Drugs Are Released Via The Process Of Diffusion Biology
Drugs are usually incorporated into some type of dosage form from which they have to be released in order to become available for pharmacologic action. In creams and ointments drugs are released via the process of diffusion. This experiment is aimed at providing us with better understanding on the influence of the different structures of creams and ointments on the diffusion rate.
Drug release from creams and ointments is dependent on a number of factors such as: the composition of the vehicle and the concentration of drug incorporated in it, concentration gradient and physical factors such as temperature and viscosity. Other factors such as the presence of air bubbles at the interface between the cream/ointment also have an effect on the diffusion rate.
In this experiment drug release is measured by placing the creams and ointments in contact with an acceptor phase. Sunset yellow is used as the drug and agar gel is used as the acceptor phase. The more soluble the drug is in the cream/ointment the faster it would be released from the cream/ointment into the acceptor phase. We can then measure the amount of drug released into the acceptor phase by measuring the distance diffused by the drug in the agar gel.Method:
Knowledge of manufacturing creams and ointments learnt from the A09 module was applied here to make 15g each of creams and ointments containing 0.4% of sunset yellow.
White soft paraffin, wool fat and polyethylene glycol were made using the fusion method by incorporating 0.4% sunset yellow into the molten base. Aqueous cream BP made with anionic emulsifying wax, aqueous cream made with cetomacrogol (non-ionic) emulsifying wax, and two creams made with different concentrations of white soft paraffin were made by triturating the molten oily phase with the aqueous phase in a drop wise manner.
The creams and ointments were left to cool and then packed into test tubes and Petri dishes containing agar using glass and plastic syringes. The test tubes and Petri dishes were labelled and sealed. The depth of diffusion was then measured at time intervals of 6 hours up to for a total of 48hours.RESULTSDiscussion
Sunset yellow which was used as the drug in this experiment is fairly soluble in water and nearly insoluble in hydrophobic materials. Agar (the acceptor phase) is considered as immobilised water thus sunset yellow will be freely soluble in it. Accumulation of sunset yellow in the agar is dependent on its release from the creams and ointments and the release of sunset yellow from these creams/ointments is dependent on the solubility of sunset yellow in these creams/ointments or in a component of it.
The rate of flow of the diffusing particles is proportional to the concentration gradient were diffusion occurs in the direction of decreasing concentration gradient of the diffusant (sunset yellow).The concentration of the diffusant in the volume element (test tube & Petri dish) changes with time and the number of particles diffusing changes with distance.
Diffusion will only stop when the concentration gradient no longer exists. In order to maintain the concentration gradient ââ‚¬Å“sink conditionsââ‚¬ have to be established were the acceptor phase is constantly removed and replaced with fresh acceptor phase ensuring that the concentration of the drug remains low in the acceptor phase. This was not the case in this experiment so we would say that diffusion stopped when the concentration gradient for sunset yellow no longer existed as sink conditions were not maintained.Graphs for 1-5
An increasing trend was observed for the 5 samples (test tubes and Petri dish) with the depth of diffusion increasing with time.
White Soft Paraffin: this ointment consists of a single phase which is hydrophobic in nature. Sunset yellow is nearly insoluble in hydrophobic materials so we would expect a little of it to dissolve in the white soft paraffin hence a minimal amount of diffusion will be observed. Distance diffused after 42hours was 0.6cm in the test tube and 1.5cm for the Petri dish. The greatest increase in the distance diffused was observed after 24hours.Distance diffused increases wit time.
Wool Fat: is also an ointment and consists of a single phase. Unlike white soft paraffin wool fat is a partially hydrophobic base. We would therefore expect sunset yellow to be more soluble in wool fat compared to white soft paraffin. Data recorded provides us with the values of distance diffused after 42hours to be 1.2cm in the test tube and 0cm in the Petri dish. Distance diffused in the test tube is 2 times higher than that of white soft paraffin in the test tube whereas, for the Petri dish no diffusion was observed which might be due reasons such as presence of air bubbles at the interface or due to the very viscous nature of wool fat.
Polyethylene Glycol: is a hydrophilic base which means that sunset yellow would be more soluble in it compared to wool fat and white soft paraffin. The more soluble the drug is in polyethylene glycol the greater would be the distance diffused. Diffusion in the test tube began almost immediately after addition of the cream to the agar. Distance diffused was 3.4cm in the test tube and 1.8cm in the Petri dish where diffusion was only observed after 6hours. Both values for distance diffused are much higher compared to values for wool fat and white soft paraffin.Aqueous cream BP with Emulsifying (anionic) wax & aqueous cream BP with Cetomacrogol (non-ionic) emulsifying wax
Both creams are o/w emulsions which consists of two phases were the emulsifying agent prevents the disperse phase from coalescing to form a large globule resulting in the disperse phase being present as tiny droplets suspended in the continuous phase (water). Sunset yellow dissolves homogeneously in the continuous phase where it is fairly soluble. Since sunset yellow is soluble in a component of this emulsion it can therefore diffuse freely into the acceptor phase. For aqueous cream made with emulsifying (anionic) wax the distance diffused was 1.9cm for the Petri dish and 2.6 for the test tube. Aqueous cream made with cetomacrogol (non-ionic) emulsifying wax had the distance diffused to be 2.8cm for the Petri dish and 3.3cm for the test tube. There is an obvious difference in the diffusion distance in both creams which is mainly due to the different emulsifying agents used. A reason might be that non-ionic emulsifying agents such as cetomacrogol are not affected by pH whereas anionic emulsifying agents such as emulsifying wax are.Graph for 7&8
7&8 are creams made the same way but with different concentrations of white soft paraffin (63% and 75%). Both consist of two phases. Data collected from other groups was used to plot a graph of distance diffused after 42hours against the various concentrations of white soft paraffin.
Overall a fluctuating trend was observed for both test tube and Petri dish samples. The highest distance diffused for the test tubes was at 67% (4cm) concentration of white soft paraffin and that of the Petri dish was at 63%(1.5cm) and 78% (1.5cm) concentration of white soft paraffin. For both Petri dish and test tube the lowest value for the distance diffused was observed at 81% concentration of white soft paraffin with values of 0cm for the Petri dish and 1.5cm for the test tube. The value of 0cm may be due to phase inversion occurring as the percentage of the disperse phase has exceeded the maximum 74% which ensures the stability of an emulsion.
We expected that as the concentration of white soft paraffin increases the diffusion distance would decrease as the solubility of sunset yellow in the creams will decrease with increasing concentration of white soft paraffin this is because of the increasing concentration of the disperse phase compared to the continuous phase were sunset yellow is more soluble.Fraction of distance diffused against square root of time
The graph shows a positive correlation which proves that the distance diffused is proportional to the square root of time. Data collected obeys the square root law thereby confirming that diffusion of molecules id driven by the random movements of the diffusing particle and also that the drug particles in this experiment exhibit pseudo-1-dimensional random walk as each drug molecule is free to diffuse in 3 dimensions. Fraction of distance diffused is proportional to the square root of time.PROBLEMS
If an experiment to examine the release of a hydrophobic drug from the same creams were to be carried out the acceptor phase needs to be changed to a hydrophobic material as the drug which is hydrophobic will only be able to diffuse into the acceptor phase if it is soluble in it. The results would be almost opposite to those gotten from this experiment. Distance diffused would be greater for ointments such as wool fat and white soft paraffin and least in polyethylene glycol because the more soluble the drug is in the cream/ointment the more it will be released from them.
The optimum range of the concentration of disperse phase in an emulsion is between 30%-60% of the total volume. If the disperse phase the disperse phase is greater than this phase inversion is likely to occur. As the concentration of the disperse phase approaches a maximum of 74% of the total volume phase inversion is likely to occur. This might be a problem for creams 7&8 as the o/w emulsion will change to w/o which would give different results.
Different factors such as temperature and viscosity have an effect on diffusion. Temperature increases the rate of diffusion while viscosity lowers the rate of diffusion. These factors (which were not constant) may give rise to anomalies in our data.
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