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Name: Shi Guo, Wong Group: B Subgroup: 4

This experiment is to investigate the effect of mixing variables on the drug content uniformity in tablets which consist of three simple components which include drug, excipient and lubricant mix. Three types of mixing method, glass mortar and pestle, Ycone blender and Turbula mixer, is used to test which has the best drug content uniformity using the same formulation for all three methods. The tablet is then punched out to be analyzed for active ingredient. The results of all three mixing are compared with the criteria in BP. In conclusion, the industry carries out testing to ensure the drugs in the tablets are evenly distributed so that they can ensure patients always get the right dose of drug.

Mixing is defined as a process where two or more components are put as close as possible in contact with particles of the other components. (Aulton M.E., 2000. Pharmaceutics: The Science of Dosage Form Design, 550). During mixing, problems like the uniformity of drug mixes, binding of drug in tablets and the release of drug arises. Problems of mixing such as these are so great that the best attainable mix is actually a random mix. Random mix is where the probability of sampling a particular type of particle is proportional to the number of such particle on the total mix. When mixing, a so-called perfect mix may be produced where each particle lies adjacent to a particle of the other component but the odds against this occurring are huge. (Aulton M.E., 2000. Pharmaceutics: The Science of Dosage Form Design, 551). For example, some particles may clump and stick together during mixing and therefore the mixing will not be homogenous. With this, lubricant is added to the mixing to enhance the flow properties of the drug granules. During the mix, various excipients are added to enhance the mix. For example, lubricants (as stated before) and diluents which are added in certain amount to ensure the right size of tablet are made. (Aulton M.E., 2000. Pharmaceutics: The Science of Dosage Form Design, 311). The diluent added should be physiologically inert and should not interfere with bioavailability. Tablet production by using a single punch tablet machine (Manesty) needs no prior manipulation. There are some advantages to this method. This saves time and cost for the pharmaceutical industry and also there is no compromise in tablet quality. Diluents can

be added to the mix without reducing the compressional properties of the former. Heat and water are not involved in this process so drug stability is not influenced. (Aulton M.E., 2000. Pharmaceutics: The Science of Dosage Form Design, 654). However, if the drug particle size is not similar to the diluent, this may lead to stratification during handling of and most importantly, the distribution of drug in tablets.

1. Drug Analysis The Beer Lambert calibration plot is used. A stock solution of the Propantheline bromide (drug) is prepared by carefully weighing 50mg of the drug on the analytical balance. It is then transferred to a 500ml volumetric flask and made up to volume with distilled water. 5 dilutions is prepared from stock in the range of 10-100mg/L. The absorbance of the standard in triplicate at max of 243nm was determined. A calibration curve of Absorbance versus concentration (mg/ml) is constructed. 2. Formulation and mixing Each tablet contained 0.5mg of drug, 49.0mg of DC Lactose (diluent) and 0.5mg of Sodium Strearyl Fumarate (lubricant). The weighing of the drug is done in the fume cupboard as it is harmful if inhaled. Mixing of the drug with the diluent and lubricant is also done in the fume cupboard. The amount of each powder required to produce 100 tablets is calculated. The required amount of each of the components to make three mixes using the same formulation is weighed. Three mixing methods are chosen. The 1st batch is the manual mixing in a glass mortar and pestle. The 2nd batch is component powder are added to a Y-cone stainless steel blender and rotated for 10 minutes. The 3rd batch is the powders are added to a vessel which is to be mixed by the Turbula mixer (Glen Creston) for 10 minutes. 3. Tabletting Instructions are given on the use of the single punch tablet machine (Manesty). The machine is set to produce 50mg tablets. The machine setting is 19 on the T-bar during the exercise. The powder mix of the 1st batch is added to the feed shoe; machine is guarded and switched on. The first 10 tablets are discarded and the later 20 tablets are collected for testing. The remainder is allowed to run to waste. The same tabletting procedure is repeated for the powder mixes of the 2nd batch and 3rd batch. When switching between batches, cleaning is not necessary. 4. Analysis of Drug Content Uniformity The following analysis is based on the guidelines of B.P. Uniformity of Content Test A (Appendix XII H). 10 tablets are sampled and each tablet is weighed individually. Each tablet is transferred to a 10ml volumetric flask. Distilled water is then added to make up to volume and the tablets are sonicated until the tablets are disintegrated. With this, the drugs have dissolved but the lubricant made the liquid look cloudy. A sample of the liquid is taken from the volumetric flask using a syringe with a millipore filter attached. The clear filtrate is then analyzed using the UV spectrophotometer. Two reading is taken for each sample. This method is repeated for each tablet. This procedure is also repeated for each batch.

The batch passed the test if the drug content of each individual tablet is between 85% and 115% of the average content of all 10 tablets. The batch fails the test if the drug content of more than one tablet is outside the above limits or the limits of 75% to 125% of the average content.

1. Drug Analysis Analytical balance readings for preparation of stock solution (by difference): Weight of drug in stock solution (mg): 51.2 Concentration of stock solution (mg/L): 102.4 Calculations for the preparation of the 5 dilutions: C1V1=C2V2 C1=102.4mg/L V1=10ml V2=100ml With this, C2=10mg/L, 30mg/L, 50mg/L, 70mg/L, 90mg/L respectively.
Table 1: Absorbance readings of the six standard solutions at max 243nm Absorbance readings at max 243nm Standard Solution (mg/L) 10 0.11 0.11 0.10 30 0.32 0.32 0.32 50 0.53 0.53 0.53 70 0.75 0.76 0.76 90 0.94 0.96 0.96 Stock=100 1.00 1.70 1.70 Figure 1: Graph of Mean Absorbance against Concentration (mg/L) Mean Abs 0.107 0.320 0.530 0.757 0.950 1.470

Graph of Mean Absorbance against Concentration (mg/L)

1.200 Mean Absorbance 1.000 0.800 0.600 0.400 0.200 0.000 0 10 20 30 40 50 60 70 80 90 100 Concentration (mg/L)

2. Formulation and mixing

Table 2: Calculation of the amount of each powder for 100 tablets according to formula Ingredients Amount/tablet (mg) Amount/100 tablets (mg) Drugs 0.50 50 Diluents 49.00 4900 Lubricant 0.50 50 Table 3: Balance readings of the ingredients of the three powder mixes, before mixing by different methods Ingredients 1st Powder mix (g) 2nd Powder mix (g) 3rd Powder mix (g) Drug 0.0510 0.0510 0.0499 Diluents 4.9095 4.9090 4.9037 Lubricant 0.0506 0.0493 0.0503 Total weight (g) 5.0111 5.0093 5.0039 Method of mixing Y-cone blender Turbula mixer mortar and pestle

3. Tabletting T-bar=19 Tabletting machine runs fine and smooth. No problems faced. All tablets from the three batches look similar with smooth and shiny surface. 4. Analysis of Drug Content Uniformity 1st batch Method of mixing: Y-cone blender
Table 4: Tablet mass, absorbance readings, drug content per tablet and % variation from the average content Tablet Drug Content % content Absorbance Mean Concentration Tablet mass per tablet from mean Readings Absorbance (mg/L) (g) (mg/10mL) content 1 0.0499 0.51 0.53 0.53 49.93 0.4993 78.52 2 0.0472 0.56 0.49 0.53 49.93 0.4993 78.52 3 0.0484 0.99 0.99 0.99 93.26 0.9326 146.66 4 0.0481 0.58 0.49 0.54 50.87 0.5087 80.00 5 0.0470 0.72 0.88 0.76 71.59 0.7159 112.58 6 0.0495 0.58 0.52 0.55 51.81 0.5181 81.48 7 0.0494 0.97 0.99 0.98 92.32 0.9232 145.18 8 0.0494 0.55 0.56 0.56 52.76 0.5276 82.97 9 0.0486 0.85 0.68 0.75 70.65 0.7065 111.10 10 0.0493 0.56 0.55 0.56 52.76 0.5276 82.97 Average content: 0.6359

2nd batch Method of mixing: Metal Turbula

Table 5: Tablet mass, absorbance readings, drug content per tablet and % variation from the average content Tablet Drug Content % content Absorbance Mean Concentration Tablet mass per tablet from mean Readings Absorbance (mg/L) (g) (mg/10mL) content 1 0.0481 0.77 0.82 0.80 74.89 0.7489 128.77 2 0.0486 0.83 0.88 0.86 80.55 0.8055 138.49 3 0.0477 0.71 0.64 0.68 63.59 0.6359 109.34 4 0.0479 0.55 0.52 0.54 50.40 0.5040 86.66 5 0.0486 0.5 0.49 0.50 46.63 0.4663 80.18 6 0.0457 0.53 0.53 0.53 49.93 0.4993 85.85 7 0.0496 0.57 0.58 0.58 54.17 0.5417 93.14 8 0.0488 0.54 0.53 0.54 50.40 0.5040 86.66 9 0.0494 0.62 0.59 0.61 56.99 0.5699 98.00 10 0.0450 0.52 0.56 0.54 50.87 0.5087 87.47 Average content: 0.5816

3rd batch Method of mixing: Mortar and pestle

Table 6: Tablet mass, absorbance readings, drug content per tablet and % variation from the average content Tablet Drug Content % content Absorbance Mean Concentration Tablet mass per tablet from mean Readings Absorbance (mg/L) (g) (mg/10mL) content 1 0.0473 0.76 0.82 0.79 74.42 0.7442 94.49 2 0.0459 0.79 0.82 0.81 75.84 0.7584 96.29 3 0.0312 0.66 0.64 0.65 61.23 0.6123 77.75 4 0.0469 0.92 0.8 0.86 81.02 0.8102 102.87 5 0.0469 1.12 1.14 1.13 106.45 1.0645 135.16 6 0.0477 0.73 0.74 0.74 69.24 0.6924 87.91 7 0.0371 0.63 0.61 0.62 58.41 0.5841 74.16 8 0.0470 1.2 1.4 1.30 122.47 1.2247 155.50 9 0.0403 0.78 0.61 0.70 65.47 0.6547 83.13 10 0.0484 0.74 0.75 0.75 70.18 0.7018 89.11 Average content: 0.7876

The calculations are as follows: Concentration= (mean absorbance)/ (slope) % content from mean content= (drug content per tablet)/ (average content)

By referring to table 4, tablet number 3 and 7 did not pass the test with% content from mean content of 146.66% and 145.18% respectively. So therefore, this particular batch of tablets has failed the test. In table 5, tablet number 1 and 2 did not pass the test with% content from mean content of 129.59% and 139.30% respectively. This batch also failed the test. In table 6, tablet number 5, 7 and 8 did not pass the test with% content from mean content of 135.16%, 74.16% and 155.50%. This batch did not pass the test. In general, all 3 batches did not pass the test. This may be due to segregation during handling of the mixing vessel. Smaller particles may fall through the gaps between larger particles to the bottom of the vessel. Density, shape and size are another contributing factor. By carrying out ordered mixing, segregation can be prevented. (Aulton M.E., 2000. Pharmaceutics: The Science of Dosage Form Design, 556). The 3rd batch which was mixed by the mortar and pestle method has higher tablet failure of 3 tablets. It may be due to the strength applied to the powders during mixing. The powders might have been crushed to smaller particles and some might not got crushed. During mixing, the mortar and pestle might have created heat through friction and thus, affected the drug stability in the powder. There is also a possibility that some mixture powders are sticking to the vessel wall or the foot of the hopper shoe. This decreases the amount of drug or excipients and the drug content variability that are to be used in a tablet. According to the tables, the irregularity of the tablet weight done by the single punch tablet machine also have influence on the results. In table 6, tablet number 3 has the less weight but still passes the test by more than 2% whereas tablet number 7 which have a slightly higher weight failed the test by almost 1%. This also shows that the mixing irregularities of the mortar and pestle method.

As a conclusion, the tablets mixed by the three mixer above have acceptable results but the three batches of tablets still failed the B.P. criteria. The aims of effect of mixing and analyze of active ingredient have been met except for the B.P. criteria matching where, as stated above, all three batches have failed the test.


Aulton M.E., 2000. Pharmaceutics: The Science of Dosage Form Design Mixing 550563, Tabletting 647-667