Comparing the dissolution of tablets and capsules. The purpose of this experiment is to test the dissolution of previously prepared capsules containing different paracetamol formulations, and commercial formulations, in order to highlight the difference

University Degree Subjects allied to Medicine

MARIAM ALHASSAN D2B PRACTICAL 4

INTRODUCTION

Dissolution involves the relocation of a solute molecule from an environment where it is surrounded by identical molecules (with which it forms intermolecular attractions) into a liquid where it is surrounded by non-identical molecules. Optimal drug dissolution is crucial to the success of oral drug therapy. Slow dissolution can be correlated with poor performance of oral dosage in vivo, and drugs of low aqueous solubility provide a major challenge during the design of oral dosage forms.

Solid oral dosage forms need to be in solution before absorption occurs; dissolution is often the rate limiting step in absorption of a drug and can control the overall bioavailability of the drug. Dissolution is important for the bioavailability of oral solid dosage . The rate of drug dissolution of solids can be described using the Noyes-Whitney equation.

Dm/dt = DA ( Cs – C)

Dm/dt = rate of drug dissolution at time t,

D = the diffusion rate constant

A= surface area of particle

Cs =Concentration of drug in the stagnant layer

C=Concentration of drug in the bulk solvent

h = thickness of the stagnant layer.

dC/dt is the rate of drug dissolved per time expressed as concentration change in the dissolution fliud. The Noyes-Whitney equation shows how factors such as solubility and surface area can affect dissolution rate. Dissolution rates may be increased by decreasing the drug particle size (this increases the available surface area to the dissolveing fluid), increasing solubility in the diffusion layer (the ionised form of the drug will have greater solubility in the diffusion layer than the unionised weak acid or weak base), and altering the pH of dissolution medium.

The purpose of this experiment is to test the dissolution of previously prepared capsules containing different paracetamol formulations, and commercial formulations, in order to highlight the differences between the formulations, including dosage form, excipients used, and prizes of brands and therefore quality, that may influence dissolution rate.

METHOD

CONSTRUCTION OF CALIBRATION CURVE

Dilutions of paracetamol stock solution (100mg/L) were carried out resulting in concentrations of 5 mg/L,10 mg/L,20mg/L, 25 mg/L,30 mg/L, and 40 mg/L. Absorbance of each solution was measured at 249nm using a UV spectrophotometer. A calibration curve was then plotted relating the concentration of drug in solution to the UV absorption.

DISSOLUTION TESTING

Each tablet and capsule was placed in one of the dissolution vessels and the motor was torned on to rotate the paddles at 50 rpm. Stop clock was started. Using the syringes provided 10ml of solution was withdrawn from each vessels every 5 minutes, the sample as passed through the 0.45 micron filter provided into a labelled vial rejecting the first ml of filtrate just incase any fibres or dust had been picked up on the downside of the filter. 10 ml of distlled water was taken from the water bath (same temperature) as the one in the vessel) and injected into the dissolution vessel to bring it back to the inital volume of 900 ml. The 5 ml sample was diluted to 100ml (20-fold dilution) in a 100ml volumetric flask. The absorbance for each sample was measured using the UV spectrophotometer. Using the calibration curve, the quantity of drug in solution and hence the quantity dissolved in the 900ml of dissolution fluid was calculated. From the average drug content of the tablet, the percentage of the content that had passed into the dissolution fluid calculated. For each formulation tested the % of drug content of the dosage form which had dissolved as a function of time was plotted. This was done to two tablets of each formulation and the bath was operated at 37o C using distilled water of volume 900ml as the dissolution medium.

Formulations used

Commercial formulations subject to dissolution testing includes

Panadol actifast (£2.74 : 20 p per tab)

500mg paracetamol,

Sodium bicarbonate, soluble starch ,povidone (gelling agent), maize starch(disintergrant and anti adherent), potassium sorbate (E20), microcrystalline cellulose (binder), magnesium stearate(lubricant and antiadherent), carnauba wax , titarium dioxide (E171), polydextrose, hypromellose, glycerol triacetate and polyethylene glycol(solution binder).

Anadin (£1.99 : 12 p per tab)

500mg paracetamol,

Croscarmellose (super disintergrant) sodium, povidine(viscosity enhancer), pregelatinised maize starch(disintergrant), stearic acid (lubricant), hydroxypropyl methyl cellulose (E464) (solution binder), polyethylene glycol(solution binder).

Paracetamol galpharm (£0.16p: 1p per tab),

500g paracetamol,

Pregelatinised maize starch BP(disintergrant),, sodium metabisulphide BP ...

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Formulations used

Commercial formulations subject to dissolution testing includes

Panadol actifast (£2.74 : 20 p per tab)

500mg paracetamol,

Anadin (£1.99 : 12 p per tab)

500mg paracetamol,

Paracetamol galpharm (£0.16p: 1p per tab),

500g paracetamol,

Pregelatinised maize starch BP(disintergrant),, sodium metabisulphide BP and magnesium stearate BP(lubricant).

Capsules manufactured from experiment 3 contained:

DISSOLUTION STUDIES ON THE MANUFACTURED CAPSULES

FORMULATIONS TESTED

Starch 1500( vessel 1 and 2)
Microcrystalline cellulose ( vessels 3 and 4)
Lactose (vessel 5 and 6)

* indicate solution is diluted by 20 fold

TABLE 1: ABSORBANCE OF VARIOUS FORMULATIONS CONTAINING DIFFERENT DISINTEGRANTS AT VARYING CONCENTRATIONS MEASURED AGAINST TIME.

Using the values obtained above, the amount of paracetamol dissolved in a one litre solution was obtained by extrapolating from the calibration curve. The calibration curve gives the concentration in mg/l. This is converted to in 900 ml by.

Example 0.745 read of the curve gives a concentration of 15.5 mg/l. Hence In 900ml (0.9L),

Xmg= 0.9 x 15.5

Xmg = 13.95 mg

For solutions with asterisks * the concentration is multiplied by 20 after being found how much is in 0.9L.

The values are shown below (table 2)

The expected normal weight is 25mg per capsule: To calculate % of drug released in solution, is the amount weighed in solution divided by expected weight multiplied by 100%. Example is percentage of in panadol five mintes = 13.95 x 100% = 55.8% 25

COMMERCIAL FORMULATIONS TESTED

Panadol actifast ( vessel 1 and 2)
Anadin ( vessels 3 and 4)
Paracetamol galpharm(vessel 5 and 6)

For tablets, all solution has been diluted by 20 fold.

To calculate the concentration, in 0.9L the concentration is read of the calibration curve; example 0.841 read off the graph is 15.45 mg/L. This is then multiplied by 20 (dilution factor). 15.45 x 20= 345mg/L : in 0.9L; 0.9 x 345= 310.5mg.

The expected normal weight is 500mg: To calculate % of drug released in solution, is the amount weighed in solution divided by expected weight multiplied by 100%. Example is percentage of in panadol five mintes = 310.5 x 100% = 62.1%

500

RESULTS AND DISCUSSION

Figure 1 is a graph that shows the % of drug content released with time for the paracetamol capsules which differed in terms of the diluent used. When comparing the formulations it is evident that the one lactose had the fastest dissolution rate as it released its total quantity of drug encapsulated into solution within 45 minutes, followed by the starch 1500 formulation and then by the microcrystalline cellulose formulation with released its totally quantity of drug into solution after 60 minutes.However the percentage of drug released being over 100% suggests that perhaps the capsule didn’t contain the correct quantity of drug to begin with this could be due to poor mixing of powder , possibly due to poor filling of the capsule due to nature of powder mix or inefficiency of machine . Moreover, these results suggest that the presence of lactose in a paracetamol capsule formulation enhances its dissolution rate, more so than either starch 1500 and microcrystalline cellulose. this could be because lactose is water soluble and also possess good disintegrant activity hence enabling the drug to be released into solution faster whiles microcrystalline cellulose has very good disintegrating properties, but is water insoluble. starch 1500 should have obtained faster dissolution rates as starch 1500 is water soluble and also possess disintegrant activity(but should be included at relatively low concentration 1-5% by weight) and the concentration range of the tablet should be up to 10% this might not have been achieved due to the above factors mentioned (poor powder mix, poor filling of capsule). Thereby the percentage of the diluent used was too large thus affecting the dissolution of the drug, where it may have been faster if a smaller quantity of diluent was used in the formulations instead.

Figure 2 is a graph that shows the % of drug content released vs. time for the commercial paracetamol formulations. It shows that the Panadol Actifast Tablet has the fastest dissolution rate in 15 minutes at 125% and anadin had the percentage of drug in solution is about 121%, and this was followed by the galpharm at 104%. Additionally, all three formulations managed to released over 100% of the drug content into solution which is not expected. This is could be due to inaccuracy in dilution of medium during course of experiment. From results anadin is just as competitive with Panadol actifast Tablet in terms of the speed at which drug is relesed into solution. The price is significantly higher because the Panadol Actifast Tablets contain more excipients like flavours and sweetening agents improving overall appearance of drug and also more excipients that improve mechanical strength of tablet and also performance of tablet as fast relief of pain.Therefore this suggests that a combination of additional excipients present in Panadol Actifast Tablets enhances its dissolution. Anadin which is very close to panadol in the dissolution profile from experiment results. This is because anadin contains croscamellose, which is a superdisintegrant, i.e. a more effective agent aiding disintegration. It has lesser excipients than panadol hence the lower price. From results percentage of Paracetamol galpharm solution is lower. Initial high percentage at 5 minutes can be due to error in carrying out experiment. Furthermore, Paracetamol galpharm has basic excipients that enhance the tablet to dissolve but no extra excipients to improve the dissolution profile, also its cheaper as there are no sweetening agents and flavours.

From graph 1 and graph 2, it can be seen that for each formulation, the % of drug content released increased with time until all the drug had been completely released, after which it steadily decreased. an increased quantity of drug is released into the solution as the formulation dissolves and time increases. But once all the drug has been released from the formulation the % of drug content decreases as there is lesser drug in solution making it more diluted, due to addition of distilled water at each time the sample is withdrawn from the dissolution apparatus.Comparison between the two reveals that tablets dissolve in solution much faster than capsules, as the tablets release their total quantity of drug present into solution quicker time between (40 -45 minutes). However, in order to carry out a comparison between dosage forms, the same excipients need to be present in both the capsule and the tablet formulation, which is not the case here, and therefore the difference observed could be entirely due to the differences in the excipients present, in particular the presence of pregelatinised maize starch which is a disintegrating agent only present in the tablets.

CONCLUSION

The results obtained enable the conclusion that paracetamol capsules containing the diluent lactose undergoes faster dissolution in comparison to formulations containing starch 1500 and microcrystalline cellulose, where microcrystalline cellulose formulations was the slowest dissolution. Additionally, the commercial paracetamol formulations results enable the conclusion that Panadol Actifast Tablets and anadin undergo faster dissolution with higher percentage of drug released compared to that of galpharm hence are more convenient when fast relief of pain is required. Furthermore, it also enables the conclusion that the more expensive the product the better its quality, as it contains more excipients that could potentially aid the dissolution of the formulation, improve mecahanical strength and flavouring and also appearance of product.

Percentage of drug content released into solution was greater than 100 prior to obtaining a mean value, but this would indicate that more drug is being released into solution than there actually is available to be released. Also an explanation, behind this is that perhaps the actual drug content in the formulation is more than that stated or that there is some other excipient in the formulation that absorbs UV light in the same wavelength range as paracetamol, causing interference in the reading thus giving higher values. A possible way to avoid this problem in future would be to use a more reliable method to assess the concentration.

From the practical it is difficult to conclude whether tablets dissolve in solution faster than capsules, as the excipients present in the formulations weren’t entirely the same. In future this practical could be further improved by formulating capsules containing the same ingredients as a tablet and then testing their dissolution to see whether differences in dosage form influence the dissolution rate. Also the entire procedure in conducting experiment is not reliable as in using the syringe to take out the solution this was not taking out the accurate volumes.

REFERENCES

Aulton’s Pharmaceutics: The Design and Manufacture of Medicines. Third Edition.

Edited by Michael E. Aulton.

Scientific principles of dosage form design, Chapter 2: Dissolution and solubility,.

Dosage form design and manufacture, Chapter 31: Tablets and compaction, page 463.