Questions in Practical 4

1. What are the objectives of the tests for uniformity of diameter and uniformity of

content ?

          The objective of the test for uniformity of diameter is to make sure the tablets produced are all uniform in size. This is important in the later process of tablet packaging either blister packaging or plastic container. The test for uniformity of content is to ensure that each tablet contains the similar amount of active ingredients and excipients so that each tablet contains correct dose of drugs. Hence, the bioavailability and efficacy carried out by the drug is the same for each of the tablet taken orally.

2. State the type of tablets and capsules that must be tested for uniformity of diameter and     uniformity of content.

          For uniformity of diameter, all tablets are applicable such as coated tablet, effervescence tablet and modified release tablet except enteric tablet, film-coated tablet and sugar-coated tablet. In this case, mostly capsules are applicable such as hard capsules, soft capsules, gastro-resistant capsules, modified-release capsules and cachets.

           For uniformity of content, normally single dose preparations are required. Tablets and capsules included are coated tablets, others than film-coated tablets containing 50mg or more of an active ingredient that comprises 50% or more of one tablet. Tablets or capsules have active ingredients less than 5% are needed. Liquid-filled soft capsules, solids packaged in single-unit containers with or without added substances and solutions for inhalation packaged in glass or plastic ampules are not applicable for testing uniformity of content.

3.  Give reasons for the non-compliance to test for uniformity of weight.

The reasons for the non-compliance to test for uniformity of weight are due to uneven feeding of granules into the die due to irregular movement of the lower punch that cause variation in capacity die space. This will result in unsatisfactory mix of ingredients at blending stage, and amount of ingredients cannot be weighed accurately. Segregation of  compound in formulation is also can happen.

4. Why does dissolution test suitable to be used for batch to batch quality control?

           Dissolution test suitable to be used for batch to batch quality control because it is easier to assess batch-to-batch consistency of solid oral dosage forms such as tablets which can be easily obtained and to predict in vivo drug release profiles. It also allows the prediction of time for complete release of the drug. This test is very effective and guarantee the quality of the pharmaceutical products by detecting deviations in manufacturing in order maintain to consistency and ensure optimum bioavailability so that the tablets can give the desired therapeutic effect.

5. Explain the difference found in the procedure for dissolution test in United States Pharmacopoeia and the British Pharmacopoeia.

            In Unites States Pharmacopoeia, typical acceptance criteria for the amount of active ingredient dissolved must be in the range of 75% to 80% whereas, in British Pharmacopoeia, the amount of active ingredient dissolved must not be less than 70%. In United States Pharmacopoeia, a retest may be carried out in three stages with different amount of tablets if the test failed. In British Pharmacopoeia, if the test failed, a retest may be carried out using the same number of units of tablets.

Practical 4 - Content of Ibuprofen (assay)

Introduction:

Ibuprofen is a non-steroidal anti-inflammatory drug (NSAID). It helps to reduce hormones that can cause inflammation and pain in the body. It is mostly used to treat pain and inflammation caused by many conditions such as headache, toothache and back pain. Ibuprofen also used to reduce fever.

Ibuprofen tablets are available in different strengths range from 200 mg to 800 mg.

Objective:

1.       To determine the given formulation of Ibuprofen.

Apparatus and materials:

1.       Conical flask

2.       Measuring cylinder

3.       Measuring balance

4.       Filter funnel

5.       Filter paper

6.       Hairdryer

7.       Retort stand

8.       Burette

9.       Pestle and mortar

10.   20 Ibuprofen tablets with strength of 400 mg.

11.    Chloroform

12.   Ethanol

13.   Phenolphthalein solution

14.   0.1M sodium hydroxide solution

Procedure:

1.       20 Ibuprofen tablets with 400 mg strength are selected at random and weighed. The total weight is measured. The tablets are then powdered.

2.       0.6467 g of the powder containing 0.5 g Ibuprofen is extracted with 20 ml chloroform for 15 minutes in fume hood. Then, it is filtered through a sintered glass crucible.

3.       The residue is washed with 3 x 10 ml chloroform and filtered again. The combined filtrate is gently evaporated using a hairdryer just to dryness in a current of air. The residue is dissolved in 100 ml with ethanol (96%) previously neutralized to phenolphthalein solution.

4.       The solution is titrated with 0.1M sodium hydroxide to end point with phenolphthalein solution as the indicator until the solution turns pink in colour. The content of ibuprofen is calculated is each ml of 0.1M sodium hydroxide is equivalent to 0.02063 g of C₁₃H₁₈O₂.

Results:

Total weight = 10.3475 g

Content of ibuprofen in 20 tablets = 0.4 g x 20

                                                                    = 8 g

10.3475 g of total weight contains 8 g of ibuprofen.

So, 0.6467 g from the total weight contains 0.5 g of ibuprofen.

Initial reading of burette = 0.00 ml of 0.1M sodium hydroxide

Final reading of burette = 22.3 ml 0.1M sodium hydroxide

1 ml of 0.1M sodium hydroxide is equivalent to 0.02063 g of C₁₃H₁₈O₂

So, 22.3 ml x 0.02063 g = 0.46 g Ibuprofen is present

Percentage error = (0.46 g – 0.5 g) / 0.5 g x 100 % = -8 %

                                                                                  = 8 %

Discussion:

In this experiment, the final result which is 0.46 g of Ibuprofen is obtained. It is slightly different compared to the actual weight which is 0.5 g. 8 % of percentage error determines that during the experiment, there are some errors involved. It includes uneven crushing of tablets resulting in not uniform powder and reduces powder flow thus not easy to dissolve. Second error is parallax error when measuring the chloroform. Eyes are not perpendicular to the measure and causing inaccurate measurement.  Error also occurred during the extraction process when the solution is not placed in fume hood causing it to evaporate. This will affect the content of ibuprofen present in the solution

Conclusion:

In conclusion, the weight of ibuprofen obtained is 0.46 g and the percentage error is 8 %. Thus, this test is suitable to determine the accurate near value of ibuprofen content but has to comply with some conditions to avoid error and to obtain good result. 

References:

1. http://web1.caryacademy.org/facultywebs/gray_rushin/StudentProjects/CompoundWebSites/1998/Ibuprofen/structibu.htm [structure of Ibuprofen]

2. BNF-65 Ed, BNF publications. (pg 671)

Practical 4 - Dosage performance tests (Dissolution)

Objective:

To investigate the percentage amount of ibuprofen dissolved

Introduction:

The dissolution test for tablet is done to ensure that the tablet dissolution rate is at the optimum and the desired value. Besides that, tablet dissolution test allows us to determine the bioavailability of the active ingredient of the drug in tablet form in the body to give the desired pharmacological effects effectively. We can also determine the specific pH value at which the tablet dissolves best. If the dissolution of the tablet is not at its optimum level as predicted, then, we will have to reformulate or find out what errors have been made during the pre-formulation procedure of the tablet.

Procedure:

1. The dissolution vessels were filled up with buffer solution to 900mL mark. The temperature was set to 37°C.

2. The temperature of the dissolution medium was kept in check to ensure the temperature was at 37 ± 0.5°C.

3. One Ibuprofen tablet was placed into each dry basket assembly.

4. The stirring speed was set to 150rpm. Then, the basket assembly was lowered into position in the vessel and the operation was started.

5. 10mL samples of the dissolution medium from each vessel were withdrawn for analysis after 30 minutes and the solution was filtered using suitable filter. Sampling was done from middle point between the surface of the dissolution medium and the top of rotating basket, and not less than 10mm from the wall of the vessel. The volume of aliquot withdrawn for analysis was replaced with the same volume of same dissolution medium.

6. A standard solution of ibuprofen was prepared by diluting 10mg of ibuprofen reference standard to 50ml with dissolution medium.

7. 2.0ml of sample solution and 2.0ml of standard solution were diluted to 25ml with dissolution medium in separate volumetric flasks.

8. The absorption of both solutions was measured in a 1cm cell at a wavelength of 221nm.

9. The percentage amount of ibuprofen dissolved was calculated using the following formula:

At/As    X     W/50     X     2/25    X     P    X     900    X    25/2    X    100/200

Where,

At = absorbance of sample solution

As = absorbance of standard solution

W = weight of ibuprofen reference standard used

 P   = purity of ibuprofen reference standard

10. From the result obtained, the tablet compliance with the requirements of the United States    Pharmacopoeia was determined.

     USP limits : Not less than 75% of the stated amount of ibuprofen dissolved in 30 minutes.

Results:

At = 0.859

As = 3.847

Percentage amount of ibuprofen dissolved:

At/As    X     W/50     X     2/25    X     P    X     900    X    25/2    X    100/200

0.859/3.847   X     10/50     X     2/25    X     98/100    X     900    X    25/2    X    100/200 = 19.69%

Discussion:

            From the calculated value, the percentage amount of ibuprofen dissolved is 19.69% . The tablet does not comply with the requirements of United States of Pharmacopoeia as the percentage is less than 75%. This indicates that there are errors made during conducting this experiment.

            One of the main errors is the expiry date of the sample of ibuprofen tablet. The ibuprofen sample may have expired and this has reduced the quality of the tablet. The ingredients must have become unstable and did not dissolve properly. Thus, this may have greatly affected and resulted in the above poor dissolution rate and absorption of wavelength during the measurement using the spectrophotometer.

Besides, the stirring speed may not have reached 150 rpm. This will cause the dissolution rate to be slow and the low speed could have affected the dissolution rate. Moreover, the temperature of the dissolution vessel might be one of the factors. We did not monitor the temperature which must be maintained at 37°C with ± 0.5°C. Low temperature may cause poor dissolution while high temperature may alter the composition of the ibuprofen tablet.

Furthermore, the presence of dissolved gas in the dissolution medium or buffer solution might lead to inaccuracy of results by slowing down the dissolution rate. The syringe filter used may absorb some of the sample during withdrawing of sample. This will reduces the percentage of dissolved ibuprofen for analysis. Thus, less ibuprofen sample was detected.

            Therefore certain precautions must be taken to ensure the accuracy of the results. First, the sample must be in good condition and the expiry date of the tablet should be checked before use. We also must make sure the dissolution vessel is calibrated before used so that we can obtain accurate results. Besides, we must always double check the setting of temperature, stirring speed and time required for stirring process to avoid unnecessary errors. To prevent the presence of dissolved gas in the dissolution medium or buffer solution, it is advisable to put the solution in ultrasonic water bath.

Conclusion:

The percentage amount of ibuprofen dissolved is 19.69%. This value is less than 75%, therefore the tablet does not comply with the requirements of United States Pharmacopoeia.

References:
1. http://www.pharmainfo.net/Dissolution/dissolution-testing-various-dosage-forms
2. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3160163/

Practical 4 - Dosage Performance Tests (Disintegration)

Objective: 

The objectives for disintegration test is to determine how long the time taken needed to tablet for disintegrate and whether it is disintegrate properly when placed in a liquid medium under the experimental condition in this experiment

Introduction:

Disintegration testing determines whether tablets or capsules disintegrate within a defined period of time when placed in a liquid medium .Tablet disintegration testing is used as a quality-assurance measure. This is because, for some cases if the disintegration time is too high; it means that the tablet is too highly compressed or the capsule shell gelatine is not of pharmacopoeial quality.

Apparatus and Materials:

Tablets , Copley Disintegration Tester, Thermometer and Distilled Water,500 mL distilled water, 500 mL beaker, disintegration machine (include disc, mechanical device to control up-down movement (28-32 cpm), device to control temperature (37 °C))

Procedure:

1. The disintegration test equipment was set up by following the instruction in the manual of                    operation.

2. 500 mL of distilled water was added into the beaker and then added to the disintegration  machine.     Then, the water was left until the temperature of water is about 37°C .

3. The time was set up to 60 minutes. Three tablet of the same types was added into each tube with         another 3 tablet from another group. Then, the disk was added into each tube before started the           operation.

4. The tablet in each tube was checked whether it is pass the test or not at the end of the operation.

5. The tablets pass the test if all 3 tablets disintegrate within 60 minutes. If there is any tablet that           does not disintegrate, we must pressed the tablet and if the tablet was disintegrate when we press, it     also means that the tablet comply with the test

Results:

Tablets	Dissolving rate	Type of tablets
Mefenamic Acid	Fully dissolve	Uncoated tablets
Methyldopa	Fully dissolve	Uncoated tablets
Methyldopa	Fully dissolve	Uncoated tablets
Ibuprofen	Fully dissolve	Uncoated tablets
Uphamol	Fully dissolve	Uncoated tablets
Erythromycin	Fully dissolve but leaving a thin sheets	Enteric coated tablets
Erythromycin	Fully dissolve but leaving a thin sheets	Enteric coated tablets
Cephalin	Fully dissolve	Uncoated tablets

Discussion:

The drug must first disintegrate into smaller particles before a tablet/hard gelatin capsule can dissolve and hence allow the active drug to be absorbed into the body,

During testing, the basket assembly is raised and lowered in simulated gastric fluid at 37 degrees C whilst the tablet is continually “hammered” by a plastic disk of defined proportions to simulate in vivo conditions. The tablet is said to pass the test providing that no tablet residue remains on the mesh after the designated test period.

But as mentioned earlier, this test is not a true predictor of how well the dosage form will release its active ingredient in vivo. This is because of some limitations it cannot follow. Firstly, It does not mimic conditions of gastrointestinal tract such as the muscle movement. Thus there’s no guarantee of clinical efficacy. Secondly, this test is controlled by experimental variables.

The error during disintegration test experiment is the water in the beaker may not heat up adequately. So, these may affect the disintegration process. Then, the tablet was expired. So, it may affect the disintegration rate.

Conclusion:

All of the tablets passed the disintegration test as it disintegrates completely in less than the specified time which is 1 hour. The experiment is  a success.

References:

1.       http://www.pharmainfo.net/disintegration-test

Practical 4 - Uniformity of weight of tablets and capsules.

Objective:

To determine the uniformity of weight of tablets and capsules.

Introduction:

            Uniformity of Content is a pharmaceutical analysis technique for the quality control of capsules or tablets. Multiple capsules or tablets are selected at random and a suitable analytical method is applied to assay the individual content of the active ingredient in each capsule or tablet. In weight variation test, measurement of contents is done by estimation of contents based on weight. Pharmacists often use and misuse this WV test by doing this test on all dosage units. If it is used correctly, this WV test can be used to measure content uniformity (CU). There are some conditions in which the weight difference can determine the percentage difference in the API in the individual dosage units. Hence this WV test can be useful in the quality control of drug production. This is an important test in technology of pharmaceutical.

Apparatus and materials:

Capsules , tablets , Weighing boats,   Weigh balance

Procedures:

Tablets: Paralgin tablet 500mg

1. 20 tablets were selected randomly and weighed. The average weight was determined.

2. The tablets were weighed individually and for each tablet, the percentage deviation of its weight         from the average weight was determined.

3. The deviation of individual weight from the average weight should not exceed the limits given           below.

Average weight of tablet	Deviation (%)	Number of tablets
Less than 80 mg	±10.0 ±20.0	Minimum 18 Maximum 2
80 mg to 250 mg	±7.5 ±15.0	Minimum 18 Maximum 2
More than 250 mg	±5.0 ±10.0	Minimum 18 Maximum 2

Capsules: Ampilin antibiotic capsule 250mg

1. 20 capsules were selected at random.

2. One capsule was weighed. The capsule was then opened and the contents were removed as                 completely as possible. The emptied shells were weighed. The net weight of its contents was               determined, that is by subtracting the weight of the shells from the weight of the intact capsule.

3. The procedure was repeated with the other 19 capsules.

4. The average net weight was determined from the sum of the individual net weights.

5. The percentage deviation was determined from the average net weight for each capsule. The               deviation of individual net weight should not exceed the limits given below.

Average net weight of capsule	Deviation (%)	Number of tablets
Less than 300 mg	±10.0 ±20.0	Minimum 18 Maximum 2
300 mg or more	±7.5 ±15.0	Minimum 18 Maximum 2

Results And Calculations:

Tablets

No.	Individual weight of tablets (g)	Percentage of deviation (%)
1.	0.6740	-0.43
2.	0.7038	+3.97
3.	0.6890	+1.79
4.	0.6762	-0.10
5.	0.6820	+0.75
6.	0.6656	-1.67
7.	0.6570	-2.94
8.	0.6726	-0.64
9.	0.6868	+1.46
10.	0.6808	+0.58
11.	0.6853	+1.24
12.	0.6811	+0.62
13.	0.6796	+0.40
14.	0.6712	-0.84
15.	0.6806	+0.58
16.	0.6611	-2.33
17.	0.6573	-2.90
18.	0.6770	+0.15
19.	0.6884	+1.70
20.	0.6684	-1.26

Results:

Total weight of 20 tablets = 13.5380 g

Average weight =  13.5380g/20

                           = 0.6769 g

**Percentage of deviation = [ (𝑖𝑛𝑑𝑖𝑣𝑖𝑑𝑢𝑎𝑙 𝑤𝑒𝑖𝑔ℎ𝑡)/(𝑎𝑣𝑒𝑟𝑎𝑔𝑒 𝑤𝑒𝑖𝑔ℎ𝑡)  x 100] -100

Capsules

No.	Individual weight of capsules (g)	Weight of emptied shells (g)	Net weight of the contents (g)	Percentage deviation (%)
1.	0.3510	0.0606	0.2904	+3.74
2.	0.3537	0.0641	0.2896	+3.47
3.	0.3543	0.0629	0.2914	+4.11
4.	0.3646	0.0625	0.3021	+7.93
5.	0.3531	0.0590	0.2941	+5.07
6.	0.3592	0.0614	0.2978	+6.40
7.	0.3631	0.0631	0.3000	+7.18
8.	0.3570	0.0631	0.2879	+2.86
9.	0.3628	0.0675	0.2953	+5.50
10.	0.3516	0.0617	0.2899	+3.57
11.	0.3667	0.0654	0.3013	+7.65
12.	0.3393	0.0617	0.2776	-0.82
13.	0.3596	0.0624	0.2972	+6.18
14.	0.3479	0.0625	0.2854	+1.97
15.	0.3642	0.0590	0.3052	+9.04
16.	0.3504	0.0630	0.2874	+2.68
17.	0.3652	0.0619	0.2973	+6.22
18.	0.3520	0.0618	0.2902	+3.68
19.	0.3630	0.0613	0.3017	+7.79
20.	0.3595	0.0648	0.2947	+5.29

Total net weight of the content of 20 capsules = 5.5989 g

Average net weight =  5.5989/20

                                 = 0.2800 g

Discussion:

For tablets, since our average weight is 676.9 mg, the deviation of individual net weight should not exceed the limits given below:

More than 250 mg

±5.0 ±10.0

Minimum 18 Maximum 2

From the results, we can see that the all the tablets are having standard deviation of ± 5.0. This is shows that 20 tablets having this type of deviation. This may indicate the uniformity of the capsules production.

However, the variation in the weight of the tablets may be explained by the following. Factors such as the flowing properties of the powder, the speed of tableting machine, the pressure used in compression and the type of machines used in tableting may affect the weight of a tablet. However the two most common causes of weight variation are the differences in the bulk densities and particle size distribution during compression

For capsules, since our average weight is 280.0 mg, the deviation of individual net weight should not exceed the limits given below:

Less than 300 mg

±10.0 ±20.0

Minimum 18 Maximum 2

From the results, all our capsules are having a deviation of ± 10%, which means that all capsules have uniform weights. This may indicate the uniformity of the capsules production. At the same time, this uniformity may also be caused by the usage of a good weighing balance. The weighing balance used for measuring the weight of capsule is more accurate as it is a more advanced balance.

If the weight variation in capsule exceeds the limit, this may be due to the defect of the capsule filling machine. The machine may have misalignment of the upper and lower capsule segments or problem in filling the capsule with the target fill weight.

Conclusion:

Both tablets and capsules tested have passed the test of weight uniformity. This uniformity may also be caused by the usage of a good weighing balance. The weighing balance used for measuring the weight of capsule is more accurate as it is a more advanced balance.

References:

1. http://apps.who.int/phint/en/p/docf/

2. Donald K. Lightfoot. (n.d.) Answers To 10 Common Questions About Capsule Filling. Retrieved date. 21st December 2013. From http://capsugel.com/media/library/answers-to-10-common-questions-about-capsule-filling.pdf

3. Dshravani. (2013) Citing Websites. Quality Control Of Capsules. Retrieved date. 21st December 2013. From http://www.pharmainfo.net/quality-control-capsules