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Original Article
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Formulation development and evaluation of diclofenac sodium injection using benzyl alcohol (co-solvent), mixed solvency concept | ||||||
Yasir Mehmood | ||||||
Faculty of Pharmacy University of Central Punjab, Lahore, Pakistan.
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Mehmood Y. Formulation development and evaluation of diclofenac sodium injection using benzyl alcohol (co-solvent), mixed solvency concept. Edorium J Drug Res 2015;1:1–8. |
Abstract
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Introduction:
Mixed solvency is a concept of solubilization of the material. For producing new formulation, especially in the form of injection it is essential to solubilize the active pharmaceutical ingredients (API) in the solvent and that must be stable throughout the shelf life. Aqueous solubility of raw materials is important for injection formulation, but in some cases if the drug is not soluble in water, oil can be used for drug solubility. In this present investigation, mixed-solvency approach has been applied for the enhancement of aqueous solubility of poorly water-soluble drugs, diclofenac sodium (selected as a model drug). Those drugs that poorly soluble in aqueous media are required fractioned oil to enhance its solubility. In most of the cases to make raw materials soluble in water, solubilizing agent in high concentration (co-solvent and surfactant) are use for drug solubility. But due to high concentration of co-solvent and use of oil can make more painful to inject. In the present study, we formulated the diclofenac sodium injection without using high concentrations of propylene glycol as co-solvent which is used in conventional formulation. Benzyl alcohol is used as preservative in conventional formulation and in this formulation benzyl alcohol uses as co-solvent for diclofenac sodium in aqueous medium and due to this, injection is less painful then propylene glycol based injection. At the end, we studied the stability, toxicity, pyrogenicity and isotonicity of the formulated injection.
Conclusion: From the various formulation studied, it was found that benzyl alcohol (6–7% v/v) is good and save solubilizing agent for preparation of injection dosage form of diclofenac sodium. This mixed solvency shall prove definitely a boon for pharmaceutical industries for the development of dosage form of poorly water soluble drugs. | |
Keywords:
Mixed solvency, Diclofenac Sodium, Benzyl alcohol
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Introduction
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Formulation has numerous benefits in drug discovery and development. It enables efficacy, toxicity, and pharmacokinetic (PK) studies. Formulation can improve oral bioavailability, shorten onset of a therapeutic effect, enhance stability of drugs, and reduce dosing frequency. More consistent dosing can be achieved by reducing food effect through formulation [1]. A drug molecule has to be water soluble to be readily delivered to the cellular membrane while retaining its hydrophobic properties and water insolubility can postpone or completely derail-important new drug formulation [2]. So, there is a much needed reformulation of currently marketed products and can be significantly affected by these type of issues. Maheshwari R. K. gives the concept of mixed solvency [3]. According to his opinion that all the substances solids, liquids and gases possess solubilizing ability and hence aqueous solutions, containing different dissolved substances can also enhance the solubility of poorly water-soluble drugs [4]. An intramuscular (IM) medication is given by needle into the muscle. It can be a solution, oil, or suspension. Drugs in aqueous solution are rapidly absorbed. However, very slow constant absorption can be obtained if the drug is administered in oil or suspended in other repository vehicles. Solubility may also be enhanced by altering the pH and using co-solvents but excess amount of these agents may have adverse effects. The vehicle should contain a minimum amount and low concentration of the co-solvent to reduce viscosity and toxicity effects. Polyethylene glycol 600, polyethylene glycol 800, and polyethylene glycol 400 used as co-solvent. Mixed solvency is the phenomenon to increase the solubility of poorly soluble drugs, using blends of solubilizing agents [5]. This technique gives the idea that additive or synergistic enhancement effect on solubility of poorly soluble drugs. By using this method in the formulation of different dosage forms made of insoluble drugs soluble and can reduce the concentration of solubilizing agents that are use in the formulation for its solubility in different solvent and minimize the side effects. In most of the conventional formulation of injection of diclofenac sodium propylene glycol is use as solubilizing agent [6]. The concentration of propylene glycol is used 25–30% [7] Urea (M.P. 130–135°C) dissolves diclofenac sodium (M.P. 283°C). This shows that melted urea act as solvent for diclofenac sodium. In supercritical fluid technology liquefied carbon dioxide acts as solvent for many insoluble substances [8]. These indicate that all substances possess some solvent character. All weaker solvents can be made strong solvent by proper selection of co-solvent. Mixed hydrotropy is another type of co-solvency [3]. Hydrotropic agents also increase the solubility of poorly water-soluble drugs [9]. Hydrotropy or mixed hydrotropy also used to enhance the aqueous solubility of poorly soluble drugs [10]. The present research is to explore the application of mixed solvency technique in the injection formulation of poorly water-soluble drug [11]. The formulation was also studied for physical and chemical stability. Diclofenac sodium is pain killer and indicated for the treatment of relative humidity rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, tendinitis, bursitis and acute gout. It is also indicated in the relief of mild to moderate pain and the treatment of primary dysmenorrhea [12]. | ||||||
Materials and Methods
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The gift sample of diclofenac sodium was provided by Ameer pharmaceuticals Pvt. Limited, Lahore, Pakistan. Benzyl alcohol, sodium hydroxide and sodium metabisulphite were purchased from local market. All other chemicals and solvents used were of analytical grade. Other material and instruments include Spectrophotometer (UV-1800, Shimadzu, Japan), FTIR (Agilent 4500 Series Portable FTIR Spectrometer), limulus amebocyte lysate reagent, sterility media, NaOH, glass ampoules, rabbit, pyrogen meter (panomax PX/PTA-461 china), stability chamber (Darwin Chambers - PH030), HPLC (DYNAMIC UV1) and pH meter (Hanna pH meter model HI 9025C). Solubility studies Procedure for preparation of solution
Evaluation of formulation batches pH measurement: The pH of the prepared formulations was measured using pH meter at 25±1°C. Particulate matter: The particulate matter in the formulation can be determined by the visual inspection by naked eye under direct light beam. Assay content for diclofenac sodium Analysis method for diclofenic sodium injection
Sample Preparation: Transfer 2 ml of solution equivalent to 50 mg of diclofenac sodium to a 100 ml volumetric flask. Dilute it to volume with the methanol. Dilute 1 ml of solution to 50 ml with the methanol. Standard Preparation: Transfer 50 mg of diclofenac sodium to a 100 ml volumetric flask. Dilute it to volume with the methanol. Dilute 1 ml of solution to 50 ml with the methanol. Measure the absorbance of both sample and standard solution at ultraviolet-visible spectrophotometer at 277 nm. Calculations
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Results | ||||||
Physical appearance pH Measurement Accelerated Stability Studies Effect of sunlight on drug degradation Effect of atmospheric oxygen on stability
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Conclusion
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From the various formulation studied, it was found that benzyl alcohol(6–7% v/v) is good and save solubilizing agent for preparation of injection dosage form of diclofenac sodium. In conclusion, the results of this study suggest that a stable aqueous injection of diclofenac sodium can be successfully developed using the concept of mixed-solvency approach. The amount of individual solubilizer required to increase the measurable solubility shall be very high which sometimes shows the toxicity. Therefore, the use of benzyl alcohol which is physiologically compatible often acts synergistically to improve the solubility and reduce the risk of toxicity. Thus it can be concluded that, with the carefully designed experimental technique, solubility of poorly water-soluble drug can be improved by using the "mixed solvency" approach. The application of the mixed solvency approach in the development of formulations shall prove to be a boon for pharmaceutical industries because the quantity of water soluble solubilizers can be selected at safe level (well below their toxic levels) for a modest increase in solubility of a water-insoluble drug. | ||||||
Acknowledgements
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I am thankful to Ameer Pharmaceutical Pvt. Ltd (Pakistan) for providing the gift sample of diclofenac sodium. I am also thankful to UCP research Center (Lahore) and A&A Pharma Company (Lahore) for providing me the facilities for research. | ||||||
References
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Author Contributions:
Yasir Mehmood – Substantial contributions to conception and design, Acquisition of data, Analysis and interpretation of data, Drafting the article, Revising it critically for important intellectual content, Final approval of the version to be published |
Guarantor of submission
The corresponding author is the guarantor of submission. |
Source of support
None |
Conflict of interest
Authors declare no conflict of interest. |
Copyright
© 2015 Yasir Mehmood. This article is distributed under the terms of Creative Commons Attribution License which permits unrestricted use, distribution and reproduction in any medium provided the original author(s) and original publisher are properly credited. Please see the copyright policy on the journal website for more information. |
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