S. No. Topic
1. Weight Variation
2. Solubility
3. Composition of simulated gastric / intestinal fluid
4. Informative Web sites
5. Empty Hard Gelatin Capsules Physical Specification
6. Weight Of Empty Hard Gelatin Capsules
7. Stability Conditions
8. Die - Punch Tooling Specification (Euro)
9. pH of Human Organs
10. Differential Scanning Calorimetry (DSC)
11. Differential Thermal Analysis (DTA)
12. Thermogravimetric Analysis (TGA)
13. Compatibility Study and Excipients Selection
14. Density of solvents
15. API: Excipients compatibility study (Stress Testing)
16. Solvent Classification
17. BCS Classification
18. RSD
19. PARA I, II, III, IV.
20. f2 Calculation (Similarity factor)
21. Dissolution Apparatus as per USP
22. Types of Drug Master Files
23. SIF & SGF
24. Tip speed Calculation
25. Ideal Property of API for Tableting
26. Weight variation
27. Hardness
28. Friability
29. Thickness
30. Disintegration
31. Coating machine
32. Glass standards (USP)
33. Tap Density apparatus (USP)
34. Equilibrium Relative Humidity or the ERH
35. Capsule (USP)
36. Powder flow
37. Injection Recommended excess volume to be added (USP)
38. STANDARD MESH SIEVE SIZES
39. Stability Testing (Climatic Zone, Evaluation)
40. Significance change (In stability testing)
41. Photo stability - Light source:
42. WHAT IS SUPAC GUIDANCE?
43. Types of Tablets
44. Tablet excipient
45. SUSPENSION INGRIDIENTS
46. Parameters used in IVIVC
47. Zeta potential
48. EMULSION INGRIDIENTS
1. Weight Variation
Weight variation of tablets (Uncoated, film coated, coated tablet other than film
coated)
2. Solubility
Solubility profile (USP)
Descriptive form Parts of solvent required for 1 Parts
of solute
Very soluble Less than 1
Freely soluble From 1 to 10
Soluble From 10 to 30
Sparingly soluble From 30 to 100
Slightly soluble From 100 ml to 1000
Very slightly soluble From 1000 to 10,000
Practically insoluble 10,000 Over
3. Composition of simulated gastric / intestinal fluid
Size Weight in mg
0 96
1 76
2 63
3 50
4 40
7. Stability Conditions
API < 5% w/w of 5%<API < 50% w/w API > 50% w/w of
target weight of FP of target weight of target weight of FP
FP
API:Diluent 1:1 and 1:25 1:1 , 1:5 1:1
API:Binder 1:1 , 1:5 1:0.5 1:0.5
API:Disintegrant 1:5 1:1 1:0.5
API:Lubricant 1:1 , 1:5 1:0.5 1:0.2
API:Preservatives/
Colour
1:0.1 1:0.1 1:0.05
Benzene 2 Carcinogen
1,2-
5 Toxic
Dichloroethane
1,1-
8 Toxic
Dichloroethene
1,1,1-
1500 Environmental hazard
Trichloroethane
TABLE 2.
CLASS 2 SOLVENTS IN PHARMACEUTICAL PRODUCTS.
*
usually 60% m-xylene, 14% p-xylene, 9% o-xylene with 17% ethyl benzene
TABLE 3.
CLASS 3 SOLVENTS, WHICH SHOULD BE LIMITED BY GMP OR OTHER QUALITY-
BASED REQUIREMENTS.
Solubility Permeability
Class I High High
Class II Low High
Class III High Low
Class IV Low Low
18. RSD
Logarithmic transformation of the sum of squares of the difference between test and
reference profiles. Its value ranges from 0 – 100.100 means test and reference profiles
are identical and 0 means the dissimilarity increases. Generally similarity value ranges
from 50 – 100.
21. Dissolution Apparatus as per USP
60x1000
Weight variation tolerances for uncoated, film coated & other than film
coated tablets:
As per U.S.P.
As per I.P
If more than 2 but not more than 6 capsules deviate from avg etween 10-
25% determine net contents of additional 40 capsules & determine avg.
content of entire 60 capsules.
Requirements:
1. Not more than 6 of 60 capsule’s differences exceed 10% of avg. net
content
2. In no case difference exceed 25%
Soft capsules:
Weigh 20 intact capsules individually to obtain their gross wts. Cut open
capsules & remove contents by washing wiyh a suitable solvent.Allow
accluded solvent to evaporate from shells at room temperature over a
period of about 30 min.Weigh individual shells& calculate net contents.
Requirements: same as hard capsules.
27.Hardness:
Force required to break a tablet in a compression test.
Also called tablet-crushing strength.
Units: Kilogram (Kg)
Newton (N)
Pound (lb)
1Kg = 9.807N
1Kg = 2.204ss lb
Test Methods:
The standard method used for tablet hardness testing is compression
testing. The tablet is placed between two jaws that crush the tablet.
The machine measures the force applied to the tablet and detects
when it fractures. This method is used for research & development and
for quality control.
3-point bend testing can be used for larger tablets i.e. washing
machine tablets. It can also be useful for research & development
purposes to determine the mechanical properties of new formulations,
e.g. Youngs Modulus and tensile strength.
Examples: Monsanto tester
Strong-cobb tester
Pfizer tester
Erweka tester
Schleuniger tester
28. Friability:
29. Thickness:
Measured by vernier caliper
Tablet thickness should be controlled within ±5% variation of a
standard value.
30. Disintegration:
Test is provided to determine whether tablets or capsules
disintegrate within the prescribed time when placed in a liquid
medium at the experimental conditions.
It is defined as that state in which any residue of the unit, except
fragments of insoluble coating/capsule shell, remaining on the
screen of test apparatus is a soft mass having no palpably firm
core.
Standards:
Basket-Rack assembly:
Beaker: capacity: 1000ml
Dimensions: 138-160mm(H)
97-115mm (D)
6 open ended transparent tubes
Dimensions: 77.5±2.5mm(L)
20.7-23mm(D)
1.2-8mm(T)
10 mesh (2mm) screen at the bottom of basket
Wire diameter: 0.57-0.66mm
Standard motor driven device- to move the basket at frequency =
28-32cycles/min through distance 53-57mm
Volume of fluid- such that at the highest point of upward stroke wire
mesh remains at least 25mm (2.5cm) below the surface of fluid &
descends to not less than 25mm (2.5cm) from the bottom of vessel
on downward stoke.
Thermostatic arrangement for heating liquid & maintaining
temperature at 35±20C.
Cylindrical disk- made up of suitable transparent plastic material
having specific gravity between 1.18-1.20
It consists of 5 holes each 2±0.1mm(D)- one in diameter & four
spaced equally on circle of radius 6mm from the center of disc.
Dimensions: 9.5±0.15mm(T)
20.7±0.15mm(D)
Sr.no Tablet/Capsule Medium Time
(min)
1 Uncoated tablet Water 15
2 Coated tablet Water 60
0.1N HCL 30
3 Enteric coated tablet 0.1N HCL 120
Mixed phosphate 60
buffer pH6.8
4 Hard capsule Water 30
5 Soft capsule Water 60
6 Soluble & Water 3
Dispersible tablet
Difference between -
Sr.No Conventional Coater Auto Coater (Gansons)
1 Open System Closed System
2 Capacity-1.5 Kg` Capacity-850 gm
3 Spray gun nozzle – Diameter 1.2 Spray gun nozzle – Diameter
mm 0.8mm
4 Exhaust on the Upper side Exhaust on the Down side
5 Temperature can not be Temperature can be controlled
controlled
6 Coating Pan-12 inch
7 Four pipes –
1) For Atomizing pressure
2) For Needle
3) For Fan Air
4) For Coating solution
USP Types
Two station tap density tester supporting both USP I and USP II
Methods of testing. The unit allows any one test to be performed at a time.
The test can also be performed as per ASTM standards using the optional
adapter for cylinder holders. Two different cylinder holders with snap-lock
mechanism are designed to hold the 100 ml and 250 ml cylinders.
To ensure a free drop of the cylinder from the required height, the two stations
are provided with virtually friction-free bearings. Each station is directly driven by
independent motors to ensure a maintenance- free drive. A simultaneous rotating
and tapping motion minimizes any possible separation of the mass during
tapping down.
The test can be performed in two different modes USP mode and USER mode in
both test methods. In USP mode, test will run in selected method with set
number of taps. At the end of the test, results like Tapped Density,
Compressibility Index and Hausner Ratio are calculated and displayed.
In User mode the number of drops can be programmed from 1 to 9999. The test
can be performed in either of the methods i.e. USP I or USP II.
During the test the user is guided through a series of prompts on the LCD
display. The on-line menus and status indicators make the operation of the
instrument user friendly. The drops / minute is validated on-line and displayed by
the instrument.
Specifications
No. of Stations 2
Drops / Min. 300 (USP I ), 250 (USP II)
Drop Height (mm) 14 ± 2 (USP I) &
3 ± 0.3 (USP II/ASTM)
Tap Count Range 1 - 9999
Cylinders 100 & 250 ml (1 each)
Cylinder Holders For 100 & 250 ml 1 each
Type of Drive Direct drive with Stepper motor
Display 24 x 2 Alphanumeric Dot Matrix backlit LCD
Power Supply 220/230 V AC, 50/60 Hz, 55 VA;
Dimensions (mm) 100/110 V AC, 50/60 Hz, 55 VA (on request)
Weight 360 L x 320 W x 200 H (Approx.) without the cylinders
The relative humidity of an air-water mixture is defined as the ratio of the partial
pressure of water vapor in the mixture to the saturated vapor pressure of water at
a prescribed temperature. Relative humidity is normally expressed as a
percentage and is defined in the following manner
where: RH is the relative humidity of the mixture being considered; p(H2O) is the
partial pressure of water vapor in the mixture; and p*(H2O) is the saturated
vapor pressure of water at the temperature of the mixture.
or lower value, or the tablets have a coating, the tablets should be crushed
in order to obtain an accurate free moisture level for the entire tablet.
Water Activity Values of Typical Pharmaceutical and OTC Drug Products
35. Capsule
Capsules are solid preparations with hard or soft shells of various shapes and
capacities, usually containing a single dose of active substance(s). They are
intended for oral administration.
The capsule shells are made of gelatin or other substances, the consistency of
which may be adjusted by the addition of substances such as glycerol or sorbitol.
Excipients such as surface-active agents, opaque fillers, antimicrobial
preservatives, sweeteners, coloring matter authorised by the competent authority
and flavoring substances may be added. The capsules may bear surface
markings.
—hard capsules;
—soft capsules;
—gastro-resistant capsules;
—modified-release capsules;
—cachets.
TESTS
TABLE 1
Weight of active Subtract from the Add to the upper
ingredients in each lower limit for limit for samples
capsule samples of of
15 10 5 15 10 5
0.12 g or less 0.2 0.7 1.5 0.3 0.8 1.8
More than 0.12g
0.2 0.5 1.2 0.3 0.6 1.5
And less than 0.3g
0.3g or more 0.1 0.2 0.8 0.2 0.4 1.0
Uniformity of weight: This test is not applicable to capsules that are required to
comply with the test for Uniformity of content for all active ingredients.
Weigh an intact capsule. Open the capsule without losing any part of the shell
and remove the contents as completely as possible. To remove the contents of a
soft capsule the shell may be washed with ether or other suitable solvent and the
shell allowed to stand until the odour of the solvent is no longer detectable.
Weigh the shell. The weight of the contents is the difference between the
weighings. Repeat the procedure with a further 19 capsules. Determine the
average weight. Not more than two of the individual weights deviate from the
average weight by more than the percentage deviation shown in Table 2 and
none deviates by more than twice that percentage.
TABLE 2
Average weight of
Percentage deviation
capsule contain
Less than 300 mg 10
300mg or more 7.5
Uniformity of content: This test is applicable to capsules that contain less than 10
mg or less than 10% w/w of active ingredient. For capsules containing more than
one active ingredient carry out the test for each active ingredient that
corresponds to the afore-mentioned conditions.
The test should be carried out only after the content of active ingredient(s) in a
pooled sample of the capsules has been shown to be within accepted limits of
the stated content.
Hard capsules comply with the test for disintegration of tablets and capsules
(2.9.1). Use water R as the liquid medium. When justified and authorised, 0.1 M
hydrochloric acid or artificial gastric juice R may be used as the liquid medium. If
the capsules float on the surface of the water, a disc may be added. Operate the
apparatus for 30 min, unless otherwise justified and authorised.
Soft capsules
Soft capsules comply with the test for disintegration of tablets and capsules
(2.9.1). Use water R as the liquid medium. When justified and authorized, 0.1 M
hydrochloric acid or artificial gastric juice R may be used as the liquid medium.
Add a disc to each tube. Liquid active substances dispensed in soft capsules
may attack the disc; in such circumstances and where authorized, the disc may
be omitted. Operate the apparatus for 30 min, unless otherwise justified and
authorized. If the capsules fail to comply because of adherence to the discs, the
results are invalid. Repeat the test on a further 6 capsules omitting the discs.
GASTRO-RESISTANT CAPSULES
For capsules with a gastro-resistant shell carry out the test for disintegration with
the following modifications. Use 0.1 M hydrochloric acid as the liquid medium and
operate the apparatus for 2 h, or other such time as may be authorised, without
the discs. Examine the state of the capsules. The time of resistance to the acid
medium varies according to the formulation of the capsules to be examined. It is
typically 2 h to 3 h but even with authorised deviations it must not be less than 1
h. No capsule shows signs of disintegration or rupture permitting the escape of
the contents. Replace the acid by phosphate buffer solution pH 6.8 R. When
justified and authorised, a buffer solution of pH 6.8 with added pancreas powder
(for example, 0.35 g of pancreas powder R per 100 ml of buffer solution) may be
used. Add a disc to each tube. Operate the apparatus for 60 min. If the capsules
fail to comply because of adherence to the discs, the results are invalid. Repeat
the test on a further 6 capsules omitting the discs.
Angle of Repose (Φ) is the maximum angle between the surface of a pile of
powder and horizontal plane. It is usually determined by Fixed Funnel Method
and is the measure of the flowability of powder/granules.
Φ = tan-1 (h / r) where, h = height of heap of pile
r = radius of base of pile
Compressibility index
Compressibility measures gives idea about flow property of the granules as per
CARR’S Index which is givan in table.
Hausner Ratio
CI Flow property HR
< 10 Excellent 1.00-1.11
11-15 Good 1.12-1.18
16-20 Fair 1.19-1.25
21-25 Passable 1.26-1.34
26-31 Poor 1.35-1.45
32-37 Very poor 1.46-1.59
>38 Very very poor >1.60
37. Injection Recomended excess volume to be added (USP):
E uropean A ll co u n tr ie s -
A m e r ica n C h ile , C a n a d a , B r a zil, J a m a ic a ,
U n ite d S ta te s V en e zu e la
A sia n C h in a , J a p a n , In d ia , P h ilip p in e s,
G u id e A p p lic a b ility T u rk e y S rMi L
in a
. n
nkoa. S iz e & t y p e
lin e o f b a tc h
IC H A fr ic a n
N e w d ru g s u b s ta n c e s S o u th A fric a , B o3 tsw a n a , GP hi lao nt as ,c a l e
N e w d ru g p ro d u c ts Z a m b ia , U g3 a n d a 2 p ilo t s c a le , 1
s m a lle r
W H O
Z im b a b w e
P r o d u c t s c o n ta in in g e a s ily d e g r a d a b le 3 P ilo t o f u ll s c a le
a cAt i vuestr
s a lia n / A u stra lia , N e w F iji, P a p u a –p rN
o de w
u c t io n
P rOo dc u e ac nt sicc o n t a i n i n g e sZt aeba lla
is n
hded and G 2u in ea D iff e r e n t p r o d u c t io n
s t a b le s u b s ta n c e s b a tc h e s
•O n g o in g s ta b ility N o .o f b a tc h e s W H O r e q u ir e m e n t
•O n e b a tc h per year
•O n e b a tc h a lte rn a te y e a r (fo r s ta b le p ro d u c ts )
•O n e b a tc h e v e ry 3 – 5 y e a rs (if s ta b ility p ro file is a v a ila b le )
U S F D A B u lk d r u g s u b s t a n c e s 1 P ilo t s c a le
S im p le d o s a g e fo r m s 1 P ilo t s c a le
O th e r s , in c lu d in g c o m p le x d o s a g e 3 2 p ilo t s c a le , 1
f o r m s a n d d r u g p r o d u c t s w it h o u t s m a lle r
s ig n ific a n t b o d y o f in f o r m a t io n
C P M P E x is t in g a c tiv e s u b s ta n c e s 2 or 3 P r o d u c t io n s c a le
C o n v e n tio n a l d o s a g e fo r m s c o n ta in in g 2 P ilo t s c a le
s t a b le a c tiv e s
C r it ic a l d o s a g e fo r m s ( p r o lo n g e d 3 2 p ilo t s c a le , 1
r e le a s e fo r m s ) o r w h e n a c t iv e s m a lle r
s u b s t a n c e s a r e k n o w n to b e u n s t a b le
Batches to be tested:
EVALUATION OF STABILITY DATA TO ESTABLISH
SHELF LIFE - For Drug Products
RE-TEST DATE - For Drug Substances
X Y
Accelerated Long Term y = 2x
(6months) (9 months OK) Shelf life / re-test date is 18
months
Accelerated Long Term y = 2x
(6months) (12 months OK) Shelf life / re-test date is 24
months
Accelerated Long Term y = x + 12
(6months) (18 months OK) Shelf life / re-test date is 30
months
Accelerated Long Term y = x + 12
(6months) (24 months OK) Shelf life / re-test date is 36
months
Accelerated Long Term y=x
(6months) (36 months OK) No extrapolation beyond 36
months
X Y
Accelerated Intermediate y = 1.5x
(6months) 12 months OK Shelf life / re-test date is 18
months
Literature Search
Pharmacology
1) Physician desk reference
2) Martindale Extra Pharmacopoeia
3) Therapeutic Drug
4) British National Formulary
5) ABPI compendium of data sheet and summaries of product characteristic
6) Anatomic Therapeutics Chemicals (ATC) and Defined daily dose (DDD)
classification
Reference: http://www.whoccc.no/atcddd
a) Anatomical group
b) Pharmacological or Therapeutic subgroup
c) Chemical subgroup
d) Therapeutic indication:
Biopharmaceutical Factors
1) Mechanism of action
2) Effect of diffusion, physical properties of drug and body on Distribution
3) Biotransformation, First pass effect, and Clearance
4) Renal, Bilayer, Mammary, Salivary and Other form of excretion
5) Metabolism
6) Bioavailability
7) Effect of Physiological changes with age sex and disease on the ADME
8) Reported pharmacokinetics parameter:
a) Vd
b) Kel
c) AUC
d) Clearance
e) Tmax
f) Cmax
g) T1/2
h) Linear or Non linear Kinetics
9) Minimum Effective concentration /Therapeutic range
10) Reported BCS Class
Reference:
http://www.tsrlinc.com/search3.cfm
http://www.fda.gov/cder/guidance/3618fnl.htm
http://www.fda.gov/cder/OPS/BCS_guidance.htm
http://www.dissolutiontech.com/DTresour/0502art/DTMay02_art1.htm
http://acronyms.thefreedictionary.com/Biopharmaceutics+Classification
http://www.absorption.com/assets/adeptiv/upload/attach/Copy%203%20of%
11) Reported pka values
12) Effect of Food
Active ingredient
Pharmacopoeial status
a) Indian pharmacopoeia (IP) and Addendum to Indian pharmacopoeia
b) USP and supplement of US pharmacopoeia and USP forum and USP/NF
c) British pharmacopoeia (BP) and Addendum to British pharmacopoeia
d) International pharmacopoeia
e) European pharmacopoeia (Ph. Eur.)
f) Japanese pharmacopoeia (JP)
Other Literature
a) Merck index
b) Florey analytical profile
c) US patent
d) EU patent
e) WO patent
f) Journal / conference
1) Active ingredient INN Name
2) Chemical name
3) IUPAC name
4) Molecular structure
5) Molecular formula
6) Molecular weight
7) CAS registry No.
8) Toxicity and Hazard class
9) Storage condition
10) Handling precaution
11) Appearance
12) Solubility in organic solvent (Having Carbon)
13) Solubility in inorganic solvent (HCl, H2SO4)
14) Solubility in water
15) Identification
16) PH of 1%w/v solution or suspension at 250C
17) Moisture
18) LOD
19) Crystallinity
20) Melting point
21) Polymorphism
22) Solvate/Hydrate
23) Specific optical rotation
24) Sulphated ash
25) Residue on ignition
26) Heavy metal
27) Related substance (RS)
28) Assay
29) Particle size distribution
(Sieve analysis plot frequency distribution curve)
30) Sieve analysis
31) Bulk density
32) Tapped density
33) Intrinsic dissolution
34) Particulate dissolution
35) Bacterial Endotoxine
36) Hygroscopicity
Note:
¾ If polymorphism reported, which form is included in product specification EU
or US patent
¾ If there any advantage of specific polymorph over other with respect to
stability and bioavaila.
¾ Record the characteristic 2Ө value and d spacing and melting point for
various polymorphs/solvates/hydrate/pseudopolymorph
¾ Whether API required control on particle size distribution. If yes record the
desired method on control the particle size distribution
¾ Whether API has tendency of degradation via hydrolysis, oxidation, heating,
isomerisation, photolysis and polymerization. Report the extent of
degradation, probable degradation and impurities
¾ Whether API exhibits isomerisation. IF yes, does it required controlling
isomeric purity with reference to therapeutic values
¾ Whether API has reported to have incompatibility with known excipients
¾ pH solubility profile
¾ pKa value
¾ Log P value
Evaluation of API from different manufacturer
1) FTIR characterization
2) H-1 and C-13 NMR characterization
3) Mass characterization
4) Elemental analysis report
5) XRPD diffract gram
6) DSC thermogram
7) Solid state discription (colour, crystalline/amorphous)
8) Bulk density
9) Tapped density
10) Compressibility index
11) Housnor ratio
12) Particle size (sieve analysis, plot frequency distribution curve)
13) Particle size (D10, D50, D90)
14) LOD at…
15) Moisture content
16) Related substance
17) Assay
Solubility study:
1. Check the solubility using USP criteria of solubility determination in various
solvents at 250C±10C
¾ Water
¾ Methanol
¾ Ethanol
¾ Propranol
¾ Dimethyl sulphoxide (DMSO)
¾ Dimethyl formamide (DMF)
¾ Acetone
¾ Tetrahydrofurane(THF)
¾ Methylene chloride (MDC)
*Purified water +0.1% SLS. Increase the concentration of SLS to upto 2% to get
the desired solubility
*Purified water +0.1% tween 80. Increase the concentration of tween 80 to upto
2% to get the desired solubility
Solubility study
1. 0.01N HCl
2. 0.1N HCl
3. HCl acid buffer pH 1.2
4. HCl acid buffer pH 2.2
5. Acid phthalate buffer pH 3.0
6. Acid phthalate buffer pH 4.0
7. Neutralized phthalate buffer pH 5.0
8. Phosphate buffer pH 5.8
9. Phosphate buffer pH 6.8
10. Phosphate buffer pH 7.2
11. Phosphate buffer pH 8.0
12. Acetate buffer pH 5.5
13. Purified water + 0.1% SLS
14. Purified water + 0.5% SLS
15. Water
pH stability profile
Determine the stability of 2%w/v solution of suspension at pH 1.2,4.5,6.8 and 8.
Stability has to be determined using stability indicating HPLC assay method.
Stability study of test sample stored at 370C to be done against freshly prepared
solution at predecides interval for 8 hr
Report the assay and % degradation.
1. Brand name
2. Generic name and strength
3. Label claim
4. Product description
5. Instruction for use
6. Rout of administration
7. Manufacturer name and address
8. Batch no
9. Mfg date
10. Exp date
11. Shelf life
12. Storage condition
13. Special handling requirement
14. Description of packing
15. Pack insert
16. Physical description/Dimension/Marking
17. Method of analysis (compendial /Non compendial)
18. DT
19. Dissolution medias (1/2/3/4/5 )
20. RS
21. Assay