o Pressure: 1atm
Electrochemical Method
A Potentiometry Top 5 strongest oxidizing
Branch of electrochemistry agents
which deals with the study and
1. Fluorine
measurement of electrode
2. H2O2
potential
3. MnO4
Potentiometer 4. Chlorine
5. Cr2O7
Tool used in potentiometry
Top 5 strongest reducing
APPLICATION
agents
1. pH determination
1. Li
2. titration endpoint
2. Na
A.1 Electrode Potential 3. Al
electric potential difference 4. 2H2
between an electrode and 5. Zn
surrounding electrolyte solution
A.2 Principle
when no current is flowing
When the pair of electrodes is
through the cell
placed in the sample solution it
Standard Electrode shows the potential difference
by the addition of titrant.
Potential
electrode potential measured A.3 Electrode
under standard conditions Used to measure voltages
o Concentration: 1M o Reference electrode
o Temperature: 25C o Indicator electrode
Reference Electrodes Consists of a thin membrane
where only ion can be
Known potential
transported
Primary standard electrodes
Standard Platinum
Hydrogen wire in
Electrodes inverted
glass tube
EP is ZERO
at all temp
Secondary standard
electrodes
Silver-silver Most widely
chloride marketed Glass Electrode
Electrode reference
Most widely used indicator
electrode
KCl saturated electrode
with AgCl Selective
Saturated Hg at Responsible for changes in
Calomel bottom concentration of hydrogen ions
Electrode covered with
solid HgCl2 Advantages Disadvantage
EP: s
+0.2422V 1. Rapid 1. Can be
response easily
Indicator Electrodes 2. Chemically broken or
resistant to damaged
Unknown potential
REDOX 2. Minute
Potential sensitive to agents abrasions,
concentration of analyte damage the
Potential is directly proportional electrode
to the ion concentration
Quinhydrone Electrode
Glass pH Least expensive
Electrode measurement
Equimolar mixture of quinone
Ion-selective Drug assay
Electrode and hydroquinone, and a
Redox REDOX analysis platinum foil electrode
Electrode Potential depends on pH
Quinhydrone Selective pH Acidic or organic solvent-
Electrode measurement based solutions
Ion Selective Indicator
A.4 Salt Bridge
AKA: SIE (Selective Ion Indicator)
Laboratory device used to Cathode: Positive
connect two half cells of
Anode: negative
galvanic or voltaic cell
o Salt should be inert B Theory
o Must nor react with
When the known potential
solution electrode immersed in the
o Should not precipitate sample solution then the
NaCl, KCl, KNO2 potential is given by Nernst
equation
A.5 Set Up
1. Separate solutions Nernst Equation
o Connected by a salt
E= E*+(0.0592/n) log c
bridge
2. Single solution
o Combination electrode Quality Assurance &
Quality Control
A Quality
Combination of attributes or
characteristics of a drug, which
when compared to a standard,
serves as a basis for measuring
the conformity of the product
and determines its degree of
acceptability
Measurable Criteria
Conforman Being within
ce prescribed
Fitness for Functionality 2. Raw Material Specification
use [RMS]
Reliability Function in a. Characteristics are
specified pharmacopeial
environment for a
b. International standard
prescribed length
of time 3. Standard Operating
Yield High degree of Procedures
acceptable units a. Says how to do the
Customer Product is safe, procedure
satisfaction pure, and b. Can be in house or
effective pharmacopeial
4. Finished Product
Specification
B Standards
a. Ready to market
b. Based on regulatory
Pharmacop Published standard
eial monographs 5. Packaging Material
USP/NF, BP, EP Standard
Identity, a. In-house
physical tests,
6. Testing Method
alcohol
content, etc. a. Pharmacopeial and in-
Regulatory Mandated by house
regulatory b. Can make own method
agencies but must be
FDA, WHO standardized and
Labelling validated
requirements
In-House Unofficial
In compliance
to GMP C QM; QA; GMP; QC
Generated by
manufacturer
Standards must cover the
FF:
1. Formula
a. In-house
b. Pharmacopeial
standard
C.1 Quality Management Quality Risk Management
Quality policy (QRM)
Intention to have a quality
Systematic process for the
product assessment, control,
communication, and review of
Total Quality Management risks to the quality of the
product
Combined team effort
C.2 Quality System E Documents
Infrastructure; organizational
Monograph
structure
Specifies all tests to be
conducted and the expected
C.3 Quality Assurance
results
Overall systemic action to meet
the quality policy Standard Operating
Totality of the organized
Procedure
arrangements
Shows the actual result of all
C.4 GMP tests conducted on a material
to show compliance with
Good Manufacturing Practices standards
Part of QA
Tool to meet quality of the Material Safety Data Sheet
product (MSDS)
C.5 Quality Control Contains information on the
potential health effects of
Part of GMP exposure to chemicals and on
Test if you have a good quality safe working procedures when
product handling chemical products
D Other Def. of Terms E.1 Official References
1. USP-NF
Product Quality Review 2. Japan Pharmacopeia
3. British Pharmacopeia
(PQR) 4. European Pharmacopeia
Regular periodic quality reviews of 5. International Pharmacopeia
all registered drug products
Identify product and process E.2 Unofficial References
improvements 1. China Pharmacopeia
2. India Pharmacopeia
3. Philippine Pharmacopeia
E.3 Complete Monograph The process of removal of
Chemical structure an appropriate number of
Chemical name items(n) from a population
Purity rubric (N)
Packaging and storage
Reference standard Three numbers required:
Identification tests
Corresponding tests for physical o N (population)
and chemical constituents o N (sample)
(Melting range, Refractive o Ac/c (acceptance)
Index)
Water content
Assay procedure
Population
totaling of all actual or
conceivable items of a
General Chapters certain class under
71 Sterility test consideration
85 Bet
281 Residue on Ignition Random sample
616 Bulked density & Tapped sample chosen in such a
density
manner that one object
621 Chromatography
701 Disintegration has a good chance of
711 Dissolution being selected as another.
786 Particle size distribution
788 Particulate contamination F.1 Acceptance Quality
811 Powder fineness Limit
905 Uniformity of dosage units AKA AQL
117 Powder flow
4 the ABC standard definition
121 Tablet friability
(America, Britain, Canada)
6
the maximum percent
defective or max number
F Sampling Plan of defects per 100 units
Definite working rule low value = serious
regarding the size and defects
frequency of sample, and high value = trivial
the basis for acceptance defects
or rejection based on the master table
Acceptance no. is
specified by AQL
N plan/ Square root system determination of
quality variation and
making inferences of
the entire batch
Quality Control Charts
1. Attribute Chart
F.2 Government Sampling Discrete data
Plan classifying no. of items
Master table is used to conforming and not
know then, AC and Re conforming to any
specified requirements
Two tables:
P chart (fraction
1. table for sampling by defective)
attributes 2. Variable Chart
a. MIL-STD-105D 105E Actual records of
b. ABC-STD- 105D numerical
2. table for sampling by measurement on a full
variables continuous scale
a. MIL-STD-414 X, R charts
G.1 Control Chart
Graphs on which the
Required information
quality of the product is
i. Batch size, AQL and plotted as
sample size code letter manufacturing is
ii. Method of sampling actually proceeding
inspection
iii. Inspection scheme: Types
normal, tightened or P-chart Proportion of
reduced defectives
Np-chart Non-proportion (no.
G Statistical Quality of defectives)
Control X bar Used for measurable
Monitoring of quality by chart characteristics
the application of
statistical methods in Warning limit
all stages of production
Alerts the operator to
Consist of proper
closely monitor the
sampling,
process
Action limit o Systematic
Alerts the operator to 3. VALIDATION OF
stop the process and MANUFACTURING
do corrective action EQUIPMENT
4. VALIDATION OF EXISTING
H Validation Vs PRODUCTS
Related to the efficiency of
Qualification
the product
o (potency, content
Validation action of proving uniformity, dissolution/
and documenting bioavailability)
that any process, Concern with processing
procedure or
characteristics
method actually
leads to the o (Moisture content,
expected results weight variation)
Qualificati action of proving 5. CLEANING VALIDATION
on that premises, Utilized instruments that can
systems or detect microgram levels of
equipment work
contaminants form product
correctly and
actually lead to and detergent residue
expected results. 6. POST-VALIDATION
H.2 Product Defects
H.1 Types of Validation Non-conformance to a
standard or requirement
1. PROCESS VALIDATION Classifications
2. ASSAY VALIDATION
According to magnitude
it is established by
laboratory studies that Critical May endanger life
the performance defect of patient
characteristics of the Major Does not endanger
defect but affects function
method meet the
of product
requirements of the
Minor Does not endanger
intended analytical defect nor affect function
applications of product
Sources of errors:
According to measurability
o Gross
o Random Variable Measured by
defect instrument Primary step in the
Attributive Measured by quality procedure
defect inspection
(steps)
According to nature 1. Inspection
2. Analysis
Ocular Can be seen by 3. Actions
defect the naked eye
Internal Cannot be seen by J Stability Studies
defect the naked eye
Performanc Defect in function Used to estimate the shelf-
e defect (major defect) life of a drug product
Evaluated over time in the
same container-closure
H.3 Product Recall system in which the drug
Removal of product from the product is marketed
market because it is either Based on ASEAN Guidelines
defective or potentially on Stability Studies
harmful
J.1 Stability
Classification Capacity of a drug to remain
Class I May cause within specification
death or Minimum Acceptable
serious adverse Potency: 90%
health
consequences Factors
Class II Temporary/
medically
reversible
adverse health
consequences
Class III Not likely to
cause adverse
health
consequences
I Inspection
Comparison of attributes and
dimensions of a product
against specifications to find
out if product is within limits
Drugs are mainly and after which it must not
be used
decomposed by:
Hydrolys Prevented by Formula
is reduction or ED= MD + SL
elimination of water
from the preparation ED: expiration date
Oxidatio Prevented by
n antioxidants MD: manufacturing date
Photolys Prevented by using SL: shelf life
is light-resistant
containers
J.2 Shelf-life
Period of time during which a
product is expected to
remain within specification
Estimated using the
Arrhenius equation
REASSAY Climatic zone
Unstable Monthly, prior
to use
Vitamins 6 months
Drugs & 1 year
dyes
Drugs & 2 years
excipients
Shelf-life/
reformulation?
?
Highly Months or prior
unstable to use
vitamins 6 months
Drugs & 1 year
Dyes Philippines: Zone IVB
Drugs & 2 years
Types of stability studies
excepients
Long- Normal conditions
term Period: 0, 3, 6, 8,
J.3 Expiration Date studies 12, 15, 28, 24, 36
Time/date to which a product Accelerat Increase the rate of
is expected to remain stable ed chemical
studies degradation by using
exaggerated storage
conditions
Period: 0, 3, 6
Stress Elucidates the
testing intrinsic stability of
the drug substance
and identify the
likely degradation
products
More severe
conditions
A.2 Warehouse Distribution
Practices
1. First in-First out [FIFO]
move first stocked products/
Electrochemical Method products bought first
2. First expiry-first out
[FEFO]
A Handling of Raw Move first the products
Material whose expiration dates are
earlier
A.1 Quarantine B Identification Test
Status of materials which are To confirm the identity of a
isolated physically while a chemical substance
decision is awaited on their
Chemical 1. Color
release, rejection or
methods reactions
reprocessing 2. Precipitation
Yello Quarantine materials 3. Evolution of
w gas
Gree Conform to tests Physical 1. Appearance
n methods 2. Odor and
Red Rejected taste
3. Solubility
Instrumen 1. Spectroscopy
tal 2. chromatograp
methods hy o Based on measurement
of transmittance
C Assay
to determine the amount of
API/ biologic activity
Methods
1. Chemical assay
a. Titrimetry
b. Instrumental methods
D Limit Test
2. Biologic assay
To measure small amounts of
a. Animal assay
impurities in a raw material
D.1 Types of Impurities
Gross Dirt/ insoluble
impurities matter
Biological Microorganism
b. Microbial assay Impurities
Methods: Chemical By-product,
Impurities degradation
I. Cylinder plate method products,
o Uses a cylinder or reagents, etc.
paper disc impregnated
with sample, placed on
a solidified nutrient
medium in a Petri dish
o Based on diameter of E Physical Tests
zone of inhibition Can be used for identification
II. Turbidimetric method and determination of
o Uses a test tube filled concentration of a
w/ fluid nutrient component
medium, where test Used to determine the
organism is inoculated presence of impurities
E.1 Specific Gravity
Ratio of the density of a
substance to a reference
o 25C
Pycnometer or Mohr- Dextrorotatory or
Westphal balance levorotatory
Polarimetry
Alcohol
Measured using a hydrometer E.4 Solubility
at 15.16C
E.2 Refractive Index (n)
Ratio of the velocity of light
in the air to the velocity of
light in the substance
o 25C
Abbe refractometer
EXAMPLE QUESTION
WHAT IS THE SOLUBILITY OF A
DRUG IF IT REQUIRES 100ML OF
SOLVENT
PER 100MG OF DRUG?
Solution:
Formula Solubility = 100mg/100mL
N = sin I / sin r Determine how many mL
per 1gram solute (1000mg)
[i= angle of incident; r = angle of 100mg = 0.1g
refracted ray] 0.1g/100mL=1g/x
x = 100ml/0.1g
E.3 Optical Rotation (a) x = 1,000 mL/g
Measure of its ability to
rotate an incident plane of Solubility = 1,000 parts
polarized light
Therefore, the solution is very
slightly soluble
E.5 Boiling/ Freezing Point Azeotropic Distillation
Indicates presence of Based on distillation of water
impurities Toluene or Xylene
(alternative)
Toluene-moisture apparatus
Gravimetry
Based on loss on drying
E.6 Loss on Drying Inorganic 110-120C
materials
Determines the amount of
Organic 105C
volatile matter driven off materials
after drying
E.7 Water Determination Water Content
(official Methods)
Karl-Fischer Titrimetry
Based on the reaction of
water and KFR
KFR Components Formula
Sulfur dioxide Main
Iodine component
Pyridine
Anhydrous
Methanol V = mL of KFR (Karl-Fischer
Reagents)
Types F = water equivalence factor
Method IA Direct Wt: mg of sample
Method IB Residual
Method IC Coulometric EXAMPLE QUESTION
CALCULATE THE WATER CONTENT
OF STREPTOMYCIN POWDER
WEIGHING 4.20G AS A SAMPLE.
THE WATER EQUIVALENT FACTOR
OF THE KARL FISCHER REAGENT
WAS FOUND TO BE 5.1, AND THE
VOLUME CONSUMED WAS
[Link] % WATER IS?
Solution:
Given: V: 11.50; F: 5.1; Wt: 4.20g
(4200mg)
%water =[(v * F)/Wt] x 100
%water =[(11.50* 5.1)/4200] x
100
%water =1.40%