Pharmaceutical Technology II [NFNF2263] : The Effect of Different Contents on the Characteristics of a Suppository Formulation

Objectives :

1. To investigate the effect of various base composition on the physical characteristics of the suppository formed.

2. To investigate the effect of various base composition on the release of drugs from the suppository.

Introduction :

Suppository is a solid dosage form meant to be inserted into body cavities such as rectum, vagina and urethra. It comes in various sizes and shapes which will either melt on mucous layer or dissolve in rectal fluid to release the drugs and produce their local or systemic effect. The suppository is usually about 32 mm long, cylindrical, and 1 or both end tapered.

The drugs will be incorporated into a base. The type and composition of base used in the formulation will determine the release of drugs from suppository. The suppository bases must be capable of melting, softening or dissolving to release drugs at body temperature. A good base should also give no interaction with the drugs and additives, physically and chemically stable, non-irritant, easy to form and permit removal from mould, and has good drug release profile. They should remain solid at room temperature and have small melting range to give rapid solidification during preparation.

Example of bases are cocoa butter, glycerinated gelatin and polyethylene glycol (PEG). PEG is a polymer of ethylene oxide and water prepared to various chain lengths, molecular weight and physical state. PEG with range of weight of 300, 400, 600 will form clear colourless liquid while >1000 will form wax-like white solids. Different base composition influence the physical characteristics of the suppository and the rate and limit of the release of drug from the suppository.

Apparatus :

Analytical balance
Weighing boats
50ml and 100ml beakers
5ml pipette and pipette bulb
5ml measuring cylinder
Spatula
Glass rod
Hotplate
Suppository mould set
Thread
Dialysis bag
Water bath 37^oC
Plastic cuvette
UV spectrophotometer

Materials :

Polyethylene glycol (PEG) 1000
Polyethylene glycol (PEG) 6000
Paracetamol stock
Distilled water
Liquid paraffin

Procedures :

Paracetamol saturated stock solution is prepared by adding 10g of Paracetamol in 5ml of distilled water.
10g suppository is prepared by using the formulation below:

Suppository	PEG 1000 (g)	PEG 6000 (g)	Paracetamol stock solution (g)	Total (g)
I	9	0	1	10
II	6	3	1	10
III	3	6	1	10
IV	0	9	1	10

3. The suppository is formed using the suppository-mould. The shape, texture and color of the suppository is observed, described and compared.

4. One suppository is placed in a beaker contained 10 ml of distilled water at 37^oC and the time required for the suppository to melt is recorded.

5. One suppository is placed inside a dialysis bag with both end tied tightly. The bag is then placed in a 100ml beaker contained 50ml of distilled water which the beaker is later placed in the water bath at 37^oC.

6. The sample is pipetted at 5 minutes interval and the release of the Paracetamol from the suppository is determined using the spectrometer UV-visible. The distilled water must be stirred first before the sample is taken.

Results :

Group	Paracetamol Stock Solution (ml)	Substance (g)		Physical appearances
Group	Paracetamol Stock Solution (ml)	PEG 1000	PEG 6000	Shape	Texture	Hardness	Colour
I	1	9	0	Bullet-shaped	Very greasy and least shining	Soft	Chalky white
II	1	6	3	Bullet-shaped	Greasy and slightly shining	Slightly hard	White
III	1	3	6	Bullet-shaped	Slightly greasy and shining	Hard	Colourless white
IV	1	0	9	Bullet-shaped	Least greasy and very shining	Very Hard	Colourless white

Amount of PEG 6000	0		3		6		9
Groups	1	5	2	6	3	7	4	8
Time (min)	31	54	27	27	40	50	73	65

Amount of PEG 6000 (g)	0	3	6	9
Average of time (min) (¯x ± SD)	42.5 ± 11.5	27.0 ± 0	45.0 ± 5.0	69.0 ± 4.0

Time (minutes)	UV Absorption
Time (minutes)	0	5	10	15	20	25	30	35	40	45	50	55	60
UV Absorption at 520 nm	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

Time (min)		Average of the UV absorption at 520nm (x ± SD)
Time (min)		0	5	10	15	20	25
Suppository	I	0.015 ± 0	0.031 ± 0.003	0.081 ± 0.008	0.063 ± 0.031	0.076 ± 0.043	0.060 ± 0.042
	II	0.021 ± 0.006	0.147 ± 0.059	0.081 ± 0.053	0.167 ± 0.035	0.077 ± 0.024	0.059 ± 0.011
	III	0.039 ± 0.025	0.017 ± 0	0.053 ± 0.034	0.057 ± 0.035	0.061 ± 0.037	0.065 ± 0.037
	IV	0.010 ± 0.007	0.016 ± 0.006	0.026 ± 0.012	0.033 ± 0.015	0.034 ± 0.015	0.036 ± 0.017

Time (min)		Average of the UV absorption at 520nm (x ± SD)
Time (min)		30	35	40	45	50	55	60
Suppository	I	0.064 ± 0.043	0.082 ± 0.060	0.075 ± 0.051	0.062 ± 0.039	0.081 ± 0.055	0.100 ± 0.018	0.035 ± 0
	II	0.048 ± 0	0.071 ± 0.024	0.066 ± 0.024	0.107 ± 0.011	0.088 ± 0.040	0.085 ± 0.031	0.077 ± 0.027
	III	0.070 ± 0.042	0.072 ± 0.044	0.075 ± 0.045	0.078 ± 0.044	0.073 ± 0.039	0.072 ± 0.036	0.082 ± 0.044
	IV	0.039 ± 0.018	0.042 ± 0.018	0.043 ± 0.017	0.045 ± 0.019	0.045 ± 0.021	0.049 ± 0.021	0.050 ± 0.024

Discussion :

1. Compare and discuss the physical appearance of the suppository formed.

Based on the results, we found that different groups have produced different physical characteristics of suppositories. This is due to the different composition of PEG 1000 and PEG 6000 in the formulation of the suppository. PEG is a suppository base that is soluble in water. It can retain drug and affect the rate of release of drug. PEG 1000 is less hydrophilic compare to PEG 6000 because PEG 6000 contain of more hydroxyl group (-OH).

When the amount of the PEG 6000 used increases, the hardness of the suppositories formed will also increase from Suppository I to IV. Thus, Suppository I is the softest while Suppository IV is the hardest. This is because there is more hydrogen bonding formed in this suppository. PEG 6000 also increases the clarity of the suppository. Suppository I is in chalky colour, Suppository II is white colour while Suppository III and IV are colourless white.

Besides that, Suppository I to IV has decreasing waxy properties due to the decreasing of the composition of PEG 1000. PEG 1000 is less hydrophilic and has more lipophilic property. Therefore, suppository with the high content of PEG 1000 composition will make the suppository more greasy as like the Suppository I, while for Suppository IV, it is less greasy due to the absent of the PEG 1000.

2. Plot a graph of time needed to melt the suppository against the quantity of PEG 6000 in the formulation. Compare and discuss the result.

From the graph, we can see that the highest amount of PEG 6000 which is 9g need the longest time to melt the suppository which is 69 minutes. This result comply with the theory. Basically, PEG 6000 has high molecular weight, which will influences the solubility of suppository in water. Increasing the amount of PEG 6000 will make the suppository more solid and thus, the rate of drug release will slow down and the time taken for the suppository to melt will increase. However, for suppository that contain 0 g and 3 g, the results show a decrease in average time needed to melt the suppository. This maybe due to the presence of PEG 1000 which influence the rate of drug release. Other than that, there are some errors occur during conducting the experiment. First of all, the incorrect measurement and transmission of ingredients during making the suppository, which can lead the result obtained is inaccurate. The suppository also may be does not solid enough when taking out from the refrigerator. This will cause the suppository to dissolve rapidly in water. Besides that, the error also occurs during the process of drug release, where the water bath temperature is not constant. This will affect the time taken for suppository to melt. There is also high possibility that during process of drug release, the beaker contained suppository was stirred which cause the suppository to melt faster.

3. Plot the graph of UV absorption against time (Procedure 6). Give your comments.

In this experiment, a drug containing paracetamol in suppository dosage form was insert into a dialysis bag and immersed in water bath, 37ºC. In real life, the dialysis bag act as the membrane in the rectum and the distilled water in the beaker act as human blood plasma. As the body temperature is 37ºC, the water bath was fixed at 37ºC to give the real body environment to the suppository. The suppository melted in the dialysis bag and the concentration of paracetamol in the dialysis bag higher. Since the paracetamol concentration in distilled water in the beaker is lower than the distilled water in the dialysis bag, the paracetamol was move out from the dialysis bag into the beaker. The aim for this experiment is to study the release rate of the paracetamol in different amount of PEG 6000. PEG 6000 act as solubilizer. Thus, higher PEG 6000 amount supposedly increase the release rate of paracetamol. Theoretically, the graph should be in sigmoid shape as the drug release rate is directly proportional until the equilibrium is achieved. Then, the release rate will be constant. Generally, the release rate of the suppository is directly proportional to the time.

According to the graph, the result shows that the amount of the paracetamol still not achieved the equilibrium as the drug constantly release from the suppository. Thus, the graph should be in form of linear increasing line. Referring to the graph, from 0 – 20 minutes, the amount of the paracetamol release is directly proportional to the time. Then, at from 20 – 25 minutes, the release of paracetamol is higher than before but then for the next 10 minutes, the graph shows that no addition in the UV absorption. The sudden increase of the release rate is due to the higher amount of the paracetamol at the wall of the suppository. Then, for the next 10 minutes, no addition of UV absorption is due to the absent of the paracetamol at the wall of the suppository. The same phenomenon also occur at 40 – 50 minutes. This phenomenon maybe due to the human error when stirring the formulation before pouring into the suppository mould or due to the student is not stirring the distilled water in the beaker during taking the sample. As the time goes on, the UV absorption for paracetamol is back to normal.

The inconsistent release rate of the paracetamol that lead to deviation in the result can be causes by several factors. The errors can be due to human or apparatus errors. In human errors, the error possibly occur during stirring the formulation before poured into the mould, not stirring when to take the sample for UV absorption test, or taking the sample is not accurately 5 minutes. For the apparatus errors can be due to the inconsistent temperature in the water bath as the lit of the water bath container was lifted frequently during taking the sample or the changes in the volume of distilled water in the beaker as the water bath accidently entered the beaker when the water bath was disturbed.

4. Plot a graph of UV absorption vs. time for other suppositories that have different formulation. Compare and discuss the results.

Theoretically, the graph should be in sigmoid shape as the drug release rate is directly proportional until the equilibrium is achieved. Then, the release rate will be constant. Suppository may initially dissolve slowly and paracetamol diffuse from the dialysis bag into water in beaker. Thus, the paracetamol concentration in water will be increased by time until all paracetamol are released and become saturated in water, then the paracetamol concentration will be constant. Generally, the release rate of the suppository is directly proportional to the time.

By referring to the graph above, the graph is not in sigmoid curve. There is some fluctuation and constant values in the result. For the formulation 1 and 2, the result shows that the UV absorption values is fluctuate from start until the end of the experiment. For formulation 3, the UV absorption values is increasing constantly except for the first and the last 15 minutes during the experiment. For formulation 4, the result shows the steady increase of the UV absorption except at certain time that the UV absorption is not change.

The result also shows that formulation 2 has the highest peak followed by formulations 1, 3 and 4. It means, the formulation 2 has the highest release rate of paracetamol followed by formulations 1, 3 and 4.

The main ingredient in the formulations that control the release of the paracetamol is PEG 6000. PEG 6000 acts as drug release enhancer. From the Journal of Applied Pharmaceutical Science, it is stated that “When PEG-6000 was used as a channeling agent in this formulation, drug release was increased accordingly but higher concentration of PEG-6000 results in decreasing release rate of drug because of increasing viscosity of the matrix channels”. It means that the PEG 6000 will acts as drug release enhancer in specific amount only. If the PEG 6000 amount is more than enough, it will not enhance the release of drug but will decrease the drug release rate by increasing the matrix viscosity. Ideal formulation for suppository to have the highest drug release rate is by using 60% PEG 6000 and 40% PEG 1000. In this experiment, formulation 3 has the ideal formulation for PEG 6000. In formulation 3, 33.3% PEG 1000 and 66.7% PEG 6000 were used.

Supposedly, formulation 3 will has the highest peak instead of formulation 2. But, the formulation 2 shows the highest peak followed by formulation 1. This is due to the experimental errors. Since the formulation 1 does not contain any PEG 6000, it suppose has the lowest release rate. This also cause by the experimental errors.

Although formulation 4 has the highest percentage of PEG 6000, it does not show the highest drug release rate. This is because too much PEG 6000 will cause the formation hydrogen bond between PEG and paracetamol. It requires the longer time to reach the highest value of drug release, as the suppository is the hardest. As a result, the drug release rate decreases.

Fluctuations and inaccuracy of the results are obtained from the experiment. This is because some errors may have occurred in the experiment especially during compounding of suppositories. Paracetamol powder may be not distributed evenly in the suppository formed. This can lead to uneven release of paracetamol from the formulation. Uneven stirring process before the content of the mixture was pipetted also can contribute to the inaccuracy of the results. Besides, the impurity present in the suppositories prepared also can contribute to inaccuracy of the results.

5. What are the functions of each of the chemicals used in the preparation of suppository? How was the used of different composition of PEG1000 and PEG6000 affected the physical characteristics of the suppository and the drug release rate from the suppository?

There are three chemicals used in the preparation of suppository which are paracetamol, polyethylene glycol (PEG) 1000 and polyethylene glycol (PEG) 6000. Paracetamol is an antipyretic and analgesic drug, which acts as active ingredient of the medication. It is used to treat fever, minor pain, and also for the relief of headache. PEG 1000 and PEG 6000 are water soluble suppository base that enable the suppository to dissolve in rectal solution. They are used as laxative for short term relief of constipation and also for bowel irrigation before surgery. PEG 1000 and PEG 6000 have different molecular weight. PEG 1000 has smaller molecular weight compared to PEG 6000. The lower the molecular weight of PEG, the higher the hydrophilicity of suppository base. This means the suppository with high proportion of PEG 1000 will dissolve rapidly in water. Meanwhile the suppository with high proportion of PEG 6000 will dissolve slowly in water. Since the drug release rate depends on the hydrophilicity of the suppository base, suppository with high amount of PEG 1000 will increase the rate of drug release from dialysis bag compared to suppository with high amount of PEG 6000.

Conclusion :

Based on the results obtained, different groups have produced different physical characteristics of suppositories. This is due to the different composition of PEG 1000 and PEG 6000 in the formulation of the suppository.

From the graph of time needed for suppository to melt versus amount of PEG 6000, we can see that the highest amount of PEG 6000 which is 9g need the longest time to melt the suppository which is 69 minutes. Increasing the amount of PEG 6000 will make the suppository more solid and thus, the rate of drug release will slow down and the time taken for the suppository to melt will increase.

From the graph of UV absorption against time. Referring to the graph, from 0 – 20 minutes, the amount of the paracetamol release is directly proportional to the time. Then, at from 20 – 25 minutes, the release of paracetamol is higher than before but then for the next 10 minutes, the graph shows that no addition in the UV absorption. The sudden increase of the release rate is due to the higher amount of the paracetamol at the wall of the suppository. Then, for the next 10 minutes, no addition of UV absorption is due to the absent of the paracetamol at the wall of the suppository. The same phenomenon also occur at 40 – 50 minutes. This phenomenon maybe due to the human error.

Next graph is a graph of UV absorption vs. time for other suppositories that have different formulation. By referring to the graph above, the graph is not in sigmoid curve. The result also shows that formulation 2 has the highest peak followed by formulations 1, 3 and 4. It means, the formulation 2 has the highest release rate of paracetamol followed by formulations 1, 3 and 4.

References :

Physicochemical Properties of Pharmacy, Florence & Attwood, 3^rd Edition.
Pharmaceutics, The Science of Dosage Form Design, Mecheal Aulton, 3^rd Edition.
http://www.clariant.com/C125720D002B963C/picklist/C0EB1376B40AC1C9C125726500432C94/$file/Polyethylene_glycols_%28PEGs%29_and_the_pharmaceutical_industry.pdf