world journal of pharmaceutical research pant et al. sjif

www.wjpr.net Vol 5, Issue 9, 2016.

633

Pant et al. World Journal of Pharmaceutical Research

FORMULATION AND EVALUATION OF FAST DISSOLVING FILM

OF METFROMIN HCL FOR FAST DISSOLVING DRUG DELIVERY

SYSTEM

Warsha Pant*, Ashutosh Badola and Preeti Kothiyal

Division of Pharmaceutical Sciences, SGRRITS Patel Nagar, Dehradun – 248001,

Uttarakhand, India.

ABSTRACT

The main objective of present study was to deal with develop fast

dissolving drug delivery system of Metformin HCl using Film Forming

Polymer (HPMC K100 M) and Saliva stimulating agent (Citric acid)

Fast dissolving forming polymeric formulation drug delivery system is

in film or thin strip form in the time of administration in the body, and

once administered, that undergoes fast release of drug from the film

formulations. Metformin hydrochloride is a novel drug in class of

biguanide used as an anti diabetic to treat the NIDDM. The

bioavailability of a drug and its therapeutic effectiveness are often

influenced by route of administration. So the reason for an attempt was

made to formulate and evaluate fast dissolving thin oral films

containing Metformin HCl as a model drug by solvent casting method using different

concentrations of polymers like HPMC K100 M. Various formulations were formulated with

different concentration of disintegrating agents like Crospovidone and Sodium starch

glycolate. Citric acid was used as saliva stimulating agent and Propylene glycol used as a

plasticizer. The prepared oral thin films were evaluated for their physicochemical and as well

as mechanical parameters such as Physical appearance, surface texture (SEM), Weight

uniformity of films, surface pH of films, uniformity in thickness, disintegration time of films,

drug content uniformity, folding endurance, in-vitro drug release for the films formulated. It

was concluded that Formulations F5, F7, F6 and F4 shows maximum release of drug. The

formulation F5 was found most optimized. The Formulation F5 is having average weight

82.53±0.31 mg, thickness 0.182±0.050 mm and maximum folding endurance 291±5.The

formulation F5 shows minimum disintegration time 08±2 second and maximum drug release

World Journal of Pharmaceutical Research SJIF Impact Factor 6.805

Volume 5, Issue 9, 633-645. Research Article ISSN 2277– 7105

*Corresponding Author

Warsha Pant

Division of

Pharmaceutical Sciences,

SGRRITS Patel Nagar,

Dehradun – 248001,

Uttarakhand, India.

Article Received on

01 July 2016,

Revised on 22 July 2016,

Accepted on 11 Aug 2016

DOI: 10.20959/wjpr20169-6787


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99.15 % in 10 minutes. Hence the formulation F5 was found to be the most optimized

formulation.

KEYWORDS: Crospovidone and Sodium starch glycolate.

INTRODUCTION

For the administration of drug the most desirable route is oral route for its patient compliance

in a good manner and its convenience. When the drug is released from the dosage form it is

absorbed from the gastrointestinal tract, but only when the drug is dissolved in intestinal and

gastric fluids. The drugs having poor water-solubility need high doses in order to reach peak

plasma concentration after the administration via oral route to show the therapeutic activity.

In case of such drugs the improvement in the extent and rate of dissolution is highly

advisable, by which the oral bioavailability is increased and more reproducible due to

improvement in the extent and rate of dissolution, which directly leads to clinically relevant

the more reliable therapy and dose reduction.[1]

60% of the total dosage forms are the solid dosage forms. As compared with other dosage

forms tablet are the most preferred dosage form due to ease of administration, manufacturing

and as well as patient compliance. But in some cases geriatric, pediatric and the bedridden

patient shows difficulties in swallowing the conventional oral dosage forms.[2]

Some other dosage forms like syrups, they may be alternate but they do not consist fixed

prescribed dose and due to the reason of stability issues syrups are not preferred. In

comparison to syrup the other route of administration like parenteral, are painful to overcome

the difficulties of various route of administration and syrups have difficulties in their dosage

uniformity so the other novel drug delivery system like fast dissolving drug delivery system

introduced.

If we talk about an alternative to conventional dosage forms for geriatric, pediatric and the

bedridden patients who shows problems and difficulties in swallowing the traditional and

conventional dosage forms, then in the late 1970 the tablet was formulated by using the

superdisintegrants and some hydrophilic ingredients which has the higher solubility,

bioavailability, quick action and as well as patients compliance, are called as fast dissolving

tablets. There is some issues in the formulation of fast dissolving tablet related to using

expensive lyophillisation process and sometimes having issues in carrying, store, and


635


handling (fragility and friability) and as well as chances of chocking of FDTs. For the

elimination of the drawbacks of FDTs a Fast dissolving films can be prepared. The oral films

are somewhere similar to ultra-thin strips of postage stamp in their morphology. Like shape,

size and thickness. FDFs are intake through or any oral mucosal tissue, instantly they get wet

by saliva present in oral cavity the films rapidly hydrates and adheres onto the site of

application after than the film get disintegrates and dissolve to release the dose for oro-

mucosal absorption or with formula modifications, will maintain the quick dissolving aspects

allow for GI absorption to be achieved when swallowed.[3] The films are the ideal intra-oral

FDDS, is easy in handling, administer and as well as maintain a simple and convenient

packaging, and it is easy in manufacturing. The film administered via place on the top or the

floor of tongue.

The film retains at the site of application and rapidly releases the active agent for local as

well as systemic absorption. It approaches to increase patient acceptance by virtue rapid

dissolution self administration without intake of water and without chewing. FDFs are more

useful whether local action desired such as local anesthetic for toothaches, oral ulcers, cold

sores or teething.[4] Oral films are based on the technology of the transdermal patches. Fast

dissolving oral films have advantages like, more stable, durable and quicker than other

conventional dosage forms, avoid first pass metabolism pleasant mouth feel, accurate dosing

rapid onset of action and no need of water with patients compliances.

There are two primary issues that have been faced by the pharmaceutical company at the

present time after the administration of less aqueous solubility and the bioavailability of

drugs in body. This issue has become the major issue inhibiting the release of new chemical

moieties into the market. Due to the above statement approximately more than 50% of the

potentially active pharmaceutical ingredients get rejected. During the last decades, there are

more than 40% of the new chemical moieties launched in the U.S. pharmaceutical market had

faces the issues related to adequate solubility.[1]

1.1- Advantages of fast dissolving films [FDF][3]

1. Improved patient compliance.

2. No need of water.

3. No need of chewing.

4. Better taste.

5. Improved and enhanced stability.


636


6. Suitable for controlled as well as fast release.

7. Ability to provide advantages of liquid mechanism in the form of solid preparation.

8. Avoid first pass metabolism.

9. Flexible and portable nature provides ease in transportation, handling, storage.

10. Quick disintegrating and dissolution in the oral cavity due to the presence of larger

surface area.

11. Provide new business opportunity like product differentiation, product promotion, patent

extension.

12. Beneficial in case like, motion sickness, acute pain, suede episode of allergic attack or

coughing, where an ultra rapid onset of action required.

MATERIAL AND METHODOLOGY

MATERIALS

Metformin HCl was procured as a gift sample from Mapromax laboratories Selaqui,

Uttarakhand. HPMC K100, Crospovidone, cirtric acid, propylene glycol, maltodextrin, and

ethanol and lactose were supplied from Central drug house (P) LT.

METHOD

Preparation of fast dissolving film of Metformin HCl[4]

Fast Dissolving Films of Metformin HCl was formulated by Solvent Casting Method. The

Disintegrants used were Crospovidone and Sodium starch glycolate. The fast dissolving films

were formulated by using different polymers such as (HPMC & PVA) and Propylene Glycol

as plasticizer. The calculated amount of polymer and PG (3 ml) was dispersed in three- fourth

amount of solvent (ethanol) with continuous stirring by using Magnetic Stirrer and the final

volume (20ml) was adjusted by solvent. Calculated amount of Metformin HCl, and

maltodextrin(2omg), Citric acid (20 mg) and Superdisintegrants in varying concentration

(2.0, 4.0, 6.0, 8.0 & 10 %) was mixed in another beaker by using magnetic stirrer, and then

incorporated in polymeric solution and stirred to form a homogenous solution. Then the

solution was poured into the petridish and then kept for drying in room- temperature for

24hrs. The films thus formed were cut into 2.5×2.5 cm2.


637


Table no. 1: Formulation composition of different batches.

Formulation

code

Drug

(mg)

HPMC

K100

(mg)

Crospovidone

(mg)

Propylene

Glycol

(ml)

Citric

acid

(mg)

Sodium Starch

Glycolate

(mg)

Maltodextrin

(mg)

Ethanol

(ml)

F1 500 100 10 0.2 20 20 10 20

F2 500 100 10 0.2 20 20 10 20

F3 500 100 15 0.2 20 20 10 20

F4 500 200 15 0.3 20 30 10 20

F5 500 200 20 0.3 20 30 10 20

F6 500 200 20 0.4 20 30 10 20

F7 500 200 25 0.4 20 40 10 20

F8 500 200 25 0.4 20 40 10 20

Evaluation parameter

4.3- Evaluation of films

1. Scanning Electron Microscopy:

2. Physical appearance and surface texture

3. Weight uniformity

4. Thickness uniformity

5. Folding endurance

6. Surface pH

7. In- Vitro disintegration time

8. Drug content uniformity

9. In-Vitro dissolution Studies

4.5.1- Scanning Electron Microscopy- Morphology of prepared films was observed under

a Scanning Electron Microscope (SEM). The samples were attached to slab surfaces with

double sided adhesive tapes and scanning electron photomicrograph was taken at 1000 X

magnification. The result shown in fig. 6.

4.5.2- Physical appearance and surface texture of films [5]- This parameter was checked

simply with visual inspection of films and evaluation of texture by feel or touch.

4.5.3- Weight uniformity of films[6]- The films of size 2.5×2.5 cm were weighed

individually using digital weighing balance and the avg wt. calculated. Results shown in

table- 4.


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4.5.4- Thickness of films[6]- Thickness of films was measured by using Venire calipers with

least count of 0.01mm at different spots of films. The thickness was measured at three

different spots of the films and average was taken. The result shown in table- 4.

4.5.5- Folding endurance of films [7]- Folding endurance measures the flexibility of films.

Folding endurance of films was measured repeatedly folding a small strip of films at the same

place till it broke. The number of times films could be folded at the same place, without

breaking lives the value of folding endurance. The average results for folding endurance of

films were shown in Table-4.

4.5.6- Surface pH of films[5]- For determination of surface pH of films, the films were

allowed in contact with 1ml of distilled water. The surface pH was noted by bringing a

combined glass electrode near the surface of films and allowing equilibrate for 1 minute.

Results shown in Table- 4.

4.5.7- In Vitro disintegration time of films[6]- Disintegration test was performed in

disintegrating time testing apparatus. Phosphate buffer pH 6.8 used as medium. The films

were placed in the tubes of the DT apparatus and disintegration time was recorded. Results of

disintegration time are shown in Table-4.

4.5.8- In-vitro Dissolution Studies[7]- In – Vitro dissolution of Metformin HCl fast

dissolving film was studied in Type 1, (rotating paddle) dissolution test apparatus, 900ml

phosphate buffer pH 6.8 was used as medium. The stirrer was adjusted to rotate at 50 rpm.

The temperature of dissolution medium was maintained at 37±0.50C throughout the

experiment. One film was used in each test. Samples of dissolution medium (5ml) were

withdrawn by means of pipette, at known intervals of time and analyzed for drug release by

measuring the absorbance at 261nm. The volume withdrawn at each interval was replaced

with fresh quantity of dissolution medium. The result of dissolution studies are shown in fig.

7 & 8.

4.5.9- Drug content[8]- Total drug content of per film was determined by random sampling

of all the prepared formulations. Film of 4sq.cm was cut and placed in 50ml volumetric flask

and dissolved in phosphate buffer 6.8. Then pipette out 1 ml of solution and dilute to 10ml

with buffer. The absorbance of the solution was measured at 233nm. The result of drug

content shown in table- 5.


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RESULT

Pre-formulation results

Table no 2: Result of Organoleptic properties.

S. no. Properties Result

1 Description Solid

2 Color White crystalline powder

3 Odor Odorless

4 Taste Tasteless

FTIR of drug sample under investigation.

METFORMIN HCL

Name

Sample 013 By Administrator Date Friday, January 29 2016

Description

4000 4003500 3000 2500 2000 1500 1000 500

42

2

5

10

15

20

25

30

35

40

cm-1

%T

3370.22cm-13173.54cm-1 1622.82cm-1

1583.73cm-1

1474.61cm-1

1447.10cm-1

1417.94cm-1

534.92cm-1

635.54cm-1

570.53cm-1

608.57cm-1

1059.00cm-1

9 3 3 . 5 3 c m - 1

736.33cm-1

417.91cm-1

1165.10cm-1

2693.86cm-1

798.62cm-1

Fig.- 1.

Solubility Analysis

Table no.3- Solubility analysis

Solvent Solubility (mg/ml) Solubility

Water 3.9mg/ml Freely soluble

Ethanol 3.78mg/ml Freely soluble

Chloroform 0.192mg/ml Insoluble

Ether 0.186mg/ml Insoluble

Melting point determination: The temperature at which the powder of the drug starts to

melt was found to be 222-226 o C.


640


UV Spectroscopy- Preparation of standard curve of Metformin HCl in distilled water

Fig. 2.

Drug excipients compatibility studies

FTIR of Metformin HCl and Crospovidone

Metformin +crospovidone

Name

Sample 010 By Administrator Date Monday, February 01 2016

Description

4000 4003500 3000 2500 2000 1500 1000 500

33

8

10

12

14

16

18

20

22

24

26

28

30

32

cm-1

%T

3371.57cm-1

3176.97cm-1

1634.16cm-1

2936.38cm-1

1471.30cm-1 1059.35cm-1

1417.62cm-1

538.62cm-1

634.87cm-1

936.18cm-1

418.53cm-1

736.45cm-1

7 9 9 . 6 7 c m - 1

Fig. 3.

FTIR of Metformin HCl and Sodium starch glycolate

Metformin+Sod.starch

Name

Sample 011 By Administrator Date Monday, February 01 2016

Description

4000 4003500 3000 2500 2000 1500 1000 500

32

56

8

10

12

14

16

18

20

22

24

26

28

30

cm-1

%T

3372.09cm-1 1038.80cm-1

1079.93cm-1

1623.03cm-12934.82cm-1

1157.35cm-1

575.92cm-1

533.90cm-1

1417.65cm-1

4 1 9 . 8 8 c m - 1

736.22cm-1

935.64cm-1

861.81cm-1

Fig. 4


641


FTIR of Metformin HCl and HPMC k100.

Fig. 5.

Scanning Electron Microscopy

Fig. 6.

Table no. 4: Evaluation parameters of fast dissolving films.

Parameter

Weight

Variation

(mg)

Thickness

(mm)

(± 0.05)

Folding

Endurance

(± 5)

Disintegrating

Time

(sec) ± SD, n=3

Surface

pH

In-vitro

drug

release

F1 84.72±0.25 0.141±0.05 219 11±0.342 6.27±0.153 92.90

F2 74.82±0.68 0.146±0.05 286 09±0.129 6.19±0.101 94.12

F3 81.02±0.29 0.152±0.05 298 10±0.179 6.97±0.124 95.16

F4 81.25±1.20 0.145±0.05 210 10±0.157 6.45±0.112 96.10

F5 82.53±0.31 0.182±0.05 291 08±0.116 6.58±0.172 99.15

F6 74.13±0.32 0.180±0.05 261 12±0.076 6.46±0.052 96.28

F7 81.91±0.33 0.187±0.50 242 13±0.105 6.86±0.061 96.45

F8 71.98±0.28 0.156±0.05 254 12±0.157 6.80±0.126 95.77


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Table no. 5: Table of drug content of Formulations F1-F8.

S. No. Formulation

code

Drug contents

(±1)

1 F1 91

2 F2 94

3 F3 98

4 F4 97

5 F5 95

6 F6 96

7 F7 91

8 F8 82

In- vitro profile of formulation 1 to 4.

Fig.7.

In- Vitro profile of formulation 5-8.

Fig. 8.


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Table no. 6: Table of correlation factor.

Formulation

code

Correlation Factor Korsmeyer

and Peppas

(N)

Zero

(R2)

First

(R2)

Higuchi

(R2)

F1 0.9982 0.9842 0.9844 0.3793

F2 0.9887 0.9777 0.806 0.3647

F3 0.9945 0.9845 0.9709 0.3295

F4 0.9746 0.9227 0.9911 0.3414

F5 0.9258 0.9291 0.9694 0.336

F6 0.9851 0.8657 0.9545 0.414

F7 0.9527 0.9391 0.9709 0.3398

F8 0.9789 0.9562 0.987 0.357

CONCLUSION

In the presented work, fast dissolving films of Metformin HCl is an anti-diabetic drug were

prepared to provide a favorable means to those patients who have difficulty in swallowing.

Advantages of fast dissolving films like it Improved patient compliance, no need of water, no

need of chewing, better taste, improved and enhanced stability, Suitable for controlled as well

as fast release, Ability to provide advantages of liquid mechanism in the form of solid

preparation, Avoid first pass metabolism, Flexible and portable nature provides ease in

transportation, handling, storage. In the present study in order to reach the goal of achieving

the fast release, superdisintegrants Crospovidone and sodium starch glycolate were used

along with film forming polymer hydroxy propyl methyl cellulose K100 M. In addition good

results were obtained with Crospovidone (6%) & sodium starch glycolate (6%).

The films were formulated by solvent casting method. The disintegration time of films was

reduced by using superdisintegrants like Crospovidone and Sodium starch glycolate.

From the finding of result following conclusions were obtained.

1. FTIR of drug individual or in combination with excipients shows that there is no chemical

interaction between Metformin HCl and the excipients used in the study.

2. The formulated films were clear and colorless. The SEM of the film formulated at 1000 X

magnification showed smooth surface with some little pores and without any scratches in

films.

3. Prepared films gives delight result for the various physicochemical evaluation parameter

of films like Physical appearance, uniformity of weight, uniformity of thickness, folding

endurance of films, surface pH of films, in-vitro disintegration time and In-Vitro

dissolution studies for the films.


644


4. The lesser values of standard deviation for average weight and average thickness indicate

weight and thickness within the films formulated.

5. On the basis of In-vitro DT for formulation F5 with 4% Crospovidone and Sodium Starch

Glycolate and F2 with 2% Crospovidone and Sodium Starch Glycolate shows between 9-

10min.Which is found promising disintegration time for the film formulation.

6. Based on In-Vitro Dissolution Study it was found that formulation F5, It was found that

formulation F5, which is containing 4% Crospovidone and 4% Sodium starch glycolate

with HPMC K100 shows 99.15% drug release in 10 minutes. And formulation F7, which

is containing 6% Sodium starch glycolate and Crospovidone shows 96.45% drug release

in 12 minutes. It was concluded that Formulations F5, F7, F6 and F4 shows maximum

release of drug.

7. The formulation F5 was found most optimized. The Formulation F5 is having average

weight 82.53±0.31 mg, thickness 0.182±0.050 mm and maximum folding endurance

291±5.The formulation F5 shows minimum disintegration time 08±2 second and

maximum drug release 99.15 % in 10 minutes. Hence the formulation F5 was found to be

the most optimized formulation.

8. It can be concluded form the present studies that fast dissolving films of Metformin HCl

can be prepared by Solvent Casting Method by using Superdisintegrants. And it is also

concluded that Sodium starch Glycolate and Crospovidone was found to be the best

among the two superdisintegrants.

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