1. Common Tableting Problems & Evaluation of Tablets
Course Teacher:
Sabrina Rahman Archie

2. Background
An ideal tablet should be free from any visual defect or functional defect.
With the development of technology, the production process had become more simplified and more mechanized.

3. Background
In olden days tablets were initially punched on small scale with hand operated machines, which suffered the problem of varied strength and integrity.
But now the tablet punching machines are all mechanized, the mechanical feeding of feed from the hopper into the die, electronic monitoring of the press, but tablet process problem still persist.

4. Background
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.

5. Background Basic Problems Weight Variation Mechanical Strength Related
Hardness
Friability
Content Uniformity
Release Profile Altered
Visual defects

6. Background
The Imperfections known as: ‘VISUAL DEFECTS’ are either related to Imperfections in any one or more of the following factors[1]:
Formulation design
Tableting process
Machine

7. Visual Defects
Process Related
Capping
Lamination
Cracking
Chipping
Formulation Related
Sticking
Picking
Binding
Machine Related
Double Impression

8. The defects related to Tableting Process..
CAPPING:
Partial or complete separation of the top or bottom of tablet due to air-entrapment in the granular material.
LAMINATION:
Separation of tablet into two or more layers due to air-entrapment in the granular material.
CRACKING:
Small, fine cracks observed on the upper and lower central surface of tablets, or very rarely on the sidewall.
CHIPPING:
Breaking of tablet edges.

9. The defects related to Formulation..
STICKING:
The adhesion of granulation material to the die wall.
PICKING:
The removal of material from the surface of tablet and its adherence to the face of punch.
BINDING:
Sticking of the tablet to the die and does not eject properly out of the die[1].

10. The defect related to Machine..
DOUBLE IMPRESSION:
Due to free rotation of the punches, having some engraving on their faces.

11. The defect related to more than one factor..
MOTTLING:
Unequal distribution of color on a tablet with light or dark areas.

12. Further, in this section, each problem is described along with its
causes and remedies which may be related to either of formulation or of machine.

13. Capping
The upper or lower segment of the tablet separates horizontally, either partially or completely from the main body and comes off as a cap, during ejection from the tablet press, or during subsequent handling.
Reason:
Due to the air–entrapment in a compact during compression, and subsequent expansion of tablet on ejection of a tablet from a die.
Fig: Capping

14. The Causes and Remedies of Capping related to ‘Formulation’

15. The Causes and Remedies of Capping related to ‘Machine’

16. Lamination
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.
Fig: Lamination

17. The Causes and Remedies of Lamination related to ‘Formulation’

18. The Causes and Remedies of Lamination related to ‘Machine’

19. Chipping
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.

20. The Causes and Remedies of Chipping related to ‘Formulation’

21. The Causes and Remedies of Chipping related to ‘Machine’

22. Cracking
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.

23. The Causes and Remedies of Cracking related to ‘Formulation’

24. The Causes and Remedies of Cracking related to ‘Machine’

25. Sticking 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.
Fig: Sticking on punch face

26. The Causes and Remedies of Sticking related to ‘Formulation’
waxy

27. The Causes and Remedies of Sticking related to ‘Machine’

28. Picking
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.
Fig: Picking[1]

29. Picking
Reason:
Picking is of particular concern when punch tips have engraving or embossing letters.
Granular material is improperly dried.

30. The Causes and Remedies of Picking related to ‘Formulation’

31. The Causes and Remedies of Picking related to ‘Machine’

32. Binding
Sticking of the tablet to the die and does not eject properly out of the die.
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:
Usually due to excessive amount of moisture in granules, lack of lubrication and/or use of worn dies.

33. The Causes and Remedies of Binding related to ‘Formulation’

34. The Causes and Remedies of Binding related to ‘Machine’

35. Mottling
Unequal distribution of color on a tablet, with light or dark spots.
Reason:
Colored drug, whose color differs from the color of excipients used for granulation of a tablet.

36. The Causes and Remedies of Mottling

37. Double Impression
Involves only those punches, which have a monogram or other engraving on them.
If the upper punch is uncontrolled, it can rotate during the short travel to the final compression stage and create a double impression.

38. Double Impression Reason:
At the moment of compression, the tablet receives the imprint of the punch.
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’.

39. The Causes and Remedies of Double Impression

40. QUALITY STANDARDS AND COMPENDIAL REQUIREMENTS
In addition to the apparent features of tablets, tablets must meet other physical specifications and quality standards.
These include criteria for:
weight
weight variation
content uniformity
thickness
hardness
disintegration and
dissolution.

41. FIGURE : Quality control in the manufacturing of tablets
These factors must be
controlled during production
(in-process controls) and
verified after the production
of each batch to ensure that
established product quality
standards are met.
FIGURE : Quality control in the manufacturing of tablets

42. Tablet Weight and USP Weight Variation Test
The quantity of fill in the die of a tablet press
determines the weight of the tablet.
The volume of fill is adjusted with the first few tablets to yield the desired weight and content.
For example, if a tablet is to contain 20 mg of a drug substance and if 100,000 tablets are to be produced, 2,000 g of drug is included in the formula.

43. After the addition of the pharmaceutical additives, such as the diluent, disintegrant, lubricant, and binder, the formulation may weigh 20 kg, which means that each tablet must weigh 200 mg for 20 mg of drug to be present.
Thus, the depth of fill in the tablet die must be adjusted to hold a volume of granulation weighing 200 mg.
During production, sample tablets are periodically removed for visual inspection and automated physical measurement.

44. The USP contains a test for determination of
dosage form uniformity by weight variation for
uncoated tablets (5).
In the test, 10 tablets are weighed individually and the average weight is calculated. The tablets are assayed and the content of active ingredient in each of the 10 tablets is calculated assuming homogeneous drug distribution.

45. Content Uniformity Test
By the USP method, 10 dosage units are individually assayed for their content according to the method described in the individual monograph.
Unless otherwise stated in the monograph, the requirements for content uniformity are met if the amount of active ingredient in each dosage unit lies within the range of 85% to 115% of the label claim and the standard deviation is less than 6%.
If one or more dosage units do not meet these criteria, additional tests as prescribed in the USP are required.

46. Tablet Thickness
The thickness of a tablet is determined by the diameter of the die, the amount of fill permitted to enter the die, the compaction characteristics of the fill material, and the force or pressure applied during compression.
FIGURE: Tablet thickness gauge. (Courtesy of Eli Lilly and Company.)

47. To produce tablets of uniform thickness during and between batch productions for the same formulation, care must be exercised to employ the same factors of fill, die, and pressure.
The degree of pressure affects not only thickness but also hardness of the tablet; hardness is perhaps the more important criterion since it can affect disintegration and dissolution.

48. Thus, for tablets of uniform thickness and hardness, it is doubly important to control pressure.
Tablet thickness may be measured by hand gauge during production or by automated equipment.

49. FIGURE: Tablet diameter testing instrument.
FIGURE: Automatic weight, hardness, thickness, and tablet diameter test instrument for quality control. Using a microprocessor and monitor for visualization, the instrument
can test up to 20 samples at a time.

50. Tablet Hardness and Friability
It is fairly common for a tablet press to exert as little as 3,000 and as much as 40,000 lb of force in production of tablets.
Generally, the greater the pressure applied, the harder the tablets, although the characteristics of the granulation also have a bearing on hardness.
Certain tablets, such as lozenges and buccal tablets, that are intended to dissolve slowly are intentionally made hard; other tablets, such as those for immediate drug release, are made soft.

51. In general, tablets should be sufficiently hard to resist breaking during normal handling and yet soft enough to disintegrate properly after swallowing.
Special dedicated hardness testers or multifunctional systems are used to measure the degree of force (in kilograms, pounds, or in arbitrary units) required to break a tablet.

52. FIGURE: Tablet hardness tester.

53. A force of about 4 kg is considered the minimum requirement for a satisfactory tablet.
Multifunctional automated equipment can determine weight, hardness, thickness, and diameter of the tablet.

54. A tablet’s durability may be determined through the use of a friabilator .
This apparatus determines the tablet’s friability, or tendency to crumble, by allowing it to roll and fall within the drum.
The tablets are weighed before and after a specified number of rotations and any weight loss is determined.
Resistance to loss of weight indicates the tablet’s ability to withstand abrasion in handling, packaging, and shipment.
A maximum weight loss of not more than 1% generally is considered acceptable for most products.

55. Tablet Disintegration
For the medicinal agent in a tablet to become fully available for absorption, the tablet must first disintegrate and discharge the drug to the body fluids for dissolution.
Tablet disintegration also is important for tablets containing medicinal agents (such as antacids and antidiarrheals) that are not intended to be absorbed but rather to act locally within the gastrointestinal tract. In these instances, tablet disintegration provides drug particles with an increased surface area for activity within the gastrointestinal tract.

56. All USP tablets must pass a test for disintegration, which is conducted in vitro using a testing apparatus such as the one shown in following Figure.
FIGURE : Tablet disintegration testing apparatus.

57. The apparatus consists of a basket and rack assembly containing six open-ended transparent tubes of USP-specified dimensions, held vertically upon a 10-mesh stainless steel wire screen.

58. During testing, a tablet is placed in each of the six tubes of the basket, and through the use of a mechanical device, the basket is raised and lowered in the immersion fl uid at 29 to 32 cycles per minute, the wire screen always below the level of the fluid.
For uncoated tablets, buccal tablets, and sublingual tablets, water at about 37°C serves as the immersion fluid unless another fluid is specified in the individual monograph.

59. For these tests, complete disintegration is defined as “that state in which any residue of the unit, except fragments of insoluble coating or capsule shell, remaining on the screen of the test apparatus is a soft mass having no palpably firm core”

60. Tablets must disintegrate within the times set forth in the individual monograph, usually 30 minutes, but varying from about 2 minutes
for nitroglycerin tablets to up to 4 hours for
buccal tablets. If one or more tablets fail to disintegrate,
additional tests prescribed by the USP
must be performed.

61. Tablet Dissolution
In vitro dissolution testing of solid dosage forms is important for a number of reasons:
It guides formulation and product development toward product optimization.
Manufacturing may be monitored by dissolution testing as a component of the overall quality assurance program.
Consistent in vitro dissolution testing ensures bioequivalence from batch to batch.

62. It is a requirement for regulatory approval of marketing for products registered with the FDA and regulatory agencies of other countries.
The goal of in vitro dissolution testing is to provide insofar as is possible a reasonable prediction of or correlation with the product’s in vivo bioavailability.

63. Drugs are placed into one of four categories as follows:

64. For a high-solubility and high-permeability Category I drug, an IVIVC may be expected if the dissolution rate is slower than the rate of gastric emptying (the rate-limiting factor).
In the case of a low-solubility and high-permeability Category II drug, dissolution may be the rate-limiting step for absorption, and an IVIVC may be expected.
In the case of a high-solubility and low permeability Category III drug, permeability is the rate-controlling step, and only a limited IVIVC may be possible.
In the case of a Category IV drug with low solubility and low permeability, significant problems are likely for oral drug delivery.

65. Tablet disintegration is the important first step to the dissolution of the drug in a tablet.
A number of formulation and manufacturing factors can affect the disintegration and dissolution of a tablet, including
particle size of the drug substance;
solubility and hygroscopicity of the formulation;
type and concentration of the disintegrant, binder, and lubricant;
Manufacturing method, particularly the compactness of the granulation and compression force used in tableting;
and any in-process variables

66. The USP includes seven apparatus designs for drug release and dissolution testing of immediate-release oral dosage forms extended release products, enteric-coated products, and transdermal drug delivery devices.
Of primary interest here are USP Apparatus 1 and USP Apparatus 2, used principally for immediate release solid oral dosage forms.

67. FIGURE :Hanson Automated Dissolution Test System
FIGURE :Hanson Automated Dissolution Test System. It features microprocessor and templates to create, edit store, and validate dissolution protocols; graphical displays with menus; and icon-based program controls.

68. Reference
Leon lachman, H. A. (2009). The Theory and Practice of Industrial Pharmacy. New Delhi: CBS Publishers and Distributors,
Ansel’s Pharmaceutical Dosage Form and Drug Delivery System
B.C. Hancock, A. M. (2006). Numerical and experimental investigation of capping mechanisms during pharmaceutical tablet compaction. Science Direct ,
Tousey, M. D. (2011). The Manufacturing process Tablet and Capsules Manufaturing. Techceuticals ,