first and second stages were analyzed by applying square-root time law and cube-root law equations, respectively. The validity of the treatments was confirmed by the fitness of a simulation curve with the measured curve. In the first stage, PPA was released from the gel layer of swollen EC in the matrix granules. In the second stage, the drug existing below the gel layer dissolved and was released through the gel layer. The effect of the binder solution on the release from EC matrix granules was also examined. The binder solutions were prepared from various EC and ethanol (EtOH) concentrations. The media changed from a good solvent to a poor solvent with decreasing EtOH concentration. The matrix structure changed from loose to compact with increasing EC concentration. The preferable EtOH concentration region was observed when the release process was easily predictable. The time and release ratio at the connection point of the simulation curves were also examined to determine the validity of the analysis.     

Analysis of the release process of phenylpropanolamine hydrochloride from ethylcellulose matrix granules III. Effects of the dissolution condition on the release process

In the pharmaceutical preparation of a controlled release drug, it is very important and necessary to understand the entire release properties. As the first step, the dissolution test under various conditions is selected for the in vitro test, and usually the results are analyzed following Drug Approval and Licensing Procedures. In this test, 3 time points for each release ratio, such as 0.2-0.4, 0.4-0.6, and over 0.7, respectively, should be selected in advance. These are analyzed as to whether their values are inside or outside the prescribed aims at each time point. This method is very simple and useful but the details of the release properties can not be clarified or confirmed. The validity of the dissolution test in analysis using a combination of the square-root time law and cube-root law equations to understand all the drug release properties was confirmed by comparing the simulated value with that measured in the previous papers. Dissolution tests under various conditions affecting drug release properties in the human body were then examined, and the results were analyzed by both methods to identify their strengths and weaknesses. Hereafter, the control of pharmaceutical preparation, the manufacturing process, and understanding the drug release properties will be more efficient. It is considered that analysis using the combination of the square-root time law and cube-root law equations is very useful and efficient. The accuracy of predicting drug release properties in the human body was improved and clarified.     

Influence of the convective term in the Nernst-Planck equation on properties of ion transport through a layer of solution or membrane

The one-dimensional boundary-value problem of steady-state ion transport, which takes into account the convective component, is formulated and solved in terms of the Nernst-Planck model. This problem is investigated in connection with the diffusion layer, which is understood in a broad sense. This can be the diffusion layer as it is usually understood, i.e., located adjacent to a hydraulically permeable membrane. In another context it can be regarded as a capillary connecting two reservoirs filled with solutions of different concentration or as an uncharged macropore permeating the membrane and separating two solutions. Finally, the solution to the problem is applied to the membrane itself, which is represented as a quasi-homogeneous gel. In the latter case, a virtual electroneutral solution in local equilibrium with a small volume of membrane is considered. The problem is investigated in dimensionless form as a function of the Peclet number. It is shown that the Peclet number is numerically equal to the absolute value of the dimensionless convection velocity. The limiting current, concentration profiles, distributions of the field strength and potential, and effective transport numbers are analyzed as functions of the convective component.     

Acyclovir release from its composites with silica as a function of the silica matrix modification and the drug loading

Acyclovir release from its composites with unmodified silica at pH 1.6 and 7.4 follows zero order kinetics for two days. Modification of the silica matrix with phenyl groups leads to dramatic decrease in the drug release level at pH 7.4 compared with pH 1.6 as well as to heterogeneous phase state of acyclovir in the phenyl modified composite with high loading of the drug.     

Analysis of the release process of phenylpropanolamine hydrochloride from ethylcellulose matrix granules IV.(1)) Evaluation of the controlled release properties for in vivo and in vitro release systems

In the pharmaceutical preparation of a controlled release drug, it is very important and necessary to understand the release properties. The dissolution test is a very important and useful method for understanding and predicting drug-release properties. It was readily confirmed in the previous paper that the release process could be assessed quantitatively by a combination of the square-root time law and cube-root law equations for ethylcellulose (EC) matrix granules of phenylpropanolamine hydrochloride (PPA). In this paper EC layered granules were used in addition to EC matrix. The relationship between release property and the concentration of PPA in plasma after administration using beagle dogs were examined. Then it was confirmed that the correlativity for EC layered granules and EC matrix were similar each other. Therefore, it was considered that the dissolution test is useful for prediction of changes in concentration of PPA in the blood with time. And it was suggested that EC layered granules were suitable as a controlled release system as well as EC matrix.     

Evidence for spontaneous release of acrylates from a transition-metal complex upon coupling ethene or propene with a carboxylic moiety or CO(2)

The development of a new synthetic approach to acrylates based on the formation of alkyl esters of acrylic acids has been studied. A preformed Pd-COOMe moiety is used as a model system to investigate the insertion of an olefin into the Pd--C bond. The fast elimination of acrylate is observed. Density functional calculations support the experimental findings and allow the characterization of transition states along the reaction pathway. The first example of olefin/CO(2) coupling with facile release of ethyl acrylate is also presented.     

New methods for the determination of the parameters of a concentration‐dependent diffusion law for molecular penetrants from transient permeation or sorption data

New methods were developed for the determination of the plasticization parameters and the limit diffusion coefficient of a penetrant whose diffusivity varies exponentially with its concentration. No specific computer softwares is required for their use and they are user friendly. The method using differential permeation data is based on the correlations between the slope of the reduced permeation flux versus time plot at the inflexion point, and the two key parameters of the concentration‐dependent diffusivity laws. For the transient sorption method, the slope of the penetrant mass uptake versus square‐root of time curve leads to the same parameters of the diffusion law via similar correlations.