Abstract:
The objective of this mini-project is to formulate two different batches of aspirin tablets and evaluate the effects of the different levels of lubricant. The first batch contains 0.5% of magnesium stearate, which is within the normal range (0.5-1%), whereas the other batch contains 2% of the same lubricant type, which is outside the normal range. Various validation tests are carried out to distinguish the effect of the different levels of lubricant on the final formulation of the aspirin tablet. Also BP limits were checked for validating that the trials have passed the tests.
Introduction:
Today aspirin is known as the most basic pain killer and is used at a large level for most of the conditions. But this discovery is not new to human society as many years back also a compound similar to aspirin was used for relieving pain. This compound was being extracted from the bark of the willow tree and records suggest that it was nearly 2400 years back since this knowledge is with the people of ancient Asia. The basic chemical of aspirin is acetylsalicylic acid. First of all, Native Americans extracted salicylic acid from the willow bark and found that it is a pain killer but plain salicylic acid had few limitations. The taste of salicylate was very bitter and it was also found that if used for a long period of time, it may lead to stomach upset. Therefore, to minimise these side effects, a German chemist Felix Hoffmann, made a compound of Salicylic acid in 1893 that is acetyl salicylic acid, which is an effective pain killer as well as has minimum side effects.The usual dose to prevent blood clots is 75 mg each day. This is a lot less than the dose for pain relief. Taking more than the recommended dose does not make aspirin work any better to prevent blood clots, but increases the risk of side-effects developing. Therefore, stick to the dose recommended by your doctor, which is usually 75 mg daily. There are other medicines which have a similar effect on reducing platelets from sticking together. They work in slightly different ways, acting on different chemicals, but with the similar end result of preventing blood clots. They include clopidogrel, prasugrel, dipyridamole and ticagrelor. As a rule, aspirin is usually the preferred medicine. Sometimes, one of these other medicines is used if there is a problem with using aspirin. Sometimes, aspirin plus another antiplatelet medicine are taken together. The situations when this is mainly advised is when there is a particularly high risk of developing a blood clot. For example, for a certain period of time after having a heart attack, a stroke or a transient ischaemic attack.
Methodology: Blending , formulation and production ,tablet testing
1-Blending: 20 g of aspirin powder and the exact amount of all excipients as illustrated in Table were individually weighed accurately for two batches. For batch 1, aspirin,croscarmellose sodium,silicon dioxide, MCC as diluent and lactose were transferred into the glass amber bottle and mixed together by a rotation machine for two minutes (not added magnesium stearate in this step).The produce mixture was placed In a 500 µm sieve. After that the sieved powder was transferred into the same bottle and blended for two minutes. Small quantity was transferred to a measuring cylinder and the initial density was recorded. Then, the cylinder was tapped several times and the tapped density was measured. Carr`s index was calculated for the two batches Table 2. Subsequently, the mixture was placed in the same bottle and kept for two weeks.The same steps were carried out in the formulation of batch2.
2- Formulation and production
The lubricant magnesium stearate was weighed to 0.5g and 2g and added to the amber bottles of batch1 and batch 2,respectively. Both batches were blended in the bottles by rotating machine (Turbuler) for two minutes. Consequently, the procedure of tabletting was undertaken at the compression force of nearly 8.5KN and at a rate of about 23 tablets per minute. 50 tablets from each batch were prepared.The name of the machine that used to compress the tablets was called Minipress MII is the smallest Riva tablet press. Being a table, single- punch off-centre tablet press, it is ideal for the production of small batches. Its properties Include, 60 KNmaximum compression force, 4mm max tablet diameter, 18mm max depth of fill, rated up to 6000 tablets/hour. Figure
3- Tablet testing
Four validation tests were applied to the final product for the two batches to confirm the quality,safety and effective usage of these formulated tablets:-
A- Weight Uniformity Test:
This test was performed to ensure that each tablet contained the exact amount of medicine.Twenty tablets of each batch were weighted out individually by using electronic balance. The mean,standard deviation (SD) and the percentage coefficient of variance were calculated by using the following formula: CV % = SD/Man X 100
B- Crushing Strenght Test:
This test demonstrates the force required to crush a tablet. It is carried out using hardness tester to ensure the tablets are strong enough and not susceptible to fraction during manufacture and product transport. Ten tablets from each batch were crushed in a machine and the force in Newtons unit was recorded for each tablet. Also the average, SD and CV % were calculated.
C- Friability Test:
This test is done to make sure no great tablet loss occurs during handling, packaging and shipping. 20 tablets of each batch were weighed out together & then placed in a friabilator which rotate 100 revolutions per 4 minutes. The weight of the tablets was measured before and after to determine, if there was any loss of weight. The percentage of weight loss was determined by using the following formula:% Friability = (W0-W) / W0 X100
D- Disintegration Time Test:
Disintegration test ensures that the tablets will disintegrate at a specific time and temperature. Disintegration tester contains two baskets and each holds six plastic tubes which are open from the top and bottom.The bottom is covered by a mesh screen. Six tablets from each batch were used and one tablet placed in one plastic tube, then the baskets were placed in a water bath at 37 °C.
Discussion Four paragraphs
Two different methods are used for preparation are direct compression (DC) and wet granulation (WG). DC is advantageous over other methods of tablet manufacturing as it requires fewer unit operations, consequently, low cost and less time consuming, generates optimum possible bioavailability, low microbial level due to absence of moisture and produces faster dissolution rates for certain compounds. This method is preferred for tablet manufacturing, especially in case of thermolabile and moisture-sensitive drugs. The advantages of the wet granulation manufacturing process include increased flowability and weight uniformity. The process uses a binder which helps in the compression process and improves the compaction of the mixture. Thus, drugs formed by wet granulation are stronger, and this prevents the segregation of drug powder particles and reduces the dust produced when handling powders. On the other hand, wet granulation is unsuitable for heat- and moisture-sensitive drugs as it increases the drug disintegration time. It involves more time, materials and personnel compared to direct compression, and is thus a more expensive process.
Acetylsalicylic acid was the active pharmaceutical ingredient and it was added to various important excipients as shown previously in Table 1,which were chosen with care and understanding about their properties to prevent any chemical reactions.The excipients play an important role in direct compression.To produce tablets with good quality ,the excipients used should have good flowability and compressibility.Lactose is the most common filler,it has high water solubility,acceptable taste, compatible with the API,inert,non-hygroscopic and inexpensive. Microcrystalline cellulose (Avicel) was the diluent and has compatibility with the API and the ability to increase hardness makes it a good diluent. However, it is hygroscopic, which causes problems for moisture sensitive drug. Croscarmellose sodium,in low concentration was used as a disintegrant ,which enhances the releasing of aspirin (API) in the digestive system. A lubricant, an additive to reduce friction, is an essential component of a drug formula since lubrication is often required to ensure the success of pharmaceutical manufacturing. Historically, use of animal fats as lubricants to reduce friction in transportation can be traced back to the Egyptian time. Magnesium stearate is used two ways in tablet making. The first and most common use is as a lubricant. Without it the tablet would bind in the die during compression, and ejection forces will break the tablet apart. The second use is to use Magnesium Stearate in a pre-blend to reduce positive charges. In this experiment, Magnesium stearate was added as a lubricant, which provides good anti-adherence activity and reduces friction during compression and ejection. Low concentration of the lubricant should be used because it could have an effect on dissolution and disintegration rates. Silicon dioxide was used as a glidant to improve the flowability of the mixture to ensure the accurate filling of the die.
Weight uniformity results show that both batches are close to each other, and there were therefore no great differences in the percentage coefficient of variance between the batches. According to BP requirements, the specified percentage of the CV of mean mass of 250mg or more should not be more than 5%, however, both batches have good uniformity, as the % of CV was less than 1%.This concludes that there no significant effect of lubricant level on the formulations. Moreover, Carr's index considered as an indirect measurement for various powder characteristic bulky densities, size and shape, surface area, moisture contents and cohesiveness of the materials. It was noticed that, a different percentage between batches might be due to the impact of glidant (Table 2). The crushing strength test also showed slight differences between the two batches. As there is no limit for this test, both batches should pass the test and this indicates that tablets are not prone to damage by handling and packaging and, most importantly, are going to disintegrate in the body.The results obtained from the friability test for the two batches were compliant with the BP standard, which limits the % of variance to ≤ 1%.Which means the tablets are ideal and not susceptible to loss of any of the contents during handling, packaging or shipping. The time of disintegration must be less than 15 minutes. Since both of the batches passed the test, it implies that there is not a significant effect of the given concentration of lubricant on the disintegration time. However, further increase in the amount of lubricant causes increase in the disintegration time in body temperature. Further tests that can be used to examine the tablet quality are appearance test (shape and size), melting point, drug content which related to tablet hardness and physical properties. Dissolution time is the most important method to study under in vitro circumstances. In order for a drug to be absorbed, it must be in a dissolved state. Consequently, the dissolution of the drug is essential for the absorption, subsequent therapeutic effects and factors affecting bioavailability.
In conclusion, the lubricant concentration has a slight impact on the formulation of the tablets. Since the high concentration of magnesium stearate causes decrease in the strength of tablets as indicated by the results of crushing test. Moreover, the disintegration time was not affected in this experiment. But, an increase in the amount of lubricant causes increase at the disintegration time in body temperature, thus influencing the bioavailability and the therapeutic level needed. 75 mg extended-release of aspirin taken one tablet daily may have a better pharmacodynamic profile than a plain formulation of aspirin. However, the rate of release of ASA is important, too slow a rate may compromise the drugs anti-platelet aggregation effect, i.e. one of the desired effects of the aspirin in the secondary prevention of thrombosis.