Granulating Fluid Research Articles

Effect of Formulation and Process Variables on the Release Behavior of Amoxicillin Matrix Tablets

The sustained release of amoxicillin is desired to be confined to the upper gastrointestinal tract to treat certain kind of infections. In vitro dissolution, at pH 1.2, of amoxicillin sustained release tablets has been studied varying the proportion of Carbopol 971P NF and sodium alginate as well as the ethanol/water proportion in the granulation fluid. Mt, the amount of drug released at time (t) and defined in terms of the total drug released over a long time period (Minf), was described by Mt/Minf = ktn. Matrices with increasing proportions of sodium alginate showed increasing values of the exponent indicative of the release mechanism (n) and increasing release constant values (k). This is attributed to a drop in the coherence of the polymeric matrix with increasing alginate proportions that produces an increasing polymer relaxation and erosion. Decreasing Carbopol 971P NF proportions reduce the amount of dissolved polymer during granulation, producing a lesser obstruction of amoxicillin dissolution. Alginate proportions of 80% produce near zero order release profiles. Granules obtained with increasing ethanol proportions showed increasing release constant values and a minor change in the exponent (n) values. This is considered a result of lower polymer dissolution during granulation that allows a lesser matrix coherence and a greater amoxicillin dissolution. Alginate matrices granulated with different ethanol/water proportions showed no significant changes in the amoxicillin release profile. There is a trend toward increasing floating times with increasing Carbopol 971P NF proportions.

Production of chitosan pellets by extrusion/spheronization

Chitosan pellets were successfully prepared using the extrusion/spheronization technology. Microcrystalline cellulose was used as additive in concentrations from 70 to 0%. The powder mixtures were extruded using water and diluted acetic acid solution in different powder to liquid ratios. The effects on bead formation using water and different acetic acid concentrations and solution quantities were analysed. Also, the morphological and mechanical characteristics of the obtained beads were investigated. With demineralized water as granulation fluid, pellets with a maximum of 50% (m/m) of chitosan could be produced. The mass fraction of chitosan within the pellets could be increased to 100% by using diluted acetic acid for the granulation step.

Use of a Moist Granulation Technique (MGT) to Develop Controlled-Release Dosage Forms of Acetaminophen

The moist granulation technique (MGT), which involves agglomeration and moisture absorption, has only been applied to immediate-release dosage forms. Our results indicate that MGT appears to be applicable in developing a controlled-release formulation. A small amount of granulating fluid (water) was added to a powder blend to activate a dry binder (such as polyvinylpyrrolidone [PVP] at 2% and 3.6%) and to facilitate agglomeration. Then, a moisture-absorbing material (microcrystalline cellulose [MCC]) was added to absorb any excess moisture. By adding MCC in this way, a drying step was not necessary. Acetaminophen (APAP) was the model drug, with diluents lactose FastFlo® and dicalcium phosphate. Hydroxypropylcellulose (HPC) was used as the controlled-release agent. The MGT was compared to conventional wet granulation (WG) and direct compression (DC) processing methods. The results indicate that MGT appears to be applicable in developing a controlled-release formulation. Particle size distribution of MGT and WG batches containing 3.6% PVP is similar.

Formulation and process considerations for beads containing Carbopol® 974P, NF resin made by extrusion-spheronization

Preliminary studies revealed that Carbopol® 974P, NF resin could be incorporated into beads manufactured by extrusion and spheronization, and can slow the release of a highly water soluble drug if calcium chloride was included in the granulating fluid to reduce the tack of the wetted polymer. In this study, the same approach was used to produce high quality chlorpheniramine maleate beads with a prolonged release duration. Because of the complex nature of the extrusion and spheronization process and the various components in the bead formulations, a statistically sound factorial experiment was considered for this study. A one-half fraction of a two level factorial design with three center points was employed to estimate the effects of simultaneously modifying multiple process and formulation variables, including the Carbopol® concentration, calcium chloride concentration, water content, and the spheronization speed and time. Product yield, average bead roundness, and the drug release profile were selected as responses. Increasing the Carbopol® content across the experimental range resulted in a significant ( P<0.05) reduction in the percentage drug released at 25, 40, and 60 min. Results suggest that combining the conditions of high Carbopol®, high water, and low calcium chloride levels with low spheronization speeds at long spheronization times produce the highest quality bead with the longest drug release duration.

Evaluation and Comparison of a Moist Granulation Technique to Conventional Methods

In the moist granulation technique (MGT), a minimum amount of liquid is used to activate a binder in a planetary mixer. Then, any excess moisture is absorbed by the addition of a moisture-absorbing substance. In the experiments described below, acetaminophen (APAP) was the model drug; polyvinylpyrrolidone (PVP) and microcrystalline cellulose (MCC) served as the binder and moisture-absorbing material, respectively. Water was used as the granulating fluid. Comparison of the MGT with direct compression (DC) and wet granulation (WG) methods was accomplished by sieve analysis (particle size) and density measurements. Moist granulation yielded an increase in particle size compared to direct compression; these results are comparable to those from the traditional wet granulation after drying and screening. Based only on the particle size, moist granulation appears comparable to conventional wet granulation for this formula. The moist granulation technique appears to have potential for the development of controlled-release formulations.

Investigations of the interactions between a novel polysaccharide controlled release matrix and model compounds using ESR

Interactions between TIMERx, a novel polysaccharide based controlled release system, and model compounds are studied using electron spin resonance (ESR). Mimicking the incorporation of a low dose drug into the matrix it is initially found that mixing the crystalline compound into the components of the system provides insufficiently even mixing, with poor dispersion of the agent. A similar situation pertains on the mixing of compounds with pre-formed granules of the TIMERx base. Wet granulation of the system, where the compound was dissolved in the granulating fluid prior to granulation provides, ideal distribution throughout the matrix, with no interaction between spin labels at the molecular level, of all the model compounds throughout the matrix. It is found that two of the four model compounds interact with residual micellar water in the matrix structure and two, despite having very similar structures and solubilities, do not. It is proposed that the two non-dissolved compounds, which have a greater capacity for hydrogen bonding, are binding more strongly to the polysaccharide components of the matrix. Evidence also suggests that this interaction can protect the compounds from reduction by dextrose. This interaction is unaffected by the drying method of the granules and does not occur during the tabletting process. The results suggest that ESR is a useful technique for measuring interactions between low molecular weight compounds and excipients.

Effect of Drug, Formulation, and Process Variables on Granulation and Compaction Characteristics of Heterogeneous Matrices: Part II. HPMC and PVP Systems

AbstractA heterogeneous matrix comprising hydroxypropyl methylcellulose (HPMC) and polyvinylpyrrolidone (PVP) at various ratios was granulated using acetaminophen and pseudoephedrine as model drugs. The effect of drug, polymer ratio, total polymer loading, and volume of the granulating fluid on granule growth, granule size distribution, compaction, and tablet properties of the matrix was studied. Formulations containing both acetaminophen and pseudoephedrine required less water to granulate than those containing only acetaminophen. Moreover, the particle sizes of granules prepared with acetaminophen and pseudoephedrine were smaller than those containing only acetaminophen. Tablet hardness increased and friability decreased considerably in all formulations containing pseudoephedrine. In general, the tablet hardness and tablet disintegration time varied with changes in total polymer loading, fraction of HPMC in the matrix, and composition of the model drug(s). All the matrix systems studied showed good flow...

The role of intra- and extragranular microcrystalline cellulose in tablet dissolution.

The objective of this study was to examine the influence of intra- and extragranular microcrystalline cellulose (MCC) on drug dissolution from tablets made by high-shear granulation. Granulations were made in a Littleford Model W-10-B (10-liter) mixer and dried in a fluid bed dryer (Niro Inc.). A Plackett-Burman screening design and 2(3) factorial design were employed to study how drug type, MCC (intra- or extra-), filler type (lactose or dicalcium phosphate), disintegrant type (sodium starch glycolate or croscarmellose sodium) and level, proportion of magnesium stearate, and impeller speed affect tablet hardness, disintegration time, and dissolution. Two model drugs were chosen based on their solubility: metoprolol tartrate (solubility > 1000 mg/ml) and hydrochlorothiazide (solubility = 1.05 mg/ml). Tablets were compressed to the same target weight (dose) and similar tablet hardness. In some cases, dissolution testing was also carried out on the loose granules. The intra-extragranular distribution of MCC was found critical to the compactibility and initial dissolution rates from these tablets. Intragranular MCC reduced drug dissolution, the effect being most marked in the case of the slightly soluble hydrochlorothiazide. For formulations containing intragranular MCC, the granulating fluid level on tablet dissolution was also important, since an increase in fluid level resulted in slower drug dissolution from both the loose granules and the tablets compressed from them. Conversely, extragranular MCC tended to increase both dissolution rates and compactibility. It may be concluded that the appropriate distribution of MCC between and within granules may optimize both dissolution and compactibility without changing overall tablet composition.

Development of Agglomerated Talc. I. Evaluation of Fluidized Bed Granulation Parameters on the Physical Properties of Agglomerated Talc

AbstractStudies were conducted to develop agglomerated talc as a tablet diluent using the fluidized-bed granulation method. A complete 23 factorial experiment was run using a Uniglatt fluidized bed granulator to determine the effects of atomizing air pressure (P), inlet air temperature (T), and the quantity of the granulating fluid (V) upon the characteristics of the resultant agglomerated talc. It was found that the atomization pressure was the most prevailing factor for controlling the growth of the agglomerates in the granulation process. With the decrease of the atomizing air pressure, the geometrical mean particle size and flowability of the agglomerates increased. The volume of the binder solution (dilution effect) affects the properties of the agglomerates in the same direction as did the atomizing air pressure. Droplet size distribution of the atomized binder solution was estimated. The result suggested that the dilution effect altered the properties of the product through its adhesivity. The flow...

Process Considerations in Reducing Tablet Friability and Their Effect onin vitroDissolution

AbstractThe tablet friability resulting from manufacturing process variations was studied for two differently sized tablets using the same formulation. Granulations containing lower moisture contents required higher compression and ejection forces to manufacture a tablet at a given hardness, although this did not influence friability. Increased tablet hardness (and to a lesser extent decreased tablet thickness) decreased the tablet friability of the larger tablet. An increase in the quantity of granulating fluid increased the granulation particle size and slightly improved compactibility without significantly affecting friability. Tablet dissolution increased as the quantity of granulating fluid was decreased. There was a strong interaction, with respect to dissolution, between moisture content and the amount of granulating fluid. Tablet hardness did not significantly influence dissolution. Doubling the quantity of magnesium stearate in the granulation in one tablet strength decreased the maximum tablet h...

Use of chitosan and chitosan malate as an excipient in wet granulation of three water soluble drugs

The drug release from granules containing two different chitosan qualities was studied, using three model drugs. Granules were prepared by standard wet granulation, starting with a dry blend of drug and chitosan followed by spraying with a granulating fluid. The resulting granules have good flow properties, except from formulations with the cationic model drug (chloroquine), which gave electrical charged granules. Theophylline granules containing from 25 to 75% of chitosan malate showed an increasing sustained release effect when the chitosan malate content was increased. Zero-order kinetics for the dissolution rate was observed for all three drugs in formulations with a content of 75% chitosan malate. This was probably due to the swelling of the granules in acidic solution. In contrast to the formulations containing chitosan malate as an excipient, theophylline granules containing 25–90% chitosan (SeaCure 452) showed more rapid dissolution than the pure drug, due to fast disintegration and a wetting effect. In dissolution medium no. 2 (pH 6.8), the swelling was less marked, but an interaction between the phosphate buffer and chitosan malate appeared to influence the drug release rate.

Application of low substituted hydroxypropylcellulose (L-HPC) in the production of pellets using extrusion/spheronization

Low-substituted hydroxypropyl cellulose (L-HPC) was used as a binder and disintegrant in granulation and tabletting. The influences of L-HPC on the extrusion process and the characteristics of pellets prepared by extrusion/spheronization were studied. In one trial the type of L-HPC was varied, in a second the amount of L-HPC LH 20. In both trials pellets were manufactured using different quantities of granulation fluid. Depending on the formulation a working range for water contents leading to beads was defined. In the upper part of the working range the quality of the spheres was good in terms of aspect ratio and sphericity. However, the dissolution rate was found to decrease as the water content of the extrudate increased. All types of L-HPC accelerated the dissolution of acetaminophen. There was no strong correlation between porosity and dissolution time, but increasing porosity tended to lead to faster dissolution. Pellets without L-HPC combined low dissolution rate with low porosity while those with L-HPC LH 20 showed the highest dissolution rate and the greatest porosity.

Influence of amount of granulation liquid on the drug release rate from pellets made by extrusion spheronisation

Pellets were prepared by extrusion spheronisation using microcrystalline cellulose as pellet forming agent and two drugs with different solubility, theophylline monohydrate and sulfamethoxazole. Different amounts of water were used for the granulation step prior to extrusion spheronisation. The amount of granulating fluid used had an influence on the drug release from the pellets. A slower release rate was observed with increasing amounts of granulating fluid. These differences in the release profiles were correlated with differences in hardness, density and structure of the pellets.

In vitro controlled release of theophylline from tablets containing a silicone elastomer latex

Abstract Two batches of controlled-release theophylline tablets were prepared using a silicone elastomer latex, one batch by the wet granulation process, the other by direct compression. In the wet granulation process, a dispersion consisting of silicone elastomer latex and fumed silica was used as the granulation fluid, whereas in the direct compression process, a dry, silica-filled silicone elastomer powder prepared from the latex was employed. The release profile of theophylline from the tablets prepared by wet granulation suggests that a matrix-diffusion controlled drug-release mechanism was at work. On the other hand, the directly compressed tablets displayed a drug-release profile that is explained by a matrix-eorosion mechanism. Tablets prepared by direct compression resulted in a faster drug-release rate when compared with the rate of those tablets prepared by wet granulation, even though both batches of tablets had the same formulation. In both the wet granulation and direct compression processes, tablets with a higher percent of silicone elastomer exhibited a slower drug-release rate. Directly compressed tablets formulated with a silicone elastomer powder containing a higher percentage of silica showed a faster drug-release rate. With all other factors unchanged, when a smaller particle size of silicone elastomer powder was used in the direct compression process, tablets with a slower drug-release rate were formed. The effect of the pH of the dissolution medium on the drug-release rate was found to be insignificant.

Influence of Granulating Fluid Properties on Physical Properties of Kneading Mass and Granules.

In the extruding granulation process, granules are prepared by moistening blended powders, sucrose and lactose, and passing the resultant mass through a screen. Many factors affect the properties of granules in this process. The properties of the granulating fluid play an important role, especially when a water/organic solvent system is employed.In this study, a water/isopropyl alcohol system was chosen and the effects of surface tension, viscosity, and the solubility of sucrose and lactose on the properties of the kneading mass and the granules were examined. Deformation behavior and cohesiveness of the kneading mass were influenced by liquid saturation and surface tension. No remarkable variation was observed in mean granule diameter, except in a pure isopropyl alcohol system. Granule hardness increased with the tensile strength of the kneading mass and the amounts of sucrose and lactose deposited; solubility was a dominant factor.

MR Imaging of Middle Ear Cholesteatomas

We prospectively evaluated MR images of 14 patients who had chronic otitis media and who were suspected of having cholesteatomas on otologic examination and/or on high resolution CT. Cholesteatomas were verified in the middle ear and/or mastoid at surgery in nine patients. Cholesteatomas appeared isointense relative to gray matter on T1-weighted spin echo MR images (T1WI) and hyperintense on T2-weighted spin echo MR images (T2WI) in eight patients. Two cholesterol granulomas appeared hyperintense on both T1WI and T2WI. In three patients with chronic otitis media the associated mixed granulation tissue and fluid collection was revealed as nonspecific, heterogeneous signal intensity in two cases. In the third case the signal intensity was similar to that found in cholesteatomas.

Evaluation of the Granulation of a Hydrophilic Matrix Sustained Release Tablet

AbstractWet granulation of a hydrophilic sustained release matrix tablet formulation has been studied. A fractional factorial experimental design was employed to identify principal influences and interacting factors from the following : granulation fluid volume, mixing time, mixer speed and inclusion of a wet screening step. Fluid volume and mixing time were primary factors affecting mean granule size. Fines in the granulation were reduced at higher fluid levels and by inclusion of a wet screening operation. There were several interacting factors influencing the particle size properties of the granulation. The factors studied had little influence on the bulk density of the granulation.The influence of granule mean particle size on flow, compressibility and drug release from finished tablets was evaluated. Flow and compressibility were influenced by granule properties and the data generated suggested that should final tablet properties deteriorate on scale up it may be possible to ameliorate the effect by ...

Granulation monitoring in a planetary mixer using a probe vibration analysis technique

A method is described for monitoring wet massing or granulation in a planetary mixer, using a probe system. Movements or vibration of the probe during massing or granulation were monitored according to changes in displacement, velocity or acceleration using a vibration level monitor. It was found that gross changes occurring during massing and granulation could be monitored most sensitively using displacement or velocity measurements. Product sampled after different granulation times or after different volumes of granulating fluid were added was analyzed according to particle size and packing density as a method of assessing changes which could be related to specific regions of the vibration record. It was found that generally the granulation end-point corresponded with formation of a plateau region in vibration analysis; further mixing or addition of fluid caused a second increase in vibration signal as an over-wet mass was formed.

Use of Mixer-Torque Measurements as an Aid to Optimizing Wet Granulation Process

AbstractInstrumentation designed for monitoring the wet granulation process is described. A Hobart mixer was instrumented with a slip ring torque sensor using a voltage of 5 volts D.C. to excite a strain gauge bridge. An amplifier was used to magnify the low signal levels produced by the strain gauge bridge and the gain was set at 179.6 so that 2 volts equals 200 inch ounce. The output was recorded using a Bascom-Turner recorder. The relative dynamic torque, was measured in millivolts as a function of granulating fluid added and time to optimize the granulation process using the planetary mixer. The instrumentation described in this paper has considerable potential for optimization and validation studies for wet granulation procedures.

Physical Aspects of Wet Granulations II: Factors Involved in Prolonged and Excessive Mixing

Evidence is presented that excessive blending in a wet granulation process shifts the packing arrangement of the wet granule, causing it to become dense and nonporous. With prolonged kneading, a larger amount of the water‐soluble excipients dissolves in the granulating fluid, and these two factors make the drying slower. This result, coupled with the previous finding that a certain time is required to attain an equilibrium size granule, explains why there exists an optimum kneading time for a wet granulation from a mechanical performance point of view.