Thursday, September 30, 2010

Operations involved in tablet manufacturing | dotty

1.7.1 Introduction

The manufacture of oral solid dosage
forms such as tablets is a complex multi-stage process under which the starting
materials change their physical characteristics a number of times before the
final dosage form is produced.

Traditionally, tablets have been made by granulation, a
process that imparts two primary requisites to formulate: compactibility and
fluidity. Both wet granulation and dry granulation (slugging and roll
compaction) are used. Regardless of weather tablets are made by direct
compression or granulation, the first step, milling and mixing, is the same;
subsequent step differ.

Numerous unit processes are involved in making tablets, including
particle size reduction and sizing, blending, granulation, drying, compaction,
and (frequently) coating. Various factors associated with these processes can
seriously affect content uniformity, bioavailability, or stability.

Various Unit Operation Sequences In Tablet  Manufacturing

Figure.20. Various Unit Operation Sequences In Tablet Manufacturing

Typical  Manufacturing Process Of Tablet

Figure.21. Typical Manufacturing Process Of Tablet

Table.22. Typical Unit Operation Involved In Wet Granulation, Dry Granulation And Direct Compression(13)




and mixing of drugs and excipients

and mixing of drugs and excipients

1. Milling and mixing of drugs and excipients

of binder solution

into slugs or roll compaction

Compression of tablet

massing by addition of binder solution
or granulating solvent

and screening of slugs and compacted powder

of wet mass

with lubricant and disintegrant

of the wet granules

of tablet

of dry granules

with lubricant and disintegrant to produce “running powder”

of tablet

1.7.2 Dispensing (weighing and measuring)

Dispensing is the first step in any
pharmaceutical manufacturing process. Dispensing is one of the most critical
steps in pharmaceutical manufacturing; as during this step, the weight of each
ingredient in the mixture is determined according to dose.

Dispensing may be done by purely manual
by hand scooping from primary containers and weighing each ingredient by hand
on a weigh scale, manual weighing with material lifting assistance like Vacuum
transfer and Bag lifters, manual or assisted transfer with automated weighing
on weigh table, manual or assisted filling of loss-in weight dispensing system,
automated dispensaries with mechanical devices such as vacuum loading system
and screw feed system.

Issues like
weighing accuracy, dust control (laminar air flow booths, glove boxes), during
manual handling, lot control of each ingredient, material movement into and out
of dispensary should be considered during dispensing.

1.7.3 Sizing

The sizing (size reduction, milling, crushing, grinding,
pulverization) is an impotent step (unit operation) involved in the tablet

In manufacturing of compressed tablet, the mixing or blending of several solid
ingredients of pharmaceuticals is easier and more uniform if the ingredients
are approximately of same size. This provides a greater uniformity of dose. A
fine particle size is essential in case of lubricant mixing with granules for
its proper function.

Advantages associated with size reduction in tablet
manufacture are as follows:

i) It increases surface area, which may enhance an active ingredient’s dissolution
rate and hence bioavailability.

ii)Improved the tablet-to-tablet content uniformity by virtue of the increased number of
particles per unit weight.

iii)Controlled particle size distribution of dry granulation or mix to promote better flow of
mixture in tablet machine.

iv)Improved flow properties of raw materials.

v)Improved colour and/or active ingredient dispersion in tablet excipients.

vi)Uniformly sized wet granulation to promote uniform drying.

There are also certain disadvantages associated with this unit operation if not
controlled properly. They are as follows:

i)A possible change in polymorphic form of the active ingredient, rendering it less
or totally inactive, or unstable.

ii) A decrease in bulk density of active compound and/or excipients, which may cause
flow problem and segregation in the mix.

iii)An increase in surface area from size reduction may promote the adsorption of air, which may
inhibit wettability of the drug to the extent that it becomes the limiting
factor in dissolution rate.

A number of different types of machine
may be used for the dry sizing or milling process depending on whether gentle screening
or particle milling is needed. The
ranges of equipment employed for this process includes Fluid energy mill,
Colloidal mill, Ball mill, Hammer mill, Cutting mill, Roller mill, Conical
mill, etc.

1.7.4 Powder blending

The successful mixing of powder is acknowledged to be more
difficult unit operation because, unlike the situation with liquid, perfect
homogeneity is practically unattainable.

In practice, problems also arise because of the inherent cohesiveness and
resistance to movement between the individual particles. The process is further
complicated in many system, by the presence of substantial segregation
influencing the powder mix. They arise because of difference in size, shape,
and density of the component particles.

The powder/granules blending
are involved at stage of pre granulation and/or post granulation stage of
tablet manufacturing. Each process of mixing has optimum mixing time and so
prolonged mixing may result in an undesired product. So, the optimum mixing
time and mixing speed are to be evaluated. Blending step prior to compression
is normally achieved in a simple tumble blender. The Blender may be a fixed
blender into which the powders are charged, blended and discharged. It is now
common to use a bin blender which blends.

In special cases of mixing a lubricant, over mixing should
be particularly monitered.

The various blenders used include “V”
blender, Oblicone blender, Container blender, Tumbling blender, Agitated powder
blender, etc.

But now a days to
optimize the manufacturing process particularly in wet granulation the various
improved equipments which combines several of processing steps (mixing,
granulation and/or drying) are used. They are “Mixer granulator” or “High shear
mixing machine”.

1.7.5 Granulation

Following particle size reduction and
blending, the formulation may be granulated, which provides homogeneity of drug
distribution in blend.

1.7.6 Drying

Drying is a most important step in the formulation and
development of pharmaceutical product. It is important to keep the residual
moisture low enough to prevent product deterioration and ensure free flowing

The commonly used dryer includes Fluidized – bed dryer,
Vacuum tray dryer, Microwave dryer, Spray dryer, Freeze dryer, Turbo - tray
dryer, Pan dryer, etc.

1.7.7 Tablet compression

After the preparation of granules (in case of wet
granulation) or sized slugs (in case of dry granulation) or mixing of
ingredients (in case of direct compression), they are compressed to get final
product. The compression is done either by single punch machine (stamping
press) or by multi station machine (rotary press).

The tablet press
is a high-speed mechanical device. It 'squeezes' the ingredients into the
required tablet shape with extreme precision. It can make the tablet in many
shapes, although they are usually round or oval. Also, it can press the name of
the manufacturer or the product into the top of the tablet.

Each tablet is made by
pressing the granules inside a die, made up of hardened steel. The die is a
disc shape with a hole cut through its centre. The powder is compressed in the
centre of the die by two hardened steel punches that fit into the top and
bottom of the die.

The punches and dies are fixed to a turret that spins round.
As it spins, the punches are driven together by two fixed cams - an upper cam
and lower cam. The top of the upper punch (the punch head) sits on the upper
cam edge .The bottom of the lower punch sits on the lower cam edge.

The shapes of the two cams
determine the sequence of movements of the two punches. This sequence is
repeated over and over because the turret is spinning round.

The force exerted on the ingredients in the dies is very
carefully controlled. This ensures that each tablet is perfectly formed. Because
of the high speeds, they need very sophisticated lubrication systems. The
lubricating oil is recycled and filtered to ensure a continuous supply.

Common stages occurring during compression

Stage 1: Top punch is withdrawn from the die
by the upper cam

Bottom punch is low in the die so powder falls in through the hole and fills the die

Stage 2: Bottom punch moves up to adjust the powder
weight-it raises and expels some powder

Stage 3: Top punch is driven into the die by upper cam

Bottom punch is raised by lower cam

Both punch heads pass between heavy rollers to compress the powder

Stage 4: Top punch is withdraw by the upper cam

Lower punch is pushed up and expels the tablet

Tablet is removed from the die surface by surface plate

Stage 5: Return to stage 1

Stage Occurring During Compression

Figure.22. Stage Occurring During Compression

1.7.8 Auxiliary Equipments (1)

I. Granulation Feeding Device:

In many cases, speed of die table is such that the time of
die under feed frame is too short to allow adequate or consistent gravity
filling of die with granules, resulting in weight variation and content
uniformity. These also seen with poorly flowing granules. To avoid these
problems, mechanized feeder can employ to force granules into die cavity.

II.Tablet weight monitoring devices:-

High rate of tablet output with
modern press requires continuous tablet weight monitoring with electronic
monitoring devices like Thomas Tablet Sentinel,
Pharmakontroll and Killan control System-MC. They monitors force at each
compression station by starin gage technology which is then correlated with
tablet weight.

III. Tablet Deduster : -

In almost all cases, tablets coming out of a tablet machine
bear excess powder on its surface and are run through the tablet deduster to
remove that excess powder.

IV. Fette machine

Fette machine is device that chills the compression
components to allow the compression of low melting point substance such as
waxes and thereby making it possible to compress product with low meting

1.7.9 Packaging

manufacturers have to pack their medicines before they can be sent out for
distribution. The type of packaging will depend on the formulation of the

'Blister packs' are a common
form of packaging used for a wide variety of products. They are safe and easy
to use and they allow the consumer to see the contents without opening the
pack. Many pharmaceutical companies use a standard size of blister pack. This
saves the cost of different tools and to change the production machinery
between products. Sometimes the pack may be perforated so that individual tablets
can be detached. This means that the expiry date and the name of the product
have to be printed on each part of the package. The blister pack itself must
remain absolutely flat as it travels through the packaging processes,
especially when it is inserted into a carton. This poses interesting problems
for the designers. Extra ribs are added to the blister pack to improve its

Key Phrases

The manufacturing of tablet involves numerous unit
processes including

ØParticle size reduction and sizing





Microscopic Wear and Corrosion Reduce the Performance and Life of Pharmaceutical Tablet Compression

To the naked eye, it is nearly impossible to spot the microscopic signs of abrasive wear and corrosion that can reduce the efficiency of pharmaceutical tablet compression tooling. The high-performance tooling used by pharmaceutical companies in the manufacture of tablets and capsules requires highly polished, scratch-free surfaces in order to maintain the surface contact necessary to compress formulation powders and develop a consistent, quality product. Unfortunately, industry-standard tooling steels such as D-series, S-series, and stainless steels (408, 440C) are all prone to abrasive wear and corrosion. As the working surfaces of the punches and dies roughen from wear and corrosion, a number of physical phenomena occur which act to reduce tableting productivity and increase manufacturing costs.

Increased Mechanical Interlocking -

When microscopic scratches and pits develop in tooling surfaces, the pharmaceutical powders can become trapped in these surface imperfections. As additional tablets are compressed, the powders will stick to the particles trapped in the surface and start to build-up on the surface. Unfortunately, due to the fact that these imperfections are nearly invisible to the human eye, the effects of these scratches and pits are not noticed until it is too late. Eventually, sticking and picking appear, and production must be halted to remove and clean the punches. The losses for the manufacturer quickly mount every second that production is offline.

Similarly, if tablet tooling surfaces corrode and rust layers build on the punch surface, powders will begin to stick to the roughened rust layers. Cleaning with detergents or solvents will remove the adhered powders but will not restore the original finish of the tooling surfaces. Tooling in this condition requires regular buffing and polishing to smooth out scratches and pits, and remove corrosion products in order to return surfaces to working conditions. Again, production must be stopped to remove and polish the machine tooling.

Increased Friction between Powders and Punch / Die Surfaces -

Whether due to scratching or corrosion, roughened surfaces will also increase frictional forces as formula powders flow across the punch faces during compression. Because pharmaceutical tablet production is an extremely precise process, the slightest imperfections in the process at any level will result in a growing number of additional problems down the line. Manufacturers use predetermined levels of materials that have been found to achieve the highest levels of efficiency. Once minor surface abrasions begin to appear in tooling, the predetermined levels of lubricants and glidants will no longer be effective. Higher compression forces may be required and the work of ejection will increase.

Reduced Life of Tablet Compression Tooling -

Constant restoration of worn and corroded punch faces by buffing and polishing has a significantly negative impact on tool life. Buffing compounds contain abrasives that actually remove thin layers of the metal surface in order to polish-out scratches and pits. Repeated buffing can reduce the critical punch dimensions in the land area at the punch tip, thus degrading the fit between the punch and die. Constant buffing also results in rapid degradation of the aspect ratios of embossed features on the punches. In both cases the usable life of the punch is dramatically reduced.

Rather than continue the cycle of abrasive wear, restoration, and subsequent further degradation, pharmaceutical manufacturers have additional options for maintaining the surface integrity of high performance tooling. There are a number of different performance coatings available, each with various advantages and disadvantages. Some precision metal coatings, such as those applied by the IBED coating process, are able to protect and enhance tablet compression tooling surfaces and are applied at low temperature, thus eliminating the possibility of tooling dimensional distortion. The result is longer life and improved efficiency for pharmaceutical tablet compression tooling.

Dr. Deutchman is currently Chairman and Director of Research and Development at Beamalloy Technologies, LLC where he is directly involved with the research, development, and application of the Beamalloy patented IBED coating process. He is the author of numerous articles published in a variety of scientific and trade journals, holds numerous patents, and lectures widely on surface engineering.

Application of gluconolactone in direct tablet compression

Gluconolactone was evaluated as an excipient for tablets prepared by direct compression using various drugs known to be difficult to compress. The physical properties of the tablets were evaluated after compression and after storage and were satisfactory. Comparative studies were conducted between gluconolactone and anhydrous lactose, a common direct compression diluent, for development of static charges during blending, flow, drug distribution, drug stratification, color distribution, compressibility, and preservation against mold growth. Gluconolactone possesses those properties necessary to produce high quality tablets by the direct compression process. Separate powdered mixtures of aspirin USP with gluconolactone, anhydrous lactose, spray-dried lactose, mannitol, and sorbitol were stored at various humidities and temperatures for specified periods and tested for the integrity of aspirin. Gluconolactone contributed least to the degradation of the drug as compared to other excipients studied. A preliminary in vivo study also was conducted on the bioavailability of aspirin from separate and similar mixtures with gluconolactone, anhydrous lactose, and starch. Gluconolactone did not show any inhibitory effect on aspirin absorption.

The influence of engravings on the sticking of tablets. Investigations with an instrumented upper punch.

The purpose of this study was to investigate the influence of engravings on the sticking of tablets. Therefore, an instrumented upper punch capable of measuring the pull-off force, which occurs when the punch detaches itself from the upper surface of a tablet, was equipped with small cones of different angles between the punch face and the cones' lateral face. The cones could be screwed into a threaded hole at the center of the punch face. The adhesion forces of two formulations known to stick to engravings during production increased with a greater steepness of the cones' lateral face. With microencapsulated acetylsalicylic acid, no quantitative differences could be found between the adhesion forces obtained with plain and modified punch faces, indicating that the sticking behavior of the substance was not affected by shear forces. Starch 1500 showed higher adhesion force signals in comparison to those obtained with a plain punch face. Microcrystalline cellulose, which gave no adhesion force signals with a plain punch face and did not stick to the cones, showed distinct pull-off signals. The instrumented upper punch equipped with shear cones is a valuable instrument for detecting the adhesion caused by engravings and is therefore a helpful tool for tablet formulation development and the design optimization of tablet identification.

Effects of surface roughness and chrome plating of punch tips on the sticking tendencies of model ibuprofen formulations.

The sticking of three model ibuprofen-lactose formulations with respect to compaction force and the surface quality of the upper punch were assessed. Compaction was performed at 10, 25 or 40 kN using an instrumented single-punch tablet press. Two sets of 12.5-mm flat-faced punches were used to evaluate the influence of surface quality. A third set of chrome-plated tooling was also used. Surface profiles (Taylor Hobson Talysurf 120) of the normal tooling upper punches indicated a large difference in quality. The punches were subsequently classified as old (Ra = 0.33 microm) or new (Ra = 0.04 microm) where Ra is the mean of all positive deviations from zero. Surface profiles of sample tablets were also obtained. Following compaction, ibuprofen attached to the face was quantified by spectroscopy. Punch surface roughness, compaction force and the blend composition were all significant factors contributing to sticking. Chrome plating of punch faces increased sticking at a low compaction force but decreased sticking at higher forces. Surface roughness of the tablets did not correlate with the corresponding data for sticking, indicating that this is not a suitable method of quantifying sticking.

Modeling of adhesion in tablet compression

Adhesion problems are usually not identified until prolonged compression runs are studied near the end of the drug development process. During tablet manufacturing, adhesion problems encountered are usually addressed by statistically designed experiments based on experience. It would be a significant benefit for the pharmaceutical industry if adhesion problems could be identified early in drug development based on molecular considerations of the drug substance and/or prototype formulations. Drug substance-punch face interactions were reported in the first of the articles in this series, and focused on the elucidation of adhesion problems in tablet compression. It was hypothesized that the intermolecular interactions between drug molecules and the punch face was the first step (or criterion) in the adhesion process, and that the rank order of adhesion during tablet compression should correspond with the rank order of these energies of interaction. That is, the interaction between the molecular structure of the drug and the metal surface determines the primary interaction event or relative potential for adhesion, while the mechanical processes and/or lubrication effects may subsequently impact the extent of adhesion. Molecular simulations and atomic force microscopy were used to establish the rank order of the work of adhesion of a series of profen compounds. The results predicted that the relative degree of drug substance-punch face adhesion should decrease in the order of ketoprofen > ibuprofen > flurbiprofen. In this study, the authors investigated whether the rank order of the work of adhesion established on the molecular level and interparticulate level holds true in the tableting environment by measuring tablet take-off force, ejection force, and visual observation of the punch surfaces for both pure drug compacts and formulated tablets. The compaction simulator was used for pure profen compacts, while the instrumented tablet press for formulated tablets. Due to the inability to extract the adhesion force component from the total ejection force measurement, tablet ejection force was not used as a criterion to judge the adhesion behavior of the model compounds. The criteria used for judgement of punch face adhesion were tablet take-off force and visual observation of the punch faces. The rank order of adhesion for both pure drug and formulated tablets was determined to follow the order of ketoprofen > ibuprofen > flurbiprofen. The effect of run time on adhesion behavior was also investigated. Therefore, the rank order of the punch-face adhesion tendencies for the series of profen compounds was determined, and found to agree with the data from the predictive methods reported in the first article.

Problems in tablet manufacturing


An ideal tablet should be free from any visual defect or functional defect. The advancements and innovations in tablet manufacture have not decreased the problems, often encountered in the production, instead have increased the problems, mainly because of the complexities of tablet presses; and/or the greater demands of quality.
An industrial pharmacist usually encounters number of problems during manufacturing. Majority of visual defects are due to inadequate fines or inadequate moisture in the granules ready for compression or due to faulty machine setting. Functional defects are due to faulty formulation. Solving many of the manufacturing problems requires an in–depth knowledge of granulation processing and tablet presses, and is acquired only through an exhaustive study and a rich experience.
Here, we will discuss the imperfections found in tablets along–with their causes and related remedies. The imperfections are known as: ‘VISUAL DEFECTS’ and they are either related to imperfections in any one or more of the following factors:
I. Tableting Process
II. Excipient
III. Machine
The defects related to Tableting Process are as follows:
i) CAPPING: It is partial or complete separation of the top or bottom of tablet due air-entrapment in the granular material.
ii) LAMINATION: It is separation of tablet into two or more layers due to air-entrapment in the granular material.
iii) CRACKING: It is due to rapid expansion of tablets when deep concave punches are used.

The defects related to Excipient are as follows:

iv) CHIPPING: It is due to very dry granules.
v) STICKING: It is the adhesion of granulation material to the die wall
vi) PICKING: It is the removal of material from the surface of tablet and its adherance to the face of punch.
These problems (v, vi, vii) are due to more amount of binder in the granules or wet granules.
The defect related to more than one factor:

viii) MOTTLING: It is either due to any one or more of these factors: Due to a coloured drug, which has different colour than the rest of the granular material? (Excipient- related); improper mixing of granular material (Process-related); dirt in the granular material or on punch faces; oil spots by using oily lubricant.
The defect related to Machine
ix)DOUBLE IMPRESSION: It is due to free rotation of the punches, which have some engraving on the punch faces.
Further, in this section, each problem is described along-with its causes and remedies which may be related to either of formulation (granulation) or of machine (dies, punches and entire tablet press).


‘Capping’ is the term used, when the upper or lower segment of the tablet separates horizontally, either partially or completely from the main body of a tablet and comes off as a cap, during ejection from the tablet press, or during subsequent handling.
Reason: Capping is usually due to the air–entrapment in a compact during compression, and subsequent expansion of tablet on ejection of a tablet from a die.
Sr. No.
Large amount of fines in the granulation
Remove some or all fines through 100 to 200 mesh screen
Too dry or very low moisture content (leading to loss of proper binding action).
Moisten the granules suitably. Add hygroscopic substance e.g.: sorbitol, methyl- cellulose or PEG-4000.
Not thoroughly dried granules.
Dry the granules properly.
Insufficient amount of binder or improper binder.
Increasing the mount of binder OR
Adding dry binder such as pre-gelatinized starch, gum acacia, powdered sorbitol, PVP, hydrophilic silica or powdered sugar.
Insufficient or improper lubricant.
Increase the amount of lubricant or change the type of lubricant.
Granular mass too cold to compress firm.
Compress at room temperature.
Sr. No.
Poorly finished dies
Polish dies properly. Investigate other steels or other materials.
Deep concave punches or beveled-edge faces of punches.
Use flat punches.
Lower punch remains below the face of die during ejection.
Make proper setting of lower punch during ejection.
Incorrect adjustment of sweep-off blade.
Adjust sweep-off blade correctly to facilitate proper ejection.
High turret speed.
Reduce speed of turret (Increase dwell time).

Lamination / Laminating

Definition: ‘Lamination’ is the separation of a tablet into two or more distinct horizontal layers.
Reason: Air–entrapment during compression and subsequent release on ejection.
The condition is exaggerated by higher speed of turret.
Sr. No.
Oily or waxy materials in granules
Modify mixing process. Add adsorbent or absorbent.
Too much of hydrophobic lubricant e.g.: Magnesium-stearate.
Use a less amount of lubricant or change the type of lubricant.
TABLE.30. The Causes and Remedies of Lamination related to MACHINE (Dies, Punches and Tablet Press)

Sr. No.
Rapid relaxation of the peripheral regions of a tablet, on ejection from a die.
Use tapered dies, i.e. upper part of the die bore has an outward taper of 3° to 5°.
Rapid decompression
Use pre-compression step. Reduce turret speed and reduce the final compression pressure.


Definition: ‘Chipping’ is defined as the breaking of tablet edges, while the tablet leaves the press or during subsequent handling and coating operations.
Reason: Incorrect machine settings, specially mis-set ejection take-off.


Sr. No.
Sticking on punch faces
Dry the granules properly or increase lubrication.
Too dry granules.
Moisten the granules to plasticize. Add hygroscopic substances.
Too much binding causes chipping at bottom.
Optimize binding, or use dry binders.

Sr. No.
Groove of die worn at compression point.
Polish to open end, reverse or replace the die.
Barreled die (center of the die wider than ends)
Polish the die to make it cylindrical
Edge of punch face turned inside/inward.
Polish the punch edges
Concavity too deep to compress properly.
Reduce concavity of punch faces. Use flat punches.


Definition: Small, fine cracks observed on the upper and lower central surface of tablets, or very rarely on the sidewall are referred to as ‘Cracks’.
Reason: It is observed as a result of rapid expansion of tablets, especially when deep concave punches are used.

Sr. No.
Large size of granules.
Reduce granule size. Add fines.
Too dry granules.
Moisten the granules properly and add proper amount of binder.
Tablets expand.
Improve granulation. Add dry binders.
Granulation too cold.
Compress at room temperature.

Sr. No.
Tablet expands on ejection due to air entrapment.
Use tapered die.
Deep concavities cause cracking while
removing tablets
Use special take-off.

Sticking / Filming

Definition: ‘Sticking’ refers to the tablet material adhering to the die wall.
Filming is a slow form of sticking and is largely due to excess moisture in the granulation.
Reason: Improperly dried or improperly lubricated granules.

Sr. No.
Granules not dried properly.
Dry the granules properly. Make moisture analysis to determine limits.
Too little or improper lubrication.
Increase or change lubricant.
Too much binder
Reduce the amount of binder or use a different type of binder.
Hygroscopic granular material.
Modify granulation and compress under controlled humidity.
Oily or way materials
Modify mixing process. Add an absorbent.
Too soft or weak granules.
Optimize the amount of binder and granulation technique.

Sr. No.
Concavity too deep for granulation.
Reduce concavity to optimum.
Too little pressure.
Increase pressure.
Compressing too fast.
Reduce speed.


Definition: ‘Picking’ is the term used when a small amount of material from a tablet is sticking to and being removed off from the tablet-surface by a punch face.
The problem is more prevalent on the upper punch faces than on the lower ones. The problem worsens, if tablets are repeatedly manufactured in this station of tooling because of the more and more material getting added to the already stuck material on the punch face.
Reason: Picking is of particular concern when punch tips have engraving or embossing letters, as well as the granular material is improperly dried.
Sr. No.
Excessive moisture in granules.
Dry properly the granules, determine optimum limit.
Too little or improper lubrication.
Increase lubrication; use colloidal silica as a ‘polishing agent’, so that material does not cling to punch faces.
Low melting point substances, may soften from the heat of compression and lead to picking.
Add high melting-point materials. Use high meting point lubricants.
Low melting point medicament in high concentration.
Refrigerate granules and the entire tablet press.
Too warm granules when compressing.
Compress at room temperature. Cool sufficiently before compression.
Too much amount of binder.
Reduce the amount of binder, change the type or use dry binders.
Sr. No.
Rough or scratched punch faces.
Polish faces to high luster.
Embossing or engraving letters on punch faces such as B, A, O, R, P, Q, G.
Design lettering as large as possible.
Plate the punch faces with chromium to produce a smooth and non-adherent face.
Bevels or dividing lines too deep.
Reduce depths and sharpness.
Pressure applied is not enough; too soft tablets.
Increase pressure to optimum.


Definition: ‘Binding’ in the die, is the term used when the tablets adhere, seize or tear in the die. A film is formed in the die and ejection of tablet is hindered. With excessive binding, the tablet sides are cracked and it may crumble apart.
Reason: Binding is usually due to excessive amount of moisture in granules, lack of lubrication and/or use of worn dies.
Sr. No.
Too moist granules and extrudes around lower punch.
Dry the granules properly.
Insufficient or improper lubricant.
Increase the amount of lubricant or use a more effective lubricant.
Too coarse granules.
Reduce granular size, add more fines, and increase the quantity of lubricant.
Too hard granules for the lubricant to be effective.
Modify granulation. Reduce granular size.
Granular material very abrasive and cutting into dies.
If coarse granules, reduce its size.
Use wear-resistant dies.
Granular material too warm, sticks to the die.
Reduce temperature.
Increase clearance if it is extruding.
Sr. No.
Poorly finished dies.
Polish the dies properly.
Rough dies due to abrasion, corrosion.
Investigate other steels or other materials or modify granulation.
Undersized dies. Too little clearance.
Rework to proper size.
Increase clearance.
Too much pressure in the tablet press.
Reduce pressure. OR
Modify granulation.


Definition: ‘Mottling’ is the term used to describe an unequal distribution of colour on a tablet, with light or dark spots standing out in an otherwise uniform surface.
Reason: One cause of mottling may be a coloured drug, whose colour differs from the colour of excipients used for granulation of a tablet.

Sr. No.
A coloured drug used along with colourless or white-coloured excipients.
Use appropriate colourants.
A dye migrates to the surface of granulation while drying.
Change the solvent system,
Change the binder,
Reduce drying temperature and
Use a smaller particle size.
Improperly mixed dye, especially during ‘Direct Compression’.
Mix properly and reduce size if it is of a larger size to prevent segregation.
Improper mixing of a coloured binder solution.
Incorporate dry colour additive during powder blending step, then add fine powdered adhesives such as acacia and tragacanth and mix well and finally add granulating liquid.

Double impression

Definition: ‘Double Impression’ involves only those punches, which have a monogram or other engraving on them.
Reason: At the moment of compression, the tablet receives the imprint of the punch. Now, on some machines, the lower punch freely drops and travels uncontrolled for a short distance before riding up the ejection cam to push the tablet out of the die, now during this free travel, the punch rotates and at this point, the punch may make a new impression on the bottom of the tablet, resulting in ‘Double Impression’.
If the upper punch is uncontrolled, it can rotate during the short travel to the final compression stage and create a double impression.
Sr. No.
Free rotation of either upper punch or lower punch during ejection of a tablet.
-Use keying in tooling, i.e. inset a key alongside of the    punch, so that it fits the punch and prevents punch rotation.
-Newer presses have anti-turning devices, which prevent punch rotation.

Problems and remedies for tablet coating


Definition: It is local detachment of film from the substrate forming blister.
Reason: Entrapment of gases in or underneath the film due to overheating either during spraying or at the end of the coating run.

Sr. No.
Effect of temperature on the strength, elasticity and adhesion of the film.
Use mild drying condition.


Definition: It is defect where the film becomes chipped and dented, usually at the edges of the tablet.
Reason: Decrease in fluidizing air or speed of rotation of the drum in pan coating.
Sr. No.
High degree of attrition associated with the coating process.

Increase hardness of the film by increasing the molecular weight grade of polymer.


Definition: It is defect of film coating whereby volcanic-like craters appears exposing the tablet surface.
Reason: The coating solution penetrates the surface of the tablet, often at the crown where the surface is more porous, causing localized disintegration of the core and disruption of the coating.


Sr. No.
Inefficient drying.

Use efficient and optimum drying conditions.
Higher rate of application of coating solution.
Increase viscosity of coating solution to decrease spray application rate.


Definition: It is defect where isolated areas of film are pulled away from the surface when the tablet sticks together and then part.
Reason: Conditions similar to cratering that produces an overly wet tablet bed where adjacent tablets can stick together and then break apart.
Inefficient drying.
Use optimum and efficient drying conditions or increase the inlet air temperature.
Higher rate of application of coating solution
Decrease the rater of application of coating solution by increasing viscosity of coating solution.


Definition: It is defect whereby pits occur in the surface of a tablet core without any visible disruption of the film coating.
Reason: Temperature of the tablet core is greater than the melting point of the materials used in the tablet formulation.

Sr. No.
Inappropriate drying (inlet air ) temperature
Dispensing with preheating procedures at the initiation of coating and modifying the drying (inlet air) temperature such that the temperature of the tablet core is not greater than the melting point of the batch of additives used.


Definition: It is defect where coating becomes dull immediately or after prolonged storage at high temperatures.
Reason: It is due to collection on the surface of low molecular weight ingredients included in the coating formulation. In most circumstances the ingredient will be plasticizer.
Sr. No.
High concentration and low molecular weight of plasticizer.

Decrease plasticizer concentration and increase molecular weight of plasticizer.


Definition: It is defect best described as whitish specks or haziness in the film.
Reason: It is thought to be due to precipitated polymer exacerbated by the use of high coating temperature at or above the thermal gelation temperature of the polymers.

Sr. No.
High coating temperature
Decrease the drying air temperature
Use of sorbitol in formulation which causes largest fall in the thermal gelation temperature of the Hydroxy Propyl Cellulose, Hydroxy Propyl Methyl Cellulose, Methyl Cellulose and Cellulose ethers.
Avoid use of sorbitol with Hydroxy Propyl Cellulose, Hydroxy Propyl Methyl Cellulose, Methyl Cellulose and Cellulose ethers.

Colour variation

Definition: A defect which involves variation in colour of the film.
Reason: Alteration of the frequency and duration of appearance of tablets in the spray zone or the size/shape of the spray zone.
Sr. No.
Improper mixing, uneven spray pattern, insufficient coating, migration of soluble dyes-plasticizers and other additives during drying.
Go for geometric mixing, reformulation with different plasticizers and additives or use mild drying conditions.


Definition: It is defect that renders the intagliations indistinctness.
Reason: Inability of foam, formed by air spraying of a polymer solution, to break. The foam droplets on the surface of the tablet breakdown readily due to attrition but the intagliations form a protected area allowing the foam to accumulate and “set”. Once the foam has accumulated to a level approaching the outer contour of the tablet surface, normal attrition can occur allowing the structure to be covered with a continuous film.

Sr. No.
Bubble or foam formation because of air spraying of a polymer solution
Add alcohol or use spray nozzle capable of finer atomization.

Orange peel/Roughness

Definition: It is surface defect resulting in the film being rough and nonglossy. Appearance is similar to that of an orange.
Reason: Inadequate spreading of the coating solution before drying.
Sr. No.
Rapid Drying
Use mild drying conditions
High solution viscosity
Use additional solvents to decrease viscosity of solution.


Definition: It is defect in which the film either cracks across the crown of the tablet (cracking) or splits around the edges of the tablet (Splitting)
Reason: Internal stress in the film exceeds tensile strength of the film.

Sr. No.
Use of higher molecular weight polymers or polymeric blends.
Use lower molecular weight polymers or polymeric blends.  Also adjust plasticizer type and concentration.

Key Phrases

  • During tablet manufacture, an industrial pharmacist usually encounters many problems. Solving these problems requires an in-depth knowledge of tablet-formulation as well as machine-operating processes.
  • Capping and Lamination are the defects arising as a result of air-entrapment in the granular material.
  • Chipping is a defect related arising due to very dry granules.
  • Cracking is due to rapid expansion of tablets, when deep concave punches are used.
  • Sticking, Picking and Binding are the imperfections related to more amount of binder in granules.
  • Mottling is an imperfection arising due to more than one factor: a coloured drug, dirt in granules or the use of an oily lubricant.
  • Double-Impression is related to a machine defect: it is caused by the free rotation of punches that have some engraving on the punch-faces.
Coating defects:
  • Blistering is related to entrapment of gases in or underneath the film due to overheating either during spraying or at the end of the coating run. Use of mild drying conditions can solve this problem.
  • Chipping is related to higher degree of attrition associated with the coating process. Increase in hardness of the film by increasing the molecular weight grade of polymer can solve this problem.
  • Cratering is related to penetration of the coating solution into the surface of the tablet, often at the crown where the surface is more porous, causing localized disintegration of the core and disruption of the coating. Decrease in spray application rate and use of optimum and efficient drying conditions can solve this problem.
  • Pitting is defect in which temperature of the tablet core is greater than the melting point of the materials used in tablet formulation. Dispensing with preheating procedures at the initiation of coating and modifying the drying (inlet air) temperature can solve this problem.
  • Blooming or dull film is generally because of higher concentration and lower molecular weight of plasticizer. So use lower concentration and higher molecular grade of plasticizer.
  • Blushing/Whitish specks/Haziness of the film is related to precipitation of polymer exacerbated by the use of high coating temperature at or above the thermal gelation temperature of the polymers.
  • Colour variation is because of improper mixing, uneven spray pattern, insufficient coating or migration of soluble dyes during drying. Geometric mixing, mild drying conditions and reformulation with different plasticizers can solve this problem.
  • Infilling is because of bubble/foam formation during air spraying of a polymer solution. Addition of alcohol or use of spray nozzle capable of finer atomization can solve this problem.
  • Orange peel/Roughness is related to inadequate spreading of the coating solution before drying. So decrease in viscosity of coating solution can counter this defect.
  • Cracking is seen when internal stresses in the film exceeds tensile strength of the film. This is common with higher molecular weight polymers or polymeric blends. So use lower molecular weight polymers or polymeric blends

Melt Granulation with polyethylene glycol in a Single Pot Processor

This study compares different processing methods to prepare a melt granulation with polyethylene glycol (PEG) in a high shear mixer / single pot processor. For melting the PEG, either the heated jacket or heated jacket supplemented with microwaves was used to supply the necessary energy. For cooling the mass after granulation, 3 methods were compared: cooling with the jacket, cooling with pressurized air and cooling with liquid nitrogen.
The results of the comparison show a significant time reduction in the process when using microwave energy for heating the product, and liquid nitrogen for cooling. No differences in granule particle size distribution could be observed.
Melt agglomeration is a process by which agglomeration – or size enlargement by which fine particles are bound together to agglomerates or granulates – is obtained through the addition of either a molten binder liquid or a solid binder which melts during the process. Agglomerates are formed by agitation of the mixture. To obtain a stable, dry granule, a cooling to ambient temperature is necessary to solidify the binder.

Recently, the interest in melt agglomeration processes from the pharmaceutical industry has grown steadily because of the advantages the technique offers over conventional wet granulation methods:
  • When the binder is added in solid form, the liquid addition step is avoided, simplifying the equipment, the process and the cleaning.
  • As no liquid is added, the drying phase – often the most time-consuming step in a conventional process – is eliminated.
  • When the binder used is insoluble in water, melt agglomeration may present a simple way to form sustained release formulations.
Many different procedures and equipment have been used for melt agglomeration. High shear mixers are very well suited to execute a melt agglomeration process: the high shear forces caused by the impeller rotation make it easier to obtain a uniform distribution of the molten binder, and generate enough frictional heat to assist the melting process. High shear mixers have also been shown to be suitable for melt pelletization, due to the high shearing forces, plus the bowl shape.

In a high shear mixer almost all procedures for melt agglomeration and melt pelletization use the heat supplied by the heated jacket of the bowl and/or the development of heat caused by friction to melt the binder. In production scale equipment the heating of the product using the jacket can be very time-consuming (1). The application of an external heating source, independent from the jacket of the bowl or from the generation of friction heat, might prove to be more time-efficient.

The first part of this study investigates the possibility of using microwave energy as an external heating source to melt the binder. These trials used pilot scale equipment and compared the process with regard to process time and granule particle size, using either the heated jacket or microwaves as the energy source.

The second part of the study focuses on the cooling phase of the process, which is necessary to obtain a dry, stable granule. In many cases, this phase is the most time-consuming of the whole melt granulation process due to the limited cooling capacity of the jacket of the high shear mixer and an insulation effect of the binder itself. The aim was to shorten the cooling time by using pressurized air or liquid nitrogen to reduce the temperature of the product.

Effervescent Dosage Manufacturing

Effervescent tablets are an interesting pharmaceutical dosage form, offering some unique advantages when compared with simple tablets. However, the manufacturing process involves some critical steps that need to be addressed carefully during formulation and factory design.

IntroductionOral dosage forms are the most popular way of taking medication, despite having some disadvantages compared with other methods. One such disadvantage is the risk of slow absorption of the active pharmaceutical ingredient (API), which can be overcome by administering the drug in liquid form and, therefore, possibly allowing the use of a lower dosage. However, because many APIs only show a limited level of stability in liquid form, effervescent tablets, which are dissolved in water before administration, have been formulated as an alternative dosage form. Advantages of effervescent tablets compared with other oral dosage forms include
  • an opportunity for formulators to improve the taste
  • a more gentle action on a patient’s stomach
  • marketing aspects (fizzy tablets may have more consumer appeal than traditional dosage forms).
The disadvantages of effervescent dosage forms are the need for larger tablets, a complex production process and, very often, the need for specialist packaging materials

Lactose in Pharmaceutical Applications

Lactose is a naturally occurring simple carbohydrate, or sugar, found only in the milk of mammals. For this reason, it is also commonly referred to as "milk sugar." All commercial lactose is obtained from the milk of cows as a by-product of the dairy industry. Chemically, lactose is the disaccharide of the simple sugars D-galactose and D-glucose (Figure 1). In other words, the lactose molecule comprises one molecule of D-galactose chemically linked to one molecule of D-glucose. Lactose exists in two isomeric forms, known as alpha and beta (designated a-lactose and b-lactose).

Pharmaceutical-grade lactose is highly pure lactose specifically produced to meet the standards of identity and purity set down in the lactose monographs of the various pharmacopoeia, including the United States Pharmacopoeia/National Formulary (USP/NF). Lactose is widely used as a filler or diluent in tablets and capsules, and to a more limited extent in lyophilized products, infant feed formulas, and a diluent in dry-powder inhalations.1-9
Lactose is widely used as a filler or filler-binder in the manufacture of pharmaceutical tablets and capsules. The general properties of lactose that contribute to its popularity as an excipient are its:
  • cost effectiveness;
  • availability;
  • bland taste;
  • low hygroscopicity;
  • compatibility with active ingredients and other excipients;
  • excellent physical and chemical stability; and
  • water solubility
Various lactose grades are commercially available that have different physical properties, such as particle size distribution and flow characteristics. The most common form of lactose used in pharmaceutical formulation is crystalline a-lactose monohydrate. This form is available in a range of milled and sifted pharmaceutical grades differing in physical properties, such as flowability, bulk density, and particle size distribution (Figure 2).

Lactose is also available in modified forms for use as a filler-binder in the production of tablets by the direct compression method. The two most important forms for this application are spray dried lactose and anhydrous lactose (Figure 3). These forms have the key property that they are inherently compactable, that is, they are able to form a solid compact (ie, tablet) under compression.

In order to make tablets or capsules, a blend of excipients and active ingredients must first be prepared. In its final form, as the tablet press or capsule filling feed material, this blend is referred to as the running powder. Three major processes are used to prepare the running powder from its components; these are:
  • wet granulation;
  • dry granulation or slugging; and
  • dry mixing.
For wet granulation, the binder can be added dry to the powder blend, or as a solution in the solvent. The solvent is usually ethanol, water, or a mixture of both. The actual granulation is performed in either a high-shear, or low-shear type mixer. Low-shear granulation requires cheaper equipment and produces a more porous granule. High-shear granulation is faster and affords good control over particle size.
The finer milled grades are commonly used as fillers in the production of tablets by the wet granulation, or in applications in which a small particle size is required. The coarser sifted grades are used when flowability is important, for example, as diluents in capsule and sachet filling applications, and as a flow improver. Some sifted grades are also used as fillers in granulation and direct compression formulations, although they must be used with a binder, as crystalline a-lactose monohydrate has little inherent compactability.
Fluid bed wet granulation is another
variation of the process in which the granulation and drying is carried out in the same vessel (a fluid bed granulator). The powder mix is fluidized by dry air inside a chamber. The binder solution is sprayed onto the fluidized powder to form the agglomerates. Air fluidizing continues until the agglomerates are dry. The process requires expensive equipment, but is simpler and produces a very porous low-density granule, which can result in faster drug dissolution. Slow drug dissolution is sometimes a problem associated with wet granulation, as the active ingredient is locked into the granule, and initial tablet disintegration liberates the granules rather than the primary drug particles.
In dry granulation, particle size enlargement is achieved by aggregating the powder particles under high pressure (ie, by compaction) then milling the compressed material to the desired size. Fines generated by milling are recycled back through the compactor. The compression step is typically carried out in a roller compactor in which the powder is compressed between two rollers.
In direct compression, the key running powder requirements (principally blend homogeneity, consistent bulk density, flow, and compactability) must be met by the dry blend of excipients as there is no further physical or chemical modification before tableting. Thus, the physical and functional properties of the excipients, particularly the filler-binder, are very important and must be consistent from batch to batch.
Anhydrous lactose for direct compression is usually produced by drying a lactose solution on the surface of a heated drum. This results in a product composed of agglomerated small crystals of anhydrous b-lactose, with some anhydrous a-lactose present. The anhydrous product has excellent compactability and high solubility due to its high b-lactose content. Tables 1 through 4 are examples of direct compression tablet formulations that use a highly compactable lactose powder composed of agglomerated micro-crystals of anhydrous beta-lactose and stable anhydrous alpha-lactose as a filler-binder.

Generally, the grade of lactose chosen is dependent on the type of dosage form being developed. In addition to the general properties of lactose, several characteristics of lactose will be beneficial to the pharmaceutical formulations if the lactose could offer BSE-free status, very high purity / low protein residue, excellent functionality, special modified forms for direct compression applications, and Calf Rennet Free pharmaceutical lactose.
  1. Zuurman K, Riepma KA, Bolhuis GK, et al. The relationship between bulk density and compactibility of lactose granulations. Int J Pharm. 1994;102:1-9.
  2. Bernabe I, Di Martino P, Joiris E, et al. An attempt at explaining the variability of the compression capacity of lactose. Pharm Technol Eur. 1997;9(1):42-51.
  3. Hwang RC, Peck GR. A systematic evaluation of the compression and tablet characteristics of various types of lactose and dibasic calcium phosphate. Pharm Tech. 2001;25(6):54-68.
  4. Shukla AJ, Price JC. Effect of moisture content on compression properties of directly compressible high beta-content anhydrous lactose. Drug Dev Ind Pharm. 1991;17: 2067-2081.
  5. Thwaites PM, Mashadi AB, Moore WD. An investigation of the effect of high-speed mixing on the mechanical and physical properties of direct compression lactose. Drug Dev Ind Pharm. 1991;17:503-517.
  6. Riepma KA, Dekker BG, Lerk CF. The effect of moisture sorption on the strength and internal surface area of lactose tablets. Int J Pharm 1992;87:149-159.
  7. �elik M, Okutgen E. A feasibility study for the development of a prospective compaction functionality test and the establishment of a compaction data bank. Drug Dev Ind Pharm 1993;19:2309-2334.
  8. Lerk CF. Consolidation and compaction of lactose. Drug Dev Ind Pharm. 1993;19: 2359-2398.
  9. Timsina MP, Martin GP, Marriott C, et al. Drug delivery to the respiratory tract using dry powder inhalers. Int J Pharm. 1994;101:1-13.

How to make tablets from potent APIs

IntroductionWhen talking today about solid dosage form production, often containment immediately becomes one of the issues. Why? The first reason is that APIs are becoming more and more potent: meanwhile more than 50% of all NCE (New Chemical Entities) are classified potent (OEL < 10 μg/m³). Secondly, health and safety authorities all around the world are putting more focus on the protection of operators dealing with these substances. The third reason is that suppliers of various hardware components have developed a huge variety of containment solutions, making it difficult to decide which is best, even for experienced people.
Before we look at the factors defining the required containment levels, and discussing the possible hardware solutions, some fundamental thoughts about containment need to be covered first.
Regulatory situation“It is the first duty of the employer to protect (the health) of his employees.” Even though the regulatory situation differs from country to country, the above statement (taken from the UK COSHH rules) should be seen as general guidance when handling potent substances.
In fact, approximately 30% of all people in western societies will develop some form of cancer during their lifetime. If one of these had been exposed to a carcinogenic substance, whilst working for a pharmaceutical company, there is the potential for a legal claim against the company. This could result in high cost compensation and in very bad publicity, unless the company can prove that the employee had been protected using best available technology.

Where as the UK COSHH rules show a clear hierarchy of control measures:
  1. Elimination at the source
  2. Substitution with a less hazardous material or form
  3. Reduction of the quantity below critical limits
  4. Engineering controls to prevent intolerable operating staff exposure (contained handling)
  5. Administrative controls
  6. Use of Personal Protection Equipment (PPE)
In many other countries no legislation enforces this hierarchy. Most of the western countries will monitor the conditions under which operators have to work in the countries from which they import as it is seen as highly unethical to support practices that create health and safety risks in other areas of the world.
There are good reasons for this order of preference, especially that PPE should only be used as a last resort (for maintenance; for necessary, but unforeseen interactions; or if any other method further up in the hierarchy has been considered without success). Why is this? Firstly, PPE only protects the operator. The hazardous substance is not contained, which means that the associated problems are increased: changing of filters, cleaning of rooms and equipment, inside and outside, become major containment issues.
Additionally, depending on the PPE system used, the levels of protection are limited. For systems taking the air from the room via a filter system, the best filters (P3 according EN 149) offer NPFs (Nominal Protection Factors) of 30. This means that if the dust concentration in a room is 3 mg/m³ (typical for open production), at best the concentration inside the system will be 100 μg/m³. Additionally, the lifetime of the filter element is limited because of the high dust loading.
The situation is different if air-fed systems are used. These systems can provide better protection levels, but there are still some areas of concern. The performance of these systems is very operator-dependant and in most countries it is not acceptable to put the responsibility for his health (or even life) into an operator’s own hands. The working conditions inside an air-suit are unpleasant: hot, humid with poor visibility and limited movement. This results in low levels of operator efficiency, and the need to take frequent breaks, reducing efficiency even further.
It is also important to notice the hidden costs associated with those systems such as:
  • large number of systems required
  • lifetime of suits and filters is limited
  • cost for clean air supply
  • requirement for extra changing and storage areas
These areas are most critical for the performance of the systems. After working in the contaminated area, the outside of the suit is contaminated with API. This contamination needs to be removed, which can be done either by air or wet showers. Whichever method is chosen, the remaining residuals, especially for very potent substances such as hormones or oncology products, can still be critical.
The effectiveness of air suits needs to be understood. It is a common misconception they provide total protection, but in reality typical NPF and APF (Applied Protection Factors) are:

Equipment Item
Air fed suit
10,000 200
Air fed half suit
2,000 100
Air fed hood
2,000 40
Filter air hood
500 40
APFs represent the reality of daily operation. Using the same example as above, this means that if the dust concentration in a room is 3 mg/m³, at best the exposure level for an operator wearing a full air-fed suit will be 15 μg/m³. Containment risksDuring most of the manufacturing process, the APIs are inside machines or vessels which are more or less ait tight. The main risk of material escaping into the environment exists whenever a connection between those pieces of equipment needs to be made or broken, when a sample needs to be taken, and when the machines need to be cleaned at the end of a manufacturing campaign. Before the risks for the operators’ health are discussed we should also spend some thoughts on the risks of cross contamination. Even in the best designed multi-product facilities cross contamination will happen. The critical question is how much cross contamination is acceptable and how it can be ensured that the real levels of cross contamination are always below the acceptance limit. Cross contamination
How much cross contamination can be allowed is mainly dictated by the potency of the products handled. The most common definition of an acceptable level is: In the maximum daily dose of product 2 only 1/1000 of the minimal daily dose of the active of product 1 should be found. If we compare now Paracetamol tablets (4000mg max daily dose) with typical oral contraceptives (containing 0,02 mg as a maximum daily dose) we see that the acceptable level of cross contamination in case 2 is by a factor of 200.000 higher than in case 1. Common ways to reduce the level of cross contamination in multi product facilities include separate production rooms, air looks and pressure cascades. These are fine for less critical products but when highly potent substances are handled, strict containment is the only way to protect both the operators’ health and the other products.
How much containment is required?In an ideal world operators would not be exposed to a single molecule of a harmful substance, but in the real world, this is simply not possible. Three main factors dictate how much containment is required and, therefore, which method of containment is best: the nature, especially the potency, of the API handled is of paramount importance; the type of process to be executed; and lastly the working regime of the operators.
The productThe potency of a substance is, in most cases, characterized either by the OEL (Occupational Exposure Limit) or by the ADI (Acceptable Daily Intake). The ADI describes the absolute amount of a specific drug substance that an operator can absorb without any negative effect on health. The OEL describes the maximum concentration of a drug substance which can be tolerated in the air of the production room, without any negative effect to the health of the operators. For established substances, these values are listed in textbooks such as ISBN 07176 2083 2 EH40/2002 OEL 2002 & ISBN 07176 2172 3 EH 40/2002 Supplements 2003. According to those, the OEL for Paracetamol is 10 mg/m³, while the OEL for Ethinyl estradiol is 35ng/m³. It is important to understand that these values are based on certain assumptions. Also, the values might change during the lifecycle of a substance especially after more toxicological data is generated. If an OEL for a substance cannot be obtained from the literature, the value can be determined as follows:
OEL  =  NOEL mg/(kg x day) x BW kg/V m³/time x SF1 x SF2 x ……..
OEL     = Occupational Exposure Limit
NOEL  = No Observable Effect Level
BW      = Body Weight
V         = Breathing Volume
SF       = Safety Factor
ADI and OEL are interconnected by the typical breathing volume of an operator (normally estimated as 10 m³/shift). Therefore;-
Additionally, it is common practice to describe the potency of a drug substance by an easy categorization system classifying all potent substances from 1 (less potent) to 5 (most potent). This allows production equipment to be classified as suitable for the production of a class X compound, plus it easily shows to operators the potency of the substance. However, when talking about this simple classification system, two important facts need to be considered: it is not totally universal, as the attached diagram shows; and nearly every company has its own classification system.
It also does not take into account the dilution of the API by excipients. The handling of a mixture containing 80% of a ’class 3 API’ can demand higher containment levels than the handling of a mixture containing 5% of a ’class 5 API’.
As we will see in the following chapters, the concept of production lines suitable for the manufacturing of all class x compounds can be questioned. It oversimplifies the situation, not taking into consideration dilution (not all substance handled is pure API, especially when dealing with very potent substances often a large percentage of the mixture is excipient), the real number of operations, or also the fact that operators might not be present all time.
The equipmentSuppliers not specialists  in the field often try to promote ’their containment equipment’ with claims such as “3 µg/m³”, “better than 1µg” or even worse “OEL 2 µg/m³”. All of these claims are meant to describe the containment performance of equipment such as extraction booths or containment valves. While the last claim obviously is wrong (OEL is a product-related number, it only has the same unit as the containment performance of a piece of equipment), the problem of the other claims is that the test conditions are not defined. This makes it extremely difficult to compare figures obtained by using different test materials, different samplers, different sampler positions or different analytical procedures.
After inventing the split-valve technology, GEA Buck Valve again took the lead to form (under the umbrella of ISPE) an expert working group, consisting of experts from pharma companies, engineering companies and containment equipment suppliers. This group developed a guideline in which all of the variants discussed above are defined. The accepted test procedure uses Lactose of a defined grade (other substances are possible), uses the equipment in a defined environment (humidity, temperature, number of air changes), and places the defined samplers in specific positions. The test includes performing the intended task, and collecting air (via the filters of the samplers) for 15 minutes. Analyzing the filters gives the quantity of lactose in a measured amount of air, which is the containment performance of the equipment. As the average of 15 minutes is taken, this performance is called STTWA (Short Term Time Weighted Average). It is important to note that the total amount of powder escaping is measured. If dealing with potent APIs, often only a small percentage of a powder mixture is active, while the rest is excipient. The LTTWA is defined as the containment performance over a longer period of time, for example one shift of 8h.
The diagram shows two different senarios:
It is important to distinguish if there is an intermittent exposure as shown on the left side generated e.g. by the docking of a container with raw materials to a fluid bed with subsequent operation of the fluid bed, or a permanent exposure as shown on the right side e.g. by a tablet press which is not totally tight.
The OperatorThe most important numbers to describe the exposure of the operator are ROI (Real Operator Intake) and RDI (Real Daily Intake). These numbers describe the amount of API which gets into the body of the operator, while being for a certain period of time in an area with a certain airborne drug concentration. If we know the breathing rate of the operator, and the dust concentration in the room, then the drug uptake can be calculated.
For example:
If the actual RDI is less than the drug specific ADI, the situation is fine. If the RDI exceeds the ADI, measures must be taken to improve the situation. In our example the most effective way would be to upgrade the granulator by a loading/unloading system with a better containment performance.
Conclusion of Fundamentals
This visualisation helps the concept to be easily understood. For real situations of course, a detailed risk analysis needs to be done in order to judge the containment performance of an existing installation, or to select the appropriate equipment for an upgrade of an existing facility, or the design of a new facility.

Roller Compaction, Granulation and Capsule Product Dissolution of Drug Formulations Containing a Lactose or Mannitol Filler, Starch, and Talc

This study investigated the influence of excipient composition to the roller compaction and granulation characteristics of pharmaceutical formulations that were comprised of a spray-dried filler (lactose monohydrate or mannitol), pregelatinized starch, talc, magnesium stearate (1% w/w) and a ductile active pharmaceutical ingredient (25% w/w) using a mixed-level factorial design. The main and interaction effects of formulation variables (i.e., filler type, starch content, and talc content) to the response factors (i.e., solid fraction and tensile strength of ribbons, particle size, compressibility and flow of granules) were analyzed using multi-linear stepwise regression analysis. Experimental results indicated that roller compacted ribbons of both lactose and mannitol formulations had similar tensile strength. However, resulting lactose-based granules were finer than the mannitol-based granules because of the brittleness of lactose compared to mannitol. Due to the poor compressiblility of starch, increasing starch content in the formulation from 0% to 20% w/w led to reduction in ribbon solid fraction by 10%, ribbon tensile strength by 60%, and granule size by 30%. Granules containing lactose or more starch showed less cohesive flow than granules containing mannitol and less starch. Increasing talc content from 0% to 5% w/w had little effect to most physical properties of ribbons and granules while the flow of mannitol-based granules was found improved. Finally, it was observed that stored at 40 °C/75% RH over 12 weeks, gelatin capsules containing lactose-based granules had reduced dissolution rates due to pellicle formation inside capsule shells, while capsules containing mannitol-based granules remained immediate dissolution without noticeable pellicle formation.
Key words  compaction - flowability - granulation - particle size - ribbon - starch

Batch production of pharmaceutical granulations in a fluidized bed I: Effects of process variables on physical properties of final granulation

The investigation concerns the effects of process variables associated with the fluidized bed granulation technique on the physical properties of the final granulation. The process variables investigated include binder solution addition rate, air pressure to the binary nozzle, inlet air temperature during the granulation cycle, and binary nozzle position with respect to the fluidized solids. When the rate at which the aqueous binder solution added to the fluidized bed of powders was increased, the ability of the solution to wet and penetrate the solids was enhanced, resulting in: (a) a larger average granule size, (b) a less friable granulation, (c) a more fluid granulation, and (d) a decreased granulation bulkiness. Similar results, also traceable to enhanced binder solution efficiency, occurred with a decrease either in the binary nozzle air pressure or in the inlet air temperature during the granulation cycle. The position of the binary nozzle with respect to the fluidized powders had significant effects upon the average granule size and granule friability. The effects upon the granulation flow properties and bulkiness, however, were slight.

Dry Granulation and Compression of Spray-Dried Plant Extracts

The purpose of this research was to evaluate the influence of dry granulation parameters on granule and tablet properties of spray-dried extract (SDE) from Maytenus ilicifolia, which is widely used in Brazil in the treatment of gastric disorders. The compressional behavior of the SDE and granules of the SDE was characterized by Heckel plots. The tablet properties of powders, granules, and formulations containing a high extract dose were compared. The SDE was blended with 2% magnesium stearate and 1% colloidal silicon dioxide and compacted to produce granules after slugging or roll compaction. The influences of the granulation process and the roll compaction force on the technological properties of the granules were studied. The flowability and density of spray-dried particles were improved after granulation. Tablets produced by direct compression of granules showed lower crushing strength than the ones obtained from nongranulated material. The compressional analysis by Heckel plots revealed that the SDE undergoes plastic deformation with a very low tendency to rearrangement at an early stage of compression. On the other hand, the granules showed an intensive rearrangement as a consequence of fragmentation and rebounding. However, when the compaction pressure was increased, the granules showed plastic deformation. The mean yield pressure values showed that both granulation techniques and the roll compaction force were able to reduce the material’s ability to undergo plastic deformation. Finally, the tablet containing a high dose of granules showed a close dependence between crushing strength and the densification degree of the granules (ie, roll compaction force).
Keywords: Dry granulation, Maytenus ilicifolia, spray-dried extracts, Heckel plot, tableting
Direct compression of powders requires materials exhibiting flowability and compressibility. Those parameters become more critical when the formulation contains large amounts of active substances with poor compressional properties. Spray-dried extracts (SDEs) from medicinal plants are very fine, light, and poorly compressible powders. Additionally, many plant constituents are sensitive to moisture and heat. To overcome these problems, several alternatives have been suggested, such as wet granulation using nonaqueous solvents,direct compression of dried extracts, and the use of different excipients to improve the extract’s properties or formulation for direct compression. However, few studies have examined the use of dry granulation to enhance particle size and consequently to improve flowability and compressibility of such materials, even though dry granulation seems to be the most appropriate technique because of the hygroscopicity of the extracts.
Dry granulation can be achieved either by slugging, using a tablet press, or by roll compaction. The desired particle size distribution can be adjusted by milling and sieving.The granulation parameters can affect the mechanical (ie, compressional) properties of the granules, which subsequently can influence the tableting behavior and tablet characteristics. Therefore, the evaluation of granule properties plays an important role in the prediction of tablet characteristics.
The Heckel plot is the method most frequently used to evaluate the volume reduction of materials when pressure is applied. It is assumed that the densification of the powder column follows a first-order kinetics. Thus, the degree of material densification is correlated to its porosity. Although the literature reveals some limitations to the Heckel’s model, the model has often been applied to study powder mixturesand to evaluate the parameters of granule manufactu
This study aimed to evaluate the physical and mechanical properties of granules containing high amounts of the SDE from Maytenus ilicifolia, prepared by either slugging or roll compaction. For this purpose, the compressional behavior of the SDE and granules prepared by those 2 methods were evaluated using the Heckel’s equation. The properties of tablets prepared from formulations containing high doses of granules were investigated.
Material and Methods
M ilicifolia aerial parts were extracted by maceration using distillated water (1:10, wt/vol). Colloidal silicon dioxide (Aerosil 200, Degussa, São Paulo, Brazil) was added to the miscella in a 2:8 ratio of adjuvant to dry residue. The dispersion was dried using a Production Minor spray-dryer (GEA, Copenhagen, Denmark) provided with a rotating disk. The operational conditions were 9500 rpm rotational disk speed, 149°C inlet temperature, 99°C outlet temperature, and 140 mL/min feed ratio.
Microcrystalline cellulose (Avicel PH 101; FMC Corp, Lehmann and Voss, Hamburg, Germany), cross-linked sodium carboxymethylcellulose (Ac-Di-Sol; FMC Corp, Lehmann and Voss), colloidal silicon dioxide (Aerosil 200; Degussa AG, Frankfurt am Main, Germany), and magnesium stearate (Otto Bärlocher GmbH, Munich, Germany) were used as received.
Extract Containing Mixture (ECM)
The SDE from M ilicifolia (191.40 g) was blended in a Turbula mixer T2C (Willy Bachofen, Basel, Switzerland) for 5 minutes with 3.0 g of Aerosil 200 and 5.6 g of magnesium stearate. Both excipients were previously sieved through a 315-μm sieve.
Slugs of 0.8 g from the ECM were produced at a compression force of 22.0 ± 1.0 kN using flat-faced tooling 17 mm in diameter on a single-punch tablet press EK 0 (Korsch AG, Berlin, Germany). The upper punch was equipped with 4 strain gauges (Model 3/120 LY-11; Hottinger Baldwin, Darmstadt, Germany) to measure the compression force. A Hottinger Baldwin carrier-frequency bridge was used as amplifier (Model K52 with A/D converter KWD 523D; Hottinger Baldwin). The compression data were acquired and processed using a Messefix v. 2.3 software (Dr. R. Herzog, Tübingen, Germany).
Roll Compaction
The ECM was compacted using a GMP Mini-Pactor (Gerteis Maschinen + Processengineering, Jona, Switzerland). The gap width between the press roll was set to 1 mm and the compactor roll speed to 2 rpm. Compaction forces of 5, 10, and 15 kN/cm (force per cm of roll width) were applied using a press roll (diameter 250 mm, width 25 mm) with a knurled surface.
The milling conditions were kept constant for compacts. The slugs from the single-punch press or ribbons from the compactor were crushed in a dry granulator (Erweka TG IIS coupled to an Erweka AR 400 multipurpose motor; Erweka GmbH, Heusenstamm, Germany) to obtain granules with a particle size < 2.00 mm. The resulting material was passed through an oscillating granulator (Erweka FGS coupled to a Erweka AR 400 multipurpose motor; Erweka GmbH) using a 1.0-mm sieve. The granule fraction between 250 and 1000 μm was chosen.
Particle Size Analysis
The particle size distribution of 50 g of each granule was determined by sieve analysis on a sieve-shaker (Retak 3D, Retsch GmbH and Co KG, Haan, Germany) using 250-, 355-, 500-, 630-, 710-, and 900-μm sieves. The cumulative size frequency was calculated, and the mean particle sizes (x´) were estimated using an RRSB-Net
Scanning Electron Microscopy (SEM)
SEM pictures of each granule batch were taken using a Zeiss DSM 940 A (Carl Zeiss, Oberkochen, Germany) secondary electron microscope at an accelerating voltage of 5 kV. Samples were mounted on aluminum pins by double adhesive tape and sputtered with gold using a Biorad Sputter Coater (Biorad, Munich, Germany) at 10−2 to 10−3 bar and 2.5 kV for 3 × 60 seconds.
Bulk and Tapped Density (Hausner´s Ratio and Carr´s Compressional Index)
The density parameters were determined using 10.0 g of each material in a 25-mL graduated cylinder (n = 3) (tapping device: J. Engelsmann AG, Ludwigshafen am Rhein, Germany). The values were used for the calculation of Hausner's rati and Carr's compressional index.
The flow properties of the sample were evaluated by the dynamic flow determination. The apparatus used according to Guyot et alconsisted of a 110-mm diameter stainless steel funnel, 30 mm in diameter discharge mouth and a wall angle of 40°. This system was coupled to a discharge funnel with an outflow orifice of 10 mm in diameter and a wall angle of 40°. It also included a support for the funnels with an electronic outflow trigger and an analytical balance connected to a personal computer. Data were acquired by the MQbal software (Microquímica, Florianópolis, Brazil). The analysis was performed 3 times with 10.0 g of each sample.
The density of each sample was measured using an air comparison pycnometer (Model 930; Beckmann Instruments Inc, Fullerton, CA).
Compression of the ECM and Granules
Exactly 0.200 g of the ECM and each granule batch were compressed at compression forces between 8 and 40 ± 0.5 kN on a single-punch tablet press EK0 (Korsch AG) using a round flat-faced tooling of 10-mm diameter. The crushing strengths of 6 tablets were determined 24 hours after production using a hardness tester (Model TBH30; Erweka GmbH).
Evaluation of the Granule Compressibility by Heckel Analysis11,12
Exactly 0.400 g of the SDE and each granule batch were compressed at 120 MPa using an eccentric tablet press EK II (Korsch AG) with a 10-mm diameter round flat-faced tooling by introducing manually preweighed material into the die. The upper punch holder was instrumented with a full Wheatstone bridge circuit of strain gauges (Model 3/120 LY-11; Hottinger Baldwin) to measure the compression force. An incremental displacement transducer (Model MT 2571; Heidenhain, Traunreut, Germany) was used to determine the upper punch displacement. The compressional data were acquired by a MGC Plus system (Hottinger Baldwin) equipped with a ML10 B voltage amplifier module (Hottinger Baldwin) to measure the compressional force and with 2 ML60 B counter modules (Hottinger Baldwin) to record the signals from the incremental displacement transducer. CATMAN v. 3.0 software (Hottinger Baldwin) was used to store and evaluate the compressional data. The system was described in detail by Dressler et al.23
The compressional behavior of the samples was evaluated using the Heckel equation (Equation 1):
ln ( 1 1 D ) = K P + A (1)
where D was the relative density of the compact at pressure P; K was the slope; and A was the intercept of the straight line obtained by linear regression from the Heckel plot. The relative densities DA and D0 were calculated from Equations 2 and 3, respectively:
D A = 1 e A (2)
D 0 = 1 e A 0 (3)
where A0 represented the intercept of the line at P = 0. The difference between DA and D0 represented the extent of particle rearrangement (DB). For each sample, 10 compressional cycles were performed.
The mean yield pressure (Py) was obtained as the reciprocal of the slope of the linear section in the curve.
Compression of Granules Containing Formulations
Tablet formulations according to Table 1 were mixed for 10 minutes in a Turbula Mixer T2C (Willy Bachofen, Basel, Switzerland); then, Aerosil 200 was sieved through a 315-μm sieve onto the mix. The final mixing was performed for 5 minutes.
Table 1. Tableting Formulation Containing High Dose of Granules

mg/tablet %/tablet

Granules (Magnesium stearate incorporated)
Avicel PH 101
Aerosil 200
Total weight
144.46* (4.00)
72.23 (2.00)

* Equivalent to 138.46 mg of the spray-dried extract or 110.77 mg of native extract per tablet.

The mixture was compressed into tablets of 0.200 g on a single-punch tablet machine EK 0 (Korsch AG) using flat-faced tooling 10 mm in diameter. Each batch was compressed at different compression force levels between 8 and 22 ± 0.5 kN.
Crushing Strength
The crushing strength of 10 tablets from each batch was determined according to the European Pharmacopoeia Supplement (2001)24 using a hardness tester (Model TBH30, Erweka GmbH).
Disintegration Time
The disintegration time of the tablets was determined according to the European Pharmacopoeia Supplement (2001)24 using a disintegration tester (Model PTZ 1, Pharmatest GmbH, Hainburg, Germany).
Results and Discussion
Technological Properties of the SDE and Granules
The mode of granule preparation and the different roll compaction forces did not influence the mean particle size (x´), as shown in Table 2. The x´ values ranged from 693 to 713 μm.
Table 2. Physical Properties of SDE, ECM, Slugged Granules, and RC Granules*

Sample Bulk Density (g/cm3) Tapped Density (g/cm3) Hausner's Ratio Carr's Index (%)

SDE 0.632 0.830 1.315 23.94 22.36†
ECM 0.500 0.690 1.375 27.50
Slug 0.659 0.706 1.071 6.59 713.00 0.9898 16.26
RC5 0.645 0.714 1.107 9.68 700.00 0.9909 15.50
RC10 0.690 0.741 1.074 6.90 701.00 0.9831 15.50
RC15 0.741 0.800 1.080 7.41 693.00 0.9734 15.87

* SDE indicates spray-dried extract; ECM, extract containing mixture; RC, roll-compacted granules at 5 (RC5), 10 (RC10), and 15 (RC15) kN/cm; RRSB indicates the correlation between granulometric distributions and the RRSB model.
† Determined by laser diffraction (Helos KA, Sympatec GmbH, Clausthal-Zellerfeld, Germany),
‡ Determination not possible due to blocking of the funnel.

The granulation process improved the technological properties of the SDE and the ECM. Concerning the granule densities, no important difference between granulation processes could be observed; however, the increase in roll compaction force produced granules with higher bulk and tapped densities. The Hausner's ratio (HR) and Carr's index (CI) are indirect and simple methods to evaluate the stability of the powder column and to estimate its flow properties. The high values of HR and CI observed for both the SDE and the ECM denote their inability to flow. The ECM’s granulation by either slugging or roll compaction significantly increased the stability of the powder bed. No significant difference was observed for HR or CI among the granule batches (Table 2).
The flow behavior of the granules dynamically measured is shown in Figure 1. There were no differences between the flow properties of slugged or roll-compacted granules. Additionally, the roll compaction force did not affect the flow properties. This result is in agreement with the technological properties suggested by HR and CI evaluation. This behavior was probably due to the similarities observed for the shape and size of the granules. Because the final flow velocity of the granules was higher than 10 g/s, they could be classified as free-flowing materials according to Guyot et al.22
Figure 1.  Flow profile of the granules. RC indicates roll-compacted granules at 5 (RC5), 10 (RC10), and 15 (RC15) kN/cm.

The morphology of the granules manufactured by slugging and by roll compaction was observed using an electron microscope (Figure 2). Slugged granules and roll-compacted granules at 5 kN/cm showed a coarse surface, probably because of the large amount of intact SDE particles. Roll-compacted granules at 10 and 15 kN/cm appeared to be denser and showed a more smooth surface than the other samples, because of higher densification of the ECM owing to the roll compaction force.
Figure 2. Scanning electron photomicrographs of different spray-dried extract–containing granules. RC indicates roll-compacted granules at 5 (RC5), 10 (RC10), and 15 (RC15) kN/cm.

Compression of the ECM and Granules
Tablets formed from granules compressed with further additives had a lower crushing strength than tablets containing nongranulated ECM (Figure 3). This reduction was similar for granules prepared by slugging and roll compaction at 5 and 10 kN/cm and more evident for granules produced by roll compaction at 15 kN/cm. The crushing strength data suggest that the increase in the compaction force (ie, densification degree) during the granulation reduces the strength of the compacted material. This reduction can be attributed to a decrease of the material’s ability to undergo plastic deformation, which ability was dissipated during the granulation process. Therefore, the reworking of the granules improved their resistance to deformation upon recompression, and a higher compression force was necessary to obtain the same crushing strength compared with tablets of powder mixture (ECM). This behavior was previously observed for sodium chloride25 and more recently demonstrated for several excipients and their mixtures.8,9,14,15 In general terms, the maximum crushing strength of the tableted granules was achieved at 25 kN of compression force. Higher compression forces revealed a capping tendency during the crushing strength test (Figure 3).
Figure 3.  Crushing strength of direct-compressed granules at different compressional forces compared with the ECM. ECM indicates extract containing mixture; RC, roll-compacted granules at 5 (RC5), 10 (RC10), and 15 (RC15) kN/cm.

Heckel Analysis
The Heckel plots for the SDE, the ECM, and granules showed no linearity at early stages of compression (Figure 4), because of particle rearrangement and the fragmentation of large aggregates under low compressional pressure.13 When the compression force is increased, the curves became linear because of plastic deformation.
Figure 4.  Heckel plots for SDE, ECM, and RC granules. Red lines show the linear portions of the compression phases. SDE indicates spray-dried extract; ECM, extract containing mixture; RC, roll-compacted granules at 5 (RC5), 10 (RC10), and 15 (RC15) kN/cm.

The slope of the linear part of the Heckel plot (Table 3) was correlated with the bulk and tapped densities. For Heckel parameters such as K, A, and Py, the values were very similar for both slug and roll-compacted granules.
Table 3. Heckel Parameters of the Materials Calculated From the Linear Portion of the Heckel Plot*

(n = 10)
Mean Yield Pressure
Py (MPa)
Extend of Particle Rearrangement
Density at Pressure (g/cm3) Coefficient of Determination

SDE† 0.0063 0.7567 158.52 0.083 1.356 0.9999
SD 0.0002 0.0062 5.94 0.002 0.00001
ECM 0.0068 0.8138 146.04 0.113 1.361 0.9999
SD 0.0001 0.0035 2.20 0.001 0.00002
Slug 0.0057 1.0290 174.58 0.269 1.387 0.9999
SD 0.0001 0.0042 2.29 0.001 0.00001
RC5 0.0057 0.9955 175.14 0.259 1.388 0.9999
SD 0.0001 0.0051 1.68 0.001 0.00001
RC10 0.0056 1.0794 178.18 0.290 1.392 0.9999
SD 0.0000 0.0036 1.31 0.001 0.00002
RC15 0.0058 1.1382 173.25 0.310 1.388 0.9999
SD 0.0001 0.0053 1.79 0.001 0.00001

* SDE indicates spray-dried extract; ECM, extract containing mixture; RC, roll-compacted granules at 5 (RC5), 10 (RC10), and 15 (RC15) kN/cm; SD, standard deviation.
† An ethanolic solution of stearolic acid 1.5% was used to lubricate the machine tools.

The extent of particle rearrangement (DB), calculated from Heckel analysis, depends on the particle surface, size, and shape and represents the particle arrangement at early compression stages.15DB results from compression force action to overcome particle interactions (ie, friction and cohesion) before particle slippage and/or arrangement. The lower DB value shown by the SDE particles was due to the physical properties of the particles such as dominant spherical shape, small particle size (22.4 μm), and no aggregated structure. Thus, the SDE did not undergo extensive particle rearrangement. The further arrangement may be due to the fragmentation of individual particles followed by plastic deformation. No significant increase of DB was observed by the addition of large amounts of magnesium stearate (2.8%, wt/wt) to the SDE (ECM). In fact, the SDE and the ECM presented almost the same value of DB. This result confirms the weak dependence of the SDE on particle slippage at an early stage of compression. However, at high pressures the presence of lubricant was effective and improved the densification of the particles.
After granulation, higher values of DB were observed. This implies that the granules presented a more extensive particle rearrangement compared with the SDE and the ECM products. At low pressures the large granules were fractured into small ones, which facilitated the further rearrangement. When the compression pressure was increased, the granules showed plastic deformation. The idea that plastic deformation was the principal mechanism was also supported by the relative high Py values. Thus, this behavior revealed a reduction of the granules’ ability to undergo plastic deformation. As observed by the crushing strength test, granulation of the SDE by roll compaction was satisfactory between 5 and 10 kN/cm. Thus, a roll compaction force higher than 10 kN/cm results in hard granules reaching plastic deformation. Therefore, reworking upon compression into tablets was difficult.
Properties of Tablets From Granule-Containing Formulations
Tablets containing a high dose of granulated dried extract from M ilicifolia were produced following the formulation described in Table 1. In Figure 5, the crushing strength of the tablets is plotted against the compression force. The tablet crushing strength showed a linear dependence of compression force for granule-containing formulations. This phenomenon was independent of the granulation method or the roll compaction force. The addition of microcrystalline cellulose to the formulation seemed to enhance the plastic deformation potential of all formulations, resulting in a linear compression force/crushing strength profile without a capping tendency and leading to tablets with crushing strength values higher than those obtained by granules that were direct-compressed at the same compression force. On the other hand, a slight decrease in tablet crushing strength was observed with increasing compaction force during roll compaction. This result indicates that the increase in the granules’ densification degree plays an important role in the tablets’ resultant resistance.8 Thus, if all operational conditions, such as roll compaction and compression forces, are taken into account, a similar crushing strength for the different formulations can be expected.
Figure 5.  Crushing strength of final tablets. Tablets containing a high dose of slugged granules or RC granules. RC indicates roll-compacted granules at 5 (RC5), 10 (RC10), and 15 (RC15) kN/cm.

Concerning the disintegration times of the tablets, no important difference was observed (Figure 6). For all cases, the disintegration time increased significantly when the compression force was increased. The maximum disintegration time, achieved at 14 kN, ranged from 8 (tablets containing a high dose of slugged granules) to 11 minutes (tablets containing a high dose of roll-compacted granules).
Figure 6.  Disintegration time behavior of tablets containing a high dose of granules. RC indicates roll-compacted granules at 5 (RC5), 10 (RC10), and 15 (RC15) kN/cm.

The dry granulation of the dried extract of M ilicifolia improved its flowability. However, the study of compressional behavior and recompressibility showed that the degree of densification reached during the dry granulation process increased the material’s resistance to further reworking. On the other hand, when plastic filler material was added to formulations, the tableting properties of granules were increased. Besides, the differences among force-crushing strength profiles were minimized. To conclude, the evaluation of granulation properties and manufacturing technologies can help predict the characteristics of final tablets containing a high dose of those granulations.
The authors gratefully acknowledge Gerteis Maschinen + Processengineering AG (Jona, Switzerland) for supplying the roll compactor. We also thank Dr. Robert Lammens (Bayer AG, Leverküsen) for helpful discussions. This work was supported by CAPES (Coordenação de Aperfeiçoamento de Pessoal de Nível Superior, Brazil) and DAAD (German Academic Exchange Service).
1. De Souza KCB, Petrovick PR, Bassani VL, González Ortega G.  The adjuvants Aerosil 200 and Gelita-Sol-P influence on the technological characteristics of spray-dried powder from Passiflora edulis var. flavicarpa. Drug Dev Ind Pharm. 2000;26:331-336.

2. Diaz L, Souto C, Concheiro A, Gomez-Amozy LM, Martinez-Pacheco R.  Evaluation of Eudragit E as excipient in tablets of dry plant extract. STP Pharma Sci. 1986;2:105-109.
3. De Souza TP, Bassani VL, González Ortega G, Dalla Costa TCT, Petrovick PR.  Influence of adjuvants on the dissolution profile of tablets containing high dose of spray-dried extract of Maytenus ilicifolia. Pharmazie. 2001;56:730-733.

4. Plaizer-Vercamen JA, Bruwier C.  Evaluation of excipients for direct compression of the spray-dried extract of Harpogaphytum procumbens. STP Pharma Sci. 1986;2:525-530.