Wet Granulation
Wet granulation is the most commonly used manufacturing process for oral dosage forms. The purpose of granulation is to enable primary powder particles to adhere to form multi-particulate entities known as granules. Wet granulation is a commonly performed method of granulation. A planetary mixer is initially used to mix the powder (dry) to achieve good homogeneity, at a high intensity. However, wet granulation remains the most robust manufacturing method. It is the method that has the ability to mask the variability in the properties of the incoming raw materials, thus to ensure a robust and a predictable performance.
Wet granulation accumulates less dust during powder handling than direct compression method. Granulation improves both the compaction characteristics and flow properties of a mix and is able to prevent segregation of the constituents of the mix. However, wet granulation is not appropriate for water or heat sensitive drugs and this lead to poor chemical stability or unpredictable drug product performance.
Method
The method has been divided into three stages:
1. Formulation
The following table highlights the basic formula the group was used to produce Aspirin 75mg tablets.
Total tablet weight (mg) = 300 mg
Total batch weight (g) = 100 g
All excipients where weighed using analytical balance within 1% +/- (g) required mass which illustrated within the table above. All the mixed of diluents, filler, disintegrant, glidant and the aspirin were transfer into a jar of tumble mixer and mixed for 2 minutes. The mixture was sieved in a 500 micron and then transferred back into a tumble mixer for 2 min. The mixture was sieved again with the aid of a plastic card and finally was transfer back into the tumble mixer.
2. TABLET MANUFACTURE
The Manesty F3 single-station tablet machine was used to compress the previously prepared formulations into 300 mg tablets. The tooling was used 10 mm concave punch and die set. The lubricant used had been saved from our last experiment. Prior to compression, tablet formulation requires lubrication. In order to ensure that the formation and ejection can occur with low friction. The required amount of lubricant was added and was blended for 5 min.
The tablet machine was set up with the compression tooling which were the upper punch, lower punch and dies and this was to familiarise how the operation work and the ways in which the tablet weight and how compression force were controlled.
The fill depth of the die was adjusted by altering the capacity regulating screw so that the tablet weight is approximately 300 mg. Target tablet weight is 300mg (± 15mg). A tablet was then compressed by manually turning the fly-wheel. The tablet machine was turned on in order to compress 40 tablets at two different compaction forces, 5KN and 10KN (low and high), they were then stored for the next practical Tablet Testing. The amount of powder (300mg) filled into the die is controlled by the position of the lower punch. The upper punch descends and exerts compression force of 10Kilo Newton. After ejection, the tablet is pushed down to a basket by the hopper shoe. 50 tablets per batch were produced and all settings remained the same.
RESULTS
10 individual tablets
10 tablets for each batches
5KN
AVERAGE MEAN FOR 5KN= 80.5 = 8.05 KP
10
Standard Deviation = 0.28382
10KN
AVERAGE MEAN FOR 5KN= 100.1 = 10.01 KP
10
Standard Deviation = 0.59151
High compression
% Friability = [W0 – W100]
W0 x 100 %
= [6069.8 – 6051.2] x 100
6069.8
= 0.306 %
Low compression
% Friability = [W0 – W100]
W0 x 100 %
= [6162.6 – 6131.9] x 100
6162.6
= 0.498 %
Disintegration
DISCUSSION
To start with, disintegrant is an excipient to ensure the breakup of tablet into small fragments when in contact with a liquid. A Glidant is used to improve the flowability of the powder. The dry binders were used as microcrystalline cellulose (MCC), grade used Avicel PH102, which result in better flow but with no significant decrease in surface area or compatibility. MCC is the most compactible of all the DC fillers and has the highest dilution potential. Finally lubricant is used to ensure that the formation and ejection can occur with low friction.
WEIGHT UNIFORMITY
Weight Uniformity is an important test that ensures the required quality standards are met. The test of uniformity of weight is a simple way to assess variation in drug dosage, which makes a useful quality control procedure during the tablet production. According to BP each 250mg of tablet or more the CV% should be less than 5% that make aspirin within the range as shown in the result 0.0725 %.
By using the test we can identify powder flow and subsequently ensure the correct active ingredients and dosage are given to the patient. Compliance with these standards helps achieve uniformity.
CRUSHING STRENGTH
Looking at crushing strength results, we found that high compression force is harder than the lowest compression and the results show that they are within the range according to BP between (4-15) KP. The crushing strength of the formulations varied. The highest crushing strength (kP) was achieved with a high compression force which was 10.01 KP, whereas the lowest crushed strength was achieved with a low compression force of 8.05 KP. These variations occurred due to the MCC, which gives degree of crystallinity. The amorphous region proved to be easier to crush as the tablet surface was softer due to high compression force used, so more energy input was needed. However when the tablets from the lower compression force batch were fractured, the mean kP was much smaller at 8.05 kP. At lower compression forces the tablet surface has a crystalline region which can be more readily fractured, thus less energy is required to crush the tablets.
DISINTEGRATION
Disintegration is useful for assessing the potential importance of formulation and process variables on the biopharmaceutical properties of the tablet. This as a control procedure to evaluate the quality reproducibility of the tablet during production. In the results it shows that the test of both variant of force compression results were within the BP range that is less than 15mins, For 42 seconds for 5KN and 55 second for 10KN as it dissolved very quickly because there was no binder present.
FRIABILITY
The friability of a tablet is indicative of the likeliness of the tablet to erode during handling when subjected to the type of forces. Typically when experienced in production and administration such as collisions and sliding motions which cause defragmentation at the tablet surface. This loss of particles from the surface will in effect alter the appearance and weight of the original tablet. Friability is a measure of the attrition-resistance of a tablet. The results from friability testing show that there were significant differences between high and low forces of compressions. 5KN lost about 0.306% and 10KN lost about 0.498% from its original weight. However both results were within the range of less than 1%.
Finally, the dissolution test could have been performed to obtain variables on the bioavailability of a drug and to indicate the performance of the formulation under any conditions. Drug dissolution might be faster from a tablet prepared by DC due to fast tablet prepared disintegration into primary drug particles
Conclusion
In conclusion, the direct compression formulation produced was successful and the result showed the most ideal tablet testing outcomes, a high crushing strength, low percentage friability, good disintegration time, weight that agreed with British Parmacopoeia (BP) range which was the fastest and simple method to carry out. In addition, the bigger the compression force, the stronger the tablets, the less friable it becomes and the longer it takes to takes for the tablet to disintegrate as it illustrate within the results for 5KN and 10 KN.
Each method has advantages and disadvantages; wet granulation is often the most popular but also the most problematic due to the introduction of the wet binder (i.e. water). Direct Compression is the simplest technique and can reduce the cost, however not all drugs (particularly high dose drugs) can be tableted by this method. Alternative methods, such as dry granulation and hot-melt granulation are also available, but require additional specialist equipment and are less frequently employed within the pharmaceutical industry.
However, despite the simplicity of the direct compression process, the pharmaceutical industry still produces most tablets by wet granulation methods.
Reference
-
Michael E.Aulton; pharmaceutics: The Design and Manufacture of Medicines 3rd edition, Churchill Livingstone Elsevier
- Tablet testing page 461-466
- Tablet excipient page 449-454
- Tablet manufacturing page 443-449
-
Jack Zheng; Formulation and Analytical Development for Low-Dose Oral Drug Products, John Wiley and Sons 2009
- Wet Granulation page 111
- Direct Compression page 159
End
Comments on your work appear in the right-hand margin and may not be visible on some devices.
This should have been a 2-page report?
Dr Imran Saleem
Liverpool John Moores University
The feedback above provides you with a guide as to how your work is progressing. To maximise the benefit of your feedback, I would like you to complete the tables below to identify the main areas where you did well, main areas for improvement, and actions that you intend to take. You might find it useful to split this window so that you can view your marked work and this page simultaneously (View > Split).
Dr Imran Saleem
Liverpool John Moores University
Your discussion of the pharmacopoeia tests performed on your two batches of tablets was very good. You attempted to compare the tablet friability, weight uniformity, crushing strength and disintegration data obtained from the various batches, the effect of altering the compression force and offered some explanation for the trends seen in the data.
Your conclusion was good - You included some key points from your report.
The aim provided was good but could be improved - The aim should have included the formulation process to be used (WG or DC) in the production of aspirin 75 mg tablets and stated that the effect compression force on tablet properties was to be investigated.
Your introduction was very good - it put the topic into context for the reader and you compared most of the important aspects of DC and WG .
You gave a good description of the blending process used - You stated and explained some steps in the procedure used, including mixing method, mixing time, sieve size used, stage of adding lubricant, etc.
Continued in the Summary section.
You gave a very good description of the tablet manufacturing process, clearly stating the key details, such as the machine used, target tablet weight and compaction force.
You gave a very good description of your tablet formulation, stating the name, type, grades and quantities of most ingredients used in the formulation
You only mentioned one further test. You should have discussed the pharmacopoeia dissolution and content uniformity tests. See British Pharmacopoeia 2011, appendix XII C and SC I E.
Your discussion of the choice of excipients for your formulation was very good. You included the rationale for your choice in grade, type and concentration of most excipients used.
Although you included a results table, it was not complete. You should have included a table of all results obtained from tests (weight uniformity, crushing strength, friability and disintegration) performed on both batches with values (mean, stdev, %CV). The table should have a clear title and each column heading with appropriate units.
You failed to include the details of the tablet testing process in your report. This should have stated the tests performed (weight uniformity, friability, crushing strength and disintegration) together with the conditions of each test
Your referencing was adequate but could be improved - you must provide citations in the text and full details of all corresponding reference sources at the end of the document
You clearly stated if your results comply with pharmacopoeia standards and your explanation was very good. You attempted to compare the results you obtained for each batch with the relevant pharmacopeia test. Explanation included method of tablet production and effect of varying compression force and offered some explanation for the trends seen in the data.
by
imona88 (student)
