1.0 Introduction
Tablet is a solid pharmaceutical dosage form consist from two parts:
The active pharmaceutical ingredient (APIs)
Excipients include: Diluent, Lubricant, Binder, disintegrate, sweetening and flavouring agents
It can be obtained by multiple or single compression of powder and granules or by moulding and extrusion technique, and it might be coated and uncoated
It comes in different shapes and categories and sizes such as: circular and cylindrical, and line to break or mark and symbols and other marking.
It’s most favourable dosage form because it’s inexpensive, easy in administration and storage, however any pharmaceutical dosage form should meeting the Britch pharmacopeia specifications standards, as well as the manufacturing process have to comply the requirements of good manufacturing practice (GMP) to ensure the quality and safety of the product and their constitution.
There are different measures should be taken during manufacturing and after that for evaluation of product like: 1.ensure the active ingredient has appropriate sold form properties (particle size, distribution, polymorphic form) and the excipients are mixing equally through the content in order of homogeneity and that is called uniformity of content and weight .
- Ensure the tablet has suitable mechanical strength to avoid crumbling or breaking on subsequent process.
- Check the Dissolution and disintegration rate of the product.
- Minimize degradation of (APIs)
- Decrease the risk of microbial and cross contamination.
2.0 Aims of the experiment:
The aim of this practical it is to explain the process of manufacturing tablet dosage form by using of wet granulation and compression techniques.
It’s a group work so each one has a specific task as well as has to share and discuss his result, furthermore it’s important to know the process of granulations and recognize the instrument which is have been used during the granulation process for manufacturing and important instructions and precautions about them. Eventually it is vital to evaluate the product through his: Uniformity of weight, resistance to crushing, friability, disintegration, dissolution, and uniformity of content test.
3.0 Composition
Batch manufacturing formulation sheet
Product code: Product name:
| Batch no. | Batch size:
800 tablets |
Manufacture date:
26/10/2015 |
| Sr No. | Raw material (grade) | % (w/w) |
Batch no. | Quantity | Weighed by | Checked by | |||
| Theoretical (g/mL) | Actual (g/mL) | Signature | Date | Signature | Date | ||||
| 1 | Active Drug | 33% | XG65799 | 132 mg | 132.19 mg | 26/04/2016 | 26/04/2016 | ||
| 2 | Lactose | 54% | 1012543 | 216 mg | 216.mg | 26/04/2016 | 26/04/2016 | ||
| 3 | Methylcellulose | 7% | SC/2543 | 28 mg | 27.9 mg | 26/04/2016 | 26/04/2016 | ||
| 4 | Magnesium stearate | 1% | A0325329 | 4 mg | 4.01 mg | 26/04/2016 | 26/04/2016 | ||
| 5 | Maize starch | 5% | H5736648 | 10 mg | 10 mg | 26/04/2016 | 26/04/2016 | ||
| 6 | Total | 100% | |||||||
| 7 | |||||||||
4.0 Methods
Manufacturing:
The materials including the active drug and the excipients (lactose, methylcellulose, magnesium stearate and maize starch) are presented on the preparation pinch in the lab
Then the quantity of each ingredients have to be calculated regarding the required number of tablets. The oven was switched on before staring the experiment and set on the required temperature.
All the ingredients are weighted calculated and picked off in separate plate and labelled.
Then added weighed amount of drug and excipient (Lactose, half quantity of maize starch) into convenient V shape bender and dry mixing stage was for five minutes and the speed of blending have to be recorded.
The binder solution was added to the mixture and it was mixed for 5_10 minutes with intermittent checking after five minutes also the speed of the blender was recorded, then the obtained wet mixture was transferred into granulator with fitted mesh size (1nm), the formed mass pass through the mesh it’s to ensure lumps are break down and the granules now it’s ready for drying. The granules was transferred to the preheated oven and dried until get the required moisture which was between 1_3% in the moisture analyser.
The granules mixed up to avoid over heating in the surface of the plate once it’s getting off from the oven to test their moisture. Then the granules transferred to analytical sieve shaker to get the desired fraction (125_710) sieve size .the amount fraction of the getting granules were weighed, the weigh was 246.97 mg.
The final amount of granules was added into the blender with both lubricant (magnesium stearate 2, 55 mg) and the half amount of disintegrate (maize starch 6,4 mg) and was blended for five minutes in order to be completely distribute through the mixture . Then the measurement of followability index of granules was detected as then the amount was transferred into electrical tabbing tube. Then the final obtained granules was transferred into compression machine to produce the required number of tablet and weight (100 tablet).
Evaluation:
Pre composition testing
Powder flow analysis- flow through an orifice:
A cylinder with loosen upper and lower thumbscrew and detach unit was present, then insert 10mm orifice and reattach cylinder and rest, the granules was poured into the the cylinder via funnel for 30 seconds.
The powder flow was occurred, and then reduced the orifice until the flow doesn’t occur, after that increase the orifice until the flow occur again, the minimum orifice yielded the flowability was recorded and this called the flowability index, the process of powder flowability was repeated for physical blend.
Powder flow analysis- tapped density
A 250 ml cylinder filled with 100 gm powder was presented, and the volume was recorded. Then it placed on tabbing device, the cylinder it secured to the machine, allow the machine to perform 100 taps, then the new volume was recorded, the process was repeated until no observed changing in the volume.
The procedure was repeated for physical blend.
Post composition testing
Preparation of standard calibration curve:
A 100 mg of drug were weighed and transferred into volumetric flask, then it filled up to 100 ml with purified water, then 1 mg/ml was taken and its consider as stock solution, then different concentration rates between 5µg/ml, 10,30,50,80,120,150,180,200 µg/ml were pipetted into into different volumetric flask, the lambda max was determined at 80 µm/ml, covering the maximum and the minimum dose concentration.
The concentrations were transferred to UV spectroscopy by using purified water as blank, the calibration curve which is obtained it shows the absorption against concentration of the drug, the derive equation from the linear part was recorded for further experiments.
Uniformity of weight:
Resistance to crushing:
10 tablets were taken and the diameter and thickness of each tablet was measured, then the tablet was placed into hardness measurement instrument which is contain two jaws, the tablet placed between two jaws in the same position for each one of them, then forces applied to compress the jaws until the tablet broken, the breaking point number was determined as well as the mean the maximum the minimum average was calculated, and all powder and small particles were removed before each sample experiment.
- Shotton, D. Ganderton (2011) the strength of compressed tablets: Part I. The Measurement of Tablet Strength and its Relation to Compression Forces. Journal pharmacy and pharmacology
Friability:
10 tablets were taken and the mass of them was 6.48 gm as W₀, the tablets were transferred to the drum of friability machine
After that the tablets were measured again the new weigh is 6.43 gm, the percentage of friability was calculated in this equation:
http://www.pharmainfo.net/friability-test
Disintegration test:
6 tablets were taken and placed into tube of the basket in disintegration instrument then the disk was added on each tablet in the tube, the temperature was set at 37 C⁰ ± 2 C⁰, and it’s immersed into the fluid, the important of disintegration it’s to determine dissolution and them absorption of the drug.
http://www.pharmainfo.net/disintegration-test
- Uniformity of content measurement:
10 tablets were taken individually, each tablet was crushed by mortar and pestle presented on the lab, then 5 ml of purified water was added to each tablet and filtered by filter paper and made the volume of volumetric flask up to 100 ml, the mortar and pestle was rinsed with purified water then passed through the filter paper
The concentration of each drug was measured in each solution by using UV spectroscopy, calculation curve was obtained to calculate the concentration of drug in each solution (Green et al., 2009; The United States Pharmacopeial Convention, 2011).
- Dissolution test:
6 tablets were placed in the apparatus, the dissolution media was 37 C⁰
The dissolution tester was operated in a specific rate and time, the samples were taken at 5,10,20,30 and 45 minutes, 5 ml sample was withdrawn from the middle of the dissolution media each time, the samples were transferred for analysis into UV spectroscopy, the absorbance of each samples was measured.
http://www.tabletdissolution.com/education/introduction
5.0 Results
| Concentration µg/ml | 5 | 10 | 30 | 50 | 80 | 120 | 150 | 180 | 200 |
| Absorption at 269 nm | 0.023 | 0.041 | 0.201 | 0.364 | 0.472 | 0.801 | 1.161 | 1.295 | 1.482 |
Table 1. Standard calibration curve
UV absorbance of drug concentration ranging from 5 µg _ 200 µg at 269 nm wavelength.
Table 2. The uniformity of the drug content
| Tablet No | Absorbance at 269 nm | Concentration (µg/ml) | Concentration (mg/ml) | Drug content (mg)
|
| 1 | 1.077 | |||
| 2 | 1.299 | |||
| 3 | 1.277 | |||
| 4 | 0.737 | |||
| 5 | 1.481 | |||
| 6 | 0.825 | |||
| 7 | 0.881 | |||
| 8 | 0.883 | |||
| 9 | 1.016 | |||
| 10 | 1.292 |
Table 3. The dissolution test
| Tablet time | 1 | 2 | 3 | 4 | 5 | 6 |
| 5 min | 0.351 | 0.566 | 0.411 | 0.423 | 0.549 | 0.519 |
| 10 min | 0.578 | 0.777 | 0.609 | 0.605 | 0.728 | 0.640 |
| 20 min | 0.865 | 1.084 | 0.851 | 0.817 | 1.038 | 0.872 |
| 30 min | 1.150 | 1.388 | 1.093 | 1.061 | 1.310 | 1.155 |
| 45 min | 1.289 | 1.425 | 1.271 | 1.303 | 1.298 | 1.459 |
Table 4. The uniformity of weight
| Tablet No | Weight | Standard Deviation |
| 1 | 563 mg | 30.2 |
| 2 | 556 mg | 23.2 |
| 3 | 512 mg | 20.8 |
| 4 | 545 mg | 12.2 |
| 5 | 560 mg | 27.2 |
| 6 | 526 mg | 6.8 |
| 7 | 540 mg | 7.2 |
| 8 | 541 mg | 8.2 |
| 9 | 506 mg | 26.8 |
| 10 | 543 mg | 10.2 |
| 11 | 520 mg | -12.8 |
| 12 | 531 mg | -1.8 |
| 13 | 535 mg | 2.2 |
| 14 | 526 mg | -6.8 |
| 15 | 533 mg | 0.2 |
| 16 | 562 mg | 29.2 |
| 17 | 523 mg | -9.8 |
| 18 | 502 mg | -30.8 |
| 19 | 517 mg | -15.8 |
| 20 | 515 mg | -17.18 |
| Total | 10656 mg | |
| Average | 532.8 mg | 5.561% |
| High limit | 569 mg | |
| Low limit | 502 mg |
According to BP if the average mass of the tablet more than 250 mg, (we got 532.8 mg average weight) and their standard deviation percentage more than 5% it wouldn’t pass the test.
- Friability test:
10 tablets were taken, the initial total weight was 6.48 gm and the final weight was 6.43 gm.
Friability was calculated by this equation
(Initial weight – Final weight) / Initial weight * 100
(6.48 – 6.43) / 6.48 * 100 = 0.77 %
According to BP if the friability be less than 1 it would pass the test
- Disintegration test:
6 tablets were taken, all the tablets disintegrates
| Tablet No | Disintegration time |
| 1 | 8.20 |
| 2 | 9.02 |
| 3 | 9.10 |
| 4 | 9.18 |
| 5 | 9.23 |
| 6 | 9.57 |
| Average | 9.06 |
According to BP if the tablets disintegrates within 15 minutes it would pass the test,
- Resistance to Crushing:
| Tablet No | Diameter | Thickness | Hardness kp/cm² |
| 1 | 11.05 mm | 5.08 mm | 8 |
| 2 | 10.04 mm | 5.77 mm | 7 |
| 3 | 10.03 mm | 5.75 mm | 6.5 |
| 4 | 10.02 mm | 5.69 mm | 7 |
| 5 | 10.04 mm | 5.70 mm | 9 |
| 6 | 10.03 mm | 5.70 mm | 6 |
| 7 | 10.03 mm | 5.73 mm | 10 |
| 8 | 10.03 mm | 5.74 mm | 8 |
| 9 | 10.04 mm | 5.79 mm | 9 |
| 10 | 10.03 mm | 5.74 mm | 8 |
| Mean | 7.95 kp/cm² | ||
| Maximum | 10 | ||
| Minimum | 6 |
According to BP the hardness range have to be between 4_6 kp/cm², the average is 7.95 kp/cm², so it is exceed the limit and the test is fail.
6.0 Discussion & Conclusion
The manufacturing process of the tablet in the lab was passed, the active pharmaceutical ingredient (APIs) and excipients such as: Lactose, Methylcellulose, Magnesium stearate,
And maize starch have been used and it’s blending and prepared by wet granulation and then compression
Each kind of excipients has a specific properties, Lactose is used as a filler to make the bulk of the formulation and enable accurate dosing of active ingredients, it’s also reducing sugar, odourless, and very convenience for wet granulation due to wetting feature of lactose which enhance their dissolution and then form a crystal layer around of the active ingredient which could retard the dissolution rate of the drug.
The using of a proper binder it’s vital because its hold the ingredients of the formulation together and formulate a wet mass and to ensure that formulation has the required mechanical strength, moreover it affects many properties of the formulations like: Dissolution, Disintegration, friability and hardness, Methylcellulose using as binder and it has hydrophilic tendency, for that reason it’s a good choice for wet granulation because it can formulate wet mass.
Magnesium stearate consider as the most extensively used as lubricant, it’s inhibit agglomeration of individual particles as well as enhance powder flow and prevent stuck of wet granulation into the machine or equipment surfaces, no sticking has been noticed .
Using of maize starch its yield both disintegration and binder efficacy in the formulation and its safe and preferable in pharmaceutical formulations, however the disintegration should added in convenient step during manufacturing process to assure that the disintegration in bended within the particles, in this experiment half quantity of maize starch were divided into two and half of the quantity was added at first blending step and other half was added with lubricant in the final blending.
All the tablets are prepared in the same condition, the formulations were white, odourless, and smooth surface, all the portions were weighed and following the manufacturing procedure.
Then after compression the tablets underwent to evaluation criteria of the tablets according to British Pharmacopeia such as: uniformity of weight, resistance to crushing, friability, uniformity of content, disintegration, in vitro drug dissolution tests.
However the uniformity of weight wasn’t within the limit of British Pharmacopeia because according to BP if the mass of the tablet more than 250 mg, (we got 532.8 mg average weight), and their standard deviation percentage more than 5% it wouldn’t pass the test.
Our standard deviation was 5.561%, so it’s exceed the limit, so test result is fail.
Hardness or resistance to crushing test result was 7.95 kp/cm²,and according to BP the hardness range have to be between 4_6 kp/cm², so the test result doesn’t met the required criteria, the test evaluate resistant of tablet to breakdown, capping cracking during storage, if the tablet it’s too hard it will affect disintegration in an appropriate time and then will not pass the dissolution test, in contrast if the tablets are not hard enough it will not be stable during other process and it might be broken .
The friability test for the drug samples was 0.77%, and according to pharmacopeia if the result less than 1% it would pass the test, the importance of this test is to make sure that tablet wouldn’t break or crack during handling on machines, packaging or shipping.
The selection of a proper binder it’s essential in detect the quality of hardness and friability as well as the quantity of the binder and the force applying during compression its important
To control the mechanical strength of the formulation.
The dissolution test it’s to determine the rate of active pharmaceutical ingredient released and dissolved in the medium and then be absorbed.
The disintegration test can measure the quality of the product as part of pharmacopeia standards, if the disintegration time is too long it means that the tablets were highly compressed or to several other reason, and if the disintegration time it’s not uniform it indicates batch inconsistency and lack uniformity of content, then this test might be the key to optimise the quality control of the product
Each step of evaluation test its very important and its related to patient safety, uniformity of content test it’s to assure that patient got the proper and required therapeutic effect of each tablet and if it’s not very well that’s could lead to prolong their diseases and even death, otherwise if the active ingredients are high that’s will lead to toxicity and adverse reactions, disintegration can affect dissolution and then absorption of the dose and the delay of absorption also lead to toxicity especially if the patient take another dose.
In conclusion the tablets were formulated in the lab by wet granulation and then it’s compressed by compression machine with direct compression method, the formulated tablet were evaluated according to the British pharmacopeia standards, uniformity of weight, resistance to crushing, uniformity of content tests were failed.
7.0 References
British Pharmacopoeia online (https://www.pharmacopoeia.com)
RAI, V.K & et al. (2009). Optimization of immediate release tablet of raloxifen hydrochloride by wet granulation method. International journal of pharmaceutical sciences and drug research. 1(1): 51-54.
Dr.Simon Mills (2012), Pharmaceutical excipients an overview including considerations for paediatric patients. World health organization.
https://www.medicinescomplete.com/mc/excipients/2012/1001941845.htm.
Rishikesh & et al. (2012). Immediate release drug delivery system. International research journal of pharmaceutical applied sciences. 2(5): 88-94.
Alison Haywood & Beverley D Glass. (2011), Pharmaceutical excipients we do we begin?
Neeraj, B, Abhishek, K, Abhilash, C, Rubia, C, Rajni, B. (2014). A review on immediate release drug delivery system. International journal of pharmaceutical and applied sciences.
