ENHANCEMENT OF ORAL BIOAVAILABILITY OF NAPROXEN BY LIQUISOLID COMPACTION TECHNOLOGY: IN VITRO, IN VIVO EVALUATION

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1 Page1359 Indo American Journal of Pharmaceutical Research, 2013 ISSN NO: Journal home page: INDO AMERICAN JOURNAL OF PHARMACEUTICAL RESEARCH ENHANCEMENT OF ORAL BIOAVAILABILITY OF NAPROXEN BY LIQUISOLID COMPACTION TECHNOLOGY: IN VITRO, IN VIVO EVALUATION Vijaykumar Nagabandi 1,2, Sridhar Thota 1,2, Anil Kumar Chandragiri 3, Pragathi Katakam 1,2 1 Vaageswari College of Pharmacy, Karimnagar, A.P, India St. Peter s Institute of Pharmaceutical Sciences, Vidyanagar, Hanamkonda, A.P, India University Institute of Pharmaceutical Sciences, Satavahana University, Karimnagar, A.P, India ARTICLE INFO Article history Received 8/121/2013 Available online 30/12/2013 Keywords Liquisolid Compacts, Oral Bioavailability, Dissolution, Naproxen. ABSTRACT The main objective of present investigation was to enhance the dissolution rate of water insoluble drug and hence oral bioavailability of Naproxen by using liquisolid compaction technique. Several liquisolid tablets were prepared by using different carrier materials such as microcrystalline cellulose, and dicalcium phosphate (DCP), and coating material such as colloidal silica. Polyethylene glycol (PEG), cremophor EL, Poloxamar 181 and propylene glycol were used as non volatile water miscible liquid vehicles. The ratio of carrier to coating material was kept constant in all formulations at 20 to 1. All the prepared formulations were compressed using 12mm punch after addition of 5 % Sodium starch glycolate to each formulation. In vitro dissolution studies were conducted by using USP six basket dissolution testing apparatus. In vitro intestinal permeation studies were conducted by using goat intestinal membrane and in vivo oral bioavailability studies were conducted to the optimized formulation, marketed formulation and pure drug sample in healthy rats by balanced block incomplete design. Plasma samples were analyzed by RP-HPLC method. Liquisolid compacts prepared with PEG as solvent, DCP as carrier and colloidal silica as coating material have shown 100 % of drug release with in 10 min and hence have been chosen for in vivo studies. And it has shown 126 % of relative bioavailability when compared with pure drug. FTIR results revealed that there was no interaction between the drug and excipients. Based on all results obtained, it can be concluded that liquisolid compaction technology is one the most promising novel approach to enhance the oral bioavailability of poorly soluble BCS class II drugs. Corresponding author Vijaykumar Nagabandi, Department of Pharmaceutics, St. Peter s Institute of Pharmaceutical Sciences, Hanamkonda, Warangal , Andhra Pradesh, India. Tel: ; Fax: ; vijaybpharm@gmail.com Please cite this article in press as Vijaykumar Nagabandi et al. Enhancement of oral bioavailability of naproxen by liquisolid compaction technology: in vitro, in vivo evaluation. Indo American Journal of Pharm Research.2013:3(12). Copy right 2013 This is an Open Access article distributed under the terms of the Indo American journal of Pharmaceutical Research, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

2 Page1360 INTRODUCTION: Solubility is an important parameter for oral absorption of drugs which are poorly soluble. Dissolution is the rate liming step for such drugs in their absorption through oral route. Oral route is a major route of administration for majority of drugs. BCS class II drugs suffer less bioavailability thereby decreased therapeutic effect problems due to poor solubility and limited dissolution rate [1,2]. Liquisolid compacts promote dissolution rate of water insoluble drugs to a greater extent and also enhances the drug flow property. The term liquisolid compact refers to immediate release formulation formed by conversion of liquid drugs, drug suspensions, or drug solution in non volatile solvents into dry, non adherent, free flowing and compressible powder mixtures by blending the suspension or solution with selected carriers and coating materials. Liquisolid medications are those in which liquid lipophilic drugs, drug suspensions or solutions of water insoluble drugs in suitable non- volatile solvent systems were formulated into dry, non volatile adherent, free flowing and readily compressible powder admixture by blending with selective carrier and coating materials [3-5]. Naproxen, (6-methyl 2-naphthyl acetic acid) non-steroidal anti-inflammatory drug, is a weak acid (pka = 4.15) which is practically insoluble in water and the major problem associated with the formulation and effectiveness of the naproxen is its variable oral absorption due to insufficient aqueous solubility at gastrointestinal ph, thus making dissolution the rate-determining step in the gastric absorption of naproxen [6]. The main objective of this work is to develop and evaluate a new formulation to enhance the bioavailability of a highly permeable and a poorly soluble non steroidal anti-inflammatory drug naproxen by liquisolid compaction technique. METHODOLOGY: Solubility Determination: The solubility of drug is an important physicochemical property because it affects the bioavailability of the drug, the rate of drug release into dissolution medium and consequently, the therapeutic efficiency of the pharmaceutical product. The solubility of material is usually determined by the equilibrium solubility method, which employs the preparation of a saturated solution of the material, obtained by stirring an excess of material in the solvent for a prolonged period of time [72hrs] until equilibrium is achieved at 25 0 C on mechanical shaker. After this period the solutions were filtered through 0.45µ Millipore filter, diluted with 7.4 ph phosphate buffer and analysed spectroscopically at respected wavelength against blank sample (blank sample containing the same concentration of specific solvent used without drug). Three determinations were carried out for each sample to calculate the solubility of drug [7]. Solvents used for solubility determination are Water, Polyethylene Glycols, Propylene Glycol, Glycerin, Tween 80, Cremophor EL/ Polyoxyl 35 Castor Oil, Poloxamer 181/ Synperonic PE/L61 and 7.4 ph Phosphate Buffer Fourier Transform Infrared Spectroscopy: The KBr disk sample preparation technique (pressed pellet technique) was used to obtain the IR spectra of the samples on an IR spectrophotometer (SHIMADZU FTIR-8400s). The scanning range was selected between 4000 and 400 cm -1. Characteristic peaks attributable to functional groups present in molecule of each drug were assigned to establish the identity [8]. Selection of non volatile Liquids: To select the suitable non volatile liquid for dissolving or suspending the drug in liquid medication, solubility studies were conducted in different non volatile solvents. The procedure for solubility study was given in previous section. The solvent should have the characteristic of a non toxic and non volatile solvent [9]. In the current investigation following list of non volatile liquids were selected for the preparation of liquisolid compacts. Polyethylene Glycol 200, Polyethylene Glycol 400, Polyethylene Glycol 600, Propylene Glycol, Glycerin, Tween 80, Cremophor EL/ Polyoxyl 35 Castor Oil, Poloxamer 181/ Synperonic PE/L61 Selection of Carriers and Coating Agents: In this approach the carrier play as a major role in obtaining the dry form of powder from the liquid medication. Each carrier has its unique property; selection of carrier will depend upon liquid holding capacity, flow ability of powder and which, requires less compression force. Carriers selected in the current study were microcrystalline cellulose, dicalicum phosphate, lactose and starch. silica was selected as the coating agent as it is ideal for coating of the formulation [12]. Preparation of various formulations: Required amount or quantity of drug was taken in a 20 ml glass beaker and then it is wetted with suitable non volatile solvent. The resulting wet medication was incorporated into calculated quantities of carrier and coating materials whose ratio is kept constant at 20:1 until it becomes as a free flowing powder. Mixing process is carried out in three steps as described by spireas et al. During the first stage, the system is blended at an average mixing rate of one rotation per second for one min in order to evenly distribute liquid medication in the powder. In the second stage, the liquid/powder admixture was evenly spreaded as a uniform layer on the surface of a mortar and left standing for 5min to allow drug solution to be absorbed in the interior of powder particles. In the third stage, the powder was scrapped off the mortar surfaces by means of aluminium spatula [11]. The prepared formulations containing drug equivalent to 100mg are compressed using 12mm punch for liquisolid formulations, 6mm punche for melt granulates and 8mm punch for solid dispersions on automated 12 station rotary compression machine. A pressure of 500 newtons/m 2 is applied for adjustment of the hardness to 3-5 kg/cm 2. The compressed tablets are evaluated for different parameters. Compositions of various formulations are given table 1-9.

3 Page1361 Table 1: of Naproxen prepared with Poly Ethylene Glycol 200 Drug (mg) Solvent Carrier Coating material Disintegrating agent Total factor (L f) NF1 100 PEG 200- MCC- silica- Sodium starch 525mg mg mg 16.45mg glycollate-25mg NF2 100 PEG 200- DCP- silica- Sodium starch 519mg mg mg 16.20mg glycollate-24mg NF3 100 PEG 200- Starch- silica- Sodium starch 526mg mg 329.5mg 16. glycollate-25mg NF4 100 PEG 200- Lactose- silica- Sodium starch 525mg mg 329mg 16.45mg glycollate-25mg Table 2: of Naproxen prepared with Poly Ethylene Glycol 400 Drug (mg) Solvent Carrier Coating material Disintegrating agent Total factor (L f) NF5 100 PEG 400- MCC- silica- Sodium starch 546mg mg 17.25mg NF6 100 PEG 400- DCP-340mg silica- Sodium starch 540mg mg NF7 100 PEG 400- NF8 100 PEG 400- Starch mg Lactose- 343mg mg silica- silica- Sodium Sodium starch starch Table 3: of Naproxen prepared with Poly Ethylene Glycol 600 Table 4: of Naproxen prepared with Propylene Glycol 546mg mg Drug (mg) Solvent Carrier Coating material Disintegrating agent Total factor (L f) NF9 100 PEG 600- MCC- silica- Sodium starch 561mg mg mg 17.78mg glycollate-27mg NF PEG 600- DCP-343mg silica- Sodium starch 547mg mg 17.18mg NF PEG 600- Starch- silica- Sodium starch 553mg mg 348.5mg 17.48mg NF PEG 600- Lactose- silica- Sodium starch mg 346mg 17.3mg Drug (mg) NF Propylene glycol-55mg NF Propylene glycol-55mg NF Propylene glycol-55mg NF Propylene glycol-55mg Solvent Carrier Coating material MCC- 330mg DCP- 325mg Starch- 338mg Lactose- 340mg silica- 16.5mg silica mg silica- 16.9mg silica- 17mg Disintegrating agent Sodium starch glycollate -25mg Sodium starch glycollate -24.8mg Sodium starch glycollate -25mg Sodium starch glycollate -25mg Total 526mg mg mg mg 0.161

4 Page1362 Table 5: of Naproxen prepared with Glycerin Drug (mg) Solvent Carrier Coating material NF Glycerin- MCC- silica- 70mg 348mg 17mg NF Glycerin- DCP- silica- 70mg 345mg 17.25mg NF Glycerin- Starch- silica- 70mg 352mg 17.6mg NF Glycerin- Lactose- silica- 70mg 355mg 17.75mg Disintegrating agent Sodium starch glycollate -27mg Sodium starch glycollate -27mg Sodium starch glycollate -27.4mg Sodium starch glycollate mg Total 562mg mg mg mg Table 6: of Naproxen prepared with Tween 80 Drug Solvent Carrier Coating material NF Tween 80-60mg NF Tween 80-60mg NF Tween 80-60mg NF Tween 80-60mg MCC- 356mg silicasilicasilicasilica- DCP- 344mg Starch- 349mg Lactose- 347mg 17.8mg 17mg 17.45mg 17.35mg Disintegrating agent 27.2mg 26mg 26.55mg 26.65mg Total 561mg mg mg mg Table 7: of Naproxen prepared with Cremophor EL Drug Solvent Carrier Coating material Disintegrating agent Total NF Cremophor EL - 54mg NF Cremophor EL - 54mg NF Cremophor EL - 54mg NF Cremophor EL - 54mg MCC- 327mg 16.35mg silica- DCP-322mg silica- 16mg Starch- silica- 328mg 16.45mg Lactose- 327mg 16.35mg silica mg 26mg 25.55mg 24.65mg Table 8: of Naproxen prepared with Poloxamer mg mg mg mg Drug Solvent Carrier Coating material Disintegrating agent Total NF poloxamer 181- NF poloxamer 181- NF poloxamer 181- NF poloxamer 181- MCC- 290mg 14.5mg silica- DCP-285mg silica mg Starch- silica- 286mg 14.3mg Lactose- silica- 288mg 14.4mg 22.5mg 22.75mg 22.7mg 22.6mg 477mg mg mg mg 0.173

5 Page1363 Table 9: Effect of hydrophilic additives on best formulation of Naproxen (PEG DCP) Drug Solvent Hydrophilic excipient Carrier (DCP) Coating material ( Silica) Disintegrating agent Total NF PEG- NF PEG- NF PEG- NF PEG- HPMC E3LV- 280mg 14mg SSG -25mg 526mg PVP K35-276mg 13.8mg SSG -25.2mg 523mg PEG mg 13.55mg SSG mg 517mg PEG 35, mg 13.45mg SSG mg 515mg Evaluation of the prepared formulations for physico-chemical characteristics: All the prepared matrix tablet were evaluated for various physico chemical characteristics such as shape, dimensions, variation, hardness, friability and disintegration. In Vitro Drug Release Studies: In vitro dissolution studies were carried out in simulated G.I. fluid (phosphate buffer of ph 7.4) using dissolution test apparatus USP XXIV rotating paddle assembly. Freshly prepared test media of 900ml was placed in dissolution vessels of dissolution test apparatus USP XXIV model. Tablets of different formulations of drug were placed in each vessel (3 tablets were tested in each formulation), paddle was immersed in dissolution media and maintained at 37±0.5 0 C and was rotated at the speed of 100 rpm. 5ml of samples were withdrawn at fixed time intervals and this was immediately replaced with same volume of test media. The samples withdrawn were filtered and estimated spectrophotometrically at 260nm at 230nm. Cumulative amount of drug released at each interval was calculated by using standard graph [13]. In Vivo bioavailability studies: The bioavailability studies in rats were conducted with permission from the ethical committee (No: 001/SRRCOPSc/KNR/IAEC/2011). Analysis of plasma samples was done by HPLC method. In Vivo bioavailability studies were conducted in total of 12 rats. Randomized Balanced Incomplete Block Design (BIBD) was followed. The bioavailability of optimized formulation was compared with bioavailability of pure drug and marketed formulation. All the rats used in the study were not medicated prior to the study. Standard diet was followed throughout study as there is no impact of diet on drug absorption. Animal dose was calculated based on K m values, by using following formula [14] AED (mg/kg) = HED (mg/kg) X K m Value of Human/ K m Value of Animal As per the above formula animal dose is approximately equivalent to 10mg/kg. All the rats used in the study were having the body of g.total study was divided into two study periods. Wash out period was maintained between study periods. Optimized formulations of drugs and marketed formulations were taken and finely powdered. Weight equivalent to 10 mg of drug was taken and suspended in 1 ml of 0.25% CMC solution. Based on body of each rat, dose required was calculated and administered into the rat through oral feeding tube. Blood samples were collected at predetermined time intervals up to 4hrs from rat retero orbital vein. Plasma was separated by centrifugation process at 5000 rpm for 5min and stored under frozen condition till the analysis was performed. Samples were analyzed by HPLC. From the obtained peak area values, plasma concentrations were determined and graph was plotted by taking plasma concentration on Y-Axis and time on X-Axis. From the concentration values obtained AUC (0-t) and all other possible pharmacokinetic parameters such as C max, t max, half-life etc, were calculated for each formulation and for each subject. RESULTS & DISCUSSION: Solubility Studies: Solubility of pure drugs was determined in different solvents by saturation solubility method and the values obtained were given in the Table 10. From the results obtained it was observed that both the drugs were insoluble in distilled water but were freely soluble in nonvolatile liquids. This might be due to the co solvent effect of the hydrophilic solvents. And it was observed that the solubility of naproxen was highest in PEG 600. IR Spectroscopy The infrared spectra of pure drugs and formulations were recorded by KBr method using shimadzu Fourier Transform Infrared Spectrophotometer. In case of formulations, drug is mixed with non volatile solvent, all carriers, coating material, and disintegrating agent and IR spectra were recorded for each solvent separately. Characteristic peaks of Naproxen were observed in pure drug IR spectra at cm -1 (Aromatic C-H stretch, carboxylic acid O-H stretch), cm -1 (C=O stretch), 1604 cm -1 (Aromatic C=C stretch), 1394 cm -1 (CH-CH 3 deformation), 1685 cm -1 (Carboxylic O-H out of plane deformation), cm -1 (C-H out of plane deformation for substituted aromatic). From the IR spectra of formulations it was evident that pure drug in formulations

6 Page1364 undergoes no chemical reaction or interaction with any of the excipients used as there was no disappearing of any peak or no change in the position of all the peaks. Overlay of IR spectra of all the formulations are given in fig.1. Table 10: Solubility of Naproxen in various solvents (n=3) S.NO Solvent Amount of Naproxen Dissolved (mg/ml) Solubility (MEAN + SD) 1 Water Insoluble 2 PEG Freely soluble 3 PEG Freely soluble 4 PEG Freely soluble 5 PG soluble 6 Glycerin Freely soluble 7 Tween Freely soluble 8 Cremophor EL Freely soluble 9 Poloxamer soluble 10 Phosphate Buffer (ph slightly soluble ) Fig.1: Overlay of IR Spectra of Naproxen formulations Evaluation of Post Compression Parameters Results of Tablet Dimensions, Weight variation, Hardness, Friability, disintegration time and assay are given in table no 11. It was found that all the results are within the acceptable range. Table 11: Evaluation Parameters of Naproxen Liquisolid Tablets (Mean + SD) (n=3) (kg/cm 2 Assay (%) Hardness Thickness Friability Weight Variation Disintegration Time ) (mm) (%) (%) (min) NF NF NF NF NF NF NF NF NF

7 Page1365 NF NF NF NF NF NF NF NF NF NF NF NF NF NF NF NF NF NF NF NF NF NF NF NF NF NF NF In Vitro Dissolution Studies % Drug release values at various time intervals were calculated. Graphs were plotted for each solvent separately in case of liquisolid compacts (Fig. 2 & 3) by taking % drug release on Y-Axis and time on X-Axis. Effect of hydrophilic additive on liquid loading factor and drug dissolution rate was studied. Drug, non volatile liquid and carrier combination which has given greater drug release in first 5min was selected to study the effect of hydrophilic additive on liquid loading factor and drug dissolution rate. Out of all the formulations, PEG600 has shown greater drug release than the remaining solvents. This might be due to the greater solubility of the drug in the respective solvent. Formulation NF10 containing PEG600 as solvent and DCP as carrier has shown greater drug release than the remaining carriers and hence has been chosen for studying the effect of hydrophilic additives. In general DCP is not having enough hydrophilicity, but in spite of this property, all the formulations prepared with DCP have shown greater drug release. This might be due to the basic ph of DCP, drug must have converted to its salt form and its solubility might have been increased. Formulation NF 33 containing PEG600 as solvent, DCP as carrier and HPMC as hydrophilic additive has highest drug release within less period of time and hence this formulation has been chosen for further studies. This might be due to the formation of hydrophilic coat of HPMC surrounding the drug particle.

8 Page1366 All liquisolid tablets showed greater than 80% drug release after 30 min except KF20 (77.08%). The reason attributed to this might be improved wetting property of the drugs due to the presence of liquid inside, drug might be dispersed at molecular level in the liquid and increased surface area available for drug dissolution. The reason is in case of liquisolid compacts hydrophilic carriers were added and in final formulation, hydrophilic additive was present in addition to the carrier. These materials might have formed a strong hydrophilic coat on the surface of drugs. Fig 2: Dissolution profiles of liquisolid compacts of naproxen with different vehicles

9 Page1367 Fig.3: Dissolution plot of Naproxen Optimized Liquisolid Tablets In Vivo Bioavailability Studies In Vivo bioavailability studies were conducted in rats for final optimized formulation of each drug, pure drugs and marketed formulations. Balanced Incomplete Block Design was followed. Blood samples were collected at various time intervals for up to 4 hrs and assayed for parent drug by RP-HPLC method. A graph was plotted by taking plasma concentration on Y- Axis and time on X- Axis and AUC values from o to t was calculated. Graph is shown in fig 4. Fig.4: Mean Plasma Concentration-Time profile of Naproxen Two Way ANOVA was applied for AUC values of all formulations. From the results it was concluded that there is a significant difference in the bioavailability (AUC) of each formulation and from the average AUC values it can be observed that final optimized formulation have shown improved bioavailability than marketed formulation and pure drugs. Hence, it can be concluded that liquisolid technique will improve the bioavailability of poorly soluble drugs. Table 12: Pharmacokinetic Parameters (Mean + SD) (n=6) FORMULATION Cmax (µg/ml) Tmax (Hrs) Half life (Hrs) NFP NFM NFO Various pharmacokinetic parameters like C max, t max and elimination half life were determined for pure drug, marketed formulation and optimized formulation and the results were shown in table 12.

10 Page1368 CONCLUSION: In the current study, an attempt was made to enhance the bioavailability of poorly water soluble drug Naproxen by a novel technique such as liquisolid compaction technique. From the results formulations prepared by liquisolid compaction technique have shown greater drug release. Hence, it is a best technique to increase the dissolution rate. In presence of hydrophilic additives, the dissolution rate was promoted, and it was higher with HPMC E3LV. Lliquisolid formulation prepared with PEG 600 as solvent, DCP as carrier, HPMC E3LV as hydrophilic additive (NF33) has shown fastest drug release (100 % drug release in 10 min) than all the other formulations and hence has been in vivo studies. From the results of In Vivo studies conducted between final optimized formulation of each drug, pure drugs and marketed formulation of both the drugs, it can be concluded that bioavailability of final optimized formulation was higher than the marketed formulation as well as pure drug. Hence, it can be concluded that, liquisolid technique could be a promising strategy in improving dissolution of insoluble drugs and formulating immediate release solid dosage forms. List of abbreviations: DCP: Dicalcium Phosphate PEG: Polyethylene glycol PG: Propylene Glycol HPLC: High performance liquid chromatography BCS: Biopharmaceutical Classification System USP: United States of Pharmacopoeia Lf: Liquid loading factor AED: Animal Equivalent Dose HED: Human Equivalent Dose AUC: Area under the curve ANOVA: analysis of variance.

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