PROBLEMS OF TABLET DURING MANUFACTURING MANUFACTURING Introduction
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: µVISUAL 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 due air-entrapment in the granular material. ii) LAMINATION: It is due 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 vi) PICKING 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 colored drug, which has different color than the rest of the granular material? (Excipient- related); improper mixing of granular material (Processrelated); 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
µCapping¶ 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. THE CAUSES AND REMEDIES OF CAPPING RELATED TO µFORMULATION¶ (GRANULATION) Sr. No. 1. 2.
3. 4.
5. 6.
CAUSES
REMEDIES
Large amount of fines in the granulation Too dry or very low moisture content (leading to loss of proper binding action). Not thoroughly dried granules. Insufficient amount of binder or improper binder.
Remove some or all fines through 100 to 200 mesh screen Moisten the granules suitably. Add hygroscopic substance e.g.: sorbitol, methyl- cellulose or PEG-4000. Dry the granules properly. 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.
THE CAUSES AND REMEDIES OF CAPPING RELATED TO µMACHINE¶ (DIES, PUNCHES AND TABLET PRESS) Sr. No. 1.
2. 3. 4. 5.
CAUSES
REMEDIES
Poorly finished dies
Polish dies properly. Investigate other steels or other materials. Deep concave punches or beveled-edge faces of Use flat punches. punches. Lower punch remains below the face of die Make proper setting of lower punch during ejection. 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: µLamination¶ 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. THE CAUSES AND REMEDIES OF LAMINATION RELATED TO FORMULATION (GRANULATION) Sr. CAUSES REMEDIES No. 1. Oily or waxy materials in granules Modify mixing process. Add adsorbent or
2.
Too much of hydrophobic lubricant e.g.: Magnesiumstearate.
absorbent. Use a less amount of lubricant or change the type of lubricant.
The Causes and Remedies of Lamination related to MACHINE (Dies, Punches and Tablet Press) Sr. No. 1.
2.
CAUSES
REMEDIES
Rapid relaxation of the peripheral regions of a tablet, on ejection from a die. Rapid decompression
Use tapered dies, i.e. upper part of the die bore has an outward taper of 3° to 5°. Use pre-compression step. Reduce turret speed and reduce the final compression pressure.
Chipping Definition: µChipping¶ 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. THE CAUSES AND REMEDIES OF CHIPPING RELATED TO FORMULATION (GRANULATION) ARE AS FOLLOWS Sr. No. 1. 2.
3.
CAUSES
REMEDIES
Sticking on punch faces Too dry granules.
Dry the granules properly or increase lubrication. Moisten the granules to plasticize. Add hygroscopic substances. Optimize binding, or use dry binders.
Too much binding causes chipping at bottom.
THE CAUSES AND REMEDIES OF CHIPPING RELATED TO MACHINE (DIES, PUNCHES AND TABLET PRESS) Sr. No. 1. 2. 3. 4.
CAUSES Groove of die worn at compression point. Barreled die (center of the die wider than ends) Edge of punch face turned inside/inward. Concavity too deep to compress properly.
REMEDIES Polish to open end, reverse or replace the die. Polish the die to make it cylindrical Polish the punch edges Reduce concavity of punch faces. Use flat punches.
Cracking Definition: Small, fine cracks observed on the upper and lower central surface of tablets, or very rarely on the sidewall are referred to as µCracks¶.
Reason: It is observed as a result of rapid expansion of tablets, especially when deep concave punches are used. 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.
3. 4.
Tablets expand. Granulation too cold.
Moisten the granules properly and add proper amount of binder. Improve granulation. Add dry binders. Compress at room temperature.
THE CAUSES AND REMEDIES OF CRACKING RELATED TO MACHINE (DIES, PUNCHES AND TABLET PRESS) Sr. No. 1. 2.
CAUSES Tablet expands on ejection due to air entrapment. Deep concavities cause cracking while removing tablets
REMEDIES Use tapered die. Use special take-off.
Sticking / Filming Definition: µSticking¶ 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.
THE CAUSES AND REMEDIES OF STICKING RELATED TO FORMULATION (GRANULATION) Sr. CAUSES REMEDIES No. 1. Granules not dried properly. Dry the granules properly. Make moisture analysis to determine limits. 2. Too little or improper Increase or change lubricant. lubrication. 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.
THE CAUSES AND REMEDIES OF STICKING RELATED TO MACHINE (DIES, PUNCHES AND TABLET PRESS) Sr. No. 1. 2. 3.
CAUSES Concavity too deep for granulation. Too little pressure. Compressing too fast.
REMEDIES Reduce concavity to optimum. Increase pressure. Reduce speed.
Picking Definition: µPicking¶ 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. THE CAUSES AND REMEDIES OF PICKING RELATED TO FORMULATION (GRANULATION)
Sr. No. 1. 2.
3. 4. 5. 6.
CAUSES
REMEDIES
Excessive moisture in granules. Too little or improper lubrication.
Dry properly the granules, determine optimum limit. Increase lubrication; use colloidal silica as a µpolishing agent¶, so that material does not cling to punch faces. Low melting point substances, may soften from Add high melting-point materials. Use high meting the heat of compression and lead to picking. point lubricants. Low melting point medicament in high Refrigerate granules and the entire tablet press. concentration. 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.
THE CAUSES AND REMEDIES OF PICKING RELATED TO MACHINE (DIES, PUNCHES AND TABLET PRESS) Sr. No. 1. 2.
3. 4.
CAUSES
REMEDIES
Rough or scratched punch faces. Embossing or engraving letters on punch faces such as B, A, O, R, P, Q, G.
Polish faces to high luster. Design lettering as large as possible.
Bevels or dividing lines too deep. Pressure applied is not enough; too soft tablets.
Plate the punch faces with chromium to produce a smooth and non-adherent face. Reduce depths and sharpness. Increase pressure to optimum.
Binding Definition: µBinding¶ 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. THE CAUSES AND REMEDIES OF BINDING RELATED TO FORMULATION (GRANULATION) Sr. No. 1.
CAUSES
REMEDIES
Dry the granules properly.
2.
Too moist granules and extrudes around lower punch. Insufficient or improper lubricant.
3.
Too coarse granules.
4.
Too hard granules for the lubricant to be effective. Granular material very abrasive and cutting into dies.
5.
6.
Granular material too warm, sticks to the die.
Increase the amount of lubricant or use a more effective lubricant. Reduce granular size, add more fines, and increase the quantity of lubricant. Modify granulation. Reduce granular size. If coarse granules, reduce its size. Use wear-resistant dies. Reduce temperature.
Increase clearance if it is extruding.
THE CAUSES AND REMEDIES OF BINDING RELATED TO MACHINE (DIES, PUNCHES AND TABLET PRESS) Sr. No. 1. 2.
3.
4.
CAUSES
REMEDIES
Poorly finished dies. Rough dies due to abrasion, corrosion. Undersized dies. Too little clearance.
Polish the dies properly. Investigate other steels granulation. Rework to proper size.
Too much pressure in the tablet press.
Increase clearance. Reduce pressure. OR
or
other
materials
or
modify
Modify granulation.
Mottling Definition: µMottling¶ 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.
THE CAUSES AND REMEDIES OF MOTTLING Sr. CAUSES REMEDIES No. 1. A coloured drug used along with Use appropriate colorants. colorless or white-coloured excipients. 2. A dye migrates to the surface of Change the solvent system, granulation while drying. Change the binder, Reduce drying temperature and Use a smaller particle size. 3. Improperly mixed dye, especially Mix properly and reduce size if it is of a larger size to prevent during µDirect Compression¶. segregation. 4. Improper mixing of a coloured Incorporate dry colour additive during powder blending step, then binder solution. add fine powdered adhesives such as acacia and tragacanth and mix well and finally add granulating liquid. Double impression Definition: µDouble 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 µDouble Impression¶.
If the upper punch is uncontrolled, it can rotate during the short travel to the final compression stage and create a double impression. THE CAUSES AND REMEDIES OF DOUBLE IMPRESSION Sr. No. 1.
CAUSE
REMEDIES
Free rotation of either upper punch or -Use keying in tooling, i.e. inset a key alongside of the lower punch during ejection of a tablet. 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 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. THE CAUSE AND REMEDY OF BLISTERING Sr. No. 1.
CAUSE Effect of temperature on the strength, elasticity and adhesion of the film.
REMEDY Use mild drying condition.
Chipping 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.
THE CAUSE AND REMEDY OF CHIPPING Sr. CAUSE No. 1. High degree of attrition associated with the coating process.
REMEDY
Increase hardness of the film by increasing the molecular weight grade of polymer.
Cratering 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. THE CAUSES AND REMEDIES OF CRATERING Sr. No. 1.
CAUSES
REMEDIES
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 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. THE CAUSES AND REMEDIES OF PICKING Sr.
CAUSE
No. 1.
Inefficient drying.
2.
REMEDY
Higher rate of application coating solution
Use optimum and efficient drying conditions or increase the inlet air temperature. of Decrease the rater of application of coating solution by increasing viscosity of coating solution.
Pitting 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. 1.
CAUSE
REMEDY
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 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. THE CAUSE AND REMEDY OF BLOOMING Sr. No. 1.
CAUSE
High concentration
REMEDY
and
low molecular
Decrease plasticizer concentration and increase molecular
weight of plasticizer.
weight of plasticizer.
Blushing 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. THE CAUSES AND REMEDIES OF BLUSHING Sr. No. 1. 2.
CAUSES
REMEDIES
High coating 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.
Decrease the drying air temperature Avoid use of sorbitol with Hydroxy Propyl Cellulose, Hydroxy Propyl Methyl Cellulose, Methyl Cellulose and Cellulose ethers.
Color 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. THE CAUSE AND REMEDY OF COLOUR VARIATION Sr. No. 1.
CAUSE
REMEDY
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 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 ³set´. 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.
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 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.
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 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.
THE CAUSE AND REMEDY OF CRACKING/SPLITTING Sr. CAUSE REMEDY No. 1. Use of higher molecular weight Use lower molecular weight polymers or polymeric blends. 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. y
Capping
and Lamination are the defects arising as a result of air-entrapment in the granular material.
y
Chipping
y
Cracking
is a defect related arising due to very dry granules. is due to rapid expansion of tablets, when deep concave punches are
used. y
y
y
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 y
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.
y
Chipping
y
Cratering
y
y
y
y
y
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. 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.
y
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.
y
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
