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     

Experimental Design for a Granulation Process with “Priori” Criterias

Optimization techniques representr analytical tools available for the best solution to a particular problem.

Pharmaceutical product and process design problems were structured as constrained optimization problems and subsequently solved by the “a priori” optimality approach using an exchange algorithm.

The effect of the amount of added water plus granulation time and impeller speed on two properties of the granulates were investigated.

Experimental results obtained for the optimal formulation agreed well with the predictions.     

Evaluation of the Granulation of a Hydrophilic Matrix Sustained Release Tablet

Wet 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 modification of granulation fluid volume or mixing time or both.

The factors studies had no influence on release of drug from finished tablets.     

Preformulation of five Commercial Celluloses in drug Development: Rheological and Mechanical Behaviour

The physical quality of pharmaceutical powders is one of the main element in quality assurance.

A particular attention must be paid to physical and physico-mechanical properties of materials in order to avoid difficulties due to the variability of physical properties, batch to batch, in industry.

Physical characterization, packing characteristics and tableting behaviour applied to five celluloses are studied.

The Authors insist on the importance of packing properties and on his influence on compacting behaviour.     

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.     

Instrumentation of a Kenwood Major Domestic-Type Mixer for Studies of Granulation

The mixer was reconstructed and equipped with a torque transducer consisting of a steel beam, with strain gauges in a full bridge circuit, which prevented the rotation of the bowl.

Repeated loadings of the separate steel beam with weights resulted in a relative standard deviation of less than 0.2%. However, tangential loading of the equipment with a dynamometer resulted in a relative standard deviation of 1.2% because of the inaccuracy of the dynamometer load. The smallest detectable load was about 98· 10^-3 N, corresponding to 1-2% sensitivity within the interesting part of the granulation curve.

The average torque was calculated.

The recording mixer was simple to handle and proved a suitable tool for granulation studies.     

Granulation in a Fluidized Bed II Effect of Binder Amount on the Final Granules

There are many parameters affecting the properties of the final granules prepared in a fluidized bed. In this study one of the product parameters, quantity of the binder, has been studied for its effect on the final granule size, size distribution and friability

Determination of granule size change as a function of binder quantity leaded us to study the growth mechanisms during fluidized bed granulation. Two mechanisms are suggested;

1) Snowballing of primary granules (nuclei)

2) Agglomeration of primary granules

It has been shown that there is a critical amount of binder at which the formation of the primary granules comes to an end if more binder is added to the system. Then granule growth occurs by agglomeration of the primary granules. The physical properties of the granules formed before and after this critical binder concentration varies significantly     

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

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 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.     

Granulation Rheology I: Equipment Design and Preliminary Testing

One of the most common pharmaceutical dosage forms is the compressed tablet, and of the several methods of preparing tablets, wet granulation remains widely used throughout the pharmaceutical industry. An apparatus was designed to follow the physical changes occurring in the granulation process. Its operation and preliminary results are presented.

As dry solid is wetted with granulating liquid, it passes through several stages, as it becomes wetter, it should exhibit a resistance to flow analagous to a viscous liquid. This resistance (force) can be measured. The test procedure follows the material from a dry powder through its maximum resistance and finally to a slurry. Such profiles could represent a characterization method for the solid and/or the liquid.

Materials tested included six common tablet excipients; these have been limited to single component granulations. Results indicate this apparatus is reproducible for these simple systems. Materials are shown to behave differently in the granulation process, and the apparatus appears capable of distinguishing between different materials.     

The Granulation of a Tablet Formulation in a High-Speed Mixer, Diosna P 25

The impeller speed, the loss-on-drying of starch, and the added amount of water significantly influenced these response variables: granule fractions of less than 0.150 mm and more than 2.00 mm; and granule median diameter. The influence of the drug concentration on the response variables was less important. All the response variables showed significant interactions.

At a fixed impeller speed, the fine fraction was reduced when the loss-on-drying of starch increased, and when water was added in increasing amounts. The coarse fraction and granule median diameter increased along with an increasing moisture content in the starch. Increasing amounts of added water had the same effect.

The response surface contours of a fraction less than 0.150 mm, and a fraction exceeding 2.00 mm, were plotted. So was the granule median diameter. Suitable levels for the processing variables involved in obtaining a granulation of the desired proportions - fine or coarse fraction - can be read from the contour plots.

Heat was generated in the mixer during kneading, which caused some evaporation of water.

The change in the rotation rate of the impeller during the addition of the granulating liquid can be used as an indication of the fraction percentages below 0.150 mm and above 2.00 mm, but not of the median diameter     

Factors Affecting Rate of Dissolution of Prednisone from Tablets

A study was carried out to evaluate some parameters which may have an effect on the dissolution rate of prednisone from tablets. The parameters examined involving formulation were: diluent proportion (Lactose-starch), dissintegrant type (starch, explotab (sodium starch glycolate) type of binder (starch paste, gelatine water solution and PVP alcoholic solution), lubricant, and dye concentration. The Manufacturing variables studied were: method of manufacture (wet granulation, direct compression and double compression), granule size in wet granulation and tablet hardness. dissolution profiles of tablets storaged 2 months at 45°C were compared with those of fresh samples. Tablets prepared with prednisone five years old, tablets with fresh active ingredient and tablets with two different prednisone concentrations (5 and 50 mg per tablet) were used for other evaluations.

In all cases micronized prednisone was used and all batches were physically and chemically evaluated before studying their dissolution following the USP basket method.

The parameters studied that affected significatively dissolution rate of prednisone were: type of binder, lubricant concentration, method of manufacture, active ingredient, age and prednisone concentration.     

Multiphase versus single pot granulation process: influence of process and granulation parameters on granules properties

High-shear wet granulation is widely used for the production of pharmaceutical dosage forms. Different equipment is available for high-shear granulation and drying. This review focuses on two main processes for granules production: multiphase consisting of high-shear granulation followed by drying in a separate apparatus, and single pot granulation/drying. At present, formulas are specifically developed with regard to the production equipment, which raises many problems when different industrial manufacturing equipment is used. Indeed, final granules properties are likely to depend on equipment design, process, and formulation parameters. Therefore, a good understanding of these parameters is essential to facilitate equipment changes.

The aim of this review is to present the influence of equipment, process, and formulation parameters on granules properties, considering both the granulation and the drying steps of multiphase and single pot processes.     

Comparison of Disintegrant and Binder Activity of Three Corn Starch Products

This study demonstrates the differences obtained when using different corn starch products as both binder and disintegrant in pharmaceutical tablets. Formulations made with Fluftex W, Tablet White and Purity 21 starches were compared. In addition, Avicel PH101 was used in this study as a benchmark component whose properties are well understood.

Four test formulations containing hydrochlorothiazide were prepared by wet granulation. Starch was incorporated in both powder and paste form. All granulations were found to possess similar traits when evaluated based upon geometric mean diameter, particle size distribution, bulk/tap densities, powder flow rate and surface characteristics.

Tablets prepared from these granulations were shown to be similar when evaluated for degree of friability, weight and content uniformity. All starch formulations disintegrated within 30 seconds and produced similar dissolution profiles. Tablets produced with Avicel, however, were found to exhibit significantly longer disintegration times than the starch formulations. In addition, these tablets displayed a dissolution profile that was significantly different than the starch formulations, particularly during the earlier stages of the dissolution process.

When monitoring compression and ejection forces required to produce tablets of the same degree of hardness (≈6kg), Fluftex W and Tablet White granulations were found to use significantly lower forces than the Purity 21 granulation. This may be indicative of Fluftex W and Tablet White's superiority over Purity 21 in terms of binder capacity.     

A Comparison Between Binders in the Wet Phase of Granulation in a High Shear Mixer

The effects of binder solutions on granule size, intragranular porosity and liquid saturation in a high shear mixer are examined during the liquid addition phase of the granulation process. The power consumption profiles of impeller motor are recorded. Five different binders (PVP, PVP-PVA-copolymer, hydrolysed gelatine and two HPMC'S) are investigated.

The PVP and hydrolysed gelatine produce granules with a higher mean granule size. This is shown to be due to the higher densification caused by these binders.

The power consumption profiles for PVP are significantly higher than for the other binder solutions. It is suggested that the high power consumption profiles are a result of the strength of mobile liquid bondings caused by the high surface tension of PVP solutions.     

In Vitro and in vivo Availability of Spironolactone from Various Oral Preparations

The dissolution rates in vitro and the bioavailability in humans were determined for 6 preparations containing 25 mg spironolactone and 5 preparations containing 100 mg spironolactone. Linear relationships were obtained by pairwise correlation of in vitro parameters with in vivo parameters. The following parameters were used.

In vitro parameters of dissolution:

1. The area under the dissolution-time-curve up to 1 h

2. The fraction of active ingredient dissolved within 20 min.

3. The slope of the dissolution-time-curve at 50 % dissolution

4. The dissolution rate constant

5. The time up to 50 % dissolution of the substance

6. The maximum slope of the dissolution-time-curve

In vivo parameters of bioavailability:

1. The time of maximum plasmaconcentration

2. The area under the plasmaconcentration-time-curve up to 1 h and 2 h after application

3. The quantities of active ingredient excreted in the urine up to 2 h after application

The highest correlation coefficient was found between the areas beneath the dissolution-time-curve and the plasmaconcentration-time-curve up to 1 h each.

No significant correlations were found between the within 1 h dissolved substance and maximum plasma-concentration, the area under the plasmaconcentration-time-curve up to 4 h and 24 h and quantities of active ingredient excreted in the urine up to 4 h after application.     

Comparison of Disintegrant and Binder Activity of Three Corn Starch Products

This study demonstrates the differences obtained when using different corn starch products as both binder and disintegrant in pharmaceutical tablets. Formulations made with Fluftex W, Tablet White and Purity 21 starches were compared. In addition, Avicel PH101 was used in this study as a benchmark component whose properties are well understood.

Four test formulations containing hydrochlorothiazide were prepared by wet granulation. Starch was incorporated in both powder and paste form. All granulations were found to possess similar traits when evaluated based upon geometric mean diameter, particle size distribution, bulk/tap densities, powder flow rate and surface characteristics.

Tablets prepared from these granulations were shown to be similar when evaluated for degree of friability, weight and content uniformity. All starch formulations disintegrated within 30 seconds and produced similar dissolution profiles. Tablets produced with Avicel, however, were found to exhibit significantly longer disintegration times than the starch formulations. In addition, these tablets displayed a dissolution profile than was significantly different than the starch formulations, particularly during the earlier stages of the dissolution process.

When monitoring compression and ejection forces required to produce tablets of the same degree of hardness (≈6kg), Fluftex W and Tablet White granulations were found to use significantly lower forces than the Purity 21 granulation. This may be indicative of Fluftex W and Tablet White's superiority over Purity 21 in terms of binder capacity.