Pharmaceutical Technology Group A: SUPPOSITORY

Objectives:

To study the effect of different composition of base on the physical characteristic of suppositories.

Introductions:

Suppositories are designed for anal administration and usually consist of the active drug and a base which is designed to melt at room temperature. Once the suppository has been rectally administered the base will then break down and the drug will be released. Good bases are not toxic, no irritation, will not interact with other drugs and also easy to be mould into a suppository. Different composition on base will affect the rate and limit of release of the drug from the suppository.The formulation and design is no more complex than this.Most suppositories are prescribed for local effects. The anal route however provides an excellent route for drug absorption and therefore can be used in patients with swallowing difficulties or for drugs where avoidance of first past effect is preferable. For this reason it is important to check the bioavailability of a suppository compared to a tablet when swapping between the two. In this experiment, the effects of the different base composition to the suppository physical characteristics and also to the drug release characteristics are evaluated.

Apparatus:

Electronic balance, Weighing boat, Spatula, 50 ml beaker, 100 ml beaker, Hotplate, 5 ml measuring cylinder, Suppository mould, Water bath (37 °C), Slape, Mortar and pestle, Dialysis bag (10cm), Threads, Glass rod , 5 ml Pipette and pipette bulb, Plastic Cuvettes, UV/Vis spectrophotometer.

Materials:

Polyethylene glycol (PEG) 1000, Polyethylene glycol (PEG) 6000, Paracetamol

Procedure:

1. Saturated Paracetamol stock (10g in 5 ml distilled water) water was prepared.

2. 10g Paracetamol suppository was prepared using following formula:

Suppository	Group	Ingredient (g)		Paracetamol stock	Total amount (g)
Suppository	Group	PEG 1000	PEG 6000	Paracetamol stock	Total amount (g)
I	1,5	9	0	1	10
II	2,6	6	3	1	10
III	3,7	3	6	1	10
IV	4,8	0	9	1	10

3. Suppository mould was used to produce suppository shape. The textures, shape and colour were described and differentiate.

4. One suppository produced was placed into the beaker that contained distilled water (10ml, 37°C) and the time for suppository to dissolve was recorded.

5. Next, one suppository was placed into the dialysis bag and the end of the bag was tightly tied. The dialysis bag was then put into beaker that contains 50 ml distilled water at 37°C.

6. At the interval of 5 minutes, 3ml of sample was pipette and the release of paracetamol from suppository was determined using UV visible spectrometer. The distilled water was stirred first before the sample was taken.

Time (min)	UV absorption
Time (min)	0	5	10	15	20	25	30	35	40	45	50	55	60
UV absorption at 310nm

Results:

Result 1

Suppository	Shape	Teksture	Color
I	Torpedo	Smooth, hard, oily	Even white
I	Torpedo	Smooth, hard, oily	Even white
II	Torpedo	Smooth, hard	Even white
II	Torpedo	Smooth, hard	Even white
III	Torpedo	Smooth, hard	Uneven white
III	Torpedo	Smooth, hard, sticky	Milky white
IV	Torpedo	Smooth, hard, oily	Uneven white
IV	Torpedo	Smooth, hard	Uneven white

Result 2

PEG 6000 content (g)	Time taken for the suppository to completely melt (min)		Average (min) (x ± SD)
PEG 6000 content (g)	I	II	Average (min) (x ± SD)
0	31	54	42.5 ± 16.26
3	27	27	27.0 ± 0.00
6	40	50	45.0 ± 7.07
9	73	65	69.0 ± 5.66

Result 3

Time (min)		Average UV absorption at 520 nm (x ± SD)
Time (min)		0	5	10	15	20	25	30	35	40	45	50	55	60
Suppository	I	0.015	0.028	0.073	0.032	0.033	0.018	0.021	0.022	0.024	0.023	0.026	0.092	0.035
	I	0.015	0.038	0.089	0.093	0.118	0.101	0.107	0.141	0.125	0.100	0.136	0.118
	Average	0.015	0.033	0.081	0.063	0.076	0.060	0.064	0.082	0.075	0.062	0.081	0.105
	SD	0.000	0.007	0.011	0.043	0.060	0.059	0.061	0.084	0.071	0.054	0.078	0.018
	II		0.088	0.028	0.020	0.100	0.069	0.048	0.094	0.089	0.096	0.127	0.115	0.103
	II		0.206	0.133	0.132	0.053	0.048	0.048	0.047	0.042	0.118	0.048	0.054
	Average		0.147	0.081	0.076	0.077	0.059	0.048	0.071	0.066	0.107	0.088	0.085
	SD		0.083	0.074	0.079	0.033	0.015	0.000	0.033	0.033	0.016	0.056	0.043
	III	0.064	0.071	0.087	0.098	0.101	0.111	0.115	0.119	0.121	0.111	0.125
	III	0.014	0.017	0.019	0.022	0.024	0.028	0.028	0.028	0.030	0.034	0.034	0.036	0.038
	Average	0.039	0.044	0.053	0.060	0.063	0.070	0.072	0.074	0.076	0.073	0.080
	SD	0.035	0.038	0.048	0.054	0.054	0.059	0.062	0.064	0.064	0.054	0.064
	IV	0.003	0.010	0.014	0.018	0.019	0.019	0.021	0.024	0.026	0.026	0.024	0.028	0.026
	IV	0.017	0.021	0.037	0.047	0.049	0.053	0.057	0.059	0.059	0.063	0.065	0.070	0.072
	Average	0.010	0.016	0.026	0.033	0.034	0.036	0.039	0.042	0.043	0.045	0.045	0.049	0.049
	SD	0.010	0.008	0.016	0.021	0.021	0.024	0.025	0.025	0.023	0.026	0.029	0.030	0.033

Question and Discussion

1. Compare the physical appearance of the suppositories and give explanation.

Suppository	Shape	Teksture	Color
I	Torpedo	Smooth, hard, oily	Even white
I	Torpedo	Smooth, hard, oily	Even white
II	Torpedo	Smooth, hard	Even white
II	Torpedo	Smooth, hard	Even white
III	Torpedo	Smooth, hard	Uneven white
III	Torpedo	Smooth, hard, sticky	Milky white
IV	Torpedo	Smooth, hard, oily	Uneven white
IV	Torpedo	Smooth, hard	Uneven white

Based on the result above, we can observe that the ratio between PEG 1000 and PEG 6000 can determine the physical properties of suppositories. As the content of PEG 1000 is increased, the suppositories produced are more oily, sticky and soft. This is because PEG 1000 is more hydrophobic compare to PEG 6000.

While, as the content of PEG 6000 is increased, the suppository produced are more solid and non-sticky. This could be explained as the physicochemical characters of PEG 6000 forms more strong and stable hydrogen bonds in the suppository compared to PEG 1000. PEG 6000 is higher molecular weight compare to PEG 1000. Thus, it also has a lot of hydroxyl groups which can form numerous hydrogen bonds between the molecules of the PEG 6000 and the molecules of Paracetamol. Hence, we could see an increase in the hardness of the suppositories in line with the increasing amount of PEG 6000.

Besides that, from suppository I to IV, the formulation reduced in PEG 1000 and increased in PEG 6000 content which causes the color change from clear, even white to opaque, uneven white. Suppository formed by higher amount of lower molecular weight polyethylene glycol is more transparent and is more lustrous in nature. Due to higher amount of PEG 6000 being used, suppositories formed will appear in white color. This is shown in Suppository II, III and IV.

As the mould made for suppositories is bullet shaped, thus all four suppositories produced are bullet shaped. This torpedo shape is suitable for a suppository according to its route of administration. As a conclusion, we must specify the amount of PEG 1000 and PEG 6000 to produce an ideal suppository. The ideal suppositories are melt in body temperature, not too stick or too rough, and balance in hardness and smoothness.

2. Plot a graph of the average time taken for the suppository to melt against the amount of PEG 6000 used in the formulation. Compare and discuss the results obtained.

PEG 6000 content (g)	0	3	6	9
Average (min) (x ± SD)	42.5 ± 16.26	27.0 ± 0.00	45.0 ± 7.07	69.0 ± 5.66

Based on the graph, the average melting point of suppository at body temperature 37C is increases as the content of PEG 6000 increases from 3g to 6g of PEG 6000 content. This is true according to the theory where it state that the melting point of suppository is proportional to their molecular weights which dominant to PEG 6000.

Therefore, increase amount of PEG 6000 used will increase melting point as well as time taken for formulation to melt. Besides that, the amount of PEG 1000 also plays a role. This is because the melting point of PEG 1000 is about 37-40 °C which is close to human body temperature; 37.5 °C, thus it will easily melt once inserted into rectum. Hence, theoretically increased amount of PEG 1000 in the formulation will decreased the melting point of suppository until the temperature around body temperature.

However, at 0g of PEG 6000 content, the melting point is slightly higher than 3g of PEG content, thus the graph starts with decreasing slop from 0g to 3g and then, increase proportionally from 3g to 9g of PEG 6000 content. The higher melting point of 0g compared to 3g might be due to impurities in the formulation or errors occurred during the experiment.

The errors can occur during measuring, and transferring of the ingredient during making of suppository. Besides that, possibility of suppository does not solid enough when we taken out from the refrigerator as the unsolidified suppository made it easier to be dissolved in water bath. The heating process using water bath also may produce this result. Some of the group might stir the beaker containing suppository which make it faster to dissolve. Lastly, the possible errors are wrongly observe the finish melting time of the suppository, dialysis beg did not seal tightly and wrongly watch the time.

3. Plot a graph of UV absorption against time. Give reasons.

In this experiment, suppository was put inside a dialysis bag then immersed into a beaker containing distilled water with temperature maintained at 37⁰C which is similar to our body temperature. This is to determine the absorption rate of drug in our body after administration of suppository via rectum route. The release of the drugs from the suppository involved the diffusion mechanism. The UV spectrometer measures the release of paracetamol from the suppository in the dialysis bag to the distilled water. The graph above showed the change of UV absorption with the amount of Paracetamol released into distilled water as the time passed. From the graph of UV absorption against time, the extent of drug release was assessed from the total amount of drug present in the dissolution medium for every 5 minutes interval. At time=0, UV absorption observed was 0.01. With increasing of time, UV absorption also increased. This showed that the amount of drug released was increased too. Hence, there is a direct proportional relationship between time and drug release. As the experiment proceeded, the content in the dialysis bag tended to become isotonic to the distilled water as amount of paracetamol was reduced after moving to the distilled water. This resulted in the reduced gradient of the graph when time passesd by. If the experiment is continued beyond 60 minutes, it may result in a straight line graph as the concentration of paracetamol in the distilled water equals to the concentration of paracetamol at the dialysis bag.

4. Plot graph of UV absorption against time for the suppository formulation with different compositions. Discuss and compare the results.

In the experiment, dialysis tube had been use to determine the ability of the paracetamol of suppository to pass through the membrane and enter into the water. The amount of the sample that passed through the dialysis tube is measured by using the ultraviolet spectrophotometry. Dialysis tube indicates the human’s biological barrier. Based on the results, we can see that UV absorption at 520 nm is increasing with time for each of the suppositories. Increasing in UV absorption indicates that there is increasing in the numbers of particle of the suppositories diffuse through the dialysis tube membrane.

From the graph above, the value that has been obtained is not accurate because in this experiment, the suppository I which has highest drug release (given as the UV absorption) release the drug in a fluctuation trend. Suppository I should be the highest among the four suppositories since it has the highest amount of the PEG 1000. The UV absorption will increase with time until it reaches a plateau stage where the entire drug has been released. Suppository II shows the higher rate of drug release than suppository III as it has higher composition of PEG 1000 and lower amount of PEG 6000 that slow the release rate of drug. This obeys to the theory.

Water solubility of the drug suppository increases as the molecular weights of PEG decrease due to the water absorbing properties of PEG. Thus, the highest rate of release is expected for suppository I due to the lowest proportion or amount of PEG 6000 in the formulation In theory, the hardness of the polyethylene glycol will increase with increasing molecular weight. So, as the suppository becomes harder, it should required longer time to dissolve the drug and passing through the dialysis tube membrane. Polyethylene glycol with molecular weight from 600 to 1000 is presence in the semisolid form and molecular weight higher than 1000 is wax-like form. Therefore, suppository I should has the highest UV absorption.

High proportion of high polyethylene glycol produce suppository which release drug slowly and also brittle. Suppository IV has the highest proportion of PEG 6000 which will produce the hard suppository that difficult to dissolve. Higher contents of PEG 6000 will give the slowest releasing rate of drug due to the strong hydrogen bond among molecules PEG 6000 with molecules Paracetamol. It released the drug slowest. The result of the experiment can be considered same as the theory. In order to prepare less brittle suppository with release drug more readily, high molecular weight should be mixing with medium or low molecular weight of polyethylene glycol.

Since PEG is nonionic substances, they are quite soluble in hard water or in other aqueous solution of various salts. Suppositories can be formulated with much higher melting point to be melting at body temperature and dissolve in body fluids. Graph become not accurate may be because of the error that has been done during the experiment. May be error occur in taking sample by pipette to measure dispersion of paracetamol using spectrometer UV-visible.

5. What is the function of each ingredient that is used in the preparation of these suppositories? How does the usage of different content of PEG 1000 and PEG 6000 affect the physical properties of suppository formulation and rate of releasing of drug from it?

Paracetamol is active ingredient in the suppositories. Paracetamol is used as analgesic and antipyretic. It appears as white, odourless and light powder. PEG 1000 and PEG 6000 are the bases for the active ingredient, paracetamol of the suppository. They allow a smoother drug delivery of the suppository into the rectal. They also allow the absorption of paracetamol by the membrane to occur. A suitable combination of PEG allows an optimum drug releasing to occur, in which the drug will not be held strongly in the base and can be easily released. This is important to allow an optimum drug bioavailability to take place as the drug can be absorbed by mucosa membrane of the rectal.

The different amount of PEG 1000 and PEG 6000 used can influence the physical characteristic and the release rate of drug from suppository base. Higher amount of PEG 6000 increase hardness of suppository formed due to stronger hydrogen bond formed between molecules. Due to this strong hydrogen bonding, the drug release rate will be lowered. Using higher amount of PEG 1000 will result in softer suppository. This is due to weaker hydrogen bond formed between the molecules. Lipophilicity of PEG 1000 is higher, thus result in greasier suppository. Drug release will be faster because the bond formed is weaker.

Different characteristic of suppositories can be formed by varying amount and molecular weight of PEG used. Therefore by varying the combinations of PEG, we can obtain desired consistency and characteristic of suppositories. A balance of lipophilicity and hydrophilicity of suppository base can be achieved by this combination. Thus, bases that fulfill desired characteristics can be used in formulation and this will lead desired rate release of drug from the suppository base.

Conclusion:

The different amount of combination of PEG 1000 and PEG 6000 in the suppository preparation affects the physical characteristics e.g. greasiness texture, and shape of the suppository as well as the rate of release of the active ingredient.

Appendix

PEG 6000 is heated until molten mixture is formed.