Formulation and Evaluation of Aceclofenac-loaded Nanoparticles by Solvent Evaporation Method

 

Suman Kumar Rathore, Brajesh Kumar Pathak

Mittal Institute of Pharmacy, Bhopal (M.P.)

 

ABSTRACT:

Nanoparticles have applications in the formulation of poorly water soluble drugs to improve their bioavailability. Preparation and evaluation aceclofenac-loaded nanoparticles by solvent evaporation method to enhance solubility and bioavailability were the primary aim of the present investigation. Nanoparticles of aceclofenac, a BCS class II drug were prepared by solvent evaporation technique and characterized using Fourier transform infrared spectroscopy, particle size and zeta potential, scanning electron microscopy and drug release studies in vitro. Data from the Fourier-transform infrared spectroscopy showed no interaction between drug and the polymers. Scanning electron microscopy images indicated that nanoparticles were spherical in shape. Water solubility of drug-loaded nanoparticles was increased as compared to the pure drug and showed improved dissolution profile, which indicated that nanoprecipitation, was simple and precise. This laboratory scale method as well as this approach could be employed for solubility and bioavailability improvement of aceclofenac.

 

 

 

INTRODUCTION:

Advanced drug delivery systems have numerous advantages over conventional multi dose therapy. Much research effort in developing such drug delivery systems has been focused on controlled release and sustained release dosage forms. Now a day effort is being made to deliver the drug in such a manner so as to get optimum benefits [1,2]. There are numerous strategies in delivering therapeutic agent to the target site in a sustained release fashion. One such strategy is using nanoparticles as drug carrier [3, 4].

 

The major nanoparticulate drug delivery system is liposomes and polymeric nanoparticles have particular advantage for site-specific drug delivery and to enhance the dissolution rate along with bioavailability of poorly water soluble drugs [5]. Formation of drug-loaded nanoparticles is actually a very promising approach. Particle size reduction tothe nanometre range can be achieved using various techniques and these techniques have been extensively described [6]. Poor solubility and low dissolution rate of Biopharmaceutical Classification System (BCS) classII drugs in the aqueous gastrointestinal fluids oftencauses insufficient bioavailability and this can only beenhanced by increasing the solubility and dissolutionrate by using various novel techniques [7]. Some of the techniques employed to improve drug dissolution rateare solid dispersion, inclusion complex formation, microparticles and nanoparticles. Nanoparticles are colloidal particles ranging from 10 to 1000nm, in which the active principles (drug or biologically active material) are dissolved, entrapped [8]. And these are of different types include, nanospheres, nanocapsules, dendrimers, solid-lipid nanoparticle, polymeric micelles and liposomes. Withthe development in nanotechnology, it is now possible to produce drug nanoparticles that can be utilized in a variety of innovative ways. New drug delivery pathways can now be used to increase drug efficacy and reduce side effects [9]. Solid-lipid nanoparticles areat the rapidly developing field of nanotechnology with several potential applications in the clinical medicine and research. Nanoparticles are receiving considerable attention for the delivery of therapeutic drugs. Depending on the physicochemical characteristics of a drug, it is now possible to choose the best method of preparation with the best polymer to achieve an efficient entrapment of the drug [10]. Different methods for the preparation of nanoparticles are available, which include, solvent evaporation, nanoprecipitation, emulsification/ solvent diffusion, salting out, dialysis, supercritical fluid technology and rapid expansion of supercritical solution, rapid expansion of supercritical solution into liquid solvent. Aceclofenac, [2-[[2-[2- [(2, 6-dichloro phenyl) amino] phenyl] acetyl] oxy] acetic acid], isa NSAID of the phenyl acetic acid group which is structurally related to diclofenac. Aceclofenac acts with preferential selective cyclooxygenase-2 (COX-2) inhibition after conversion into active metabolite [11-13]. Which could be extremely beneficial in ocular inflammation? Aceclofenac possess its action by inhibiting the secretion of tumor necrosis factor (TNF-α) and interleukin-1. Moreover, aceclofenac possesses good anti-inflammatory and analgesic activities and have better gastric tolerance in comparison with other NSAIDs such as indomethacin and diclofenac. Aceclofenac is a BCS class II drug, which has low solubility and high permeability [14]. Aceclofenac is not stable and gets easily hydrolyzed in aqueous environment. Present work deals with the preparation and evaluation of aceclofenac-loaded nanoparticles by solvent evaporation technique.

 

MATERIALS AND METHODS:

Aceclofenac was received as gift from and Ranbaxy Research Laboratotries (Gurgaon, India). Ethyl cellulose, Chitosan, HPMC K100 was procured from Qualikems Fine Chem. Pvt Ltd Vadodhara. Ethanol, Polyvinyl alcohol, dichloromethane was purchased from CDH chemical Pvt. Ltd. New Delhi. Dialysis membrane of Mol Wt cutoff 1200 was purchased from Himedia Laboratory, Mumbai. Double distilled water was prepared freshly and used whenever required. All other ingredients and chemicals used were of analytical grade.

 

Preformulation study

Preformulation is the first step in rationale development of any pharmaceutical dosage form of a new drug. Preformulation study focuses on those physicochemical properties of the new compound that can affect drug performance and development of an efficacious dosage form. These preformulation investigations confirm that there are no significant barriers to the compounds development. Melting point of aceclofenac was determined by open capillary tube method. FTIR spectra of pure drugs, polymers used and blends were recorded on KBr disk method using Brukers Alpha Spectrophotometer with IR solution software to confirm the compatibility between drug and excipients. Sample powder was thoroughly mixed by triturating with potassium bromide ina glass mortar with pestle and compressed into disks ina hydraulic press (Techno Search Instruments, India). FTIR spectra of all the samples were recorded over a spectral region from 4700 to 400 cm^-1 using 20 scans with 4 cm^-1 resolution.

 

Determination of absorption maxima:

A solution of containing the concentration 20μg/ml was prepared in 0.1N HCl. UV spectrum was taken using Double beam UV/VIS spectrophotometer (UV-1700 Shimadzu Corporation, Japan). The solution was scanned in the range of 200-400nm.

 

Preparation calibration curve:

Accurately weighed 10 mg of drug was dissolved in 10 ml of 0.1N HCl solution in 10 ml of volumetric flask separately. The resulted solution 1000µg/ml and from this solution 1 ml pipette out and transfer into 10 ml volumetric flask and volume make up with 0.1N HCl solution. Prepare suitable dilution to make it to a concentration range of 5-35μg/ml. The spectrum of this solution was run in 200-400 nm range in U.V. spectrophotometer (UV-1700 Shimadzu Corporation, Japan). The absorbance of these solutions was measured at 274 nm 0.1N HCL as a blank. Linearity of standard curve was assessed from the square of correlation coefficient (r²) which determined by least-square linear regression analysis.

 

Method of preparation:

Nanoparticles prepared by polymers like chitosan, ethyl cellulose, hydroxyl propyl methyl cellulose and polyvinyl alcohol by solvent evaporation method. Disperse phase consisting of aceclofenac (300mg) and requisite quantity of polymers dissolved in 20 ml solvent (dichloromethane) was slowly added to a definite amount of PVA in 100ml of aqueous continuous phase. The reaction mixture was stirred at 1000 rpm for two- three hours on a magnetic stirrer. The nanoparticles formed were collected by filtration through whatman filter paper and dried in oven at 50⁰C for 2 hours. The dried nanoparticles were stored in vaccumdesicater to ensure the removal of residual solvent [15] Table 1.

 

Table 1 Formulation of aceclofenac nanoparticles

Formulation Code	INGREDIENTS
	Aceclofenac (mg)	Ethyl cellulose (mg)	Chitosan (mg)	HPMC K100 (mg)	Polyvinyl alcohol (%w/v)	Dichlro Methane (ml)	Distilled water (ml)
F1	300	300			0.2	20	100
F2	200	600			0.2	20	100
F3	300	900			0.2	20	100
F4	300	1200			0.2	20	100
F5	300		300		0.2	20	100
F6	300		600		0.2	20	100
F7	300		900		0.2	20	100
F8	300		1200		0.2	20	100
F9	300			300	0.2	20	100
F10	300			600	0.2	20	100
F11	300			900	0.2	20	100
F12	300			1200	0.2	20	100

 

Characterization of nanoparticles:

Organoleptic properties of the nanoparticles like colour, odour and physical appearance were observed visually and recorded. Practical yield was calculated using the Eqn., PY (%) = amount of product obtained/amount of total solid used (polymer+drug)×100.

 

Drug content:

Sample containing 100 mg equivalent aceclofenac nanoparticles are dissolved and the volume is made upto 100ml with 0.1 N HCl. From the above solution 10 ml is pipette out and made upto 100 ml with 0.1 N HCl. The Absorbance of resulting solution is determining at λmax (274 nm) using UV spectrophotometer (UV-1700 Shimadzu Corporation, Japan) and the drug content is estimated using 0.1 N HCl blank.

 

Drug entrapment:

The various formulations of the aceclofenac nanoparticles were subjected for drug content. 10 mg of nanoparticles from all batches were accurately weighed and crushed. The powder of nanoparticles were dissolved in 10 ml 0.1 N HCl and centrifuge at 1000 rpm. This supernatant solution is than filtered through whatmann filter paper No. 44. After filtration, from this solution 0.1 ml was taken out and diluted up to 10 ml with 0.1 N HCl. The percentage drug entrapment was calculated using calibration curve method.

 

Measurement of mean particle size

The mean size of the nanoparticleswas determined by Photo Correlation Spectroscopy (PCS) on a submicron particle size analyzer (Horiba Instruments) at a scattering angle of 90°. A sample (0.5mg) of the nanoparticles suspended in 5 ml of distilled water was used for the measurement.

 

Determination of zeta potential:

The zeta potential of the drug-loaded nanoparticles was measured on a zeta sizer (Horiba Instruments) by determining the electrophoretic mobility in a micro electrophoresis flow cell. All the samples were measured in water at 25°C in triplicate.

 

Shape and surface characterization of nanoparticles by scanning electron microscopy (SEM):

Morphological evaluation of the selected nanoparticles formulation is carried out in scanning electron microscope (SEM) (Hitachi X650, Tokyo, Japan). All samples are examined on a brass stub using carbon double-sided tape. Powder samples are glued and mounted on metal sample plates. The samples are gold coated (thickness ≈15–20 nm) with a sputter coater (Fison Instruments, UK) using an electrical potential of 2.0kV at 25 mA for 10 min. An excitation voltage of 20 kV was used in the experiments [16-19].

 

In-vitro release studies:

The drug release rate from nanoparticles was passed out using the USP type II (Electro Lab.) dissolution paddle instrument. A weighed amount of nanoparticles equivalent to 100 mg drug were dispersed in 900 ml of 0.1 N HCI maintained at 37 ± 0.5°C and stirred at 55rpm. One ml sample was withdrawn at predetermined intervals and filtered and equal volume of dissolution medium was replaced in the vessel after each withdrawal to maintain sink condition. The collected samples analyzed spectrophotometrically at 274 nm to determine the concentration of drug present in the dissolution medium [20-24].

 

Mathematical treatment of in-vitro release data: The quantitative analysis of the qualities got in dissolution/ release tests is simpler when mathematical formulas that express the dissolution comes about as an element of a portion of the measurement frames attributes are utilized.

 

1. Zero-order kinetics:

The pharmaceutical dosage frames following this profile release a similar measure of medication by unit of time and it is the ideal method of medication release keeping in mind the end goal to accomplish a pharmacological prolonged action. The following relation can, in a simple way, express this model:

 

Q_t = Q_o+ K_ot

Where Q_t is the amount of drug dissolved in time t, Q_o is the initialamount of drug in the solution (most times, Q_o=0) and K_ois the zero order release constant.

 

2. First-order kinetics:

The following relation expresses this model:

 

Where Q_t is the amount of drug dissolved in time t, Q_o is the initial amount of drug in the solution and K₁is the zero order release constant.

 

Along these lines a graphic of the decimal logarithm of the released measure of drug versus time will be linear. The pharmaceutical dosage shapes following this dissolution profile, for example, those containing water-solvent drugs in permeable frameworks, discharge drug in a way that is corresponding to the measure of drug staying in its inside, in such way, that the measure of drug released by unit of time reduce.

 

3. Higuchi model:

Higuchi built up a few theoretical models to ponder the arrival of water-solvent and low dissolvable medications in semi-strong or potentially strong grids. Mathematical expressions were acquired for sedate particles scattered in a uniform grid acting as the diffusion media. The simplified Higuchi model is expressed as:

 

Where Q is the amount of drug released in time t and K_H is the Higuchi dissolution constant. Higuchi model describes drug release as a diffusion process based in the Fick’s law, square root time dependent. This relation can be utilized to portray the drug dissolution from a few kinds of modified release pharmaceutical dosage structures, for example, transdermal systems and mucoadhesive tablets with water-dissolvable drugs.

 

4. Korsmeyer-Peppas model:

Korsmeyer et al. used a simple empirical equation to describe general solute release behaviour from controlled release polymer matrices:

 

Where M_t/M_¥is fraction of drug released, a is kinetic constant, t is release time and n is the diffusional exponent for drug release. ’n’ is the slope value of log M_t/M_¥ versus log time curve. Peppas stated that the above equation could adequately describe the release of solutes from slabs, spheres, cylinders and discs, regardless of the release mechanism. Peppas used this n value in order to characterize different release mechanisms, concluding for values for a slab, of n =0.5 for fickian diffusion and higher values of n, between 0.5 and 1.0, or n =1.0, for mass transfer following a non-fickian model. In case of a cylinder n =0.45 instead of 0.5, and 0.89 instead of 1.0. This equation can only be used in systems with a drug diffusion coefficient fairly concentration independent. To the determination of the exponent n the portion of the release curve where M_t/M_¥< 0.6 should only be used. To use this equation it is also necessary that release occurs in a one-dimensional way and that the system width-thickness or length-thickness relation be at least 10. A modified form of this equation was developed to accommodate the lag time (l) in the beginning of the drug release from the pharmaceutical dosage form:

 

When there is the possibility of a burst effect, b, this equation becomes:

 

In the absence of lag time or burst effect, l and bvalue would be zero and only atⁿ is used. This mathematical model, also known as Power Law, has been used very frequently to describe release from several different pharmaceutical modified release dosage forms.

 

Stability studies:

The nanoparticle formulation was subjected to stability studies according to ICH guidelines by storing at 25⁰C/60% RH and 40⁰C/75% RH for 60 days. These samples were analyzed and checked for changes in physical appearance, drug content and entrapment efficiency, invitro drug release studies at regular intervals. The formulation subjected for stability study was stored in borosilicate container to avoid any interaction between the formulation and glass of container.

 

RESULTS AND DISCUSSION:

Solubility of aceclofenac was freely soluble in methanol, DMSO, acetone and ethanol, soluble in 0.1N HCL and 6.8 pH phosphate buffers, insoluble in water. The melting point of aceclofenac was 154-156ºC and λ _max of aceclofenac was found to be 274 nm by using U.V. spectrophotometer (UV-1700 Shimadzu Corporation, Japan) in linearity range 5-35µg/ml Figure1. Partition coefficient of aceclofenac was found to be 1.85.

 

Figure 1Determination of λ_max of aceclofenac

 

From the spectra of aceclofenac physical mixture of drug and selected ingredients it was observed that all characteristic peaks of aceclofenac were present in the combination spectrum, thus indicating compatibility between drug and selected ingredients. FTIR Spectra shown in Figure 2 and 3.

 

Figure 2 FTIR spectra of pure aceclofenac

 

Figure 3 FTIR Spectra of aceclofenac nanoparticle

 

Practical yield, drug content and EE were given inTable 2. Practical yield of the prepared nanoparticles was in the range of 24.43±1.37to 64.51±0.97%. The yield of nanoparticles decreased with increasing the concentration of drug and polymer ratio, which might be due to generation of stickiness by polymer. It was found that with increasing the amount of polymer, the actual drug loading and EE increased. The EE was found to be in the range from 55.36±0.83to91.88±1.38%. The drug content of nanoparticles was found to be in the range of 84.56±1.27to 97.20±1.46%. It was observed that the drug content and encapsulation efficiency depends on the concentration of polymer, solvent ratio and stirring rate. On the basis of high yield, actual drug content and encapsulation efficiency batch F2, 6, 10 was observed as optimized batch for the preparation of nanoparticles.

 

Table 2 Practical yield, drug loading and entrapment efficiency of nanoparticles

S. No.	F. Code	(%) Practical yield	(%) Drug content	(%) Entrapment efficiency
1.	F1	62.09±0.93	91.22±1.37	68.56±1.03
2.	F2	43.61±1.65	94.01±1.41	75.96±1.14
3.	F3	29.71±0.45	88.57±1.33	64.53±0.97
4.	F4	24.43±1.37	85.88±2.29	67.84±1.02
5.	F5	64.51±0.97	84.56±1.27	68.66±2.03
6.	F6	41.51±2.62	97.20±1.46	91.88±1.38
7.	F7	32.42±0.49	91.17±0.37	74.93±1.12
8.	F8	25.06±1.38	91.34±1.37	55.36±0.83
9.	F9	62.11±0.93	91.03±1.37	68.85±3.03
10.	F10	44.79±1.67	95.03±2.43	75.57±1.13
11.	F11	31.07±0.47	91.46±1.37	61.33±1.92
12.	F12	25.87±2.39	87.33±1.31	59.15±0.89

 

 

The nanoparticles were evaluated for in vitro dissolution studies in 0.1N HCl for 12 hours. The results of in-vitro drug release revealed that the aceclofenac was released in a controlled manner from F2, 6, 10 the formulations where formulation F6 showed maximum drug release i.e. 98.07±0.73% at the end of 12^th hour. The results of release studies of formulations F2, 6, 10 are shown in Table 3 and Figure 4. The in vitro drug release data of the optimized formulation F6 was subjected to goodness of fit test by linear regression analysis according to zero order, first order kinetic equation, Higuchi’s and Korsmeyer’s models in order to determine the mechanism of drug release. When the regression coefficient values of were compared, it was observed that ‘r’ values of Peppas model was maximum i.e 0.9924 hence indicating drug release from formulations was found to follow zero order kinetics Table 4 and  Figure 5-8.

Table 3In-vitro drug release study of nanoparticles

S. No.	Time in hours	Cumulative % Release
		F2	F6	F10
1.	1	2.84±0.35	2.77±0.25	2.08±0.06
2.	2	12.32±2.05	17.05±0.71	10.65±0.15
3.	3	21.81±0.23	20.91±0.68	22.47±2.02
4.	4	26.95±0.26	29.57±0.33	32.03±0.46
5.	5	32.96±1.48	35.95±0.91	37.09±0.92
6.	6	37.39±1.55	42.96±1.14	43.55±0.94
7.	7	44.87±0.65	49.73±0.81	50.22±0.85
8.	8	52.41±0.93	57.59±1.16	58.46±1.11
9.	9	58.28±0.68	67.51±1.03	65.99±0.85
10.	10	64.38±1.14	77.28±0.47	72.55±1.21
11.	11	80.49±1.84	88.37±1.81	80.48±1.01
12.	12	87.07±1.07	98.07±0.73	90.02±0.77

 

 

Figure 4 In-vitro drug release study of nanoparticles

 

 

Table 4 Regression analysis data of aceclofenac nanoparticle

Batch	Zero Order	First Order	Higuchi	Korsmeyer-Peppas
	r²	r²	r²	r²
F5	0.9924	0.9371	0.9710	0.9413

 

 

Figure 5 Zero order release Kinetics

 

 

Figure 6First order release kinetics

 

 

Figure 7 Higuchi release Kinetics

 

 

Figure 8Korsmeyer-Peppas release Kinetics

 

The results of measurement of mean particle size of optimized formulation F6 of aceclofenac nanoparticle was found 195 nm Figure 9. Results of zeta potential of optimized formulation F6 of aceclofenac nanoparticle was found -26.6mV Figure 10. The morphology of the nanoparticles by solvent evaporation method was investigated by Scanning electron microscopy (SEM). It was observed that the nanoparticles were uniformly spherical in shape Figure 11.

 

Figure 9 Particle size data of optimized nanoparticle formulation F6

 

Figure 10 Zeta potential data of nanoparticle formulation F6

 

Figure 11 SEM image of optimized nanoparticle formulation F6

 

Stability studies results indicated no significant changes in the parameter even when it was subjected to testing for 2 months when F6 was studied for short term storage conditions, the drug content in the formulation within the 95% confidence interval and hence slight decrease in the drug content was statistically not significant. From the stability studies it was confirmed that nanoparticle formulations of aceclofenac remained more stable at storage conditions Table 5.

 

Table 5. Stability study of optimized formulation (F6) of aceclofenac nanoparticles formulation

Storage Temperature	25°C ±20C /65%RH			40°C ±20C /70%RH
Parameter	% Drug content	% Entrapment efficiency	Cumulative % drug Release	% Drug content	% Entrapment efficiency	Cumulative % drug Release
Initial	97.20 ±1.46	91.88 ±1.38	98.07 ±0.73	97.20 ±1.46	91.88 ±1.38	98.07 ±0.73
30 Days	96.92 ±1.23	91.73 ±1.45	97.54 ±1.16	96.48 ±1.22	90.91 ±1.44	96.66 ±1.15
60 Days	96.85 ±1.16	91.26 ±1.75	97.15 ±1.23	96.41±1.15	90.44 ±1.73	96.27 ±1.22

 

 

CONCLUSION:

Aceclofenac loaded nanoparticles were prepared by solvent evaporation technique. The obtained nanoparticles were characterized by Scanning electron microscopy. The images clearly reveal that the particles were in nano range. The drug content was found to be 97.20±1.46 %. The entrapment efficiency of nanoparticles was observed as 91.88±1.38. Thus, this study concluded that the aceclofenac nanoparticles are suitable candidates that provide the best anti-inflammatory and analgesic activities prolong action of the drug nanoparticles.

 

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Received on 10.07.2020         Modified on 16.07.2020

Accepted on 21.07.2020       ©A&V Publications All right reserved