INTRODUCTION:

Flurbiprofen [2-(3-fluoro-4-biphenyl) propionic acid], is a phenylalkanoic acid derivative and non-steroidal anti-inflammatory agent, with analgesic and antipyretic activity and has chiral center. It is one of the most potent inhibitors of platelet aggregation, generally prescribed for rheumatoid arthritis, osteoarthritis, gout, musculoskeletal disorders, rheumatic diseases, post-operative pain, sunburn, and dysmenorrhoea.^1-3The model drug exerts its effect by reversible inhibition of cyclooxygenase (COX), the enzyme that bring out conversion of arachidonic acid to prostaglandin G2 (PGG2) and PGG2to prostaglandin H2 (PGH2) this results in adequately declining the concentration of prostaglandins involved in inflammation, pain, swelling and fever. Flurbiprofen, most potent NSAIA in terms of prostaglandin inhibitory activity is a non-selective COX inhibitor and inhibits the activity of both COX-1 and COX-2.

FLB belongs to BCS Class II and exhibit low solubility and low dissolution rates and suffers from poor oral bioavailability constraints due to its poor water solubility of 5-10µg/mL.^4-6Generally drugs with low aqueous solubility (usually lower than 100μg/ml) show dissolution-limited, incomplete absorption from the gastrointestinal tract of animals and humans and are hydrophobic.⁷ Poor aqueous solubility is prime limiting factor with many new drugs in their successful set up in market despite of their full potential pharmacokinetic activity. Molecules that would have highly constructive effect on their physiological target would not be further developed if their bioavailability is limited by their aqueous solubility.

Thus solubility is a most valued contributor in the formulation of finished pharmaceuticals. These molecules need enhancement in low solubility, dissolution rate and bioavailability which is featured to drug’s success. Among all solubility enhancement technique use of solubilizer is a valuable approach for enhancing the solubility, dissolution rate and bioavailability of BCS Class II drugs due to simplicity of process.^8-9

Literature survey put forward various approaches such as use of hydrophilic carriers^10-11, liquisolid compact technique^12-13, supercritical carbon dioxide¹⁴, use of surfactant^15-17microemulsions¹⁸, complexation with cyclodextrins^18-20, solid dispersion^21-28, adsorption of nifedipine on porous calcium silicate²⁹and the use of conventional solubilizer such as polysorbates, PEG 400to elevate the solubility of Flurbiprofen. But there is no focus on novel solubilizer such as sepitrap, soluplus, povacoat, dendrimers for FLB.

Thus considering the supremacy of adding novel solubilizer such as sepitrap to drug the present investigation was carried out to contribute the promotion of the solubility of poorly water-soluble drug, FLB via solubilization using sepitrap 80 and sepitrap 4000 as an auxiliary substance, which to our knowledge has not been reported yet.

MATERIALS AND METHODS:

FLB was obtained as a gift sample from FDC Limited, Ahmadabad, India. Sepitrap 4000, Sepitrap 80 were gifted by Seppic, Mumbai. All other chemicals and solvents used were of pharmaceutical and analytical grade.

Determination of maximum wavelength of FLB:

Flurbiprofen, 10mg was dissolved in 10ml of methanol and then the volume was made up to 100ml with distilled water. The concentration of the resulting solution was 100μg/ml and this stock solution was diluted with distilled water to get 2μg/ml. The absorbance of the resulting solution was measured using UV-Visible spectrophotometer in the wavelength range of 200-400 nmby a method previously developed and validated.^30-31

Preparation of FLB and sepitrap physical mixture:

The 100mg of FLB weighed accurately and physical mixtures of FLB with sepitrap 80 and sepitrap 4000 was prepared by simple spatulation method in the various proportions like 1:1,1:2 and 1:3^32-33 The various proportion used for physical mixtures is given in table no.1

Table No 1: Composition of various physical mixtures of FLB with sepitrap 80 and sepitrap 4000

Batch No	Drug (mg)	SEPITRAP 80 (mg)	SEPITRAP 4000 (mg)
PM1	100	100 (1:1 ratio)	---
PM2	100	200 (1:2 ratio)	---
PM3	100	300 (1:3 ratio)	----
PM4 PM5 PM6	100 100 100	--- --- ---	100 (1:1 ratio) 200 (1:2 ratio) 300 (1:3 ratio)

Drug content determination:

Physical mixtures of Flurbiprofen and sepitrap 80 and sepitrap 4000 were transferred to 100ml volumetric flask. Add 50ml methanol and shake the flask thoroughly. Make the volume with 100ml with methanol. Dilute the solution if required and estimate the drug content spectrophoto metrically at 248nm. Drug content was calculated from the standard curve of Flurbiprofen.

Saturation solubility studies:

A saturation solubility study was performed to determine increase in the solubility of pure drug compared with the physical mixtures of FLB with Sepitrap 80 and sepitrap 4000. Excess amount of the drug and physical mixtures of were separately introduced into the 250mL stoppered conical flasks containing 25mL of double distilled water. Then flasks were covered with cellophane membrane to avoid loss of solvent and kept in rotary shaker for 48 h at 37±0.5⁰C. Aliquots were then withdrawn and filter through What man filter paper. The concentration of FLB was determined by using UV visible spectrophotometer at 248nm (Shimadzu UV spectrophotometer 1800) after appropriate dilution. To calculate the solubility of FLB three determinations were carried out for each physical mixture. The solubility of FLB and percent increase in solubility by the solubilizer were determined.³⁰

Fourier transform infrared spectrophotometer studies:

FT-IR has been employed as a useful means to identify drug excipient interaction. Samples were analyzed by the potassium bromide pellet method in an IR spectrophotometer (Alpha T Bruker) in the region from 4000 to 400 cm^-1. The FT-IR spectra of pure Flurbiprofen, physical mixture of Flurbiprofen-sepitrap 80 and physical mixture of FLB- sepitrap 4000 are given in figure No.2

Differential scanning calorimeter (DSC) analysis:

The solid state interaction of drug with physical mixtures examined very well by differential scanning calorimetry (DSC) one of the most widely used calorimetric techniques. Samples of the pure drug and physical mixture of drug sepitrap were taken in flat-bottomed aluminum pans and heated over a temperature range of 30 to 300°C at a constant rate of 10°/min with purging of nitrogen (50 ml/min) using alumina as a reference standard in a differential scanning calorimeter (Mettler Toledo, Staresw 920). The DSC thermogram of pure Flurbiprofen, physical mixture of FLB- Sepitrap 80 and physical mixture of FLB- Sepitrap 4000 are shown in Figure No.3

Powder X-ray diffractometry (PXRD) analysis:

The PXRD study was carried out by using X-ray diffractometer (Miniflex 600 X-ray diffract to meter, Rigaku Corporation Japan). The Powder X-ray diffraction technique has been utilized broadly along with DSC to study the interaction and to obtain the changes in the crystallanity of the physical mixtures of drug and sepitrap prepared. For this the samples of pure drug, physical mixtures of Flurbiprofen-sepitrap 80 and FLB-sepitrap 4000 were irradiated with monochromatised CuKα radiation and analyzed between from 5^° to 60^° (2θ). The PXRD diffract to grams of pure Flurbiprofen, physical mixture of FLB with sepitrap 80 and sepitrap 4000 are shown in figure no.4

Scanning electron microscopy (SEM) studies:

A scanning electron microscope (VEG A3 TESCAN), under accelerating voltage of 15 keV was used to study the surface morphology of pure FLB and physical mixture of FLB with Sepitrap 80 and sepitrap 4000 by fixing samples on SEM stub with double-sided adhesive tape and then coated in a vacuum with thin gold layer before investigation. The SEM images of FLB and its physical mixtures with sepitrap 80 and sepitrap 4000 are shown in figure no.5

Dissolution studies:

The FLB and its physical mixture equivalent to200 mg of FLB were placed into dissolution tester, USP Type-II (EDT 08LX Electrolab). The drug and its physical mixture were placed in 900 ml of dissolution medium and maintained at 37±0.5°C, stirring rate at 50 rpm using 0.1 N HCl (pH 1.2) and distill water pH(7). At appropriate intervals, 5 ml of samples were taken and filtered through a 0.45 micron filter (Millipore, USA) and analyzed at 248nm by UV-Visible spectrophotometer. The withdrawn volume was replenished immediately with the same volume of the prewarmed (37°C) dissolution medium to maintain sink condition. The mean of three determinations was used to calculate the drug release from each of the formulations.^34-35

Zeta potential:

Surface charge on sepitrap loaded physical mixture was determined using Zetasizer, (HORIBA scientific SZ-100). Physical mixture was diluted in deionized water (1/10 w/v) and was plaecd in measument cell for 60 sec for detemination of average zeta potential and charge on the physical mixture.

Stability study:

Stability study for selected physical mixture PM5 was carried out with the help of stability chamber (Remi SC-19 Plus) by storing 1gm of physical mixture in an ambered colored screw capped glass bottles at accelerated and controlled temperatures 40⁰C and relative humidities (75%) for a period of 3 months.^36-40Physical mixture was evaluated for physical appearance and in-vitro dissolution at the end of three months.

RESULT AND DISCUSSION:

Determination of maximum wavelength of FLB:

The absorbance measured using UV-Visible spectrophotometer of the 2μg/ml in the wavelength range of 200-400 nm and maximum wavelength was found at248nm.

Drug content determination:

The drug content of physical mixtures was determined using previously reported method.³³The practical drug content of physical mixtures was found to be 48.56±1.13,32.12±1.32and23.91±1.63respectively which corresponded to the ratio of the drug with solubilizer. The theoretical drug content, practical drug content is summarized in table No.2

Saturation solubility studies:

The solubility of pure FLB in distilled water was determined to be only 8.15±0.03μg/mL. Remarkable enhancement in the solubility of FLB in presence of sepitrap 80 and sepitrap 4000 compared to pure FLB alone was observed in the saturation solubility studies. The physical mixtures of FLB with sepitrap 80 in the proportion of 1:1, 1:2 and 1:3 exhibited a solubility of 14.32±0.04, 20.90±0.05 and 22.60±0.03μg/mL respectively. The physical mixtures of FLB with sepitrap 4000 in the proportion of 1:1,1:2 and 1:3 exhibited a solubility of 20.23±0.07, 29.59±0.03 and 30.25±0.04μg/ mL respectively. 261% increase in the solubility in case of physical mixture of FLB with sepitrap 80 with proportion 1:2 whereas 369.87% increase in the solubility in case of physical mixture of FLB with sepitrap 4000 with proportion 1:2 was observed. The solubility increased sharply upon addition of the solubilizer, reaching a maximum at solubilizer proportion between 1:1 and 1:2 but then it declined somewhat upon further addition of solubilizer. The enrichment in solubility of FLB in presence of sepitrap 80 and sepitrap4000 clearly expresses the novel solubilizer in powder form that is polysorbate 80(sepitrap 80) and polyoxyl 40 hydrogenated castor oil (sepitrap 4000) is promising approach for enhancement of solubility of poorly soluble drug FLB. The solubility of FLB and percent increase in solubility due to use of sepitrap 80 and sepitrap4000 are given in figure no.1

Figure No. 1: Saturation solubility of FLB in distilled water with different proportions of sepitrap 80 and sepitrap 4000

Fourier transform infrared spectrophotometer studies:

The FT-IR analysis has been carried out in order to characterize the possible interactions between FLB and solubilizer in solid state. FTIR spectrum of pure FLB exhibited IR absorption bands at 1706 cm-l (C=O stretching of carboxylic acid), 958 cm−1 (O-H bending), 1219cm−1 (C-F stretching of an halogen), 2860cm−1 (CH-CH₃stretching), 2934 cm−1 (C-H stretching), 2980cm−1 (C-H stretching),and broad peak of FLB in the range of 2500-3300cm−1 due to hydrogen bonding. The physical mixture did not show new peaks indicating that no chemical bonds were created in. The FT-IR spectrum of physical mixture retains principle IR absorption bands of drug with no substantial shifting of the position of the functional groups and indicating no major interaction between FLB and solubilizer, sepitrap 80 and sepitrap 4000 and also may be expressive of uniform FLB dispersion as a consequence of the physical mixing with solubilizer.

Figure No. 2 FT-IT Spectra of A] Pure Flurbiprofen, B] sepitrap 80 C] sepitrap 4000D] Physical Mixture of FLB - sepitrap 80 E] Physical Mixture of FLB –sepitrap 4000

Differential scanning calorimeter (DSC) analysis:

Thermal analysis was also performed using DSC technique to evaluate parameter of the physical mixture determined as a function of temperature and to demonstrate any unexpected interaction between FLB and solubilizer. The DSC thermogram of pure FLB and sepitrap 4000 are shown in fig no. 3. Crystalline nature of FLB was indicated bya sharp endothermic peak with an onset of 120⁰C and peak at 122.18⁰C with end set at 125⁰C recorded as function of temperature representing melting point of drug. The sharp endothermic peak appeared in drug almost completely disappeared and shown with reduced intensity in physical mixture of sepitrap 4000. The characteristic peak of FLB was unchanged, illustrating an absence of strong interaction between drug and solubilizer in physical mixture. There were no appearance of new peaks; this revealed that there is no significant and unexpected interaction between drug and sepitrap 4000.

Figure No. 3: DSC thermogram of A] Pure Flurbiprofen B] Physical Mixture of FLB –sepitrap 4000

Powder X-ray diffractometry (PXRD) analysis:

The Powder X-ray diffractometry (PXRD) is used as structural analysis technique to assess the degree of crystallanity of the given sample. Powder X-ray diffraction pattern of FLB displayed sharp peak at diffraction angle representing typical crystalline nature. Crystallanity of the sample was reduced with its conversion into amorphous nature with the generation of physical mixture of the sample with the solubilizer sepitrap 80 and 4000. Hence physical mixture showed few, less intense peaks. Change of crystalline nature to amorphous ensured solubility amelioration of poorly soluble FLB.

The powder X-ray diffract to grams of pure FLB showed various distinctive peaks at 11.68, 11.70, 11.72, 11.74, 16.12 etc that indicated a high crystallanity. No new peak was detected and hence there was no unfavorable interaction of the drug with sepitrap. The physical mixtures of FLB with sepitrap 80 and sepitrap 4000 demonstrated distinctive peaks but reduced peak intensity in terms of counts. IR and DSC studies support the same data, which is confirmed by x‐ray diffractometry. The PXRD Diffract to grams of pure FLB, physical mixture of FLB with sepitrap 80 and sepitrap 4000 are shown in figure no.4

Figure No.4: PXRD patterns of A] Pure Flurbiprofen, B] Physical Mixture of FLB - sepitrap 80 C] Physical Mixture of FLB –sepitrap 4000

Scanning electron microscopy (SEM) study:

The SEM was executed to investigate surface morphology of the drug and its significant changes when mixed with solubilizer in powder form in various proportions as a physical mixture. The scanning electron micrographs of FLB powder appeared smooth and exhibiting loose aggregates of rectangular shape. The SEM images of sepitrap 4000–drug physical mixture shows slight changes in its surface structure due to polyoxyl40 hydrogenated castor oil incorporated in solid form. The slight change in surface morphology suggest that pure drug and solubilizer, sepitrap were mixed thoroughly and may be responsible for the enhancement of solubility when it comes in contact with fluid medium. The scanning electron micrographs of FLB and its physical mixture with sepitrap 4000 are displayed in Figure 5

Figure No. 5 SEM images of A] Pure FLB, B] Physical Mixture of FLB –sepitrap 4000 1:2 ratio

In-vitro dissolution studies in SGF and Distilled water:

FLB and its physical mixtures were evaluated for dissolution properties and compared with the pure FLB alone. The in-vitro dissolution results were assessed on the basis of cumulative percentage drug release, dissolution efficiency and correlation coefficient (r). Figure No.7 and 8 shows the dissolution profiles of FLB and various physical mixtures in SGF and distilled water pH 7 respectively. Dissolution of pure FLB at pH 7 was comparatively greater but decreased at acidic pH 1.2 and hence rapidly absorbed from small intestine and not well absorbed from upper GIT considering poor solubility in acidic environment. Physical mixtures of FLB showed enhanced dissolution in the lower pH with sepitrap 4000improving its absorption from upper gastro intestinal track. The pure FLB showed drug dissolution of 16.24 and 19.63% in 30 min in SGF and distilled water respectively, physical mixture of FLB with sepitrap 80 in 1:2 proportion showed 49.36 and 55.29% drug dissolution in 30 min while physical mixture of FLB with sepitrap 4000 in 1:2 proportion showed 60.23 and 63.96% drug dissolution in SGF and distilled water respectively. The dissolution of FLB was significantly enhanced by use of solubilizer sepitrap in 1:2 proportions. Increase in both wettability and solubility may be attributed to enhancement in FLB dissolution. The solubility of pure FLB increased due to localized solubilization because in minimal time more than80% of the solubilizer is desorbed from sepitrap and is available for solubilizing the drug. Sepitrap 80 as well as 4000 is free flowing with good ability to settle, and have particle size lesser than 200µm and widely chosen for their solubilization potential. Sepitrap 4000 is more potential and effective solubilizer as compared to sepitrap 80 in exactly half proportion to that of sepitrap80 because physical mixture containing FLB–sepitrap 80 in 1:2 proportion showed identical dissolution compared to the physical mixture containing FLB–sepitrap 4000 in 1:1.

Fig. 7. The dissolution profile of pure drug and physical mixtures in SGF

Fig. 8. The dissolution profile of pure drug and physical mixtures in distilled water

Zeta potential determination:

The zeta potential is highest measured parameters for determination of overall charges gain by particles in specific medium and which is considered as important factors for stability. Value away from zero is considered as optimum one (±30 mV), providing maximum stability to particle in dispersed medium. The zeta potential of physical mixture of flurbiprofen with novel soilubilizer sepitrap 4000(1:2) was found to be −19.1mV Figure 9 indicate zeta potential of physical mixture.

Figure 9: Zeta potential of physical mixture (PM5) flurbiprofen with novel soilubilizer sepitrap 4000(1:2)

Stability study:

There was no significant change in the physical appearance, drug content and percent drug dissolution in the FLB physical mixtures. A stability results clearly indicate that the physical mixtures were sufficiently stable under accelerated and controlled conditions.

CONCLUSION:

Poor water solubility has been attributed to almost half of the new molecular entities manufactured annually by pharmaceutical sector, and is claimed to lessen the performance of more than 10% of successfully marketed drugs. Novel solubilizer, sepitrap helps to find out solutions to utilize more effectively poorly water soluble new chemical entities (NCE) and develop these API into effective new drugs. It increases bioavailability of Flurbiprofen by solubilization of API in the medium and acts by increasing solubility.

ACKNOWLEDGMENT:

Authors are thankful to FDC limited Mumbai (India) for providing Flurbiprofen drug as a gift sample.

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Received on 17.02.2020 Modified on 10.04.2020

Research J. Pharm. and Tech. 2021; 14(1):21-27.

DOI: 10.5958/0974-360X.2021.00005.6

Batch No	Sepitrap 80 Theoretical % Drug content	Sepitrap 80 Practical % Drug content	Solubility in water (μg/mL)
PM1	50	48.56±1.13	14.32±0.04
PM2	33.33	32.12±1.32	20.90±0.05
PM3	25	23.91±1.63	22.60±0.03
Batch No	Sepitrap 4000 Theoretical % Drug content	Sepitrap 4000 Practical % Drug content	Solubility in water (μg/mL)
PM4	50	49.32±1.59	20.23±0.07
PM5	33.33	32.56±1.46	29.59±0.03
PM6	25	24.65±1.58	30.25±0.04