INTRODUCTION

Oral drug delivery is the most widely utilized route of

administration compared to all other routes for the

delivery of drugs. In conventional oral drug delivery

systems, there is little or no control over release of the

drug and effective concentration at the target site can be

achieved by intermittent administration of grossly

excessive doses. This kind of dosing pattern result is

constantly changing, unpredictable and sub or supra

therapeutic plasma concentrations, leading to marked

side effects in some cases. Hence better dosage form

design and delivery can minimize many of these

problems.

The role of novel drug delivery system is to develop an

optimized product that would be therapeutically

effective with additional benefits such as maintenance of

constant blood levels within the therapeutic window,

enhanced bioavailability, reduced inter-patient

variability, decreased dosing frequency, improved

patient compliance, reduced side effects[1,2].

Research has led to development of novel drug delivery

system among which osmotic controlled drug delivery

system (OCDDS) utilize osmotic pressure for controlled

delivery of drug. Drug delivery from these systems is

independent of physiological factors of gastrointestinal

tract. Release of drug from the formulation is dependent

on various formulation factors such as, solubility of

drug, osmotic pressure gradient of the system, size of the

delivery orifice, nature and thickness of rate controlling

membrane (semi permeable membrane)[3-17] (fig. 1).

Zero order release rate is expected in OCDDS (i.e.

release rate is independent on concentration of the drug).

The semi permeable nature of the rate-controlling

Journal of Pharmaceutical Research and Therapeutics

2020; Volume 1 (Issue 02); 89-96

Research Paper

Formulation Development and Evaluation of Glipizide Controlled Release Tablets

KUNISETTI NAGENDRA BABU*

Shri Vishnu College of Pharmacy, Vishnupur, Bhimavaram-534202, India

Babu: Formulation Development and Evaluation of Glipizide Controlled Release Tablets

Abstract:

The purpose of the present study was to develop an oral push-pull osmotic drug delivery system for the

glipizide, which is BCS class II drug (low soluble and high permeable). The osmotic control release tablets

were prepared by wet granulation method using sodium chloride as osmotic agent and poly ethylene glycol

as polymer. The granules were compacted by double compression method and were coated with cellulose

acetate and laser drilled. Different batches were manufactured with various concentrations of excipients to

study the effect of drug release up to 24 hours. Dissolution was assessed using USP dissolution apparatus 2

(Paddle) at 50 RPM in 900 ml of pH 7.4 phosphate buffer. Molecular weight of poly ethylene oxide and

sodium chloride in push and pull layers have played a main role in drug release, less molecular weight of

poly ethylene oxide in push layer and high molecular weight of poly ethylene oxide in pull layer and increase

in concentration of sodium chloride lead to satisfactory drug release and followed zero-order release. It was

concluded that the push-pull osmotic tablet of glipizide was able to deliver the drug in a controlled pattern

for a prolonged period. This type of formulation could be used in conditions like type II diabetes where the

patient compliance can improve by reducing the dosing frequency and maintain drug plasma levels between

maximum effective and safe concentration and it leads to less side effects.

Keywords: Controlled drug delivery systems, push pull osmotic drug delivery systems

*Address for Correspondence: Kunisetti Nagendra Babu Shri Vishnu College of Pharmacy, Vishnupur, Bhimavaram-534202, India, E-mail: k.nagendrapharmacy@gmail.com

Article History: Received 05 April 2020 Revised 31 May 2020 Accepted 12 June 2020

J Pharm Res Ther 2020;01(02):89-96

89 Journal of Pharmaceutical Research and Therapeutics July-September 2020

membrane (cellulose acetate) with push and pull layers

and the design of delivery orifice present in push layer,

drug dose is released in a uniform concentration at the

site of absorption in controlled manner and thus after

absorption, allow maintenance of plasma concentration

within therapeutic range, which minimizes side effects

and also reduces the frequency of administration, so a

high degree of in vivo-in vitro correlation (IVIVC) is

achieved (fig. 2).

Glipizide is US FDA approved drug for the use in type

II diabetes mellitus. Glipizide having half-life 1-6 h. So,

this drug is useful to sustain drug release up to 24 h using

push pull osmotic drug delivery systems[18-33].

MATERIALS AND METHODS

Antidiabetic drug glipizide USP obtained from Orchid

Health Care, Chennai, India. Poly ethylene oxide NF

(PEO Grades – 6,50,70 lakhs MW), Opadry cellulose

acetate in house and opadry pink in house from

Colorcon®, microcrystalline cellulose NF (MCC;

Avicel pH 101) used from FMC, magnesium stearate NF

from Peter Grevens, iron oxide yellow in house from

Sensient, NaCl and acetone and other analytical grades

were obtained from Merck. Dissolution medium: 900 ml

of pH 7.5 phosphate buffer using Basket (USP II

Apparatus) at 50 rpm at time points of 1, 2, 4, 8, 16 h as

dissolution media used for this study. Reference product

- Glucotrol XL 10 mg, was procured from Pfizer.

Method of preparation:

Based on literature search the manufacturing of bi-

layered push pull osmotic tablet using wet granulation

method represented in fig. 3[29].

Drug/pull layer:

Glipizide, micro crystalline cellulose, poly ethylene

oxide and sodium chloride sifted through 30# sieve to

separate the agglomerates, and then dry mixed in rapid

mixer granulator for 10 min. Hydro-alcoholic solution

Fig. 1: Plasma drug concentration of conventional and controlled release dosage form

Fig. 2: Push pull drug delivery system and drug release pattern from osmotic pump

Fig. 3: Manufacturing procedure for push-pull osmotic tablet[25]

Conventional release dosage

form Conventional release

dosage form

Controlled release dosage

form

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July-September 2020 Journal of Pharmaceutical Research and Therapeutics 90

(ethanol (85 %) and water (15 %)) was used as the binder

solution (30 % to dry mix blend). Granulation was done

by added binder solution for a period of 2 min and

thereafter kneaded for 2 min and 30 s at slow RPM (150)

speed of Impeller. Wet mass transferred to fluid bed

drier and dried for a period of 30 min at blower speed of

25-30 % Hz and temperature of 40°. Loss on drying of

dried granules was confirmed by subjecting it to below

1.5 % moisture content at a temperature of 105° in auto

mode using Mettler Toledo moisture analyser. Dried

granules were sifted through #25 mesh using vibratory

sifter. #25 mesh retained granules were milled through

Mobile Cone mill using 1 mm sieve at 500 rpm. Milled

granules were sifted through #25 mesh. These granules

were lubricated with magnesium stearate for a period of

2 min in octagonal blender at 10 RPM[30,34-38].

Push layer:

Poly ethylene oxide, micro crystalline cellulose, sodium

chloride and iron oxide sifted through #30 mesh to

separate the agglomerates and remaining procedure is

similar to pull layer[35]

Bi layer compression:

The bilayer tablet was compressed using blends of push

and pull layers with Cadmach double rotary compression

machine using 9.5 mm round shape shallow concave

both sides plain “D ” tooling punches.

Semi permeable coat:

Preparation of coating solution: Opadry cellulose

acetate was dissolved in a mixture of acetone and water

(9:1) and stirred for a period of 45 min using magnetic

stirrer. Coating was done by using Ganson’s coater with

inlet temperature (45º), bed temperature (32º) using pan

speed of 2-6 rpm and dried at 45º temperature with 1

RPM pan speed[38]

Colour coat:

Preparation of coating solution: Opadry pink was

dissolved in a purified water and stirred for a period of

45 min using magnetic stirrer. Coating was done by

using Ganson’s coater and dried tablets at 45º

temperature with 1 RPM pan speed. Orifice diameter

ranges from 0.4-0.6 mm was drilled on the non-coloured

portion using laser drill technology with the help of

Colorcon. The dissolution study performed for prepared

tablets to select best formulation matching with

reference product.

Formulation development:

Trials were performed in two stages: 1. Optimization of

core tablet: (A) optimization of PEO in push and pull

layer; (B) optimization of NaCl in push layer; 2.

Optimization of semi-permeable membrane coating

percent.

Optimization of PEO in pull and push layer:

From the literature survey and viscosity studies,

reference product (Glucotrol XL) having PEO of low

and high molecular weight in pull and push layers

respectively. For optimization of pull layer first high

molecular weight polyethylene oxide (6 lakhs) was used

with various concentrations initially from F1-F3 trials,

since the results were unsatisfactory to increase the drug

release, it was replaced with polyethylene oxide (3

lakhs) and trials F4-F6 were performed. Similarly in

push layer first polyethylene oxide (50 lakhs) was used

with various concentrations initially from trials F1-F6,

since the drug release is slow, it was replaced by high

molecular weight polyethylene oxide (70 lakhs) and

trials F7-F9 were performed.

Optimization of NaCl in push layer:

To reduce initial lag phase, trials F10 and F11 were

performed by decreasing and increasing the

concentration of NaCl in push layers.

Optimization of semi permeable membrane:

Optimized trial F11 was further selected for checking the

effect of coating weight gain on drug release, trials F12,

F13, F14 were taken for 8, 10 and 12 % weight gain,

respectively.

Evaluation of osmotic tablets:

Twenty tablets were crushed into a fine powder by

mortar and pestle, 100 mg of the crushed powders was

weighed in 100 ml volumetric and diluted in a flask with

7.5 phosphate buffer. After sonication for 15 min the

diluted solution was filtered. The total amount of drug

for each tablet was analysed using UV

spectrophotometer.

Weight variation: 20 tablets of each formulation were

weighed individually using a Sartorius analytical

electronic balance (Item no.: QUINTIX224-1SKR) and

compared with average value, the test was performed

according to the official standards.

Hardness: Ten tablets were randomly picked from each

batch and checked for hardness using Varian hardness

tester.

Friability: Ten tablets were weighed accurately and

placed in the Roche friability apparatus, After 100

revolutions, the tablets were weighed and the percentage

loss in tablet weight was determined.

Thickness: Ten tablets from each batch were randomly

picked and checked for thickness using vernier caliper.

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91 Journal of Pharmaceutical Research and Therapeutics July-September 2020

The uniformity of coating among the tablets was

estimated by determining the weight, thickness, and

diameter of tablets before and after coating using 20

individual tablets and their average values.

In vitro dissolution test was performed using (USP type

II apparatus) paddle type dissolution apparatus, using

900 ml of pH 7.5 phosphate buffer as dissolution

medium at temperature 37°±2°, samples were

withdrawn at time intervals of 1, 2, 4, 8, 16 h.

RESULTS AND DISCUSSION

Physical properties and dissolution profile of reference

product (Glucotrol XL 10 mg; mfg. by Pfizer) are shown

in Table 1 and 2. Various formulation trials of glipizide

prepared using push-pull technology are discussed in the

Table 3-5. It was evident from the Table 6 all the trial

formulations comply with the standard.

Specifications mentioned as per USP for assay, average

weight, weight variation and friability and in house for

thickness and hardness. The orifice diameter was found

to be in the range of 0.5-0.7 mm. Dissolution profile

results for various formulation trials of bilayer osmotic

drug delivery system are as follows. From the results of

% drug release (Table 7) it was observed that, trials F5

and F6 showed zero order release kinetics. F6 showed a

higher % drug release and close matching with innovator

as compared to F5. Based on dissolution profile of F7 to

F9 (Table 8) it was found that, as the concentration of

PEO in the push layer is increases, % drug release is also

increased. From the above trials it was found that batch

F9 showed a zero order release kinetics. Since F9

showed a good % cumulative release close to innovator

hence it was selected for further optimization.

From physical observation and dissolution profile of

trials F10 and F11 (Table 9, 10) it was found that as the

concentration of NaCl in push layer is increased, the

initial drug release was increased, F11 showed release

rate closer to innovator, among the two trials F11 had the

greater f2 value and was matching with that of the

innovator hence it was taken for final core formula (fig.

4).

From the results of % cumulative release, it was seen that

all the trials showed good zero order release kinetics.

Batches F12 and F13 showed faster % cumulative

release compared to batch F14. However batch F14

showed similar release profile when compared with

innovator (R square value is 0.99). The f1 and f2 values

obtained are within the limit specified in the FDA

guidelines. So the prepared F14 batch tablets are found

to be bioequivalent with innovator. Hence F14 was

selected as the final optimized batch (Table 11, 12).

Optimized formulation was kept for stability studies and

checked for the assay, and dissolution profile and related

substance after 1, 2 and 3 mo. There were no significant

changes in in vitro release profile. It shows that

TABLE 1: PHYSICAL PROPERTIES OF INNOVATOR PRODUCT Sr. no. Parameters Innovator / Reference Product details

1 Product Name Glucotrol XL 10 mg

2 Label Claim Each Tablet contains 10 mg of Glipizide

3 Dosage form Extended Release tablet

4 Composition Cellulose acetate, hypromellose, Magnesium stearate, PEG,

Polyethylene oxide, Synthetic iron oxide, BHT, NaCl.

5 Storage Store at 15-300C (59-860F)

6 Manufactured by Pfizer

7 Average weight (mg) 392.25

8 Average thickness (mm) 5.55

9 Average diameter (mm) 9.82

10 Orifice diameter (mm) 0.5 (present on pull layer)

11 Hardness (KP) 25

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July-September 2020 Journal of Pharmaceutical Research and Therapeutics 92

TABLE 2: DISSOLUTION PROFILE OF INNOVATOR PRODUCT

Time (h) % drug released

0 0

2 3

4 20

8 45

16 98

20 100

24 100

Fig. 4: Comparative dissolution profile of Innovator vs test

formulations

(▬▬) Innovator; (▬■▬) F12; (▬▲▬) F13; (▬×▬) F14

0

20

40

60

80

100

120

0 10 20 30

% d

rug

rele

ase

time (h)

formulation F14 was found to be stable. All process

parameters were found to be satisfactory. The

dissolution profile was compared with the reference

product. Since the F2 value was found to be above 50 the

dissolution profile was said to be similar with that of the

innovator.

Conclusion:

From trials F1- F3, PEO[35] of molecular weight 6 lakhs

and PEO of molecular weight 50 lakhs were used in pull

and push layers respectively with varying

concentrations, the drug release profile showed very

slow release, to enhance the drug release, trials F3-F6

were adopted using PEO of 3 lakhs molecular weight,

which is of low molecular weight when compared to

previous trials, same molecular weight PEO of 50 lakhs

was used in push layer, the release profile showed zero

order release but the drug release is slow compared to

innovator. To enhance the drug release further, trials F6-

F9 were done using PEO of higher molecular weight 70

lakhs in push layer, and PEO of 3 lakh molecular weight

in pull layer, a good release profile was showed and it

was similar to innovator, but initial drug release was

slow. Trials F10 and F11 were performed to overcome

the initial slow release of drug, by varying concentration

TABLE 3: OPTIMIZATION OF PEO IN PULL AND PUSH LAYERS

Pull layer ( drug layer)

Ingredients F1 F2 F3 F4 F5 F6

API 10.00 10.00 10.00 10.00 10.00 10.00

PEO (6lakhs MW)

145.00 160.00 175.00 --- --- ---

PEO (3lakhs MW)

--- --- --- 145.00 160.00 175.00

NaCl 10.00 10.00 10.00 10.00 10.00 10.00 MCC 45.00 30.00 15.00 45.00 30.00 15.00

Magnesium stearate 1.00 1.00 1.00 1.00 1.00 1.00 Total 211.00 211.00 211.00 211.00 211.00 211.00

Push layer

PEO (50 lakhs MW)

85.00 85.00 85.00 85.00 85.00 85.00

NaCl 30.00 30.00 30.00 30.00 30.00 30.00 MCC 15.00 15.00 15.00 15.00 15.00 15.00

Iron oxide Yellow 1.00 1.00 1.00 1.00 1.00 1.00 Magnesium stearate 1.00 1.00 1.00 1.00 1.00 1.00

Total 132.00 132.00 132.00 132.00 132.00 132.00

Coating of semi-permeable membrane (14 % gain)

Opadry CA 48.00 48.00 48.00 48.00 48.00 48.00 Total 391.00 391.00 391.00 391.00 391.00 391.00

Colour coat (3.11% weight gain)

Opadry pink 12.00 12.00 12.00 12.00 12.00 12.00 Total 403.00 403.00 403.00 403.00 403.00 403.00

TABLE 4: OPTIMIZATION OF PEO AND NACL IN PUSH LAYERS Pull layer ( drug layer)

Ingredients F7 F8 F9 F10 F11

API 10.00 10.00 10.00 10.00 10.00 PEO

(3 lakh MW) 175.00 175.00 175.00 175.00 175.00

NaCl 10.00 10.00 10.00 10.00 10.00 MCC 15.00 15.00 15.00 15.00 15.00

Magnesium stearate 1.00 1.00 1.00 1.00 1.00 Total 211.00 211.00 211.00 211.00 211.00

Push layer

PEO (70 lakhs MW)

80.00 85.00 90.00 90.00 90.00

Sodium chloride 30.00 30.00 30.00 20.00 40.00 MCC 20.00 15.00 10.00 20.00 0

Iron oxide Yellow 1.00 1.00 1.00 1.00 1.00 Magnesium stearate 1.00 1.00 1.00 1.00 1.00

Total 132.00 132.00 132.00 132.00 132.00

Coating of semi-permeable membrane (14 % gain)

Opadry CA 48.00 48.00 48.00 48.00 48.00 Total 391.00 391.00 391.00 391.00 391.00

Colour coat (3.11 % weight gain)

Opadry pink 12.00 12.00 12.00 12.00 12.00 Total 403.00 403.00 403.00 403.00 403.00

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93 Journal of Pharmaceutical Research and Therapeutics July-September 2020

of NaCl in push layer, by increasing the concentration of

NaCl the drug release was fast and the release profile

was similar to innovator.

All the above trials were performed by coating with

cellulose acetate as semi permeable membrane to get 14

% weight gain, based on information available from

patent and literature. To check the effect of weight gain,

trials F12, F13, F14 were performed by coating with

cellulose acetate to obtain, 8, 10, 12 % weight gain

respectively, 8 and 10 % showed fast release where as

12 % showed similar release when compared with

innovator (f2 = 92), to avoid extra weight gain when

compared to previous trials 12 % is selected as optimized

weight gain, concluding F14 as optimized batch and

continuing further studies to scale-up batches. Stability

studies were conducted at 40º/75 % RH for 3 mo. Assay,

TABLE 5: OPTIMIZATION OF SEMI-PERMEABLE MEMBRANE

Pull layer (drug layer)

Ingredients F12 F13 F14

API 10.00 10.00 10.00 Polyethyleneoxide

(3 lakhs MW) 175.00 175.00 175.00

NaCl 10.00 10.00 10.00 MCC 15.00 15.00 15.00

Magnesium stearate 1.00 1.00 1.00 Total 211.00 211.00 211.00

Push layer

Polyethylene oxide (70 lakhs MW)

90.00 90.00 90.00

Sodium chloride 40.00 40.00 40.00 Iron oxide Yellow 1.00 1.00 1.00

Total 132.00 132.00 132.00

Coating of semi-permeable membrane

8% 10% 12% Opadry CA 27.40 34.80 41.00

Total 370.00 377.00 384.00

Colour coat (3.11 % weight gain)

Opadry pink 12.00 12.00 12.00 Total 382.00 388.00 396.00

TABLE 6: COMPRESSION PARAMETERS OF TRIALS F1-F14

Batch No

Assay (%)

Average Weight (bilayer

tablet) mg

Hardness (kp)

Thickness (mm) Friability (%) Weight

variation

F1 98.06±0.15 341.3±0.56 13±0.26 4.95±0.13 0.118 Complies F2 102.3±0.02 343.8±1.26 14±0.36 4.92±0.24 0.137 Complies F3 99.1±0.25 344.8±1.53 14.8±0.4 4.93±0.19 0.154 Complies F4 103.2±0.02 343.4±0.29 14±0.28 4.93±0.26 0.241 Complies F5 101.0±0.21 341.6±2.10 13±0.40 4.94±0.22 0.148 Complies F6 98.7±1.20 342.6±0.12 13.6±0.25 4.93±0.16 0.160 Complies F7 102.07±0.34 342.8±2.01 13.5±0.33 4.90±0.28 0.213 Complies F8 98.6±1.02 344.8±1.02 14.8±0.38 4.91±0.22 0.256 Complies F9 99.8±0.46 341.2±2.06 13±0.22 4.92±0.17 0.222 Complies F7 100.06±1.89 342.3±1.05 13.7±0.24 4.93±0.26 0.248 Complies F8 97.05±1.08 344.5±0.08 14.7±0.33 4.92±0.30 0.286 Complies F9 97.8±0.09 343.2±0.96 14±0.36 4.92±0.26 0.241 Complies F10 96.7±0.56 345.4±0.75 15±0.28 4.91±0.15 0.157 Complies F11 100.8±1.28 341.5±1.96 13±0.40 4.90±0.23 0.250 Complies F12 98.6±0.36 342.2±1.25 13.8±0.62 4.93±0.15 0.231 Complies F13 101.2±1.06 343.6±0.46 14±0.23 4.95±0.13 0.168 Complies F14 99.05±0.96 341.3±0.26 13±0.26 4.96±0.08 0.226 Complies

TABLE 7: PERCENTAGE CUMULATIVE DRUG RELEASE DATA Time (h) Innovator F1 F2 F3 F4 F5 F6

0 0 0 0 0 0 0 0 1 0 0 0 0 0 0 0 2 3 1±0.23 2±0.41 1±0.36 1±0.33 1±0.45 1±0.25 4 20 10±0.86 13±0.23 11±0.46 9±0.63 10±0.75 13±0.27 8 45 24±0.45 30±0.25 25±0.36 28±0.86 32±0.66 28±0.45 16 98 45±0.54 48±0.46 55±0.53 74±0.45 70±0.33 77±0.69 20 100 55±0.46 58±0.46 63±0.56 77±0.75 77±0.45 82±0.96 24 100 56±0.36 62±0.75 65±0.86 78±0.55 80±0.55 84±0.85

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July-September 2020 Journal of Pharmaceutical Research and Therapeutics 94

dissolution profile of optimized formulation F14

complies was found to be stable.

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TABLE 8: PERCENTAGE CUMULATIVE DRUG RELEASE DATA Time (h)

Innovator F7 F8 F9 F10 F11 F12 F13 F14

0 0 0 0 0 0 0 0 0 0 1 0 0 0 0 0 0 6±0.53 2±0.63 0 2 3 1±0.63 1±0.75 1±0.56 1±0.64 1±0.36 9±0.65 4±0.96 1±0.23 4 20 7±0.56 9±0.86 10±0.33 8±0.36 15±0.63 30±1.2 22±0.89 17±0.63 8 45 28±0.23 26±0.96 33±0.26 30±0.96 4±0.64 62±0.96 56±0.45 49±0.46 16 98 68±0.76 77±0.53 93±0.54 93±0.45 99±0.86 100±0.28 100±0.56 99±0.33 20 100 82±0.96 91±0.25 96±0.96 95±0.36 99±0.01 100±0.87 100±0.96 100±0.75 24 100 84±0.45 92±0.56 96±0.23 96±0.96 100±0.01 100±0.96 100±0.23 100±0.23

TABLE 9: PHYSICAL CHARACTERISTICS OF LUBRICATED BLEND F14 Parameters Pull layer Push layer

Bulk density(g/ml) 0.45 0.51 Tapped density(g/ml) 0.52 0.58

Carr’s index (%) 14.2 12.3 Hausner’s ratio 1.15 1.14 Angle of repose 26.5 24.7

TABLE 10: PARTICLE SIZE ANALYSIS RESULTS % weight retained on sieve 20# 30# 40# 60# 80# 100# Pan

Pull layer 0 5.6 7.9 20.2 21.4 10.9 33.8 Push layer 0.4 2 3.2 33.6 21 8.2 31.6

TABLE 11: PHYSICAL CHARACTERISTICS OF THE COATED TABLETS OF F14 BATCH Sr. No. Parameters F14

1 Average weight 396.8+1.96 2 Friability (%) 0.19

3 Hardness (kp) 25±2.1

4 Thickness (mm) 5.66±0.06 5 Average diameter 9.0±0.8

TABLE 12: STABILITY DATA OF F14 BATCH

S. No Test Initial 40º/75 % RH

1 month 40º/75 % RH

2 month 40º/75 % RH

3 month

1. Assay 99.05±025 99.56±0.63 98.99±0.75 100.20±0.58 2. Dissolution 100±0.01 98.8±0.63 97.9±0.67 99.8±0.58

3.

Related

substance

Individual impurity

0.26 0.32 0.29 0.38

Total impurity

0.48 0.56 0.52 0.60

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95 Journal of Pharmaceutical Research and Therapeutics July-September 2020

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