INTRODUCTION:

Gums are complex polysaccharides with the high molecular mass and may be classified as acidic (tragacanth, albizia, acacia), neutral (asparagus gum, Plantago seed gum) or basic. Natural gums are known to be either acidic or neutral as there are no naturally-occurring basic gums Natural gums have a large variety of composition and rheological properties that cannot be easily mimicked by a synthetic polymer. There are many advantages associated with the natural gum low cost, free from side effects, biocompatible, environmentally friendly processing and local availability.^1-2 The oral route is well known, advantageous, important and appealing drug delivery system with ease of administration, self-medication and cost-effective.

Tablet adopted its popularity and availability in the market due to its ease of manufacturing, administration convenience, dosing accurateness and better stability than other dosage forms.³ Sustained release matrix tablets have given a new evolution towards novel drug delivery of pharmaceutical technology.⁴ These dosage forms are a type of reservoir designed to release drug constantly and continuously over a satisfactory prolonged period to maintain plasma drugs concentration within the therapeutic level.⁵ Sustained release tablets provide patient convenient and compliance with cost effective made from improved disease management. Recently the role of these gums in enveloping controlled drug delivery systems has increased significantly.^6-8 In this study, Ketoprofen was used as a drug model. It is an NSAID and a derivative of propionic acid which has been widely used for pain relief and inflammation reduction. Ketoprofen is clinically used for treatments of osteoarthritis and rheumatoid arthritis.⁹ Ketoprofen is a nonsteroidal anti-inflammatory drug (NSAID) dedicated for anti-inflammatory, analgesic and antipyretic.⁵ Ketoprofen is a relevant model drug in formulating controlled release dosage forms due to its short plasma elimination half-life and poor solubility in water^..¹⁰ In the present investigation, ketoprofen was selected as model drugs for the development of matrix tablets. The main objective of the work is to formulate sustained or prolonged dosage form by adopting wet granulation method using natural gums (Neem gum) at different concentrations using wet granulation technique¹¹

MATERIALS AND METHODS:

Materials:

Neem gum obtained from the Neoteric DCBA ideas, Tamil Nadu, India. Ketoprofen was obtained from Yarrow Chem Limited, Mumbai. Micro Crystalline Cellulose was obtained from SD fine chem limited, Mumbai. PVP K- 30 was obtained from Loba Chemi, Mumbai. All other reagents and chemicals were of analytical grade.

Extraction of Neem Gum:

Crude neem gum (CNG) was collected from the incised bark of A. Indica trees from Neoteric DCBA Ideas. The collected neem gum was hydrated insufficient amount of distilled water for 5 days with intermittent stirring, and extraneous materials were removed by filtering using a Buchner funnel under negative pressure. The gum from the filtered slurry was precipitated with 99.8% ethanol; the precipitated gum was filtered, washed several times with acetone, and dried in a hot air oven at 30°C for 96 h before milling and sieving with a mesh 60 and then stored in an amber-colored bottle until needed.¹²

Fourier transform infrared spectroscopy (FT-IR) Studies:

FTIR studies were performed on drug, placebo and the optimized formulation. Fourier transform infrared spectrophotometry study was done with Bruker Alpha II with wave no. range 4000 to 400 cm-1.¹²

Preparation of sustained release of Ketoprofen:

Sustained release tablet was prepared by wet granulation method according to the formula given in the table. Various concentrations levels of 10%, 20%, 30%, and 40% natural polymers were used. Polyvinyl pyrrolidine K 30 was used as a binding agent at 1% concentration level. Total of four formulations was developed using a constant 200mg of ketoprofen with varying amount of excipients. The polymers being used in formulations are neem gum. The drug and polymer was mixed by a small portion of both each time and blend it to get a uniform mixture and kept aside. Then all the ingredients weighed and kept aside. Then all the ingredients weighed are mixed in geometrical order excluding magnesium stearate and talc to get a uniform blend. All ingredients were mixed for 20 minutes and triturated well using mortar. Isopropyl alcohol solvent was added dropwise until to get granular mass. Then the compact mass was passed to the 8 mesh sieve and dried at 70°C using hot air oven. After the drying, the dried product was passed through 16 mesh sieve separately. The drug and polymer was mixed by a small portion of both each time and blend it to get a uniform mixture and kept aside. Then all the ingredients weighed and kept aside. Then all the ingredients weighed are mixed in geometrical order excluding magnesium stearate and talc to get a uniform blend. Finally, the mixture is blended with magnesium stearate and tablets were compressed of 8 mm sized concave round punch to get tablet using Shakti 8 station tablet compression machine. Compositions of all batches are represented in Table 1.

Table 1: Composition of Ketoprofen sustained released tablets.

S. No.	Ingredients	KNS1	KNS2	KNS3	KNS4
1	Ketoprofen	200	200	200	200
2	Neem Gum	40	80	120	160
3	MCC (Avicel pH 101)	148	108	68	28
4	Talc (1%)	4	4	4	4
5	Magnesium stearate (1%)	4	4	4	4
6	PVP K30 (1%)	4	4	4	4
Total weight(mg)		400	400	400	400

*KNS- Ketoprofen Neem Gum Sustained released tablet, PVP K30- Poly Vinyl Pyrrolidine K 30 grade

Micromeritic evaluation:

The flow characteristics of powder (i.e., a mix of powders before compression) were assessed by measure the angle of repose by stationary funnel technique and Carr’s compressibility index by normal standard tapping technique Hausner ratios were determined.¹³

Hausner ratio = Dt/Db,

Compressibility Index (%) = [(Dt-Db) × 100]/Dt,

where, Dt is the tapped density, Db is the bulk density.

The tablets were characterized for weight variation and hardness employing a Monsanto hardness tester and friability employing a Roche friabilator equipment.

Drug content:

At random 10 tablets were chosen from completely different batches of formulations. The tablets were then pulverized, mixed by mortar. An accurately weighed amount of pulverized tablets was extracted with methanol. The solution was filtered through a 0.45 μ membrane filter, diluted suitably and the absorbance of the resultant solution was measured by using UV-Visible spectrophotometer at 260 nm using pH 7.4 phosphate buffers.¹⁴The solution was then filtered and created appropriate dilutions and absorbance was calculable at 260 nm. The results were shown in Table 4.

Release kinetics:

The analysis of drug release is an important mechanism but, complicated process and is practically evident in the case of matrix systems as a model dependent approach. The dissolution data were fitted into zero, and first order for establishing drug release kineticsand Higuchi diffusion model. According to the Korsmeyer Peppas equation, the release exponent ‘n' value is used to characterize different release mechanisms. For a dosage form in a cylindrical shape, if the n value is 0.45 or less, the release mechanism follows Fickian diffusion. If ‘n’ value is 0.45<n>0.89, the mechanism follows non-Fickian (anomalous) diffusion and when ‘n’ value is 0.89 it will be non-Fickian case II transport and if n>0.89 it will be non-Fickian super case II transport.¹⁵

RESULTS:

Drug Polymer Interaction/Compatibility study using FT-IR:

A physical mixture of drug and polymer was characterized by FT-IR spectral analysis for any physical as well as chemical alteration of drug characteristics. The spectra’s of ketoprofen, ketoprofen -neem gum mixture were shown in Figure 1. From results, it was concluded that there was no interference in the functional group as the principle peaks of ketoprofen was found to be unaltered in the drug polymer physical mixture was shown in table 2.

Table 2: FT-IR Spectral Analysis of Ketoprofen, Ketoprofen with Neem gum

Functional groups	Characteristic peak	Observed peak
C=O (AMIDE)	1680	1675
C=C	1650	1653
C−H Stretching	3000	2978
C-N Stretching	2250	2254
Functional Group	Characteristic Peak	Observed Peak
C=O (AMIDE)	1680	1697
C=C	1650	1653
C-H Stretching	3000	2977
Phenyl Group	690	695

Figure 1: FT-IR Spectral Analysis of Ketoprofen,

FT-IR spectral analysis of Physical mixture of Drug and polymer

Table 3: Physical Properties of Pre Compression Blend

Formulation Code	Angle of repose (°)	Bulk C (g/mL)	Tapped Density (g/mL)	Carr’s Index (%)	Hausner’s ratio
KNS1	22.5±0.44	0.607±0.014	0.647±0.042	6.18±0.17	1.06±0.001
KNS2	21.6±0.12	0.566±0.016	0.626±0.016	9.58±0.24	1.1±0.014
KNS3	28.4±0.24	0.556±0.024	0.612±0.025	9.15±0.15	1.14±0.024
KNS4	27.2±0.17	0.55±0.029	0.62±0.045	11.29±0.45	1.12±0.026

*Mean±S.D,n=3

Table 4: Physical Evaluation of Sustained Release Tablets.

Formulation code	*Average weight variation(mg)**	*Hardness (Kg/cm²)**	Friability (%)**	*Drug content (%)**
KNS1	399±2.6	5.5±0.110	0.54±0.244	99.1±0.18
KNS2	398±1.6	5.9±0.112	0.44±0.112	98.2±.0.51
KNS3	399±1.8	6.2±0.642	0.26±0.198	99.13±0.41
KNS4	397±1.3	6.8.±0.751	0.21+±0.163	97.9±0.14

^*Mean±S.D, n=3, ^**Mean±S.D, n=20

The Bulk density of various powder mixed blends prepared with different excipients was measured by a graduated cylinder. The bulk density was found in the range of 0.55- 0.607g/ml. The Tapped density was found in the range of 0.62- 0.652g/ml. Compressibility index was calculated. It was found in the range of 6.12- 11.29%. Hausner’s ratio was calculated. It was found in the range of 1.06- 1.14. The angle of repose ranged from 21.6- 27.2°. The press coated tablets were characterized concerning the angle of repose, bulk density, tapped density, Carr's index, and drug content was shown in table 3. The angle of repose was less than 35° and Carr's index values were less than 12 for the raw material of all the batches indicating good to fair flowability and compressibility. Hausner’s ratio was less than 1.5 for all the batches indicating good flow properties. Pre formulation properties were shown in table 3.

The results of the uniformity of weight, hardness, thickness, friability, and drug content of the tablets are given in table 4. All the tablets of different batches complied with the official requirements of uniformity of weight as their weights varied between ±5mg. The hardness of the tablets ranged from 5.5 to 6.8Kg/cm² and the friability values were less than 1% indicating that the matrix tablets were compact and hard. All the formulations satisfied the content of the drug as they contained 97.9 to 99.13% of ketoprofen and good uniformity in drug content was observed. Thus all the physical attributes of the prepared tablets were found to be practice within control.

In vitro dissolution studies are performed sustained release tablets of Ketoprofen using different concentrations of the neem gum as a release retardant polymer in buffer 7.4 pH for twelve hours using USP dissolution apparatus type II. The dissolution rate was found to increase linearly with increasing concentration of polymer. The release profiles were shown in figure 3 The formulations KNS1 released 99.97% of drug in 6 hours, KNS2 released 99.5% of drug in 10 hours, KNS3 released 99.2 of drug in 12 hours and KNS4 released 90.13% of drug in 12 hours Formulation KNS 3 containing 120mg of neem gum have recorded percentage of drug release was 98.2 respectively in 12 hours and selected as optimized formulation for sustained release.

Figure 3: Zero order release rate profiles of formulations using neem gum

Kinetic analysis of dissolution data:

To analyze the drug release mechanism the in vitro release data was fitted into various release equations and kinetic models zero order, first order, Higuchi and Korsmeyer Peppas model. The release kinetics of Optimized formulation is shown in table 5.

DISCUSSION:

In vitro drug release data of all the sustained formulations was subjected to the goodness of fit test by linear regression analysis according to zero order and first order kinetic equations, Higuchi's and Korsmeyer Peppas models to ascertain the mechanism of drug release. The release kinetics was evaluated by fitting the drug release data to five kinetic models. The kinetic model with the highest correlation coefficient value (r²) was selected as the model that best described the dissolution data. The results of correlation coefficients (r²) are summarized in table 7 and plots are shown in figures from 4 and 5. From the above data, it can be seen that the optimized formulation of KNS3 shows zero order release kinetics (‘r²’ values in the range of 0.943). From Higuchi and Peppas data, it was evident that the drug is released by fickian diffusion mechanism (0.5<n). From the kinetic data of factorial formulations in table 5, it is evident that KNS3 formulation has shown drug release by zero order kinetics. This data reveals that drug release follows fickian diffusion case –II transport mechanism Peppas model.

CONCLUSION:

Once daily sustained release tablet of ketoprofen has achieved the objective of controlled drug delivery with prolonged drug release, cost effective, low dose and frequency of administration and hence improved patient compliance. Thus it may be concluded that the once daily tablet of ketoprofen sustained release tablet can be the best alternative to conventional dosage forms with more frequency of administration. The sustained release tablet can be administered to patients. The present study was undertaken to design oral sustained release tablet of ketoprofen. Results indicated that the release of the drug from the ketoprofen tablets using neem gum as polymers for sustained release layer showed desired drug release. So, Sustained release tablets could be a potential dosage form for delivering ketoprofen. The success of the In vitro drug release studies recommends the product for further in vivo studies. Formula KNS3 using neem gum at 30% concentration level released 98.2% drug in 12 hours is selected as optimized formula, it is evident that KNS3 formulation has shown drug release by zero order kinetics. This data reveals that drug release follows erosion, fickian diffusion case –II transport mechanism Peppas model.

ACKNOWLEDGEMENT:

We, authors wish to thank all those who helped us to do this research work. Thankful to Principal, Correspondent In Charge, St Ann’s College of Pharmacy, Andhra University, Vizianagaram, Andhra Pradesh, India for providing necessary facilities.

CONFLICT OF INTEREST:

The authors declare no conflict of interest.

ABBREVIATIONS:

FT-IR: Fourier Transformer Infrared Spectrometer; NSAID: Non Steroidal Anti-Inflammatory Drug;

CNG: Crude Neem Gum;

PVP: Polyvinyl Pyrrolidine,

SQRT: Square Root Time.

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Received on 24.10.2019 Modified on 29.01.2020

Research J. Pharm. and Tech. 2021; 14(2):817-822.

DOI: 10.5958/0974-360X.2021.00144.X

Formulation Code	Zero order(R²)	First order(R²)	Higuchi plot(R²)	Pappas plot (R²)	n	Hixson Crowell(R²)
KNS1	0.931	0.849	0.991	0.991	0.387	0.907
KNS2	0.903	0.901	0.979	0.949	0.438	0.936
KNS3	0.943	0.912	0.994	0.984	0.468	0.954
KNS4	0.951	0.972	0.996	0.987	0.523	0.964