FORMULATION DEVELOPMENT & IN VITRO EVALUATION OF GASTRO

RETENTIVE DRUG RELEASE OF FLOATING ORAL LIQUID IN-SITU GELS

CONTAINS HMG-CoA REDUCTASE INHIBITOR FLUVASTATIN BY USING
NATURAL POLYMERS

Mrs. Mortha. Lakshmi Prasanna*, Dr. Shailaja Pashikanti

Dr.Shailaja Pashikanti, Associate Professor, Department of Pharmaceutical Technology, College of Pharmaceutical

Sciences, Andhra University, Visakhapatnam- 530003.

Mrs. Mortha. Lakshmi Prasanna, Research Scholar (Part time), Department of Pharmaceutical Technology, College
of Pharmaceutical Sciences, Andhra University, Visakhapatnam- 530003.

Abstract: Gastrointestinal drug delivery systems have been widely used to increase the retention
time of drug in the gastrointestinal tract. A floating oral in-situ gel formulation between different
approaches offers controlled drug release and prolongs gastric retention with the added benefit
of liquid oral dosing. The present study is an attempt to design, development and evaluate the
floating oral in-situ gel of antihyperlipidemic drug fluvastatin using only natural polymers
such as Konjac gum, ⠀ Xyloglucan, ⠀ Xanthan gum, ⠀ Karaya gum , Locust bean⠀ gum,
Gellan gum, Sodium Citrate, Calcium chloride. Which undergo a sol-gel transition at gastric pH,
thus increasing the gastric retention time of the drug in the stomach. Sodium alginate has been
used as a natural polymer gelling agent, where the source of calcium ions occurs in the form of
calcium chloride. The drug and polymer were subjected to compatibility studies using FTIR
studies, which revealed no interaction between the drug and the polymer. Evaluation was carried
out for in vitro parameters such as gel properties total floating time, drug content, viscosity and
in vitro dispersion. Study Among all the formulations, the formulation F24 containing
Combination of Konjac gum and Xanthan gum was selected as the optimal formulation, which
showed the highest drug release at the end of 12 hrs and had good floating properties and gastric
retention. The optimized formulation from kinetic studies showed zero-order release by super
carrier transport mechanism II.
KEYWORDS: In-situ gel, Fluvastatin, Konjac gum, Xanthan gum, gellan gum Locust bean
gum, karaya gum, xyloglucan.
Introduction on in-situ gel:
The development of in-situ gelation systems has received considerable attention in the last
few years. In-situ gel drug delivery systems are capable of sustained drug release while
maintaining a constant drug concentration in blood plasma. These hydrogels are liquid at room
temperature but gel in contact with body fluids or when the pH changes. Compared to conventional
dosage formulations In-situ gel drug delivery systems have potential advantages such as simple
manufacturing process, ease of administration, reduced frequency of administration, improved
patient compliance, and convenience.1-2 in-situ gel drug delivery system is one type of drug delivery
system unlike very strong gels, liquid medications can be easily Administered into absorption sites.
At the drug absorption site a strong gel is formed. It has a capable of extending the duration of the
drug release. Natural and synthetic polymers can be used to produce in-situ gels. In-situ gel
formation is induced by one or a combination of different stimuli such as pH change, temperature
modulation, and ion exchange. Thus in-situ gels are administered by oral, occlular, rectal, vaginal
injection, and peritoneal routes and recent advances in in-situ gels have allowed us to exploit
changes in physiological specificity in different areas of the GI tract to increase drug absorption as
well as the comfort and satisfaction of the patient.3-6

1.2 Advantages of in-situ gels:

 In-situ gels are used to increase the gastric residence time of drug in absorption site.
 Provide maximum therapeutic effectiveness.
 Enhancing of rate of permeation of the drug through the biological membrane.
 Improve local bioavailability.
 In-situ gel system available in liquid form after administration it changes into gel hence it
is easy to administration by the patients.
 Floating oral in-situ gels is a Non invasive process.
 Dosing frequency decreases.
 Improve patient compliance.
Disadvantages
Not suitable for drugs that irritate the stomach example of those drugs are Aspirin and Non-
steroidal anti-inflammatory drugs.

1.3 Approaches to produce in-situ gel:

Various approaches and mechanisms used or involved in in- situ gel formation are as
follows8-12
 It is based on producing physical changes.
 It is based on producing chemical changes.
 Based on physiological stimuli.
 Dilution-sensitive.
 Electrical signal-sensitive.
  Light-sensitive.
 Glucose-sensitive

1.3.1 In-situ gel formation by physical changes:

This approach involves is a phenomenon of pouring or diffusion. In this system swelling the
polymer by absorption of the surrounding water and swells to form an adhesive gel (such as
glycerol mono oleate). Solution or dispersed drug solution and polymer diffuse into the surrounding
tissue and cause precipitation of polymer (eg: methyl pyrrolidone) to form a gel.
1.3.2 In-situ gel formation based on chemical changes or stimuli:
Changes in the chemical environment of the system can produce polymer cross-linking and
lead to gel formation.
1.3.3 Ionic cross linking:
With the presence of various ions in body fluids, such as Na+, K+, Ca2+, Fe3+, etc., ionic
sensitive polysaccharides such as gellan gum, pectin etc. undergoes a liquid phase is changes as a
gel due to the the cross linking cross linking of the polymer. Sodium alginate forms a gel in the
presence of calcium chloride.
METHODOLOGY:

2.1. Preformulation studies1-18

2.1.1. Solubility studies

Solubility of Fluvastatin was carried out in different solvents like 0.1N HCl, Water and
6.8 pH buffer. Saturated solutions were prepared by adding excess drug to the vehicles and
keep it for a period of 24 hrs at 25⸰C under constant vibration. Filtered sample (1ml) were
diluted appropriately with suitable buffer and solubility of Fluvastatin was determined
spectrophotometrically at 267 nm.
 Figure.No.5.1: Solubility studies of fluvastatin
2.1.2. Drug-excipient compatibility study

a) FTIR spectroscopy The physical compatibility between the pure drug and polymers used in
the research was tested by Infra Red (IR) spectroscopy. FTIR absorption spectra for pure
drug and physical mixture were recorded in the range of 400-4000 cm - 1 by KBr disc method
using FTIR spectrophotometer.

FTIR plot of pure Fluvastatin

Figure 5.2 FTIR plot of pure Fluvastatin

 Fig. No. 5.3 FTIR plot of the optimized formulation

4.1.3. Determination of Absorption maxima by UV spectrophotometer: 10 mg

of Fluvastatin was dissolved in 10 ml of buffers so as to get a stock solution of 1000
µg/ml concentration. From this 1ml solution was withdrawn and diluted to 10ml to
get a concentration of 100 µg/ml (SS-II). From this stock solution pipette out 1 ml
of the solution and makeup the volume to 10ml using buffer to get the concentration
of 10 µg/ml concentration, this solution was scanned under UV Spectroscopy using
200-400 nm.

Figure.No.7.4:Absorption maximum (λmax) of Fluvastatin267nm.

4.1.4. Preparation of standard calibration curve of Fluvastatin: 10 mg
of Fluvastatin was dissolved in 10 ml of 0.1N HCl by slight shaking (1000 µg /
ml). 1 ml of this solution was taken and made up to 10 ml with 0.1N HCl, which
gives 100 µg/ml concentrations (stock solution). From the stock solution,
concentrations of 4 , 8 , 12, 1 6 , 20 and 2 4 µg /ml in 0.1N HCl were prepared.
The absorbance of diluted solutions was measured at 267 nm and a standard plot
was drawn using the data obtained. The correlation coefficient was calculated.

Table No.5.2: Fluvastatin calibration curve data in 0.1N HCl

Concentration(µg/ml) Absorbance

0 0
5 0.141

10 0.275
15 0.412

20 0.542
25 0.678

Standard Calibration curve of Fluvastatin

0.8
0.7
0.6 f(x) = 0.0270285714285716 x + 0.00347619047618958
R² = 0.999892143037401
0.5
Absorbance

Absorbance
0.4
Linear (Absorbance)
0.3
0.2
0.1
0
0 5 10 15 20 25 30
Concentration(µg/ml)

Fig No: 5.5. Fluvastatin calibration curve in 0.1N HCl

 Table No.4.1: Formulation development of Fluvastatin Floating oral liquid in-situ gels F1 to F24

Ingredients (gm) F1 F2 F3 F4 F5 F6 F7 F8 F9 F10 F11 F12 F13 F14 F15 F16 F17 F18 F19 F20 F21 F22 F23 F24

Fluvastatin 0.4 0.4 0.4 0.4 0.4 0.4 0.4 0.4 0.4 0.4 0.4 0.4 0.4 0.4 0.4 0.4 0.4 0.4 0.4 0.4 0.4 0.4 0.4 0.4
(20mg/5ml)
Sodium Alginate 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5
(gm)
Calcium chloride 0.05 0.05 0.05 0.05 0.05 0.05 0.05 0.05 0.05 0.05 0.05 0.05 0.05 0.05 0.05 0.05 0.05 0.05 0.05 0.05 0.05 0.05 0.05 0.05
(%w/v)
Sodium citrate 0.17 0.17 0.17 0.17 0.17 0.17 0.17 0.17 0.17 0.17 0.17 0.17 0.17 0.17 0.17 0.17 0.17 0.17 0.17 0.17 0.17 0.17 0.17 0.17
(gm)
Konjac 0.5 0.75 1.0 1.5 _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 0.25 0.375 0.5 0.75
Gum(gm)
Xyloglucan _ _ _ _ 0.5 0.75 1.0 1.5 _ _ _ _ _ _ _ _ 0.25 0.375 0.5 0.75 _ _ _ _
(gm)
Xanthan gum _ _ _ _ _ _ _ _ 0.5 0.75 1.0 1.5 _ _ _ _ _ _ _ _ 0.25 0.375 0.5 0.75
(gm)
Karaya _ _ _ _ _ _ _ _ _ _ _ _ 0.25 0.375 0.5 0.75 _ _ _ _ _ _ _ _
Gum (gm)
Locust bean _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 0.25 0.375 0.5 0.75 _ _ _ _
gum(gm)
Gellan gum (gm) _ _ _ _ _ _ _ _ _ _ _ _ 0.25 0.375 0.5 0.75 _ _ _ _ _ _ _ _
Propyl paraben 0.01 0.01 0.01 0.01 0.01 0.01 0.01 0.01 0.01 0.01 0.01 0.01 0.01 0.01 0.01 0.01 0.01 0.01 0.01 0.01 0.01 0.01 0.01 0.01
(%w/v)
Aspartame 0.2 0.2 0.2 0.2 0.2 0.2 0.2 0.2 0.2 0.2 0.2 0.2 0.2 0.2 0.2 0.2 0.2 0.2 0.2 0.2 0.2 0.2 0.2 0.2
(gm)
Purified Water 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100
(ml)
 4.1.5. Method of Preparation of In-situ Gel:

Floating in-situ gel formulations of Fluvastatin were prepared using

compositions given in Table No. 4.1. Take 100 ml beaker add sodium alginate and

polymer then mix with 60ml distilled water, now heat the mixture at 60 ○C till
solution occurs using a heating magnetic stirrer .Take another 100ml beaker in
this add sodium citrate along with Calcium chloride then mix with 30ml distilled

water heat the mixture at 60○C till solution occurs. Now take another beaker (100

ml) to this add 5ml methanol with drug, then three mixtures are mixed at 60 ○C

After cooling this solution below 40○C keep the above mixture in mechanical
stirring well for 30 minutes to get the final preparation which was stored in amber
colour bottles until further use.

Fig No.4.1 Preparation of in-situ gel in a magnetic stirrer with hot plate

4.2 EVALUATION PARAMETERS OF ORAL IN-SITU GELS:

4.2.1. Visual appearance and Clarity:
Visual appearance and clarity was perform fluorescent lights on white and black
backgrounds to detect the presence of particulate matter. All the prepared in-situ
gel formulations of Fluvastatin were evaluated for clarity by visual observation
against a black and white background. After administration of the prepared
solution in (0.1N HCl, pH 1.2)
4.2.2. pH measurement
After adding all the ingredients, the pH of the prepared in-situ gel system was
measured using a digital pH meter. The measurement of pH of data were in
triplicate and the Average values given in table below.

Formulation Code Clarity pH

F1 Clear 7.2

F2 Clear 7.4

F3 Clear 7.3

F4 Clear 7.0

F5 Clear 6.9

F6 Clear 7.2

F7 Clear 6.8

F8 Clear 7.3

F9 Clear 7.4

F10 Clear 7.8

F11 Clear 7.4

F12 Clear 7.0

F13 Clear 6.7

F14 Clear 6.6

F15 Clear 6.9

F16 Clear 7.4

F17 Clear 7.1

F18 Clear 7.5

F19 Clear 7.3

F20 Clear 7.0

F21 Clear 6.8

F22 Clear 6.9

F23 Clear 7.1

F24 Clear 6.8

Table.No.5.3: Visual appearance & pH of Fluvastatin In-situ gels

Discussion: All the formulations were observed to be clear and the pH was
maintained in between 6.6 to 7.8.
4.2.3. Determination of drug content:

Accurately 5ml of formulation from different batches was

measured and transferred into a 100 ml volumetric flask. To this was added 50-
70mL of 0.1 N HCl and sonicated for 30 minutes. The volume was set to 100
ml. The complete dispersion of the content was visualized and the dispersion
was filtered using Whattman Filter Paper. A 1 ml sample was taken from this
solution and diluted to 10 ml with 0.1 N HCl. Fluvastatin content was measured
by UV-Visible spectrophotometer at maximum absorption at 267 nm.
Table.No.5.4:Percentage Drug content of Fluvastatin In-situ gels

Formulation code Drug content(%)

F1 97.45±0.01
F2 98.17±0.21
F3 98.34±0.11
F4 99.13±0.37
F5 98.05±0.24
F6 98.48±0.03
F7 98.76±0.02
F8 99.29±0.10
F9 97.69±0.13
F10 97.96±0.17
F11 99.26±0.05
F12 99.54±0.21
F13 97.26±0.23
F14 97.68±0.32
F15 98.44±0.02
F16 99.37±0.03
F17 97.32±0.22
F18 98.24±0.31
F19 98.38±0.11
F20 99.44±0.25
F21 98.48±0.30
F22 98.75±0.34
F23 99.25±0.02
F24 99.92±0.06
4.2.4. In vitro floating study: The internal floating test was performed by
introducing 5 ml of the formulation without too much disturbance in 100 ml of
HCl 0.1N, ( pH 1.2) at 37 ⸰C . The continuous floating time (floating time) of the
formulation in the dissolution medium was recorded.

Fig No 5.6: In vitro floating studies

Formulation code Floating lag time (s) Total floating Time (hr)
F1 89±0.54 07±0.03
F2 74±0.27 08±0.04
F3 69±0.43 09±0.16
F4 55±0.28 10±0.38
F5 78±0.42 07±0.53
F6 66±0.53 08±0.18
F7 53±0.16 09±0.32
F8 49±0.21 10±0.67
F9 65±0.25 07±0.50
F10 52±0.07 08±0.19
F11 47±0.23 09±0.26
F12 43±0.33 10±0.42
F13 78±0.22 07±0.05
F14 65±0.56 08±0.19
F15 55±0.67 09±0.04
F16 46±0.51 10±0.16
F17 76±0.16 07±0.25
F18 63±0.08 08±0.28
F19 54±0.01 09±0.16
F20 46±0.18 10±0.11
F21 69±0.26 06±0.06
F22 56±0.05 08±0.27
F23 44±0.18 10±0.12
F24 30±0.27 12±0.38

Table No.5.7 : In vitro floating studies F1 to F24

4.2.5. Gel strength and In vitro gelation time:
Formulation Code Gelation time (s)±SD Gel strength (N/m2)

F1 28±0.01 2.31±0.01

F2 25±0.06 3.81±0.15

F3 18±0.03 2.21±0.31

F4 13±0.01 1.86±0.28

F5 26±0.02 2.25±0.31

F6 21±0.07 1.84±0.01

F7 17±0.09 3.04±0.05

F8 12±0.04 1.87±0.17

F9 25±0.01 2.20±0.01

F10 23±0.23 3.01±0.18

F11 19±0.01 1.83±0.01

F12 16±0.05 2.23±0.01

F13 19±0.21 3.05±0.18

F14 16±0.28 2.78±0.28

F15 15±0.01 3.09±0.04

F16 12±0.07 1.85±0.01

F17 18±0.02 2.48±0.25

F18 15±0.06 3.07±0.03

F19 12±0.08 4.86±0.28

F20 10±0.03 5.04±0.02

F21 09±0.05 6.78±0.28

F22 07±0.03 8.02±0.03

F23 05±0.02 9.43±0.21

F24 02±0.01 10.82±0.12

Gel strength is indicating tensile strength of the gelled polymer in-situ gel mass
to evaluate the formulations for dispersibility in vitro and also able to withstand
the peristaltic movements in in vivo system. This study was conducted by using
fabricated gel strength apparatus and it was done in triplicate.
Table.No.5.5: Gel strength and In-vitro gelation time

4.2.6. In-situ gel system viscosity measurement:

 The viscosity of the dispersion was determined using a Brookfield Digital
Viscometer (NDJ-5S Viscometer). Samples (5 ml) were spun at 10 rpm /min
using spinner 2 at room temperature. For each sample, adhesion measurements
were performed in triplicate, each measurement lasting approximately 30
seconds.

4.2.7. In Vitro Release Studies:

The drug release study was carried out using a USP Type II paddle-type
apparatus using 900 ml of 0.1 N HCl (pH 1.2) at 37 ± 0.5ºC and 50 cycles. An
in situ gel (5ml) equivalent to 20 mg of Fluvastatin was used for the
experiment. The sample solution (5 ml) was withdrawn at predetermined time
intervals, filtered through a 0.45 μm membrane filter, measured by UV
spectrophotometric LABINDIA 8000 at 267 nm, and analyzed accordingly.
Fresh solvent was replaced after the test sample was withdrawn to maintain
precipitate conditions. The elution test was carried out for 12 hrs.

4.2.8. RELEASE KINETICS:80-81

In the present study, the in vitro release data were fitted to various kinetic
equations and models to describe the release kinetics of Fluvastatin from the gel
in situ. The kinetic model used is zero order equation, first order, Higuchi and
Korsmeyer-Peppas model.
Kinetic studies Mathematical models:
Various release kinetic equations (zero order, first order, Higuchi equation and
Korsmeyer-Peppas equation) are used to describe the release rate from the
matrix system for optimal formulation. A better fit is considered with a hig
 Table.No.5.8: In vitro drug release of Fluvastatin floating in-situ gel {F1-F12}

TI F1 F2 F3 F4 F5 F6 F7 F8 F9 F10 F11 F12

M
E

(h)

0 0 0 0 0 0 0 0 0 0 0 0 0

1 35.24 34.58 32.26 24.36 34.26 29.45 23.15 19.76 31.25 25.37 29.46 21.28
±0.19 ±0.23 ±0.27 ±0.21 ±0.05 ±0.17 ±0.19 ±0.02 ±0.09 ±0.23 ±0.23 ±0.03

2 46.37 47.59 40.58 30.65 47.34 39.26 34.16 25.19 48.36 37.15 36.85 28.48
±0.09 ±0.07 ±0.35 ±0.06 ±0.32 ±0.05 ±0.25 ±0.07 ±0.18 ±0.01 ±0.03 ±0.10

3 57.36 56.25 48.69 36.48 55.21 46.25 45.25 36.75 55.78 48.26 47.64 33.25
±0.17 ±0.36 ±0.47 ±0.11 ±0.41 ±0.23 ±0.13 ±0.25 ±0.04 ±0.05 ±0.11 ±0.27

4 70.24 64.84 57.65 46.72 63.42 53.16 49.37 42.14 72.31 59.47 53.16 40.26
±0.08 ±0.29 ±0.07 ±0.23 ±0.09 ±0.07 ±0.06 ±0.15 ±0.21 ±0.07 ±0.23 ±0.29

5 79.48 78.95 65.30 53.24 76.21 69.26 57.87 52.46 80.25 67.28 66.39 46.28
±0.21 ±0.12 ±0.26 ±0.31 ±0.25 ±0.28 ±0.25 ±0.25 ±0.16 ±0.08 ±0.07 ±0.33

6 85.59 85.64 71.78 59.68 84.36 77.15 68.29 57.36 87.36 77.10 75.28 53.69
±0.26 ±0.15 ±0.23 ±0.15 ±0.03 ±0.08 ±0.21 ±0.34 ±0.19 ±0.10 ±0.12 ±0.23

7 98.65 90.47 77.65 67.45 98.74 89.26 83.47 66.75 98.45 85.49 80.24 65.74
±0.39 ±0.34 ±0.17 ±0.08 ±0.34 ±0.15 ±0.06 ±0.15 ±0.11 ±0.06 ±0.10 ±0.34

8 98.85 85.26 76.56 98.98 89.67 99.21 86.39 73.69

±0.28 ±0.20 ±0.26 ±0.08 ±0.27 73.10 ±0.23 ±0.24 ±0.28
±0.01

9 98.95 89.64 98.12 86.75 99.36 85.26

±0.25 ±0.04 ±0.01 ±0.28 ±0.06 ±0.32

10 98.35 98.78 98.84

±0.18 ±0.05 ±0.02

11

12
 Table.No.5.9 : In vitro drug release of Fluvastatin floating in-situ gel {F13-F24}

TIME F13 F14 F15 F16 F17 F18 F19 F20 F21 F22 F23 F24

(h)

0 0 0 0 0 0 0 0 0 0 0 0 0

1 32.15±0.02 25.14±0.21 21.25±0.01 22.36±0.03 35.15±0.03 36.14±0.04 26.58±0.23 32.36±0.03 39.48±0.2 32.49±0.07 24.15±0.36 25.85±0.01
4

2 47.26±0.03 36.25±0.19 29.36±0.06 30.25±0.12 42.26±0.01 47.25±0.09 35.16±0.35 46.16±0.21 45.24±0.3 46.26±0.15 37.69±0.25 36.19±0.06
1

3 55.64±0.06 44.25±0.04 37.15±0.17 38.15±0.07 55.14±0.17 56.28±0.39 42.36±0.41 51.96±0.05 59.15±0.0 58.12±0.23 46.28±0.32 43.18±0.15
5

4 69.58±0.21 53.69±0.10 43.26±0.21 45.65±0.17 67.21±0.04 63.15±0.05 55.25±0.01 58.24±0.09 71.26±0.3 62.25±0.03 54.96±0.06 50.75±0.17
6

5 76.15±0.32 59.74±0.25 49.28±0.31 50.12±0.04 78.26±0.21 74.28±0.21 63.28±0.03 65.25±0.23 88.13±0.0 75.19±0.11 62.74±0.19 58.26±0.04
7

6 87.26±0.34 67.58±0.11 57.69±0.27 57.63±0.25 82.26±0.10 89.29±0.04 79.28±0.01 71.26±0.06 98.92±0.1 83.56±0.08 69.43±0.23 67.12±0.07
8

7 98.78±0.06 80.25±0.26 68.74±0.02 65.26±0.01 98.15±0.08 93.25±0.31 88.64±0.23 79.65±0.10 92.75±0.10 76.25±0.34 73.26±0.09

8 98.36±0.18 76.25±0.08 74.36±0.08 98.36±0.10 93.26±0.06 85.26±0.17 98.54±0.35 84.36±0.07 80.12±0.02

9 98.14±0.27 80.26±0.16 98.45±0.37 89.64±0.06 93.27±0.13 85.26±0.03

10 98.45±0.26 98.10±0.07 99.39±0.06 93.56±0.01

11 97.62±0.10

12 99.85±0.09
 Fig No: 5.13. In-vitro dissolution profile of F1-F24

Table No5.10 : Comparative In-vitro dissolutionprofile of reference with optimised

formulation

Referenc
Time e F24
0 0 0
1 28.25 25.85
2 39.19 36.19
3 47.26 43.18
4 58.46 50.75
5 67.14 58.26
6 78.21 67.12
7 85.27 73.26
8 93.59 80.12
9 99.65 85.26
10 93.56
11   97.62
12   99.85

Comparative In-vitro dissolution profile of reference with optimised formulation

 Figure.No.5.13 Comparative In-vitro dissolutionprofile of reference with optimised

formulation F24

Zero order release kinetics: F24

Figure.No.5.14: Zero order release graph

First order release kinetics: F24
 Figure.No. 5.15: First order release graph

Higuchi release plot: F24

Figure.No.5.16: Higuchi release graph

Peppas release plot:F24

Fig.No. 5.17 Peppas release graph

Table No: 5.12. R2 & n Values of different kinetic models

R2 values n values

Zero First Korsmeyar Korsmeyer

Formulation Higuchi
order order peppas peppas (n)

F24 0.978 0.739 0.990 0.624 1.122

The in vitro dissolution data for the optimised formulation were fitted to different kinetic
models, i.e. zero order, first order, Higuchi and Korsemeyer-Peppas equations. The optimized
F24 formula shows an R2 value of 0.958. Since its value nearer to the ‘1’ it is conformed as it
follows the Zero order release. The mechanism of drug release is further confirmed by the
korsmeyer and peppas plot, if n = 0.45 it is called Case I or Fickian diffusion, 0.45 < n < 0.89
is for anomalous behavior or non-Fickian transport, n = 0.89 for case II transport and n > 0.89
for Super case II transport.

For the optimized formula (F24), the value of "n" is 1.122, that is, the value of n indicates the
super case II transport mechanism. The release kinetics for the optimized formulation are
presented in the table.
 CONCLUSION:

From the in vitro drug release studies of Fluvastatin oral in-situ gels using different polymer
ratios.

Among the all 24 trails F1-F4 trails were formulated using konjac gum in four different
concentrations the drug release time was increased with increase in the polymer
concentration. F1 formulation 98.65% of drug release at the end of 7hrs, while F2
formulation shows 98.85% of drug release at the end of 8hrs, While F3 formulation show
98.95% of drug release at the end of 9 hrs, whereas F4 formulation shows 98.35% of drug
release at the end of 10 hrs. Among all the four formulations cannot sustained the drug
release for 12hrs. So further formulations were prepared using Xyloglucan.

Then F5-F8 trails were formulated using Xyloglucan in four different concentrations, the
drug release time was increased with increase in the polymer concentration. F5 formulation
shows 98.74% of drug release at the end of 7 hrs, while F6 formulation shows 98.98% of
drug release at the end of 8 hrs, while F7 formulation shows 98.12% of drug release at the
end of 9 hrs, whereas F8 formulation shows 98.78% of drug release at the end of 10 hrs.
Among all the four formulations cannot sustained the drug release for 12 hrs. Further
formulations were prepared using Xanthan gum.

Then F9-F12 trails were formulated using Xanthan gum in four different concentrations. F9
formulation shows 98.45% of drug release at the end of 7 hrs, while F10 formulation shows
99.21% of drug release at the end of 8 hrs, while F11 formulation shows 99.36% of drug
release at the end of 9 hrs, whereas F12 formulation shows 98.84% of drug release at the end
of 10 hrs. Among all the four formulations cannot sustained the drug release for 12 hrs.
Further formulations were prepared using combination of karaya gum and gellan gum.

Then F13-F16 trails were formulated using combination of karaya gum and gellan gum in
four different ratios. F13 formulation shows 98.78% of drug release at the end of 7 hrs, while
F14 formulation shows 98.36% of drug release at the end of 8 hrs, while F15 formulation
shows 98.14% of drug release at the end of 9 hrs, whereas F16 formulation shows 98.45% of
drug release at the end of 10 hrs. Among all the four formulations cannot sustained the drug
release for 12 hrs. Further formulations were prepared using combination of Xyloglucan and
locust bean gum gum.
Then F17-F20 trails were formulated using combination of Xyloglucan and locust bean gum
Gum in four different ratios. F17 formulation shows 98.15% of drug release at the end of
7hrs, while F18formulation shows 98.36% of drug release at the end of 8 hrs, while F19
formulation shows 98.45% of drug release at the end of 9 hrs, whereas F20 formulation
shows 98.10% of drug release at the end of 10 hrs. Among all the four formulations cannot
sustained the drug release for 12 hrs. Further formulations were prepared using combination
of Xanthan gum and konjac gum.

Then F21-F24 trails were formulated using combination of Xanthan gum and konjac gum in
four different ratios. F21formulation shows 98.92% of drug release at the end of 6 hrs, while
F22 formulation shows 98.54% of drug release at the end of 8 hrs, while F23 formulation
shows 99.39% of drug release at the end of 10hrs, whereas F24formulation shows 99.85% of
drug release at the end of 12 hrs.Among all the four formulations F21, F22 and F23 cannot
sustained the drug release for 12hrs. But Formulation F24 can sustained the drug release for
12hrs.

Among the all 24formulations, based upon the in vitro drug release studies F24 formulation
containing higher concentration of Xanthan gum and konjac gum choosen as optimized
formulation, and has higher viscosity nature the formulation with higher concentration of
Xanthan gum and konjac gum maintains controlled drug release.

Further Study was carried out by Comparing the dissolution profile of optimised
formulation F24 with Reference product available brand name in the market is LESCOL
XL. Optimised Formulation shows the drug release 99.85% at the end of the 12hrs.
Reference product shows the drug release 99.65% at the end of the 9 hrs. By this study
optimised formulation 24 can controlled the drug release for 12hrs.

So the drug release kinetics were performed for the F24 formulation. Optimised Formulation
F24 shows the drug release 99.85% at the end of the 12hrs. Reference product shows the drug
release 99.65% at the end of 9 hrs. By this study optimised formulation F24 can controlled
the drug release for 12hrs. F24 Formulation containing drug content was found to be
99.92%. floating time of the Formulation F24 was found to be 12 hrs. Viscosity of the
formulation F24 was found to be 412 cps. The in-vitro gelation study of formulation F24
was found to be (+++) Gelation lasts for a long time. The release kinetics of the optimized
formulation best fit the Higuchi model (R2 = 0.990) and showed super case II zero order (R 2 =
0.958). From the stability studies data Formulation F24 From the experimental results above,
 it can be concluded that Fluvastatin was chosen as a model candidate for the development of
an in situ oral gel because it is a system in which drugs should be formulated with controlled
drug delivery.

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