Manufacturing and Testing of Sustain Release and Dispersible Tablets

Manufacturing and testing of sustain release and dispersible tablets

Introduction

When assessing tablet quality several tests are conducted to ensure that the tablet is at maximum compliance for the patient and that the tablets that are produced are in accordance to standards that have been set by the BP. There are two sets of these tests, pharmacopoeia tests and non- pharmacopoeia tests (Pharmapproach.com 2019). The Pharmacopeia test includes: the uniformity of tablet weight, friability test and disintegration time.

The Uniformity of tablet weight is measured to make sure that all the tablets have the same amount of the active ingredient- in this case riboflavin. This also ensures that the dosage amount that has been given is all equal, so no dose is larger than another. The limits for this are that the average mass for 250mg or more has to have a %CV of +/- 5%.

The Friability test imitates the forces that have been applied when the tablet undergoes shipping, packaging and handling, as the tablets will slide over one another and will collide. This can affect the appearance of the tablet, so the patient may be less willing to take them if they were fractured. The limit for this is that the percentage friability has to be within 1%

In order for the drug to be readily available to the body it needs to be broken down; the disintegration time assesses the time required for the tablet to break down into particles, so the body can accept it easily. The limit for this is that it should not exceed 3 minutes for dispersible tablets and 15 minutes for the sustain release tablets in the case of the tablets that have been produced.

There are also non-pharmacopoeia tests which do not have any specific limits set by the BP and those are the crushing test, assessing thickness and diameter and the dissolution test.

The crushing test measures how much force is needed to break the tablet. For sustain release this would be relatively higher so that the therapeutic effect can take place straight away but also this effect can remain in the body for a longer period of time. The crushing strength effects the disintegration time, so if the tablet is too hard it may not disintegrate very quickly. Analysing the thickness and diameter isused to assess the tablet compaction, so it is identifiable whether the correct punches have been applied from the machine to form the tablet.

Lastly the dissolution test is used todetermine the amount of time required for a proportion of drug substance that is in a tablet to dissolve in a solution. This is done using instructions which helps to provide the correct analysis behind the physiological availability of the drug substance. This also shows the proportion released and from these results, we can analyse them and compare to a control batch which has been proven to have an effect in terms of their clinical uses and the bioavailability inside. The limit for this is, for dispersible tablets 80% has to be dissolved.

Methods

For the sustain release tablet a direct compression process was used. The formulations included:

4% riboflavin- API- vitamin (10g)

19% Hypromellose kloomp- binder (15.2g)

10% talc- glidant (5.51g)

64% sucrose course- sweetener (51.2g)

3% stearic acid- lubricant (3g)

For the dispersible tablet the wet granulation process was used. The formulation included:

4% riboflavin- API-vitamin (10g)

15% microcrystalline cellulose (PH101)-disintegrant

43% sucrose fine- sweetener

30% talc- glidant

2% stearic acid-lubricant

QS – Povidone 10% solution 40,000 solution binder- binder

The tests involved used a physical and chemical testing approach. The physical tests were uniformity of tablet weight, crushing test and thickness and diameter and the friability test. For uniformity of tablet weight 20 tablets were used, and each tablet was taken individually from the manufactured batch and weighed. From these a mean value and %CV was calculated. To test the crushing strength and thickness/diameter an automatic tablet tester was used, and five tablets had been tested. From this the mean and %CV was calculated. For the friability testing 10 tablets were weighed before and then placed into a friabilator for a given amount of time. Once the time was over, the tablets were reweighed, and friability loss is then calculated.

The chemical tests were assessing the disintegration time and dissolution rate. To test the disintegration time an in vitro method which used basket rack that contains six open ended transparent tubes. These were held vertically, and a tablet was placed in each of the tubes. Using a mechanical device, the basket was then lowered and raised in the fluid (in this case water) where this raising and lowering occurred in approximately 30 cycles per minute for up to 15 minutes or until all tablets had disintegrated. The mean and %CV were then calculated for the timing of the six tablets. Lastly to test the proportion dissolved the dissolution test was used. This is anin vitro method in which one tablet was placed into a stainless-steel basket. The stirrer motor, dissolution vessel and basket were assembled, and the stirrer motor was then switched on to a speed of 10rpm. 500cm^3 of the dissolution medium (warmed at approx. 37 degrees) was added into the vessel and the stop clock was immediately started. A 5cm^3 sample was then removed from the dissolution vessel in time intervals using a syringe with a wide gauge cannula. The sample that was removed had then been replaced with an equal volume of fresh dissolution medium (5cm^3). These samples were then analysed using a UV spectroscopy.

Results

Physical testing sheet for sustain release tablet

Results for mean and %CV could not be calculated for the disintegration time as for al of the tablets it had been more than 15 minutes

physical testing for dispersible tablets

Results for mean and %CV could not be calculated for the disintegration time.

Dissolution testing for sustain release tablets

Dissolution testing for dispersible tablets

calibration plot:

Dissolution profile for dispersible and sustain release tablets:

Results show how the proportion dissolved for the sustain release tablet is much higher than that of the dispersible tablet. The proportion dissolved had reached a maximum of 81.9% whereas for the dispersible the maximum amount of dissolution was 6.61%.

Discussion

A test that both the tablets pass is the uniformity of tablet weight as the %CV deviated by less than 5%. This had shown that majority of the tablets had not deviated from the amount of active ingredient, so the same amount of riboflavin was active in majority of the tablets. The sustain release tablet had passed the friability test as its friability was less than 1% however the dispersible tablet failed because it had a friability of above 1%. This could be due to an increase in the amount of binder added which had increased the friability. The crushing strength had deviated quite a lot in comparison to its mean showing how when crushing the sustain release tablets and dispersible tablet had also failed the disintegration test as it had not disintegrated in 3 minutes. This is because the ability for a tablet to disintegrate is affected by how hard it is, therefore with the tablets being very hard it was difficult for the particles to break down. Also, the %CV had been very low for tablet diameter and thickness for both tablets showing how the correct punches were applied by the single punch machine and how they had been made at the same size as well. Lastly the dispersible had failed the dissolution test as only 6% had dissolved where for the tablet to work it had to be 80%.

The dispersible tablet failed several tests due to an error in the formulation of the tablet, where a large amount of talc was added. Talc is a very hydrophobic compound, making it non-polar so it will repel against water and because of this, there will difficulty in dissolving the tablet at a faster rate.  This had led to the failure of the disintegration test as the particles were unable to break down as fast. Also, by adding in the povidone solution (granulating fluid) too quickly added to the source of error as this affected the granulation, making the product less than expected. This had altered the size of the granules making them bigger and more time was required to create granules that were firm and could be packed. To improve the formulation for the sustain release tablet could be to add less of the binder, as the tablet could not disintegrate in 15 minutes due to a high amount of binder.

In this instance, if the compression force had increased the rate of disintegration would’ve been affected as the particles would be tightly packed together so it would be harder for these particles to break down within the tablet. However, if this was done too lightly then the friability would be affected. The friability would be affected as the tablets would fracture much easily if the force applied to punch the tablets was too light as the granules are then not compact.

Lastly an improvement that could’ve been made to the testing methodology was, for dissolution, taking concentrations for timings above 45 minutes – 60 minutes. This is because the therapeutic effect had not reached completion at our cut off point of 45 minutes- 60 minutes therefore by increasing the timing to 75 minutes, the therapeutic effect may have been more apparent within the results for the dispersible tablet, showing a higher proportion of the drug dissolved.

References

• Pharmacopoeia.com. (2019). Tablets – British Pharmacopoeia. [online] Available at: https://www.pharmacopoeia.com/bp-2019/formulated-general/tablets.html?date=2019-01-01&page=2 [Accessed 26 Feb. 2019].
• Pharmapproach.com. (2019). Quality Control Tests for Tablets – Pharmapproach.com. [online] Available at: https://www.pharmapproach.com/quality-control-tests-for-tablets/ [Accessed 15 Feb. 2019].