Higuchi Square Research Articles

Calcium pectinate gel beads for controlled release drug delivery: II. Effect of form ulation and processing variables on drug release

The effect of four formulation and processing variables, calcium concentration, drying condition, concentration of hardening agent and hardening time on the bead properties and the release characteristics of a model drug from calcium pectinate gel (CPG) beads were studied. A poorly soluble compound, indomethacin, was used as the model drug. The investigated variables affected the bead size, the entrapment efficiency and the release of indomethacin from CPG beads. Drug release was found to be a function of the formulation and processing variables. The slower drug release was achieved from the formulations with higher calcium concentration, higher concentration of hardening agent and longer hardening time. The drying condition, however, did not influence the drug release. The mechanism of indomethacin release from CPG beads followed the diffusion controlled model for an inert porous matrix. All drug release data fitted well to the Higuchi square root time expression.

Kinetics and Mechanism of Release from Glyceryl Monostearate-Based Implants: Evaluation of Release in a Gel Simulating in Vivo Implantation

he overall objective of the study was to design an implantable delivery system based on glyceryl monostearate (GMS) for the site-specific delivery of antibiotics for the prevention of surgical wound infection. To design the implant, a release method had to be developed that simulate the in vivo implantation conditions to be able to predict the release characteristics from the implants when they are actually used in vivo. Also, identifying the release kinetics and mechanism and evaluating the factors that influence the release of drugs from the GMS-based matrix were necessary to allow further design of implants that could yield a desired release rate. The release of cefazolin was monitored from GMS matrixes implanted into agar gel, simulating subcutaneous tissues with respect to viscosity and water content. The gel method resulted in observation of spatial and temporal concentration profiles in the immediate vicinity of the implants, indicating the benefits of local drug delivery; however, there was no significant difference between the cumulative release profiles by the gel method or the vial release method. The release of cefazolin from the GMS-based matrix with the vial method followed Higuchi's square root of time kinetics. The release rate Q/t was found to be directly proportional to cefazolin load (A) and the surface area (SA) of the matrix as expressed by the following equation: Q/t=0.24ASA. On the basis of this equation, one can design a variety of GMS matrixes that would result in a desired release rate or release duration. This also indicated that cefazolin release followed the release kinetics of a freely soluble drug from an insoluble matrix and hence it is a diffusion-controlled process. The effect of drug solubility on the release kinetics was determined by comparing the release kinetics of the poorly water soluble ciprofloxacin (0.16 mg/mL) to that of the highly water soluble cefazolin (325 mg/mL). The release duration of ciprofloxacin (80 h) was longer than that of cefazolin (25 h) from identical GMS matrixes. Although ciprofloxacin release was initially controlled by the matrix, agitation accelerated disintegration of the matrix and release due to its poor solubility, and ciprofloxacin release appeared to be a dissolution-controlled process following zero-order release kinetics.

Salt effects on the diffusion and release rate of propranolol from poloxamer 407 gels

In this report we show that salts commonly included in the formulation of poloxamer 407 (P407) gels can dramatically change the release rate of a drug from the gel. We used a model drug, propranolol, and measured its diffusion from a 21% P407 gel into an aqueous medium at 37°C through a cellulose membrane. The data followed the Higuchi square root law during the first hour of release. The release rate and diffusion coefficient of propranolol were significantly reduced when NaCl, Na 2SO 4, NaH 2PO 4, MgSO 4 and CaCl 2 were added to the gels. The magnitude of the effect on release rate depends on the nature and concentration of the salt. Since propranolol is expected to be located outside the micelles in the gel, we attribute these salt effects to an increase in microviscosity of the aqueous regions of the gel, rather than to a change in micellization behavior. This is analogous to the change in the aggregation and phase behavior of aqueous solutions of non-ionic surfactants in the presence of salts.

Influence of pH and phospholipid species on release of acetaminophen from tablets containing phospholipids.

The release of acetaminophen (AAP) from tablets containing phospholipids was examined using hydrogenated soybean phospholipid (HSL) and its main components, phosphatidylcholine (PC), phosphatidylethanolamine (PE) and phosphatidylinositol (PI), although the PI was not well purified (PI rich). Tablets compressed with 400 kgf had about 9% porosity and 2-4 kgf hardness. The release patterns of AAP from the tablets were fitted to Higuchi's square root of time law. The release rate was influenced by the pH of the medium, though solubility of AAP did not change with pH. PC tablets showed faster release at pH of less than 3 than that at pH of above 3, whereas PI rich and HSL tablets showed faster release at pH of above 3 than that at pH of less than 3. The release rate from PE tablets was little affected by pH. A linear relationship exists between the release rate of AAP and the rate of water absorption by the tablet. The ionization state of the phospholipids changes with the pH of the medium, and affects the hydration characteristics. The fully ionized state, at pH of less than 3 in the case of PC and above 3 in the case of PI is most effective on hydration. PE does not fully ionize because of intermolecular hydrogen bonding.

Box-behnken design for the optimization of formulation variables of indomethacin coprecipitates with polymer mixtures

Numerous reports explain the dissolution release mechanisms and certain matrix type formulations follow the Higuchi's square root of time model. Earlier screening experiments have shown that compression of indomethacin coprecipitates prepared using Eudragit polymer mixtures yielded matrix tablets which release 80% of the drug in 24 h. The present study deals with optimization of formulation variables to improve dissolution characteristics of the matrix formulation. A three-factor, three-level Box-Behnken design with drug to polymer ratio (X 1), polymer to polymer ratio (X 2) and solvent ratio (X 3) as the independent variables were selected for the study. The dependent variable was cumulative percent of drug released in 24 h. As a novel approach, constraints were placed on the dependent variable such that the ideal release characteristics of a matrix formulation would be obtained for the 24-h release formulation. Based on the experimental design, different indomethacin release rates and profiles were obtained. The dependent and independent variables were related using mathematical relationships and surface response plots. The model predicted a 100.7% release with the X 1, X 2 and X 3 levels of 7.813, 0.9586 and 1.5, respectively. The optimized formulation prepared according to predicted levels provided release rates which were close to predicted values. Also, the observed and predicted response values fell in the range of calculated values as obtained from the Higuchi's model. Further, the optimized formulation was compared with solid dispersions and physical mixtures. All the formulations were characterized by X-ray diffraction, IR DSC and dissolution studies.

Drug release from a multiparticulate pellet system.

Multiparticulate pellet systems are used as both immediate and modified release dosage forms. Previous work has classified uncoated pellet systems prepared from microcrystalline cellulose as an inert matrix. The Higuchi square root of time equation, derived to describe drug release from a single planar system, is the accepted method to evaluate drug release from both planar and spherical heterogeneous inert granular matrices. A second equation of interest, the Higuchi cubic equation, was derived to describe drug release from a spherical pellet. Both equations predict a linear relationship between drug release and the square root of time or time. The purpose of the present study was to evaluate drug release from a multiparticulate pellet system using both equations and to study any differences when both equations are used to describe the same drug release data. By evaluating dissolution data from various pellet mesh cuts representing different bead radii and surface areas, changes in the slopes of both plots would be expected. Pellets were manufactured using extrusion/spheronization technology and consisted of 90% microcrystalline cellulose and 10% acetaminophen. Statistical comparison indicates that the Higuchi cubic equation seems to be more sensitive to changes in pellet size. While the square root of time equation describes the drug release data from granular, inert, spherical pellets, it may be better to utilize the Higuchi cubic equation because it is more sensitive to changes in particle size.

Influence of diluents and manufacturing method on the in vitro dissolution of carteolol hydrochloride matrix tablets

The release behaviour of carteolol hydrochloride matrix tablets was investigated as a function of filler nature (Emcompress ®, mannitol, PEG 6000 and lactose), type of wetting liquid (Eudragit ® L 12.5% and isopropanol-acetone mixture 6:4) and mode of filler incorporation. The values of the technological parameters suggest that hardness was the most significantly affected by the three formulation factors considered. The strongest influence over the technological parameters was exerted by the mode of filler incorporation. The kinetic data conformed with the Higuchi square root equation, except for the lots containing mannitol and isopropanol-acetone mixture that conformed to a first-order plot. The lot containing Emcompress ® and isopropanol-acetone mixture displayed acceptable linearity with both plots. Therefore, a non-linear regression procedure and reduced time method were used to define with precision the kinetic model followed by this formulation. Release parameters such as the Higuchi rate constant, ts0 and dissolution efficiency were calculated. Lots containing mannitol presented more rapid release rates due to the high solubility of this filler. On the other hand, the use of PEG 6000 as diluent significantly decreased drug release. The influence of technological parameters on the release of these systems was also examined, an inverse relationship between hardness and dissolution efficiency being found.

Processing factors affecting particle size and in vitro drug release of sustained-release ibuprofen microspheres

Ibuprofen microspheres were prepared using an aqueous dispersion method. The method was adapted so that two processing factors, cooling time and stirring rate, could be altered. The subsequent effects of altering these parameters on the characterisation of the microspheres and the drug release kinetics were investigated. Particle size analysis showed that both stirring rate and cooling time significantly affected the mean particle size although the effects were independent of each other. In vitro release data were fitted to several models, the Higuchi square root of time model (with appropriate limits) giving the best fit for the release data. Increasing the cooling time or decreasing the stirring rate decreased the release of drug from the system. By using this method of manufacture, which allows alteration of processing parameters, it would be relatively straightforward to produce microspheres with tailored in vitro release characteristics.

Preparation of the Solid Dispersion of Indomethacin with Phosphatidylcholine by Heating Method.

The solid dispersion (SD) preparation method of indomethacin (IM, mp 161°C) with phosphatidylcholine (PC) was investigated. The melting point of PC is high, above 200°C, making a melting method inapplicable. However, PC shows a phase transition at about 100°C when its acyl chains are stearic acid and it is an anhydride. In the case of mole fraction of IM in SD being 0.50, X-ray diffraction patterns suggest that IM is in an amorphous state after heating at 90°C for 1h, at 110°C for 10min or at 180°C for 6min. When the mole fraction of IM is as low as 0.25 or 0.33, IM is also present in an amorphous state after heating at 70°C for 2h and at 90°C for 10min. The obtained SD showed endothermic peaks from about 40°C to 70°C upon thermal analysis. It is possible to prepare SD above 70°C, but this requires a long heating time; therefore, heating at above the phase transition temperature is most suitable. The dissolution patterns of IM from SD compressed into tablet form were fitted to Higuchi's square root equation and the dissolution rate was found to be 1.5-fold that from a physical mixture of the same composition.

酢酸クロルマジノンを含有するシリコーン製植込み型雌犬用発情抑制剤の薬剤学的特性

We developed a new subdermal silicone elastomer implants containing chlormadinone acetate (CMA), which was effective for prevention of estrus in bitches. The implants gave a continuous CMA release over a year. The CMA release from the implants was dependent on the CMA loading level and surface area of the implants. The CMA release patterns both in vitro and in vivo system fitted well with the Higuchi square root low. The dissolution test using organic solvents was found to be useful for the brief estimation of CMA release from the implants.

Preparation and characterisation of sustained-release ibuprofen-cetostearyl alcohol spheres

Spherical ibuprofen-cetostearyl alcohol matrices were prepared using a technique involving melting and suspension of drug-containing cetostearyl alcohol in an aqueous medium. The resulting emulsion was cooled under rapid stirring to produce the spheres. Release of ibuprofen from the pellets was modelled using standard drug-release equations. Numerical fits indicate that the contracting sphere model (the cube root equation) was the most appropriate one for describing the complete release profiles. Within the range of drug release rates of 20–80% the model was indistinguishable from the Higuchi square root of time model. Using the slopes from the latter model, the effects of drug loading, particle size and stirring speed during the preparation of the pellets were investigated. Differential scanning calorimetry was used to explain some unusual observations and it was shown that eutectic formation between ibuprofen and cetostearyl alcohol may account for the unusually high ibuprofen release rates from pellets containing ibuprofen, at levels close to the eutectic composition.

In vitro and in vivo evaluation of sustained-release and enteric-coated microcapsules of diclofenac sodium

AbstractThis work examines the release of diclofenac sodium from ethylcellulose (EC) microcapsules made up of different drug to polymer ratios. The release process was found to follow the Higuchi square root equation and not the zero-order or first order equations. However, for drug to polymer ratio of 1:1, a critical time (θ) was reached beyond which the release rate was lower than that predicted on the basis of the Higuchi square root equation. Dissolution experiments in 0.1N HCL revealed that less than 1.5% of the encapsulated drug was released in 6 h. This finding indicates the suitability of the EC microcapsules for enteric-coated preparations. The in vitro release of diclofenac sodium from microcapsules of different drug to polymer ratios was compared with that from a commercial sustained-release product. A distinct similarity between the release profile of the commercial product with that obtained for the 1:2 drug to polymer microcapsules was noted. The in vivo work included determination of the se...

Mechanical and drug-release properties of atenolol-Carbomer hydrophilic matrix tablets

The potential of three varieties of Carbomer (934,940 and 941) as excipients for hydrophilic matrix tablets containing the hydrosoluble drug atenolol was assessed. The technological variables, type and proportion of polymer and maximum force applied over the compression cycle, were varied according to a 2 × 2 factorial experimental design to investigate their influence on the mechanical and drug release properties of the tablets, identifying those that were significant with the corresponding ANOVA. The influence of each significant variable was quantified by way of multiple stepwise sequential linear regression, which gave, on the whole, acceptable fits. Similar mechanical and release properties were observed for all the varieties of Carbomer. In all cases, drug release profiles fitted Higuchi's square root kinetics and showed strong dependence on the proportion of polymer; the compression force and the microporous structure were not important in this respect.

Design and manufacture of a zero-order sustained-release pellet dosage form through nonuniform drug distribution in a diffusional matrix.

A theoretical basis is presented for the design of dosage forms containing a drug which is initially distributed throughout a noneroding diffusional matrix in a nonuniform manner, for the purpose of achieving zero-order release. Modeling of these dosage forms is based on Higuchi's square root of time diffusional model. Derivations of theoretical drug release profiles for both flat slab and spherical geometry are included. Pellets were prepared utilizing this nonuniform distribution concept using fluid bed suspension layering technology. A gradient pumping system used in conjunction with a specially fabricated miniature fluid bed apparatus was utilized to prepare pellets containing drug nonuniformly dispersed. Actual drug release profiles were obtained for pellets containing drug distributed in the traditional uniform manner and the nonuniform manner described above. Nonuniform distribution of drug in a noneroding diffusional matrix, in theory and practice, is shown to linearize dissolution profiles.

Controlled release of local anaesthetic agents from liquid-solid emulsion gels

The release of lignocaine from emulsion films, made from gelatin and a homologous series of alkanols, is studied. The release profiles are modelled. Using the standard Higuchi square root of time diffusion equation, it is shown that the solution matrix model holds to different extents with the different alkanols, in line with the changes in the drug partition coefficient between the continuous and dispersed phases. Although suspension matrix models have been used for modelling drug release from emulsions, it is shown that this approach is also limited by the fact that as release proceeds, drug activity within the film decreases. The Bruggeman equation which takes account of the permeability coefficient of the drug in both continuous and dispersed phases was useful in predicting drug release at high partition coefficients but its value deteriorates badly as the partition coefficient decreased. Effective diffusion coefficients of lignocaine in the four alkanols are calculated and these show that no single model adequately predicts the observed values.

Controlled release of nifedipine from gelatin microspheres and microcapsules:in vitrokinetics and pharmacokinetics in man

Nifedipine was embedded in a gelatin matrix to develop a prolonged release dosage form. The effects of polymer/drug ratio, size of the beads, cross-linking with formaldehyde and ethylcellulose coating of the gelatin microspheres on the in vitro release rate of the drug were investigated. The data were analysed according to different laws that can govern the release mechanism: first-order, Higuchi square root of time, spherical matrix and zero-order. The in vitro release kinetics of nifedipine from gelatin microspheres were mainly first-order; from formaldehyde hardened gelatin microspheres, complied with the diffusion model for a spherical matrix, and from ethylcellulose-coated gelatin microspheres, obeyed zero-order kinetics. These findings suggest the possibility of modifying the formulation in order to obtain the desired controlled release of the drug for a convenient oral sustained delivery system. The pharmacokinetic parameters of nifedipine, after administration of a single oral dose of nifedipine-loaded hardened gelatin microspheres to volunteers, suggest that the preparation can be considered as a sustained release delivery system for nifedipine.

Dissolution kinetics of commercially available controlled-release theophylline preparations

The in vitro release kinetics of 8 commercially available controlled-release theophylline preparations were studied at pH 1.0 and pH 7.5 using the USP dissolution apparatus with the basket and paddle assemblies. The kinetics of the dissolution process were determined by analyzing the dissolution data using 4 kinetic equations, namely, the zero-order equation, the first-order equation, the Higuchi square root equation and the Hixson-Crowell cube root law. The results obtained at all the dissolution conditions obey both the first order and the Higuchi square root equations showing that the dissolution process is diffusion- and dissolution-controlled. The dissolution process is accompanied by a change in the diffusion pathlength and surface area of the dissolving tablets or beads as indicated from its fitness to the Hixson-Crowell cube root law. This was further substantiated by plotting the values of the first-order dissolution rate constant vs the values of the Hixson-Crowell cube root dissolution rate constants where a straight line was obtained with a slope of approximately one. The results obtained in this work show that the dissolution kinetics of the tested products are independent of the pH of the dissolution medium or the dissolution method employed.

Efficacy of sustained-release radioprotective drugs in vivo.

In previous publications from this laboratory we suggested the use of radioprotective drugs in a sustained-release form as a practical way to cope with their high toxicity and quick metabolism and excretion. Cysteine and cysteamine, well-established radioprotectants, were used as model drugs and compressed at various concentrations (0-65%) into an insoluble tablet matrix, composed of ethylcellulose and stearic acid at various ratios and compression pressures. We demonstrated in vitro that when the release rate of the radioprotectants was measured under nitrogen, the kinetic data conformed with the Higuchi square root of time equation, indicating that the release of both drugs correlates with Higuchi's diffusional mechanism. In the present in vivo study, tablets containing cysteine or cysteamine in a slow-release matrix were implanted, into the stomachs of female rats. The rats were irradiated at various time intervals up to 12 h after implantation and their survival recorded daily. Utilizing a 1:3 ratio of ethylcellulose:stearic acid as a matrix, the protective effect of the drugs was remarkable eight hours after tablet implantation. The results reported indicate that slow-release tablet formulation is a possible method for delivering of radioprotective drugs over an extended period of time.

Square Root of Time Dependence of Matrix Formulations with Low Drug Content

One of the conditions of derivation of the Higuchi square root law is that A/∈ S/2 where A is drug content per cubic centimeter of matrix tablet, ∈ is the porosity, and S is the solubility of the drug in the dissolution medium. In actuality, A/∈ should be larger than S. It is shown in this work that a similar square root equation can be derived when A/∈ < S. Experimental data are presented supporting the equation Q = A(Dt)1/2, where Q is the amount of drug released per square centimeter at time t and D is the diffusion coefficient.

The Higuchi square root equation applied to matriceswith high content of soluble drug substance

It is shown that dissolution of a soluble drug in high concentration from an insoluble matrix follows the Higuchi square root equation, except an initial lag phase and a terminal diffusion phase exist. The parameters (φ) involved in these correspond to one another. The diffusional cross-sectional area is an almost linear function with time. The slopes obtained from square root plots are in reasonable agreement with theoretical values, and the diffusion coefficient for the terminal phase correlates with the actual diffusion coefficient of the drug used (diphenhydramine hydrochloride).