INTRODUCTION:

Pectin has good binding and wetting properties which can be utilized in formulation design.¹ Its major limitation of being highly hydrophilic, if optimized to an appropriate level of hydrophobicity, could lead to an improvement in its swelling property and ability to retard the release of drug from their composite matrix. In the process of chemical modifications of pectin by optimizing its hydrophilicity, hydrophobicity, swelling and adhesive properties the possibility of obtaining a polymer with properties desirable of an universal excipient cannot be overlooked.²

Netaglinide is use as monotherapy to lower blood glucose in patients with Type 2 diabetes, whose hyperglycemia cannot be adequately controlled by diet and physical exercise and have not been chronically treated with other anti-diabetic agents. It is practically insoluble in water.³Nateglinide is rapidly and almost completely (greater than or equal to 90%) absorbed from an oral solution. Absolute oral bioavailability is estimated to be 72%. The nateglinide which has a half life of about 1hr.⁴ Thus this drug was thought to be appropriate candidates for evaluating the modified polymers through design and evaluation of their sustained release formulations employing these polymers.

The present work was proposed to chemically modified Pectin with its hydrophilicity reduced. The subsequent approach of physically entrapping the drug in the process of cross linking pectin using appropriate non-toxic cross linking reagent (chloroacteylchloride) and subsequent formulation development also produced promising results in terms of achieving a release profile for a once daily dosage form. Release profile of the designed formulations is comparable to that obtained using eudragit RL100.⁵ Masking of the undesirable properties of the excipient and subsequent release at a consistently uniform rate for sustained action has been achieved through this formulation design.

MATERIALS AND METHODS:

MATERIALS:

Nateglinide were procured from Glenmark Pharmaceuticals, Nasik. Hydroxypropyl methylcellulose K100M was Dow Chemical Product and kindly gifted by Colorcon Asia Pvt. Ltd. Goa. Pectin was kindly gifted by Krishna Pvt. Ltd. Jalgaon. All other chemicals used for analysis were of analytical grades.

METHODS:

FT-IR Studies:

Nateglinide samples were analyzed by infrared spectroscopy (spectrophotometer FT-IR Jasco 4100) to characterize the probable structural modification produced. The samples were analyzed in the region of 4000 and 400 cm^-1.⁶

Procedure for Pectin Modification:

Method A:Physical entrapment of drug by cross-linking the pectin (Modified pectin-1) (MP1P2):

Weighed quantity of 5gm of crude pectin and 2.5gm of Nateglinide were triturated in mortar with the help of pestle .Then 100mL of cold distilled water was added and stirred upto 1hr on magnetic stirrer. Freshly prepared ice cold solution of 10mL of Chloroacetyl chloride in 10 mL of Diethyl ether was transferred into burette and 5 mL of it was added into the saturated solution of pectin dropwise over a period of 45min. It was kept for stirring for further 45minutes.⁷ The product was dried in a vacuum tray dryer at 45°C.

Method B: Coupling of drug to pectin by an ester linkage (Modified pectin-2) (MP2P2):

A reflux condenser was fitted on a 100mL two-necked round bottom flask. In it 0.80mL of redistilled thionyl chloride was placed and the flask was gently heated on water bath. To this flask 3.5gm of nateglinide was slowly added over a period of 30-40 min. Solid nateglinide acid chloride was then dissolved in sufficient volume of diethyl ether and added into the saturated solution of 7gm pectin and stirred for 2hrs.⁸ The product was collected and dried in vacuum tray dryer at 45°C.

Method C: Coupling of drug to pectin by an amide linkage (Modified pectin-3) (MP3P2):

A reflux condenser was fitted on a 100mL two-necked round bottom flask. In it excess of redistilled thionyl chloride was placed and the flask was gently heated on water bath. To this flask 5 gm of pectin was slowly added over a period of 30-40 min. Solid pectinoyl chloride was then dispersed in sufficient volume of chloroform. Then 2.5gm of nateglinide was added into pectinoyl chloride and strred for 2 hrs.⁹The product was collected and dried in vacuum tray dryer at 45°C.

Physicochemical Characterization:

Gelling or swelling factor:

Weighed quantity of 100mg of modified pectin was taken into a watch glass and sufficient quantity of water was gradually added till a limit, when no further absorption could be visibly observed. Swelling index/gelling capacity of the modified pectin was determined by the difference in the weight of watch glass before and after addition and absorption of water.¹⁰

Solubility:

Weighed quantity of 100mg of modified pectin was added to 10mL of particular solvent in a 50mL beaker and was shaken for 24hrs on an orbital shaker. After 24 hrs, the solution was filtered through already weighed Whatman filter paper no. 41. Paper was weighed after complete drying.¹¹ The solubility of the modified pectin in a particular solvent was determined by the difference between the final weight and initial weight of paper.

Determination of acid value, acid value, saponification value and ester value:

Pectin modified by method A without containing drug was evaluated for its acid value, saponification value and ester value.¹²

Evaluation of Modified Polymers:

FT-IR studies:

Unmodified pectin, modified pectin samples were analysed by infrared spectroscopy to characterize the probable structural modification produced. The sample was placed in the sample holder and spectra were recorded over the wave number 400-4000 cm^-1.¹³

NMR studies:

The samples comprising nateglinide coupled with pectin by an amide linkage were analyzed by NMR spectroscopy, model Bruker 300 Advance II.¹⁴

Preparation and evaluation of Granules:

The prepared all types of modified pectins were triturated and then evaluated with various parameters like, angle of repose, bulk density, tapped bulk density, Carr’s Compressibility Index, hausner’s ratio was calculated.¹⁵

Drug Content:

Assay of modified polymers containing nateglinide:

100mg of modified polymer was hydrolysed with 0.2M NaOH solution (100mL) at 50°C. This solution was filtered with whatmann filter paper. 1 mL withdrawn and diluted to 5mL with distilled water to get 0.04M NaOH solution. 1mL of this was withdrawn and diluted to 10ml with 0.04M NaOH solution. The UV absorbance of this was taken at suitable wavelength. Drug content was then calculated by using calibration curve of pure drug in 0.04M NaOH.¹⁶

Preparation of Matrix Tablets:

Tablet containing modified pectin powder equivalent to 120mg of nateglinide, 3mg Magnesium stearate, 4% sodium starch glycolate were prepared by direct compression method. This composition was compressed into flat 8mm diameter tablets for nateglinide using KBr press (single punch compressor) under pressure of 1 ton. Tablet compositions was given in table 1. The tablets were also prepared by using unmodified pectin, separately for comparison with chemically modified pectins.¹⁷

Table 1: Composition of Matrix Tablets

Ingredient	Quantity in mg*
Ingredient	MP1P2	MP2P2	MP3P2
Nateglinide	382	385	372
Sodium starch glycolate (SSG)	15	15	15
Magnesium stearate	3	3	3

*Concentration of SSG is given as 4% of modified pectin granules

Physical Properties of Tablets:

The average weight of tablets was obtained from individually weighed tablets. The thickness of tablets was measured individually using a Mitutoyo Digimatic Caliper. The hardness of tablet was determined by using a Monsanto hardness tester. The friability was determined by using a Roche friabilator subsequently calculated as percentage of weight lost.¹⁸

In vitro Drug Release Studies:

Tablets prepared by using all the three types of chemically modified pectins for drug nateglinide was evaluated for their drug release in the physiological environment of stomach and intestine under conditions mimicking mouth-to-colon transit. These studies were carried out according to USP XXIII, using (model TDT-08L, Electrolab, India) USP apparatus type II (apparatus 1, 50rpm, 37.5±0.5°C). The dissolution media 0.1N HCl and phosphate buffer pH 6.8 were used. 1% of Sodium lauryl sulphate (SLS), which was previously optimized, was added in 0.1N HCl and phosphate buffer to maintain the sink condition for tablets containing nateglinide. The tablets were tested for drug release for 2hrs in 0.1N HCl, as the average gastric emptying time is about 2 hrs. After this, all the 0.1N HCl was replaced with phosphate buffer pH 6.8 as a dissolution media and the study was continued at for 10hrs. At the end of each hour, 5mL samples were withdrawn from the dissolution media and were replenished with 5mL of fresh dissolution media to maintain the sink condition. The samples were filtered through a Whatman filter paper no. 41 and the filtrate was analyzed at suitable wavelength using UV spectrophotometer. Dissolution study software (PCP-Disso-v 2.08) was used for the dissolution studies.¹⁹

Comparative Study:

Data obtained from drug release studies from chemically modified pectins was compared with the data obtained from tablets designed using eudragit RL100 as coating polymer and data obtained from tablets prepared using unmodified pectin.²⁰

Preparation of Core Tablet:

Wet granulation method was used for the preparation of the core tablets containing nateglinide. Tablet containing 120mg nateglinide, HPMC K100M 20% of drug and other excipients were prepared by wet granulation using 5% (w/v) starch paste as binder. The dried granules were evaluated for various physical parameters. Then granules were lubricated with magnesium stearate and compressed into flat 8 mm tablets using KBr press under pressure of 1 ton.²¹Core tablet compositions was given in table 2.

Table 2: Composition of Core Tablet

Ingredients	Core tablet Batches in mg
Ingredients	NTGT
Nateglinide	120
HPMC K100M	24
Lactose	20
Magnesium stearate	3
Starch paste (5%)	25

Evaluation of Granules:

The prepared granules were evaluated for following properties: Angle of repose, Bulk density, Compressibility index, Hausner’s ratio.

Physical Properties of Tablets:

The preparation of core tablet, granules were compressed by KBR press. The tablets were evaluated for various physical parameters like average weight, thickness, diameter, hardness, friability.

Coating of Core Tablets:

The core tablets prepared were coated with coating solutions of 4% w/v, 8% w/v, 12% w/v strength of Eudragit RL100 in dichloromethane. The tablets were coated in pan coating machine at various specifications given in table 3. ^22,23

Table 3: Composition and Conditions of Coating Process of Tablet

Particulars	Polymer coats
Particulars	Eudragit RL100 (4%w/v)	Eudragit RL100 (8% w/v)	Eudragit RL100 (12% w/v)
Solvent composition	DCM (25ml)	DCM (25ml)	DCM (25 ml)
Coating pan speed (RPM)	30±2	30±2	30±2
Inlet air temp. (°C)	50±3	50±3	50±3
Product bed temp. (°C)	48±2	48±2	48±2
Flow rate (ml/hr)	10	9.5	9

Physical properties of coated tablets:

The tablets were evaluated for various physical parameters like average weight, thickness, diameter, hardness, friability.

In vitro Drug Release Studies:

In vitro drug release studies were carried out according to USP XXIII, using (model TDT-08L, Electrolab, India) USP apparatus type II (50rpm, 37.5±0.5°C). The dissolution media of 0.1 N HCl and phosphate buffer pH 6.8 was used. The SLS was added to maintain sink condition. The tablets were tested for drug release for 2 h in 0.1N HCl for 2h. After this, all the 0.1 N HCl was replaced with phosphate buffer pH 6.8 and the study was continued at this pH for 10h. At the end of each hour, 5 mL samples were withdrawn from the dissolution media and were replenished with 5mL of fresh dissolution media to maintain the sink condition. The samples were filtered through a Whatman filter paper no. 41 and filtrate was analyzed at appropriate wavelength. using UV spectrophotometer.^24-27

RESULTS AND DISCUSSION:

FT-IR spectral studies The FT-IR spectra of the Nateglinide shown in figure 1.

Figure 1: FT-IR Spectra of Nateglinide

Modification of Pectin:

Chemical modification of pectin is effected by changing the active functional groups, introducing complexed metal ions, cross-linking etc., and by synthesizing pectin polymers. Advantages of such approaches are due to the ability to selectively enhance or mask desired properties of pectin to suit the formulation requirements. It has one major limitation of being highly hydrophilic and if increase its hydrophobicity to an optimum level; its swelling property and the ability to retard the release of drug could get improved. Pectin is widely useful in the targeted delivery of the drug in various part of the gastrointestinal tract (GIT). So the modification of pectin was to couple the drug chemically to pectin by using available functional groups and access the use of that modified pectin for modified drug release formulations. This chemical modification may lead to retardation of release of drugs in proximal parts of GIT and the modified pectin could have physiochemical properties desirable of a universal excipient.

Physicochemical characterization of modified pectin:

Results of physicochemical characterization of modified pectins are given in following table 4, 5, 6.

Table 4: Gelling or swelling factor

Sr. No.	Polymer quantity	Solvent	Quantity of water uptake in gm
1	100 mg	DW	MP1P2	MP2P2	MP3P2
			0.203	0.217	0.193

Table 5: Studies on solubility parameter

Sr. No	Polymer quantity	Solvent	Quantity of polymer dissolved in mg
Sr. No	Polymer quantity	Solvent	MP1P2	MP2P2	MP3P2
1	100 mg	DW	60	68	56
2	100 mg	Chloroform	14	17	11
3	100 mg	Methanol	08	12	07

Table 6: Data for acid value, saponification value and ester value

Polymer	Acid value	Sap. value	Ester value	Ester %
Unmodified pectin	142.08	355.06	212.98	59.98
Modified pectin 1 without drug	84.15	361.41	277.26	76.71

Determination of acid value, saponification value and ester value:

Evaluation of modified polymers:

NMR spectral studies:

The broadened multiplet of the secondary amido proton and the hydrogen on the α-carbon as is evident from the NMR spectra of the modified pectin (MP3P2) clearly indicates that a substantial quantity of the acid chloride generated from chlorination of the carbohydroxyl group of pectin has acylated either of these two positions in Nateglinide. Presence of aromatic protons also confirms the chemical bonding between pectin and the drug. NMR spectra of Modified Pectin 3 (MP3P2) shown in fig.2

Figure 2: NMR spectra of Modified Pectin 3 (MP3P2)

Evaluation of granules:

The granule properties of all chemically modified pectins were depicted in table 7. The result indicates good packing capacity of granules. Carr’s index of MP2P2 indicate good flow and that of MP1P2, MP3P2 indicate fair to passable flowability. Hausner’s ratio of MP1P2 was above 1.25, which indicate poor flow, while that of MP1P2, MP3P2 were below 1.25 indicating good flow. The angle of repose of MP2P2 are within the range of 20°-30°, which indicate good flow, while that of MP1P2, MP3P2 were found to be in fair to passable range.

Table 7: Granule Properties of all the Modified Pectins*

Batch code	Bulk density (g/cm3)	Tapped density (g/cm3)	Carr’s index (I_C)	Hausner Ratio (H_R)	Angle of repose (q)
MP1P2	0.6462 ± 0.02	0.8284 ± 0.04	21.24 ± 0.06	1.2820 ± 0.03	35.04± 0.13
MP2P2	0.4854 ± 0.04	0.5453 ± 0.06	10.98 ± 0.09	1.1235 ± 0.07	29.41 ± 0.17
MP3P2	0.4807 ± 0.01	0.5007 ± 0.01	22.92 ± 0.07	1.0416 ± 0.02	33.25 ± 0.12

* Indicates three reading ± SD

Drug content:

The values of drug content are given in table 8. Total drug content was in range of 93.48 % to 96.63% indicating good percentage recovery of drug. A few percentage of free drug was present in each of the chemically modified pectins, which might be due to unreacted drug.

Evaluation of matrix tablets:

All the formulations were evaluated for various parameters, like weight variation, thickness, diameter, friability and hardness; values are shown in table 9. All batches were no significant change in thickness and diameter of tablets; it shows that powder blends were consistent in particle size and uniform behavior during compression process. Tablet hardness reflects differences in tablet density and porosity. The values of friability are within the limit.

Table 8: Drug content of all the chemically modified Pectin*

Batch code	Total drug content (mg/100mg)*	% Recovery of drug	Free drug content (mg/ 100mg)*	% of free drug to total drug
MP1P2	31.41 ± 0.0462	94.23	09.14 ± 0.0761	29.11
MP2P2	31.16 ± 0.0731	93.48	11.72 ± 0.0379	37.63
MP3P2	32.21 ± 0.0852	96.63	08.80 ± 0.0547	27.34

* Indicates three reading ± SD

Table 9: Physical Properties of Matrix Tablets*

Batch code	Weight (mg)	Thickness (mm)	Diameter (mm)	Friability (%)	Hardness (kg/cm2)
MP1P2	392 ± 0.070	3.78 ± 0.02	8.08 ± 0.04	0.07	8.22 ± 0.40
MP2P2	395 ± 0.071	3.90 ± 0.06	8.05 ± 0.03	0.08	7.18 ± 0.27
MP3P2	383 ± 0.059	3.67 ± 0.02	8.07 ± 0.08	0.06	6.70 ± 0.35

* Indicates separate three reading ± SD

In vitro drug release studies:

Tablets were prepared on KBr press by blending modified pectins and other excipients and evaluated for their drug release characteristic. Data of dissolution studies was given in figure 3. The release of nateglinide from the modified pectin based matrix tablets followed Peppas kinetic, which is totally depend on the diffusion of drug and erosion mechanism. As pectin was an anionic biopolymer of high hydrophilicity, it is readily hydrated upon contact with water. When it was modified with some of the chemical reagent to reduce its hydrophilicity and increase its hydrophobicity to some extent and was used in the formulation of matrix type tablets, significant enhancement in time to release nateglinide from tablets with a Peppas model kinetic was confirmed shown in table 10.

From the release profile of nateglinide was found that batch MP3P2, i.e. formulations containing nateglinide, linked with an amide linkage to pectin, were the best for sustaining the release of drug. As is evident from the overlain release profiles shown the net release at the end of 12 hrs from the designed formulations was about 81.36% for Nateglinide the rate of release, after the initial burst was consistently uniform for over 8 hrs.

Figure 3: Overlain release profile of Nateglinide from all batches under investigation

Table 10: Regression Analysis Data for Release of Nateglinide from Chemically Modified Pectins

Batch code	0.1 N HCl		Phosphate buffer pH (6.8)
Batch code	R	Best fit model	R	Best fit model
MP1P2	0.9976	Peppas	0.9801	Peppas
MP2P2	0.9485	Peppas	0.9455	Peppas
MP3P2	0.9349	Peppas	0.9536	Peppas

Evaluation of Granules:

The results for granule properties of NTGT have been given, Bulk densities and Tap densities of NTGT granules were found to be 0.3473 ± 0.06 and 0.3690 ± 0.13, which indicate good packing capacity. Carr’s index of NTGT granules were found to be 5.88 ± 0.11, which indicate excellent flow properties. Hausner ratio of NTGT granules were found to be 1.0621± 0.05, which indicate excellent flow properties. Angle of repose of NTGT granules were found to be 15.28±0.14, which indicate excellent flow properties. The results for physical properties of core tablets have been given, weight variation of NTGT tablets were found to be within the limits as per IP standards 183±0.0024. The hardness of NTGT tablets was satisfactory 5.20± 0.40. The Thickness, Diameter, Friability found to be2.84± 0.03, 2.84± 0.03 and 0.07 respectively. Percentage drug contents were within the limits 97.32± 0.0352. The results for physical properties of eudragit coated tablets have been given in table 11. There was increase in weights, thickness and diameter of tablets after coating with 4%, 8% and 12% eudragit RL100 coating solutions. The friabilities of tablets were decreased slightly.

In vitro Drug Release Studies:

Release profile of NTGEUD1, NTGEUD2, NTGEUD3 for nateglinide have been given in the figure 4 and the Regression Analysis Data was shown in table 12. Comparative evaluation of the designed formulations with the formulations, the release of nateglinide from tablets coated with eudragit RL100 was progressively prolonged, as concentration of eudragit in the coating solution was increased about 63.91 % at 12 hr of NTGEUD3 batch. The drug release sustaining capacity of eudragit RL100 was somewhat greater than that produced by the designed formulations but the release in the first 3 hrs was minimal from the eudragit RL100 coated formulations. Thus the selected formulations produced using pectin had an added advantage over formulations coated with eudragit RL100 in terms of releasing a initial basal concentration of the NTGT in the first 3 hrs followed by a consistently uniform release for a period of over 8 hrs. This release profile is quite similar to the desired release profile for an ideal once daily dosage form for the chosen pharmacological class of drugs.

Table 12: Regression Analysis Data for Release of Nateglinide from Chemically Modified Pectins

Batches code		0.1 N HCl		Phosphate buffer pH (6.8)
Batches code		R	Best fit model	R	Best fit model
NTGEUD1	Nateglinide	0.9860	Matrix	0.9849	Matrix
NTGEUD2	Nateglinide	0.9920	Matrix	0.9924	Matrix
NTGEUD3	Nateglinide	0.9928	Matrix	0.9997	Matrix

Figure 4: Overlain release profile of nateglinide from eudragit coated batches

Conclusion:

Pectin with its chemical modification does not ensure retardation of drugs release beyond 6hrs. The formulations MP1P2 after optimization to limit the release in the first 3h could also be equally effective as the once found to be the best. The release profile indicates about 80% release in the first 3 hrs and hence this approach could be suitable for objectives of decreasing gastric irritation but not for sustaining release. Comparative evaluation of the designed formulations with the formulations, the release of nateglinide from tablets coated with eudragit RL100 was progressively prolonged, as concentration of eudragit in the coating solution was increased about 63.91% at 12 hr of NTGEUD3 batch. The subsequent release at a consistently uniform rate for sustained action has been achieved through this formulation design.

ACKNOWLEDGEMENT:

Authors are wish to acknowledge Glenmark Pharmaceuticals, Nashik. India, for providing Nateglinide as gift sample. Hydroxypropyl methylcellulose K100M was procured Dow Chemical Product and kindly gifted by Colorcon Asia Pvt. Ltd. Goa. Pectin was kindly gifted by Krishna Pvt. Ltd. Jalgaon. Authors are also grateful to Principal Dr. H. N. More, Bharati Vidyapeeth College of Pharmacy, Kolhapur for providing excellent facility to carry out this work.

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Received on 26.08.2022 Modified on 03.02.2023

Research J. Pharm. and Tech 2023; 16(12):5775-5781.

DOI: 10.52711/0974-360X.2023.00935

Batch code	Weight (mg)	Thickness (mm)	Diameter (mm)	Friability (%)	Hardness (kg/cm2)
NTGEUD1	192 ± 0.037	2.95 ± 0.04	8.29 ± 0.04	0.07	5.32 ± 0.22
NTGEUD2	211 ± 0.024	3.04 ± 0.05	8.37 ± 0.03	0.06	5.34 ± 0.32
NTGEUD3	224 ± 0.045	3.15 ± 0.03	8.47 ± 0.08	0.05	5.40 ± 0.18