FORMULATION AND EVALUATION OF AMOXICILLIN TRIHYDRATE MODIFIED RELEASE DOSAGE FORMS

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PREFORMULATION STUDIES 6, 50
It can be defined as an investigation of physical and chemical properties of a drug substance alone and when combined with excipients. The overall objective of preformulation testing is to generate information useful to the formulation in developing stable and bioavailable dosage forms that can be mass-produced. The type of information needed will depend on the dosage form to be developed.
Preformulation studies are the first step in the rational development of dosage form of a drug substance. The objective of preformulation studies is to develop a portfolio of information about the drug substance, so that this information will be useful to develop different dosage forms. Preformulation can be defined as investigation of physical and chemical properties of drug substance with excipients.

Preformulation investigations are designed to identify those physicochemical properties and excipients that may influence the formulation design, method of manufacture, and pharmacokinetic-biopharmaceutical properties of the resulting product.

A.    API characterization
a)    Organoleptic characteristics
b)    Determination of melting point
c)    Angle of Repose (funnel method)
d)    Bulk Density
e)    Compressibility Index (Carr’s Index)
f)    Hausner Ratio

B.    Excipients characterization
C.    Drug-excipients Compatibility studies

A.    API characterization:
API characterization like, determination of melting point range, physico mechanical characterization like Bulk density, True density, Haussner’s Ratio, Carr’s/Compressibility Index etc.

a)    Organoleptic characteristics:
The color, odor, and taste of the drug were characterized and recorded using descriptive terminology.

b)    Determination of melting point: Melting point was determined by taking small amount of amoxicillin trihydrate in a capillary tube closed at one end.  The capillary tube was placed in an electrically operated melting point apparatus and the temperature at which the drug melts was recorded. This was performed thrice and average value was noted.

c)    Angle of Repose: (funnel method)
The angle of repose values of amoxicillin trihydrate determined by the funnel method. The accurately weighed drug was taken in a funnel. The height of the funnel was adjusted in such a way that the tip of the funnel just touches the apex of the heap of the powder. The powder was allowed to flow through the funnel freely onto the surface. The diameter of the powder cone was measured and angle of repose was calculated using the following equation
ø = tan-1 (h/r) ----------- (6)
where,  h = the height of the powder cone ;
r = the radius of the powder cone
Flow properties for different values of angle of repose are given below.

Table 4.7: Comparison between Angle of Repose and flow property

PREFORMULATION STUDIES 6, 50

Angle of Repose (degrees)

Flow property

25-30

Excellent

31-35

Good

36-40

Fair- aid not needed

41-45

Passable-may hang up

46-55

Poor-must agitate, vibrate

56-65

Very poor

Very, very poor

>66

d)     Bulk Density:
Loose bulk density (LBD) and tapped bulk density (TBD) of amoxicillin trihydrate determined using bulk density apparatus.Accurately weighed drug was placed in a 100 ml graduated measuring cylinder. Initial volume was observed. The cylinder was tapped initially 500 times from a distance of 14 + 2 mm.  The tapped volume (Va) was measured to the nearest graduated unit.  The tapping was repeated additional 750 times.  Again the tapped volume was measured to the nearest graduated unit. The same thing was done for powder blends of the tablets. The LBD and TBD were calculated in g per ml using following formula;

LBD = weight of the powder / volume of the packing ------------- (7)
TBD = weight of the powder / tapped volume of the packing ----- (8)

e)        Compressibility Index (Carr’s Index)
The compressibility of the powder was determined by the Carr’s compressibility index.

Carr’s index (%) = [(TBD – LBD) x 100] / TBD ----------- (9)

Table 4.8: Comparison between % Compressibility and flow property

% Compressibility

Flow ability

<10

Excellent

11-15

Good

16-20

Fair

21-25

Passable

26-31     

Poor

32-37

Very poor

>38

Very, very poor

f)         Hausner Ratio
The Hausner ratio of the powder was determined by the following equation.

Hausner ratio = TBD / LBD ----------- (10)

Table 4.9: Comparison between Hausner Ratio value and flow property

Hausner Ratio

Flow character

1.00-1.11

Excellent

1.12-1.18

Good

1.19-1.25

Fair

1.26-1.34

Passable

1.35-1.45

Poor

1.46-1.59

Very poor

>1.60

Very, very poor

B.     Excipients characterization
Excipients characterization like bulk density, tapped density, compressibility index and hausner ratio evaluated for its flow property and compressibility.

C.    Drug-excipients Compatibility studies
In the preparation, drug and polymer may interact as they are in close contact with each other, which could lead to the instability of drug. Preformulation studies regarding the drug-polymer interaction are therefore very critical in selecting appropriate polymers. FT-IR spectroscopy was employed to ascertain the compatibility between amoxicillin trihydrate and the selected polymers.  The pure drug and drug with excipient were scanned separately.

Procedure: Potassium bromide was mixed with drug and/or polymer in 9:1 ratio and the spectra were taken.  FT-IR spectrum of amoxicillin trihydrate was compared with FT-IR spectra of amoxicillin trihydrate with polymer. Disappearance of amoxicillin trihydrate peaks or shifting of peak in any of the spectra was studied.

FORMULATION DEVELOPMENT
The theoretical drug release profile calculation is important to evaluate the formulation with respect to release rates and to ascertain whether it releases the drug in a predetermined manner.Theoretically drug release profile was calculated by using the pharmacokinetic data.

Development of the formulation in the present study was mainly based on the type and concentration of polymers and the properties of the drug. Various polymers in different combinations were used so as to get dissolution profile that matches with the theoretical drug release profile. Furthermore it compared to different hardness to achieve desired drug release profile.

Manufacture of amoxicillin trihydratedosage forms:
Amoxicillin trihydrate tablets and capsules (775 mg) were manufactured for the thirteen batches T1 to T13 and C1 to C6 using the ingredients mentioned in the Table 4.10 and Table 4.11 respectively.

Table 4.10: Formulations of amoxicillin trihydrate tablet

INGREDIENTS

FORMULATIONS

T1

T2

T3

T4

T5

T6

T7

T8

T9

T10

T11

T12

T13

Amoxicillin trihydrate(mg)

775

775

775

775

775

775

775

775

775

775

775

775

775

Ethyl cellulose (%)

-

-

-

8

6

4

2

95:5

85:15

75:25

65:35

55:45

50:50

METHOCEL (HPMC)

-

-

-

-

-

-

-

PVP K-30 (mg)

23.16

-

-

-

-

-

-

1.5

1.5

1.5

1.5

1.5

1.5

MCC (mg)

26.8

-

-

-

-

-

-

-

-

-

-

-

-

HPMC K4M (mg)

-

291

291

-

-

-

-

-

-

-

-

-

-

Coating I (%)*

8

-

8

8

8

8

8

-

-

-

-

-

-

Coating II (%)#

8

-

8

8

8

8

8

-

-

-

-

-

-

Brilliant blue

qs

-

-

-

-

-

-

-

-

-

-

-

-

Magnesium stearate (mg)

5

5

5

5

5

5

5

5

5

5

5

5

5

Total (gm)

1.065

1.212

1.300

1.044

1.025

1.006

0.988

0.99

0.99

0.99

0.99

0.99

0.99

HPMC: Hydroxy Propyl Methyl Cellulose,
PVP: polyvinyl pyrrolidone,
MCC: microcrystalline cellulose

*Coating I:mixture of methacrylic acid copolymer (L-100), triethyl citrate, titanium dioxide, and talc.

#Coating II:mixture of methacrylic acid copolymer (S-100), titanium dioxide, talc and triacetin

Table 4.11: Formulations of amoxicillin trihydrate capsule

INGREDIENTS

C1

C2

C3

C4

C5

C6

Amoxicillin trihydrate(mg)

775

775

775

775

775

775

Ethyl cellulose (%)

-

-

-

8

15

20

PVP K-30 (mg)

23.16

-

-

-

1.5

1.5

MCC (mg)

26.8

-

-

-

-

-

HPMC K4M (mg)

-

291

291

-

-

-

Coating I (%)*

8

-

8

8

-

-

Coating II (%)#

8

-

8

8

-

-

Brilliant blue

Qs

-

-

-

-

-

Magnesium stearate (mg)

5

5

5

5

5

5

Total (gm)

1.065

1.212

1.300

1.044

1.054

1.10

HPMC: Hydroxy Propyl Methyl Cellulose,
PVP: polyvinyl pyrrolidone,
MCC: microcrystalline cellulose

*Coating I: mixture of methacrylic acid copolymer (L-100), triethyl citrate, titanium dioxide, and talc.

#Coating II:mixture of methacrylic acid copolymer (S-100), titanium dioxide, talc andtriacetin

Table 4.12: List of materials are used in present study with use

Sr. no.

Ingredients name

Function

1

Amoxicillin trihydrate

Drug

2

HPMC K4M

Delayed release Polymer

3

Ethyl cellulose (ETHOCEL STANDARD 7 PREMIUM ID48253)

Delayed release Polymer

4

METHOCEL E6 PREMIUM LV HPMC

Modified release polymer

5

PVP k-30

Binder

6

MCC (101)

Diluent

7

Magnesium stearate

Lubricant

8

Talc

Lubricant

9

Coating I (OPADRY ENTERIC 940580000 WHITE)

Delayed release coating

10

Coating II (OPADRY ENTERIC 95K580000 WHITE)

Delayed release coating

11

Brilliant blue

Colouring agent

12

Isopropyl alcohol

Solvent

13

Methylene chloride

Solvent

Amoxicillin trihydrate is active pharmaceutical ingredient. Pvp k30 act as binder in all formulations. Ethyl cellulose, HPMC K4M, methocel is polymers used to modified the drug release from dosage form. Coating I and coating II are the coating material which modified the release of drug from dosage form. Magnesium stearate used as a lubricant. Brilliant blue used as a colouring agent in the formulation.

Procedure: T121
In the formulation procedure of for the batch T1, total dose of amoxicillin trihydrate divided in three parts. Amoxicillin trihydrate divided as 45%, 30% and 25% in part I, part II and part III respectively.

Part I (immediate release granules) containing amoxicillin trihydrate and MCC and it binds with the PVP K30 which is dissolved in the mixture of isopropyl alcohol and methylene dichloride.Coarse screening of wet mass using a suitable sieve (10# screens).Drying of moist granules under sunlight for 15minutes. Screening of dry granules through a suitable sieve (20 # screen). From part I granules drug release in the stomach.

Part II (1st delayed release granules) granules containing amoxicillin trihydrate and MCC, it binds with the PVP K30 which is dissolved in the mixture of isopropyl alcohol and methylene dichloride. These prepared granules coat with the extended release polymer coating I. From part II granules drug release in the upper small intestine.

Part III (2nd delayed release granules) granules containing amoxicillin trihydrate and MCC, it binds with the PVP K30 which is dissolved in the mixture of isopropyl alcohol and methylene dichloride. These prepared granules coat with the extended release polymer coating II. From part II granules drug release in the upper small intestine.

It prepared by the taking all different immediate release granules, 1st delay release granules and 2nd delay release granules and mix with lubricant. Compress it in a tablet form by using D-tooling 16- station compression machine.

Procedure T2:
Dry mixing of drug and polymer like HPMC for 10 min.Lubricate it by Blend of tablet mix with lubricant for 10min.Compress the blend into tablets using D-Tooling 16- station compression machine.

Procedure T3 to T7:
Dry mixing of drug and polymer for 10 min. granules prepared by wet granulation method. Mixture of drug and polymer binds with Isopropyl alcohol.Coarse screening of wet mass using a suitable sieve (10 # screens).Dry the granules under sunlight for 10min. Screening of dry granules by passes it from sieve (20 # screens).Divide the granules ratio as per trial basis release of drug required. All granules divide in to three portions. First portion is the immediate release of drug and other two for the delayed release of drug. Coating the two portion of delayed release granules with the different coating material. All granules were mixed and lubricate with magnesium stearate. Compress the blend into tablets using D-Tooling 16- station compression machine.

Procedure T8 to T13:
Dry mixing of drug and polymer for 10 min. granules prepared by wet granulation method. Mixture of drug and polymer binds with Isopropyl alcohol.Coarse screening of wet mass using a suitable sieve (10 # screens).Dry the granules under sunlight for 10min. Screening of dry granules by passes it from sieve (20 # screens).Lubricate with magnesium stearate. Compress the blend into tablets using D-Tooling 16- station compression machine.

Procedure C1 to C4 (capsules):
Granules preparations of the capsule from batches C1 to C4 are same as the tablet. And those granules fill in to two 00size empty hard gelatin capsule shell by using hand operated capsule filling machine.

Procedure C5 and C6 (capsules):
Dry mixing of drug and polymer, given in table 4.11 for 10 min. granules prepared by wet granulation method. Mixture of drug and polymer binds with Isopropyl alcohol.Coarse screening of wet mass using a suitable sieve (10 # screens).Dry the granules under sunlight for 10min. Screening of dry granules by passes it from sieve (20 # screens).Lubricate with magnesium stearate. Compress the blend into tablets with higher hardness using D-Tooling 16- station compression machine.Crush tablet and pass it from sieve 14#. Fill it in a two 00size hard gelatin capsule shell by using hand operated capsule filling machine.

EVALUATION OF GRANULES
Granules flow properties determined like angle of repose, Bulk density, Tapped density, Haussner’s Ratio, Carr’s/Compressibility Index. All these measured as per above methods.

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