The Implications of Powder Flow on the Quality of Pharmaceutical Tablets and Capsules PDF

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Powder flow lab report from the infections case...

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Name: Onella Edde Student number: 14806952

The Significance of Powder Flow on the Quality of Pharmaceutical Capsules and Tablets Abstract Powders are broadly used in the pharmaceutical industry in a variety of dosage forms. They can be used in dosage forms which involve tablet and capsules, which are used for the oral route. Powder flowability can be significant in the manufacturing of pharmaceutical tablets and capsules as it can determine whether they contain the correct amount of active pharmaceutical ingredient. The British Pharmacopoeia devised a series of quality control tests and guidelines of tablets, capsules and powder flow. These tests include uniformity of mass, uniformity of diameter, hardness, friability, bulk density and angle of repose. The results show that the sample batch of tablets passed the uniformity of diameter, uniformity of mass and friability tests but failed to passed the hardness test. The results do not give enough information on the quality of these tablets so further tests would be done. The results also show that the sample batch of capsules passed the uniformity of mass test which suggests that each capsule contains the right amount of the active drug. Bulk density and angle of repose of powder flow was investigated with 4 different concentrations of magnesium stearate, used a glidant. It is found that the glidant concentration that produces optimal powder flowability is 0.5% w/w. These guidelines are important for the pharmaceutical industry as it can confirm that the dosage forms contain the optimal amount of the active drug.

Introduction Powders are important in the pharmaceutical industry as they are broadly utilized in pharmaceuticals in a range of dosage forms. They can be used as a foundation to various dosage forms such as tablets, capsules, suspensions and many more. They can also be used as a dosage form in their own right. In order to use them in pharmaceuticals, powders must have suitable flow properties to guarantee the quality of the powder in the dosage form and that the dose is accurate. Flowability is described as the ease at which the powder will flow under a specific set of conditions [1]. The flowability of a powder is dependent on the forces acting on the powder including driving forces (e.g. mechanical forces, gravity) and drag forces (e.g. cohesion, adhesion, surface tension). These forces can either benefit or inhibit flow. The extent to which these forces have an effect is influenced by a range of physical particle properties which include particle size, shape and density. Other factors affecting powder flow include packaging geometry and surface tension. The flowability of a powder can be improved by adding the right amount of glidant or anti-adherent, in order to moderate or decrease the adhesive and cohesive forces acting on the powder characteristics. Powder flowability can be determined from its bulk density and angle of repose. The bulk density of a powder is the mass it occupies divided by its total volume occupied. The fluff density (V0) is when the powder occupies the maximum volume and the tapped density (V ƒ) is taken after the powder has been compacted [2]. Hausner ratio and Carr’s index are indicators of powder flowability and can be calculated as shown below in figure 1.

Name: Onella Edde Student number: 14806952

Figure 1: Carr’s index and Hausner ratio formulae [3].

The angle of repose is important in determining the powder flowability. It indicates how easily particles in a powder roll over one another. When a powder is transferred onto a flat surface, it forms a cone. The angle of repose is the angle between the slope of the powder stack and the flat surface on which the powder lies on [4]. In a more co-adhesive powder, the powder stacks up and forms a steeper slope. The steeper the slope, the larger the angle of the repose and the poorer the flowability. On the other hand, in a less co-adhesive powder, the particles will slide down the slope, form a less steep slope and therefore will have a smaller angle of repose and better flowability. The table below shows the relationship between powder flowability, Hausner ratio, Carr’s index and the angle of repose. Table 1: Relationship between powder flowability, Hausner ratio, Carr’s index and the angle of repose [5].

Tablets are the most widely used dosage form via the oral route. They are compacted solids that are designed to break down in the stomach and release the drug in the process. They are produced by a tablet press which works by compressing powders or granules. The process in which a tablet is made includes mixing, granulation, compressing, coating and packing. Various excipients such as anti-adherents, lubricants, glidants, are added during these stages to improve the quality of tablets. In order to ensure that the tablets and capsules are able to use, they must meet certain quality standards. The British Pharmacopeia has a number of quality control tests including: friability, hardness, uniformity of mass and uniformity of content. Throughout this study, a number of tests were done to investigate the effect of powder flow.

Name: Onella Edde Student number: 14806952

Method Quality control of tablets Uniformity of mass A sample of 20 tablets that contained 500mg of an unspecified drug were used in this test. The 20 tablets were accurately weighed to the nearest 0.1mg and the mass was recorded for each one as shown in appendix 1. The average mass tablet was calculated and recorded as shown in table 4. To pass the uniformity of mass test, no more than 2 tablets should deviate from the average mass by the percentage deviation (D) shown in table below, and none from twice that limit. The maximum and minimum tablet masses that correspond to these limits were calculated and the batch of tablets were investigated whether they pass the test. Table 2: Test parameters for uniformity of tablet mass [6].

Uniformity of diameter 10 tablets were used to measure the diameter of each one using the callipers provided. To measure the diameter, the widest part of the tablet was placed in between the jaws of the callipers and held in place. The diameter was measured individually and recorded as shown in appendix 2. To pass the test none of the tablets shall deviate from the average diameter by more than 5%. Friability The friabilator was cleaned, re-dusted and then 10 tablets were weighed. Their total mass was recorded in table 6. The tablets were then placed in the drum of the friabilator Copley FR200 and the drum was closed. The drum was rotated at 100 rotations and then the tablets were removed from the friabilator and their total was re-weighed. The percentage loss was calculated and recorded in table 6. The percentage mass loss must not exceed 1.0% to pass the test. Hardness 10 tablets were used for the hardness test using the Holland C50. The results were recorded in appendix 3. To pass the test, the hardness values of all the tablets must have a hardness value within 95-105% of the sample average. Powder flow and capsules The powder samples provided were lactose which contained different concentrations of magnesium stearate as the glidant. Four different concentrations of magnesium stearate were used and investigated in the 2 parts of this experiment. Determining bulk density Large clumps of the powder sample were removed by using a 1.18mm sieve and 100g of the powder sample was weighed into the cylinder. The unsettled powder volume was weighed,

Name: Onella Edde Student number: 14806952

recorded in the table shown in appendix 4, and the cylinder was loaded securely onto the tapping apparatus. 3 series of 50 taps were performed and if the powder volume differed by more than 2mL, then an additional series of 50 taps was done again. The final tapped volume was recorded in appendix 4 and using the tapped volume and fluff (unsettled) volume, Hausner ratio and Carr’s index were calculated as shown in table 8. This was repeated for the other 3 glidant concentrations. Angle of repose Large clumps of the powder were removed by using a 1.18mm sieve and the powder was moved into the closed funnel. The digital height gauge was adjusted to zero fitting to the test platform where the powder cone would appear. To allow the powder to form a cone, the funnel shutter was opened and excess powder was allowed to overflow over the cone which was collected in a retaining tray around the test platform. If the powder didn’t flow, a stirrer was used to stir the powder in the funnel. The height of the scriber of the digital height gauge was adjusted so that it exceeds the height of the powder cone. The height was recorded and the angle of repose was calculated as shown in table 8 and appendix 4. The procedure was repeated for the other 3 glidant concentrations. Quality control of capsules Manufacture of capsules 5 empty capsule shells with the capsule size of 00 were weighed and recorded in appendix 5. The capsules were then filled with lactose BP using a manual capsule-filling machine and then re-weighed. The total mass was recorded and the capsule fill density for lactose was calculated. The capsule-filling machine was cleaned thoroughly and the procedure was repeated for ferrous fumarate. The mass that was needed to fill 60 capsules with ferrous fumarate and lactose was calculated. All the calculations and masses were recorded in appendix 5. The powders were then accurately weighed to the nearest 0.1mg and were mixed in a sealed polyethylene bag until the colour was evenly distributed. 60 capsules were filled with the mixed content. Uniformity of mass test for capsules From the batch of capsules that was manufactured, 20 capsules were weighed individually and the mass was recorded. The content of the capsule was completely emptied and the empty capsule was weighed as shown in appendix 6. The difference of the filled capsule and the empty capsule was calculated as shown in table 9. In order to pass this test, no more than 2 capsules must deviate from the average mass by the percentage shown in table 3 below and none must deviate from twice that limit. All calculations were recorded in table 10. Table 3: Test parameters for uniformity of capsule mass

Name: Onella Edde Student number: 14806952

Results Table 4: Uniformity of mass test results

The table shows that the batch of tablets passed the test as no more than 2 tablets deviated from the average mass +/- 5% and none twice that limit. Table 5: Uniformity of diameter test results

The table shows that the tablets passed the uniformity of diameter test as none of the tablets deviated from the average diameter by more than 5%. Table 6: Friability test

The table shows that the tablets passed the friability test as the relative loss of mass percentage is less than 1%.

Name: Onella Edde Student number: 14806952

Table 7: Hardness test

The table shows that the batch of tablets failed the hardness test as 8 tablets have a hardness value outside of the 95-105% of the sample average. Table 8: Powder flow results

The table shows the Hausner ratio, Carr’s index and the angle of repose of the 4 different Glidant concentrations. Table 9: Mass of capsule content

Name: Onella Edde Student number: 14806952

This table shows the capsule content of 20 capsules which was calculated by difference between the filled capsule and the empty capsule. Table 10: Summary of capsule test results

This table shows the results of 20 randomly selected capsules that have been measured. The average mass of the capsules content was 745.13 and so the limits of deviation was set at 7.5%. As no more than 2 tablets were outside of the limits defined by D and none outside the limits of 2D, the capsules passed the test.

Name: Onella Edde Student number: 14806952

Figure 2: Glidant concentration vs Hausner ratio

The glidant concentration vs Hausner ratio 1.45 1.4

Hausner ratio

1.35 1.3 1.25 1.2 1.15 1.1 1.05 1 0

1

2

3

Glidant conc. (% w/w)

Figure 2 shows a graph of the glidant concentration against Hausner ratio. The Glidant concentration of 0% w/w had the highest Hausner ratio of 1.4 whereas the the other 3 glidant concentrations had similar Hausner ratios.

Figure 3: Glidant concentration vs Carr’s index

Figure 3 shows a graph of the glidant concentration against Carr’s index. The glidant concentration of 0% w/w had the highest Carr’s index of 28 whereas the other 3 glidant concentrations had similar Carr’s index values. Figure 4: Glidant concentration vs angle of repose

Name: Onella Edde Student number: 14806952

Figure 4 shows the glidant concentration against the angle of repose. At first as the glidant concentration increases, the angle of repose decreases. Then from concentration 1% w/w, the angle of repose increases.

Discussion Quality control The British Pharmacopoeia allows no more than 2 tablets or capsules to deviate from the average mass in order for tablets to pass the uniformity of mass test. This test is carried out to ensure that each dosage form contains the right amount of the active pharmaceutical ingredient in a tablet. From the results, the batches of tablets and capsules have passed the uniformity of mass test as no more than 2 tablets or capsules were outside the limits defined by D and 2D. This indicates that the single-punch press device and the manual capsule-filling machine was efficient and consistent when producing tablets. Deviations in mass could be due to too much or not enough active drug. [7]. This could potentially mean patients not receiving the correct amount of the drug in order to produce a therapeutic response. In the uniformity of mass test for capsules, one capsule deviated from the limits of the average mass. This could be due to the capsule-filling machine – as it was manual, there could have been some human error while manufacturing the capsules which could affect the amount of ferrous fumarate or lactose added to the capsules. Furthermore, as both the lactose and the ferrous fumarate were mixed manually in a polyethylene bag and then transferred onto the capsule-filling machine, there could have been errors as both components could have not been mixed accurately. To improve the amount of content in the capsules, an automatic filling machine that produces capsules with better uniformity of mass and a mixing machine could reduce the amount of human errors enforced in this experiment. In order for the tablets to comply with the quality standards of the British Pharmacopoeia, none of the tablets shall deviate from the average diameter by more than 5%. The results show that the deviations below and above the average are not more than 5%, so the sample batch of tablets pass the test. The die and the punches of the tableting pressed used in the compression process determines the diameter of the tablet. Less curved punches will produce

Name: Onella Edde Student number: 14806952

flatter tablets and punches that are more curved will result in tablets that are more curved. Slight changes in the tablets’ diameter could be due to the rough surface of punch and die throughout compression or due to less accurate measurement of the tableting instrument. In order for tablets to pass the friability test, the total percentage loss of mass must not exceed 1%. Friability tests are also referred to as attraction resistance methods. Attraction resistance methods are made to imitate the kind of forces, tablets endure during handling. The results show the tablets passed the test as the percentage loss of mass is less than 1%. This implies that the tablets aren’t friable. A friable tablet is one that is likely to be destroyed mechanically during handling as they are subjected to damage due to collisions from other tablets. This can result in the removal of particles from the surface of the table which can result in a deduction of tablet weight and a change in the appearance. Friability is closely related to the hardness of the tablet and can be affected by external and internal factors. External factors include the punches of the tableting machine which could be worn out or in poor condition resulting in peeling at the edges of the tablets. Internal factors include the moisture content of the tablets. The sample passing this test suggests that tablets can tolerate the attraction resistance forces applied when handling and are fit for commercial use. Another test that was performed was hardness. Tablets need to have a certain hardness to overcome mechanical damage so that they don’t break easily. In order to pass the hardness test, all tablets must have a hardness value within the range of 95-105% of the sample average. The results show that the tablets failed the hardness test as 8 tablets have failed to have a hardness value within the range. The hardness of tablets can affect their disintegration. If the tablet is too hard, it may not disintegrate in the required period of time and if the tablet is too soft, it will not be able to withstand the stresses during handling or may have little bioavailability. A tablet’s hardness can also affect the dissolution rate. If a tablet is too hard, it may not be able to dissolve properly. From other studies it is shown that when the hardness of the tablets increased, the dissolution rate decreased [8]. The batch of tablets failing this test may indicate that they won’t be able to be used therapeutically. There are various factors that affect tablet hardness. These factors include: compression of the tablet and the compressive force; amount of binder and method of granulation. To improve the hardness of the tablets, a dry binder would be used and a deduction in the compression speed would be better. Powder flow Bulk density is how the material will be compacted under various loads and can be an indicator of flow. For the bulk density, two calculations performed for the bulk density were Hausner ratio and Carr’s index. The results show that the lower the glidant concentration, the higher the Hausner ratio and Carr’s index. The powder sample that contained 0% w/w glidant concentration, had a high ratio and Carr’s index. Glidants are used to enhance powder flow by decreasing particle cohesion and adhesive forces including friction. This ensures content uniformity such as size, shape and weight in capsules or tablets. As no glidant was present in this powder sample, it had poor powder flowability as the powder particles were more likely to stick together. The other three powder samples that contained glidant concentrations of 0.5, 1.0 and 3.0% w/w, had low Hausner ratio and Carr’s index. From table 1, this suggests that they have very good powder flowability. This indicates that the glidant concentrations of these 3 powder samples are suitable to use in pharmaceuticals. The angle of repose is another factor which affected the powder flowability. The angle of repose is the angle between the horizontal surface and the slope of the powder. An angle

Name: Onella Edde Student number: 14806952

lower than 40o, implies good powder flowability whereas an angle above 40 o suggests poor powder flowability which could be due to cohesion of the powder particles. All of the powder samples had angle below 40 o which indicates that each of the glidant concentrations had good powder flowability. However, the powder sample that contained 0.0% w/w glidant concentration had the highest angle of repose which indicates that without a glidant, the angle of repose may be a bit higher than with a glidant but can still be enough for the powder to have good flowability. A glidant can improve the angle of repose as it will aid flowability as the particles wouldn’t show any cohesion or adhesion. This will allow the particles to roll over one another and form a smaller slope and hence, produce a small angle of repose. As all glidant concentrations presented good powder flowability, this implies that the glidant concen...