Objective: The objective of this research was to formulation and evaluation of flurbiprofen aqueous injection.

Methods: The flurbiprofen aqueous injection was successfully developed by mixed hydrotrophy technique, using sodium benzoate, sodium acetate, and propylene glycol, glycerin, peg200, peg400, peg4000, peg6000, urea and ethanol as solvent in various proportions in combination. Further, the prepared aqueous injection were characterized for qualitative solubility, quantitative solubility, dilution study, effect of ph extractable volume test, viscosity, visual check, bet test, sterility test, particulate contamination, compatibility studies (FTIR) and stability studies.

Results: The consequences of solvency studies are exhibited. It appears from the outcomes that the watery dissolvability of flurbiprofen was expanded more circumstances in hydrotropic mix specialists (PG25%+PEG10%+S5%), (SB5%+PEG 25%+S10%).¹ In hydrotropic arrangement which additionally utilized for group assembling and testing reason all cluster demonstrates great soundness and manufactured products show stable results.

Conclusion: The dissolvability assurance of flurbiprofen was completed in distilled water, hydrotropic arrangements containing diverse convergences of hydrotropic. It is possible to make further more studies to develop for industrial manufacturings.

Keywords: flurbiprofen, hydrotropic, aqueous injection

Flurbiprofen is used to treating rheumatoid arthritis or osteoarthritis andanklosing spondylitis. It is BCS class II drug (low soluble & high permeable).² It is basically available as tablet form solubility was carried out using various co-sovents and hydrotrops. It may also be used for other conditions as determined by doctor. Flurbiprofen is an NSAID. Flurbiprofen are indicated for the acute or long-term symptomatic treatment of rheumatoid arthritis, osteoarthritis and anklosing spondylitis. After conducting patent search & literature survey on formulations containing drugs of certain class such as nonsteroidal anti-inflammatory drugs, development of flurbiprofen injection using mixed solvency and hydrotropic method not patented. Based on literature review & marketed products, it was concluded that there is opportunity for working in area of development of injection containing flurbiprofen for rheumatoid arthritis or osteoarthritis.³

The drug provide by montage labs. pvt ltd, himatnagar. Excipients used as LR grades.

Prefomulation study

Standard curve of flurbiprofen in methanol: the standard curve of flurbiprofen was prepared in methanol as shown in Figure 1 & Table 1.

Figure 1 Flurbiprofen Curve.

Solubility trials in different solvents and ph solutions

All the sample of saturated solution of drug at different pH were shaken in an orbital shaker for 6 hours at 25°C and 60 RPM^4,5 and further equilibrated for next 48 hr after centrifugation and filtration the absorbances were recorded at 247 nm suing respective solution as blank.

Procedure for 20% and 40% concentrations

Solubility of flurbiprofen invarious solution was determined by shack flask method. Excess amount of drug was added to 10ml Stoppard volumetric flask. Various hydrotropes in 20% and 40% Concentration solution in distilled water were filled in the volumetric flask. The flask was shaken for 6 hr in orbital shaker at 25°C and 60 RPM speed. The solution was allowed to equilibrate for the next 24hr. The solutions were then centrifuged for 10min at 1000rpm. Supernatant of each sample were filtered through 0.45 membrane filter and analyzed for drug content spectrophotometrically at 247nm after suitable dilutions.⁶

Procedure for 5 %, 25% and 10% concentrations

Solubility of flurbiprofen in various solutions was determined by Shak flask method. Excess amount of drug was added to 10ml stoppered volumetric flask. Various hydrotropes in 5%, 25% and 10% concentration solution in distilled water were filled in the volumetric flask. The flask was shaken for 6 hr in orbital shaker at 250°C and 60rpm speed. The solution was allowed to equilibrate for the next 24hr. The solution was then centrifuged for 10min at 1000rpm. Supernatant of each sample were filtered through 0.45 membrane filter and analyzed for drug content spectrophotometrically at 247nm after suitable dilutions (Table 2) (Table 3).⁷

Ftir study

FTIR graph obtaine from ftirintrumentsaples prepared by mixing of equipment with drug E.G with Glycrine, PH bubber4, buffer 7, gycerine, PEG 400 (Figure 2).

Figure 2 FTIR Graph of Flurbiprofen.

Procedure of batch manufacturing

1. Step 1: Weighing of drug: accurately 2gm under laminar air flow (Figure 3) (12-13mm of pressure) (at 22- 25°C temperature) (28-32 % of relative humidity).⁸
2. Step 2: Preparation of solvent system: the solvent system “s” comprise of PEG200, PEG400, glycerin, and propylene glycol in equal concentrations. Add drug to the solvent system with continuous stirring and flush nitrogen in the solution for 15mins (Figure 4).


Figure 3 FTIR Graph of Flurbiprofen with PG.



Figure 4 FTIR Graph of Flurbiprofen with PEG 400.

3. Step 3: Washing: 5ml clear vials washed with dm water using auto jet vial washing machine (200 vials).

Wash room, and all other facility areas                          class      1, 00,000
Air locks to sterile area entry & manufacturing                class          10,000
Sterile area                                                              class      1000
Storage, filling sealing area under LAF                            class      100

4. Step 4: Dry heat sterilization of vials: 100 vials are sterilized using drier at 200°C temperature for 3hr.
5. Step 5: Sterilization of filtration assembly and GBRS: wash 13mm grey butyl rubber stoppers with 0.1% teepol solution and make them foreign matter free, followed by washing with de-mineralized water to make them free from fibers and particulate matter. The filtration assembly sterilized before use, filter assembled in filtration assembly and autoclaved at 121°C temperature, 15lbs pressure, for 30mins)
6. Step 6: Filtration procedure: Filter the solution using 0.2 micron filtration assembly.
7. step 7: Filling of solution: 5ml accurate volume of solution filled in each vial using syringe under laminar air flow, (12-13mm of pressure laf) (at 22- 25°C temperature) (28-32% of relative humidity).

Post formulation study

Assay: Reference Solution Preparation the 100ml of stock reference solution for each formulation was prepared. The composition of the reference⁹ stock solution was similar to that of the respective formulations excluding the drug and also they were diluted similarly as the formulation were diluted using water. This resulting solution is used as reference solution (blank) in comparison with prepared formulation to measure the % drug content by measuring absorbance suing UV spectrometer. The amount of flurbiprofen was determined from standard curve (Table 4).

Dilution study: Precipitation of drug often occurs upon injecting a formulation into body fluid; the amount of precipitation can be correlated with the rate at which drug injected. Method for determination of such effect is dilution study. The serial dilutions of formulations were prepared in ration of 20:25 to 20:125 and stored at room temperature and examined visually foe the appearance of crystals and turbidity up to 24hrs (Table 5).¹⁰

Effect of PH: The 5ml of each prepared formulation 1 and 2 were kept at different temperature and/conditions such as refrigeration, room temperature, 37°C, 40°C,45°C.^11‒14 At regular time interval the sample were examined for pH changes for 2weeks using digital pH meter (Table 6).

Observation: Not more considerable changes found in both formulations, which indicate stability of both formulations. Extractable volume test: extractable volume should be not less than 5ml not more then 5.2ml (Table 7).

Viscosity: Viscosity levels had significant impact on perceived injection pain, specifically; less pain was associated with high viscosity. Visual check: after filling all vials checked for glass particles, black particles, white fibers, against black and white visual hoods.

BET test (bacterial endotoxin test): The gel-clot technique used for BET test. This method is a photometric test measuring increments in reactant turbidity. Result of BET TEST (Table 8).^15‒17

Sterility test: Method used-direct inoculation. Media-alternative thioglycolate media. Incubation time-14 days.

Stability study: 1 Vial from each batch stored at 25°c /60% rh, 5°c /30% rh, 40°c /65% rh, there is no change in physically, not found any color change (Table 11). After filling all vials checked for glass particles, black particles, white fibers, against black and white visual hoods (Table 9). The gel-clot technique used for bet test. This method is a photometric test measuring increments in reactant turbidity (Table 10).^18‒20

It appears from the outcomes that the watery dissolvability of Flurbiprofen was expanded more circumstances in hydrotropic mix specialists (PG25%+PEG10%+S5%), (SB5%+PEG25%+S10%) in hydrotropic arrangement which additionally utilized for group assembling and testing reason all cluster demonstrates great soundness and manufactured products show stable results. It is possible to make further more studies to develop for industrial manufacturing’s.

None.

Author declares that there is no conflict of interest.

1. Dongare SD, Mali SS, Prasad VP. Sterile parenteral products: a narrative approach. Journal of Drug Delivery & Therapeutics. 20115;5(1):41‒48.
2.  Reddy BV, Reddy BV, Reddy, et al. A review on parenteral production technology. Pharmaceutical Sciences. 2013;3(1):596‒610.
3. Flurbiprofen chemical name and properties.
4. Raymond C, Paul J, Marian E. Handbook of Pharmaceutical Excipients. 6th edn UK; 2006. p. 283‒517.
5. Flurbiprofen molecular structure and molecular description.
6. Patil SK, Wagh KS, Parik VB, et al. Strategies for solubility enhancement of poorly soluble drugs. Review Article. 2011;8(2):1‒7.
7. Pande VV, Kadam PS, SM Vibhte SK, et al. Exploration of mixed hydrotropy strategy in formulationand development of Etodolac injection. Journal of Nanomedicine Research. 2016;3(4):1‒7.
8. Pawar PB, Rawat SS, Mahajan YY, et al. Formulation development and evaluation of aqueous injection of poorly soluble drug made by novel application of mixed solvency concept. International Journal of Drug Delivery. 2013;5(2):152‒166.
9. Maheshwari RK, Shilpkar R. Formulation development and evaluation of injection of poorly soluble drug using mixed solvency concept. International Journal of Pharma and Bio Sciences. 2012;3(1):1‒7.
10. Maheshwar RK, Jawade S, Fouzdar A. Formulation development of aqueous injection of poorly soluble drug using mixed hydrotropic solubilization concept and its evaluation. Int J Pharma Sci Drug Res. 2015;7(1):8‒12.
11. Gurumurthaih SS, Yadav P, Gondkar D, et al. Preparation and evaluation of sparfloxacin parenteral dosage form. International Journal of Advances In Pharmacy Biology And Chemistry. 2013;2(1):1‒12.
12. Nagaraja YS, Nagaraja TS, Bharathi DR, et al. Formulation and evaluation of ofloxacin aqueous injection. Int J Res Dev Pharm L Sci. 2012;3(10):1‒6.
13. Kalariya N, Asija S, Patel C, et al. Formulation and evaluation of sulphasalazine injetion made by mixed solvency solubilization technique. International research journal of pharmacy. 2012;3(5):1‒7.
14. Russell Jones G, Himes R. Water-in-oil microemulsions for effective transdermal delivery of proteins. Expert Opin Drug Deliv. 2011;8(4):537‒546.
15. Omar HEP, Gamal MZ, Abdelhafezp AW. Formulation And Evaluation Of Flurbiprofen Sustained Release Matrix Tablets Using An Alternative Technique As Potential Economic Approach. International Journal of Current Pharmaceutical Research. 2015;7(1):450‒456.
16. Aiswarya G, Hussan K, Kumaravel R. Development, evaluation, and optimization of flurbiprofen nanoemulsions gel using quality by design concept. Asian J Pharmacol. 2015;5(1):1‒9.
17. Bhaskar D, Rama RT. Formulation and in vitro evaluation of flurbiprofen-polyethylene glycol 20000 solid dispersions. Journal of Applied Pharmaceutical Science. 2014;4(07):76‒81.
18. Girish B, Pasha I, Gowda DV. Formulation and Evaluation Of Sustained Release Matrix Tablets of Flurbiprofen Using Guar Gum. International Journal of Pharmacy and Pharmaceutical Sciences. 2012;8(2):1‒5.
19. Chandra D, Kumar A, Verma S, et al. Formulation And Evaluation of Proniosomal Gel of Flurbiprofen. International Journal of Universal Pharmacy and Life Sciences. 2013;3(5):1‒18.
20. Indian Pharmacopoeia. 2014.