PHARMACEUTICAL CHEMISTRY 3

Quality Control I
ANALYTICAL CHEMISTRY
Outline of Discussion
I. Introduction to Quality Control
II. General Principles in Quality Control
III. Methods Used in Pharmaceutical
Analyses
I. Titrimetric Analysis
II. Gravimetric Analysis
III. Special Methods of Analysis
IV. Sample Problems
Drug quality as our main business
The Grim Reality

• Poor quality medicines do not meet

official standards for
STRENGTH
QUALITY

PURITY
PACKAGING
LABELING
The Grim reality

• Poor quality drugs result in serious

health implications including:
treatment failure
adverse effects
increased morbidity
mortality
development of drug resistance
wasted resources
Drug quality in the world…

• availability of substandard and

counterfeit drugs in disturbing
proportion in many low-income
countries
• lack of reliable drug quality
assurance systems in many
developing countries
Qualitative and quantitative
pharmaceutical chemistry
 Analytical chemistry

QUALITATIVE

What is in the sample?

QUANTITATIVE

How much is present in

the sample?
What it is…
• Application of the procedures of
qualitative and quantitative analytical
chemistry
– To the analysis and determination of the
purity and quality of drugs and chemicals
used in pharmacy
– To the analysis of the chemical constituents
found in the human body whose altered
concentrations during disease states serve
as diagnostic aids
– To the analysis of medicinal agents and their
metabolites found in biological systems
 Therefore, QPC has value in…

Manufacturing Human Physiology

Product Formulation PRODUCT PATIENT Biochemistry

Drug Quality Pharmacokinetics
Drug
Process validation Quality Clinical Pharmacy

DRUG EFFECT

Pharmacodynamics Pharmacology Toxicology

What is 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
effect and safety
Quality control guarantees
within reasonable limits that a
drug product…
• is free of impurities
• is physically and chemically stable
• contains the amount of active
ingredients as stated in the label
• provides optimal release of active
ingredients when the product is
administered
Quality control for quality
drugs
• SHEWHART Cycle  PDCA (Plan-
Do-Check-Act) approach
 FACTORS
CONTRIBUTING TO
QUALITY PRODUCTS

Personnel
Validated processes
Procedures

Starting materials Equipment

Packing materials
Premises
Environment
Types of analysis
 Based on sample size

• Ultra micro: < 1 mg

• Micro: 1-10 mg
• Semi micro: 10-100 mg
• Macro: 100 – 1000 mg
Based on extent of determination

Proximate
Total amount of a CLASS or
GROUP of active constituents

Ultimate
Amount of a SINGLE CHEMICAL
SPECIES in a sample
 Classification of Analysis
Proximate Ultimate

• Total alkaloidal assay • Atropine

of deadly nightshade determination of
(Atropa belladonna) deadly night shade

• Volatile oil content of • Menthol content of

peppermint peppermint
Based on nature of methods

Tritrimetry
CLASSICAL Gravimetry

Spectrometry
INSTRUMENTAL Polarimetry

Water Content
MISCELLANEOUS Ash Content
Acid Value
General principles
in quality control

STANDARDS and
MONOGRAPHS
The USP/NF

• A book of public pharmacopeial

standards
• Contains standards for medicines,
dosage forms, drug substances,
excipients, medical devices, and
dietary supplements
Parts of a Monograph
Halazone

C7H5Cl2NO4S 270.09
Benzoic acid, 4-[(dichloroamino)sulfonyl]-
P-(Dichlorosulfamoyl)benzoic acid [80-13-7]

>> Halazone contains not less than 91.5 per cent and
not more than 100.5 per cent of C7H5Cl2NO4S,
calculated on the dried basis.
Parts of a Monograph
Halazone -----------------> OFFICIAL TITLE

EMPIRICAL FORMULA
C7H5Cl2NO4S 270.09 MOLECULAR WEIGHT
Benzoic acid, 4-[(dichloroamino)sulfonyl]-
P-(Dichlorosulfamoyl)benzoic acid [80-13-7]

>> Halazone contains not less than 91.5 per cent and
not more than 100.5 per cent of C7H5Cl2NO4S,
calculated on the dried basis.

CAS Registry Number

OFFICIAL DEFINITION
Parts of Monograph

• Official title
– generic or non-proprietary name of the
drug
• Structural formula
– a formula which shows the
arrangement of the elements making
up the compound and how these
elements are bonded to one another
such that stability is attained
Parts of Monograph
• Empirical formula
– the simplest formula of the
compoundgeneric or non-proprietary
name of the drug
• Molecular weight
– Overall weight of the compound
obtained by multiplying the atomic
weight of each element (of the
compound) by its subscript and then
getting the sum of all the products
Parts of Monograph
• Chemical Abstracts Service Number
– Code numbers assigned by CAS to the
chemical substance which provides a unique
and universal identifier for the substance.
(The numbers do not have any inherent
meaning.)
• Other chemical names
– Include names based on other systems of
nomenclature or naming like IUPAC name
by International Union of Pure and Applied
Chemistry
Parts of Monograph

• Official definition
– A statement of purity and composition
of the compound or drug which has
been predetermined by the
Pharmacopeia to be the purity at
which the drug may generally be
regarded as relatively harmless to
living organisms
Other Parts of Monograph

• Packaging and storage

• Identification
• Loss on drying
• Chapter Number (where a more
detailed discussion of the test can
be found)
• Assay
 General principles
in quality control

ACCURACY and PRECISION

Accuracy and Precision
Accuracy (Validity)
• the degree to which information
matches true or accepted values
• degree to which the results of a
measurement estimates underlying
true value
• an issue pertaining to the quality of
data and the number of errors
contained in a dataset
Accuracy and Precision
Precision (Reliability)
• degree to which measurements
fluctuates around a central measurement
• Precise attribute information may specify
the characteristics of features in great
detail; however, that precise data--no
matter how carefully measured--may be
inaccurate.
• reproducibility or repeatability
 Accuracy and Precision

High precision and low accuracy

High accuracy and low precision

Accuracy and Precision
General principles
in quality control

ERRORS
Indeterminate errors

• manifest themselves by slight

variations in a series of observations
made by the observer under
identical conditions
• intangible and difficult to detect

e.g. differences in the judgement

and skill of analyst
Determinate errors

• Recur in a constant manner in each

of a series of determinations
• Possible to partially determine their
value and reduce their effect on the
final result
Determinate errors
Arise from:
• Personal errors made by the individual
analyst (e.g. inability to judge color
changes sharply  habitual reading of
endpoints too late)
• Errors of method caused by faulty
procedure (e.g. incorrect sampling,
contamination of precipitates, improper
selection of indicators)
Determinate errors

Arise from:
• Apparatus error due to poor
construction or calibration (e.g.
inaccuracy in the calibration of
burets or pipets, inequality in the
length of the arms of the balance,
incorrect weights)
Titrimetric analysis
Titrimetric Analysis

A titration is a method of analysis

determines the precise endpoint of a
reaction and therefore the precise
quantity of reactant in the titration
flask. A buret is used to deliver the
second reactant to the flask and an
indicator or pH Meter is used to
detect the endpoint of the reaction.
Essentials in titration

Analyte

Titrant the active Indicators

constituent to be
analyzed;
the TITRAND

Volumetric
Chemicals
or standard
capable
solution
of changing
of known
at or near
concentration
the endpoint
Equivalence Point

• Point when added titrant is

chemically equivalent to the analyte
in the sample
• aka STOICHIOMETRIC POINT
• Non-observable to the naked eye
Endpoint

• Experimental approximate of the

equivalence point
• observable
Titrimetric Analysis

Begin by preparing
the buret. It should
be conditioned and
filled with titrant
solution. The analyst
should check for air
bubbles and leaks,
before proceeding
with the titration.
Titrimetric Analysis

Take an initial volume

reading and record it in the
notebook. Before
beginning a titration, the
analyst should always
calculate the expected
endpoint volume.
Titrimetric Analysis

Prepare the solution to be

analyzed by placing it in a clean
Erlenmeyer flask or beaker. If
your sample is a solid, make
sure it is completely dissolved.
Put a magnetic stirrer in the
flask and add indicator.
Titrimetric Analysis

Use the buret to deliver a

stream of titrant to within a
couple of mL of your
expected endpoint. You will
see the indicator change
color when the titrant hits the
solution in the flask, but the
color change disappears
upon stirring.
Titrimetric Analysis

Approach the endpoint

more slowly and watch
the color of the flask
carefully. Use a wash
bottle to rinse the sides of
the flask and the tip of the
buret, to be sure all titrant
is mixed in the flask.
Titrimetric Analysis

Approaching the endpoint,

one may need to add a
partial drop of titrant. This
can be done with a rapid
spin of a teflon stopcock or
by partially opening the
stopcock and rinsing the
partial drop into the flask
with a wash bottle.
Titrimetric Analysis
Make sure you know what the
endpoint should look like. For
phenolphthalein, the endpoint is
the first permanent pale pink.
The pale pink fades in 10 to 20
minutes.

If you think you might have

reached the endpoint, you can
record the volume reading and
add another partial drop.
Sometimes it is easier to tell
when you have gone past the
endpoint.
Titrimetric Analysis

If the flask looks

like this, you
have gone too
far!
Titrimetric Analysis
When you have reached the
endpoint, read the final
volume in the buret and
record it in your notebook.
Subtract the initial volume to
determine the amount of
titrant delivered. Use this, the
concentration of the titrant,
and the stoichiometry of the
titration reaction to calculate
the number of moles of
reactant in your analyte
solution.
Titrimetric Analysis

Titration with a pH meter

follows the same procedure
as a titration with an indicator,
except that the endpoint is
detected by a rapid change in
pH, rather than the color
change of an indicator.
Arrange the sample, stirrer,
buret, and pH meter electrode
so that you can read the pH
and operate the buret with
ease.
Titrimetric Analysis

To detect the
endpoint
accurately, record
pH vs. volume of
titrant added and
plot the titration
curve as you
titrate.
Thank you very much.
Have a nice day!