ShenyangPharmaceuticalUniversity LAB4:TABLETS PHARMACEUTICS I
LABORATORY 4: Preparation of tablets and factors influencing tablets qualities
- LABORATORY OBJECTIVES
a) To learn the preparation method of tablets by wet granulation.
b) To learn how to use a single punch tableting machine.
c) To know the evaluation methods for tablets.
d) Toinvestigate the influence of compression pressure and types of disintegrants onthe hardness and disintegration time of tablets.
- INTRODUCTION
Tablet is an important solid dosage form which is usually prepared with the aid of suitable pharmaceutical excipients. Tablets may vary in size, shape, weight, hardness, thickness,disintegration and dissolution characteristics and in other aspects, depending on their intended use and method of manufacture.
Compressed tablets may be manufactured by three basic methods: wet granulation, dry granulation, and direct compression. Wet granulation is a widely used method for the production of compressed tablets. The steps are (a) weighing and blending of the ingredients, (b) preparing a damp mass, (c) converting the damp mass into wet granules, (d) drying the granules, (e) sizing the granules by dry screening, (f) adding lubricant and blending, and (g) forming tablets by compression. Figure 1is the schematic description of the wet granulation method.
During the preparation process, each step may influence the quality of tablets produced. Prior to processing, all the active ingredients and excipients must be dried, milled, and sieved (80-100 mesh). Specified amounts of active ingredients, fillers, and disintegrating agents are mixed by means of a powder blender or mixer until a homogeneous mixture is formed. A liquid binder is subsequently added to the powder mixture to facilitate agglomeration of the powder particles. A damp mass resembling a dough is formed and further processed into granules. The amount of binding agent added is usually determined by the operatorbased on the observation that the binder-powder mixture forms a compact wet mass when being squeezed in the hands. However, care must be exercised not to over-wet or under-wet the power. Over-wetting can result in granules that are too hard for proper tablet formation and under-wetting can result in tablets that are soft and prone to crumbling. The wet mass is forced through a screen to form wet granules. This may be done by hand or with a granulation equipment which is used to prepare granules by extruding the wet mass through a screen as part of the equipment. The resultant wet granules are spread evenly on a large piece of paper in a shallow tray for drying. Granules may be dried in a thermostatically controlled oven with the monitoring of time, temperature, and humidity.
Figure 1. Process of tablets preparation by the wet granulation method.
After drying, the granules are forced through a screen of a smaller mesh size than that used to prepare the wet granulation. The degree to which the dried granules are reduced depends on the size of the punch to be used for tablet compression. In general, the smaller the tablet to be produced, the smaller the granules should be prepared as shown in Table 1. Screens of 10 to 20 mesh size are generally used for this purpose. After dry screening, a lubricant (sometime with a portion of the disintegrant) is added to the dried granules through a fine-mesh screen, followed by proper powder mixing. It is essential to measure the drug content in the final granules before tableting in order to calculate the weight of the tablet using the following equation:
Unless otherwise stated in the monograph of CP, the requirements for content uniformity should be met if the amount of active ingredients in each dosage unit lies within the range of 90% to 110% of the label claim.
The screen size and punch diameter can be selected based on the tablet weight according to Table 1. However, the parameters should be adjusted with the change of drug density.
In addition to the appearance, tablets must meet other physical specifications and quality standards, including the criteria for weight variation, content uniformity, thickness, hardness, disintegration, and dissolution. In-process controls must be performed during production and these criteria must be verified after the production of a batch to ensure that established product quality standards are met. Furthermore, the hardness and disintegration time of tablets will be affected by the type and concentration of disintegrants and lubricants added and the compression pressure applied during tablet preparation.
Table 1. The relationship amongtablet weight, screen size, and punch diameter
Tablet weight (mg) / Screen size for wet granulation / Screen size for sizing / Punchdiameter (mm)50 / 18 / 16-20 / 5-5.5
100 / 16 / 14-20 / 6-6.5
150 / 16 / 14-20 / 7-8
200 / 14 / 12-16 / 8-8.5
300 / 12 / 10-16 / 9-10.5
500 / 10 / 10-12 / 12
- METHODS
3.1 Influence of compression pressure on the hardness and disintegration time of aspirin tablets
3.1.1 Formulation:
Aspirin (acetylsalicylic acid) 20g
Starch 2g
Citric acid q.s.
10% starch mucilage q.s.
Talc 1g
3.1.2 Procedures
a) Preparation of 10% starch mucilage:Dissolve 0.2gof citric acid in 20mLof distilled water followed by addingand dispersing 2gof starch. The final mixture is heated on a water bath until the starch is gelatinized giving rise to mucilage.
b) Granulation: Mix the specified amount of aspirin andstarch until uniformusing the geometric dilution method. A damp mass of this powder mixture is prepared by adding appropriate amount of the 10% starch mucilage and kneading by hand.The wet mass is subsequently forced through a 16-mesh screen to form the wet granules.The resultant granules are spread evenly on a large piece of paper in a tray and dried at 40-60oC in an oven. After drying, the granules are passed through a 16-mesh screen and mixed with 5% talc.
c) Tableting under different pressures：Using the aspirin granules prepared above, tablets areprepared under a high and a low compression pressure. Measure the hardness and disintegration time of the tablets and record the results in Table 3.
3.1.3 Notes
a) Aspirin will be discolored (red) upon the contact with ironware particularly in the presence of moisture. Therefore, ironware should not be used during the preparation process. Nylon screens and stainless steel containers should be used instead. Fast drying is advised but the drying temperature should not be too high to avoid accelerating the hydrolysis of aspirin.
b) Preparation ofthe starch mucilage：Either direct heating or water bath can be used. When using direct heating, it is important to stir continuously to avoid over-heating or burning.
c) Temperature of the mucilage: After preparation, the mucilage should be cooled down before adding to the aspirin powder mixture. If it is too hot, the high temperature will cause degradation of Aspirin. If it is cooled down too much, it may be too thick and make the wet granulation process (kneading) difficult.
3.2 Influence of the types of disintegrants and surfactants on the disintegration time of acetaminophen tablets
3.2.1Formulation:
Acetaminophen 20g
15% starch mucilage q.s.
Disintegrant q.s.
Magnesium stearate q.s.
3.2.2Procedures
a) Preparation of a Starch-Tweenmixture：Dissolve 0.5gof Tween-80 in 15mLof ethanol, add the solution to 15gof starch, and mix until uniform. Dry the mixture at 70℃ and thenpass the dry mixture through a 100-mesh screen.
b) Preparation of 15% starch mucilage：6g starch is dispersed in 40mLof distilled water and gelatinized usinga water bath.
c) Preparation of acetaminophen granules：Weigh 20g of acetaminophen and add appropriate amount of 15% starch mucilage to prepare the damp mass. The wet mass is subsequently forced through a 16-mesh screen by hand to give rise towet granules. The resultant granules are spread evenly on a large piece of paper in a tray and dried at 60℃ in an oven. After drying, the granules are passed through a 16-mesh screen.
d) Addition of different types of disintegrants or surfactants: The dried acetaminophen granules (c) were divided into three equal portions. Add 6% dry starch, 6% sodium carboxymethyl starch(CMS-Na) and 6% Tween-starch to each portion respectively.Add 1% magnesium stearate to the each mixture and mix until uniform. These threegranulations are subsequently tableted using the same compression pressure and the disintegration times of the tablets are measured.
3.2.3Notes
Dry starch: Starch should be dried for 2 hours at 105℃ and the water content should be less than8%.
3.3 Influence of hydrophobic lubricants on the disintegration time of sodium bicarbonate tablets
3.3.1 Formulation:
Sodium bicarbonate 20g
Starch 2g
10% Starch mucilage q.s.
Magensium stearate q.s.
3.3.2Procedures
a) Preparation of 10% starch mucilage：2g starch is dispersed uniformly in 20mLof distilled water and gelatinized using a water bath.
b) Preparation of sodium bicarbonate granules：Mix 20g of sodium bicarbonate and 2g of starch until uniform using the geometric dilution method.Prepare the damp mass by adding appropriate amount of 10% starch mucilage. The wet mass is forced through a 16-mesh screen by hand to prepare the wet granules. The resultant granules are dried at 50℃ in an oven. After drying, the granules are passed through a 16-mesh screen.
c) Adding different percents of hydrophobic lubricants: Divide the dried sodium bicarbonate granules (b) into two equal portions. Add 0.6% and 3% magnesium stearate to each portion respectively and mix until uniform. The granules are compressed under the same pressure. Measure the disintegration time of the tablets.
3.4 Preparation of Vitamin C tablets
3.4.1 Formulation:
Vitamin C 50.0g
Starch 20.0g
Dextrin 30.0g
Tartaric acid 1.0g
50% alcohol q.s.
Magnesium stearate 1.0g
3.4.2．Procedures
Mix a specified amount of Vitamin C, starch, and dextrin until uniformusing the geometric dilution method. Dissolve tartaric acid in an appropriate amount of 50% alcohol and add to the powder mixture to prepare the damp mass by hand kneading. The wet mass is forced through a 18~20 mesh screen to prepare the wet granules. The resultant granules are dried at60℃ and the final water content of the dry granules should be less than 1.5%. After drying, the granules are passed through a screen of 18~20 mesh. The fine powder in the granules (separated by sieving) is first mixed with the specified amount of magnesium stearate, and then combines with the dry granules prior to tableting.
3.4.3Notes
a) Vitamin C will decompose and change its color in the presence of moisture, especially upon the contact with metals such as copper and iron. To avoid this from happening, the granulation process should be fast and the granules should be dried below60℃.
b) In the formulation, tartaric acid is used as a chelating agent which can prohibitthe discoloration of vitamin C upon the contact with metal ions. Similarly, 2% citric acid can be used as a chelating agent. Due to the small amount of tartaric acid in the formulation, it should be dissolved in 50% alcohol before adding to the powder to ensure its uniform distribution.
3.5 Quality test and evaluation
Tablet hardness, friability, disintegration and weight variationshould be tested using the methods described in the attachment 1 and results should be recorded in Table 2 and Table3.
- RESULTS AND DISCUSSION
4.1 Record the results in Table 2and 3.
Table 2.Influence of compression pressure on the hardness
and disintegration time of tablets
No / Pressure / Hardness (kg) / Disintegration time (min)1 2 3 4 5 6 average / 1 2 3 4 5 6 average
1
2 / High
Low
Conclusion
Table 3.Influence of typesof disintegrantsand surfactants
on the disintegration time of tablets
No / Hardness (kg) / Disintegration time (min)1 2 3 4 5 6 average / 1 2 3 4 5 6 average
3 6% dry starch
4 6% CMS-Na
5 6% Tween-starch
6 Vitamin C tablet
7 Compound liquorice tablet
4.2 Based on the experimental results, summarize the factors influencing tablet disintegration time and the possible disintegration mechanism.
4.3 Based on the experimental results, summarize the relationship between the properties of the active ingredient and the selection of excipients.
- QUESTIONS
a)How to avoid the hydrolysis of aspirin during tablet preparation? What type of lubricants should be selected?
b)If tablets disintegrate within the prescribed time, is it necessary to determine the dissolution rate?
c)What is the difference between the preparation method for traditional Chinese extract tablets and tablets of chemical drugs?
Attachment 1
All the following parameters should be tested according to CP 2005.
1. Hardness test
A tablet should possess some degree of mechanical strength to withstand the mechanical shocks caused by handling during manufacturing, packaging, shipping, and dispensing.
The main principle of hardness measurement of a tablet involves subjecting the tablet to an increasing load until the tablet breaks or fractures. A method of testing the hardness of a circular tablet is performed by placingthe tablet on its edge in a vertical position between the two tablet holding plates (jaws) of the hardness tester. A controlled pressure is applied to the tablet by one plate and transmitted to the other plate which is connected to a pressure gauge. The maximum pressure is recorded when the tablet breaks. Oral tablets normally have a hardness of 4 to 10 kg; however, hypodermic and chewable tablets are much softer (3 kg) and some sustained release tablets are much harder (10-20 kg).
2. Tablet friability
This test is performed to determine, under defined testing conditions, the friability of uncoated tablets, which is extent of damage of the tablet surfaces, lamination or fragmentation caused by the impact of falling and attrition between tablets. Commercially available apparatuses known as friability testers are used for the test. Basically, it consists of a drum with a diameter between 283mm and 291mm and a width of 36mm–40 mm andis made of transparent plastic material (Fig. 1). The drum is attached to the horizontal axis of a rotating device that rotates at 25 ±1 rpm. The tablets are tumbled at each turn of the drum by following a curve projection with an inside radius of 75.5mm–85.5mm that extends from middle of the drum to the outer wall. Thus, at each turn, the tablets roll or slide and fall onto the drum wall or onto each other. Usually, a sample of 10 tablets are tested at a time, unless the tablet weight is 0.65 g or less, where 20 tablets are tested. The tablets should be carefully dedusted prior to testing. Accurately weigh the tablet sample and place the tablets in the drum. After 100 turns, remove any loose dust from the tablets and reweigh the tablet sample. If the reduction in the total mass of the tablets is more than 0.8% (1% in USP), the tablet sample fails the friability test. Generally, the test isdone once. If cracking, capping, or fragmentation of the tablets is observed, the sample also fails the test.
Fig. 1 Schematic of a friability Fig. 2 Schematic of a tablet
testing apparatus. disintegration apparatus.
3. Disintegration test
A disintegration test is performed to determine how fast a tablet disintegrates into aggregates and/or finer particles. This test allows the determination of whether the tablets disintegrate within the prescribed time when placed in a liquid medium under the experimental conditions. However, disintegration does not imply complete dissolution of the active ingredient(s) from the tablet. Complete disintegration is defined as the state in which any residue of the unit, except fragments of insoluble coating or capsule shell, remaining on the screen of the test apparatus or adhering to the lower surface of the disk, if used, is a soft mass having no palpably firm core.
The basket-rack assembly method: The apparatus consists of a basket-rack assembly, a 1000-mL beaker for the immersion fluid, an heating element for thermostatic heating of the fluid between 35 and 39°C, and a device for raising and lowering the basket in the immersion fluid at a constant frequency rate between 29 and 32 cycles per minute through a distance of not less than 53 mm and not more than 57 mm(Figure 2). The volume of the fluid in the vessel is kept at a level that at the highest point of the upward stroke the wire mesh remains at least 15 mm below the surface of the fluid and descends to not less than 25 mm from the bottom of the vessel on the downward stroke. At no time should the top of the basket-rack assembly become submerged. The time required for the upward stroke is equal to the time required for the downward stroke and the change in stroke direction is a smooth transition, rather than an abrupt reversal of motion. The basket-rack assembly moves vertically along its axis. There is no appreciable horizontal motion or movement of the axis away from the vertical position.
The basket-rack assembly consists of six open-ended transparent tubes, each 77.5 ± 2.5 mm long and having an inside diameter of 20.7 to 23 mm and a wall 1.0 to 2.8 mm thick; the tubes are held in a vertical position by two plates, each 88 to 92 mm in diameter and 5 to 8.5 mm in thickness, with six holes, each 22 to 26 mm in diameter, equidistant from the center of the plate and equally spaced from one another. Attached to the under surface of the lower plate is a woven stainless steel wire cloth, which has a plain square weave with 1.8- to 2.2mm apertures and with a wire diameter of 0.57 to 0.66 mm.
Place 1 tablet in each of the six tubes of the basket, and operate the apparatus, using water maintained at 37 ± 1C as the immersion fluid. At the end of the time limit specified (15min. for uncoated tablets), lift the basket from the fluid and observe the tablets to see whether all of the tablets have disintegrated completely. If 1 or 2 tablets fail to disintegrate completely, repeat the test on 12 additional tablets. The requirement is met if not less than 16 of the total of 18 tablets tested pass the test.
Although this test is prescribed for some products in the pharmacopeias, its use is generally diminishing in favor of drug dissolution testing.
4. Weight variation
Weigh individually 20 tablets and calculate the average weight. The requirements are met if the weights of not more than 2 of the tablets differ from the average weight by more than the percentage listed in Table 4and no tablet differs in weight by more than double that percentage.
Table 4. Weight variation tolerance for uncoated tablets
Average weight of tablets / Percentage differenceLess than 0.30g / ±7.5%
0.30g or more than 0.30g / ±5%
References
[1]H. C. Ansel, N. G. Popovich and L. V.Allen, Jr. Pharmaceutical Dosage Forms and Drug Delivery Systems, , 8th ed., Williams and Wilkins, Baltimore, 2005.
[2] M.E. Aulton. Pharmaceutics: The science of dosage form design. 1988.
(Shirui MAO)
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