Introduction to Pharmaceutical Analysis o Staff of QC operations

Quality  Are responsible for sampling, analytical

 Sum of all factors which contribute directly or testing of raw materials, packaging
indirectly to the safety, effectiveness, and components and labeling materials
reliability of the product  Conducts monitoring of parameters like in-
 Ensures that drug products are designed and process testing, environmental
produced to meet or exceed customer monitoring, operations compliance and
requirements for efficacy and safety release tests on dosage forms
Quality Management System Quality Assurance
- A coordinated set of activities that directs and - part of quality management focused on
controls an organization with regard to providing confidence that quality
quality requirements will be fulfilled
Quality Control - defined as planned and systematic activities
- Application of quantitative and qualitative that can demonstrate a product’s capacity to
pharmaceutical chemistry to the analysis of: fulfill requirements for quality
o Purity and quality of drugs and chemical - Department that is responsible for quality
constituents policies are adopted, identification and
o Diagnostic testing for chemicals found in preparation of policies and standard
the body in altered concentrations operating procedures and determines
o Analysis of medicinal agents and product meets applicable specifications set by
metabolites in biological systems internal standards and good manufacturing
- Considered as Process control practices
- Monitors activities related to analytical - Functions:
examination of testing o Quality monitoring, audit function
- Goals Basic Principles of Pharmaceutical Analysis
o Detect, evaluate and correct errors due to Definition of Important Terms:
system failure, environmental conditions 1. Specification- a document that contains a
and operational performance list of tests, references to analytical
- Guarantees of QC in relation to products: procedures and appropriate acceptance
o Product is free of impurities criteria
o Product is physically and chemically stable a. Categories include: intended use of a
o Product contains the amount of active product, acceptance criteria for release
ingredients as stated in the label testing & stability testing
o Product provides optimal release of active 2. Compendia – a collection of data gathered
ingredients when the product is and presented in the form of a book.
administered Examples include: USP/NF, BP, EuPharm
- Types of QC processes 3. Monograph - A written standard that
o Quantitative examinations describes an article like a drug substance,
 Measured as a numerical value drug product, excipients or compounded
o Qualitative examinations preparation
 Measures presence or absence of a. Contents include: name of substance,
a substance definition, packaging requirements,
o Semi-qualitative examinations storage requirements, labelling
 Values are an estimate of requirements, information on tests to
measured analyte, usually in a ensure identity, strength, safety,
range or a scale 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 Important things to remember in alkalimetric
the endpoint to manifest in a titration titrations:
process 1. The normality of the solution obtained by
5. Equivalence point/Stoichiometric Point – dissolving the acidic substance must be
point at which titrant is chemically approximately the same as that of the
equivalent to the analyte titrant.
6. Endpoint – an observable physical change 2. The liquid acidic substance to be titrated
in the titration process indicating the must be brought to room temperature
reach of the equivalence point (25°C) before titration, because many
7. Primary Standard - a highly purified indicators offer different values at
compound that is used as a reference different temperatures
standard in titration processes (high 3. The quantity of acid to be taken should be
purity, stable in air, independent of calculated in such a manner that
humidity, readily available, reasonably approximately 30 to 40 ml of the
soluble, large formula weight) previously standardized base shall be
8. Secondary Standard - a standard used that utilized for the assay.
does not meet requirements for a primary Criteria for Indicators in Acid Base Titrations
standard but is available with sufficient 1. Can produce a sharp contrast between
purity and properties to be acceptable as two colors which it exhibits in acid and
such (should be standardized using a alkaline mediums
primary standard, stable and reacts 2. The change in color will take place over a
completely and rapidly with analyte very small range of pH values.
9. Standardization - This is a process where Rules for Use of indicators in Acid-Base Titrations
the concentration of a solution is 1. 3 drops of indicator should be used unless
determined directed
10. Direct titration – a process where the 2. Strong acid + strong base =
titrant is added to the analyte until a phenolphthalein, methyl red or methy
reaction goes to. orange
11. Back titration (residual) - where 3. Weak base + strong acid =
completion excess reagent is added to phenolphthalein
the analyte, and then the excess of 4. Strong acid + weak base = methyl red
this added reagent is determined. Titrimetric Methods: Non – Aqueous Titrations
Usually performed when an analyte reacts This involves the titration of weak acids and bases
slowly with the titrant in direct titration using non-aqueous titrants. Temperature should
processes be monitored in titration process due to high
12. Indirect Titration - a process where a coefficient of expansion of solvents used
substance is reacted with the analyte and Advantages of Non-aqueous titrimetry
liberates a compound that can be 1. Elimination of poor solubility of analytes
determined by titrimetric methods 2. Enhancement of weak reactivity of certain
analytes
Titrimetric Methods: Neutralization Reactions 3. Selectivity of titrations using a suitable
(Aciddimetry and Alkalimetry) solvent
Acidimetry – involves the analysis of inorganic and 4. Maintenance of speed, precision, accuracy
organic alkaline/basic substances using an acid and simplicity comparable with classical
Alkalimetry – involves the analysis of acidic methods of analysis
substances using a basic solution 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 Titrimetric Methods: Complexation Methods
0.05%. Complexation Methods are based on complex
3. Standardization & titration should be formation between the analyte and titrant and is
carried out as far as possible at the same used for titration of polyvalent metal ions using
temperature because of high coefficients EDTA as titrant
of expansion common among organic Terms to remember in Compleximetric Titrations:
solvents. 1. Complex – formed by the combination of a
Solvent types used in non-aqueous titrations: metal ion with a molecule capable of
1. Protophilic Solvents – basic in nature and donating electrons
react with acids to form solvated protons 2. Chelate – complex formed between a
2. Protogenic Solvents – acidic in nature and polyvalent metal ion with a molecule that
promotes a leveling effect on bases can donate electrons
3. Aprotic Solvents – chemically inert 3. Ligand – molecule that affords groups for
substances and neutral in nature attachment to metal ions
4. Amphiprotic Solvents – solvents that 4. Masking agent – used in covering metal
possess both protogenic and protophilic ions that are not meant to be analyzed in
properties compleximetric titrations; should act by
Titrimetric Methods: Precipitation Methods precipitation, should form complexes that
Titrations involved here are limited to use of silver are more stable than the interfering metal
as titrant to analytes containing halogens and ion and color formed should not obscure
thicyanate. Due to the nature of the process, a the endpoint
colored solution is necessary as an endpoint. Things to remember in compleximetric titrations:
Limitations include: 1. pH should be adjusted to stabilize
1. Co-precipitation effects do not give a real complexes and to achieve distinct color
composition of the precipitate, and changes to the titration process
2. Choice of appropriate indicator is very 2. temperature should be controlled in order
much limited. to stabilize the complex formed, giving
Parameters for a good precipitation analysis accurate data for calculations
1. Precipitate formed must be insoluble, 3. the disodium salt of EDTA is used due to
2. Precipitation process should be fast and increased solubility in water
rapid, Titrimetric Methods: Redox Titration Methods
3. Co-precipitation effects must be minimal, In this titration method, changes in the net
and electron charge of the compound is the measure
4. Detection of equivalence point must be for reactions in titration processes
apparently visible. Assay Methods include:
Titration methods: 1. Permanganate methods – use of
Mohr’s Method (Direct) – determination of potassium permanganate in the analysis of
chlorides using silver nitrate; indicator: Potassium pharmaceutical substances; titration
Chromate = red coloration procedures are self-indicating; KMnO4
Volhard’s Method (Residual) – it uses ammonium should not come in contact with carbon
thiocyanate to determine concentration of related products (cellulose, paper and
chlorides in a solution using nitric acid; indicator: etc.) to avoid unnecessary oxidation
Ferric Ammonium Sulfate = red coloration 2. Indirect titration methods – compounds
Fajan’s Method (Direct/Residual) – adsorption are converted to an equivalent of oxalate
method using adsorption dyes, change in color salt before they can be oxidized by
marks the endpoint; indicators: potassium permanganate; example: Assay
dischorofluorescien, eosin y, of malic acid in cherry juice
tetrabromophenolphthalein ethyl ester.
 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 √ √