tablet-problems-evaluation-handout

COMMON TABLETING PROBLEMS

AND

EVALUATION OF TABLETS

Tablet: Problems in tablet 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.

The imperfections found in tablets along–with their causes and related remedies are discussed here. 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 due to air-entrapment in the granular material.

ii) LAMINATION: It is 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

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 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, 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

‘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 1. The Causes And Remedies Of Capping Related To ‘Formulation’ (Granulation)

Sl. 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 amount 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 2. The Causes And Remedies Of Capping Related To ‘Machine’ (Dies, Punches And Tablet Press)

Sl. 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

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 3. The Causes And Remedies Of Lamination Related To Formulation (Granulation)

Sl. 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. 4. The Causes and Remedies of Lamination related to MACHINE (Dies, Punches and Tablet Press)

Sl. No.	CAUSES	REMEDIES
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

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 5. The Causes and Remedies of Chipping Related To Formulation (Granulation) Are As Follows

Sl. 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 6. The Causes and Remedies of Chipping Related To Machine (Dies, Punches and Tablet Press)

Sl. 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

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 7. The Causes And Remedies Of Cracking Related To Formulation (Granulation)

Sl. 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 8. The Causes And Remedies Of Cracking Related To Machine (Dies, Punches And Tablet Press)

Sl. 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

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 9. The Causes And Remedies Of Sticking Related To Formulation (Granulation)

Sl. 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 10. The Causes And Remedies Of Sticking Related To Machine (Dies, Punches And Tablet Press)

Sl. 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

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 11. The Causes And Remedies Of Picking Related To Formulation (Granulation)

Sl. 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 12. The Causes And Remedies Of Picking Related To Machine (Dies, Punches And Tablet Press)

Sl. 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

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 13. The Causes And Remedies Of Binding Related To Formulation (Granulation)

Sl. 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 14. The Causes And Remedies Of Binding Related To Machine (Dies, Punches And Tablet Press)

Sl. 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

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 15. The Causes And Remedies Of Mottling

Sl. 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

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 16. The Causes And Remedies Of Double Impression

Sl. 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.

Evaluation and Quality Control Tests for Tablets

    To design tablets and later monitor tablet production quality, quantitative evaluations and assessments of a tablet's chemical, physical. and bioavailability properties must be made. Not only could all three property classes have a significant stability profile, but the stability profiles may be interrelated, i.e., chemical breakdown or interactions between tablet components may alter physical tablet properties, greatly changing the bioavailability of a tablet system.

    General Appearance. The general appearance of a tablet, its visual identity and overall "elegance." is essential for consumer acceptance, for control of lot-to-lot uniformity and general tablet-to-tablet uniformity, and for monitoring trouble-free manufacturing. The control of the general appearance of a tablet involves the measurement of a number of attributes such as a tablet's size, shape, color, presence or absence of an odor, taste, surface texture, physical flaws and consistency, and legibility of any identifying markings.

Size and Shape. The size and shape of the tablet can be dimensionally described, monitored, and controlled. A compressed tablet's shape and dimensions are determined by the tooling during the compression process. The thickness of a tablet is the only dimensional variable related to the process. At a constant compressive load, tablet thickness varies with changes in die fill, with particle size distribution and packing of the particle mix being compressed, and with tablet weight, while with a constant die fill, thickness varies with variations in compressive load. Tablet thickness is consistent batch to batch or within a batch only if the tablet granulation or powder blend is adequately consistent in particle size and size distribution, if the punch tooling is of consistent length, and if the tablet press is clean and in good working order.

The crown thickness of individual tablets may be measured with a micrometer, which permits accurate measurements and provides information on the variation between tablets. Other techniques employed in production control involve placing 5 or 10 tablets in a holding tray, where their total crown thickness may be measured with a sliding caliper scale. This method is much more rapid than measurement with a micrometer in providing an overall estimate of tablet thickness in production operations, but it does not as readily provide information on variability between tablets; however, if the punch and die tooling has been satisfactorily standardized and the tablet machine is functioning properly, this method is satisfactory for production work

The physical dimensions of the tablet, along with the density of the materials in the tablet formulation and their proportions, determine the weight of the tablet. The size and shape of the tablet can also influence the choice of tablet machine to use, the best particle size for the granulation, production lot sizes that can be made, the best type of tablet processing that can be used, packaging operations, and the cost to produce the tablet.

Unique Identification Markings. Pharmaceutical companies manufacturing tablets often use some type of unique markings on the tablet in addition to color, to aid in the rapid identification of their products. These markings utilize some form of embossing, engraving, or printing. A look into the product identification section of the current Physician's Desk Reference (PDR) provides a quick reference to the multitude of marking variations, both artistic and informational, that can be produced.

Organoleptic Properties. Many pharmaceutical tablets use color as a vital means of rapid identification and consumer acceptance. The color of a product must be uniform within a single tablet (nonuniformity is generally referred to as "mottling"), from tablet to tablet, and from lot to lot. Nonuniformity of coloring not only lacks esthetic appeal but could be associated by the consumer with nonuniformity of content and general poor quality of the product.

Efforts to quantitate color evaluations have used reflectance spectrophotometry, tristimulus colorimetric measurements, and the use of a microreflectance photometer to measure the color uniformity and gloss on a tablet surface.

The presence of an odor in a batch of tablets could indicate a stability problem, such as the characteristic odor of acetic acid in degrading aspirin tablets; however, the presence of an odor could be characteristic of the drug, (vitamins have a characteristic odor), added ingredients (flavoring agents have pleasant odors), or the dosage form (film-coated tablets usually have a characteristic odor).

Taste is important in consumer acceptance of chewable tablets. Many companies utilize taste panels to judge the preference of different flavors and flavor levels in the development of a product.

A tablet's level of flaws such as chips, cracks, contamination from foreign solid substances (e.g., hair, drops of oil, and "dirt"), surface texture ("smooth" versus "rough"), and appearance ("shiny" versus "dull") may have a zero-defect specification, but the visual inspection techniques used for detecting or evaluating these characteristics are subjective in nature. Electronic devices that are currently being developed hold promise for making inspection a more quantitative and reproducible operation.

Hardness and Friability. Tablets require a certain amount of strength, or hardness and resistance to friability, to withstand mechanical shocks of handling in manufacture, packaging, and shipping. Adequate tablet hardness and resistance to powdering and friability are necessary requisites for consumer acceptance. More recently, the relationship of hardness to tablet disintegration, and perhaps more significantly, to the drug dissolution release rate, has become apparent. The monitoring of tablet hardness is especially important for drug products that possess real or potential bioavailability problems or that are sensitive to altered dissolution release profiles as a function of the compressive force employed.

Historically, the strength of a tablet was determined by breaking it between the second and third fingers with the thumb acting as a fulcrum. If there was a "sharp" snap, the tablet was deemed to have acceptable strength. More recently, however, tablet hardness has been defined as the force required to break a tablet in a diametric compression test. To perform this test, a tablet is placed between two anvils, force is applied to the anvils, and the crushing strength that just causes the tablet to break is recorded. Hardness is thus sometimes termed the tablet crushing strength. Several devices operating in this manner have been and continue to be used to test tablet hardness: the Monsanto tester, the Strong-Cobb tester, the Pfizer tester, the Erweka tester, and the Schleuniger tester. The principle of measurement involves subjecting the tablet to an increasing load until the tablet breaks or fractures. The load is applied along the radial axis of the tablet. Oral tablets normally have a hardness of 4 to 8 or 10 kg; however, hypodermic and chewable tablets are much softer (3 kg) and some sustained release tablets are much harder (10-20 kg).

1) Monsanto hardness tester

          

    2)  Strong-Cobb Tester

3) Pfizer Tester

              

4) Erweka Tester

All Erweka instruments for hardness, diameter and thickness measurement offer the    following features and specifications:

Hardness 3 - 500N ± 1 N (optional 3 - 1.000 N) Diameter/length 0.10 - 26.00 mm ± 0.05 mm (optional 0.10 - 70.00 mm) Thickness 0.10 - 12.00 mm ± 0.05 mm

ERWEKA Tablet Hardness and Combination Testers now offer the choice of testing under "Constant-Speed" as well as "Constant-Force" measurement conditions.

While using "Constant-Speed" the test-jaw is moved at a constant speed (adjustable from 0.05 - 3.00 mm/sec.) for breaking, with the "Constant-Force" System the test-jaw increases the pressure to the sample linear constantly (adjustable from 10 - 200 N/sec.).

The choice of which measurement principle should be used is up to the user and can be selected within seconds using the integrated Adjustment Menu of each Tester.

TBH450TD is equipped with a 10 chamber rotary magazine and provides fully automatic measurement of hardness, diameter and thickness. Brushes between each sample chamber ensure that the hardness test station is kept free from tablet debris. A maximum of 10 samples can be loaded for one run.

      

5) Schleuniger Tester

Operates in a horizontal position. An anvil driven by an electric motor presses the tablet at a constant load rate against a stationary anvil until the tablet breaks. A pointer moving along a scale indicator provides the breaking strength value. The instrument reads in both kilograms and Strong Cobb units. This instrument is currently the most widely employed and has the advantage of being both fast and reproducible.

i) 0 - 200 N, 0 - 20 Kp range ii) 0 - 200 N, 0 - 28 SC range iii) 0 - 20 Kp, 0 - 28 SC range iv) 0 - 100 N, 0 - 10 Kp range v) 0 - 100 N, 0 - 14 SC range vi) 0 - 10 Kp, 0 - 14 SC

Unfortunately, these testers do not produce the same results for the same tablet. Studies have shown that operator variation, lack of calibration, spring fatigue, and manufacturer variation contribute greatly to the lack of uniformity. Even those testers designed to eliminate operator variability have been found to vary.

The hardness of a tablet, like its thickness, is a function of the die fill and compression force. At a constant die fill, the hardness values increase and thickness decreases as additional compression force is applied. This relationship holds up to a maximum value for hardness and a minimum value for thickness, beyond which increases in pressure cause the tablet to laminate or cap, thus destroying the integrity of the tablet. At a constant compression force (fixed distance between upper and lower punches), hardness increases with increasing die fills and decreases with lower die fills.

When uniform tooling is used, the die-fill/ force relationship makes control of tablet hardness a useful method of physically controlling tablet properties during a production operation, particularly when this measurement is combined with measurements of tablet thickness. The fill/force relationship is also the basis for instrumenting tablet machines.

In general, tablets are harder several hours after compression than they are immediately after compression. Lubricants can affect tablet hardness when they are used in too high a concentration or mixed for too long a period. Large tablets require a greater force to cause fracture and are therefore "harder" than small tablets. For a given granulation, a flat beveled tool produces a tablet harder than a deep cup tool.

Tablet hardness is not an absolute indicator of strength since some formulations, when compressed into very hard tablets, tend to "cap" on attrition, losing their crown portions. Therefore, another measure of a tablet's strength, its friability, is often measured. Tablets that tend to powder, chip, and fragment when handled lack elegance and consumer acceptance, and can create excessively dirty processes in such areas of manufacturing as coating and packaging. They can also add to a tablet's weight variation or content uniformity problems.

The laboratory friability tester subjects a number of tablets to the combined effects of abrasion and shock by utilizing a plastic chamber that revolves at 25 rpm, dropping the tablets a distance of six inches with each revolution.

Some chewable tablets and most effervescent tablets undergo high friability weight losses, which accounts for the special stack packaging that may be required for these types of tablets. When capping is observed on friability testing, the tablet should not be considered for commercial use, regardless of the percentage of loss seen.

   When concave and especially deep concave punches are used in tabletting, and especially when the punches are in poor condition or worn at their surface edges, the tablets produced result in "whiskering" at the tablet edge. Such tablets have higher than normal friability values because the "whiskers" are removed in testing. Tablet friability may also be influenced by the moisture content of the tablet granulation and finished tablets. A low but acceptable moisture level frequently acts as a binder. Very dry granulations that contain only fractional percentages of moisture often produce more friable tablets than do granulations containing 2 to 4% moisture.

The traditional hardness and friability evaluations performed on tablets involve only a small sample of tablets. How the tablets withstand the mechanical shocks of a production environment is related to the large number of tablets involved, the production equipment used, and the skill of the production personnel. Rough handling tests can be performed to give an indication of how well a tablet will hold up in its specified package and shipping container during shipment. Rough handling tests usually include a vibration test, a drop test, and an incline plane impact test. Some investigators have actually shipped bottled products across the country and back again to estimate the strength of the new tablet product in shipment.

    Drug Content and Release.   As mentioned earlier, a physically sound tablet may not produce the desired effects. To evaluate a tablet's potential for efficacy, the amount of drug per tablet needs to be monitored from tablet to tablet and batch to batch, and a measure of the tablet's ability to release the drug needs to be ascertained.

Weight Variation. With a tablet designed to contain a specific amount of drug in a specific amount of tablet formula, the weight of the tablet being made is routinely measured to help ensure that a tablet contains the proper amount of drug. In practice, composite samples of tablets (usually 10) are taken and weighed throughout the compression process. The composite weight divided by 10, however, provides an average weight but contains the usual problems of averaged values. Within the composite sample that has an acceptable average weight, there could be tablets excessively overweight or underweight. To help alleviate this problem the United States Pharmacopeia (USP)/National Formulary (NF) provides limits for the permissible variations in the weights of individual tablets expressed as a percentage of the average weight of the sample.

The USP weight variation test is run by weighing 20 tablets individually, calculating the average weight, and comparing the individual tablet weights to the average. The tablets meet the USP test if no more than 2 tablets are outside the percentage limit and if no tablet differs by more than 2 times the percentage limit. The weight variation tolerances for uncoated tablets differ depending on average tablet weight.

TABLE. Weight Variation Tolerances for Uncoated Tablets

Average Weight    Maximum Percentage

of Tablets (mg)    Difference Allowed

130 or less    10

130-324    7.5

More than 324    5

The potency of tablets is expressed in terms of grams, milligrams, or micrograms (for some potent drugs) of drug per tablet and is given as the label strength of the product. Official compendia or other standards provide an acceptable potency range around the label potency. For highly potent, low-dose drugs such as digitoxin, this range is usually not less than 90% and not more than 110% of the labeled amount. For most other larger-dose drugs in tablet form, the official potency range that is permitted is not less than 95% and not more than 105% of the labeled amount.

In general, official potency analytic methods require that a composite sample of the tablets be taken, ground up, mixed, and analyzed to produce an average potency value. In composite assays, individual discrepancies can be masked by use of the blended sample. Even though the average assay result looks acceptable, it could mask a wide variation in potency, with the result that a patient could be variably underdosed or overdosed. With such a drug as digitoxin, in which the safe and effective level and the toxic level are close (or even overlapping), exceeding the official or accepted potency range is not only undesirable, but possibly dangerous.

Three factors can directly contribute to content uniformity problems in tablets: (1) nonuniform distribution of the drug substance throughout the powder mixture or granulation, (2) segregation of the powder mixture or granulation during the various manufacturing processes, and (3) tablet weight variation. The use of weight cannot be used as a potency indicator, except perhaps when the active ingredient is 90 to 95% of the total tablet weight. In tablets with smaller dosages, a good weight variation does not ensure good content uniformity, but a large weight variation precludes good content uniformity.

To assure uniform potency for tablets of low dose drugs, a content uniformity test is applied. In this test, 30 tablets are randomly selected for the sample, and at least 10 of them are assayed individually. Nine of the 10 tablets must contain not less than 85% or more than 115% of the labeled drug content. The tenth tablet may not contain less than 75% or more than 125% of the labeled content. If these conditions are not met, the tablets remaining from the 30 must be assayed individually, and none may fall outside of the 85 to 115% range. In evaluating a particular lot of tablets, several samples of tablets should be taken from various parts of the production run to satisfy statistical procedures.

The purity of official tablets is usually assured by utilizing raw materials, both active drug and all excipients, that meet official or other rigid specifications. Extraneous substances present in a raw material or a drug that are not specifically allowed by compendial specifications or well-defined manufacturer's specifications may render the product unacceptable for pharmaceutical use. These extraneous substances may be toxic on acute or long-term use or may have an unpredictable or deleterious effect on product stability or efficacy. Certain well-defined impurities often appear in the specification of raw materials or drug substances, or if they are the product of unavoidable decomposition of the drug, they may be listed with an upper tolerance limit. For example, aspirin tablets as specified by the USP may contain no more than 0.15% of free salicylic acid relative to the amount of aspirin present.

Disintegration.  A generally accepted maxim is that for a drug to be readily available to the body, it must be in solution. For most tablets, the first important step toward solution is breakdown of the tablet into smaller particles or granules, a process known as disintegration. The time that it takes a tablet to disintegrate is measured in a device described in the USP/NF.

The USP device to test disintegration uses 6 glass tubes that are 3 inches long, open at the top, and held against a 10-mesh screen at the bottom end of the basket rack assembly.

 To be in compliance with the USP standards, the tablets must disintegrate, and all particles must pass through the 10-mesh screen in the time specified.

If any residue remains, it must have a soft mass with no palpably firm core. Procedures are stated for running disintegration times for uncoated tablets, plain-coated tablets, enteric coated tablets, buccal tablets, and sublingual tablets. Uncoated USP tablets have disintegration time standards as low as 5 min (aspirin tablets), but the majority of the tablets have a maximum disintegration time of 30 min. Enteric coated tablets are to show no evidence of disintegration after 1 hour in simulated gastric fluid. The same tablets are then tested in simulated intestinal fluid and are to disintegrate in 2 hours plus the time specified in the monograph.

Research has established that one should not automatically expect a correlation between disintegration and dissolution. However, since the dissolution of a drug from the fragmented tablet appears to control partially or completely the appearance of the drug in the blood, disintegration is still used as a guide to the formulator in the preparation of an optimum tablet formula and as an in-process control test to ensure lot-to-lot uniformity.

Dissolution. The original rationale for using tablet disintegration tests was the fact that as the tablet breaks down into small particles, it offers a greater surface area to the dissolving media and therefore must be related to the availability of the drug to the body. The disintegration test, however, simply identifies the times required for the tablet to break up under the conditions of the test and for all particles to pass through a 10-mesh screen. The test offers no assurance that the resultant particles will release the drug in solution at an appropriate rate. For this reason, dissolution tests and test specifications have now been developed for nearly all tablet products. The rate of drug absorption for acidic drug moieties that are absorbed high in the GI tract is often determined by the rate of drug dissolution from the tablet. If the attainment of high peak blood levels for the drug is a product objective, obtaining rapid drug dissolution from the tablet is usually critically important. The rate of dissolution may thus be directly related to the efficacy of the tablet product, as well as to bioavailability differences between formulations. Therefore, an evaluation as to whether or not a tablet releases its drug contents when placed in the environment of the gastrointestinal tract is often of fundamental concern to the tablet formulator.

The most direct assessment of a drug's release from various tablet formulations or products is accomplished through in vivo bioavailability measurements. The use of in vivo studies is restricted, however, for several reasons: the length of time needed to plan, conduct, and interpret the study; the highly skilled personnel required for human studies, the low precision and high variability typical of the measurements; the high cost of the studies; the use of human subjects for "nonessential" research; and the necessary assumption that a perfect correlation exists between diseased patients and the healthy human subjects used in the test. Consequently, in vitro dissolution tests have been extensively studied, developed, and used as an indirect measurement of drug availability, especially in preliminary assessments of formulation factors and manufacturing methods that are likely to influence bioavailability. As with any in vitro test, it is critically important that the dissolution test be correlated with in vivo bioavailability tests.

Two objectives in the development of in vitro dissolution tests are to show (1) that the release of the drug from the tablet is as close as possible to 100% and (2) that the rate of drug release is uniform batch to batch and is the same as the release rate from those batches proven to be bioavailable and clinically effective. Since 1970, the United States Pharmacopeia and the National Formulary have provided procedures for dissolution testing. They determine compliance with the limits on dissolution as specified in the individual monograph for a tablet (or a capsule). The US/NF 2007 specifies that either of two apparatuses be used for determining dissolution rates.

Apparatus 1. In general, a single tablet is placed in a small wire mesh basket fastened to the bottom of the shaft connected to a variable speed motor (Fig. A). The basket is immersed in the dissolution medium (as specified in the monograph) contained in a 100-ml flask. The flask is cylindric with a hemispherical bottom. The flask is maintained at 37°C ± 0.5°C by a constant temperature bath. The motor is adjusted to turn at the specified speed, and samples of the fluid are withdrawn at intervals to determine the amount of drug in solution.

Apparatus 2. The same equipment as in apparatus 1 is used, except that the basket is replaced by a paddle, formed from a blade and a shaft, as the stirring element (Fig. B). The dosage form is allowed to sink to the bottom of the flask before stirring. Dosage forms may have a "small, loose piece of nonreactive material such as not more than a few turns of wire helix" attached to prevent them from floating. Description of a dissolution test in a USP/NF monograph specifies the dissolution test medium and volume, which apparatus is to be used, the speed (rpm) at which the test is to be performed, the time limit of the test and the assay procedure. The test tolerance is expressed as a percentage of the labeled amount of drug dissolved in the time limit. For example, for methyldopa tablets, the dissolution test calls for a medium of 900 ml of 0. 1N HCI, apparatus 2 turning at 50 rpm, and a time limit of 20 min. The accepted amount dissolved in 20 min is not less than 80% of the labeled amount of methyldopa (based on the cited assay procedure).

Dissolution testing and interpretation can be continued through three stages if necessary. In stage 1(S1), six tablets are tested and are acceptable if all of the tablets are not less than the monograph tolerance limit (Q) plus 5%. If the tablets fail S1, an additional six tablets are tested (S2). The tablets are acceptable if the average of the twelve tablets is greater than or equal to Q and no unit is less than Q minus 15%. If the tablets still fail the test, an additional 12 tablets are tested. The tablets are acceptable if the average of all 24 tablets is greater than or equal to Q and if not more than 2 tablets are less than Q minus 15%.

Industrial pharmacists routinely test their formulations for dissolution. Their results are plotted as concentration versus time. Values for t50%, t90%, and the percentage dissolved in 30 min are used as guides. The value for t50% is the length of time required for 50% of the drug to go into solution. A value for t90% of 30 min is often considered satisfactory and is an excellent goal since a common dissolution tolerance in the USP/NF is not less than 75% dissolved in 45 min.

FIG.        A, USP dissolution apparatus 1.            B, USP dissolution apparatus 2.  

PDF LINK: https://www.facebook.com/download/1538142443165240/tablet-problems-evaluation-handout.pdf