Studies in Process Validation of Ranitidine Hydrochloride Tablet 75 mg Dosage Formulation

 

Hapse S.A.* and Tarkase K. N.

harmacy, Vilad Ghat, MIDC, Ahmednagar (MS)-4141 11

 

ABSTRACT:

Documented evidence with a high degree of assurance that a process will consistently produce product, meeting its predetermined quality attributes is nothing but a process validation. In short process validation is checking of reproducibility of result. The critical process parameter was identified and evaluated by challenging its lower and upper release specification. The three process validation batches (PVB1, PVB2, PVB3) of same size, method, equipment and validation criteria was taken. The critical parameter involved in blending, compression, coating for our Ranitidine tablet were identified and evaluated as per the validation master plan. From the result we have found that in the same environmental condition there was no significant batch to batch variation and all the parameter studied were in accordance with the BMR

 

KEYWORDS: Ranitidine Hydrochloride tablet, Process validation, BMR.

 

 

INTRODUCTION:

Act of establishing documented evidence that provides a high degree of assurance that a specific process will consistently produce a product meeting its predetermined specification and quality attributes is said to be validation(3).

 

According to Indian GMP validation is the essential part of GMP. Those required to be done as per the predetermined protocols(4). The validation is carried out during development stage by means of a risk analysis of the production process which is broken down into individual steps. This present work deals with identification of critical stage and their consequent evaluation by challenging its upper and lower specification. A written report summarizing results and conclusion should be recorded, prepared and stored(5).

 

MATERIAL METHODS:

Ranitidine Hydrochloride IUPAC name dimethyl{5-[2-(1- methylamino-2-nitrovinylamino) ethylthiomethyl]furfuryl}- amine hydrochloride.

 

Fig. 1 Chemical structure of Ranitidine Hydrochloride.

 

Other material used was microcrystalline cellulose, Crosscarmallose Sodium, Talc, Colloidal silicon dioxide, magnesium stearate.

 

Category: Histamine H2-receptor antagonist

 

MACHINERIES:

Machineries and equipment used was as Weighing balance, sifter (20#,30#,40#), Double cone blender (1200 lit.), Compression machine 45 station double rotary Mark IV , Coating machine Ganscoater, Dissolution  test apparatus USP (Tab. machine).

 

DRY GRANULATION:

Tablet was manufactured by dry granulation method using ingredient shown in table no.2. During manufacturing temperature NMT 250 C and RH NMT 30% was maintained. After dispensing of material they are sifted through sifter as shown in table no.2.

 

Fig.1 Illustrative diagram of Double Cone Blender (DCB) and sampling locations

 

Top samples            : 3 (U1, U2, U3)                                Lower samples : 3 (L1, L2, L3)

Middle samples        : 5 (M1, M2, M3, M4, M5)               Bottom sample  : 1 (B0)

 

Fig.2 Illustrative diagram of Ganscoater and sampling locations

 

L-1) Right Back side Layer; L-2) Right Front Side Layer; L-3) Middle Layer

L-4) Left Back Side Layer; L-5) Left Front Side Layer

 

PROCESS FLOW CHART

Equipment Process Process Variables Tests be performed

 

Compression of Batches:

Tablets were compressed using 12.7 standard concave shaped punches with hard chrome plated tips.

Machine was set at different speeds of  32,42 and 52 RPM

Number of stations :    45

Type of tooling       :  “D” type

 

Table no. 1 Specifications for tablet was as per following table

Sr. No.

Parameter

Standards

1

Individual weight variation

122.5mg ± 5%

2

Hardness

4 to 8Kg/cm2

3

Thickness

3.4 mm – 3.8 mm

4

Disintegration time

NMT 10 min.

5

Friability

NMT 1% w/w

 

Process validation stage, control variables and measuring justification:

Table no.2- Composition of various process validation batches.

Ingredient

PVB 1

PVB 2

PVB 3

Mesh

Ranitidine HCL

252kg

252kg

252kg

20

Microcrystalline cellulose

94.86kg

94.86kg

94.86kg

30

Crosscarmellose Na

3.75kg

3.75kg

3.75kg

30

Talc

7.5kg

7.5kg

7.5kg

40

Colloidal silicon Dioxide

5.64kg

5.64kg

5.64kg

40

Magnesium Stearate

3.75kg

3.75kg

3.75kg

40

Total Batch Size

367.5kg

367.5kg

367.5kg

 

 

RESULT AND DISCUSSION:

Table no. 3 Content uniformity result at blending stage:

 

PVB 1

PVB 2

PVB 3

Minimum (%)

96.0

98.6

98.6

Maximum (%)

103.2

101.7

101.6

Average (%)

98.5

99.8

99.8

RSD (%)

1.8

1.0

1.0

% RSD was calculated by taking mean of all 12 location {Upper (Three location), Middle (Five location), Lower (Three location) and Bottom (One location)}

 

 

Table no. 4 Blending Stage Result:

Test

Acceptance criteria

PVB 1

PVB 2

PVB 3

Description

White free flowing powder

complies

complies

complies

Bulk density g/ml

For information only

0.36

0.35

0.36

Tapped density g/ml

For information only

0.48

0.48

0.48

Sieve test % retained

For information only

20

40

60

100

20

40

60

100

20

40

60

100

Nil

10.2

26.6

45.7

Nil

10.2

26.6

45.7

Nil

10.23

26.68

45.90

Assay

73.12 to 76.87 mg per 122.5mg blend

99.6

102.1

101.5

 

Remarks :

After analyzing and reviewing the results of the three batches of Ranitidine blend, it can be concluded that 7 min of blending gives an uniform distribution of the drug in the blend.  Based on the above discussion, it is recommended to carry out the blending of Ranitidine for 7 min ( 5 min of pre lubricant mixing followed by additional 2 min of post lubricant blending) in order to obtain an acceptable drug distribution pattern in the blend.

 

Table no.5 Compression Stage Result:

Parameter

Speed

PVB 1

PVB 2

PVB 3

Appearance

Minimum

Ok

Ok

Ok

Maximum

Ok

Ok

Ok

Optimum

Ok

Ok

Ok

Average wt. (mg)

Minimum

122.8

122.7

122.8

Maximum

122.8

122.9

122.8

Optimum

123.8

123.4

123.7

Hardness (kg/cm2 )

Minimum

6.0-7.0

6.0-7.0

6.0-7.0

Maximum

6.0-7.0

6.0-7.0

6.0-7.0

Optimum

6.0-7.0

6.0-7.0

6.0-7.0

Thickness (mm)

Minimum

3.57-3.67

3.55-3.64

3.60-3.68

Maximum

3.52-3.63

3.56-3.63

3.58-3.65

Optimum

3.52-3.63

3.60-3.68

3.52-3.65

Friability (% w/w)

Minimum

0.2

0.3

0.3

Maximum

0.2

0.3

0.4

Optimum

0.2

0.2

0.2

Disintegration time (Min.)

Minimum

5

4

5

Maximum

4

4

4

Optimum

4

5

4

Weight variation (%)

Minimum

± 4.0

± 3.8

± 4.1

Maximum

± 4.2

± 4.0

± 3.6

Optimum

± 3.6

± 3.4

± 3.8

Dissolution (%)

Minimum

96.8

100.6

96.3

Maximum

98.6

96.9

100.3

Optimum

94.8

98.6

96.9

Assay (w/w)

Minimum

102.1

101.9

102.6

Maximum

102.4

102.4

102.3

Optimum

102.5

102.1

102.4

 

Remark:

All physical parameters of tablets were well within the specification limits in all the three batches at the Minimum speed (32 RPM), Maximum speed (52 RPM), Optimum speed (42RPM).

 

Table no.6 Coating stage result:

Batch no.

Description

Average weight

Weight gain

Acceptance criteria

White, round, standard concave tablet debossed with W on one side and other side plain

127.88 mg± 2.5% (124.68 – 131.07)

3.0 – 4.0 %

PVB 1

Lot no /Sampling point

L1

L2

L3

L4

L5

I

Complies

126.8

126.9

127.0

126.8

126.2

3.45

II

Complies

126.4

126.4

127.8

127.6

127.1

3.49

III

Complies

127.1

127.8

127.7

126.7

126.7

3.01

PVB 2

I

Complies

126.7

126.5

126.4

126.7

127.1

3.50

II

Complies

125.6

126.1

126.3

125.7

126.1

3.20

III

Complies

127.1

126.1

126.8

126.8

125.7

3.20

PVB 3

I

Complies

126.3

126.1

125.7

125.7

126.1

3.30

II

Complies

126.1

125.9

126.1

126.1

126.0

3.28

III

Complies

125.8

125.9

126.1

125.8

125.7

3.30

 

 

Table no.7-Dissolution Profile for Three Batches.

Time (min)

 

PVB 1

PVB 2

PVB 3

10

Minimum %

60.20

82.85

86.61

Maximum %

82.11

100.72

94.44

Mean %

67.58

94.68

89.16

20

Minimum %

76.28

96.57

88.07

Maximum %

94.81

102.30

97.20

Mean %

86.58

100.22

92.25

30

Minimum %

81.70

98.57

86.35

Maximum %

94.46

103.65

95.71

Mean %

89.03

101.15

92.96

45

Minimum %

86.92

99.43

87.29

Maximum %

96.15

105.74

94.41

Mean %

91.61

101.63

92.71

60

Minimum %

86.90

99.76

91.41

Maximum %

95.44

104.24

95.77

Mean %

91.33

102.09

93.26

 

Remark :

Dissolution study was done on 12 units of tablet and from that minimum, maximum, and mean was calculated. All parameters of coated tablets were well within the specification limits as per the BMR in all the three batches.

 

CONCLUSION:

Blending-

Blend uniformity samples for lubricated blend and pooled sample was found meeting to the acceptance criteria, based on the data a prelubrication duration of 05 min and a lubrication duration of 02min in double cone blender can be consider as satisfactory.

 

Compression:

In order to get satisfactory physical parameters of tablet during compression samples were collected at different speeds of machine i.e. 32,42 and 52RPM. After evaluating the data it was concluded that compression of tablets at 42 RPM, was found to be satisfactory using Mark-4 compression speed.

 

Coating:

In order to optimize coating parameters samples were collected and tested for weight build up, and dissolution. From the result it was concluded that the coating spray rate 40 to 60g/gun/min and inlet temp.650±7 was found to be satisfactory to get optimum weight build up and dissolution.

 

The process validation data of Ranitidine tablets reveals that there was no significant variation between batch to batch and all the process variables were studied. Therefore it can be concluded that the process of Ranitidine tablet for the batch size 30Lakh stands validated.

 

ACKNOWLEDGEMENT:

The authors are very much thankful to Wockhardt ltd. Aurangabad for providing all the requirement and facility for our work

 

REFERENCES:

1.        United state pharmacopoeia, XXIV. The unites state pharmacopoeia convention Inc. Rockville mani Land 2000,pp 1812-1814.

2.        K. Kathiresan, K.Kiran, “Basics of Validation-Pharmaceutical Perspective”, KK publishers, First edition, Nov.2005

3.        IRA R. Berry, Robert A. Nash, “Pharmaceutical process validation” Marcel Dekker. March 2003.

4.        WHO-supplementary guideline on GMP: Validation,2005

5.        U.S.FDA-“Guideline on process validation” updated 1/1/1997.

6.        Guidance for industry “Powder blend and finished dosage units-stratified in process dosage unit sampling and assessment” CDER, FDA. Oct.2003

 

Received on 07.04.2011

Accepted on 15.04.2011        

© A&V Publication all right reserved

Research Journal of Pharmaceutical Dosage Forms and Technology. 3(3): May-June 2011, 96-99