Development and Evaluation of Hydrodynamically Balanced System of Tramadol Hydrochloride By Using Chitosan And Locust Bean Gum

Development and Evaluation of Hydrodynamically Balanced System of Tramadol Hydrochloride By Using Chitosan And Locust Bean Gum

Development And Evaluation Of Hydrodynamically Balanced System Of Tramadol Hydrochloride By Using Chitosan And Locust Bean Gum

ABSTRACT

The main purpose of the study was development and evaluation of hydrodynamically balanced capsule of Tramadol HCl by using chitosan and locust bean gum as a natural polymer that prolongs the gastric residence time. Chitosan with different grade (low molecular weight, medium and high molecular weight) and locust bean gum were used as a drug release retarding agents. The hydrodynamically balanced capsule of tramadol HCl were prepared by ordered mixing technique. The concentration of both the polymers was optimized in order to achieve the sustained release of drug (TH) for 10 hours. Then the prepared capsules were evaluated for buoyancy test and in vitro drug release were performed. And other characterization analysis was also considered like FTIR study, DSC/DTG/TGA study and interaction study were also performed on the basis of characterization analysis. From these studies it was confirmed that there is no interaction observed between drug and excipient. The drug release studies shows that the retarding drug release pattern is dependent on the concentration and molecular weight of polymer as the concentration /molecular weight increases the retarding drug release pattern was also improved. And the synergistic action of retarding drug release was observed by the addition of another polymer i.e locust bean gum. Release pattern was fitted with the different kinetic model like Zero order, First order, Higuchi model and Korsmeyer peppas and it was concluded from the models that the drug release pattern obeys zero order model which signifies high therapeutic efficacy and minimum side effects.

Keywords: Tramadol HCl, Chitosan, Locust bean gum, Hydrodynamically Balanced System, Buoyancy, Gastric Residence Time.

Author details-Pravjot Kaur1* Surabhi Ghildiyal2 and Dr. Shashank Soni3

Corresponding Author Address-1Department of Pharmacy, Sardar Bhagwan Singh Post-graduate Institute of Biomedical Sciences and Research, Dehradun, Uttarakhand, India; E-mail: pravjotkaur@gmail.com

1Department of Pharmacy, Sardar Bhagwan Singh Post-graduate Institute of Biomedical Sciences and Research, Dehradun, Uttarakhand, India; E-mail: subighildiyal@gmail.com

2Amity Institute of Pharmacy, Amity University Uttar Pradesh, Lucknow, India; E-mail: ssoni@lko.amity.edu

INTRODUCTION

Oral route has been declared the most suitable and broadly acknowledged path of drug delivery system. Therefore oral controlled release dosage forms owes a remarkable benefit and this route is being considered as the remarkable point in the field of pharmaceutical sciences to achieve the set of goals of therapeutic advantages such as: reduced dosing frequency, better patient comforts and compliance, variation in the plasma drug level is less, Lesser total dose, reduced gastro intestinal tract side effects, improved safety and efficacy ratio.

Several difficulties has been arises in developing oral controlled release system for enhancing absorption and better bioavailability.

Difficulties include:

· Facing inability to target the drug dosage form in the area of desire in stomach.

· Drug absorption is a complicated process and owing many variables

· Rapid transit time of GIT can hinder the drug release behaviour in the absorption zone and minimises the safety and efficacy of the drug dose etc.

A novel drug delivery system was accomplish to overcome all such processed variables and one of the attempts is gastro retentive system. Gastro retentive drug delivery system is design in such way that by improve the gastric residence time of drug it resides in the gastric region for the numerous hours, by improving the gastric retention time it improves the absorption and bioavailability, decreases the drug waste and improve the solubility of drug which are less soluble in gastric pH environment (Sharma et al., 2014).

Gastro retentive drug delivery system also helps to provide a remarkable better availability of new product with new valuable therapeutic possibilities and substantial benefit for patients. Access of floating drug delivery system is most beneficial and commonly used because this system is most advantageous leads to gastric retention effervescent which liberates Co2 when comes to the contact with GI fluids and makes effort to float the dosage form. System having less density (<1.004 gm/cm³) than gastric fluid and hence it support the buoyant behaviour in the fluid and shows controlled release behaviour of drug dosage form. GI tract helps to maintain the efficient drug concentration for the extent of time in a systemic circulation. (Singh et al., 2011)(Aslam et al.,2014)

After the swallowing of the drug delivery dosage form it should be reside in the stomach and delivery of the drug in the controlled design to its absorption site for continuous release of drug.

1.1 ANATOMY OF STOMACH

Figure 1.1- Anatomy of stomach (Sabale et al., 2010)

1.2 CONCEPT OF HYDRODYNAMICALLY BALANCED SYSTEM

Gastric emptying process of the dosage form is tremendously a variable process and the ability of the dosage form to extend and maintain the gastric emptying time is a remarkable consideration, and to abide in the stomach for the extensive interval than conventional dosage form. Various difficulties arise to design the controlled systems with an aim of better absorption and improving bioavailability. Among this one of the major issues are to reside the drug dosage form in an aim area of gastrointestinal tract. Drug absorption is very complicated phenomenons and it subject to variable process because it is associated to the contact time with small intestinal mucosa. Therefore the transit time of small intestine is very important parameter for the drug absorption. (Sabale et al.,2010)(Jain et al.,2011)

Hydrodynamically balanced systems are design in such a way that by extending the gastric residence time of drug it can abide in the gastric area for several hours and significantly prolonging the gastric retention timeof drug and this enhanced the bioavailability, decrease the drug waste and modify the solubility of drug. With the action of extending the gastric retention time of delivery system is valuable for achieving therapeutic benefit for the drug substances.

By implementing various principles like flotation, expansion, sedimentation, mucoadhesion, or by modifying shape system the controlled retention time of drug dosage forms can be achieved. (Garg et al.,2008)

1.2 MECHANISM OF HYDRODYNAMICALLY BALANCEDS SYSTEM

Figure1.2-Working principle of hydrodynamically balanced capsule

(Nasa et al.(2010)

According to this principle, hydrodynamically balanced capsule is composed of drug and gel molding hydrocolloid polymer or a matrix forming polymer. After the swallowing of this drug dosage form it comes in the contact with gastric fluid and swells, it maintains the integrity of shape and its bulk density reduces less than 1 gm/ml.

Then the air trapped between the swollen cast and convey buoyancy to this dosage form. When this drug dosage form comes in the contact with aqueous medium the hydrocolloid polymer forms a gelatinous barrier and controls the diffusion rate of solvent in and drug out from the dosage form. When the drug dosage form which is consist of drug and mixture of hydrocolloid polymer, the capsule shell dissolves and the polymer swells lead to form a gelatinous barrier and shows buoyant behaviour in the gastric fluid for extend period of time.(Patil*et al.,2005)

1.6PROPERTIES OF POLYMER THAT ARE USED IN GASTRORETENTIVE DELIEVERY SYSTEM

1.6.1 Controlled drug release

When by the process of simple drug dissolution, by membrane control, by diffusion, by osmotic systems, by erosions, retardation mediated by ionic interaction the sustained release cannot be supplied. By the use of anionic polymeric excipient controlled release for the cationic drugs can be achieved. The relation between the chitosan and therapeutic agents can be more prominent by using polyanionic drug and depend on ionic cross linking in addition form a stable complex so that the drug can be released in more prolonged duration of time.

1.6.2 Mucoadhesive property

This property is mostly based upon its cationic character and sometimes the hydrophobic interactions. Various anionic polymer excipients like hyaluronic acid, carbine, polycarbophyl their mucoadhesive properties are weak. In order to achieve high mucoadhesive properties the polymer need to display high cohesive properties like adhesive bond or else abort within mucoadhesive polymer rather than in mucus gel case and polymer.

1.6.3 In situ gelling properties

In situ gelling property offers by the hydrogels containing polymer when their pH dependent hydaratability properties are demonstrated properly and these in situ gelling property was enhanced by the thiolation process.

1.6.4 Transfection enhancing properties

For small molecules where controlled drug release for ionic drugs can be developed and large polyanionic polymer molecules like DNA-based drugs and siRNA form stable complexes. Alike nanoparticles exhibit a positive zeta potential when there is a high ratio of cationic polymer. Due of these small particles and net positive charge endocytosis can be achieved when the size is below 100nm. Few of the polymer found to have low transfection enhancing properties the polysaccharides developed the different strategies to enhance its properties. This property can also be enhancing by self branching substitution technique.

1.6.5 Permeation enhancing properties

This mechanism of permeation improving properties is totally depend on the positive charge of the polymer which shows a interact with the cell membrane leads in resulting a structural rearrangement in tight junction paired with properties.

Based on degree of acetylation and molecular mass the announced the permeation enhancing property. Polymers having high degree of acetylation and of high molecular mass demonstrate the high epithelial permeability. This result in increase the permeation enhancing effect along with rising molecular mass also observed.

By the process of thiolation technique this permeation enhancing property can also be increased by a number of folds.

1.6.6 Efflux pump inhibitory properties

If the molecular mass is in the range of 150kDa at least for chitosan derivative polymer to the most marked inhibition. (Bernkop-Schnurch et al.,2012)

3.1 AIM

Development And Evaluation Of Hydrodynamically Balanced System Of Tramadol Hydrochloride By Using Chitosan And Locust Bean Gum.

3.2 OBJECTIVE

The objective of past work was to designed and developed a hydrodynamically balanced system of Tramadol HCl as single unit gastro retentive capsules. Various weight grade of density polymers along with or without gas producing ingredient (CaC03) can be encorporating for this system. The system develop is to expected to remain in the upper part of stomach which helps in improving the gastro retention in the upper part of stomach which have a limited absorption frame.

3.2.1 Selection of drug

TH is a synthetic codeine analog and weak µ-opoid receptor against having an anormous potential impending in analgesia. A specific absorption window limited only to the upper part of small intestine coupled with high frequency of drug administration (4-6 hrs) and small dose of 50-100mg and small biological half life. It comes under the category of BCS class Ì therapeutic agent which has characteristics of highly soluble and highly permeable. By employing gastro retentive technology, after the swallowing improves the gastric residence time, reduces the drug loss and drug bioavailability and decrease the side effects of drug is insomnia, constipation, hallucination etc.(Singh et al., 2010).

3.2.2 Selection of polymer

Chitosan is a polysaccharide which are isolated from the cells of crustaceans like shrimp, crab and other sea crustaceans which include Pandalus borealisand cell wall of fungi and chemically it is 2-amino 2-deoxy-b-d-glucopyronose which has a molecular formula(C6H11O4N)N .It is also called a soluble chitin and it is practically insoluble in water, acid and alcohol.

Molecular weight ranges from 3800-20000 Daltons. It has a pka value of ~ 6.5 which lead to the protonation in acidic to neutral solution with having charge density depend on pH and deacetylation value which makes the property of soluble in nature.

Basically chitosan is cationic polymer which binds to the negative charge surface of mucosal membrane and lead to the mucoadhesion to the mucosal membrane and this all property makes the chitosan as a ideal polymer for gastro retentive. It enhances the transport of hydrophilic drug across the epithelial surface. It has also property of hydrogel development when it arrives in the open contact with aqua it forms a hydrogel structure which helps in retarding the drug from the matrices.

Locust bean gum used as sustained release carriers and release modifier for delivery of TH. It is a neutral plant galactomannans extracted from the seeds (kernels) of the carob tree Ceratonia siliqua L fabaceae. Nowadays it is focussing polymer and a lot of researchers are focussing for exploring the potential in topical drug delivery, colonic drug delivery , oral sustained drug delivery, ocular drug delivery, buccal drug delivery,

4.1 MATERIALS

Table 4.1 Materials used for formulation

S.No

Materials

Suppliers

1.

Tramadol HCl

Yarrow Chem

2.

Chitosan

Aldrich

3.

Locust bean gum

Yarrow Chem

4.

Calcium chloride

CDH026035

5.

Syringe

4.1.1. EQUIPMENT REQUIRED

Table 4.2 Equipment required for formulation

S.No.

Equipments/ Instruments

Suppliers

Model

1.

Digital Weighing Balance

SHIMADZU

FLB 300

2.

Mechnanical Stirrer

REMI ELECTROTECHNIK LIMITED

KFU25353

3.

Magnetic Stirrer

PERFIT

KFU25353

4.

U.S.P. Dissolution test apparatus

ELECTROLAB

1301014

5.

UV-Visible Double Beam Spectrophotometer

SHIMADZU

2101

6.

Digital pH meter

SYSTRONICS MK

886131

7.

Hardness Tester

Monsanto

EHO1P

9.

FourierTransformInfra Red (FTIR)

SHIMADZU, MUMBAI,INDIA

10.

Scanning electron microscopy(SEM)

435 VF

LEO, India

11.

Digital Melting point apparatus

1013 A

PERFIT Instruments, Mumbai, India

12.

Hot Air Oven

NSW- 143

NARANG SCIENTIFIC WORK Pvt, ltd, India

METHODS

5.1. FORMULATION TABLE-

Formulation code

TH

(mg)

LMWCH (mg)

MMWCH (mg)

HMWCH (mg)

LBG

(mg)

LF1

200

60

---

---

---

LF2

200

70

---

---

---

LF3

200

80

---

---

---

LF4

200

60

---

---

LF5

200

70

---

---

35

LF6

200

80

---

---

40

MF1

200

---

60

---

---

MF2

200

---

70

---

---

MF3

200

---

80

---

---

MF4

200

---

60

---

30

MF5

200

---

70

---

35

MF6

200

---

80

---

40

HF1

200

---

---

60

---

HF2

200

---

---

70

---

HF3

200

---

---

80

---

HF4

200

---

---

60

30

HF5

200

---

---

70

35

HF6

200

---

---

80

40

All the compositions of drug and excipients were chosen on the basis of initial trial studies for buoyancy studies and drug retarding pattern

TH- Tramadol hydrochloride LMWCH- Low Molecular Weight Chitosan MMWCH- Medium Molecular Weight Chitosan HMWCH- High Molecular Weight Chitosan LBG-Locust Bean Gum

Drug retarding polymer of chitosan (high, medium, low) depends on degree of acetylation and viscosity. In LMWCH the degree of deacetylation is low and this degree of acetylation is high in HMWCH and this acetyl group is responsible for binding with drug and form a drug-polymer complex and it also depend upon the charge present on the drug. As the pka value of TH is approx 9.3 which is highly basic in nature and posses the negative charge as well as the pka value of chitosan is 6.5 and it posses positive charge and hence they easily bind with each other and form a complex and this resulted complex retards the drug discharge pattern in gastric surface.

With chitosan another natural based polymer LBG is also encorporated with drug formulation to analyze the drug discharge pattern. Hence it was observed that by the addition of LBG with chitosan it promotes the retardation pattern of drug release.

In this the mechanism involves, that by encorporating the polymers with drug it forms a gelatinous barrier over the drug when arrives in the open contact with the gastric fluid and lead to the decrease in the density of dosage form and it exhibits buoyant behaviour to dosage form and the aqueous medium penetrates in the polymeric strand then the dosage form maintains the diffusion rate by solvent in and drug out technique. So in this case as the concentration of polymer increases the binding efficiency will also improves and hence it retards the drug release pattern.

5.1.3 Preparation of HBS-TH capsules

Hydrodynamically balanced system capsulesl was prepared by ordered mixing technique by placing the drug between the layers of polymers in a borocil glass vial (10mg) and shaken vigorously by hand for 5 min followed by encapsulation colourless hard gelatincapsule shell(size#00). The procedure have advantage that it does not cause the size reduction neither drug nor polymers during mixing that it would believe to effect the release profile of formulation (Soni et al., 2013)

RESULTS AND DISCUSSION

6.1PREFORMULATION STUDIES

6.1.1Physical characteristics

The obtained Tramadol HCl sample was found white or almost white and was in accordance with Merck Index.

6.1.2 Melting point determination

To determine the melting point of the powdered drug was first filled in capillary tube with one end open and one end closed and then the capillary was placed in Digital melting point apparatus and the temperature at which the powdered API first start melting was noted as the melting point. It was found to be 179°C against the range of 179°C-181°C.

Depicted value (drug bank.ca)

Observed value(°C)

181°C

179°C-181°C

6.1.3 Solubility profile of drug in 0.1N HCl

Solubility of (TH) in 0.1N HCl was found to be 0.73mg/ml.

Table 6.1 Observation table of solubility of TH in 0.1N HCl

Solvent

Solubility (mg/ml)

0.1N HCl

0.73 mg/ml

6.1.4 Partition coefficient of drug

The partition coefficient of drug was found to be 8.5. Thus, the drug is classified to be hydrophilic in nature.

6.2. Analytical study Studies of Drug

6.2.1 Determination of λmax of drug in 0.1N HCl

In 0.1N HCl, the λmax of the drug was found to be 215nm.

Figure 6.1 Spectrum of drug in 0.1N HCl

Table 6.2 Calibration curve data of Tramadol Hydrochloride in 0.1N HCl

Concentration

(µg/ml)

Absorbance

(units)(1)

Absorbance

(units)(2)

Absorbance

(units)(3)

Average

Absorbance

±S.D

0

0

0

0

0

0

0.2

0.230

0.230

0.231

0.230

0.00058

0.4

0.346

0.348

0.348

0.347

0.00115

0.6

0.472

0.474

0.471

0.472

0.00153

0.8

0.636

0.636

0.636

0.634

0.00132

1.0

0.794

0.796

0.796

0.795

0.001

1.2

0.988

0.988

0.983

0.986

0.00280

Figure 6.2 Calibration curve data of Tramadol Hydrochloride in 0.1N HCl

6.2.3THERMAL CHARACTERIZATION USING DSC/DTG/TGA

Differential Scanning Calorimetry (DSC) was performed by EXSTAR TG/DTA 6300. DSC was employed to find out the characteristic peak (exothermic and endothermic) and exact melting point of the drug, excipient and drug excipient samples used in the present investigation. The DSC analysis was carried out over melting point at a rate of 5°C, in presence of inert nitrogen (N2) using duplicate samples of 5mg in crimped aluminium pans (Reetika Ganjoo et.al.2016).

6.2.3 Thermal Analysis Study:

Figure 6.3 Thermal Analysis of pure drug Tramadol hydrochloride(TH)

Thermal Analysis of pure drug Tramadol hydrochloride(TH)

Figure 6.3 shows DTG thermogram of TH represents that the drug is stable at 264°C and maximum loss of mass occurs from 200°C to 315°C which is represented by biphasic thermogram and maximum loss of mass occurs is 8.4%. The DSC thermogram represents the small endothermic peak at 182°C is melting point of TH another broad endothermic peak at 271°C and broad endothermic peak at 556°C represents the degradation of TH under the experimental condition.

Figure6.4 Thermal Analysis of chitosan

Thermal Analysis of chitosan

Figure 6.4 shows the thermal behaviour of chitosan . DTG thermogram shows that chitosan is stable upto temperature of 295°C which is characterized by exothermic peak. It also shows the small exothermic peak at 77°C. This shows the vapourization of water molecule from the void spaces and from the surface of chitosan degradation and maximum loss of water molecule represented by thermogram and it shows the biphasic curve maximum loss of mass takes place from temperature 200°C-300°C and this period about 61.6% loss of mass takes place. The DSC thernogram of chitosan represents 1 broad exothermic peak 304°C (enthalpy-6.31Joule/mg) which results in the slow degradation of chiotosan.

Figure 6.5 Thermal Analysis locust bean gum

Thermal Analysis of locust bean gum

Figure6.5 shows the DTG thermogram of locust bean gum suggests the polymer is stable at 291°C and maximum loss of mass takes place between temperature 200°C-312°C and 199°C-557°C showing the %loss of mass 48.7%and 33.3% respectively. The DSC thermogram explains the glass transition temperature at 302°C by broad exothermic peak at 607°C represents the rapid degradation of polymer under experimental conditions.

Figure 6.6 Thermal Analysis of tramadol hydrochloride, chitosan and locust bean gum mixture

Thermal Analysis of tramadol hydrochloride, chitosan and locust bean gum mixture

Figure 6.6 represents the thermogram of physical mixture under experimental condition. DTG thermogram at 259°C represents that the physical mixture is stable at 259°C. The maximum loss of mass occurs from 200°C-300°C and 400°C-500°C showing the % loss of mass 34.02% and 28.84% respectively. DSC thermogram explains that there is two endothermic peaks shows the melting point at 182°C and 268°C, the first endothermic shows the melting point of TH and this endothermic peak is also presence.

Figure1 second endothermic peak represents the glass transition temperature at 268°C. The broad exothermic peak at 517°C, 557°C and at 884°C represents the slow degradation of physical mixture in experimental condition. From the thermogram interpretation we can reveal that there is no any possible drug excipient interaction takes place.

6.2.4 FTIR STUDY:

Figure 6.7 FTIR of Tramadol HCl

Figure 6.7 FTIR of Tramadol HCl (jagadeesh et al,2017)

Table6.3- FTIR interpretation of Tramadol HCl

Functional group

Type of Vibration

Wavelength (cm-1)

Reported value

(cm-1)

Peak Characterization (cm-1)

N-H

Stretching

3305

3300

3000-3700

C-H

Stretching

2933

2961

2960-2850

C=C

Stretching

1465

1461

1450-1600

C-N

Stretching

1048

936

1000-1410

C-O

Stretching

940

1044

900-1410

C-C

Stretching

855

836

800-1200

FTIR of chitosan-

Figure 6.8 FTIR of chitosan

Table 6.4- FTIR interpretation of chitosan

Functional group

Type of Vibration

Wavelength (cm-1)

Peak Characterization (cm-1) (Ganjoo et al.2016).

C-H

Stretching

2920

2500-3200

O-H

Stretching

3290

Near about 3000

CH2

Stretching

1384

1000-1500

C-O-C

Stretching

1151

1000-1500

N-H(1)

Stretching

3500-3300

Near about 3000

Figure 6.9 FTIR of locust bean gum

Table6.5- FTIR interpretation of locust bean gum-

Functional group

Type of Vibration

Wavelength (cm-1)

Peak Characterization (cm-1)

O-H

Stretching

3339

3200-3500

C-H

Bending/wagging

2888

2800-2950

C-OH

Stretching

1022

1000-1100

C=O

Stretching

1722

1680-1750

C-O-C

Stretching

1413

1000-1500

FTIR of Physical mixtures (trmadol HCl, locust bean gum and chitosan mixture)-

Figure 6. 10 FTIR of Physical mixtures (tramadol HCl, locust bean gum and chitosan mixture)

Table 6.6- FTIR interpretation of Physical mixtures (trmadol HCl, locust bean gum and chitosan mixture)-

Functional group

Type of Vibration

Wavelength (cm-1)

Peak Characterization (cm-1)

N-H

Stretching

3301

3000-3700

O-H

Stretching

3447

3200-3500

CH2

Stretching

2625

2500-3200

C-H

Stretching

2933

2500-3200

C=C

Stretching

1465

1450-1100

C-N

Stretching

1179

1000-1410

C=O

Stretching

1722

1700-1750

C-O-C

Stretching

1413

1000-1500

C-OH

Stretching

1011

1000-1100

C-O

Stretching

1290

1000-13200

6.2.5 Buoyancy and Lag Time Studies

Table 6.7 showing Buoyancy and Lag time

FORMULATION

FLOATING TIME (Hours)

LF1

LF2

3

LF3

3.5

LF4

3

LF5

3

LF6

3.5

MF1

3

MF2

3

MF3

3.5

MF4

3

MF5

3

MF6

3.5

HF1

3

HF2

3

HF3

3.5

HF4

3

HF5

3

HF6

3.5

6.2.6 In vitro drug release-

Table 6.7 %Cumulative drug release of formulation LF1-LF6

TIME

(hours)

Cumulative % Drug Release ± S.D

LF1

LF2

LF3

LF4

LF5

LF6

0

0

0

0

0

0

0

1

26.859±0.25

21.328±0.13

20.248±0.32

15.512±0.46

19± 0.37

14.125±0.21

2

40.8± 0.41

38.7780.22

35.579±0.31

24.848±0.25

29.911±0.30

31.241±0.13

3

45.56± 0.27

41.055±0.43

28.523±0.56

42.549±0.46

34.263±0.14

25.120±0.25

4

54.164±0.22

49.1590.26

31.37± 0.21

43.389±0.14

42.216±0.26

28.021±0.31

5

72.56± 0.32

57.53± 0.42

33.901±0.36

51.634±0.23

50.704±0.32

30.122±0.31

6

76.347±0.43

63.378±0.20

48.005±0.38

58.78± 0.39

58.758±0.45

45.311±0.21

7

81.358±0.14

64.649±0.34

62.378±0.20

78.544±0.11

61.64±0.344

58.111±0.12

8

92.417±0.25

84.192±0.35

77.071±0.30

87.27±0.26

76.93±0.37

75.322±0.13

9

95.417±0.125

89.652±0.27

84.50± 0.29

91.82± 0.36

87.814±0.35

82.510±0.31

Figure 6.11 %Cumulative drug release of formulation LF1-LF6

Table 6.8 %Cumulative drug release of formulation MF1-MF6

Time(hr)

% Cumulative drug Release

MF1

MF2

MF3

MF4

MF5

MF6

0

0

0

0

0

0

0

1

12.845±0.2

12.067±0.36

11.678±0.32

11.547±0.13

11.540±0.46

10.878±0.21

2

29.652±0.1

28.481±0.36

23.177±0.22

26.990±0.21

25.647±0.25

22.922±0.36

3

35.882±0.32

32.999±0.34

32.237±0.12

33.117±0.37

30.732±0.36

31.174±0.20

4

47.38±0.14

41.637±0.30

40.059±0.28

45.994±0.45

37.060±0.34

39.496±0.32

5

58.370±0.22

57.471±0.20

52.702±0.28

56.193±0.11

53.180±0.12

48.526±0.34

6

66.693±0.45

64.892±0.36

64.702±0.12

64.311±0.24

61.631±0.30

60.767±0.11

7

72.391±0.31

74.420±0.21

76.111±0.55

68.330±0.36

73.123±0.28

75.147±0.32

8

84.638±0.12

82.626±0.26

80.118±0.30

82.011±0.11

81.257±0.20

78.669±0.38

9

93.638±0.55

91.472±0.11

90.717±0.54

92.748±0.30

89.257±0.43

88.36±0.31

Figure 6.12 %Cumulative drug release of formulation MF1-MF6

Table 6.9 %Cumulative drug release of formulation HF1-HF6

Time (Hours)

Cumulative % Drug Release ± S.D

HF1

HF2

HF3

HF4

HF5

HF6

0

0

0

0

0

0

0

1

12.845±0.13

12.067±0.46

8.678±0.30

11.547±0.41

12.54±0.47

8.878±0.21

2

19.652±0.21

20.481±0.25

23.481±0.41

18.99±0.45

25.647±0.30

21.988±0.35

3

30.882±0.31

32.999±0.36

30.237±0.43

29.944±0.66

30.732±0.23

31.174±0.20

4

47.838±0.11

39.088±0.34

37.059±0.20

370117±0.55

37.06±0.14

35.496±0.34

5

52.37±0.24

48.637±0.120

43.702±0.36

51.193±0.31

43.18±0.31

41.526±0.11

6

60.693±0.35

58.471±0.30

57.390±0.28

59.33±0.26

55.351±0.0

54.767±0.32

7

67.391±0.22

64.892±0.20

64.675±0.12

69.311±.55

74.123±0.25

75.147±0.38

8

74.08±0.34

74.42±0.26

72.118±0.54

72.066±0.43

72.257±0.54

70.669±0.49

9

91.638±0.52

86.472±0.46

82.717±0.52

89.748±0.41

84.803±0.45

80.577±0.48

Figure 6.12 %Cumulative drug release of formulation HF1-HF.

As the weight of chitosan increases in formulation(LF1-LF3) the drug release pattern was retarding with increase in molecular weight whereas in addition of locust bean gum (LF4-LF6) with increasing concentration it results in synergistic action in retarding drug release pattern as compared with (LF1-LF3). The same effect was observed with medium molecular weight chitosan formulation (MF1-MF6) and with high molecular weight chitosan (HF1-HF6). But as increasing the molecular weight of chitosan (low, medium, high) in different batches, there is decresae in the drug release pattern as shown above. This retardation of drug release is due to the degree of deacetylation, as the molecular weight of chitosan increase there is more amino and hydroxyl group present in our polymer for binding with moiety and hence there will be strong cross linking complex with increase in molecular weight of chitosan, and as well as the locust bean gum posses a good gelling property so with the addition of this polymer it improves the gelatinous barrier over the drug and retards the drug release pattern.

6.2.7 DRUG RELEASE KINETICS

Table 6.10 -Table showing data for release kinetics

Formulation no.

r2

n value

Zero Order

First order

Higuchi

Korsmeyer

Peppas

LF1

0.608

0.537

0.984

0.608

1.23

LF2

0.973

0.844

0.845

0.963

1.32

LF3

0.970

0.582

0.956

0.651

1.25

LF4

0.983

0.659

0.928

0.731

1.36

LF5

0.995

0.722

0.920

0.815

1.46

MF1

0.989

0.667

0.934

0.739

1.35

MF2

0.991

0.722

0.894

0.777

1.39

MF3

0.992

0.695

0.915

0.764

1.38

MF4

0.993

0.724

0.897

0.786

1.38

MF5

0.986

0.724

0.897

0.786

1.41

MF6

0.972

0.732

0.884

0.809

1.47

HF1

0.990

0.695

0.927

0.772

1.39

HF2

0.988

0.712

0.899

0.773

1.39

HF3

0.992

0.730

0.902

0.816

1.46

HF4

0.995

0.718

0.905

0.786

1.41

HF5

0.995

0.698

0.920

0.769

1.39

HF6

0.994

0.710

0.918

0.791

1.43

In this release kinetic data were fitted to various different models like Zero order, First order, Higuchi model and Korsmeyer peppas kinetics in order to know about the release pattern. By using MS EXCEL statistical functions various release data were processed.

From the above kinetic drug release table 6.10 it was concluded that all formulation follows zero order model, it means the drug release pattern is independent on the concentration of drug, so it depicts that if the concentration of polymers rises the delayed of drug release declines and the diffusion of drug takes place from high conc. to the low concentration. Therefore if maximum formulations follows zero order model this lead the high therapeutic efficacy and minimum side effects. (Dubey et al., 2015)

From the n value it was depicted that it follows super case II transport model because this n value which was observed is greater than 1. Hence it means that the drug release is through erosion of polymeric chain stresses and state-transition in hydrophilic polymers which swell in water or biological fluids.

CONCLUSION

The present study was aimed at development of hydrodynamically balanced system of Tremadol hydrochloride by using chitosan and Locust Bean gum, use of chitosan and locust bean gum proved to form an ideal formulation as it retarded the time period of the drug for the extended period of time. This formulation can help in retardation of drug for extended period of time due to the effect of polymer and it will cause no toxicity as we employed natural polymer such as chitosan which we get from shrimp shells and locust bean gum which is plant based polymer, so when the polymer will bind with the mucin layer no side effect will happen to the layer. The Locust Bean gum will help in forming gel type structure when it will come in contingence with intestinal fluid due to its swelling properties. A proper evaluation of the dosage form was carried out along with various studies such as DSC/DTG/DTA, FTIR, In vitro drug release, buoyancy ,and release kinetics were found out.

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02468101200.230.347000000000003190.472000000000000310.636000000000009340.795000000000000040.98599999999999999

Concentration (µg/ml)

Absorbance

28

0510

0

50

100

LF1

LF2

LF3

LF4

LF5

Time (Hours)

Cumulative % Drug Release

0510

0

50

100

MF1

MF2

MF3

MF4

MF5

MF6

Time (Hours)

Cumulative % Drug Release

0510

0

50

100

HF1

HF2

HF3

HF4

HF5

HF6

Time (Hours)

Cumulative % Drug Release