Introduction to Pharmaceutical Analysis
Quality
— Sum of all factors which contribute directly or
indirectly to the safety, effectiveness, and
reliability of the product
— Ensures that drug products are designed and
produced to meet or exceed customer
requirements for efficacy and safety
Quality Management System
- A coordinated set of activities that directs and
controls an organization with regard to
quality
Quality Control
- Application of quantitative and qualitative
pharmaceutical chemistry to the analysis of:
o Purity and quality of drugs and chemical
constituents
o Diagnostic testing for chemicals found in
the body in altered concentrations
o Analysis of medicinal agents and
metabolites in biological systems
- Considered as Process control
- Monitors activities related to analytical
examination of testing
- Goals
o Detect, evaluate and correct errors due to
system failure, environmental conditions
and operational performance
- Guarantees of QC in relation to products:
o Product is free of impurities
o Product is physically and chemically stable
o Product contains the amount of active
ingredients as stated in the label
o Product provides optimal release of active
ingredients when the product is
administered
- Types of QC processes
o Quantitative examinations
§ Measured as a numerical value
o Qualitative examinations
§ Measures presence or absence of
a substance
o Semi-qualitative examinations
§ Values are an estimate of
measured analyte, usually in a
range or a scale
o Staff of QC operations
§ Are responsible for sampling, analytical
testing of raw materials, packaging
components and labeling materials
§ Conducts monitoring of parameters like in-
process testing, environmental
monitoring, operations compliance and
release tests on dosage forms
Quality Assurance
- part of quality management focused on
providing confidence that quality
requirements will be fulfilled
- defined as planned and systematic activities
that can demonstrate a product’s capacity to
fulfill requirements for quality
- Department that is responsible for quality
policies are adopted, identification and
preparation of policies and standard
operating procedures and determines
product meets applicable specifications set by
internal standards and good manufacturing
practices
- Functions:
o Quality monitoring, audit function
Basic Principles of Pharmaceutical Analysis
Definition of Important Terms:
1. Specification- a document that contains a
list of tests, references to analytical
procedures and appropriate acceptance
criteria
a. Categories include: intended use of a
product, acceptance criteria for release
testing & stability testing
2. Compendia – a collection of data gathered
and presented in the form of a book.
Examples include: USP/NF, BP, EuPharm
3. Monograph - A written standard that
describes an article like a drug substance,
drug product, excipients or compounded
preparation
a. Contents include: name of substance,
definition, packaging requirements,
storage requirements, labelling
requirements, information on tests to
ensure identity, strength, safety,
quality and purity
 b. Guarantees include the provision 2. Precision includes three parameters
of a public standard consumed in a Parameter Analyst Operating Time Equipment
global marketplace Conditions Interval
Repeatability Same Same Short same
4. Universal Tests – are conducted to all drug Intermediate Different Same Different Same
products it includes: Precision
a. Description: appearance testing Reproducibility Different Same Different different
b. Identification: verification of identity 3. Quantification limits lowest amount of the
c. Assay: quantitative measure of compound in analyte in the sample that can be
a sample quantified (usually impurities and
d. Impurities: threshold presence of degradation products)
related/degradation substances in the drug 4. Linearity - ability of an analytical
sample procedure to obtain test results of variable
Analytical Method Validation data which are directly proportional to the
Reasons for Analytical Method Validation: concentration in the sample
1. Regulatory Requirements 5. Range – interval between the upper and
2. Proper practice of Good Science lower concentration of the analyte in the
3. Quality Control Requirements set by FDA sample
Process of Analytical method Validation includes: 6. Robustness – measure of the method to
1. Planning and deciding on the method remain unaffected by small but deliberate
validation experiments variations in method parameters during
2. Writing and approval of method validation normal usage
protocol Control of Quality in Analytical Methods
3. Analysis of the method validation data Error – defined as the difference in the numerical
4. Reporting the analytical method validation values between a measured value and the true
5. Finalizing the analytical method procedure value, Types of errors include:
Content Of a Validation Protocol Includes: 1. Determinate Errors – errors that have a
1. Objective of the protocol definite value and reasonable cause
2. Validation parameters that will be 2. Indeterminate Errors – cannot be
evaluated pinpointed and are random in nature
3. Acceptance criteria for all validation Minimization of Errors can be done by:
parameters evaluated 1. Calibration of Instruments
4. Details of the experiments to be 2. Performing a parallel control
performed determination
5. Draft analytical procedure 3. Blank determination
Information that should be included in the final 4. Cross checking of results with different
analytical procedure includes: methods of analysis
1. Rationale of the analytical procedure and 5. Method of standard addition
description of the capability of the method 6. Method of internal standards
2. Proposed analytical procedure Pharmaceutical Analysis
3. List of permitted impurities and its levels Important Terms to remember:
in an impurity assay 1. Titration – method of analysis that
4. Validation data determines the precise endpoint of the
Validation Characteristics include: reaction = identifying the precise quantity
1. Accuracy – closeness of values obtained of reactant in the titration flask
from true value (trueness) 2. Analyte – compound meant to be
assayed/analyzed
3. Titrant / Standard solution – solution of
known concentration used for analysis
 4. Indicator – solution/compound that allow
the endpoint to manifest in a titration
process
5. Equivalence point/Stoichiometric Point –
point at which titrant is chemically
equivalent to the analyte
6. Endpoint – an observable physical change
in the titration process indicating the
reach of the equivalence point
7. Primary Standard - a highly purified
compound that is used as a reference
standard in titration processes (high
purity, stable in air, independent of
humidity, readily available, reasonably
soluble, large formula weight)
8. Secondary Standard - a standard used that
does not meet requirements for a primary
standard but is available with sufficient
purity and properties to be acceptable as
such (should be standardized using a
primary standard, stable and reacts
completely and rapidly with analyte
9. Standardization - This is a process where
the concentration of a solution is
determined
10. Direct titration – a process where the
titrant is added to the analyte until a
reaction goes to.
11. Back titration (residual) - where
completion excess reagent is added to
the analyte, and then the excess of
this added reagent is determined.
Usually performed when an analyte reacts
slowly with the titrant in direct titration
processes
12. Indirect Titration - a process where a
substance is reacted with the analyte and
liberates a compound that can be
determined by titrimetric methods
Titrimetric Methods: Neutralization Reactions
(Aciddimetry and Alkalimetry)
Acidimetry – involves the analysis of inorganic and
organic alkaline/basic substances using an acid
Alkalimetry – involves the analysis of acidic
substances using a basic solution
Important things to remember in alkalimetric
titrations:
1. The normality of the solution obtained by
dissolving the acidic substance must be
approximately the same as that of the
titrant.
2. The liquid acidic substance to be titrated
must be brought to room temperature
(25°C) before titration, because many
indicators offer different values at
different temperatures
3. The quantity of acid to be taken should be
calculated in such a manner that
approximately 30 to 40 ml of the
previously standardized base shall be
utilized for the assay.
Criteria for Indicators in Acid Base Titrations
1. Can produce a sharp contrast between
two colors which it exhibits in acid and
alkaline mediums
2. The change in color will take place over a
very small range of pH values.
Rules for Use of indicators in Acid-Base Titrations
1. 3 drops of indicator should be used unless
directed
2. Strong acid + strong base =
phenolphthalein, methyl red or methy
orange
3. Weak base + strong acid =
phenolphthalein
4. Strong acid + weak base = methyl red
Titrimetric Methods: Non – Aqueous Titrations
This involves the titration of weak acids and bases
using non-aqueous titrants. Temperature should
be monitored in titration process due to high
coefficient of expansion of solvents used
Advantages of Non-aqueous titrimetry
1. Elimination of poor solubility of analytes
2. Enhancement of weak reactivity of certain
analytes
3. Selectivity of titrations using a suitable
solvent
4. Maintenance of speed, precision, accuracy
and simplicity comparable with classical
methods of analysis
Rules to observe in non-aqeous titrations:
1. Moisture and carbon dioxide should be
avoided using non aqueous procedures.
 2. Moisture should be held to less than
0.05%.
3. Standardization & titration should be
carried out as far as possible at the same
temperature because of high coefficients
of expansion common among organic
solvents.
Solvent types used in non-aqueous titrations:
1. Protophilic Solvents – basic in nature and
react with acids to form solvated protons
2. Protogenic Solvents – acidic in nature and
promotes a leveling effect on bases
3. Aprotic Solvents – chemically inert
substances and neutral in nature
4. Amphiprotic Solvents – solvents that
possess both protogenic and protophilic
properties
Titrimetric Methods: Precipitation Methods
Titrations involved here are limited to use of silver
as titrant to analytes containing halogens and
thicyanate. Due to the nature of the process, a
colored solution is necessary as an endpoint.
Limitations include:
1. Co-precipitation effects do not give a real
composition of the precipitate, and
2. Choice of appropriate indicator is very
much limited.
Parameters for a good precipitation analysis
1. Precipitate formed must be insoluble,
2. Precipitation process should be fast and
rapid,
3. Co-precipitation effects must be minimal,
and
4. Detection of equivalence point must be
apparently visible.
Titration methods:
Mohr’s Method (Direct) – determination of
chlorides using silver nitrate; indicator: Potassium
Chromate = red coloration
Volhard’s Method (Residual) – it uses ammonium
thiocyanate to determine concentration of
chlorides in a solution using nitric acid; indicator:
Ferric Ammonium Sulfate = red coloration
Fajan’s Method (Direct/Residual) – adsorption
method using adsorption dyes, change in color
marks the endpoint; indicators:
dischorofluorescien, eosin y,
tetrabromophenolphthalein ethyl ester.
Titrimetric Methods: Complexation Methods
Complexation Methods are based on complex
formation between the analyte and titrant and is
used for titration of polyvalent metal ions using
EDTA as titrant
Terms to remember in Compleximetric Titrations:
1. Complex – formed by the combination of a
metal ion with a molecule capable of
donating electrons
2. Chelate – complex formed between a
polyvalent metal ion with a molecule that
can donate electrons
3. Ligand – molecule that affords groups for
attachment to metal ions
4. Masking agent – used in covering metal
ions that are not meant to be analyzed in
compleximetric titrations; should act by
precipitation, should form complexes that
are more stable than the interfering metal
ion and color formed should not obscure
the endpoint
Things to remember in compleximetric titrations:
1. pH should be adjusted to stabilize
complexes and to achieve distinct color
changes to the titration process
2. temperature should be controlled in order
to stabilize the complex formed, giving
accurate data for calculations
3. the disodium salt of EDTA is used due to
increased solubility in water
Titrimetric Methods: Redox Titration Methods
In this titration method, changes in the net
electron charge of the compound is the measure
for reactions in titration processes
Assay Methods include:
1. Permanganate methods – use of
potassium permanganate in the analysis of
pharmaceutical substances; titration
procedures are self-indicating; KMnO4
should not come in contact with carbon
related products (cellulose, paper and
etc.) to avoid unnecessary oxidation
2. Indirect titration methods – compounds
are converted to an equivalent of oxalate
salt before they can be oxidized by
potassium permanganate; example: Assay
of malic acid in cherry juice
 3. Residual Titration Methods – has two
categories:
a. [Standard Oxalic acid + analyte] =
excess oxalic acid is titrated with
KMnO4
b. [Standard KMnO4 + analyte] =
excess KMnO4 is either: titrated
using standardized oxalic acid or
use of ferrous ammonium
sulphate and then back titrated
with more standard KMnO4
4. Dichromate Titration Methods – more
stable in aqueous solution compared to
KMnO4 but lacks self-indicating ability as
that of KMnO4
5. Ceric Sulfate Titration Methods –
reduction method applied when analytes
require boiling for complete reaction
Titrimetric Methods: Potentiometric Methods
Potentimetric titrations require the use of
electrochemical cells that generate electrode
potential to determine the ionic species in a
solution. It covers all reactions discussed above. Its
advantage over other methods is that
measurements can be done in colored solutions
whereas its disadvantage is that readings take
time to stabilize. Automatic potentiometers are
also used in the industry to avoid the hassle of use
in titrimetric methods.

Summary of Titrimetric Methods

Titration Direct Residual Indirect
Type
Acidimetry √ √
Alkalimetry √ √
Precipitation √ √
Complexation √ √
Redox √ √ √
Iodimetry √ √
Iodometry √ √