Industrial Pharmacy Lec 3 PDF

Lec. 3: Tablet Evaluations Mohammed Albarki, PhD Almustaqbal University/ College of Pharmacy  Advantages and Disadvantages of Tablet Advantages Disadvantages Unit Dosage Form (accurate dose)...

Lec. 3: Tablet Evaluations Mohammed Albarki, PhD Almustaqbal University/ College of Pharmacy  Advantages and Disadvantages of Tablet Advantages Disadvantages Unit Dosage Form (accurate dose) Some drugs resist compression Easy to handle, store and dispense Not ideal to hide bad taste or smell of some API Easier than capsules in shipping and Difficult to formulate for drug with poor packaging wetting properties (will be difficult for other dosage forms too) Manufacturing cost is lower than most Some drugs degrade if administered orally other dosage forms (will be difficult for other dosage forms too) Their release profile is easy to control and manipulate 2 College of Pharmacy- Industrial Pharmacy II- 5th stage- First Semester Tablet Evaluations  Types of Tablets 3 College of Pharmacy- Industrial Pharmacy II- 5th stage- First Semester Tablet Evaluations  Granulation Fine powder drug mostly has poor flow properties. Granules have better flowability and compressibility than individual ingredients. It ensures the consistent spread of API in the formulation. 4 College of Pharmacy- Industrial Pharmacy II- 5th stage- First Semester Tablet Evaluations  Compression Compression is the final step in the tablet formulation process. Requires a set of variables to be evaluated which are beyond the scope of this class. 5 College of Pharmacy- Industrial Pharmacy II- 5th stage- First Semester Tablet Evaluations  Tablet Evaluation General appearance: its visual identity and overall “elegance” which is essential for: 1. Consumer acceptance. 2. Control lot-to-lot uniformity. 3. General tablet-to-tablet uniformity. 4. Monitor trouble-free manufacturing. Controlling a tablet's general appearance involves measuring several attributes such as the tablet’s size, shape, color, presence or absence of an odor, taste, surface texture, physical flaws, consistency, and legibility of any identifying markings. 6 College of Pharmacy- Industrial Pharmacy II- 5th stage- First Semester Tablet Evaluations  Unique Identification Markings Print is used for rapid identification of products. The information included usually indicates company name, product code, and potency. Tablet prints must be clear and free of flaws. 7 College of Pharmacy- Industrial Pharmacy II- 5th stage- First Semester Tablet Evaluations  Organoleptic Properties (color, odor, taste, visual flaws) Color is a vital means of rapid identification and consumer acceptance. The color of a product must be uniform within a single tablet. Poor color uniformity is a problem called Mottling (more details later). Mottling affects patient acceptance because patients will think this is a bad tablet quality and may cause some unwanted effects. Odor in a batch of tablets could indicate a stability problem. Such as the characteristic odor of acetic acid in degrading aspirin tablets. Note: The presence of odor may be a characteristic of the drug such as vitamins. 8 College of Pharmacy- Industrial Pharmacy II- 5th stage- First Semester Tablet Evaluations  Organoleptic Properties (color, odor, taste, visual flaws) Taste is an important property in consumer acceptance especially in chewable tablets. Tablet visual flaws: Chips, cracks, contamination from foreign bodies (for example: hair, oil drops, and dirt). Surface texture ("smooth" versus "rough"). Appearance ("shiny" versus "dull"). These flaws will affect patient acceptance and may indicate a formulation problem. 9 College of Pharmacy- Industrial Pharmacy II- 5th stage- First Semester Tablet Evaluations  Size and Shape Tablet shape and diameter are determined by die shape. (fixed) Tablet thickness is the only dimensional variable related to the process. Tablet thickness can be changed during the process. The thickness should be consistent from batch to batch (indicate good manufacturing): If it was not consistent: 1. This may indicate a content uniformity problem. 2. Affect patient acceptance of the dosage form. 3. This may result in packaging problems. 10 College of Pharmacy- Industrial Pharmacy II- 5th stage- First Semester Tablet Evaluations  Size and Shape Tablet thickness is measured using a micrometer caliper (vernier caliper). Thickness variation should not be more than ± 5%. If more than that it will indicate a poor manufacturing technique. It also will lead to packaging problems since the package is designed for a certain thickness and an increase in that thickness will lead the tablet to not fit in the packaging. 11 College of Pharmacy- Industrial Pharmacy II- 5th stage- First Semester Tablet Evaluations  Tablet Hardness (Non-Official) Tablets must withstand mechanical strength during manufacturing, packaging, shipping, and handling. Tablet hardness is related to disintegration time (hard tablets may undergo slow disintegration). Tablet hardness can be varied with: 1. Die filling 2. Compression force. 3. Amount of binder added At a constant die fill, hardness values increase, and thickness decreases as additional compression force is applied (to a certain limit). 12 College of Pharmacy- Industrial Pharmacy II- 5th stage- First Semester Tablet Evaluations  Tablet Hardness (Non-Official) Hardness can change also with variable die fill when the compression force is constant, hardness increases with increased die fill and decreases with lower die fills. Intact and uniform tablets are an important requirement for patient acceptance. The tablet hardness test is the force required to break the tablet in a diametric compression test (it is called tablet crushing strength). The test can be done by Monsanto or Pfizer hardness tester. https://youtu.be/q7PFpwa_hg4 13 College of Pharmacy- Industrial Pharmacy II- 5th stage- First Semester Tablet Evaluations  Tablet Friability (USP official test) Tablet hardness is not an absolute indicator of good tablets è we need a friability test Another measure of a tablet’s strength is its friability. A friability test is performed to ensure the tablet stays intact under mechanical pressure during shipping and handling. Tablets that tend to powder, chip, and fragment when handled, lack elegance and consumer acceptance. 14 College of Pharmacy- Industrial Pharmacy II- 5th stage- First Semester Tablet Evaluations  Tablet Friability The laboratory friability tester is known as the Roche friabilator. It revolves at 25 rpm, dropping the tablets a distance of six inches with each revolution. Test limit: Conventional compressed good tablets are expected to lose less than 1% of their weight. 15 College of Pharmacy- Industrial Pharmacy II- 5th stage- First Semester Tablet Evaluations  Drug Content and Release A physically sound tablet may not produce the desired effects. To evaluate a tablet’s potential for efficacy, the amount of drug per tablet must be monitored from tablet to tablet and batch to batch, and a measure of the tablet’s ability to release the drug must be ascertained. è other tests are needed! Other tests for tablet Evaluation: (Official USP tests) 1. Weight variation test. 2. Content uniformity test. 3. Disintegration test. 4. Dissolution test. 16 College of Pharmacy- Industrial Pharmacy II- 5th stage- First Semester Tablet Evaluations  Weight variation (USP official test) The weight of the tablet is routinely measured to help ensure that a tablet contains the proper amount of the drug. (more details will be in the lab) Tablet-to-tablet weight must be within the USP weight variation limit. Factors that lead to weight variation can be: Poor flow of tablet formulation. Poor machine setup. (more on that at the end of the lecture). 17 College of Pharmacy- Industrial Pharmacy II- 5th stage- First Semester Tablet Evaluations  Weight Variation 1. The weight variation test is a good indicator of content uniformity in a case where the active ingredients represent a good percentage of tablet weight. Such as the Aspirin tablet, the acetylsalicylic acid represents about 90% of the tablet’s weight.è Here, the weight variation test is an important test for content uniformity. 2. On the other hand, a weight variation test is of limited importance in very potent drugs where the effective dose is very small. For example, digoxin tablet contains less than 1% API. Average weight of Tablets (mg) Maximum Percentage Difference Allowed 130 or less ±10 % 130- 324 ±7.5 % More than 324 ±5 % 18 College of Pharmacy- Industrial Pharmacy II- 5th stage- First Semester Tablet Evaluations  Content Uniformity Test (USP official test) It is performed to ensure the variation of active pharmaceutical ingredients is within the limit. At least the contents of 9 of 10 tablets must be within 85%-115% of the theoretical drug contents and only one tablet is allowed to be within 75%-125%. Three factors can directly contribute to content uniformity problems in tablets: 1. Nonuniform distribution of the drug substance throughout the powder mixture or granulation (maybe because of poor mixing), 2. Segregation of the powder mixture or granulation during the various manufacturing processes. 3. Tablet weight variation. 19 College of Pharmacy- Industrial Pharmacy II- 5th stage- First Semester Tablet Evaluations  Disintegration Test (USP official test) The disintegration process is the process of tablet breakdown into smaller particles or granules. To test if the tablet is able to disintegrate inside the body within a reasonable time we need a disintegration test. è The disintegration test can be performed using the USP disintegration apparatus. Test Limit: Generally, tablet disintegration time is below 30 minutes. An enteric-coated tablet is required to stay intact at least for one hour in the apparatus. 20 College of Pharmacy- Industrial Pharmacy II- 5th stage- First Semester Tablet Evaluations  Dissolution Test (USP official test) Is required to make sure that the tablet material after disintegration is able to go into the solution at an appropriate rate. The drug in solution means it is ready for absorption. This means that dissolution testing will give us an idea about formulation efficacy and bioavailability. The easiest way to test that is using the simulation apparatus which is called the USP dissolution apparatus. (more on that in the lab). 21 College of Pharmacy- Industrial Pharmacy II- 5th stage- First Semester Tablet Evaluations  Importance of Dissolution Testing 1. It guides formulation and product development toward product optimization. 2. Manufacturing may be monitored by dissolution testing as a component of the overall quality assurance program. 3. Consistent in vitro dissolution testing ensures bioequivalence from batch to batch. 4. It is a requirement for regulatory approval of marketing for products registered with the FDA and regulatory agencies of other countries. 22 College of Pharmacy- Industrial Pharmacy II- 5th stage- First Semester Tablet Evaluations  Dissolution Dissolution results is plotted as a release % vs time. 23 College of Pharmacy- Industrial Pharmacy II- 5th stage- First Semester Tablet Evaluations  Tablet Evaluations Non - Official Official General Content and Hardness Test Friability test Appearance Release Testing Identification Weight and Marking Variation Test Odor, color, Content Taste Uniformity Disintegration Size test Test Dissolution Test 24 College of Pharmacy- Industrial Pharmacy II- 5th stage- First Semester Tablet Evaluations  Processing Problems MUC- Pharmacy Department- Industrial Pharmacy I- 4th stage. – Spring 2023 Mohammed A Albarki, PhD 25  Processing Problems A final tablet formulation can undergo several problems after they being compressed even after packaging, shipping, storing, and patient handling. Three types of problems: 1. Problems Related to tablet processing and manufacturing. 2. Problems related to excipient. 3. Combination of both. 26 College of Pharmacy- Industrial Pharmacy II- 5th stage- First Semester Tablet Evaluations  Problems Related to Tablet Processing Capping and Lamination Capping: Partial or complete separation of tablet top or bottom crown from the main body of the tablet. Lamination: Complete separation of the tablet into two or more distinct layers. These processing problems are readily apparent immediately after compression. These also may happen later (after hours or even days). è This is easily diagnosed during a friability test. https://youtu.be/APl-htdlBv0?si=iyaxYJgMBVR-NNWJ 27 College of Pharmacy- Industrial Pharmacy II- 5th stage- First Semester Tablet Evaluations  Problems Related to Tablet Processing Causes of capping and lamination: 1. In the past, the problem was attributed to air entrapment in the granular material that is released after compression. 2. However, research has shown that capping and lamination are due to the deformational properties of the formulation during and immediately after compression. (see next slide). This is the main reason for this problem. 3. The choice of excipient especially the binder may be a reason for this problem. 4. Too dry granules produce a tablet that tends to cap or laminate for lack of cohesion. 5. Incorrect compression machine setup (secondary reason). 28 College of Pharmacy- Industrial Pharmacy II- 5th stage- First Semester Tablet Evaluations  Causes of Capping and Lamination Deformational changes (reason 2 from the previous slide): During compaction particles undergo plastic deformation to produce die wall pressure greater than what can be relieved by the elastic recovery when punch pressure is removed. This will initiate a crack that will cause fracture upon decompression. As the compact is ejected, the die-wall pressure falls to zero. The emerging portion of the compact expands while the confined portion cannot, thus concentrating shear stresses at the edge of the die and causing a break to develop. Tablets that do not fracture have the ability to relieve the shear stresses developed. This stress relaxation is time-dependent; therefore, the occurrence of tablet fracture is also time-dependent.è it may happen later on time. 29 College of Pharmacy- Industrial Pharmacy II- 5th stage- First Semester Tablet Evaluations  Problems Related to Tablet Processing Note: In addition to the previous reasons, lamination can also result from the following: It can also result from over compression in which strong force will result in particles flattening and not binding correctly with each other. If the tablet is too thick this will not allow the particles to be compressed and bind with each other correctly. è we have 7 possible reasons for capping and lamination and reason 2 is the most probable (important) one 30 College of Pharmacy- Industrial Pharmacy II- 5th stage- First Semester Tablet Evaluations  Solution for Capping and Lamination: 1. Slow down the compression speed and decrease the main compression pressure to allow air to escape and decrease the relaxation pressure. 2. Use the precompression step in which the tablet is compressed with light force to pre-form the tablet before main compression. 3. Make sure you are using the right excipients. 4. Using another tablet shape may resolve the problem for example the flat-end tablet has a lower tendency to fracture. A deep concave punch produces a tablet that caps. Because the curved part of such tablets expands radially while the body of the tablet cannot. 31 College of Pharmacy- Industrial Pharmacy II- 5th stage- First Semester Tablet Evaluations  Problems Related to Tablet Processing Cracking: The appearance of small cracks on the tablet surface (top or bottom) rarely appears on the sides. 1. This is due to the rapid expansion of the tablet after compression. 2. Also, poor granulation (dry) and working in a cold environment. The solution is to improve tablet formulation and adjust the amount of binder used in granulation. 32 College of Pharmacy- Industrial Pharmacy II- 5th stage- First Semester Tablet Evaluations  Problems Related to Excipients Chipping: Breaking edges of the tablet after compression or during shipping and handling. 1. The cause could be poor particle flow due to insufficient lubrication in which tablets are sticking in the machine. 2. It could be a poor formulation setup in which insufficient drying. The solution is to adjust the amount of lubricant and tablet formulation. 33 College of Pharmacy- Industrial Pharmacy II- 5th stage- First Semester Tablet Evaluations  Problems Related to Excipients Sticking: Tablet material sticking to the die wall or punch faces (tablet is still intact tablet). Serious sticking can cause chipping. The cause could be: 1. Too much moisture, 2. Inadequate lubricant and/or 3. Too much binder. 4. In addition, low melting point excipients such as stearic acid (lubricant) may soften if the temperature gets too high during the compression process which may cause sticking. The solution is to properly formulate tablet granules and adjust the amount of lubricant in the formulation. 34 College of Pharmacy- Industrial Pharmacy II- 5th stage- First Semester Tablet Evaluations  Problems Related to Excipients Picking: A small portion of the tablet surface sticks to the punch faces. Mostly occurs with tablets with imprints, especially with letters like B, O, and A. The solution is to: 1. Adjust the amount of lubricant and properly dry the granules. 2. Also, lettering should be designed as large as possible. 35 College of Pharmacy- Industrial Pharmacy II- 5th stage- First Semester Tablet Evaluations  Problems Related to Excipients Mottling: 1. Unequal distribution of color on a tablet. It can happen when using a drug that has a color that differs from the color of excipients or a drug whose degradation products are colored. It also can happen due to improper use of dyes. Generally, this problem occurs when using a colorant material. To solve this: 1. Mix the dye well during granulation and/or 2. Change the solvent system for the dye. 3. Make sure that the dye is sieved before adding to the mixture so no big chunk is present in the dye powder. 36 College of Pharmacy- Industrial Pharmacy II- 5th stage- First Semester Tablet Evaluations  Other Problems Weight variation: Tablets have different weights that are outside USP limits for weight variation. Causes: A- Die Filling problems occur when: 1. There is a variation in the lower punch length by a few thousandths of an inch. This will cause die filling to be different and lead to weight variation problems. 2. There is a variation in granule size and size distribution of granules. Non-homogenous granules will affect how void spaces between particles are filled. 37 College of Pharmacy- Industrial Pharmacy II- 5th stage- First Semester Tablet Evaluations  Weight Variation B- Poor flow: Insufficient lubricant and glidant. Poor design of the hooper. C- Poor Mixing: This may cause lubricant and glidant not to be thoroughly distributed. Solution: Proper formulation, tooling, and control program will minimize the weight variation problem. 38 College of Pharmacy- Industrial Pharmacy II- 5th stage- First Semester Tablet Evaluations  Other Problems Double impression: Occurs in tablet with print or score line. Causes: The punch rotates slightly when compressing the tablet which might result in an unclear print or line. Note: This problem is more common with machines that use pre-compression. The solution is to control the compression process and maintain the machine. 39 College of Pharmacy- Industrial Pharmacy II- 5th stage- First Semester Tablet Evaluations  Other Problems Uneven breakage: Tablets don’t break evenly. The causes are: 1. coarse granules and 2. improper mixing. The solution is to mix well and reduce the size of granules. 40 College of Pharmacy- Industrial Pharmacy II- 5th stage- First Semester Tablet Evaluations