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In Process Quality Control Tests (IPQC) for Pharmaceutical Products

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 In Process Quality Control Tests
(IPQC) for Pharmaceutical Products
 1

In Process Quality Control Tests (IPQC) for Pharmaceutical Products

Mr. Sagar Kishor Savale

M. Pharm (Pharmaceutics)
 2

In Process Quality Control Tests (IPQC)

IPQC is concerned with providing accurate, specific, & definite descriptions of the
procedures to be employed, from, the receipt of raw materials to the release of the finished
dosage forms.

 In process Quality Control, IPQC tests are mostly performed within the production
area.
 They should not carry any risk for the quality of product.
 In process testing enables easier identification of problems. It sometime identifies
a defective product batch that can be corrected by rework, whereas once that batch
has been completed, this may not be possible.
 Failure to meet in process control specification indicates either that procedure were
not followed or some factor (S) out of control.
 3

Instrument used in IPQC department

 Disintegration apparatus

 Dissolution apparatus

 Analytical balance Muffle furnace

 Friability testing apparatus

 Bulk density apparatus

 Tablet hardness tester

 Infra-red moisture content measuring apparatus

 U.V Spectroscopy

 Abbe Refractometer

 T.L.C. kit

 Karl fisher Titrimeter

 4

Official and Unofficial Tests for Evaluation of Tablets

Official Tests
[1] Weight variation

[2] Disintegration

[3] Dissolution

[4] Drug content

Non-Official Tests
[1] Hardness

[2] Friability
 5

1. Weight variation test (uniformity of weight)

Weigh 20 tablet selected at random, each one individually. X1, X2, X3… Xz

Determine the average weight. X= (X1+X2 +X3+…+ Xz)/20

Limit:

 Upper limit = average weight + (average weight * % error)

 Lower limit = average weight - (average weight * % error)
 The individual weights are compared with the upper and lower limits.
 Not more than two of the tablets differ from the average weight by more than the
% error listed, and no tablet differs by more than double that percentage.

Weight Variation Tolerances for Uncoated Tablets

USP XX-NF STANDARDS

Sr. No Average wt. of tablet(mg) Max. % difference allowed

1 130 or Less 10%
2 130-324 7.5%
3 More than 324 5%

IP STANDARDS
Sr. No Average wt. of tablet(mg) Max. % difference allowed
1 84 or Less 10%
2 84-250 7.5%
3 More than 250 5%
 6

2. Content Uniformity Test

Randomly select 30 tablets. 10 of these assayed individually. The Tablet pass the test if 9

of the 10 tablets must contain not less than 85 % and not more than 115 % of the labeled

drug content and the 10th tablet may not contain less than 75 % and more than125 % of the

labeled content. If these conditions are not met, remaining 20 tablet assayed individually

and none may fall outside of the 85 to 115 % range.

3. Disintegration test (U.S.P.)

 It is the time required for the tablet to break into particles, the disintegration test is
a measure only of the time required under a given set of conditions for a group of
tablets to disintegrate into particles.
 It is performed to identify the disintegration of tablet in particular time period.
 Disintegration test is not performed for controlled & sustained release tablets.
 According to the test the tablet must disintegrate and all particles must pass through
the 10 mesh screen in the time specified. If any residue remains, it must have a soft
mass.
 7

Disintegration test apparatus

Disintegration Media

 Water,
 Simulated gastric fluid (pH = 1.2 HCl), or Simulated intestinal fluid (pH = 7.5,
KH2PO4 (phosphate buffer) + pancreatic enzyme + NaOH)
 8

Disintegration Testing Conditions and Interpretation

Sr. no. Type of tablets Medium Temperature limit

1 Compressed 37 ± 2 0C 15 minutes or as per

uncoated individual monograph

2 Sugar coated Water 37 ± 2 0C 60 minutes or as per

individual monograph
If 1 or 2 tablets fail 0.1 N HCL

3 Film coated water 37 ± 2 0C 30 minutes or as per

individual monograph

4 Enteric coated 0.1 N HCL & 37 ± 2 0C 1 hr or as per individual

monograph
Phosphate
buffer pH 6.8

5 Dispersible/ water 37 ± 2 0C LST < 3 minutes or as

Effervescent per individual
monograph

6 Buccal 37 ± 2 0C 4 hr or as per individual

monograph

U.S.P. method for uncoated tablets

 Start the disintegration test on 6 tablets.

 If one or two tablets from the 6 tablets fail disintegrate completely within 30 min
repeat the same test on another 12 tablet. (i.e. the whole test will consume 18
tablets).
 Not less then 16 tablets disintegrate completely within the time
 If more than two tablets (from the 18) fail to disintegrate, the batch must be rejected.
 9

For Coated tablets

 To remove or dissolve the coat, immerse the tablet in distilled water for 5min.
 Put the tablet in the apparatus in water or HCL for 30 min at 37oC (according to the
U.S.P). If not disintegrated, put in intestinal fluid.
 If one or two tablets fail to disintegrate, repeat on 12 tablets. So 16 tablets from the
18 must completely disintegrate within the time, if two or more not disintegrated
the batch is rejected.

U.S.P. and B.P Method for Enteric coated tablets

 Put in distilled water for five minutes to dissolve the coat.

 Then put in simulated gastric fluid (0.1M HCL) for one hour.
 Then put in simulated intestinal fluid for two hours.
 If one or two tablets fail to disintegrate, repeat this test on another 12 tablets. So 16
tablets from 18 should completely disintegrate. If more than two fail to disintegrate
the Batch must be rejected.

4. Dissolution Test
 Dissolution is performed to check the percentage release from the dosage forms.
i.e. Tablet.
 Tablet breaks down into small particles which offers a greater surface area to the
dissolving media.
 Disintegration test does not give assurance that particles will release drug in
solution at an appropriate rate, that’s why dissolution tests & its specifications
developed for all tablet products.
 10

 Dissolution is mass transfer process.

 Dissolution is mainly depend on aqueous solubility of drug.
 It is process in which solid mass transfer in liquid medium.
 Dissolution based on four process – 1. wetting 2. Solubility 3. Swelling 4.
Diffusion.
 Particle size, shape, surface area is important factor can affect the rate of
dissolution of drug.
 The aqueous solubility is increases, increases rate of dissolution drug.

 Dissolution- solid mass transfer process in to liquid medium.

 Diffusion- diffusion is mass transfer process of individual molecules of atoms
having continuous random molecular motion contain in concentration gradient is
known has Diffusion.
 Dialysis- separation of easily diffusible particle from poorly diffusible particle
through semipermeable Membrane.
 11

 Ultrafiltration- separation of colloidal particle from sub colloidal particle through

semipermeable membrane.
 Osmosis- The passage of solvent molecule into solution through semipermeable
membrane.
 Semipermeable membrane – Thin layer that can separate two phases.
 Steady sate- Mass transfer process is remains constant per unit time.
 Non steady state- Mass transfer process is not remains constant per unit time.
 Osmotic pressure- The pressure is exerted in walls of semipermeable membrane
through concentration gradient.
 Diffusant (penetrant) - the amount of material transport in semipermeable
membrane.
 Con. Gradient- concentration of material transport in region of high con. To region
of low con.

Mechanism of Dissolution
 Dissolution is a mass transfer process.
 Sink condition – The concentration of receptor compartment is maintain lower
level as compared to Donor compartment is known as sink condition.
 Non sink condition – The concentration of receptor compartment is not
maintain at lower level as compared to donor compartment.
 12

Theories of Drug Dissolution

 Diffusion layer model/Film Theory
 Danckwert’s model/Penetration or surface renewal Theory
 Interfacial barrier model/Double barrier or Limited solvation theory
 13

Factor affecting dissolution rate

 Physicochemical Properties of Drug
 Drug Product Formulation Factors
 Processing Factors
 Factors Relating Dissolution Apparatus
 Factors Relating Dissolution Test Parameters

Dissolution test apparatus

IP apparatus
[1] First is Paddle apparatus (IP)
[2] Second is Basket apparatus (IP)

USP apparatus
1. Apparatus 1 (rotating basket)
2. Apparatus 2 (paddle assembly)
3. Apparatus 3 (reciprocating cylinder)
4. Apparatus 4 (flow-through cell)
5. Apparatus 5 (paddle over disk)
6. Apparatus 6 (cylinder)
7. Apparatus 7 (reciprocating holder)
 14

USP Dissolution apparatus I (Basket method)

A single tablet is placed in a small wire mesh basket attached to the bottom of the shaft
connected to a variable speed motor. The basket is immersed in a dissolution medium (as
specified in monograph) contained in a 1000 ml flask. The flask is cylindrical with a
hemispherical bottom. The flask is maintained at 37 ± 0.50C by a constant temperature
bath. The motor is adjusted to turn at the specified speed and sample of the fluid are
withdrawn at intervals to determine the amount of drug in solutions.
 15

USP Dissolution apparatus II (Paddle method)

It is same as apparatus-1, except the basket is replaced by a paddle. The dosage form is
allowed to sink to the bottom of the flask before stirring. For dissolution test U.S.P.
specifies the dissolution test medium and volume, type of apparatus to be used, rpm of the
shaft, time limit of the test and assay procedure for. The test tolerance is expressed as a %
of the labeled amount of drug dissolved in the time limit.
 16

Dissolution Testing and Interpretation IP Standards

Sr.no. Quantity Number of Acceptance criteria

Stage/level tablets tested
1 S1 6 Each unit is < D* + 5 percent**

2 S2 6 Average of 12 units (S1 +S2) is equal to or greater

than (> )D, and no unit is less than D - 15 percent**
3 S3 12 Average of 24 units (S1+S2+S3) is equal to or
greater than (> )D, not more than 2 units are less
than d-15 percent** and no unit is less than d-25
percent**
*D is the amount of dissolved active ingredient specified in the individual monograph, expressed
as a percentage of the labelled content.
** Percentages of the labelled content.
 17

Dosage from conducted dissolution study

Immediate release tablet (conventional tablet)
1. Dissolution apparatus – Type 1 and Type 2 (USP)
2. Temperature - 37±0.5˚C
3. Time – 30 min
4. Time of interval – 5, 10, 15, 20, 25, 30.
5. Media – PH 1.2 Acidic Buffer, PH 4.5 Acetate buffer, PH 5.8 Phosphate buffer.
(depending upon tablet)
6. Rpm – 75 -100 rpm
7. Volume – 900 ml

Procedure: The tablet was added into cylindrical vessel containing 1000 ml dissolution
media having rpm 75 and tem.37±0.5˚C. Dissolution of tablet was conducted 30 min,
in 5 min. of interval, after 5 min 5 mL sample was removed and appropriate quantity
of sample take absorbance by using U.V. spectroscopy technique and determine rate of
dissolution of tablet.

Sustained release tablet

1. Dissolution apparatus – Type 2 (USP)
2. Temperature - 37±0.5˚C
3. Time – 7 hrs
4. Media – PH 1.2 Acidic Buffer, PH 6.8 Phosphate buffer.
5. Rpm – 75 – 100.
6. Volume – 900 ml.

Procedure - The tablet was added into cylindrical vessel containing 1000 ml PH 1.2 Acidic
media having rpm 75 for next two hours and tem. 37±0.5˚C. Dissolution media was
changes tablet was added in to PH 6.8 Phosphate buffer for next five hour for 1 hr. of
interval. After 1 hr. 5 mL sample was removed and appropriate quantity of sample take
absorbance by using U.V. spectroscopy technique and determine rate of dissolution of
tablet.
 18

Capsule
1. Dissolution apparatus – Type 2 (USP)
2. Temperature - 37±0.5˚C
3. Time – 5 hrs.
4. Media – PH 1.2 Acidic Buffer, PH 6.8 Phosphate buffer.
5. Rpm – 75 – 100.
6. Volume – 900 ml.

Procedure - The Capsule was added into cylindrical vessel containing 1000 ml PH 1.2
Acidic media having rpm 75 for next two hours and tem. 37±0.5˚C. Dissolution media was
changes Capsule was added in to PH 6.8 Phosphate buffer for next three hour for 1 hr. of
interval. After 1 hr. 5 mL sample was removed and appropriate quantity of sample take
absorbance by using U.V. spectroscopy technique and determine rate of dissolution of
Capsule.

Suppositories
1. Dissolution apparatus – Type 1 (USP)
2. Temperature - 37±0.5˚C
3. Time – 60 min
4. Time of interval – 10, 20, 30, 40, 50, 60.
5. Media – PH 7.4 Phosphate buffer.
6. Rpm – 50 – 75 rpm
7. Volume – 900 ml.

Procedure – The Suppository was added into cylindrical vessel containing 1000 ml
dissolution media (PH 7.4 Phosphate buffer) having rpm 75 and tem.37±0.5˚C. Dissolution
of Suppository was conducted 60 min, in 10 min. of interval, after 10 min 5 ml sample was
removed and appropriate quantity of sample take absorbance by using U.V. spectroscopy
technique and determine rate of dissolution of Suppositories.
 19

5. Hardness
Tablet requires a certain amount of strength or hardness and resistance to friability to
withstand mechanical shocks of handling in manufacture, packaging and shipping.
Hardness generally measures the tablet crushing strength.

Importance
 To determine the need for pressure adjustments on the tableting machine.
 Hardness can affect the disintegration.
 So if the tablet is too hard, it may not disintegrate in the required period of time.
And if the tablet is too soft, it will not withstand the handling during subsequent
processing such as coating or packaging.
 In general, if the tablet hardness is too high, we first check its disintegration before
rejecting the batch.
 If the disintegration is within limit, we accept the batch.
 If Hardness is high + disintegration is within a time accept the batch.

Factors Affecting the Hardness

[1] Compression of the tablet and compressive force.
[2] Amount of binder. (More binder à more hardness)
[3] Method of granulation in preparing the tablet (wet method gives more hardness
than direct method, Slugging method gives the best hardness).

Limits
5 kilograms minimum and 8 kilograms maximum.
Make hardness test on 5 tablets and then take the average hardness.
 20

6. Friability
Friability of a tablet can determine in laboratory by Roche friabilator. This consist of a
plastic chamber that revolves at 25 rpm, dropping the tablets through a Distance of six
inches in the friabilator, which is then operate for 100 revolutions. The tablets are
reweighed. Compress tablet that lose less than 0.5 to 1.0 % of the Tablet weigh are consider
acceptable.
 21

Friability apparatus

Evaluation of Precompressional Characteristics of tablets or

Rheological Characteristics of granules
Particle Size & Shape Determination
 Size affects the average weight of tablet, Disintegration Time, weight variation,
friability, flow ability & drying rate.
 The size & shape depends upon processing requirements & during granulation.
 The methods for determining size & shape are
1. Sieving
2. Sedimentation rate.
3. Microscopy (SEM)
4. Light Scattering
Surface area
 It is not commonly used for granules but generally used for drug substances.
 If required particle size is measured & from this surface area is measured.
 Most method used is gas absorption & air permeability.
 22

 In gas absorption, gas is absorbed as monolayer on particles this is in term of

calculated & converted to surface area.
 In air permeability method the rate of air permeates a bed of powder, is used to
calculate surface area of powder sample.

Density
 Density may influence compressibility, tablet porosity & dissolution.
 Dense hard granules may require higher load to produce cohesive compact to
reduce free granules seen on the surface of tablets.
 ↑ Compressibility ↑ DT, Dissolution, if DT is slower dissolution is indirectly
hampered.
 Dense granules have less friability but cause a problem in releasing the drug.
 Three Methods to determine density
Bulk Density
Bulk density is given by equation,
ρb = M / V b
Where,
ρb- bulk density of granules,
M is mass of granules in gm,
Vb – volume of granules in measuring cylinder in ml.
More compressible bed of particulate - less flowable powder or granules.
If less dense/compressible - more flowable powder or granules.

True/tapped density
Tapped/true density is given by equation,
ρt = M / Vb
Where,
ρt- bulk density of granules,
M is mass of granules in gm,
 23

Vt – volume of granules in measuring cylinder after tapping in ml.

Granular density
It is determined by Pycnometer method.
 Two methods are used to determined granular density.
 In one intrusion fluid used-Mercury, and other
Any solvent of low surface tension e.g. Benzene
 The accuracy of these method depends upon ability of intrusion fluid to penetrate
the pores of granules.
 Liquids should not masks granules solubilies in it, & having property to penetrate
the pores.
 Density is then determine from volume of intrusion fluid displaced in pycnometer
by giving mass of granulation.
It is calculated by using equation,
Granular Density (D) = M / Vp -Vi
Where, Vp-Total volume of Pycnometer, Vi- Volume of intrusion fluid (ml) containing
Mass (gm) (M) of granules required to fill pycnometer.
 24

Angle of repose – It is measured by two methods

 Static angle of repose
 Dynamic angle of repose
Equation is, tan θ = h/r.
Where, θ - angle of repose, h – height of pile, r – radius of pile.

Acceptance limits of angle of repose

Sr. no. Angle of repose (o) Type of flow
1 < 25 Excellent
2 25-30 Good
3 30-40 passable
4 > 40 Poor
 25

Hausner's Ratio

 Hausner’s ratio was related to interparticulate friction and as such could be

used to predict powder flow characteristics.
 It showed that powder with low particular friction such as coarse sphere had ratio
of approximately 1.2, whereas more as cohesiveness- less free flowing powders
such as flaks have Hausner’s ratio greater than 1.6.

Formula

Hausner’s ratio = Tapped density / Bulk density

Moisture content
 The amount of moisture present in the granule is called moisture content.
 Generally the granules contain 2 % moisture. It is required for the binding of the
powder or granules during compression in die cavity.
 Percentage of moisture is calculated by using “moisture Balance” or “IR Balance”.
 IR Balance consist of simple balance which is placed I to the casing in which the
IR bulb is attached which produce heat inside the chamber.
 The small amount of sample taken from oven to measure moisture content & place
in the moisture balance.
 Initial reading should be note down after that we are initiated the IR Bulb as IR
bulb is initiated the moisture is removed from the granules via heating after that
note down the reading.
% of moisture is calculated by,
% moisture content = Initial wt. - Final wt./ initial weight X 100
 26

Compressibility Index
 It is directly related to the relative flow rate cohesiveness & particle size.
 It is simple fast & popular method of presiding powder flow characters.
It can be obtained from bulk density measurements is the % Compressibility index (C).
% Compressibility index = Tapped density - Bulk density / Tapped density X 100.
OR
I = (1 – V/ Vo) x 100
Where,
I – % Compressibility index,
V – Volume occupied by powder/ granules after tapping, Vo - volume of powder/granules
before tapping

Acceptance limit Compressibility index

Sr. no. % Compressibility index Type of flow
1 5-15 Excellent
2 12-16 Very good
3 18-21 Good
4 23-25 Passable
5 33-38 Poor
6 > 40 Very poor
 27

Process control by means of in-process controls

 28

Example of an IPQC structure

 29

Example of Approval for Tablet Production

*************************************************************

Contact:
Mr. Sagar Kishor Savale
+919960885333
[email protected]

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