Preface

THIS WILL BE PUBLISHED PER CHAPTERS: PART 3/8.

During my final year of my bachelor of pharmacy, I had the joy of doing a project in pharmaceutics on topical corticosteroids. My colleague and I achieved a distinction for this project but we do admit that we can see some mistakes in our project. This project took us 6 months to accomplish and it mainly taught us about research, reading the literature and to attempt at making a pharmaceutics project. This was more of an introduction to a masters degree path and also taught us to work on our own and be supervised with an allocated supervisor. All in all, we learned a great deal and we were thankful for it.

Authors: Andréas L.P. Astier, Priyanka Naidoo

Supervisors: Professor R. Walker, Dr S.M. Khamanga

Location: Pharmaceutics Department, Rhodes University, Grahamstown, 6140, South Africa.

CHAPTER THREE

The Development of Formulations and the Analysis of Clobetasol Propionate in Aqueous Cream

3.1. Introduction

When an active pharmaceutical ingredient (API) is incorporated into a formulation, a rate of release of that API occurs. This is the case with a variety of formulations. Clobetasol and various surfactants that were incorporated into aqueous cream during this experiment followed this concept. The release profile of clobetasol from the aqueous cream after extemporaneous compounding under pharmacy setting conditions was determined. Dissolution using USP apparatus 2 was employed to simulate the conditions in which rate of release occurs and spectrophotometry was used to determine the absorbance and thus a concentration of clobetasol released under these simulated conditions of the body. The textural profile of CBP in aqueous cream was determined for four creams. Spreadability was determined objectively using two glass plates and brass weights as well as subjectively using one’s own powers of determination based on the overall aesthetic appeal of the formulation.

3.2. CBP aqueous cream formulation

The CB aqueous cream was formulated with the following excipients as shown in Table 3.1.

Table 3.1. Excipients used for the formulation studies of CB aqueous cream

3.2.1. Clobetasol propionate (CBP)

Clobetasol propionate is a topically used corticosteroid with glucocorticoid activity (50). It is a white crystalline powder that is practically insoluble in water and sparingly soluble in alcohol. It is also freely soluble in acetone (50). Clobetasol propionate is used to treat various skin disorders and is usually formulated as a cream, ointment, gel, scalp application, shampoo, or foam containing 0.05% (50).

3.2.2. Sodium lauryl sulphate

Sodium lauryl sulphate is an anionic surfactant that is a mixture of sodium alkyl sulphates consisting mainly of sodium dodecyl sulphate (51). It comes in the form of a white or pale yellow powder or crystals that have a characteristic odour (51). It is freely soluble in water (soluble 1 in 10 parts of water) which results in an opalescent solution (51). Sodium lauryl sulphate is also partly soluble in alcohol (51). It is also a detergent and wetting agent and is effective in both acid and alkaline solutions and hard water. Sodium lauryl sulphate is used in shampoos, kinds of toothpaste, skin cleansers and Emulsifying Wax. It may also be used as a tablet lubricant (51).

3.2.3. Cetrimide

Cetrimide is a quaternary ammonium compound (52). It is a white or almost white, voluminous, free-flowing powder that is freely soluble in water and in alcohol (52). Cetrimide in water froths copiously when shaken (52). Cetrimide has typical cationic surfactant actions and uses (52). It dissociates in aqueous solution into a complex cation that results in surface activity (52). It has bactericidal activity against Gram-positive organisms mostly (52). It is most effective in neutral or slightly alkaline solutions whilst acid media reduces its bactericidal activity (52).

3.2.4. Cetomacrogol

Cetomacrogol is a mixture of macrogol cetostearyl ethers (53). It is a white or yellowish-white waxy, unctuous mass, pellets, microbeads or flakes (53). It can solidify between a range of 32 to 52°C (53). Cetomacrogol is a non-ionic surfactant and is used as either for its surfactant and emulsifying properties (53).

3.2.5. Chlorocresol

A white or almost white, crystalline powder or compacted crystalline masses supplied as pellets or colourless or white crystals (54). Melting point is 64 degrees to 67 degrees. Slightly soluble in water; very soluble in alcohol; freely soluble in fatty oils (54). It dissolves in solutions of alkali hydroxides. Protect from light. Incompatible with non-ionic surfactants (54). It is also used as a preservative in cosmetics and in creams and other preparations for external use that contain water (54).

3.2.6. Dovate®

An aqueous cream containing 0.05% of CBP (16). It is white, smooth, non-gritty, and smells appealing. The cream aesthetically correct and is sold on the South African market (16). CBP is a corticosteroid used topically for its glucocorticoid activity in the treatment of various skin disorders (14). It is usually used as a cream, ointment, gel, scalp application, shampoo, or foam containing 0.05% (14).

3.2.7. Aqueous cream

It is white, smooth, non-gritty, and smells appealing. The cream was aesthetically correct. Aqueous cream contains emulsifying ointment 300 g, phenoxyethanol 10 g or chlorocresol 0.1 %, purified water, freshly boiled and cooled sufficiently to produce 1000 g (55, 56). The suitability of the cream for use as a diluent should be confirmed before use (55, 56).

3.3. Formulation development of laboratory-scale of clobetasol aqueous cream

3.3.1. Development of CBP aqueous cream

In Table 3.2 is a list of excipients used for each formulation respectively.

Table 3.2. List of excipients used for each formulation

3.3.2. Method of preparing the CBP aqueous cream

CBP aqueous cream was prepared as follows. The predetermined amount of CBP for each formulation was weighed out using an analytical scale. Next, chlorocresol was weighed out for each formulation using an analytical scale. After this, predetermined amounts of cetrimide, sodium lauryl sulphate and cetomacrogol wax were weighed out separately using an analytical. Commercial aqueous cream was weighed out for formulation one and placed into a container. CBP was added to the aqueous cream. Sodium lauryl sulphate was added next and then chlorocresol was crushed and added in increments. The formulation was then homogenised for ten minutes at the fifth speed using a homogeniser. Formulation two was made next by adding aqueous cream to a container. CBP was added to the container and cetrimide along with crushed chlorocresol was added. Formulation two was then homogenised. For formulation three, aqueous cream was added to a container. Cetomacrogol wax was melted in an evaporating dish over a water bath. Whilst the cetomacrogol melted, CBP was added next to the container. Once the wax was melted, chlorocresol was added and was left to dissolve. The mixture once melted, was added to the third formulation and the formulation was then homogenised. The last formulation was made to serve as a standard for comparison. Aqueous cream was added to a container. CBP was added to the aqueous cream and then four tubes of dovate were squeezed into the container. The formulation was then homogenised.

3.3.3. Amount of excipients in each formulation

Table 3.3. Formulation 1 with the allocated excipients

Table 3.4. Formulation 2 with the allocated excipients

Table 3.5. Formulation 3 with the allocated excipients

Table 3.6. Formulation 4 with the allocated excipients

3.3.4. Formulation challenges

During the manufacture of these formulations, two main challenges were encountered. The first was that the homogenisation of these formulations was not standard despite having used the same parameters for the machine. The reason why the homogenisation cannot be viewed as standard or constant is because the container must be held for each formulation. This adds an element of human error as the container is not held at the exact same height every time and is moved differently with each formulation, therefore, affecting the constancy of homogenisation and thus distribution of excipients. Secondly, the loss of API for formulation four proved to be a challenge as not all cream could be removed from the Dovate® tube and placed into the formulation.

3.3.4.1. Formulation 1

The first formulation was made using CBP, commercial aqueous cream, chlorocresol and sodium lauryl sulphate an anionic surfactant. The resultant formulation had a runny in viscosity, was white and contained a sterile odour.

3.3.4.2. Formulation 2

The second formulation contained the same excipients as formulation one apart from the same surfactant. Formulation 2 contained cetrimide, a cationic surfactant, instead of sodium lauryl sulphate. The resultant formulation was viscous, white and sterile smell.

3.3.4.3. Formulation 3

Formulation 3 was again similar to the above two with all the same excipients apart from the surfactant. The surfactant used for this formulation was cetomacrogol wax. This is a non-ionic surfactant and required melting in an evaporating dish over a hot water bath before being incorporated into the rest of the formulation. The resultant formulation was viscous, white and sterile smell.

3.3.4.4. Formulation 4

The final formulation contained only CBP powder, CBP cream (Dovate®), commercial aqueous cream and chlorocresol. CBP powder was added in order to produce a formulation of 0.1% that was reminiscent of the more potent topical corticosteroids available for treatment guidelines. The resultant formulation was used as a standard for comparison with the other formulation. Formulation four was of high viscosity, higher than the other formulations and was white and sterile smelling.

3.4. Analysis of the aqueous cream formulation

All four creams were analysed in order to determine the rate of release of API and the concentration and amount released. The aesthetic appeal and textural profile of each cream were also analysed using a mix of objective and subjective assessments were used. Dissolution testing was used as a form of in vitro testing. A spectrophotometer was used to determine the absorbance and thus the concentrations of the API released. Objectively, spreadability was also assessed. This was done by placing two grams of a formulation between two glass plates with a brass weight of two grams on top. The visual appearance and skin feel of the formulations were assessed as a form of subjective assessment.

3.4.1. Visual and feel of the textural profile

Consumer preference for semi-solid products depends on various properties of the preparation. This is collectively known as the textural profile, which includes appearance, odour, extrudability, initial sensations upon contact with the skin, spreading properties, tackiness, and residual greasiness after application (57, 58). Over time the semi-solid preparation could have changed in some properties showing instability, for example, is it still aesthetically appealing such as a change in texture, like odour and colour, can show contamination and as such the introduction of a preservative is needed (57, 58). Test to investigate if the viscosity and emoliency overtime still meet the requirements for that particular semi-solid preparation are important. These are critical tests as the patient(s) will have these semi-solid preparations for days or up to months (4, 16, 28, 29). Hence, a semi-solid preparation needs to stay stable and aesthetically appealing until the end of the usage and if it is not, it shows an error in manufacturing, packaging and/or storage of the semi-solid preparation (57, 58).

The resultant formulations were all white and sterile smelling. They were all viscous except for formulation one which was runny and contained many tiny bubbles due to the runniness. The most viscous formulation was formulation four. Viscosity remained more or less constant during the experiment period. All the formulations made were smooth in texture and free from grittiness. None of the formulations displayed any visible microbial contamination over the entire duration of the experiment.

3.4.2. Spreadability

A change in the semi-solid preparation over time could indicate a change of the rheological properties such as the viscosity, elasticity, thixotropy, and flowability which had been affected in some way within the semi-solid preparation (59). This would insinuate instability characteristics of the semi-solid preparation due to the compound(s) changing, and hence the interaction within the semi-solid preparation is also changing from the normal and original interactions (59). These instabilities will influence the patient’s perception of the semi-solid preparation which may be negative.

Published 2nd August 2019. Last reviewed 30th December 2021.

Reference

4. Division of Clinical Pharmacology Faculty of Health Sciences, 2014. South African Medicines Formulary, 11th Ed., Cape Town, South Africa.

14. Martindale: The Complete Drug Reference, 2016. Clobetasol Propionate. [Online] Available at: https://0-www.medicinescomplete.com.wam.seals.ac.za/mc/martindale/current/1069-x.htm?q=clobetasol&t=search&ss=text&tot=389&p=1#m1069-a3-v [Accessed 21st September].

16. Division of Clinical Pharmacology Faculty of Health Sciences, 2016. South African Medicines Formulary, 12th Ed., Cape Town, South Africa.

28. WebMed, 2016. Clobetasol Topical. [Online] Available at: http://www.webmd.com/drugs/2/drug-4403-723/clobetasol-topical/clobetasol---topical/details [Accessed 21st September].

29. Drugs, 2016. Clobetasol Cream. [Online] Available at: https://www.drugs.com/pro/clobetasol-cream.html [Accessed 21st September].

50. Martindale: The complete drug reference, 2016. Clobetasol. [Online] Available at: https://www.medicinescomplete.com/mc/martindale/current/1069-x.htm?q=clobetasol&t=search&ss=text&tot=389&p=1#_hit [Accessed 25th September].

51. Martindale: The complete drug reference, 2016. Sodium lauryl sulphate. [Online] Available at: https://www.medicinescomplete.com/mc/martindale/current/6024-n.htm?q=sodium%20lauryl%20sulphate&t=search&ss=text&tot=123&p=1#_hit [Accessed 25th September].

52. Martindale: The complete drug reference, 2016. Cetrimide. [Online] Available at: https://www.medicinescomplete.com/mc/martindale/current/2216-d.htm?q=cetrimide&t=search&ss=text&tot=315&p=1#_hit [Accessed 25th September].

53. Martindale: The complete drug reference, 2016. Cetomacrogol. [Online] Available at: https://www.medicinescomplete.com/mc/martindale/current/ms-10485-r.htm?q=cetomacrogol&t=search&ss=text&tot=10&p=1#_hit [Accessed 25th September].

54. Martindale: The Complete Drug Reference, 2016. Chlorocresol. [Online] Available at: https://0-www.medicinescomplete.com.wam.seals.ac.za/mc/martindale/current/2226-h.htm?q=chlorocresol&t=search&ss=text&tot=55&p=1#_hit [Accessed 22nd September].

55. Martindale: The Complete Drug Reference, 2016. Chlorocresol. [Online] Available at: https://0-www.medicinescomplete.com.wam.seals.ac.za/mc/martindale/current/999901-n2660-j.htm?q=simple%20cream&t=search&ss=text&tot=33&p=1#_hit [Accessed 22nd September].

56. British Pharmacopoeia, 2016. Aqueous cream. [Online] Available at: https://www.pharmacopoeia.com/bp-2016/formulated-specific/aqueous-cream.html?date=2016-07-01&text=aqueous+cream [Accessed 22nd September].

57. Barry, B., Grace, J. Sensory Testing of Spreadability: Investigation of Rheological Conditions Operative During Application of Topical Preparations. Journal of Pharmaceutical Science, 61 (1972) 335-34.

58. Vennat, B., Gross, D., Pourrat, A. Procyanidin Gels Based on Cellulose and Carrageenan Derivatives. Drug Development and Industrial Pharmacy, 18 (1992) 1535-1548.

59. Pharmtech, 2016. Pharmaceutical Technology. [Online] Available at: http://images.alfresco.advanstar.com/alfresco_images/pharma/2014/08/22/c0e3f1152d30-47c3-8a80-c478037fd1cf/article-30365.pdf [Accessed 27th September].