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181 | P a g e International Standard Serial Number (ISSN): 2319-8141
Full Text Available On www.ijupbs.com
International Journal of Universal Pharmacy and Bio Sciences 6(2): March-April 2017
INTERNATIONAL JOURNAL OF UNIVERSAL
PHARMACY AND BIO SCIENCES IMPACT FACTOR 2.96***
ICV 6.16***
Pharmaceutical Sciences RESEARCH ARTICLE …………!!!
“PROCESS VALIDATION & DESIGN SPACE STUDY OF CAPTOPRIL
TABLETS 50 MG”
Komal Kaneria1, Samarth Shihora
2
Department of Quality Assurance, Parul Institute of Pharmacy, Vadodara.
KEYWORDS:
Captopril Tablets,
Concurrent process
Validation, Design Space
study.
For Correspondence:
Komal P. Kaneria*
Address:
Department of Quality
Assurance, Parul Institute
of Pharmacy, Vadodara.
ABSTRACT
The Aim of this work was to perform Concurrent process
validation & Design Space Study of Captopril Tablets. Three
consecutive process validation batches of same size, Method,
Equipment and Validation criteria were taken and subjected to
validation. The critical parameters involved in sifting, granulation,
drying, blending and compression were identified and evaluated as
per validation master plan. At the stage of granulation, mixing for
5-15 minutes was required to achieve the blend uniformity which is
within the limit. % LOD of dried granules was found to be within
limit (1.5 % - 2.5% w/w) at inlet temperature 50˚C, at the stage of
lubrication. The compression data of all the three batches were
indicated that compression speed would be 12 rpm.
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1. INTRODUCTION:
In the mid 1970’s , Food and Drug Administration (FDA) officials, Ted Byers and Bud Loftus first
proposed the concept of validation in order to improve the quality of pharmaceuticals. Validation is
a work of demonstrating and documenting that any process, procedure and activity will consistently
lead to the expected results. Validation is a concept that has been evolving continuously since its
first formal appearance in the United States in 1978. [1-5]
“Validation is act of demonstrating and documenting that any procedure, process and Activity will
consistently lead to the expected results.”[6]
Design space study is a relationship between process inputs (material attributes & process
parameters) and Critical Quality Attributes (CQA’s). It is also called as “challenge testing” with
respective to process & equipment functioning. Working with Design Space is not consider as
change, movement out of Design space to be a change and would normally initiate regulatory post
approval change process. If design spaces are accurately developed and all essential aspects of the
manufacturing process are within the design space, the Critical quality attributes are assured of
being acceptable.[7-9]
IUPAC name: 2S)-1-[(2S)-2-methyl-3-sulfanylpropanoyl] pyrrolidine-2-carboxylic acid
1. Empirical formula: C9H15NO3S
2. Molecular weight: 217.285 gm/mol
3. Solubility: Freely soluble in water
4. Melting Point: 106 °C
5. Pharmacological class: Antihypertensive Agents Angiotensin-converting Enzyme Inhibitors
6. Uses: treatment of hypertension
7. Storage: Captopril should be stored at 25˚c temperature and away from moisture.
8. Mechanism of Action: Captopril is a potent, competitive inhibitor of angiotensin-converting
enzyme (ACE), the enzyme responsible for the conversion of angiotensin I (ATI) to angiotensin II
(ATII). ATII regulates blood pressure and is a key component of the renin-angiotensin-aldosterone
system (RAAS).
183 | P a g e International Standard Serial Number (ISSN): 2319-8141
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9. pKa (strongest acidic): 4.02
(Strongest basic): -1.2[10]
2. MATERIALS AND METHOD:
Anti-Hypertensive Captopril tablets are currently manufacturing at S Kant Healthcare Ltd Vapi. So
at the time of manufacturing Captopril Tablets, it became necessary to validate the whole process of
Captopril tablets from dispensing to packing.
Process validation was performed on the three batches of Captopril Tablet. The three consecutive
batches were labelled as (Batch A, Batch B, Batch C).The protocol includes list of raw materials,
list of equipments used, process flow diagram, critical process parameters, standard specification
and acceptance criteria & sampling plan as given below. During the manufacturing process samples
were collected and sent for analysis to Q.C. department.
2.1 Material used:
Table 1.1 List of Raw materials
Name of Ingredient Unit Formula (mg) Batch Formula (kg)
Dry Mixing
Captopril USP 50.00 25.00
Maize Starch BP 170.00 85.00
Lactose Anhydrous BP 194.82 97.410
Sodium Starch Glycolate BP 10.00 5.00
Wet Granulation
Purified Water BP Q.S Q.S
Methyl Hydroxybenzoate BP 0.4 0.2
Propyl Hydroxybenzoate BP 0.08 0.040
Maize Starch BP 13.7 6.850
Lubrication
Purified Talc BP 4.00 2.00
Sodium Starch Glycolate BP 5.00 2.50
Magnesium Stearate BP 2.00 1.00
Maize starch(Additional) BP 18.37 9.185
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2.2 Sampling Plan
2.2.1 Sample label:
Each Sample was labelled with Product Name, Batch No, Batch Size, Mfg. Date, Exp. Date, Stage,
Sample Quantity, Sample No, Sampled By/Date as Follows. For Three Batches.
2.2.1. (A) Dry Mix: RMG
Table 1.2 Sampling Plan for RMG
Stage Sample Location Sample
Quantity
Test To Be
Performed Label Detail
Dry mixing:
RMG
5 Points from TOP of bed,
5 points from Bottom of bed,
1 point from middle of bed
From of RMG
Approx.
1100 mg /each
location
Blend
uniformity
Dry-mixing
powder
Drying : FBD From 4 corner & 1 center of
FBD Dryer 5 gm LOD Dried granules
Lubrication :
RMG
Dry mixing
5 Points from TOP of bed,
5 points from Bottom of bed,
1 point from middle of bed
From of RMG
Approx.
1100 mg /each
location
Blend
uniformity
Dry-mixing
powder
2.3 Compression:
Table 1.3 Compression Machine Setting & Operation Details
Compression
Parameter Specification Tablet Parameter Specification
Compression
Machine
Double rotary (35
station) Appearance
white colour, circular, flat,
beveled edge, Uncoated Tablet
having a Central break line on 1
side & plain on other sides
Punch Size 11.30 mm Average weight 450.0 mg
Punch Shape Circular Flat
punches Weight of 20 tablets 450.0 mg± 2%
Upper Punch
(11.30 mm)
With central break
line
Diameter 11.30mm±0.2mm
Lower Punch (11.30 mm)
Plain Thickness 3.60mm±0.2 mm
Dies 11.30mm
Hardness NLT 40 N
Friability NMT 1 % w/w
Disintegration time NMT 15 min
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Withdraw samples as per the required quantity as per below mentioned respective column. Quantity
of IPQC tests will be double in case of LHS & RHS
Table 1.4 Sampling Plan for Compression
1.4 Sampling Procedure:
2.4.1 At Dry Mixing Stage
By using SS sampling rod sample was withdrawn from each sampling point as shown in the RMG
sampling (Figure2.1) after 5, 10, 15 minute. Each sample quantity should be at least equivalent to
one to three times of the dosage unit. Average weight of single dosage unit is 425.0 mg. sample
quantity to be taken is about 1100.0 mg of dry mix for each location to check uniformity of mixing.
Figure 2.1:Sampling Location forRMG
2.4.2 At Drying Stage
Withdraw Sample from the FBD bowl as shown in the FBD sampling (Figure 2.2) and collect about
5.0 gm of dried granules from each location to check loss on drying.
Stage Run Sample Quantity Label Detail
Compression
Minimum, Optimum,
Maximum Speed 3x100 Nos.
Compressed Tablet
(uncoated)
Optimum Speed (Initial) 150 Nos.
Optimum Speed (Middle) 150Nos
Optimum Speed (End) 150Nos
Composite Sample 150Nos
186 | P a g e International Standard Serial Number (ISSN): 2319-8141
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Figure 2.2: Sampling Locations for FBD
2.4.3 At Lubrication Stage
By using SS sampling rod sample was withdrawn from each sampling point as shown in the RMG
sampling (Figure 2.1) after 5, 10, 15 minute. Each sample quantity should be at least equivalent to
one to three times of the dosage unit. Average weight of single dosage unit was 425.0 mg. sample
quantity to be taken is about 1100.0 mg of dry mix for each location to check uniformity of mixing.
2.4.4 At Compression Stage
Samples of approximately 150 nos. tablets each from LHS & RHS was collected at the initial,
middle and end of compression. 150 Nos. Make a composite sample of 150 Nos. tablets. Tablets
were to be tested for description, average weight, weight uniformity, diameter, thickness, friability,
hardness.
2.5 Testing Procedure:
2.5.1 Identification:
A. By Thin Layer chromatographic Identification Test:
Test Solution: Transfer a portion of powdered tablets, equivalent to about 100 mg of Captopril, to a
conical flask. Add 25 ml methanol, stir for 30 minutes using a magnetic stirrer and centrifuge. Use
the clear supernatant.
Standard Solution: 4 mg/ml in methanol. (40mg 10ml)
Application volume: 50µL, as streaks.
Developing Solvent System: a mixture of toluene, glacial acetic acid, and methanol (75:25:1)
Procedure: Locate the spots on the plate by lightly spraying with a freshly prepared mixture of 1
volume of ammonium hydroxide and 6 volumes of a solution of 0.04% 5, 5’dithiobis (2-
nitrobenzoic acid) in methanol.
The solvent front has moved about three-fourths of the length of the plate. Remove the plate from
the developing chamber, mark the solvent front, and allow the solvent to evaporate. Unless
187 | P a g e International Standard Serial Number (ISSN): 2319-8141
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otherwise directed in the individual monograph, locate the spots on the plate by examination under
short-wavelength UV light.
Observation: The Rf value of the principle spot obtained from the test solution corresponds to that
obtained from the Standard solution.
2.5.2 Average weight:
Select 20 tablets randomly from the analytical sample and weigh find out the average weight of a
tablet.
2.5.3 Uniformity of weight:
This test was performed on 20 tablets. Using a calibrated and suitable balance.
Individual 20 tablets weights from the average weight by more than ± 5.0% and none deviates by
more than ± 10.0%.
2.5.4 Diameter
Measure the diameter of 10 tablets using Vernier calipers record minimum, maximum and reports
average value.
2.5.5 Thickness:
Measure the thickness of 10 tablets using Vernier calipers record minimum, maximum and reports
average value.
2.5.6 Hardness:
Check the hardness of the ten tablets with hardness tester and record minimum, maximum and
report average value.
2.5.7 LOD:
LOD of the powder was checked by placing 5 g of sample in I.R. moisture balance which was
previously calibrated and recording the % LOD at 55˚C.
2.5.8 Bulk density and tapped density:
Bulk density was measured by weighing powder of approximately 10 grams and poured in 100 ml
glass cylinders, the initial volume occupied by material (in ml) was noted and volume occupied by
material after 100 taps in the bulk density apparatus was noted (in g/ml), then bulk density and
tapped density was calculated by using the following formula
Bulk density = weight of the material taken (in gm) / volume occupied by the
Material (in ml)
Tapped density = weight of the material taken (in gm) / volume occupied by
Material (in ml) after tapping.
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2.5.9 Dissolution: (UV Absorption)
(a) Dissolution medium: 0.01 N Hydrochloric acid, 900 ml.
(Note: Completely deaerate the Dissolution medium to minimize exposure of Captopril to air, and
analyze the samples immediately).
Apparatus: Basket
RPM: 50 rpm
Test time: 20 minutes.
(b) Standard Solution:
Dissolve accurately weighed 55.0 mg of Captopril WS in 100 ml volumetric flask, and dilute with
dissolution medium. Take 2 ml of this solution dilute with 100 ml dissolution medium (55 mg
100 ml 2 ml 100 ml).
(c) Sample Preparation:
1 Tablet 900ml with dissolution medium.
Withdraw 10 ml of aliquot at the specified time interval and filter. Take a 10 ml filtrate in a 50 ml
volumetric flask & Dilute up to mark with dissolution medium.
(1 tablet 900 ml 10 ml 50 ml)
(d) Procedure:
Determine the amount of Captopril dissolved by employing UV absorption at the wavelength of
maximum absorbance at about 205 nm on filtered portion of the solution under test, suitably diluted
with dissolution having a known concentration of Captopril WS in the same amount of medium.
Calculate the % of Captopril dissolved in 20 min.
Sample Abs. Std. Wt. (mg) 2 900 50 Std. potency 100
= ------------------ x------------------x---- x ------x ----- x-----------------x ------------------
Std. Abs. 100 100 1 100 100 Label amount
2.5.10 Friability Test (%)
This test was performed on a sample of whole tablets weight of 6.5 g tablets.
The tablets should be carefully dedusted prior to testing. Accurately weigh the tablet sample and
place the tablets in the drum. Rotate the drum 100 times & remove the Tablets. Remove any loose
dust from the tablets as before, and accurately weigh.
Loss in weight x 100
% Friability = ----------------------------------------------
Wt. of whole tablets (about 6.5 g)
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2.6 Deviation (If Any) From Protocol
The protocol shall be followed. Planned changes of the approved protocol must receive QA
approval prior to implementation. The proposed change to the protocol shall be provided with
justification and scientific rationale for change.
Any deviations like deviations from the protocol, batch record, or sampling plan shall be reported
to the Validation team and QA. These deviations shall be managed through deviation handling
system and a systematic, documented investigation and CAPA shall be performed and shall be
closed and approved by QA. The reference of the deviation shall be given in the protocol.
2.7 Design Space Study of Captopril Tablets
During manufacturing of Captopril Tablets Speed of machine is major variable. So Design Space
Study is performed on this variable. Content Uniformity is determined for Speed Challenge Study.
Parameters Checked during Speed Challenge Test Study Are:
Appearance
Average weight
Diameter
Thickness
Hardness
Friability
Disintegration
Hardness of Tablet is also important variable. It will indirectly affect the dissolution of the tablets.
So Dissolution is performed for hardness Challenge Study.
Thus Design Space Study of Captopril Tablets was performed on below parameters:
A) Machine Speed
B) Hardness of Tablets
2.8 RESULTS AND DISSCUSSION:
2.8.1 Process Validation Report:
Process Validation Report of Captopril Tablet USP was as Follows:
This report describes results obtained during the different processing steps to evaluate and qualify
the acceptability of the manufacturing process of Captopril Tablets. This report was also been
evident the reproducibility of process and results with consecutiveness.
2.8.2 Dry Mixing
Dry mixing was carried out in Rapid Mixer Granulator for 05, 10, 15 minutes and Samples were
collected from 11 different locations to test the content Uniformity. The results are as follows:
190 | P a g e International Standard Serial Number (ISSN): 2319-8141
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Table 1.5 Content uniformity after dry mixing
Batch Time Average SD %RSD Acceptance criteria
Batch A
5 99.74 1.70 1.70
Content Uniformity
Should be 85 % -
115 % and % RSD
is NMT 3 %
10 98.54 2.53 2.56
15 98.95 2.11 2.13
Batch B
5 99.83 1.72 1.72
10 99.76 1.59 1.29
15 100.13 1.29 1.28
Batch C
5 99.87 1.22 1.22
10 98.49 0.98 0.98
15 98.81 1.29 1.29
2.8.3 Evaluation:
%RSD of Captopril for all three validation batches were found within the limit of acceptance criteria.
It was evident that the dry mixing was in proper manner throughout the sampling locations.
2.8.4 Wet Mixing & Drying
2.8.4. a Wet Mixing:
Granulate the material at slow speed of impeller with chopper off and binder solution was added
slowly. Then start impeller at fast speed and chopper at slow/fast speed. Granulate the mass till dough
like consistency is formed and record the time for wet mixing.
Table 1.6 Wet Mixing Time Record
2.8.4. b Drying
Drying was performed at inlet temperature (at 55˚C) and samples were collected from 5 different
locations and % LOD is check. The results are as follow.
Batch Start End Duration Impeller
Speed
Chopper
Speed
Additional
Water
(if any)
Granulation
End Point
Batch A
16:30 16:32 2 min Slow Off NA (Impeller)
26.0Ampere
(Chopper) --
16:32 16:33:30 1 min. 30
sec. Slow Slow NA
16:33:30 16:36:30 3 min. Fast Slow NA
Batch B
13:25 13:27 2 min Slow Off NA (Impeller)
26.1 Ampere
(Chopper) --
13:27 13:28:30 1 min. 30
sec. Slow Slow NA
13:28:30 13:31:30 3 min. Fast Slow NA
Batch C
9:50 9:52 2 min Slow Off NA (Impeller)
25.8 Ampere
(Chopper) --
9:52 9:53:30 1 min. 30
sec. Slow Slow NA
9:53:30 9:56:30 3 min. Fast Slow NA
191 | P a g e International Standard Serial Number (ISSN): 2319-8141
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Table 1.7 Results of % LOD
2.8.4. c Evaluation:
% LOD of dried granules of Captopril were within the range for all three validation batches, which
were within the limit of specification.
2.8.5 Milling
Mill the dried granules through Sifter using 1.50 mm screen.
Table 1.8 Parameters of wet mixing, drying, sifting and sizing process
Sample Location % LOD Acceptance
Criteria Batch A Batch B Batch C
Left 2.05% 2.10% 2.28% % LOD of dried
granules at 50°
c
Should be 1.5 %
- 2.5% w/w
Right 2.10% 1.98% 2.20%
Centre 2.12% 2.01% 2.10%
Front 2.11% 2.10% 2.15%
Back 2.10% 2.10% 2.08%
Stage Results
Wet mixing
Batch A Batch B Batch C
Additional Quantity of Purified Water
Added NA NA NA
Total Quantity of Purified Water
Added 58.85 Lit. 58.85 Lit 58.85 Lit
Duration
of
Wet
Mixing
Impeller slow without
Chopper 2 min. 2 min 2 min.
Impeller slow with Chopper
slow 1 min. 30 sec. 1 min 30 sec 1 min. 30 sec.
Impeller fast with Chopper
slow 3 min. 3 min 3 min.
Additional mixing with
addition of additional water NA NA NA
End Point Value (Ampere)
Impeller :
26.0
Chopper : Off
Impeller : 26.1
Chopper : Off
Impeller :
25.8
Chopper : Off
Drying
Total Drying Time 170 min. 175 min. 175 min.
Inlet Temp. of FBD (50-55)˚C 50˚C 50˚C 50˚C
Outlet Temp. of FBD 38˚C 38˚C 38˚C
Sizing
Size of screen used for milling through
1.50mm 1.5 mm 1.5 mm 1.5 mm
Duration of sizing 30 min. 25 min. 25 min.
192 | P a g e International Standard Serial Number (ISSN): 2319-8141
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2.5.8.a Evaluation:
All the Parameters during Milling Stage were found satisfactory and were within Limit of
specification.
2.5.9 Lubrication
Blending was carried out in Rapid Mixer Granulator for 05, 10, 15 minutes and samples were
collected from 11 different locations to test the Blend Uniformity. Once composite Sample was
collected, loss on drying, and physical properties determination tests were performed on it. The
results are as follow
Table 1.9 Analytical Data for Lubricated Blend
2.5.9. aEvaluation:
% RSD of Captopril for all three validation batches were found within specification limit, it was
evident that there was no segregation or demixing occurs in the RMG and mixing is homogeneous
throughout the sampling locations for all three batches.
The physical parameter such as description, bulk density, tapped density, Angle of repose, and
particle size distribution for three validation batches were satisfactory and found consistent.
Significant observation related to the flow of the blend was observed throughout the compression
activity. Assay of Composite Blend for three validation batches was within the specification.
2.5.10 Compression
During compression, samples from compression machine at minimum speed, Maximum speed, and
Optimum speed were collected. At the initial, middle and end of compression from all the three
consecutive batches, samples were collected to test various in-process checks i.e. description,
Process Parameters &
Quality Attributes Batch A Batch B Batch C
Pre lubrication Time 5 min. 5 min. 5 min.
Lubrication Time 3 min. 3 min. 3 min.
Average of content uniformity 101.32% 99.96% 101.21%
%RSD (NMT 3 %) 1.31% 1.58% 1.55%
Composite Sample
Description(white coloured powder) Complies Complies Complies
Bulk Density(Untapped) 0.678gm/ml 0.678 gm/ml 0.678 gm/ml
Bulk Density(Tapped) 0.73 gm/ml 0.74 gm/ml 0.75 gm/ml
Angle of Repose 23.55 23.55 23.55
Loss on Drying 2.50% 2.24% 2.03%
Sieve Analysis
Pass thru. 20# 98.43% 98.44% 97.95%
Pass thru. 60# 74.88% 74.79% 74.79%
Pass thru. 80# 69.19% 68.20% 66.20%
Pass thru. 100# 58.69% 58.68% 58.72%
Assay (97.0 to 105.0%) 100.1% 100.3% 100.6%
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average weight, Uniformity of weights, thickness, hardness, friability, and disintegration test. QC
test parameter like Assay was also performed. The results are as follows,
A. Inprocess check Results of physical Parameter at various speed
Table 1.10 Inprocess check Results of Physical parameter at various speed
Test Acceptance
Criteria
Observation
10 RPM
(Minimum)
12 RPM
(Optimum)
15 RPM
(Maximum)
Average
Weight 450.0 mg± 2 %
452.3 mg –
448.3 mg
450.5 mg –
541.8 mg
449.7 mg - 450.8
mg
Uniformity
of weight
450 mg ± 3
%
Min. 443 mg – 442
mg
442 mg - 443
mg 441 mg – 443 mg
Max. 460 mg - 458
mg
457 mg - 460
mg 458 mg – 460 mg
Diameter 11.30 mm
± 0.2 mm
Min. 11.31 mm -
11.29 mm
11.30 mm -
11.31 mm
11.29 mm – 11.31
mm
Max. 11.38 mm -
11.37 mm
11.39 mm –
11.40 mm
11.37 mm – 11.39
mm
Hardness NLT
40 N
Min. 49.20 N – 60.3
N 50.3 N – 60.3 N 51.7 N – 54.8 N
Max. 70.6 N – 76.4 N 72.4 N – 80.1 N 69.3 N - 73.4 N
Avg. 59.3 N – 68.3 N 62.3 N – 69.4 N 60.4 N – 63.5 N
Thickness 3.60 mm±
0.2mm
Min. 3.52 mm – 3.60
mm
3.57 mm – 3.59
mm
3.59 mm – 3.60
mm
Max. 3.64 mm - 3.70
mm
3.62 mm – 3.69
mm
3.63 mm – 3.69
mm
Friability NMT 1.0% w/w Nil – 0.01% Nil - 0.01% Nil – 0.01%
Disintegrati
on NMT 15 minute
2 min. 31 sec. –
2 min. 51 sec.
2 min. 37 sec. –
3 min. 12 sec.
2 min. 28 sec. – 3
min. 28 sec.
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2.5.10. a Evaluation:
The Results of all Physical parameters and Uniformity of weight at different speed of machine (10-
15RPM) were found within the limit of acceptance criteria for all three batches. Hence at the
specified machine speed the compression stage is validated.
2.5.11 Finished Product Specification:
Table 1.11 Finished Product Test and Observation
Test Parameter Observation Acceptance
Criteria Batch-A Batch-B Batch-C
Identification By TLC
The Rfvalue of
the principle spot
obtained from the
test solution
corresponds to
that obtained
from the Standard
solution.
The Rfvalue of
the principle spot
obtained from the
test solution
corresponds to
that obtained
from the Standard
solution.
The Rfvalue of
the principle spot
obtained from the
test solution
corresponds to
that obtained
from the Standard
solution
The Rfvalue of the
principle spot
obtained from the
test solution
corresponds to that
obtained from the
Standard solution
Average weight 450.1 mg 452.3 mg 452.0 mg 450.0 mg ± 5 %
Uniformity of
Weight
Min. -1.38% -1.30% -1.55% ± 5% of Average
Wt. Max. +2.13% +1.13% +1.33%
Diameter Min. 11.40 11.38 11.39 11.30 mm ± 0.2
mm Max. 11.45 11.44 11.45
Thickness Min. 3.55 3.60 3.56 3.60 mm ±
0.2 mm Max. 3.75 3.73 3.73
Hardness Min. 45.2 48.9 56.0
NLT 40 N Max. 62.8 56.1 79.6
Dissolution Min. 88.1 88.4 88.5
NLT 80%(Q)(i.e.
85%) of labelled
amt. release in 20
minutes Max. 96.6 95.3 96.2
Disintegration 6 min 30 sec 6 min 30 sec 6 min 50 sec NLT 40 N
Friability 0.13% 0.18% 0.15% NMT 1.0%
Uniformity of Dosage 5.6 6.9 6.1
Acceptance Value
NMT 15.0 for first
Dosage units(L1)
Limit of Captopril
Disulfide 0.495% 0.488% 0.324% NMT 3.0%
Assay content of Captopril
USP 50 mg 99.9% 100.3% 100.1%
NLT 90.0% &
NMT 110% of L.A
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2.5.11 Design Space Study (Challenge Study) Of Captopril Tablets
2.5.12.aSpeed Challenge Study
Table 1.12 Speed Challenge Study
Test
Parameter
Specification
Low speed
High speed
Machine Speed To be Established 10 rpm 15 rpm
Avg. Wt. 450.0 mg ± 5 % 448.3 mg -
452.3 mg 449.7 mg - 450.3 mg
Diameter 11.30 mm ± 0.2
mm
11.29 to
11.38mm
11.29 to
11.39 mm
Thickness 3.60mm±0.2 mm 3.52 to
3.70 mm
3.59 to
3.69 mm
Hardness NLT 40 N 49.20 to
74.6 N
51.70 to
73.40 N
Disintegration NMT 15 minutes
2 min. 31 sec.
- 2 min. 45
sec
2 min. 30 sec - 2 min. 53 sec
Friability NMT 1.0 % 0.01% 0.01%
2.5.12. b Hardness Challenge Study
Table 1.13 Hardness Challenge Study
Test
Parameter
Specification Low Hardness Hard Hardness
Avg. Wt. 450.0 mg ± 5 % 449.3 mg – 451.1 mg 449.4 mg – 450.1 mg
Diameter 11.30 mm ± 0.2 mm 11.30 to 11.37mm 11.30 to 11.38 mm
Thickness 3.60mm±0.2 mm 3.52 to 3.70 mm 3.56 to 3.68 mm
Hardness NLT 40 N(40- 60N) 49.2 to 50.6 N 62.8 N to 76.6 N
Disintegration NMT 15 minutes 2 min. 40 sec. - 2 min.
45 sec.
5 min. 20 sec. – 6 min 30
sec
Friability NMT 1.0 % 0.01% 0.01%
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2.5.12. b Dissolution For Hardness Challenge Study
Table 1.14 Dissolution for Hardness Challenge Study
Acceptance
Criteria
Dissolution
Batch A Batch B Batch C
Low
Hardness
(NMT 40 N)
High
Hardness
(NLT 60 N)
Low
Hardness
(NMT 40 N)
High
Hardness
(NLT 60 N)
Low
Hardness
(NMT 40 N)
High
Hardness
(NLT 60 N)
NLT
80%(Q) i.e.
85%
dissolved in
20
min
Min. 88.2% 92.0% 92.1% 92.1% 92.0% 97.7%
Max
. 99.7% 99.1% 99.4% 99.4% 99.1% 99.7%
Avg. 95.23% 96.03% 95.15% 96.91% 94.66% 98.81%
2.6 ACKNOWLEDGEMENT:
The authors are thankful to the authorities for providing the facilities to carry out the present work.
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