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ORIGINAL ARTICLE
Year : 2018  |  Volume : 6  |  Issue : 2  |  Page : 72-76

Stability testing of extemporaneous preparation of methyl salicylate ointment


1 Pharmacy Practice Research Unit, Department of Clinical Pharmacy, College of Pharmacy, Jazan University, Jazan, Kingdom of Saudi Arabia
2 Department of Pharmaceutics, College of Pharmacy, Jazan University, Jazan, Kingdom of Saudi Arabia
3 Department of Pharmaceutical Chemistry, College of Pharmacy, Jazan University, Jazan, Kingdom of Saudi Arabia
4 Pharmacy Department, King Fahad Central Hospital, Jazan, Kingdom of Saudi Arabia

Date of Web Publication2-Apr-2018

Correspondence Address:
Dr. H A Makeen
College of Pharmacy, Jazan University, P.O. Box 114, Jazan 45142
Kingdom of Saudi Arabia
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DOI: 10.4103/jhs.JHS_14_18

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  Abstract 


Background: Pharmacist in community pharmacy, hospital or nursing home may be left with only option of preparing extemporaneous formulation using traditional compounding techniques when none of the available commercial dosage forms is appropriate to meet the special needs of some special patients. It is essential to make available safe, effective and stable drug formulation that is well-tolerated by the patient of particular age and condition, but the biggest concern is quality, particularly the stability of extemporaneous preparations which are not subjected to testing like a product approved for market. Unavailability of stability data limits the availability of many medicines for special patients.
Aim: The dermatological formulations constitute a large proportion of extemporaneously compounded drugs and condition at which such extemporaneous products shall be stored to maintain the quality of product until use needs to be determined. This research was undertaken to carry out the stability testing of extemporaneous methyl salicylate ointment to determine the shelf life.
Materials and Methods: Methyl salicylate analgesic ointment prepared extemporaneously as per extemporaneous preparation manual of King Fahad Central Hospital, Jazan, was subjected to stability study at 25°C ± 5°C and 2°C–8°C for 120 days.
Results: The shelf life (t90%) of extemporaneously prepared methyl salicylate ointment was found to be 131 days at room temperature (25°C ± 5°C) and 176 days in the refrigerator (2°C–8°C).
Conclusion: The methyl salicylate present in extemporaneous ointment preparation is fairly stable at cool temperatures but shows faster degradation at higher temperature conditions. Therefore, it is recommended that an expiry date of 4 months can be safely mentioned when stored in cool.

Keywords: Extemporaneous preparations, methyl salicylate ointment, shelf life, stability study


How to cite this article:
Makeen H A, Pancholi S S, Alhazmi H A, Ezzi A A, A Hazzazi A J, Meraya A M. Stability testing of extemporaneous preparation of methyl salicylate ointment. J Health Spec 2018;6:72-6

How to cite this URL:
Makeen H A, Pancholi S S, Alhazmi H A, Ezzi A A, A Hazzazi A J, Meraya A M. Stability testing of extemporaneous preparation of methyl salicylate ointment. J Health Spec [serial online] 2018 [cited 2018 Dec 12];6:72-6. Available from: http://www.thejhs.org/text.asp?2018/6/2/72/229021




  Introduction Top


The process by which a pharmacist, using traditional compounding techniques, produces a medicinal product that is suitable for fulfilling some special needs of a particular patient or a category of patients is called extemporaneous preparation. There may be other, safer and more effective ways of delivering the required dose, but there arise circumstances when none of the available commercial dosage form is appropriate to meet the special needs of some patients and pharmacist may be left with the last option of extemporaneous preparation of formulation using traditional compounding techniques. Extemporaneous compounding of several formulations may be desired in different situations that may include a community pharmacy or in hospitals and nursing homes. The potential risks of extemporaneous dispensing for pediatric patients have been well documented. It is possible to reduce the risks which are associated with extemporaneous dispensing using it as a last resort.[1]

It is essential to make available safe, effective and stable drug formulation that is well-tolerated by the patient of particular age and condition, but the biggest concern is quality, particularly the stability of these extemporaneous preparations which poses a great risk. An extemporaneous product prepared by a pharmacist is not subjected to tests for evaluation of its quality, safety and efficacy as is the case for commercially available licensed products. The pharmacist under whose authority the extemporaneous preparation of such formulations is undertaken is responsible for assuring their quality and safety to attain the desired therapeutic goal. The pharmacist is obliged under the statutory code of conduct to carefully consider the appropriateness of dispensing an extemporaneous preparation and satisfy himself that such supply is essential and will add value to the care of the patient.[2] Thus, the pharmacists and pharmaceutical technicians working in different situations responsible for making extemporaneous formulations need to master the key skill of compounding accurate and effective pharmaceutical formulation.

The compounding pharmacist needs to make a number of considerations on receiving a prescription for an extemporaneous product before starting the preparation of formulation. In addition to organoleptic considerations, the proper design and formulation of a dosage form shall require the consideration about the properties of drug substance and pharmaceutical ingredients to be used that can influence the efficacy and stability of the formulated product and accordingly suitable ingredients and processes should be selected and followed. It is utmost important to conduct stability studies before any monograph is developed, to establish a valid expiry date for the compounded preparation.[3]

Stability of a formulation is an indication of the chemical and physical reliability of each dosage unit and its ability to keep safeguard against microbiological contamination. The term expiry date or before use date or shelf life is used to imply the time after which a given formulation will not retain more than 90% of potency against the label claim, that is the preparation will remain stable up to this period if stored under recommended conditions.[4],[5],[6],[7] There could be several causes of instability of the product and most common of them being hydrolysis, oxidation, reduction, thermolytic or photolytic decomposition, etc. The problem of instability of many formulations can be handled by preventing undesired interaction between the active drug and excipients and proper selection of vehicle, preservative, viscosity enhancer, pH modifier, etc., and the use of a suitable non-interacting storage container for dispensing of extemporaneous products.[8],[9]

A large proportion of compounded prescriptions include semisolid dosage forms, especially for patients with dermatological indications. Ointment formulations include preparations that are emulsifiable with the skin secretion or may be miscible or immiscible. The ointments which are miscible with the secretions of skin are hydrophilic in nature and possess less emollient action. The hydrophobic ointments and water-emulsifying ointments are suitable for application on the skin or certain mucous membranes when desired to be used for emollient, protective, therapeutic or prophylactic purposes, where a degree of occlusion is desired. Frequently, active ingredients and excipients used to prepare ointment are added as aqueous or alcoholic solutions. The different ointment bases vary greatly in properties of solubility, water miscibility, adsorption etc., and a compounding pharmacist has to decide which base is most suitable to use when considering the amount of water, alcohol, or any similar solvent needed to compound the preparation.

An instruction of storage condition in addition to the date of product expiry is often required to be mentioned on the label of products dispensed extemporaneously. It is a practice to assign the expiry date of the extemporaneous preparation empirically or on the basis of data published for a particular formulation in some research journals. The semisolid topical formulations such as ointments and pastes are generally dispensed in a wide mouth amber glass or opaque container or in the collapsible tube and shall be stored in cool conditions to preserve it for a nominal expiry date of 3 months.[10],[11]

In this research methyl salicylate ointment, prepared by the pharmacists of King Fahad Central Hospital, Jazan, was taken for stability study. Methyl salicylate is naturally available as oil of wintergreen; chemically, it is an organic ester of salicylic acid and methanol. It can also be produced by synthetic means. It is an analgesic and anti-inflammatory agent (non-steroidal anti-inflammatory drug [NSAID]), used to treat minor aches in joint and muscle pain due to arthritis, strains, sprains and bruises.[12],[13],[14] In the body, methyl salicylate is metabolised into salicylates, including salicylic acid, a known NSAID.[15]


  Materials and Methods Top


Materials

The freshly prepared extemporaneous methyl salicylate ointment was collected from the King Fahad Central Hospital, Jazan, Saudi Arabia. The pure drug, methyl salicylate, used in the present study for preparation of standard curve was obtained from Sigma chemicals. All other materials are of analytical grade and conform to specifications of pharmacopoeia.

Drug profile

Chemical name: Methyl 2-hydroxybenzoate [Figure 1].
Figure 1: Structure of methyl salicylate

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Molecular formula: C8H8O3.

Molecular weight: 152.147 g/mol.

Description: Available as a liquid which is yellow or reddish and has the odour of wintergreen.

Solubility: dissolves freely in organic solvents such as carbon bisulphide, ether, chloroform, alcohol and glacial acetic acid, however, sparingly soluble in water. Category: non-steroidal anti-inflammatory agent.

Determination of λmax

The solution of drug methyl salicylate (10 μg/ml) was prepared by dissolving in methanol and scanned between wavelength 200–400 nm to determine the λmax [Figure 2] using an ultraviolet-visible (UV-VIS) spectrophotometer (8-scanning auto cell, UVD-3200, Labomed, USA).
Figure 2: Ultraviolet scan of methyl salicylate

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Determination of standard curve of methyl salicylate

The stock solution of the strength 100 μg/ml was prepared in methanol, and standard solutions of 2, 4, 6, 8, 10 μg/ml strength were prepared by further dilution with methanol. The absorbance of respective solutions was measured in a spectrophotometer at 237 nm using methanol as blank. Standard curve [Figure 3] was obtained by plotting the observed UV-absorbance against the given concentration of the standard solution.
Figure 3: Calibration curve of methyl salicylate

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Preparation

An appropriate dosage form needs to be formulated to achieve the therapeutic goals, and selection of proper ointment base requires consideration of factors involved in local and systemic biological disposition. The formulations for which stability data is not available may be prepared by carrying out special calculations to determine quantities of components and following the procedure steps devised especially for the making of individualised dosage units extemporaneously. As per the hospital manual, the methyl salicylate ointment is required to contain 10% v/w of methyl salicylate in a suitable water-emulsifying base. Extemporaneous preparation of ointment was done by melting 100 g of white soft paraffin, cooling and then adding methyl salicylate 10 ml with stirring until cold. The ointment has a characteristic odour. The ointment was transferred to a suitable wide mouth container and labelled adequately. Some containers which are made from polystyrene plastic, are not suitable for packing of methyl salicylate ointment.[16]

Stability studies

Stability studies were conducted as per the protocol that extended for the duration of 120 days (4 months). The preparations were kept in small containers at room temperature (25°C ± 5°C) and in a refrigerator (2°C–8°C). Samples were withdrawn at frequent time intervals (0, 30, 60, 90, 120 days) and assayed spectrophotometrically. The percent degradation or stability was calculated for each preparation and the time required for the concentration of drug in the sample to reduce to 90% was calculated on the basis of extrapolation of the % drug remaining versus time plot [Figure 4].
Figure 4: Stability profile of extemporaneous methyl salicylate ointment

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  Results and Discussion Top


To confirm identity, quality and purity of the ingredients procured and used in preparation, the chemical and physical properties should be evaluated and therefore a UV-scan of diluted solution of methyl salicylate in methanol was carried out and λmax for methyl salicylate was found at 237 nm [Figure 2] that matches fairly with reported values and can be considered to show that the procured and used drug is methyl salicylate and pure. The same λmax 237 nm was used as analytical wavelength for the determination of methyl salicylate quantitatively.

The standard dilutions of methyl salicylate were subjected to measurement of absorbance at 237 nm using methanol as blank, and the data of absorbance versus concentration were plotted to obtain a calibration curve that was found to be a straight line with linearity calculated as R2 value 0.9964 [Figure 3]. This calibration curve was used for estimation of drug content in different samples of methyl salicylate ointment in stability studies.

The correct calculation of ingredients followed by accurate and precise measurement with a prudent pharmaceutical judgement shall govern the safety, efficacy and other quality attributes of compounded preparations. The master formula and standard procedure described in extemporaneous pharmaceutical preparation manual were followed every time while making the preparation and a complete compounding record was maintained to preserve data important for quality assurance purposes. The compounding pharmacist needs to assure that all activities and processes involved in the compounding of each preparation confirm to the standards. Packaging has to done in an appropriate airtight and light-resistant container made from physically and chemically inert material that meets the USP standards. In addition to beyond-use date, the label should include the information for handling precaution and storage condition as well as a statement that the preparation is extemporaneously compounded.[17]

A reliable beyond-use date needs to be established for the final preparation to ensure that it maintains its accepted potency, purity, quality and characteristics, during the period of use. The stability properties of extemporaneous preparations were investigated to improve their therapeutic uses and predict the periods of their stable storage. The formulation was considered stable if it retained 90% of the initial drug concentration. There was no physically instability observed in terms of colour or general appearance for any sample until the last withdrawn sampling date of 120 days.

The results of quantification of drugs after storage at different conditions and periods carried out by UV-VIS spectrophotometer with standard deviations of three repeated studies are provided in [Table 1]. Zero-order kinetics, of decomposition was observed with faster degradation rate indicated by the steep slope of the curve when the samples were exposed to higher temperature, i.e., in normal room temperature condition (25°C ± 5°C) [Figure 4].
Table 1: Stability of methyl salicylate stored at different temperatures

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The shelf life of methyl salicylate ointment stored at room temperature (25°C ± 5°C) and in a refrigerator (2°C–8°C) was determined by extrapolation of respective stability profile curves as time required for drug concentration to reduce up to 90% and it was found to be 131 days at room temperature (25°C ± 5°C) and 176 days in refrigerator (2°C–8°C).


  Conclusion Top


The data of calculated shelf life (t90%) of extemporaneously prepared methyl salicylate ointment are at room temperature (131 days) and in the refrigerator (176 days) fairly indicates that the methyl salicylate drug present in extemporaneous ointment preparation undergoes faster degradation on storage at higher temperature conditions. Therefore, it is recommended that these extemporaneous preparations should be kept or stored in cool place and the expiry date of 4 months can be safely mentioned.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Nunn AJ. Making medicines that children can take. Arch Dis Child 2003;88:369-71.  Back to cited text no. 1
    
2.
Guidance for Pharmacists on Extemporaneous Dispensing, Pharmaceutical Society of Ireland, Version 1. p. 1-4. Available from: http://www.thepsi.ie/Libraries/Folder_Pharmacy_Practice_Guidance/02_Guidance_for_Pharmacists_on_Extemporaneous_Dispensing_V1_0.sflb.ashx. [Last accessed on 2015 Jun].  Back to cited text no. 2
    
3.
Nahata MC, Allen LV Jr. Extemporaneous drug formulations. Clin Ther 2008;30:2112-9.  Back to cited text no. 3
    
4.
Glass BD, Haywood A. Stability considerations in liquid dosage forms extemporaneously prepared from commercially available products. J Pharm Pharm Sci 2006;9:398-426.  Back to cited text no. 4
    
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Rehmington WK. The Science and Practice of Pharmacy. 21st ed. Philadelphia: Published by Philadelphia College of Pharmacy and Science; 2005. p. 1025-33.  Back to cited text no. 5
    
6.
Patrick JS. Martin's Physical Pharmacy and Pharmaceutical Sciences. 6th ed. New Delhi: Published by Wolters Kluver Health (India) Pvt. Ltd.; 2009. p. 428-32.  Back to cited text no. 6
    
7.
Lachman L, Lieberman HA. The Theory and Practice of Industrial Pharmacy. Special Indian Edition. New Delhi: CBS Publishers and Distributors Pvt. Ltd.; 2009. p. 772-7, 849.  Back to cited text no. 7
    
8.
VandenBussche HL, Johnson CE, Fontana EM, Meram JM. Stability of levofloxacin in an extemporaneously compounded oral liquid. Am J Health Syst Pharm 1999;56:2316-8.  Back to cited text no. 8
    
9.
Winckler SC. Extemporaneous compounding: A return to regulatory limbo? J Pain Palliat Care Pharmacother 2002;16:71-8.  Back to cited text no. 9
    
10.
Nagel K, Ali F, Al-Khudari S, Khan A, Patel K, Patel N, et al. Extemporaneous compounding of medicated ointments. Int J Pharm Compd 2010;14:472-8.  Back to cited text no. 10
    
11.
Langley CA, Belcher D. Fastrack; Pharmaceutical Compounding and Dispensing. Pharmaceutical Press, London 2008. p. 1-3, 107.  Back to cited text no. 11
    
12.
Mehta NJ, Patadiya ND, Patel J, Shastri DH, Shelat PK. Development and evaluation of antiarthritic herbal ointment. RJPBCS 2013;4:221.  Back to cited text no. 12
    
13.
Niazi SK. Handbook of Pharmaceutical Manufacturing Formulations-Semisolid Products. Vol. 4. Washington: CRC Press, LLC; 2004. p. 192.  Back to cited text no. 13
    
14.
Wiedenmayer K, Summers RS, Mackie CA, Gous AGS, Everard M, Tromp D. Developing pharmacy practice: focus on patient care. Handbook. Geneva: World Health Organization and International Pharmaceutical Federation, 2006.  Back to cited text no. 14
    
15.
Mason L, Moore RA, Edwards JE, Derry S, McQuay HJ. Topical NSAIDs for chronic musculoskeletal pain: Systematic review and meta-analysis. BMC Musculoskelet Disord 2004;5:28.  Back to cited text no. 15
    
16.
Allen LV Jr. Standard operating procedure for performing physical quality assessment of ointments/creams/gels. IJPC 1998;2:308-9.  Back to cited text no. 16
    
17.
Allen LV. The GAP analysis for nonsterile compounding: Current & practical compounding information for the pharmacist. Secundum Artem 2012;17:4.  Back to cited text no. 17
    


    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4]
 
 
    Tables

  [Table 1]



 

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