EVALUATION PARAMETERS.pdf

Evaluation parameters for pharmaceutical dosage forms.

1. Index
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

2. 1. Weight Variation


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 Fr om 100 ml to 1000
Very slightly soluble From 1000 to 10,000
Practically insoluble 10,000 Over


Weight variation of tablets (Uncoated, film coated, coated tablet other than film
coated)

Avg weight of the tablet, mg Percentage
difference
References
80 or less 10
More than 80 but less than 250 7.5
IP
250 or more 5
1996 edition, vol-
2, page-736
80 or less 10
More than 80 but less than 250 7.5
250 or more 5
Capsule and granules (uncoated, single dose and
powder, single dose)
Less than 300 mg 10
300 mg or more 7.5
Powders for parenteral use
More than 40 mg 10
Suppositories and pessaries
BP
All mass 5
2005 edition, vol-
4, page-A 291
130 or less 10
From 130 through 324 7.5
USP
More than 324 5
USP-28, page-
2781
Avg weight of the tablet,mg Percentage
difference
80 or less 10
More than 80 but less than 250 7.5
250 or more 5
Capsule and granules (uncoated, single dose and
powder, single dose)
Less than 300 mg 10
300 mg or more 7.5
EP -5.0,vol-1,
page-233
Powders for parenteral use
More than 40 mg 10
Suppositories and pessaries
JP
All mass 5

3. 3. Composition of simulated gastric / intestinal fluid

Sl. No. Composition of simulated
gastric fluid
Composition of simulated intestinal
fluid
1 Sodium chloride Monobas ic potassium phosphate.
2 Purified pepsin Sodium hydroxide.
3 HCl Water.
4 Water Pancreatin.
5 - NaOH or HCl (pH 6.8±0.1).

4. Informative Web sites
Sl.no. Web sites Purpose
1. vidal.fr Composition of innovators
2. luhs.com Image and information of innovator
3. tsrlinc.com/search3.cfm BCS classification
4. drugs.com Information of drug
5. rxlist.com Innovator and its information
6. Answers.com Answer
7. Drugsearcher.com
8. Sengpielaudio.com/convForce.htm Conversion of units
9. Emc.medicines.org.uk/ About API
10. Dissolution.com(By-law) Sending mail for disso problems
11. Fda.gov/cder/ogd/
12. Pharmacopoeia.cn/usp.asp
13. google.com
14. Orange book Innovators
15. Uspto---homepage---patent---
search I)issued patent---QS
2)published patent---Q.S

16. europianpatent---homepage---
@spanet homepage---AS

17. Cder---freedom of information---
index---cder---search

18. Drugbank---homepage
19. www.aapspharmsci.org Literatures
20. Pat2pdf Full Patent Pdf
Books references
21. Merk Index
22. Martindale
23. PDR
24. Medicine Compendium
25. Therapeutic Drugs
26. British Pharmacopoeial Codex
27. Florey
28. USP
29. Ph EP
30. BP
31. JP
32. CP
33. Niazi

4. 5. Empty Hard Gelatin Capsules Physical Specification

Size Outer
Diameter
(mm)
Height/ Lock
length (mm)
Actual
volume (ml)
Typical fill weight
(mg) 0.7 powder
density
000 9.91 26.14 1.37 960
00 8.53 23.30 0.95 665
0 7.65 21.70 0.68 475
1 6.91 19.40 0.50 350
2 6.35 18.00 0.37 260
3 5.82 15.90 0.30 210
4 5.31 14.30 0.21 145
5 4.91 11.10 0.13 90

6. Weight Of Empty Hard Gelatin Capsules









7. Stability Conditions


Storage
Condition
Study Condition Period
(month)
Testing
Frequency in
(month) Long term 25
0
C±2
0
C/60±5%RH
30
0
C±2
0
C/65±5%RH
12 0, 3, 6, 9 & 12
Intermediate 30
0
C±2
0
C/75±5%RH 6 0, 3 & 6
At room
temperature
Accelerated 40
0
C±2
0
C/75±5%RH 6 0, 3 & 6
Long term 5
0
C±3
0
C 12 0, 3, 6, 9 & 12 In refrigerator
Accelerated 25
0
C±2
0
C/60±5%RH 6 0, 3 & 6 In freezer Long term -20
0
C±5
0
C 12 0, 3, 6, 9 & 12

8. Die - Punch Tooling Specification (Euro)


Max Tab Size
PUNCH TOOLING
Punch Diameter (mm)
Die Diameter (mm)
Round Tablet (mm)
Shaped Tablet (mm)
BB 19.05 24 13 14
B 19.05 30.16 16 19
BD 25.4 30.16 19 19
D 25.4 38.1 25 25



Size Weight in mg
0 96
1 76
2 63
3 50
4 40

5. 9. pH of Human Organs

Organs pH Liver
Stomach
Large Intestine
Small Intestine
Colon



10. Differential scanning calorimetry or DSC is a
thermoanalytical technique in
which the difference in the amount of
heat required to increase the temperature
of a sample and reference are measured as a function of temperature. Both the
sample and reference are maintained at nearly the same temperature throughout
the experiment. Generally, the temperature program for a DSC analysis is
designed such that the sample holder temperature increases linearly as a
function of time. The reference sample should have a well-defined
heat capacity
over the range of temperatures to be scanned. The basic principle underlying this
technique is that, when the sample undergoes a physical transformation such as
phase transitions, more (or less) heat will need to flow to it than the reference to
maintain both at the same temperature. Whether more or less heat must flow to
the sample depends on whether the process is
exothermic or endothermic. For
example, as a solid sample
melts to a liquid it will require more heat flowing to
the sample to increase its temperature at the same rate as the reference. This is
due to the absorption of heat by the sample as it undergoes the endothermic
phase transition from solid to liquid. Likewise, as the sample undergoes
exothermic processes (such as
crystallization) less heat is required to raise the
sample temperature. By observing the difference in heat flow between the
sample and reference, differential scanning
calorimeters are able to measure the
amount of heat absorbed or released during such transitions. DSC may also be
used to observe more subtle phase changes, such as
glass transitions. DSC is
widely used in industrial settings as a quality control instrument due to its
applicability in evaluating sample purity and for studying polymer curing



11. DTA is a
thermoanalytic technique, similar to differential scanning
calorimetry. In DTA, the material under study and an inert reference are heated
(or cooled) under identical conditions, while recording any temperature difference
between sample and reference. This differential temperature is then plotted
against time, or against temperature DTA curve or thermogram.

6. 12. Thermogravimetric Analysis or TGA is a type of testing that is performed
on samples to determine changes in weight in relation to change in temperature.
Such analysis relies on a high degree of precision in three measurements:
weight, temperature, and temperature change. As many weight loss curves look
similar, the weight loss curve may require transformation before results may be
interpreted. A derivative weight loss curve can be used to tell the point at which
weight loss is most apparent. Again, interpretation is limited without further
modifications and deconvolution of the overlapping peaks may be required.
TGA is commonly employed in research and testing to determine characteristics
of materials such as polymers, to determine degradation temperatures, absorbed
moisture content of materials, the level of inorganic and organic components in
materials, decomposition points of explosives, and solvent residues. It is also
often used to estimate the corrosion kinetics in high temperature oxidation.
13. Compatibility Study and Excipients Selection
Plan for Study
1. API alone
2. API + API (for combined doses)
3. API + individual excipients in proportion as in FPS.
4. All excipients blend
5. API + all excipients in proportion as in FPS.


API < 5% w/w of
target weight of FP
5%<API < 50% w/w
of target weight of
FP
API > 50% w/w of
target weight of 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


15. Density of Solvents


Solvent Density (g/ml)
Water 0.997
IPA 0.786
MDC 1.325
Acetone 0.790
Methanol 0.791

7. 14. API: Excipients compatibility study and Excipients selection
API Forced degradation study: (Stress Testing)

Stress
factor
Conditions Concentration of
API
#

Time Evaluation
parameter
Heat 60
0
C API only 15 Days Visual &
Chemical
Humidity 40
0
C with 5%
moisture in
sealed glass
vial
Solid state API 15 Days Visual &
Chemical
Acid 0.1 N HCL at
25
0
C
2:1 in 0.1 N HCL 1-10 Days Chemical
Base 0.1 N NaOH at
25
0
C
2:1 in 0.1 N HCL 1-10 Days Chemical
Oxidation 3% H 2O2 at
25
0
C
1:1 in 3% H
2O2 1-3 hours Chemical
Solution
stability
Rom temp.
solution stability
study at
different pH
2%
solution/suspension
over pH range of
1.2 to 8.0
4-24 hour Visual &
Chemical
Photolysis
(Optional)
Expose the test
compound to
1.2 million
lux.hr florescent
light and to
near UV energy
of not less than
200 watt
hours/m
2
.
Metal halide,
Hg, Xe, or UV-
B fluorescent
lamp
1:1 with diluent 1-10 Days Visual &
Chemical
Metal ions
(Optional)
0.05 M Fe 2+ or
Cu
2+
1:1 with solution of
metal ions
1-10 days Chemical
Control sample
2-8
0
C Solid state API 15 Days If required
# - When testing degradability of APIs in combination, the APIs should be in
same ratio as in the FDC.
- In each case, the diluent is either excipients or all excipients in the
formulation in the same ratios as in the formulation.

8. 16. Solvent Classification
TABLE 1.

CLASS 1 SOLVENT IN PHARMACEUTICAL PRODUCTS
(SOLVENTS THAT SHOULD BE AVOIDED)

SOLVENT CONCENTRATION
LIMIT (PPM)
CONCERN
Benzene 2 Carcinogen
Carbon
tetrachloride
4
Toxic and
environmental hazard
1,2-
Dichloroethane
5 Toxic
1,1-
Dichloroethene
8 Toxic
1,1,1-
Trichloroethane
1500 Environmental hazard
TABLE 2.
CLASS 2 SOLVENTS IN PHARMACEUTICAL PRODUCTS.

SOLVENT PDE
(MG/DAY)
CONCENTRATION LIMIT
(PPM)
Chloroform 0.6 60
Chlorobenzene 3.6 360
Dichloromethane (MDC) 6.0 600
Ethylene Glycol 6.2 620
Methanol 30.0 3000
Cyclo Hexane 38.8 3880
1,2-Dichloroethene 18.7 1870
1,1,2-Trichloroethene 0.8 80
Acetonitrile 4.1 410
1,2-Dimethoxyethane 1.0 100
N,N-
Dimethylacetamide
10.9 1090
N,N- Dimethylformamide
8.8 880
1,4-Dioxane 3.8 380

9. 2-Ethoxyethanol 1.6 160
Formamide 2.2 220
Hexane 2.9 290
2-Methoxyethanol 0.5 50
Methylbutyl ketone 0.5 50
Methylcyclohexane 11.8 1180
N-Methylpyrrolidone 48.4 4840
Nitromethane 0.5 50
Pyridine 2.0 200
Sulfolane 1.6 160
Tetralin 1.0 100
Toluene 8.9 890
Xylene* 21.7 2170

*
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.

Acetone (1500 ppm) Acetic acid
2-Propanol (IPA) Æ (5000 ppm) Heptane
Ethanol (1000 ppm) Isobutyl acetate
Anisole Isopropyl acetate
1-Butanol Methyl acetate
2-Butanol 3-Methyl-1-butanol
Butyl acetate Methylethyl ketone
tert-Butylmethyl ether Methylisobutyl ketone
Cumene 2-Methyl-1-propanol
Dimethyl sulfoxide Pentane
Propyl acetate 1-Pentanol
Ethyl acetate 1-Propanol
Ethyl ether Tetrahydrofuran
Ethyl formate Formic acid

10. 17. BCS Classification:

Solubility Permeability
Class I High High
Class II Low High
Class III High Low
Class IV Low Low
18. RSD








19. PARA I, II, III, IV
• Para I - The drug has not been patented
• Para II - The patent for the drug has already expired
• Para III - The patent for the product exists but the generic company wants to enter the
markets after the date of patent expiry passes.
• Para IV - Patent is not infringed upon or is invalid



20. f
2 Calculation (Similarity factor)

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.

11. 21. Dissolution Apparatus as per USP

Apparatus 1 Basket
Solid dosage form

Apparatus 2 Paddle
Solid dosage form

Apparatus 3 Reciprocating Cylinder
Modified release solid dosage form

Apparatus 4 Flow Through Cell
Modified release solid dosage form with limited
Solubility
Apparatus 5 Paddle Over Disc
Transdermal Patches

Apparatus 6 Rotating Cylinder
Transdermal Patches

Apparatus 7 Reciprocating Holder
Non-disintegrating oral modified release oral dosage
form and Transdermal Patches.

22. Types of Drug Master Files
Type I: Manufacturing Site, Facilities, Operating Procedures, and Personnel
Type II: Drug Substance, Drug Substance Intermediate, and Material Used in
Their Preparation, or Drug Product
Type III: Packaging Material
Type IV: Excipients, Colorant, Flavor, Essence, or Material Used in Their
Preparation
Type V: FDA Accepted Reference Information

23. SIF & SGF -
SIF:
As used herein, "simulated intestinal fluid" or "SIF" means a composition
prepared by dissolving 6.8 g of monobasic potassium phosphate in 250 ml of
water, then adding 190 ml of 0.2 N NaOH, 400 ml of water and 10 g of
pancreatin, and finally adding 0.2 N NaOH to adjust the pH to 7.5, and then
diluting with water to 1000 ml.

SGF : As used herein, `simulated gastric fluid` or `SGF` means a composition
prepared by dissolving 2 g of NaCl and 3.2 g pepsin in 7 ml of HCl, and then
adding water to 1000 ml. The resulting fluid has a pH of about 1.2.

24. Tip speed Calculation

Tip speed= π nd
______ ____ ____ ___ ____ ____ ___ ____ ____ ____ ___ ____ ____ ___ __

60x1000

where n = rpm of impeller
d = diameter of the impeller in mm)

12. 25. Ideal Property of API for Tableting
Property Reason Remedy
High purity Impurities can catalyze
series of reaction
---------
High Stability should be stable against
photolysis, oxidation,
hydrolysis, etc.
----------
Good compatibility with excipients

Optimum bulk powder properties
I) Prevent segregation.
ii) Have optimum size
tablet particularly for low
potency-low density API.
iii) Have good flow.


Optimum and Uniform
particle size-particle size
distribution

It has pronounce effect
on uniformity of content,
uniformity of weight,
disintegration time,
granule friability, drying
rate kinetics of wet
granulation, flowability,
compressibility, stability,
dissolution,
bioavailability, etc.

Spherical shape

The shape of particles
decides flowability

Good flowability
Flow is important for having uniformity of weight and uniformity of
drug content. It can be
measured using angle of
repose, Carr’s index and
Hausner ratio.

-Addition of glidants
-Addition of fines
-By wet granulation
-By densification with
help of slugging
Optimum moisture
content

-Total lack of moisture
results into brittle tablet.
-Moisture affects flow
-High amount of moisture
gives stickiness
-Picking/sticking
-Use of anhydrous salts.
-Use of non-aqueous
solvent
-Optimum drying time
-Addition of finely
powdered adsorbent like
magnesium oxide
Good compressibility

good compressibility
depends upon its intrinsic
nature like 1.Elasticity
2.Plasticity 3.Brittle
fracture

13. Absence of static charge
on surface
-For uniformity of dose
and weight variation
-It may cause
segregation
-Charged API may
adhere to feed frame
-Granulation, addition of
diluents or lubricant,
surface coating with help
of colloidal silica, etc.
Good organoleptic
properties 1.colour
2.Taste
Ideally should be
colorless
Ideally should be
Tasteless
Apply coating
Use small particle of
colored API
Taste- Cyclodextrin
approach, Sweeteners,
Ion exchange absorbent,
Pro-drug approach
Miscellaneous points
-API should not exhibit sublime characteristics.
- Liquid APIs are less suitable for tablet formulation. (mix liquid API with
adsorbents) Valproic acid and Sodium Valproate is a typical example of
converting a liquid into pseudosolid.
- BCS class IV drugs are difficult to formulate if dissolution and
bioavailability requirements are to meet as per regulatory agencies.

26. Weight variation:
Uncoated & Film coated tablets:
Weigh 20 tablets individually & calculate average weight. Compare
individual tablet weight with average weight. Requirements are met if not
more than 2 tablets are outside % limit.
Coated tablets (other than film-coated):
Weigh 20 tablets individually & calculate average weight. If the coated
tablets do not conform to the criteria as given in table, place 20 tablets in a
beaker of water at 37
0
& swirl gently for not more than 5 min. dry the cores
at 50
0
for 30 min. Weigh accurately 20 individual tablet cores & calculate
the avg. wt. compare individual tablet weight with average weight.
Requirements are met if not more than 2 tablets are outside % limit.

Weight variation tolerances for uncoated, film coated & other than film
coated tablets:
As per U.S.P.

Avg. wt of tablet (mg) Maximum % difference allowed
130/less 10
130-324 7.5
>324 5

As per I.P

Avg. wt of tablet (mg) Maximum % difference allowed
80 10
80-250 7.5
>250 5

14. Hard gelatin capsules:
Weigh 20 intact capsules individually & determine avg. wt
Requirement: Individual wt should be within limits of 90% & 110% of avg.
wt.
If not all the capsules fall within given limits weigh 20 capsules individually.
Remove contents of each capsule with emptied shell individually &
calculate net wt of its content by subtracting wt of shell from sum of
individual net wts. Determine avg. net content from sum of individual net
wts. Then determine difference between each individual net content &
avg. net content.
Requirements:
1. Not more than 2 of differences are greater than 90% of avg. net
content
2. In no case difference is greater than 25%

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

15. 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:




‰ Another measure of tablet’s strength
‰ E.g. Roche friabilator
Standards:

‰ Drum: 283-291mm (ID)
36-40 mm (Depth)
‰ Drop height: 158±2mm
‰ RPM: 25±1 rpm
‰ Central ring- outer diameter: 25±0.5m
‰ Curved projection- inside radius: 80.5±5mm
‰ Loss in weight of tablets: not more than 1%
‰ For tablets with unit wt =/<650mg- take sample of whole tablet
~6.5gm
‰ For tablets with unit wt >650mg = 10 tablets

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

16. 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±2
0
C.
‰ 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)

17. 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
buffer pH6.8
60
4 Hard capsule Water 30
5 Soft capsule Water 60
6 Soluble &
Dispersible tablet
Water 3

31. COATING MACHINE Types of coating Machine (Macleods Pharma)
1) Conventional
2) Auto Coater.
Parts: - a) Coating Pan
b) Air Blower
c) Exhaust
d) Spray Gun
e) Peristaltic Pump
f) Baffles

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
mm
Spray gun nozzle – Diameter
0.8mm
4 Exhaust on the Upper side Exhaust on the Down side
5 Temperature can not be
controlled
Temperature can be controlled
6 Coating Pan-12 inch
7 Four pipes –
1) For Atomizing pressure 2) For Needle
3) For Fan Air
4) For Coating solution


32. Glass Standards
USP Types

Various standards govern the classification of glass into types
suitable for specific uses. These standards include ASTM

18. (American Society for Testing and Materials), EP (European
Pharmacopoeia), and USP (United States Pharmacopoeia).
The following classifications were determined by USP criteria. The
applicability of a particular container to an end use cannot be
determined by this criteria alone. Other general criteria has been
developed to assist with the use of the USP classifications in
selecting containers.
USP Type I borosilicate glass is the least reactive glass available
for containers. It can be used for all applications and is most
commonly used to package water for injection, UN-buffered
products, chemicals, sensitive lab samples, and samples requiring
sterilization. All lab glass apparatus is generally Type I borosilicate
glass. Examples of Type I borosilicate glass include Corning®
Pyrex® 7740 and Wheaton 180, 200, and 400. Though Corning®
Vycor® 7913 is not classified as a Type I glass, it does meet or
exceed USP Type I requirements.
In most cases Type I glass is used to package products which are
alkaline or will become alkaline prior to their expiration date. Care
must be taken in selecting containers for applications where the pH
is very low or very high, as even Type I glass can be subject to
attack under certain conditions. Although Type I borosilicate has
the least pH shift of any glass, there still may be some sensitivity
with certain packaged products.
Surface treatment is not usually required, however it will further
enhance the desirable characteristics of an already superior
container. This surface enhancement may become especially
important for small containers because of the high ratio of container
surface area to the volume of the container contents.
USP Type II de-alkalized soda-lime glass has higher levels of
sodium hydroxide and calcium oxide. It is less resistant to leaching
than Type I but more resistant than Type III. It can be used for
products that remain below pH 7 for their shelf life.
USP Type III soda-lime glass is acceptable in packaging some dry
powders which are subsequently dissolved to make solutions or
buffers. It is also suitable for packaging liquid formulations that
prove to be insensitive to alkali. Type III glass should not be used
for products that are to be autoclaved, but can be used in dry heat
sterilization. Examples of Type III soda lime glass include Wheaton
800 and 900.
USP Type NP soda-lime glass is a general-purpose glass and is
used for non-parenteral applications where chemical durability and
heat shock are not factors. These containers are frequently used
for capsules, tablets and topical products. Examples of Type NP
glass include Wheaton 810 and 910.

19. 33.Tap Density apparatus (USP)


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

20. instrument user friendly. The drops / minute is validated on-line and displayed by
the instrument.








Specifications



Test Methods USP I and USP II,
ASTM (optional)

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

34. Equilibrium Relative Humidity or the ERH :-

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

RH = p(H2O)/p*(H2O) Multyply by100

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.
Equilibrium Relative Humidity or the ERH of a material is the relative humidity
when the movement of moisture from a material to the environment (and vice
versa) have equalized. This Equilibrium Relative Humidity or ERH balance is
achieved when vapour pressures (within the material and the environment) have
equalized. At this point the moisture level of a material can be expressed in terms
of equilibrium relative humidity (ERH).
Water activity (aw), or equilibrium relative humidity (ERH) is a measure of the
free water in a pharmaceutical dosage form. It is defined as the ratio of the water

21. vapor pressure of the substance (p) to the vapor pressure of pure water (po) at
the same temperature; aw = p/po . Equilibrium relative humidity is water activity
expressed as a percentage; ERH = aw x 100. . Water associated with a
substance is classified as either free or bound.




Pharmaceutical Importance of ERH
¾ Water activity (aw) influences the chemical stability, microbial stability,
flow properties, compaction, hardness, and dissolution rate of dosage
forms of pharmaceuticals, proteins, biopharmaceuticals, nutraceuticals
and photochemicals.
¾ Water activity over water content provides useful information for
formulation design, manufacturing conditions and packaging
requirements.
¾ Sophisticated techniques are being developed to understand the role
played by water molecules in pharmaceutical products. It is known that
these products lose and gain water from the atmosphere. The water
molecules are located at various sites within the mixture of ingredients, the
extent of which depends on the ingredients themselves. Physical changes
can occur e.g. crystallinity resulting in polymorphism. Chemically the
active ingredient can degrade resulting in undesired impurities. Less
understood is the movement of water molecules between ingredients.
These processes involving water are driven by relative humidity and may
be dependant on the ERH of the materials.
¾ Microbial Growth
Water activity is a better index for microbial growth than water content.
The water activity concept has served the microbiologist and food
technologist for decades and is the most commonly used criterion for
safety and quality. Microorganisms have a limiting aw below which they
cannot grow. Knowledge of the behavior of microorganisms in
pharmaceutical products at different aw levels is important in meet Federal
Food, Drug and Cosmetic Laws.
¾ Component Compatibility
The importance of water activity as opposed to total water is used in
preformulation compatibility studies involving moisture-sensitive drugs.
Hygroscopic excipients (starch, cellulose and magaldrate) have
successfully been formulated for use with moisture sensitive drugs. The
excipients may preferentially bind moisture and make the dosage form
less susceptible to changes in relative humidity during manufacture,
shipment, storage or patient use, thus extending shelf life. This is also
applicable to other polymer systems of Pharmaceutical interest, such as
proteins (gelatin, keratin) and various synthetic hydrogels.
¾ Stability
Protein, enzyme and biopharmaceutical stability is influenced significantly
by water activity due to their relatively fragile nature. Great care must be
taken to prevent aggregation under pharmaceutically relevant conditions.
Most proteins, enzymes and biopharmaceuticals also must maintain
integrity to remain active. Maintaining critical water activity levels to
prevent dissolution, aggregation and conformational changes from
occurring is important to deliver the correct dosage

22. ¾ Additional Applications
Water activity of powders effects the flow, caking, compaction and
strength properties of solid dosage forms. Additionally, aw is used in the
study of shelf-life, aging and packaging requirements of pharmaceuticals.
Water activity also has uses in design and development of coating
technology. Understanding the response of solid dosage forms to
changing environments aids in determination of formulation and packaging
requirements. When tablets are in the process of equilibrating to a higher

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

24. 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.

Several categories of capsules may be distinguished:

—hard capsules;

—soft capsules;

—gastro-resistant capsules;

—modified-release capsules;

—cachets.

25. TESTS
Content of active ingredients: Determine the amount of active ingredient(s) by
the method described in the Assay and calculate the amount of active
ingredient(s) in each capsule. The result lies within the range for the content of
active ingredient(s) stated in the monograph. This range is based on the
requirement that 20 capsules, or such other number as may be indicated in the
monograph, are used in the Assay. Where 20 capsules cannot be obtained, a
smaller number, which must not be less than 5, may be used, but to allow for
sampling errors the tolerances are widened in accordance with Table 1. The
requirements of Table 1 apply when the stated limits are between 90 and 110%.
For limits other than 90 to 110%, proportionately smaller or larger allowances
should be made.

TABLE 1
Weight of active
ingredients in each
capsule
Subtract from the
lower limit for
samples of
Add to the upper
limit for samples
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 And less than 0.3g
0.2 0.5 1.2 0.3 0.6 1.5
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
capsule contain
Percentage deviation
Less than 300 mg 10
300mg or more 7.5

26. 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.
Disintegration (Hard capsules)

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.

36. Powder flow
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.

27. Φ = tan
-1
(h / r) where, h = height of heap of pile
r = radius of base of pile


Flow property Angle of repose(degree)
Excellent 25-30
Good 31-35
Fair 36-40
Passable 41-45
Poor 46-55
Very poor 56-65
Very very poor >66
Compressibility index
Compressibility is the ability of powder to decrease in volume under pressure.
Compressibility is a measure that is obtained from density determinations.
% Compressibility = (Tapped density – Bulk density/Tapped density)*100

Compressibility measures gives idea about flow property of the granules as per
CARR’S Index which is givan in table.
Hausner Ratio
Flow property is very important parameter to be measured since it affects the
mass of uniformity of the dose. It is usually predicted from Hausner Ratio and
Angle Of Repose Measurement.
Hausner Ratio = Tapped Density / Bulk Density
Scale for CI & HR
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

28. 37. Injection Recomended excess volume to be added (USP):

Label size For mobile liquids For viscous liquids
0.5 ml 0.10 ml 0.12 ml
1.0 ml 0.10 ml 0.15 ml
2.0 ml 0.15 ml 0.25 ml
5.0 ml 0.30 ml 0.50 ml
10 ml 0.50 ml 0.70 ml
20 ml 0.60 ml 0.90 ml
30 ml 0.80 ml 1.20 ml
50 ml or more 2 % 3 %

38. STANDARD MESH SIEVE SIZES

Sieve Designation
Standard
Sieve Designation
Alternate "Mesh" ASTM
Sieve Designation Alternate
"Mesh" BSS
Nominal Wire Diameter (mm)
125 mm 5 8
106 mm 4.24 - 6.3
100 mm 4 - 6.3
90 mm 3 1/2 - 6.3
75 mm 3 - 6.3
63 mm 2 1/2 - 5.6
53 mm 2.12 - 5
50 mm 2 - 5
45 mm 1 3/4 - 4.5
37.5 mm 1 1/2 - 4.5
31.5 mm 1 1/4 - 4
26.5 mm 1.06 - 3.55
25 mm 1 - 3.55
22.4 mm 7/8 - 3.55
19 mm 3/4 - 3.15
16 mm 5/8 - 3.15
13.2 mm 0.53 - 2.8
12.5 mm 1/2 - 2.5
11.2 mm 7/16 - 2.5
9.5 mm 3/8 - 2.24
8 mm 5/16 - 2
6.7 mm 0.265 - 1.8
6.3 mm 1/4 - 1.8
5.6 mm No. 3.5 - 1.6
4.75 mm No. 4 - 1.6
4 mm No. 5 4 1.4
3.35 mm No. 6 5 1.25
2.8 mm No. 7 6 1.12
2.36 mm No. 8 7 1
2 mm No. 10 8 0.9
1.7 mm No. 12 10 0.8
1.4 mm No. 14 12 0.71
1.18 mm No. 16 14 0.63
1 mm No. 18 16 0.56
850 µ No. 20 18 0.5
710 µ No. 25 22 0.45
600 µ No. 30 25 0.4
500 µ No. 35 30 0.315
425 µ No. 40 36 0.28
355 µ No. 45 44 0.224
300 µ No. 50 52 0.2
250 µ No. 60 60 0.16
212 µ No. 70 72 0.14

29. 180 µ No. 80 85 0.125
150 µ No. 100 100 0.1
125 µ No. 120 120 0.09
106 µ No. 140 150 0.071
90 µ No. 170 170 0.063
75 µ No. 200 200 0.05
63 µ No. 230 240 0.045
53 µ No. 270 300 0.036
45 µ No. 325 350 0.032
38 µ No. 400 400 0.03
32 µ No. 450 - 0.028
25 µ No. 500 - 0.025
20 µ No. 635 - 0.02




39. Stability Testing (Climatic Zone, Evaluation)


Distribution of nations into different climatic zones:





Batches to be tested:



Region Zones I & II Zones III & IV
European All countries -
American Chile, Canada,
United States
Brazil, Jamaica,
Venezuela
Asian China, Japan,
Turkey
India, Philippines, Sri Lanka
African South Africa,
Zambia,
Zimbabwe
Botswana, Ghana,
Uganda
Australian /
Oceanic
Australia, New
Zealand
Fiji, Papua – New
Guinea



G uide
lin e
Applicability M in. no.
of batch
Size & type
N ew drug substances 3 Pilot scale IC H
N ew drug products 3 2 pilot scale, 1
s m a lle r
Products containing easily degradable
actives
3 P ilo t o fu ll s c a le
production
Products containing established and
stable substances
2 D ifferent production
batches
WHO
•O ngoing stability N o.of batches W H O requirem ent
•O ne batch per year
•O ne batch alternate year (for stable products)
•O n e b a tc h e v e ry 3 – 5 y e ars (if stab ility p ro file is a v a ila b le )
Bulk drug substances 1 Pilot scale
Sim ple dosage form s 1 Pilot scale
USFDA
O thers, including com plex dosage
form s and drug products without
significant body of inform ation
3 2 pilot scale, 1
s m a lle r
Existing active substances 2 or 3 Production scale
C onventional dosage form s containing stable actives
2 P ilo t s c a le
CPMP
C ritical dosage form s (prolonged
release form s) or when active
substances are known to be unstable
3 2 pilot scale, 1
s m a lle r

30. EVALUATION OF STABILITY DATA TO ESTABLISH
SHELF LIFE - For Drug Products
RE-TEST DATE - For Drug Substances


X Y
Accelerated
(6months)
Long Term
(9 months OK)
y = 2x
Shelf life / re-test date is 18
months
Accelerated
(6months)

Long Term
(12 months OK)
y = 2x
Shelf life / re-test date is 24
months
Accelerated
(6months)

Long Term
(18 months OK)

y = x + 12
Shelf life / re-test date is 30
months
Accelerated
(6months)

Long Term
(24 months OK)
y = x + 12
Shelf life / re-test date is 36
months
Accelerated
(6months)
Long Term
(36 months OK)

y = x
No extrapolation beyond 36
months



EVALUATION OF STABILITY DATA TO ESTABLISH
SHELF LIFE For Drug Products RE-TEST DATE For Drug Substances
If accelerated stability data for 6 months is NOT OK.


X Y Accelerated
(6months)
Intermediate
12 months OK
y = 1.5x
Shelf life / re-test date is 18
months

Accelerated
(6months)

Intermediate
9 months OK

y = 1.5x
Shelf life / re-test date is 13.5
months

Accelerated
(6months)

Intermediate
9 months NOT OK
& if long term
9 months OK

y = x + 3
Shelf life / re-test date is 12
months


40. SIGNIFICANT CHANGE
What does significant change means...
For Drug Substance: Failing to meet its specification.
For Drug Products:
9 5% assay variation from its initial value.

31. 9 Failure to meet the acceptance criteria for potency when using biological /
immunological procedures.
9 Any degradation products exceeding acceptance criteria.
9 Failure to meet acceptance criteria with respect to:
1 Appearance 2 Color 3 Phase separation
4 Re-suspendibility 5 Caking 6 Hardness
7 pH 8 Dissolution on 12 units
Some acceptable factors such as softening of suppositories & melting of
creams may be
accepted at accelerated conditions.

41. Photo stability - Light source:
Option 1: Artificial daylight fluorescent lamp combining visible and UV outputs,
xenon or metal halide lamp. or
Option 2: A cool white fluorescent lamp & a near UV fluorescent lamp having a
spectral emission range from 320 nm to 400 nm
Level of exposure for stability study:
1.Overall illumination of not less than 1.2 million lux hours and an integrated near
UV energy of not less than 200 watt hours/m2. This can be monitored by either
Quinine actinometry, calibrated radiometers or lux meters
2.To exclude the thermal effect, a protected control sample (wrapped in
aluminum foil) may be exposed side by side.








42.WHAT IS SUPAC GUIDANCE?
•A communication that represents the best scientific judgement of the Agency at
this time regarding certain scale-up and post-approval issues:
•TYPES OF SUPAC CHANGES
1.Components and Composition
2. Site Changes
3. Batch Size (Scale-Up/Scale-Down)
4. Manufacturing (Equipment/Process)
Level I changes
:
Which are unlikely to have any detectable impact on formulation quality
and performance
Level II changes:
Which may have significant impact on formulation quality and performance
Level III changes:
Which have a significant impact on formulation quality and performance.

43. Types of tablets
1:-ORAL TABLETS FOR INGESTION:
Standard compressed tablets
B) Multiple compressed tablets

A) Layered tablets – two to three component system.
B) Compression coated tablets – tablet within a tablet.

C) Inlay tablet – coat partially surrounding the core.

32. Modified release tablet
Delayed action tablet
Targeted tablet
I.Gastro retentive Tablet
II. Colonic tablets
F) Chewable tablet
G) Dispersible tablet

2: -TABLETS USED IN THE ORAL CAVITY
A) Lozenges and troches
B) Sublingual tablet
C) Buccal tablet
D) Dental cones
E) Mouth dissolved tablet

3: - TABLETS ADMINISTERED BY OTHER ROUTES:
A) Vaginal tablet
B) Implants

4: -TABLETS USED TO PREPARE SOLUTION
Effervescent tablet
Hypodermic tablet
Soluble tablet






44. Tablet excipient:

TYPE EXCIPIENT FUNCTION EXCIPIENT
Diluents or Fillers Diluents make the required
bulk of the tablet when the
drug dosage itself is
inadequate to produce
tablets of adequate weight
and size.
Starch, Powdered
cellulose,
Microcrystalline cellulose,
Calcium phosphates
Lactose, sucrose,
mannitol, sorbitol etc.
Binders or
Granulating agents
or Adhesives
Binders are added to tablet
formulations to add
cohesiveness to powders,
thus providing the necessary
bonding to form granules,
which under compaction
form a cohesive mass or a
compact, which is referred
to as a tablet.
Sucrose, Liquid glucose,
Acacia, Tragacanth,
Gelatin, Starch paste,
Pregelatinised starch,
Alginic acid, Cellulose,
HPMC, HPC, Sodium
carboxy methyl cellulose,
PVP, PEG, Polyvinyl
alcohol, Polymethacrylate

Disintegrants A disintegrant is added to
most tablet formulations to
facilitate a breakup or Starch USP(5-20), Starch
1500(5-15), Avicel
®
(PH
101, PH 102) (10-20),

33. disintegration of the tablet
when placed in an aqueous
environment. Solka floc
®
(5-15), Alginic
acid (1-5), Na alginate (2.5-
10), Explotab
®
(2-8),
Polyplasdone
®
(XL)(0.5-5),
Amberlite
®
(IPR 88) (0.5-5),
Methyl cellulose, Na CMC,
HPMC (5-10), Cellulose
and its derivatives,
Microcrystalline cellulose
(MCC), Alginates,
Polyplasdone®XL
,Polyplasdone®XL10,
Superdisintegrants
Crosscarmellose
®
,

Ac-Di-
Sol
®
,Nymce ZSX
®
,Primellose
®
,

Solutab
®
,Vivasol
®
, Crosspovidone,
Crosspovidon M
®
,

Kollidon
®
,

Polyplasdone
®
,Sodium
starch glycolate Explotab
®
,

Primogel
®
Alginic acid,NF
Satialgine
®
,

Soy
polysaccharides,Emcosoy
®
,

Calcium silicate
Antifrictional Agents
Lubricants Lubricants are intended to
reduce the friction during
tablet formation in a die and
also during ejection from die
cavity.
Streates(Mg. Streate, Ca.
Streate, Na Streate) Talc,
Waxes, Glyceryl
Behapate, Liquid paraffin
Antiadherents Antiadherents are added to
reduce sticking or adhesion
of any of the tablet
granulation or powder to the
faces of the punches or to
the die wall.
Talk, Corn starch,
Colloidal silica, Sterates,
SLS, DL-leucine
Glidants Glidants are intended to promote the flow of tablet granulation or powder
mixture from hopper to the
die cavity by reducing
friction between the
particles.
Starch (10%) , colloidal
silica i.e. syloid,
pyrogenic silica (0.25%),
hydrated sodium
silioaluminate (0.75%)
are also successfully
used to induce flow.
MISCELLANEOUS
Wetting agents Wetting agents are added to
tablet formulation to aid
water uptake during
disintegration and assist
drug dissolution.


SLS, Sodium diisobutyl
sulfosuccinate (used for
hydrophobic drugs)
Dissolution Dissolution retardants as the Waxy material like

34. retardants name suggest, retards the
dissolution of active
pharmaceutical
ingredient(s). stearic acid
and their
esters (for controlled
release of drug)
Dissolution enhancers
Dissolution enhancers as the name suggest, enhance the dissolution rate of active
pharmaceutical
ingredient(s). Fructose
, Povidone,
Surfactants
Adsorbents Adsorbents are capable of
retaining large quantities of
liquids without becoming
wet; this property of
absorbent allows many oils,
fluid extracts and eutectic
melts to be incorporated into
tablets.
anhydrous calcium
phosphate,
starch
,
magnesium carbonate,
bentonite, kaolin,
magnesium silicate,
magnesium oxide
and
silicon dioxide.
Buffers Buffers are added to provide suitable micro environmental pH to get improved stability
and / or bioavailability.
sodium bicarbonate,
calcium carbonate, and
sodium citrate.
Antioxidants Antioxidants are added to maintain product stability, they act by being
preferentially oxidized and
gradually consumed over
shelf life of the product.
ascorbic acid and their
esters , alpha-tocopherol
, ethylene diamine tetra
acetic acid , sodium
metabisulfite , sodium
bisulfite , Butylated
Hydroxy Toluene (BHT) ,
Butylated Hydroxy
Anisole (BHA) , citric acid
, and tartaric acid .
Chelating agents Chelating agents are added
to protect against
autoxidation; they act by
forming complexes with the
heavy metal ions, which are
often required to initiate
oxidative reactions.
Ethylenediamine
tetracetic acid and its
salts, Dihydroxy Ethyl
Glycine, Citric Acid and
Tartaric Acid
Preservatives Preservatives are added to
tablet formulation in order to
prevent the growth of
microorganisms.
Parabens like methyl,
propyl, benzyl, butyl p-
hydroxy benzoate are
used as preservatives.
Colours Colours are added to tablet
formulation for following
purposes: to disguise off
colour drugs, product
identification and for
production of more elegant
product.
Erythrosine, Allura red
AC, Tartrazine, Sunset
yellow, Brilliant blue,
Indigotine, Fast Green.
Flavours Flavours are added to tablet
formulation in order to make
them palatable enough in
Oil or aqueous Flavours
are added.

35. case of chewable tablet by
improving the taste.
Sweeteners Sweeteners are added to tablet formulation to improve the taste of chewable
tablets.

Sucrose, Dextrose,
Mannitol, Lactose,
Saccharine, Cyclamate,
Aspartame etc.

45. SUSPENSION INGRIDIENTS

TYPE OF
INGREDIENT
FUNCTION EXAMPLE
Drug Ideally, one would prefer a uniform Size; however size
reduction is carried out for uniform size distribution,
Wetting Agent Wetting agents are surfactants that reduce the
Surface tension of an
aqueous medium, coat
the surface of suspension
particles, and thereby
Facilitate the wetting of each
particle. The goal is to
displace air from the particle
surface and to separate each
particle from adjacent
particles Using the minimum
concentration necessary
SLS (Anionic), Docisate
sodium (Anionic),
Polysorbate 80
(Nonionic)
Suspending Agent Suspending agents are
materials added to
suspensions to
increase viscosity and retard
sedimentation. Most
suspending agents are either
neutral or
negatively charged and
generally effective in a
concentration range of 1 to
5%.


Methylcellulose (N1-5%),
HPMC (N 0.3-2%),
Sodium
carboxymethylcellulose
(A 1-2), MCC with Na
carboxymethylcellulose
(A 0.5-2),Bentonite (A 1-
6), Mg Allu. Silicate (A
0.5-5), Carbomer (A 0.1-
0.4), Povidone (N 5-10),
Xanthan gum (A 0.3-3),
carrageenam (A 1-2)
Protective Colloid A protective colloid is a
polymeric suspending agent
absorbed on the surface of a
hydrophobic suspension
particle giving the particle a
hydrophilic surface.


Flocculating Agent Flocculating agents enable
suspension particles to link
together in loose aggregates
or flocs. These flocs settle
Electrolytes, surfactants,
and polymers;

36. rapidly but form a large fluffy
sediment which is easily
redispersed.

Sweetener Sweeteners are added to suspensions to produce a more palatable preparation, to
cover the taste of the drug
and other ingredients.

Sucrose, Mannitol,
Sodium Saccharine,
Aspartame etc.
Preservative Preservatives are required in most suspensions because suspending agents and
sweeteners are good growth
media for microorganisms.

Ethanol (>20), Propylene
Glycol (15-30), Benzyl
Alcohol (0.5-3),
Quaternary Amines,
Benzalkonium Chloride
(0.004-0.02), Sorbic Acid
(0.05-0.2),
Benzoic Acid (0.1-0.5),
Methylparaben (0.2),
Propylparaben (0.05)


Buffer The optimal pH is chosen to
minimize solubility of the drug,
control stability of the drug,
and to ensure compatibility
and stability of other
ingredients

Flavor Flavoring agents enhance
patient acceptance of the
product, which is particularly
important in pediatric patients

Colour Colorants are intended to
provide a more aesthetic
appearance to the final
product.


Sequestering
Agent
Sequestering agents may be
necessary to bind metal ions
to control oxidative
degradation of
Either the drug or other
ingredients.




46. Parameters used in IVIVC

37. 47. Zeta potential
Colloidal particles dispersed in a solution are electrically charged due to their
ionic characteristics and dipolar attributes.
Each particle dispersed in a solution is surrounded by oppositely charged ions
called the fixed layer. Outside the fixed layer, there are varying compositions of
ions of opposite polarities, forming a cloud-like area. This area is called the
diffuse double layer, and the whole area is electrically neutral.
When a voltage is applied to the solution in which particles are dispersed,
particles are attracted to the electrode of the opposite polarity, accompanied by
the fixed layer and part of the diffuse double layer, or internal side of the "sliding
surface".

38. Zeta potential is considered to be the electric potential of this inner area including
this conceptual"sliding surface". As this electric potential approaches zero,
particles tend to aggregate.
Zeta Potential (Smoluchowski’s Formula)





48. EMULSION INGRIDIENTS
TYPE OF
INGREDIENT
FUNCTION EXAMPLE
Drug A drug can be dissolved or disper sed in either the oil or aqueous
phase of an emulsion, which serves as the vehicle. This mode of
drug incorporation can be used for oral and/or topical
administration.
Oil phase The consistency of the oil phase
can be altered by the addition of
waxes, such as beeswax or
paraffin wax, or waxy solids,
Vegetable or mineral oil

39. such as fatty alcohols, acids, or
esters, e.g., cetyl alcohol, stearic
acid, or glycerol monostearate.
Aqueous phase The aqueous phase is composed
of the water soluble components in a formulation,

Thickening agents Thickening agents are materials
added to an emulsion to increase viscosity and retard
sedimentation.
Acacia, Tragacanth
Sweeteners Sweeteners are added to
emulsions to produce a more
palatable preparation.
Sorbitol, corn syrup and
Sucrose, sodium saccharin
and aspartame,
Preservative Preservatives are required in most emulsions because thickening (suspending)
agents, emulsifiers and
sweeteners are good growth
Media for microorganisms.

Buffer The optimal pH is chosen to
ensure activity of the emulsifier,
control stability of the drug and
to ensure compatibility and
stability of other ingredients.

Flavour Flavoring agents enhance
patient acceptance of the
product, which is particularly
important for pediatric
patients.

Colour Colorants are intended to
provide a more aesthetic
appearance to the final
product.
Emulsions are generally not
colored with the exception of
some topical products.

Sequestering agents Sequestering agents may be
necessary to bind metal ions in
order to control oxidative
degradation of either the drug or
other ingredients.

Humectants Humectants are water soluble
polyols that prevent or hinder
the loss of water from semi-
solid emulsions,
Glycerin, propylene glycol,
sorbitol



Antioxidants Antioxidants are often added to
prevent oxidation of vegetable oils and/or the active drug.
Water soluble: Na. Bisulfite, Pot. Metabisulfite, Lipid soluble: Butylated
hydroxyanisole, Butylated
hydroxytoluene, Alpha
tocopherol
Emulsifiers Emulsifiers are substances that O/W Acacia, Lacithin,

40. have the ability to concentrate at
the surface of a liquid or
interface of two liquids, many of
them reducing the surface or
interfacial tension.
Potassium laurate,
Triethanolamide stearate,
SLS,W/O Cholestrol, Sorbitan
fatty acid esters, Depends on
phase vol. Ratio- Bentonite,
Magnesium hydroxide,
Surfactants are added like
Sorbitan monoleate,
Polysorbate 80, Polyoxyl 40
stearate,



























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:

41. 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) V
d
b) K
el
c) AUC
d) Clearance
e) T
max
f) C
max
g) T
1/2
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

42. 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 25
0
C
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

43. 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 25
0
C±1
0
C
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)







2.Aqueous solubility to be checked at various pH levels ranging from 1 to 8 at
37±1
0
C. It is done at least at:
pH = pKa
pH = pKa +1
pH = pKa –1
pH=1
pH=7

To be performed if sufficient data not available in literature.
Use the highest dose streanght in 10 ml of following. Add measured volume of
respective solvent in increament of 10 ml. the maximum volume can be 250 ml

44. In case of aqueous solubility is less than 0.3 %, use the solubility improving
techniques for improving the in vitro solubility. Check the solubility in :

*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

Determine the pH of solution in which drug is soluble to maximum extent
Determine the saturation solubility point

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 37
0
C to be done against freshly prepared
solution at predecides interval for 8 hr
Report the assay and % degradation.










Selection of comparator product and its dissolution criteria and its
dissolution criteria and preparation of tentative specification for target
product

For development of generic version of the reference drug product, the
requirement is to establish the pharmaceutical equivalence, bioequivalence, and
therapeutics equivalence of test product witj that of reference product.
Justification for the selection:
Following are the basic guideline for the selection of comparator product

45. 1. Innovator product
2. Reference listed product
3. Pioneer product
Procure reference product from 2-3 batches from different markets and if
possible in smallest and largest pack size

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


















API: Excipients compatibility study and Excipients selection
API Forced degradation study:

Stress
factor
Conditions Concentration of
API
#

Time Evaluation
parameter
Heat 60
0
C API only 15 Days Visual
&chemical

46. Humidity 40
0
C with 5%
moisture in
sealed glass
vial
Solid state API 15 Days Visual
&chemical
Acid 0.1 N HCL at
25
0
C
2:1 in 0.1 N HCL 1-10 Days Chemical
Base 0.1 N NaOH at
25
0
C
2:1 in 0.1 N HCL 1-10 Days Chemical
Oxidation 3% H 2O2 at
25
0
C
1:1 in 3% H
2O2 1-3 hours Chemical
Solution
stability
Rom temp.
solution stability
study at
different pH
2%
solution/suspension
over pH range of
1.2 to 8.0
4-24 hour Visual &
chemical
Photolysis
(Optional)
Expose the test
compound to
1.2 million
lux.hr florescent
light and to
near UV energy
of not less than
200 watt
hours/m
2
.
Metal halide,
Hg, Xe, or UV-
B fluorescent
lamp
1:1 with diluent 1-10 Days Visual $
Chemical
Metal ions
(Optional)
0.05 M Fe 2+ or
Cu
2+
1:1 with solution of
metal ions
1-10 days Chemical
Control sample
2-8
0
C Solid state API 15 Days If required
# - when testing degradability of APIs in combination, the APIs should be in same
ratio as in the FDC.
- In each case, the diluent is either an excipients or all excipients in the
formulation in the same ratios as in the formulation.
Observation summary and conclusion:

Procurement and evaluation of suitable container-closure system
Quality control of packaging components

A. Primary packaging materials:
Manufacturer’s Name and Address:


Sr.No. Parameter Observation
Physical characteristics
1. Description
2. Dimentional criteria:
Shape
Neck
Finish

47. Wall thickness
3. Design tolerances
4. Unit weight/grammage
5. Vapour transmission rate
6. Light resistant test
Performance characteristics
1. Metering valve delivery volume
Chemical Composition
1. Materials of construction
2. Extraction profile for the polymeric and
elastomeric components*


• *For inhalation drug products for which batch-to-batch monitoring of this is
routine.

A. Primary packaging material: Same table as above.
B. Associated components:
Associated components are packaging components that are typically
intended to deliver the dosage form to the patient but are not stored in contact
with the dosage form for its entire self life.