Effectiveness of Lubricants and Lubmcation Mechanism in Tablet Technology

Abstract

A method for quantitative evaluation of the effectiveness of the lubricant used in tablet technology has been recentey proposed by the authors It was based on the ejection force determination expressed as relationship between the force on the lower punch and the time (ejection curve).

The proposed methodology allows now quantitative analysis of the tablet ejection, considering that the lot of the parameters linked to the conditionning, tooling and operative procedure that can negatively affect the measurement, were optimized During the methodology development, series of ejection curves, relative to different type of diluent and a variety of lubricants, were collected Certain relationship between the form of ejection curve and the capacity of lubricant to reduce frictions was observed.

Starting from these observations, the aim of this work was to analyze quantitatively the ejection curves obtained with the proposed methodology, in order to have a measure of the effectiveness of the lubricant in the formulation. The ejection curve must be considered as an effective means for this type of analysis, mainly because its pattern modifies according to formulative parameters such as compression force and lubricant amount.

Moreover, the product of ejection peak value and area under the ejection curve gives a dependent parameter that appears to be very sensitive to the conditions affecting tablet manufacturing in terms of lubrication Because of its informative quality, this lubrication index could be profitably be used in the optimisation procedures for formula preparation.     

Instrumented and Computer Interfaced Single Punch Tablet Press for the Rapid Evaluation of Compression and Lubrication Behaviour

A low cost instrumented and computer interfaced single punch tablet press was developed for the rapid data aquisition of compression and lubrication properties of powders arid processed materials.

A Manesty type F3 tablet machine has been modified to enable the fitting of piezo electric load cells to both upper and lower punch assemblies. The paper describes how the modifications permit interchangability of a range of punch sizes and shapes and yet ensure good accuracy and reproducibility of compression end lubrication data.

The instrumentation is interfaced with a dedicated A. I. M. 65 microcomputer for the rapid conversion of the instrumentation outputs into compression force units and for statistical evaluation. The computer software also incorporates a novel method for the evaluation of lubrication properties from a single or a series of pre-determined compression events, using the some sensitivity for force measurement from the lower punch lord cell.

The compression data and the physical properties of the compacts can be stored and retreived as fingerprints using a P. E. T. microcomputer and a digital plotter. A date bank may then be developed for the evaluation of raw materials, product development, monitoring of production performance and trouble shooting.

The paper further describes the evaluation of new lubricants in comparison with magnesium stearate using the instrumentation described.     

Disintegrating Force and Tablet Properties

The development of a disintegrating force inside the tablet due to the liquid/solid contact depends on a proper wetting of the material and occur according to saturation kinetics.

The aim of the present work is the evaluation of such a force development in relation to the characteristics of the tablet in particular to the compression force.

For this purpose, the disintegrating force of different tablets formulations has been measured by means of a previously described apparatus.

The results obtained show that a new evaluation of a compact disintegration characteristics may be obtained through the determination of such parameters as the maximum force developed (y₀) and the time of the half maximum force development (b).     

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.     

Disintegration Mechanisms of Tablets Containing Starches. Hypothesis About the Particle-Particle Repulsive Force

The disintegration of a tablet immersed in a liquid appears to be essentially a mechanical phenomenon: penetration of liquid then destruction of compressed structure

For a number of authors, the starch granule swelling is the mechanical force which destroys the tablet.

Indeed, a study on a series of experimental carboxymethylstraches indicates that those that do not swell, show the same disintegration time to those that do swell.

We can also notice that the carboxymethylstarches wich swell much less in a gastric medium, produce even shorter disintegration times in this medium.

The destruction of the cohesion forces between the constitutive elements of the tablet under the action of water may be ascribed to the creation of a repulsive force when the elements of the tablet enter into contact with water, or to a simple annihilation of the hydrogen bonds or of the capillary cohesion forces.

The hydrophilic nature of starch seems to be determinant: water penetrates into the tablet owing to hydrophilic porosity under the action of an important hydrostatic pressure.     

Evaluation of Two New Tablet Lubricants -Sodium Stearyl Fumarate and Glyceryl Behenate. Measurement of Physical Parameters (Compaction, Ejection and Residual Forces) in the Tableting Process and the Effect on the Dissolution Rate

A comparison of two new tablet lubricants, sodium stearyl fumarate and glyceryl behenate, was made with magnesium stearate. Physical parameters such as compaction force, ejection force and residual force were investigated and quantified. The effect of these lubricants on a biopharmaceutical parameter such as dissolution rate was also evaluated. The results indicate that where magnesium stearate cannot be used due to problems of compaction, lubrication, stability or for biopharmaceutical reasons, sodium stearyl fumarate should be used as the tablet lubricant of choice, followed by glyceryl behenate as the next alternative     

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.     

The Effect of Magnesium Stearate Admixing in Different Types of Laboratory and Industrial Mixers on Tablet Crushing Strength

It is generally known that hydrophobic lubricants such as magnesium stearate can have a strong negative effect on the binding properties of directly compressible filler-binders. It was found that the decrease in binding forces is not only dependent on the tablet ingredients and the lubricant concentration used, but especially on the mixing time and mixing procedure. Most studies were performed, however with small laboratory scale mixers. In order to evaluate the effect of magnesium stearate admixing in different types of laboratory-scale and industrial mixers, the decrease in crushing strength was measured for a test formulation during mixing with the lubricant in different mixers. The formula used consisted of 90% a-lactose monohydrate 100 mesh, 9.5% microcrystalline cellulose and 0.5% magnesium stearate. The mixers used were two laboratory scale mixers: a 2 litre Turbula mixer and a 13 litre cubic mixer and five production scale mixers: a 45 litre drum mixer, 90 litre, 200 litre and 900 litre planetary mixers and a 1.000 litre V-shaped mixer, respectively. For the test formulation used, it was found that the effect of lubricant admixing on tablet crushing strength was strongly dependent on type, size and rotation speed of the mixer used.

When operated at the same rotation speed, the decrease in crushing strength was much faster for the large industrial mixers than for the small laboratory mixers. These differences were explained by differences in shear forces during the mixing process and the efficiency of the mixing procedure.

For the industrial mixers the decrease of the tablet crushing strength as an effect of lubricant admixing was mainly determined by the rotation speed and only to a small extent by the type and size of the apparatus. Moreover no effect of load could be observed between the mutual industrial mixers used.

For a prediction of the effect of lubricant admixing on tablet crushing strength in large mixers, efficient laboratory mixers, operating at high rotation speeds can be used. For this purpose a 2 litre Turbula mixer is a valuable tool in preformulation work.     

Evaluation of Two New Tablet Lubricants -Sodium Stearyl Fumarate and Glyceryl Behenate. Measurement of Physical Parameters (Compaction,Ejection and Residual Forces) in the Tableting Process and the Effect on the Dissolution Rate

Abstract

A comparison of two new tablet lubricants, sodium stearyl fumarate and glyceryl behenate, was made with magnesium stearate. Physical parameters such as compaction force, ejection force and residual force were investigated and quantified. The effect of these lubricants on a biopharmaceutical parameter such as dissolution rate was also evaluated. The results indicate that where magnesium stearate cannot be used due to problems of compaction, lubrication, stability or for biopharmaceutical reasons, sodium stearyl fumarate should be used as the tablet lubricant of choice, followed by glyceryl behenate as the next alternative     

Disintegrants in Solid Dosage Forms

The dynamic approach to tablet disintegration, which is based on the measurement of the force that develops inside the compact upon water entrance, is basically taken up.

The combined measurements of force development and water uptake, simultaneously effected on the same compact, provide a novel parameter that is proposed to quantify and compare the efficiency of disintegrants.

The new parameter, which is based on the “force-equivalent” concept, expresses the capability of a disintegrant of transforming water uptaken into swelling (or disintegrating) force. A few examples, that illustrate the usefulness of this parameter for disintegrant characterization, are given.

In parallel to the quantification of swelling (or disintegrating) efficiency inside compacts, attention is also being paid to the characterization of swelling disintegrants as pure materials.

In particular the case of the so-called limited swelling materials, for which the quantification of intrinsic swelling (particle volume increase in swelling media) is critical, is considered.

The applicability of an instrumental method, which is based on the employment of a Coulter Counter, is discussed alternatively to microscopic methods.

Disintegrant characterization may also be considered in view of new possible exploitations of the swelling properties of polymers in controlling drug release.     

Statistical Optimization of a Controlled Release Formulation Obtained by a Double Compression Process: Application of an Hadamard Matrix and a Factorial Design

A formulation containing an antiinflammatory agent (diclofenac sodium), two inert matrices (ethylcellulose and polyvinyl chloride) and two lubricants (magnesium stearate and talc) was optimized by a double compression process

In a first stage, preliminary trials were performed in order to study the effect of lubricants added before and after precompression

An Hadamard matrix H(8) was applied to estimate the main effects of four parameters: applied force at the upper punch (UPF) during precompression, particle size range after grinding, UPF during the final compression and concentration of ethylcellulose added before the final compression

Following the Hadamard matrix, a factorial design 2² was built. The complete linear models were fitted by regression for each response reflecting the compression behaviour and dissolution kinetics

In an optimal point, the validation was carried out with the area under the dissolution curve, being the major response to be optimized

The dissolution curves were well fitted by the Weibull distribution     

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.     

Granulation Surface Area as Basis for Magnesium Stearate Concentration in Tablet Formulations

Tablets provide drug delivery in a convenient and uncomplicated manner. Despite this apparent simplicity, they must comply with a formidable number of physico-chemical compendial requirements defined by specifications and test methods. What these specifications indirectly control is that each dosage form or each lot of dosage form my vary but the variance is held within stated limits.

This communication focuses on the weight variation of formulation ingredients that my be allowed in general and for magnesium stearate in particular and to define a relationship between the lubricant level and granulation surface area of a calcium phosphate matrix to obtain optimal tablet properties.     

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     

A Computer Aided Investigation on Strain Movements in Compacts Under Constant Stress Within the Die

A 2.54cm diameter punch and die set has been used in conjunction with a Mayes Hydraulic Machine to examine strain movements within the die of compacts maintained at constant stress. These were prepared from the bases Avicel PH 101 (AV), Sta-Rx 1500 (ST), Paracetamol DC (PC), Emdex (ED) and Eacompress (EC).

Compression force and punch movements were simultaneously monitored using a CBM nicroconputer with disk storage of data.

All compacts showed time dependent consolidation under constar. stress when held at 'holding time' of up to 60s. PC, AV and ST exhibited comparable movements but that of ED and EC ware less.

Elastic recovery on sudden release of load was followed using machine code logging over a period of 90ms. Large recoveries were recorded for AV, PC and ST. If load release was immediate (zero holding time) then the recovery was greater when compared with recovery after holding tines of 30 and 60s, suggesting that some elastic energy was dissipated during the holding time. Elastic recovery of ED and EC was about half that of the other bases. Although these bases also showed reduced recovery with holding tine, percentage reduction was smaller than for the other bases.

Following elastic recovery, a much slower viscoelastic movement could be demonstrated. It was difficult to clearly demarcate the division between viscoelastic and elastic movement but it appeared that the movement on viscoelastic consolidation was comparable to that en recovery when the load was removed.

There are many references to tine dependent effects during tablet compression to be found in the literature. One of the earliest was due to Rees and Shotton (1) who found that the crushing strength of sodium chloride tablets could double after the lapse of one hour from ejection. This has recently been shown by Rue and Barkworth (2) to be due to the existence of a work hardened outer shell which inhibits relaxation by viscoelastic flow.

Several authors (3,4,5) have investigated the stress decay that occurs when a tablet is held at a nominally constant force. Thus Wells and Langridge (5) monitored the fall from a peak pressure of 332MN/m²on a tablet prepared in a single punch machine turned by hand. Similar techniques have been described by Rees and Rue (3), Kiestand and others (4) and Shlanta and Milosovich (6). However as Rees and Rue have pointed out, these methods measure stress relaxation under constant strain conditions. Their results and conclusions differed from those of David and Augsburger (7) who compressed the same direct compression bases on a rotary tablet machine. In a rotary machine compression takes place under virtually constant, stress conditions because of the buffer effect of the powerful springs fitted to the compression wheels.

This paper describes some techniques and observations on the compression of some direct compression bases using a Mayes Hydraulic Testing Machine (WH Mayes (Windsor) Ltd) which is capable of maintaining constant stress conditions on a compact formed in a punch and die set mounted between the platens.     

Optimization of Disintegration Time and Crushing Strength of a Tablet Formulation

In an experiment with a factorial design, the following aspects were scrutinized: the impact on disintegration time and crushing strength caused by the loss-on-drying of the granulation; the granule-size distribution; the lubricant concentration; the compression force; and the pre-compression. Both with regard to disintegration time and crushing strength, these factors were found to have a significant influence: the loss-on-drying of the granulation; the fraction less than 0.150 mm; the concentration of magnesium stearate; and the compression force. A reduction of the tablet disintegration time was obtained by means of an increase of the granulation moisture; by an increase of the fine fraction; or by a reduction of the lubricant concentration or the compression force. The tablet crushing strength was increased by reducing the deviation of the granulation loss-on-drying from approximately 4.6 %; by a reduction of the fine fraction; by decreasing the lubricant concentration; or by increasing the compression force. The fraction larger than 0.300 mm had no significant influence; nor did the pre-compression. Further, there were no significant interactions.

By means of superimposing contour plots of disintegration time and crushing strength, a region was obtained where the requirements of disintegration time and crushing strength could be satisfied by controlling the processing variables.     

An Investigation into the use of Creep Viscometry for in Vitro Characterisation of the Raft Forming Properties of tablets Containing Alginic acid and antacid Components

The established methods for assessing the strength of rafts formed in-vitro by alginic acid/antacid containing formulations rely on the determination of forces required to disrupt the raft structure. Creep viscometry is proposed as an alternative, non-destructive means of investigating the characteristic parameters of this type of product. Several commercial chewable tablet formulations were investigated using this technique. The instantaneous compliance and the Newtonian viscosity were calculated from the creep compliance curves obtained for these products and were used as raft strength indicators.

Differences found in the raft strength parameters of the different products were attributed to interactions between the formulation components. Additional studies conducted on experimental batches established that such interactions could be estimated using this technique. It was concluded that creep viscometry could be usefully employed in investigations of alginate rafts and, possibly, other oral dosage forms which rely on the formation of visco-elastic structures to modify drug release properties.     

Quantification of Lubricant Activity of Magnesium Stearate by Atomic Force Microscopy

Magnesium stearate (MgSt) is commonly used in pharmaceutical formulations as a lubricant to facilitate tablet release from the die after compression. In this study, we quantify the effect of MgSt on the interaction forces between microcrystalline cellulose (MCC) and steel surfaces. A quantitative approach to better understand the mechanism by which MgSt affects powder performance will assist in improved control and formulation design. We find that the forces between MgSt and steel surface are stronger than the interactions between MgSt itself, between MgSt and an MCC particle, and an MCC particle and a steel surface. These quantitative findings offer an explanation how MgSt facilitates lubrication during tablet ejection.     

Evaluation of Tack Behaviour of Coating Solutions

A new apparatus was constructed and a method was suggested to measure the tackiness of tablet coating solutions. The method is simple, rapid, reproducible and it can be used to fulfil either researchal or control investigations.

Water solutions/or dispersions/of seven different coating materials widely used in the industry were investigated. On the basis of experimental results it was concluded that increase in concentration of solution led to increase in tackiness. By the evaluation of the data gained from the tack values vs. concentration curves it was possible to choose the concentration of coating solution which proved to be the most favorable from the aspects of both producing requirements and tackiness.

The construction and the evaluation of the so called “Tack curves” showing the change of tackiness in time. The data of these curves add further useful informations to the optimization of the production parameters of coating.     

Quantification of lubricant activity of magnesium stearate by atomic force microscopy

Magnesium stearate (MgSt) is commonly used in pharmaceutical formulations as a lubricant to facilitate tablet release from the die after compression. In this study, we quantify the effect of MgSt on the interaction forces between microcrystalline cellulose (MCC) and steel surfaces. A quantitative approach to better understand the mechanism by which MgSt affects powder performance will assist in improved control and formulation design. We find that the forces between MgSt and steel surface are stronger than the interactions between MgSt itself, between MgSt and an MCC particle, and an MCC particle and a steel surface. These quantitative findings offer an explanation how MgSt facilitates lubrication during tablet ejection.