Monday, December 13, 2010

Problems in tablet manufacturing

Introduction

(62,63)
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.
vii) BINDING
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

(1,5)
‘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.
TABLE.27. THE CAUSES AND REMEDIES OF CAPPING RELATED TO ‘FORMULATION’ (GRANULATION)
Sr. No.
CAUSES
REMEDIES
1.
Large amount of fines in the granulation
Remove some or all fines through 100 to 200 mesh screen
2.
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.
3.
Not thoroughly dried granules.
Dry the granules properly.
4.
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.
5.
Insufficient or improper lubricant.
Increase the amount of lubricant or change the type of lubricant.
6.
Granular mass too cold to compress firm.
Compress at room temperature.
TABLE.28. THE CAUSES AND REMEDIES OF CAPPING RELATED TO ‘MACHINE’ (DIES, PUNCHES AND TABLET PRESS)
Sr. No.
CAUSES REMEDIES
1.
Poorly finished dies
Polish dies properly. Investigate other steels or other materials.
2.
Deep concave punches or beveled-edge faces of punches.
Use flat punches.
3.
Lower punch remains below the face of die during ejection.
Make proper setting of lower punch during ejection.
4.
Incorrect adjustment of sweep-off blade.
Adjust sweep-off blade correctly to facilitate proper ejection.
5.
High turret speed.
Reduce speed of turret (Increase dwell time).


Lamination / Laminating

(1,5)
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.
TABLE.29. THE CAUSES AND REMEDIES OF LAMINATION RELATED TO FORMULATION (GRANULATION)
Sr. No.
CAUSES REMEDIES
1.
Oily or waxy materials in granules
Modify mixing process. Add adsorbent or absorbent.
2.
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.
CAUSES REMEDIES</ b>
1.
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°.
2.
Rapid decompression
Use pre-compression step. Reduce turret speed and reduce the final compression pressure.

Chipping

(1)
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.

TABLE.31. THE CAUSES AND REMEDIES OF CHIPPING RELATED TO FORMULATION (GRANULATION) ARE AS FOLLOWS

Sr. No.
CAUSES REMEDIES
1.
Sticking on punch faces
Dry the granules properly or increase lubrication.
2.
Too dry granules.
Moisten the granules to plasticize. Add hygroscopic substances.
3.
Too much binding causes chipping at bottom.
Optimize binding, or use dry binders.

TABLE.32. THE CAUSES AND REMEDIES OF CHIPPING RELATED TO MACHINE (DIES, PUNCHES AND TABLET PRESS)
Sr. No.
CAUSES REMEDIES
1.
Groove of die worn at compression point.
Polish to open end, reverse or replace the die.
2.
Barreled die (center of the die wider than ends)
Polish the die to make it cylindrical
3.
Edge of punch face turned inside/inward.
Polish the punch edges
4.
Concavity too deep to compress properly.
Reduce concavity of punch faces. Use flat punches.


Cracking

(1)
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.

TABLE.33. THE CAUSES AND REMEDIES OF CRACKING RELATED TO FORMULATION (GRANULATION)
Sr. No.
CAUSES REMEDIES
1.
Large size of granules.
Reduce granule size. Add fines.
2.
Too dry granules.
Moisten the granules properly and add proper amount of binder.
3.
Tablets expand.
Improve granulation. Add dry binders.
4.
Granulation too cold.
Compress at room temperature.

TABLE.34. THE CAUSES AND REMEDIES OF CRACKING RELATED TO MACHINE (DIES, PUNCHES AND TABLET PRESS)
Sr. No.
CAUSES REMEDIES
1.
Tablet expands on ejection due to air entrapment.
Use tapered die.
2.
Deep concavities cause cracking while
removing tablets
Use special take-off.


Sticking / Filming

(1)
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.

TABLE.35. THE CAUSES AND REMEDIES OF STICKING RELATED TO FORMULATION (GRANULATION)
Sr. No.
CAUSES REMEDIES
1.
Granules not dried properly.
Dry the granules properly. Make moisture analysis to determine limits.
2.
Too little or improper lubrication.
Increase or change lubricant.
3.
Too much binder
Reduce the amount of binder or use a different type of binder.
4.
Hygroscopic granular material.
Modify granulation and compress under controlled humidity.
5.
Oily or way materials
Modify mixing process. Add an absorbent.
6.
Too soft or weak granules.
Optimize the amount of binder and granulation technique.

TABLE.36. THE CAUSES AND REMEDIES OF STICKING RELATED TO MACHINE (DIES, PUNCHES AND TABLET PRESS)
Sr. No.
CAUSES REMEDIES
1.
Concavity too deep for granulation.
Reduce concavity to optimum.
2.
Too little pressure.
Increase pressure.
3.
Compressing too fast.
Reduce speed.


Picking

(1)
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.
TABLE.37. THE CAUSES AND REMEDIES OF PICKING RELATED TO FORMULATION (GRANULATION)
Sr. No.
CAUSES REMEDIES
1.
Excessive moisture in granules.
Dry properly the granules, determine optimum limit.
2.
Too little or improper lubrication.
Increase lubrication; use colloidal silica as a ‘polishing agent’, so that material does not cling to punch faces.
3.
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.
4.
Low melting point medicament in high concentration.
Refrigerate granules and the entire tablet press.
5.
Too warm granules when compressing.
Compress at room temperature. Cool sufficiently before compression.
6.
Too much amount of binder.
Reduce the amount of binder, change the type or use dry binders.
TABLE.38. THE CAUSES AND REMEDIES OF PICKING RELATED TO MACHINE (DIES, PUNCHES AND TABLET PRESS)
Sr. No.
CAUSES REMEDIES
1.
Rough or scratched punch faces.
Polish faces to high luster.
2.
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.
3.
Bevels or dividing lines too deep.
Reduce depths and sharpness.
4.
Pressure applied is not enough; too soft tablets.
Increase pressure to optimum.


Binding

(1)
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.
TABLE.39. THE CAUSES AND REMEDIES OF BINDING RELATED TO FORMULATION (GRANULATION)
Sr. No.
CAUSES REMEDIES
1.
Too moist granules and extrudes around lower punch.
Dry the granules properly.
2.
Insufficient or improper lubricant.
Increase the amount of lubricant or use a more effective lubricant.
3.
Too coarse granules.
Reduce granular size, add more fines, and increase the quantity of lubricant.
4.
Too hard granules for the lubricant to be effective.
Modify granulation. Reduce granular size.
5.
Granular material very abrasive and cutting into dies.
If coarse granules, reduce its size.
Use wear-resistant dies.
6.
Granular material too warm, sticks to the die.
Reduce temperature.
Increase clearance if it is extruding.
TABLE.40. THE CAUSES AND REMEDIES OF BINDING RELATED TO MACHINE (DIES, PUNCHES AND TABLET PRESS)
Sr. No.
CAUSES REMEDIES
1.
Poorly finished dies.
Polish the dies properly.
2.
Rough dies due to abrasion, corrosion.
Investigate other steels or other materials or modify granulation.
3.
Undersized dies. Too little clearance.
Rework to proper size.
Increase clearance.
4.
Too much pressure in the tablet press.
Reduce pressure. OR
Modify granulation.


Mottling

(1)
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.

TABLE.41. THE CAUSES AND REMEDIES OF MOTTLING
Sr. No.
CAUSES REMEDIES
1.
A coloured drug used along with colourless or white-coloured excipients.
Use appropriate colourants.
2.
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.
3.
Improperly mixed dye, especially during ‘Direct Compression’.
Mix properly and reduce size if it is of a larger size to prevent segregation.
4.
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

(1)
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.
TABLE.42. THE CAUSES AND REMEDIES OF DOUBLE IMPRESSION
Sr. No.
CAUSE REMEDIES
1.
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


Blistering

(1,64)
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.

TABLE.43. THE CAUSE AND REMEDY OF BLISTERING
Sr. No.
CAUSE
REMEDY
1.
Effect of temperature on the strength, elasticity and adhesion of the film.
Use mild drying condition.

Chipping

(1,64)
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.
TABLE.44. THE CAUSE AND REMEDY OF CHIPPING
Sr. No.
CAUSE
REMEDY
1.
High degree of attrition associated with the coating process.

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


Cratering

(1,64)
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.

TABLE.45. THE CAUSES AND REMEDIES OF CRATERING

Sr. No.
CAUSES
REMEDIES
1.
Inefficient drying.

Use efficient and optimum drying conditions.
2.
Higher rate of application of coating solution.
Increase viscosity of coating solution to decrease spray application rate.


Picking

(1,64)
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.
TABLE.46. THE CAUSES AND REMEDIES OF PICKING
Sr.
No.
CAUSE
REMEDY
1.
Inefficient drying.
Use optimum and efficient drying conditions or increase the inlet air temperature.
2.
Higher rate of application of coating solution
Decrease the rater of application of coating solution by increasing viscosity of coating solution.


Pitting

(1,64)
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.
TABLE.47. THE CAUSE AND REMEDY OF PITTING

Sr. No.
CAUSE
REMEDY
1.
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.

Blooming

(1,64)
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.
TABLE.48. THE CAUSE AND REMEDY OF BLOOMING
Sr. No.
CAUSE
REMEDY
1.
High concentration and low molecular weight of plasticizer.

Decrease plasticizer concentration and increase molecular weight of plasticizer.


Blushing

(1,64)
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.

TABLE.49. THE CAUSES AND REMEDIES OF BLUSHING
Sr. No.
CAUSES
REMEDIES
1.
High coating temperature
Decrease the drying air temperature
2.
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

(1,64)
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.
TABLE.50. THE CAUSE AND REMEDY OF COLOUR VARIATION
Sr. No.
CAUSE
REMEDY
1.
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.

Infilling

(1,64)
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.

TABLE.51. THE CAUSE AND REMEDY OF INFILLING
Sr. No.
CAUSE
REMEDY
1.
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

(1,64)
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.
TABLE.52. THE CAUSES AND REMEDIES OF ORANGE PEEL/ROUGHNESS
Sr. No.
CAUSES
REMEDIES
1.
Rapid Drying
Use mild drying conditions
2.
High solution viscosity
Use additional solvents to decrease viscosity of solution.

Cracking/Splitting

(1,64)
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.
TABLE.53. THE CAUSE AND REMEDY OF CRACKING/SPLITTING

Sr. No.
CAUSE
REMEDY
1.
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

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