Solid Dispersion Granules Research Articles

Development of novel sustained-release system, disintegration-controlled matrix tablet (DCMT) with solid dispersion granules of nilvadipine

The goal of this study is to develop a novel sustained-release (SR) system for poorly water-soluble drugs by applying solid dispersion (SD) technique for improving the solubility. The developed SR system, disintegration-controlled matrix tablet (DCMT), consists of hydrogenated soybean oil (HSO) as wax and SD granules containing low-substituted hydroxypropylcellulose (L-HPC) as a disintegrant. In this study, nilvadipine (NiD) was chosen as a model compound. Sustained-release profiles of NiD from DCMT were identically controlled in several dissolution mediums in spite of varying pH and agitation speed. The release of NiD from DCMT was sustained more effectively by increasing the amount of wax or by decreasing the amount of disintegrant, and supersaturation of NiD was achieved without any re-crystallization in dissolution medium. The release rate of NiD from DCMT was controlled by the disintegration rate of tablet. The release profile of NiD was described by the Hixson–Crowell's model better than zero-order kinetics, first-order kinetics and Higuchi's model, which supports that the release of NiD from DCMT is regulated by the disintegration of the tablet. From this study, it was clarified that DCMT was one of the promising SR systems applying SD for the poorly water-soluble drugs.

The use of an in vitro dissolution and absorption system to evaluate oral absorption of two weak bases in pH-independent controlled-release formulations

The aim of this study was to compare the oral absorption of two weak bases including their pH-independent controlled-release preparations using an in vitro evaluation system. This system is able to simulate dissolution of drugs, pH change and permeation of drugs through the epithelial cell membrane in the gastrointestinal tract. Albendazole-polymers solid dispersion and pH-independent sustained-release granules of dipyridamole were prepared by using a solvent method. Elution profiles and predicted absorption of these preparations in gastric pH conditions similar to those in healthy subjects and patients with achlorhydria were compared with those of a physical mixture and commercial tablets. When a physical mixture or commercial tablets were used, the elution profile and predicted absorption of both albendazole and dipyridamole were extremely pH-dependent. On the other hand, when a solid dispersion and granules were used, elution and predicted absorption were not affected by changes in pH of the flowing solution in a drug-dissolving vessel. These results are in agreement with the results of our previous in vivo study using gastric acidity-controlled rabbits. Our results suggest that this in vitro system is useful for the evaluation of oral absorption of pH-independent controlled-release preparations.

Controlled release of drug via methylcellulose-carboxyvinylpolymer interpolymer complex solid dispersion

The purpose of this research was to examine the controlled release of phenacetin (PHE) from solid dispersion by the formation of an interpolymer complex between methylcellulose (MC) and carboxyvinylpolymer (CP). The PHE/polymer composition ratio was fixed at 20:80 (w/w) in the solid dispersion. The effect of the MC/CP ratio and molecular weight of MC on the PHE release was studied. The release of PHE from the solid-dispersion granules depended on the MC/CP ratio, with a ratio of 50:50 giving the lowest rate of release. In aqueous solution, this MC/CP ratio resulted in the lowest transmittance, suggesting a maximal extent of interpolymer complex formation between MC and CP. Furthermore, at a MC/CP ratio of 50:50, the release of PHE from the solid dispersion granules decreased as the molecular weight of the MC increased, reaching a plateau at molecular weights >or=180,000. The contributions of diffusion and polymer relaxation to PHE release increased as the molecular weight of the MC increased. This study shows that it is feasible to control the release of PHE from MC-CP solid dispersion granules by modulating complex formation between MC and CP, which can be accomplished by altering the MC/CP ratio and the molecular weight of MC.

Application of nilvadipine solid dispersion to tablet formulation and manufacturing using crospovidone and methylcellulose as dispersion carriers.

Nilvadipine (NIL) solid dispersion using crospovidone (Cross-linked-N-vinyl-2-pyrolidone, cl-PVP) and methylcellulose (MC) as carriers was applied to tablet formulation. Several grades of cl-PVP and MC were used, and their influence on tablet properties such as hardness, disintegration, dissolution and chemical stability were investigated. The agitation granulation method was used for preparation of solid dispersion granules, and the granules were compressed using a rotary tableting machine, and finally the obtained tablets were coated with film. As the particle size of cl-PVP decreased, hardness and apparent solubility were increased, while dissolution rate was lowered. When a higher viscosity grade of MC was used, hardness and dissolution rate were increased, and apparent solubility did not change. All batches of tablets were chemically stable at 40 degrees C, 75% relative humidity (R.H.) for six months. Finally, tablets with enhanced dissolution properties were obtained by using Polyplasdone XL-10 and Metolose SM-25 as the grades of cl-PVP and MC, respectively. These formulation tablets showed higher solubility and dissolution rate during storage as well as initial indicating good physical stability.

Hydrogen bonding with adsorbent during storage governs drug dissolution from solid-dispersion granules.

To investigate changes in drug dissolution on storage of ternary solid-dispersion granules containing poorly water-soluble drugs. Hot-melt granulation was used to prepare ternary solid-dispersion granules in which the drug was dispersed in a carrier and coated onto an adsorbent. Seven drugs including four carboxylic acid-containing drugs (BAY 12-9566, naproxen, ketoprofen, and indomethacin). a hydroxyl-containing drug (testosterone), an amide-containing drug (phenacetin), and a drug with no proton-donating group (progesterone) were studied. Gelucire 50/13 and polyethylene glycol (PEG) 8000 were used as dispersion carriers whereas Neusilin US2 (magnesium aluminosilicate) was used as the surface adsorbent. Two competing mechanisms have been proposed to explain the complex changes observed in drug dissolution upon storage of solid dispersion granules. Conversion of the crystalline drug to the amorphous hydrogen bonded (to Neusilin) state seems to increase dissolution, whereas, the phenomenon of Ostwald ripening can be used to explain the decrease in drug dissolution upon storage. The solubility of the drug in Gelucire is a crucial factor in determining the predominant mechanism by governing the flux toward the surface of Neusilin. The mobility for this phenomenon was provided by the existence of the eutectic mixture in the molten liquid state during storage. A competitive balance between hydrogen bonding of the drugs with Neusilin and Ostwald ripening determines drug dissolution from solid-dispersion granules upon storage.

Mechanism for Further Enhancement in Drug Dissolution from Solid-Dispersion Granules upon Storage

The present study was performed to investigate the further increase in drug dissolution on storage of ternary solid-dispersion granules containing poorly water-soluble drugs. Ternary solid-dispersion granules of the drug, a dispersion carrier, and a surface adsorbent were prepared using hot-melt granulation. Two proton-donating drugs, BAY 12-9566, naproxen, and a nonproton-donating drug, progesterone, were studied. Gelucire 50/13 and polyethylene glycol 8000 were evaluated as solid-dispersion carriers with low melting point. Neusilin US2 (magnesium aluminosilicate), a proton acceptor, was used as the surface adsorbent. The proposed mechanism for further increase in drug dissolution (BAY 12-9566 and naproxen) on storage at 40°C/75% RH (relative humidity) is based on hydrogen bonding between the proton-donating drugs and the surface adsorbent, Neusilin US2 (proton acceptor). We propose that there is enough mobility in the solid-dispersion granules at elevated temperatures of storage to allow an increase in the ratio of the hydrogen bonded drug to the crystalline drug. These changes are mediated through the saturated solid solution state, and manifest themselves as increased drug dissolution upon storage. Fourier transform infrared spectroscopy studies are indicative of an increase in the amount of drugs (BAY 12-9566 and naproxen) hydrogen bonded to Neusilin on storage. A corresponding decrease in the crystallinity of these drugs was measured using x-ray powder diffractometry. Granules containing progesterone (a nonproton-donating drug) do not show an increase in the amount of drug hydrogen-bonded to Neusilin upon storage. In contrast to the proton-donating drugs, decreased drug dissolution was found on storage of progesterone-containing granules.

Preparation of Solid Dispersion Granules of a Therapeutic Drug of Cerebrovascular Disorders and Its Evaluation

Preparation of Solid Dispersion Granules of a Therapeutic Drug of Cerebrovascular Disorders and Its Evaluation

Studies on Production of Higher Functional Pharmaceutical Preparations by Using Various Additives. III. Application of Hollow Glass Beads for Intragastric Floating Granules.

In our previous paper, we developed intragastric floating and sustained release granules using the characteristically porous structure of calcium silicate. In this paper, we investigated the preparation of floating granules using hollow glass beads (GB, density 0.15 g/cm3) as a carrier and introducing them to the solid dispersion in order to produce a higher floating ability. A 20/5/75 weight ratio of oxprenolol hydrochloride (OXP) as a model drug, hydroxypropylcellulose (HPC) and ethylcellulose (EC) was dissolved in ethanol. Zero, 20, 40, 60 and 80 weight percent of GB to the total weight of OXP, HPC and EC were added to the ethanol solution, and the solvent was then evaporated by rotating the vessel at 50°C. Several types of solid dispersion which contain suspended and dispersed GB were obtained. The granules having different GB contents were obtained after being dried at 80°C in vacuo and were crushed using a coffee mill for sieving. The density, floating property and drug release profile of the granules were than studied. The density of granules without GB, namely the solid dispersion granules, was 1.18 g/cm3 and therefore did not have floating properties. The densities of all types of granules containing GB were less than 1 g/cm3 and these granules floated for a long time in the floating test. It was found that release rates of OXP from granules decreased with decreasing GB content, since the surface area of granules was decreased and a thick layer of solid dispersion was formed. These results suggest that it is possible to prepare floating granules by using GB.

Preparation, Physical Characterization, Mechanisms of Drug/Polymer Interactions, and Stability Studies of Controlled-Release Solid Dispersion Granules Containing Weak Base as Active Substance

AbstractVerapamil hydrochloride solid dispersion granules were prepared using solvent evaporation technique. Ethyl cellulose, hydroxypropyl cellulose, Eudragit L or Eudragit S were used as polymers for controlling the dissolution rate of the drug substance, and to avoid the continuous decrease of drug dissolution rate at higher pH values. By incorporating Eudragit L in ethyl cellulose network it is possible to prepare controlled-release formulation with increased release rate of active substance (weak base) at higher pH values without causing abrupt drug release at lower pH values. The release rate at low pH values was not highly influenced by Eudragit L content. The behavior of Eudragit L and Eudragit S in coprecipitates was different relating to the solubilization effect and the release of active substance. In order to understand the drug release mechanism better, the release data were tested assuming Higuchi model and first-order kinetic model. Since the calculated correlation coeflcients were very clo...

Physical Characterization and Dissolution Properties of Verapamil. HCI Coprecipitates.

Verapamil hydrochloride coprecipitates were prepared using solvent-evaporation technique. Ethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose phtalate HP 55 were used as polymers. The solid dispersions obtained were grounded and sieved to prepare solid dispersion granules. The dissolution behavior of solid dispersion granules was studied using buffer solutions with pH 1.5; 6.8 and half-change method during 24 hours. The drug release rate was found to be dependent on the ratio of the polymers in coprecipitates. In order to understand the drug release mechanism better, the release data were tested assuming common kinetic models. The best fit kinetic model was diffusion model and the dissolution rate constants calculated using Higuchi equation, demonstrated that dissolution rate increased with increasing the ratio of HPMCP HP 55 in coprecipitates. Physical characterization was made using X-ray diffractometry, IR spectrophotometry and DTA studies. Prepared coprecipitates were X-ray amorphous. Also, after nine months real time studies they remain amorphous, with no changes in their IR spectra and DTA curves. The dissolution rate of the test dispersions showed no significant changes during the stability studies, reflecting the stability of X-ray amorphous drug phase.

Application of the Solid Dispersion Method to the Controlled Release of Medicine. V. Suppression Mechanism of the Medicine Release Rate in the Three-Component Solid Dispersion System.

Solid dispersions were prepared with a highly water soluble medicine (oxprenolol hydrochloride (OXP)), water insoluble ethylcellulose (EC) and water soluble hydroxypropyl cellulose (HPC). The release profiles of OXP from the solid dispersion granules at various composition ratios of the components, and the suppression mechanism of the release rate in the OXP-EC-HPC system, were studied.The release rate of OXP reached a minimum level at the HPC composition ratio of 5-10%. It was difficult to control the release rate with more than 10% HPC. It was found that a marked decrease in the release rate at the HPC composition ratio of 5-10% was caused by the formation and retention of the swelled phase of HPC in the EC matrix. At more than 10% HPC, because OXP molecules enclosed by HPC molecules or incorporated in the swelled HPC phase increased and most of the OXP molecules were released together with HPC by erosion, the release rate of OXP increased drastically in the early stages of the release process. At the OXP composition ratio of 30% or more, the diameter and volume of the pores formed by the OXP release markedly increased, since the aggregates of OXP molecules that showed crystallinity began to be formed in the solid dispersion.

Application of the Solid Dispersion Method to the Controlled Release of Medicine. VI. Release Mechanism of a Slightly Water Soluble Medicine and Interaction between Flurbiprofen and Hydroxypropyl Cellulose in Solid Dispersion.

Solid dispersion (SD) was prepared with a slightly water soluble medicine (flurbiprofen (FP)) and a water soluble polymer (hydroxypropyl cellulose (HPC)) having five grades of different molecular weights. The release mechanism of FP from the SD granules and the interaction between FP and HPC in the SD were studied.The release rate of FP from the SD granules increased with decreasing HPC molecular weight or increase in the composition ratio of HPC. The powder X-ray diffraction patterns and DSC curves suggest that FP exists in an amorphous state in the SD. The IR spectra show an interaction of hydrogen bonding between FP and HPC. The percent of FP forming a hydrogen bond with HPC in the SD increased with decreasing HPC molecular weight or increase in the composition ratio of HPC. A linear relationship was found between the release rate of FP and the percent of the hydrogen bonded FP in the SD. An increase in the dispersibility of FP and the degree of mixing of FP and HPC will cause an increase in the effective surface area of FP and HPC for dissolution, thus increasing the release of FP and the percent of hydrogen bonded FP.

Application of the solid dispersion method to the controlled release of medicine. III. Control of the release of slightly water soluble medicine from solid dispersion granules.

In order to control the release rate of slightly water soluble medicine by using the solid dispersion (SD) method, the SD was prepared with a water soluble polymer and the slightly soluble medicine, and the medicine release from the solid dispersion granules was studied. The SD granules were prepared by the evaporation of ethanol after dissolving into ethanol a slightly water soluble medicine (flurbiprofen (FP)) and soluble polymers (hydroxypropyl cellulose (HPC)). HPC has four grades of molecular weight. The release rate of FP from SD was measured by the rotating basket method (JP XII). The release rate of FP from the SD granules was markedly larger than that from FP powder, and it was larger with a lower HPC molecular weight. It is speculated that these results were mainly based on the molecular dispersion state of FP and HPC in SD.

Application of the solid dispersion method to the controlled release of medicine. IV. Precise control of the release rate of a water soluble medicine by using the solid dispersion method applying the difference in the molecular weight of a polymer.

Solid dispersions were prepared by the evaporation of ethanol after dissolving into ethanol a water soluble medicine (oxprenolol hydrochloride (OXP)), four grades of water insoluble ethylcellulose (EC) and four grades of water soluble hydroxypropyl cellulose (HPC), both having different molecular weights. The precise control of the release rat of a water soluble medicine by applying the difference in the molecular weight of polymers was attempted. The pore size distribution in solid dispersion granules was measured before and after the dissolution test by mercury intrusion porosimetry to clarify the mechanism of medicine release from the granules when the molecular weights of polymers were different. The state of medicine in the solid dispersions was analyzed by thermal analysis and X-ray diffractometry. Although the difference was slight, the release rate of OXP from the granules of the OXP-HPC system decreased as the molecular weight of HPC increased. The release behavior of OXP in the OXP-EC system was scarcely affected by the molecular weight of EC. However, in the OXP-EC-HPC system, the release rate markedly decreased with a larger molecular weight of EC. It was thought from the results of the pore size distribution that there were two types of release routes for OXP; dissolving directly into the dissolution medium and diffusing in the swelled HPC phase, caused by the addition of HPC. The decrease in the release rate of OXP in the OXP-EC-HPC system was caused by the increase in the ratio of OXP dissolving via the latter route, occurring with a larger molecular weight of EC. These results suggest that it is feasible to precisely control the release of a water soluble medicine by varying the molecular weight of the polymers in the solid dispersion.

Application of the Solid Dispersion Method to Controlled Release of Medicine. II. Sustained Release Tablet Using Solid Dispersion Granule and the Medicine Release Mechanism.

In our previous paper, the utility of the solid dispersion for the control of medicine release was studied and the solid dispersion was prepared by the evaporation of ethanol after dissolving a water soluble medicine (oxprenolol hydrochloride), soluble hydroxypropyl cellulose and insoluble ethylcellulose into ethanol. In this paper, the tableting of the above mentioned solid dispersion granule and mechanism of medicine release from this solid dispersion granule were studied. Microcrystalline cellulose was used as the excipient in this tableting. The disintegration time, crushing strength and porosity were measured for the obtained tablets. The pore size distribution in the solid dispersion granules was measured before and after the dissolution test with a mercury porosimeter to clarify the mechanism of medicine release from the granules. The state of medicine in the granules was analyzed by infrared spectrometry, thermal analysis and X-ray diffractometry.As a result, it was clarified that oxprenolol hydrochloride in ethylcellulose was released from the granules by diffusing and dissolving into the medium in the channels formed by the dissolving of hydroxypropyl cellulose and oxprenolol hydrochloride, as inferred in the previous paper. Furthermore, the compression pressure and pH scarcely affected the dissolution behavior of oxprenolol hydrochloride from the granules. It was thought that the homogeneity of the content of oxprenolol hydrochloride in the granules was very high, and the dissolution rate from the granules could be controlled by the particle size of the granules and the composition ratio of ethylcellulose and hydroxypropyl cellulose in the granules. These results suggest the solid dispersion granule and the tablet prepared with this granule are useful for the sustained release granule and tablet.

Application of the solid dispersion method to controlled release of medicine. I. Controlled release of water soluble medicine by using solid dispersion.

The release of medicine from solid dispersion which was prepared by evaporation after dissolving or suspending water-soluble medicine into an organic solvent was studied. Oxprenolol hydrochloride was used as a water soluble medicine. Eudragit RS, methylcellulose, ethylcellulose, polyvinylpyrrolidone, hydroxy propyl cellulose and pullulane were used as the polymers. These polymers and oxprenolol hydrochloride were suspended in or dissolved into ethanol under heating, and the ethanol in these solutions was evaporated to solid dispersion. Solid dispersion granules were prepared by grounding and sieving the solid dispersions obtained. The dissolution behavior of oxprenolol hydrochloride was studied by the dissolution test (JP XI).As a result, it was clarified that in a solid dispersion granule composed of 25% oxprenolol hydrochloride, 70% ethylcellulose and 5% hydroxypropyl cellulose, the dissolution behavior of oxprenolol hydrochloride from this granule was of a leaching type for the matrix and was not affected by pH. Furthermore, various dissolution behaviors could be obtained by changing the particle size and the ratio of the polymer in the granule. These results suggest that this granulating method by the evaporation of the solvent is useful in preparing a sustained release preparation.