Process Validation of Galantamine Hydrobromide Tablets

N Kanakadurga Devi*, V Visweswara Reddy, B Sai Mrudula and B Radha Madhavi

KVSR Siddhartha College of Pharmaceutical Sciences, Vijayawada-10.

ABSTRACT:

Documented evidence with a high degree of certainty that a process will consistently produce product, meeting its predetermined quality attributes is said to be process validation. Here we have done the validation of critical steps during manufacturing such as blending, compression, coating and dissolution for our Galantamine hydro bromide tablets with the support of process validation protocol.

Selected 8mg Galantamine HBr tablets to be manufactured and divided in to sub batches which differ by bracketing, matrixing and the various loads were taken and various compression forces were used during compression of the tablets.

Finally we have monitored and recorded all the environmental conditions during every step of manufacturing for all the sub batches. Various parameters like premixing time, pre lubrication time, lubrication time during blending and the optimum machine speed followed during the compression of the tablets were recorded and we have checked whether the thickness and hardness for all the tablet sub batches and pan rpm, spray rate were within the limits as per BMR(Batch Manufacturing Record) during coating. Also we have compared the dissolution profile for all the sub batches (X, Y, Z) with the exhibit batch (E).

From the results we have found that temperature and RH were maintained well within the specified limits and there was no significant batch to batch variation and all the parameters studied were in accordance with BMR.

KEYWORDS: Galantamine HBr tablets , BMR, Process validation , SOP.

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 specifications and quality attributes is said to be validation⁽¹⁾.

Validation studies are essential part of good manufacturing practice and should be conducted in accordance with predefined protocols⁽²⁾. Any new master formula or method of preparation should be validated to demonstrate its stability. Significant amendments to the manufacturing process, including any change in equipment or materials, which may affect product quality or reproducibility of process, should be validated^(3,4). Even the well established process and procedures should be revalidated periodically to ensure that they remain capable of achieving intended results. A written report summarizing results and conclusions should be recorded, prepared and stored^(5,6).

We selected Galantamine for our work whose IUPAC name is (4aS,6R,8aS)-4a,5,9,10,11,12-Hexahydro-3-methoxy-11-methyl-6H-benzofuro[3a,3,2-ef] [2]benzazepin-6-ol having the molecular weight 287.354g/mol and melting point of 269-270°c.It comes under the category of Nootropic agents and parasympathomimetic⁽⁷⁾.(Fig 1)

Fig 1: Chemical Structure of Galantamine HBr

The objectives of our present work are to define the validation process for Galantamine hydro bromide tablets 8mg,to manufacture the validation batch as per the approved master production record, to assess the powder mix uniformity, to correlate the dissolution profile of all the three validation sub batches which differ by matrixing and bracketing among the Galantamine HBr tablets and finally to generate the process validation report to establish documented evidence that product when manufactured at production scale operation meets all quality and design specifications.

PROCEDURE:

The manufacturing formula used was shown in the Table 1.For dispensing, we have checked and ensured that the dispensing booth was clean and as per current SOP (Standard Operating Procedure). We have checked and ensured that balance was not due for calibration and checked for zero error in the balance. We have Checked and ensured that all materials were issued as per BPR. For sifting, we have checked and recorded the temperature and relative humidity in processing area and they were maintained at 24°c + 2°c and RH 45 + 5%.We have Checked and ensured visually all the equipment and equipment parts were cleaned and we have Checked the integrity of the sieves before and after sifting through out, the processing activity. Later we have mixed the active ingredients and other additives by dry mixing using Column Mounted Bin Blender. The parameters like Bulk density (apparent), Bulk density (tapped) and compressibility index and particle size distribution were observed and recorded for the compression batch.

TABLE 1: Manufacturing formula

TABLET STRENGTH		Quantity Per Tablet in mg(8mg)
INGREDIENT	RATIONALE
Galantamine Hydro bromide	Active ingredient	10.42
Lactose monohydrate (Pharmatose DCL 11)	Diluent	0.24
Microcrystalline Cellulose(Avicel pH 102)	Diluent	6.10
Hypromellose	Binder	3.00
Colloidal Silicon Dioxide	Glidant	33.24
Magnesium Stearate	Lubricant	65.00
Tablet weight in mg		120
Opadry white	Coating	4.00
Purified water USP	Vehicle	28

Blending step was performed by loading sifted materials in to the double cone blender except magnesium stearate. We have started the blender in each mode and checked for any leakage of material. On ensuring that there is no leakage, we have blended for 20min and then magnesium stearate was loaded in to the blender and blended for 5min. Physical characteristics of dry mix were shown in the Table 2 and blend uniformity was shown in the Table 3. We have compressed the Galantamine HBr tablets as per BMR using the upper punch of 7.00mm round shaped FFBE punches and the lower punch of 8.00mm round shaped FFBE punches and the dies of 7.00mm with 32 station tablet machine press. Depending upon the load sizes chosen and build up percentage we have divided the compression batch in to 3 sub batches as (X,Y,Z) .These were compressed at different compression speeds like 15 rpm, 20 rpm and 40 rpm. The manufacturing details were shown in Table 4. The coating process was carried out as per BMR and after that the dissolution profile of coated tablets was tested.

TABLE 2 :Physical characters of dry mix.

S. NO	Parameter	Observations
1	Bulk density (apparent)g/ml Bulk density (tapped )g/ml	0.588 0.719
2	Particle size distribution(%W/W)	Cumulative % retained on
	# 60	1.99 21.04 32.32 80.19 92.67 6.54 18.18
	# 80
	# 100
	# 200
	# 325
	% in fines collector
3	Compressibility index

TABLE 3: Blend uniformity.

S.NO	All individual values are within + 10% of mean and RSD< 5.0%
1	98.7
2	97.7
3	98.7
4	98.5
5	99.0
6	98.8
7	97.2
8	99.5
9	97.4
10	97.2
Max	99.5
Min	97.2
Mean (%)	98.3
RSD (%)	1.2

The parameters like group weight variation, individual weight variation, thickness, hardness, friability, disintegration and dissolution were tested at the above mentioned speed changes and from the results obtained it was found that the compression speed of 40 rpm is optimum for the manufacturing of tablets with desired qualities. The dissolution process was carried out by using purified water as dissolution medium by using USP Type ІІ apparatus at 50 rpm and temperature was maintained at 37+ 0.5°c.

RESULTS AND DISCUSSION:

The environmental conditions during the manufacturing of Galantamine HBr tablets were monitored and recorded stage wise. During sifting and milling the environmental conditions were monitored and recorded as 21 - 23°c / 45 – 49 % RH. During blending it was recorded as 21 - 23°c / 46 – 49 % RH and during compression the range was 21 - 24°c / 41 – 49 % RH and during coating of tablets the range was found to be 22 - 23°c / 46 – 48 % RH.

TABLE 4 :Manufacturing details

S.NO	UNIT OPERATION	DETAILS	OBSEVATION
1	sifting	a)Equipment	Mechanical stirrer
		b)mesh used	# 60
2	premixing	a)Equipment b)Load size(kg) c)Pre mixing time	Column mounted bin blender 60.692 10min
3	Blending	a) Equipment b)Load size(kg) c)Pre Lubrication time d) post Lubrication time e) Capacity utilization of the Double Cone Blender	Column mounted bin blender 60.597 25min 5min 72.88%
			X	Y	Z
4	compression	a) Equipment b) Machine speed (target:40 rpm)	Sejong compression machine 40 rpm	Sejong compression machine 40 rpm	Sejong compression machine 40 rpm
5	Coating	a) Equipment b) Load size (kg) c) Build up	Neocota – 24 A 15.46 3.0%	Neocota – 24 A 16.10 3.0%	Neocota – 24 A 16.56 3.0%

TABLE 5 :Tablet characteristics at optimum or target speed of 40 rpm.

Galantamine Hydro bromide tablets 8mg ( Batch X, Batch Y, Batch Z )
S.NO	PARAMETER	LIMITS	TARGET SPEED ( 40 rpm )
			X		Y		Z
			Min	Max	Min	Max	Min	Max
1	Weight of 10 tablets (g)	1.170 – 1.230	1.195	1.203	1.198	1.200	1.186	1.199
2	Weight variation (mg)	111 – 129	117	122	117	124	115	121
3	Thickness (mm)	2.6 – 3.2	2.9	2.9	2.9	3.0	2.9	3.0
4	Hardness (kp)	5 – 10	6	10	6	8	5	8
5	Disintegration time	NMT 15 min	3	3	3	3	3	3
6	Friability (%)	NMT 0.8 %	0.0	0.0	0.1	0.1	0.1	0.1
7	Assay	NLT 90.0 % & NMT 110.0 % of the labeled amount of Galantamine.	99.4 %		98.1 %		98.4 %

	% of Galantamine 8mg tablets dissolved ( X,Y,Z,E )
	X			Y			Z			E
	10min	20min	30min	10min	20min	30min	10min	20min	30min	10min	20min	30min
Tablet 1	90	95	98	89	93	94	93	96	96	95	100	101
Tablet 2	93	97	100	91	96	98	90	96	98	72	85	93
Tablet 3	93	97	100	94	85	98	96	100	100	96	100	100
Tablet 4	88	94	98	92	98	100	91	96	97	79	88	91
Tablet 5	94	98	102	71	97	98	98	101	101	93	96	97
Tablet 6	91	97	100	89	94	95	93	99	100	91	96	97
Tablet 7	92	97	100	89	94	94	95	100	101	92	96	97
Tablet 8	94	99	102	91	94	95	92	9	98	84	94	93
Tablet 9	88	94	98	91	97	98	92	96	98	83	96	99
Tablet 10	92	97	100	92	93	94	98	100	100	86	93	92
Tablet 11	93	97	99	94	98	100	92	97	99	94	97	98
Tablet 12	90	96	98	89	97	98	91	96	97	75	87	91
Average	92	97	100	89	95	97	93	98	99	87	94	96
SD	2.1	1.5	1.4	6.1	3.6	2.3	2.7	2.0	1.7	8.1	4.9	3.6
% RSD	2.3	1.6	1.4	6.8	3.8	2.4	2.9	2.0	1.7	9.4	5.2	3.7

TABLE 6:Dissolution profile of Galantamine HBr tablets 8mg

From the results it was found that the temperature and RH are maintained well within the specified limits i.e.,(Temp. NMT 30°c and RH NMT 60%) throughout the manufacturing.

Tablet characteristics at optimum or target speed of 40 rpm for the tablets were shown in the Table 5. This report overall summarizes the data of Galantamine HBr Tablets. The process has been validated with the support of process validation protocol, with the predetermined process parameters.

The following parameters were observed during the processing of all the tablets.

І. BLENDING:

Pre mixing time: 10minutes.

Prelubrication time: 25minutes.

Lubrication time: 5minutes.

ІІ. COMPRESSION:

Optimum Machine speed for Galantamine HBr Tablets is 40 rpm.

Galantamine HBr Tablets 8mg (X, Y, Z)

Thickness: 2.9 to 3.0 mm (limit: 2.6 – 3.2 mm)

Hardness: 5 to 10 KP (limit: 5 – 10 KP)

ІІІ. COATING: % COATING BUILD UP :

Among all the sub batches (X,Y,Z) of Galantamine HBr Tablets , the coating parameters like pan rpm, temperature, spray rate, gun to bed distance and air pressure which effects the coating and final appearance of the tablets were checked out and was found to be in accordance with BMR.

ІV. DISSOLUTION PROFILE COMPARISION:

The dissolution profiles of tablets were shown in Table 6.Dissolution profile of the validation batch (X, Y, Z) was compared with exhibit batch (E) and the graph was shown in Fig 2. The data shows that dissolution profiles of all the sub batches were comparable to exhibit batch.

FIGURE 2 :Dissolution profile of Galantamine HBr tablets 8mg

Product : Galantamine HBr tablets 8mg.

Batches : X,Y,Z and Reference : E

CONCLUSION:

Our study includes the validation of critical steps of manufacturing such as blending, compression, coating and dissolution for tablets. We have tested parameters like mixing time during blending, machine speed and compression force during compression, and finally content uniformity, coating and dissolution profile and from the results we have come to conclusion that they were in accordance with BMR.

Finally we can conclude that the Process Validation of Galantamine HBr tablets showed that there was no significant batch to batch variation and all the process variables studied were in accordance with BMR.

ACKNOWLEDGEMENT:

The authors are very much thankful to Dr.Reddy’s Laboratories, Generics, Hyderabad and The Principal , K.V.S.R Siddhartha College of pharmaceutical sciences, Vijayawada for generously providing all the requirements and facilities for our work.

REFERENCES:

1. Irar Berry, Rober A, Nash, pharmaceutical process validation 1933, p 25-48.

2. WHO-Supplementary guidelines on GMP: Vlaidation.2005.

3. Walter Lund, The pharmaceutical Master Validation plan, st.Luicie press, New York 2001, p 3-5, 102-104.

4. Syed Imtiaz haider, pharmaceutical Master Validation plan, St.luicie press, New York 2001, p 3-5,102-104.

5. Validation guidelines for pharmaceutical dosage forms, August 2004.Health products and food branch, Health Canada.

6. U.S.FDA- “Guidelines on process validation” updated 1/1/1997.

7. Scott LJ, Goa KL.Adis Review: Galantamine: a review of its use in Alzheimer’s disease.