Effect of Eudragit Type Polymers on the Drug Release from Magnesium Oxide Granules Produced by Laboratory Fluidization

Abstract

The differences in the bioavailability of different drug products are most frequently caused by differences in the dissolution rates of the active ingredient. In case of magnesium oxide the drug release can be directly determined by reaction kinetics method based on acid neutralization.

For a more precise study of the factors influencing the kinetical characteristics of the neutralization rates it is advisable to use homogeneous granule fractions. Before the granulation the substance was pretreated with silicone oil. The granulation of the obtained grains having hydrophobe surface was carried out in an AEROMATIC STREA-I type laboratory fluidization equipment with Eudragit polymer solved in isopropyl alcohol.

For determining the acid neutralization kinetics of the granules the “constant pH” method and the Rossett-Rice test were used.

As a result of the granulation the neutralization rate decreased. The granules can be considered as an Eudragit matrix which contains the pretreated magnesium oxide in embedded form. During the chemical reaction the resulted salt (magnesium chloride) leaves the surface of the unreacted magnesium oxide unless having a chemical reaction with the polymer. Meanwhile the residual matrix forms a mesh which increases the viscosity of the solution and the thickness of the diffusion layer. The dissolution rate decreases in both cases.

Under the same conditions the kinetic values of the neutralization change by several magnitudes depending on the utilized methods. In this way different systems of medicine, which alter their reaction capacity according to the expected physiological purposes, can be created.     

Effect of Microsphere Size and Formulation Factors on Drug Release from Controlled-Release Furosemide Microspheres

Controlled-release furosemide microspheres were prepared with various combinations of Eudragit L: Eudragit RS and Eudragit S: Eudragit RS and release of drug from microspheres containing these polymers in different ratios was studied. A wide range of release rates of drug can obtained by a simple change in the ratio of polymers. An increase in Eudragit RS content of polymer microsphere matrix brought about a decrease in the release rate.

On the other hand, the effect of particle size on the drug release rate from furosemide microspheres was also investigated. The effect of microsphere sizes on release rate depends on the type of Eudragit. The decrease in release rates of small microspheres may be due to agglomerate formation. Dissolution data indicated that the release followed Higuchi's matrix model kinetics.     

Evaluation of Spray-Drying as a Method to Prepare Microparticles for Controlled Drug Release

The possibility to obtain microcapsules or microspheres for controlled release by spray-drying is evaluated. Drugs of different solubilities like theophylline and sodium sulfamethazine, with Eudragit RS as coating polymer, are chosen.

The polymer is used, either dissolved in an hydroalcoholic solution or suspended (pseudolatex) in water, in different weight ratios with the drug. The obtained solution or suspension is spray-dried.

Scanning electron microscope analysis of the powders reveals no sign of microencapsulation. Moreover, only a fraction of the particles has a spherical shape.

For each spray-dried powder, a part of the obtained particles is compressed into tablets, and the rest is stored.

Dissolution studies in distilled water at 37 C are performed on powders and tablets.

While the uncompressed microparticles do not give any controlled release, the tablets show an ability in slowing down drug delivery greater than the one obtained with the traditional methods.     

The Release Rate of Indomethacin from Solid Dispersions with Eudragite

The coprecipitates were prepared by a solvent technique using Eudragit E as carrier and indomethacin as a model drug.

X-Ray diffractometry, differential scanning calorimetry (DSC) and wettability tests were employed to investigate the physical state of the studied formulations. Up to 50% of indomethacin can be dispersed in an amorphous state in Eudragit E.

The influence of the pH on the in vitro release of solid dispersions has been evaluated. Because of the good solubility of Eudragit E at pH 1.2 a fast dissolution rate of the drug was observed while a marked delay was noticed at pH 7.5 where the polymer is only permeable to water. At pH 5.8 the kinetics of drug release can be modulated by the drug/polymer ratio. The dissolution rate of the drug can be increased by decreasing its amount in the coevaporate.     

Preparation of Acetaminophen Microcapsules by Coaservation-Phase Separation Method

In this study, it was aimed to prepare prolonged action microcapsules of acetaminophen with short biological half-life by a non-solvent addition method which is one of the conservation-phase separation techniques.

For this purpose, the three different particle size ranges of acetaminophen (0.088-0.177 mn, 0.250-0.354 mn, 0.420-0.500 mn) were used. The solution of polyisobuthylene in cyclohexane as a non-solvent and Eudragit RS and Eudragit RL as coating polymers were also used. The prepared mi crosapsules were compressed by a hydraulic press using different types of direct tableting agents such as Ludipress, Avicel PH 101 and Lactose EP D 30. Dissolution rates of each tablet containing 160 mg of microencapsulated acetaminophen were examined by continuous flow-through cell method

The results of this study showed that the release rate of drug from microcapsules prepared with Eudragit RS was lower than that of microcapsules prepared with Eudragit RL. However different particle size ranges of drug didn't affect significantly the release rate; but different types of direct tableting agents were effective on the release rate of drug.     

Preparation and Evaluation of Sustained-Release Solid Dispersions of Drugs with Eudragit Polymers

Coevaporates of paracetamol and rifampicin with Eudragit polymers of different natures (anionic, cationic, and zwitterionic) were prepared. Determination of dissolution rate of these coevaporates in dissolution media simulating those of the gastrointestinal tract (GIT) revealed that the release rate of paracetamol is retarded from all the coevaporates studied. In this respect, Eudragit L100-SS shows the highest sustainment of drug release, while Eudragit E100 shows the lowest. Conversely, the release of rifampicin from its coevaporates with the anionic Eudragit S100 polymer is more retarded than the corresponding coevaporate with the zwitterionic Eudragit RL100 or from coevaporates with equal mixtures of the two polymers.

Increasing the polymer weight fraction in rifampicin coevaporates with Eudragit S100 up to 0.5 resulted in a corresponding decrease in the dissolution rate. However, beyond this weight fraction, the polymer effect on the dissolution rate of the drug becomes minimized. The results confirmed that the process of dissolution of the two drugs from their coevaporates is a diffusion-controlled release process.

The biological performance of paracetamol coevaporates was monitored in rabbits; paracetamol level in plasma was found to follow first-order kinetics. for all the investigated paracetamol coevaporates, the peak plasma level was less than 50 μg/ml compared to a value of 60, μg/ml for the drug per se. The coevaporates of the drug with Eudragit L100-55 showed slowest rates of absorption and elimination as well as greatest half-peak and half-life times. Biological peformance of rifampicin coevaporates was assessed in human subjects receiving a single oral dose equivalent to 300 mg of the drug. The results depicted sustainment of drug release as a function of polymer weight fraction. A strict correlation was shown to exist between the total amount of drug excreted during 24 hr post dosing of the coevaporates and its in vitro dissolution rate.

The results depicted that paracetamol can be formulated in the form of a coevaporate with Eudragit L100-55 to prepare a more safe sustained-release formulation with minimal side effects, and also revealed the advantages of administration of rifampicin in the form of a coevaporate with Eudragit S100 (4:1) at a single oral dose equivalent to 600 mg of drug.     

Carboxymethylstarches in Wet Granulation

Commercialized carboxymethystarches (CMS) are both carboxyme-thylated and cross linked potato starch.

The influence of carboxymethylation and cross linkage on the disintegrating properties of starch are studied.

Tablets are made with acetaminophen as drug, Emcompress as diluant, Magnesium stearat as lubricant, and potato starch or its derivatives as disintegrants.

Tablets are prepared by direct compression or by wet granulation with the disintegrant intervening only in internal phasis.

Five disintegrants were studied, with two different concentrations:

native potato starch

potato starch simply cross linked

potato starch simply carboxymethylated

two potato starches both cross linked and carboxymethylated at two different degrees

Compressibility of powders blending and grain for compression are discussed.

The hardness, the tablet disintegration and the rate of drug dissolution are studied.

The results showed that the simply carboxymethylated starch has a totally different behaviour after direct compression or wet granulation. The poor results after wet granulation could be imputed to the bursting of starch granules during grain drying. Since it has lost its granular structure, the carboxymethylated starch will only allow a poor disintegration and a slow dissolution of the drug.

A very similar behaviour of native and simply cross linked starch: the results of which are bad for tablets either prepared by wet granulation or direct compression.

A very similar behaviour of the starches both carboxymethylated and cross linked, allowing a very good disponibility, either with tablets prepared by direct compression or wet granulation. These experiments prove :

the need for an sufficient cross linkage for CMS in a wet granulation process     

Optimal Massing Liquid Volume Determination by Energy Consumption Measurement: Study of the Influence of Some Physical Properties of Solvents and Products Used

This study tried to investigate, by the power comsumption technique, the influence of the powder's and solvent's properties on wet granulation.

It could be shown that the required amount of granulation liquid decreases when the particle size of the powder to be granulated increases. This relationship is however only true when the particle size distribution of the powder to be granulated is rather narrow.

Powders having the same solubility in different solvents require the same optimal liquid quantity for granulation, but the properties of resulting granules depend on surface tension and wetting properties of the solvent.

When the powder to be granulated contains crystallisation water, the temperature rising in the mixer can be sufficient to liberate this water, which must be taken into account in the optimal granulation liquid requirement.

The effect of a macromolecular binder (PVP, HPMC) has also been studied: the optimal liquid quantity required changes with the kind of binder used and the manufacturing process (binder used in solution or added as dry powder).

It was also shown that in the case of lactose, the optimal quantity of PVP or HPMC can be determined from the power consumption records and from the granules friability studies     

Dissolution OP Nalidixic Acid Solid Dispersions 1. Nal-Hydrotropic salts and NAL-Hyrj systems

The effect of solid dispersion techniques on the dissolution rate of nalidixic acid powder was investigated.

The thermodynanic parameters of all tested systems revealed a spontaneous reaction with no complex affinity to the drug.

Hexamine and sodium citrate showed very powerful solubilizing capacity towards NAL powder.

For piperazine citrate in spite of its low interaction with NAL in the aqueous phase, it proved to be efficient carrier in the solid dispersion system. Hyrj 59 caused the greatest enhancement in NAL dissolution rate of all carriers examined. After 5 minutes, the RDR of the four-fold NAL-HyrJ 59 co-precipitate system was 16.5 times the untreated drug.     

Effect of Granulating Method on Content Uniformity and Other Physical Properties of Granules and their Corresponding Tablets. II

Various properties of dexamethasone and sulfadiazine granules and tablets prepared by microgranulation, slugging, wet granulation and direct compression were compared.

The dexamethasone tablets showed comparable disintegration rates by all methods. The sulfadiazine tablets prepared by slugging did not meet the USP XIX limit, whereas those by microgranulating were satisfactory.

It was found that granule-homogeneity was not only dependent on the particle size and distribution, but also dependent on the granulating method. For either drug, the microgranulating procedure gave the best weight and content uniformity.     

Matrix Type Tablet Formulation for Controlled Release of Highly Water Soluble Drugs

Matrix type formulations with dicalcium phosphate dihydrate (DCPD) using a polymeric binder (Eudragit RSPM®) to obtain controlled release of highly water soluble drugs has been investigated.

The drug, DCPD and Eudragit RSPM® were granulated using isopropyl alcohol with and without a plasticizer (Diethyl phthalate, DEP). Addition of Eudragit did not appear to affect the release profile. However, addition of a plasticizer had a significant effect on the rate of release. The release appears to follow first order kinetics and the rate constant decreased linearly with increasing DEP concentration.

A directly compressible mixture was also formulated by coating DCPD particles with DEP with and without Eudragit RSPM®.     

Carbamazepine Modified Release Dosage Forms

The preparation of sustained release dosage forms of Carbamazepine (anti-epileptic drug characterized by a very low water solubility and by a short half life on chronique dosing) was carried out.

These formulations were obtained in two different steps:

a) modified release granules were prepared by the loading of cross-linked sodium carboxymethylcellulose (swellable polymer), with the drug and an enteric polymer. Cellulose acetate phthalate, methacrylic acid - methacrylic acid methyl ester copolymer (usually employed as enteric coating agents) and cellulose acetate trimellitate (a new enteric polymer) were used in different weight ratios.

b) some sustained release dosage forms were prepared tabletting physical mixtures of the modified release granules with different weight ratios of hydroxypropylmethylcellulose.

In vitro dissolution tests of modified release granules in gastric fluid (USP XXI) showed a modulation of the drug release, while in intestinal fluid (USP XXI) a quick drug dissolution was observed.

In vitro dissolution tests of sustained release dosage forms, performed varying during the test, the pH of the dissolution medium, (hydrochloric acid pH 1 from 0 to 2 hours and phosphate buffer pH 6.8 from 2 to 18 hours) showed that the determining factors in the controlling release of the drug are: the type and amount of enteric polymer constituting the granules and the amount of hydroxy-propylmethylcellulose mixed with them.     

Studies on Drug Release from a Carbomer Tablet Matrix

The purpose of this investigation was to study the drug release mechanisms for tablet matrices of carbomer. Carbomer is a polymer of acrylic acid which is cross-linked with polyalkenyl polyether. The drug and the carbomer were blended and directly compressed into tablets using a laboratory Carver press. The influence of the level of carbomer, the type of drug, and the pH of dissolution media were investigated by measuring drug release kinetics. In general, the release of a relatively neutral molecule (e.g. theophylline) in the pH 7.2 phosphate buffer solution appears to exhibit nearly zero-order kinetics via a diffusion-controlled mechanism for all polymer levels studied (10-85%).

The drug release process based on diffusion can be described by the general expression:

M_t = k₁t^1/2 + k₂t

where M, represents the amount of the drug released at time t, and k₁, k₂ are related to kinetic constants characteristic of the drug delivery systems. The release kinetics are modified when an ionic species, such as sodium salicylate, is incorporated into the tablet matrix.     

In Vitro Adsorption of Propranolol Hydrochloride by Various Antacids

The purpose of this study was to investigate by in vitro methods whether an interaction takes place between propranolol hydro-chloride and adsorbents when antacids are taken concomitantly with the beta-blocker or when excipients having adsorbent properties are present in formulations of the drug products containing propranolol hydrochloride.

Specific surface areas of magnesium trisilicate, magnesium oxide, magnesium hydroxide, dihydroxy aluminum sodium carbonate, magnesium carbonate and kaolin were calculated from nitrogen adsorption isotherm using single pint method and it was found. that magnesium trisilicate has the largest specific surface area.

The adsorption of propranolol hydrochloride to these adsorbents was investigated by in vitro methods. The adsorption isotherms were drawn and the adsorptive capacities of the adsorbents were calculated from the slopes. It was found that magnesium tri-silicate, magnesium hydroxide arid dihydroxy aluminum sodium carbonate possess the highest adsorptive capacities while kaolin and magnesium carbonate possess the lowest.

The results of the adsorption studies indicate that the concomitant use of propranolol hydrochloride and the above mentioned adsorbents could affect the bioavailability of the beta-blocker adversely.     

Aqueous Acrylic Resin for Coating an Original Theophylline Granulate

Spherical granules of theophylline, microcrystalline cellulose and lactose are prepared in a high speed granulator using an original method. Successively, the fraction of granules selected is coated with Eudragit RS 30D in a fluid bed coating machine using the bottom spray system and the wurster column. Finally, these granules are compressed into tablets of different hardnesses.

Dissolution studies reveal a zero order release of theophylline from the coated granules. After compression, the kinetics is modified but the tablets remain efficient to control the theophylline release during 8 hours.     

Studies on Sustained release XI: Lipid Granules of Sulfamethizole

The aim of this study was to prepare a sustained release granule of sulfamethizole, employing hydrogenated castor oil (Cutina HR). After the dosage form design was made, different formulations were prepared as granules by the fusing technique. The granules manufactured were analysed with sieves between 0.5 and 1 mm openings. The fractions obtained were tested for dissolution rate for a period of seven hours with fluids of varying pHs with the continuous flow-through cell apparatus.

Upon the kinetic evaluation of dissolution data, it was seen that the target release rates were achieved. The results showed that, the drug release rates increase with increasing amounts of PEG 4000 added to the formulations; up to a certain percentage. No increase beyond this point was noticed.

The drug release rates mostly followed zero-order and modified Hixson-Crowell kinetics.     

Eudragit RL and RS Pseudolatices: Properties and Performance in Pharmaceutical Coating as a Controlled Release Membrane for Theophylline Pellets

Theophylline Active pellets were coated with Eudragit RL and RS pseudolatices in a fluidized bed. The effects of polymer ratio, additional oven drying, addition of dispersed solids, and addition of water miscible organic solvents on sustained drug release through the lates film were determined by using a modified U.S.P. Paddle dissolution method.

The release rate of theophylline can be varied by changing the polymer ratio. permeability to the drug increases with an increase in the content of Eudragit RL. Additional oven drying at 60°C for 10 hours caused no significant change in the dissolution profiles. The addition of dispersed solids such as talcum and silica resulted in an increase in drug release rate. There is no significant change in dissolution profiles when 50% methanol or acetone was added to the Eudragit RS pseudolatex.     

Controlled Release from Glycerol Palmito-Stearate Matrices Prepared by Dry-Heat Granulation and Compression at Elevated Temperature

Diprophylline release from glycerol palmito-stearate “precirol” matrices containing different direct compression (DC) excipients, with variable dissolving/disintegrating ability, is investigated. The matrices are formed by employing dry-heat granulation and compression at elevated temperature.

Greater drug release prolongation is achieved with the dissolving DC excipients than with the swelling ones. The release is described on the basis of two biexponential first order models and the Weibull function as well.

The effect of compression conditions (temperature and pressure) on the drug release is found to be related to the compaction behaviour of the DC excipients, i.e. plastic deformation or fragmentation.     

Manufacturing Method of Stable Enteric Granules of a New Antiulcer Drug (Lansoprazole)

In our previous studies, we clarified that enteric granules are an appropriate dosage form for lansoprazole, and we demonstrated that enteric granules could be produced when magnesium carbonate was added as an alkaline stabilizer.

These granules however were found to be some unstable under severe conditions because some of the excipients are incompatible with lansoprazole. We therefore attempted granulation not using these incompatible excipients and could obtain more stable enteric granules using a centrifugal fluid-bed granulator instead of an extruder-spheronizer. We also compared the absorption and dissolution properties of the enteric granules manufactured by these two methods.     

Wet Granulation in a Small Scale High Shear Mixer

Wet granulation of lactose and corn starch in a 10 litre high shear mixer was examined. The effect of the amount of water added, granulation time and impeller speed on five properties of the granules was investigated by a response surface design.

It was shown that moisture level as a major effect on geometric mean diameter and flow rate of the granules. The impeller speed markedly influences the geometric mean diameter, geometric standard deviation, compactability index and percentage of granules smaller than 1250 μm. Finally the granulation time has an evident influence on compactability index.

Theoretical optimum conditions were obtained for the five response variables and are comparable with the experimental results.