Factors Affecting Rate of Dissolution of Prednisone from Tablets

Abstract

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.     

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     

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.     

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.     

Effect of Scaling-Up and Formulation Factors on the Qualities of Prednisone Tablets

Four different tablet manufacturing techniques were scaled-up from a bench scale to a semi-large scale in order to study the effect of scaling-up on weight variation and content uniformity of prednisone tablets. One method was further scaled-up to a production scale, and the tablets obtained were tested for content uniformity. The effect of binders and lubricants on tablet hardness, disintegration, dissolution and chemical stability was investigated. It is shown that scaling-up of some techniques affect content uniformity of tablets. The various tablet parameters have been also found to be influenced by the type of binder and lubricant used and by aging of the tablets at normal and accelerated conditions. The presence or absence of intragranular starch as disintegrant appears to affect some of the tablet qualities.     

Evaluation of sorghum starch as a tablet excipient

The suitability of sorghum starch as a binder and disintegrant at various concentrations in diverse tablet formulations have been investigated. Sodium bicarbonate and calcium carbonate were used as soluble and insoluble inorganic medicinal substances in various tablet formulations.

The effect of sorghum starch on the physical properties of the tablets were compared with those formulated with maize starch using the same concentrations of binder and disintegrant under the same experimental conditions.

The observations show that sorghum starch can be used as binder and disintegrant in tablet formulations. The indication is that the starch exhibit about twice the disintegrant power and about the same binding efficacy compared to maize starch.     

Evaluation of the impact of sodium lauryl sulfate source variability on solid oral dosage form development

Objective: The objective of this study was to investigate the effects of sodium lauryl sulfate (SLS) from different sources on solubilization/wetting, granulation process, and tablet dissolution of BILR 355 and the potential causes. Methods: The particle size distribution, morphology, and thermal behaviors of two pharmaceutical grades of SLS from Spectrum and Cognis were characterized. The surface tension and drug solubility in SLS solutions were measured. The BILR 355 tablets were prepared by a wet granulation process and the dissolution was evaluated. Results: The critical micelle concentration was lower for Spectrum SLS, which resulted in a higher BILR 355 solubility. During wet granulation, less water was required to reach the same end point using Spectrum than Cognis SLS. In general, BILR 355 tablets prepared with Spectrum SLS showed a higher dissolution than the tablets containing Cognis SLS. Micronization of SLS achieved the same improved tablet dissolution as micronized active pharmaceutical ingredient. Conclusions: The observed differences in wetting and solubilization were likely due to the different impurity levels in SLS from two sources. This study demonstrated that SLS from different sources could have significant impact on wet granulation process and dissolution. Therefore, it is critical to evaluate SLS properties from different suppliers, and then identify optimal formulation and process parameters to ensure robustness of drug product manufacture process and performance.     

An evaluation of starch obtained from pearl millet - Pennisetum typhoides. As a binder and disintegrant for compressed tablets

The binding and disintegrant properties of millet starch obtained from Pearl Millet - Pennisteum typhoides (Staph. Burn, and Hubb.) Fam. Gramineae have been evaluated using tablet formulations of four drugs.

The results showed that Millet starch compared favourably with Maize starch with regards to most of the parameters used to evaluate the tablets. It can be safely concluded that millet starch is suitable for use as a binder and disintegrant in tablet formulations.     

III. Segregation of Active Constituents from Tablet Formulations During Grinding: Effects on Coated Tablet Formulations

Grinding or milling coated tablets in preparation for their assay can cause the physical separation of an active ingredient from the coating and other tablet components. This phenomenon has been shown to partially account for the poor reproducibility between duplicate assays, and for discrepancies among assays for the same group of tablets but which were composited by different methods.

The effect of compositing methods on the assay results is shown with commercial enteric coated aspirin tablets from various manufacturers. Samples for assay were prepared by manual grinding with a glass mortar and pestle, mechanical grinding with an electric tablet grinder, direct dissolution of the tablets in a suitable solvent, and uncoating of the tablets with an organic solvent prior to their manual grinding.

Suggestions are offered to minimize the effects of segregation of an active tablet ingredient during grinding or milling on the assay results.     

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.     

Development of a New Tablet Formulation of Theophylline: In Vitro and in Vivo Studies

The preparation of a new scored 250 mg theophylline tablet is described, for which effects of particle size of the active principle, aspects of granulation and changes in tabletting settings were investigated.

In vitro studies showed the dissolution rate from tablets prepared from theophylline of commercial quality (50 μm) or of selected particle size (30 μm) to be faster than that from tablets prepared from micronized theophylline (10 μm). In vivo studies in dog showed that only the tablet from theophylline of selected particle size has the same bioavailability as an aqueous solution.

The scale up study showed that the characteristics of the tablets, including dissolution rate, are independent of the formulation factors.     

Investigation of Prolonged Drug Release from Matrix Formulations of Chitosan

A hydrocolloidal matrix system containing complexes of chitosan was investigated for preparation of sustained release tablets and examined in-vitro.

Theophylline tablets using chitosan as a sustained release base were evaluated. It was found that when chitosan is used in a concentration of more than 50% of tablet weight, an insoluble non-erosion type matrix was formed. Tablets prepared with a chitosan concentration of less than 33% were fast releasing.

Chitosan used in a concentration of about 10% acted as a disintegrant and the drug was dissolved within an hour.

Citric acid slowed down the release rates of chitosan based theophylline tablets. Theophylline tablets using carbomer-934P as a sustained release base were evaluated. Carbomer-934P in lower concentrations forms an erosion type matrix. In order to produce a twenty-four (24) hour sustained release tablet, more than 10% concentration of carbomer-934P is needed. Combination with chitosan and carbomer-934P produced slower releasing tablets.

A hydrocolloidal erosion type matrix was formulated using chitosan, carbomer-934Pand citric acid. Only 10% of chitosan was needed to prepare theophylline sustained release tablets in these mixtures.

The dose dumping potential of chitosan tablets due to rapid disintegration in alkaline media was eliminated by preparing hydrated erosion type matrix systems.     

Hydroxypropylmethylcellulose sustained release technology

The use of polymers in controlling the release of drugs has become important in the formulation of pharmaceuticals. Watersoluble polymers such as polyethylene glycol and polyvinylpyrrolidone may be used to increase the dissolution rates of poorly soluble drugs (Ford)¹ and slowly soluble, biodegradable polymers such as polylactic acid may be used for controlled release implants (Rak et a1.²), Hydrogels provide the basis for implantation, transdermal and oral-controlled release systems. Hydroxypropylmethylcellulose (HPMC) are cellulose ethers which may be used as the basic for hydrophilic matrices for controlled release oral delivery.

In tablet matrix systems the tablet is in the form of compressed compact containing an active ingredient, lubricant, excipient, filler or binder. The matrix may be tabletted from wet-massed granules or by direct compression.

This review article examines a previously published series of work and concentrates on the following aspects of the subject; the relationship between release rate and quantity of polymers, such consideration allow a certain predicability in release rates to be made. Also the effect of drug particle size, tablet shape and the presence of additional diluents in the formula are examined.     

Dissolution properties of direcet compression tablets containing an agglomerated cellulose powder

In previous studies a novel agglomerated cellulose powder was shown to own advantageous properties for direct compression. Due to the favourable particle and powder properties this material has good binding and disintegration ability in direct compression tablets. In this study the dissolution properties of direct compression tablets containing the agglomerated cellulose powder as a fillerbinder were evaluated. Especially the effect of the amount of cellulose, the porosity of tablets, the solubility of drug material and the amount and the amount and mixing method of lubricant, magnesium stearate were studied.

Tablets containing different amounts of cellulose with dicalcium phosphate as a filler and 10 wt % of water soluble sodium tolmetin as a drug were compressed at a constant pressure of 150 MPa. The breaking strength of tablets increased with increasing amounts of agglomerated cellulose powder. However, the dissolution of drug accelerated up to cellulose amount of 50 wt %. This was due to the ability of the agglomerated cellulose powder to enhance the water penetration into powder compact and the loosening of tablet structure, i.e. formation of cracks.

Tablets containing 20 wt % of cellulose material and 10 wt % of drug material were compressed to different porosities. Tablet porosity had no effect on dissolution of poorly water soluble tolfenamic acid. Also the dissolution of water soluble sodium tolmetin was only slightly affected by the porosity of tablets. This supports the suggested disintegrant mechanism of the agglomerated cellulose powder. The expansion of cellulose agglomerates, which have been deformed, under compression, is widely responsible for the disintegration of the tablets. An increase in the amount as well as in the mixing intensity of magncsium stearate decreased the dissolution of sodium tolmetin from tablets containing 20 wt % of agglomerated cellulose. However, the intrinsic wetting and dissolution phenomens were practically unchanged when the amount of magnesium stearate was below 2 wt %. Thus, the retardation of drug dissolution was acceptable at low lubricant concentrations.

The properties of tablets containing the agglomerated cellulose were compared to those containing microcrystalline cellulose. In all cases tablets containing the agglomerated cellulose powder liberated drug clearly faster and more properly than corresponding microcrystalline cellulose tablets.     

Carboxymethylstarches in Wet Granulation

Abstract

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     

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.     

Dextrose monohydrate as a non-animal sourced alternative diluent in high shear wet granulation tablet formulations

The feasibility of dextrose monohydrate as a non-animal sourced diluent in high shear wet granulation (HSWG) tablet formulations was determined. Impacts of granulation solution amount and addition time, wet massing time, impeller speed, powder and solution binder, and dry milling speed and screen opening size on granule size, friability and density, and tablet solid fraction (SF) and tensile strength (TS) were evaluated. The stability of theophylline tablets TS, disintegration time (DT) and in vitro dissolution were also studied. Following post-granulation drying at 60?°C, dextrose monohydrate lost 9% water and converted into the anhydrate form. Higher granulation solution amounts and faster addition, faster impeller speeds, and solution binder produced larger, denser and stronger (less friable) granules. All granules were compressed into tablets with acceptable TS. Contrary to what is normally observed, denser and larger granules (at ≥21% water level) produced tablets with a higher TS. The TS of the weakest tablets increased the most after storage at both 25?°C/60% RH and 40?°C/75% RH. Tablet DT was higher for stronger granules and after storage. Tablet dissolution profiles for 21% or less water were comparable and did not change on stability. However, the dissolution profile for tablets prepared with 24% water was slower initially and continued to decrease on stability. The results indicate a granulation water amount of not more than 21% is required to achieve acceptable tablet properties. This study clearly demonstrated the utility of dextrose monohydrate as a non-animal sourced diluent in a HSWG tablet formulation.     

The Effect of Recompression on the Swelling Kinetics of Wet Massed Tablets, Containing 'Super' Disintegrants

The effect of recompression on the swelling force kinetics of tablets employing a wet massed Avicel matrix and those containing extra-granular super disintegrants has been investigated. Explotab, unlike the Ac-Di-Sol and Polyplasdone XL systems, was found to give a high initial compact swelling force at low tablet porosities, but the rework process reduced the maximal swelling forces for all systems. However, the measured maximal swelling forces did not correlate with tablet disintegration time.

The rate of fluid penetration into the compacts was found to be controlled by tablet porosity but the penetration rates for all disintegrant systems were essentially identical. However the penetration rates for reworked compacts were significantly lower than those for tablets produced by first compression possibly due to the effects of increased lubricant distribution and relubrication causing poorer wettability.

Tablet disintegration times were found to correlate with a fluid penetration kinetic function involving lag time and time for 50% tablet swelling. Also, the retention of disintegration efficiency following rework correlated with the retention of the rate of fluid penetration. It is concluded that lubricants can play an important role in the efficiency of compact disintegration following tablet rework.     

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.     

Optimizing a wet granulation process to obtain high-dose sustained-release tablets with Compritol 888 ATO

Context: Niacin (vitamin B3) is a micronized active pharmaceutical ingredient (API) with poor flow properties making the production of high-dose sustained-release tablets by direct compression a challenge.

Objective: We evaluated various wet granulation processes as a simple and efficient approach to obtain high-dose (500 and 1000?mg) niacin sustained-release lipid matrix tablets.

Materials and methods: A high melting-point lipid (Compritol® 888 ATO) was used as the sustained-release agent. Tablets were prepared by various wet granulation techniques, with different process parameters and binder concentrations to identify the optimal process conditions.

Results: A binder (PVP) was needed to increase particle bonding and tablet strength. Process parameters, such as spray rate and quantity of liquid, had only a slight impact on the properties of the granules and resultant tablets, in the presence of low binder concentrations. Increasing binder concentration improved granule wetting, resulting in significant granule growth and improved flow properties. Sustained-release over 12?h was observed for all the compacted granules, irrespective of the drug dose. The sustained-release kinetics for 1000?mg niacin matrix tablets with Compritol 888 produced with the identified optimal parameters were similar to those for the market reference product, Niaspan® FCT 1000?mg. The tablets were stable for up to six months when stored at 25 and 40?°C.

Conclusions: Wet granulation with Compritol 888 presents an effective approach to improve material flow and compressibility. High-dose lipid matrix tablets with sustained release profiles can be successfully produced.