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Quality Control (PRELIMS)

Essays:
1. What is the purpose of Q.C of drug products? Enumerate/ Explain
2. Enumerate 5 rules for caring weighing balance.
3. Describe the term constant weight
4. How is proper “washing” of precipitates done?
5. How is drying and ignition of Sx and ppt. carried out?

Quality- sum of all factors which contribute directly or indirectly to the safety, effectiveness and reliability of a product.

A course in quantitative pharmaceutical chemistry should be designed to meet the following objectives:
1. Knowledge of basic principles.
2. Awareness of drug quality and quality control.
3. Basic principles of clinical laboratory methods.
4. Basic chemical concepts.

Quantitative Pharmaceutical Chemistry- may be defined as the application of the procedures of quantitative analytical
chemistry:

1. Analysis and determination of the purity of drugs (USP, NF)


2. Chemical Analysis of the chemical constituents found in the human body, which serve as diagnostic aids.
3. Analysis of medicinal agents and their metabolites found in biological systems.

When the quality of a drug product is challenged by a physician, the pharmacist is responsible for initiating steps to
determine if the product is defective. This may be accomplished by:
1. Calling and advising the drug manufacturer of the problem involving the product.
2. Analyzing the preparation in the prescription laboratory barrowing needed equipment from a clinical laboratory if
necessary.
3. Sending a portion of the sample to a private laboratory for analysis.
4. Combination of all these steps.

*Improper labeling, discoloration, the presence of cloudiness, crystals, or precipitates in products known to be solutions.

Quality- sum of all factors which contribute directly or indirectly to the safety, effectiveness and reliability of a product.

Quality Control guarantees with reasonable limits that a drug product:


1. Free from impurities
2. Physically and chemically stable
3. Contains the amount of active ingredient(s) as stated on the label
4. Provides optimal release of the active ingredient(s) when the product is administered

United States Pharmacopeial Convention, Inc., a nonprofit corporation composed of representatives from all accredited
colleges and schools of pharmacy and medicine in U.S.

Methods of analysis in quantitative pharmaceutical chemistry may be appropriately subdivided according to the following
procedures, each of which requires a special technique.

Volumetric analysis is the determination of the volume of a solution of known concentration required to react with a given
amount of a substance to be analyzed.

Physicochemical methods of analysis are based on some specific physical or chemical property or properties of the
substance being analyzed. In many assays the measurement of these properties requires the utilization of an instrumental
technique (e.g. Chromatographic, Spectrophotometric, Electrometric, Thermal Conductimetric, Refractometric, and
Polarimetric ).
Gravimetric analysis is the separation by extraction, precipitation, or other means of the constituent to be determined
either in the natural state or in the form of a definite compound the composition of which is known to the analyst, and the
weighing of the resulting product.

Special methods are those which require a distinct type of technique, such as alkaloidal assaying.

Official assay method serve as an exact measure of the purity of a substance only when the results are considered in
conjunction with the qualitative tests.

Part 1 GENERAL METHODS USED IN OFFICIAL PHARMACEUTICAL ANALYSES

Chapter 1
REMARKS AND GENERAL DIRECTIONS

Success as an analyst
Important objective in studying qpc is the acquisition of a fundamental knowledge of the theory as well as a practical ability
in the application of analytical methods. The analyst must require skill of technique, patience, neatness and accuracy.

Accuracy and Honesty


It is absolutely essential that all quantitative work be performed without even a slight loss of material or gain of extraneous
matter. Absolute integrity is demanded of every quantitative analyst.

Notebooks
The date is very important in all scientific work. Numerous legal decision have been lost through the failure of the analyst to
affix the date at the time of analysis.

Economy of time
Clean desk, clean apparatus, label all solutions, keep two operations going at one time, utilize all times between operations.

Cleaning Solution
200 g sodium dichromate in 100 ml water, adding 1500 ml sulfuric acid (XIX (U.S.P.,p.675))

Wash Bottles
Used in quantitative work. Consist of rubber-stoppered, flat-bottomed flasks of 500- to 100-ml capacity fitted with
smoothly bent tubes and a jet made flexible by means of a rubber joint. Wash bottles made of polyethylene are also suitable
for quantitative analysis.

Policeman
Is a piece of soft rubber tubing fitted to the end of a glass rod. It is used to loosen from the walls containing vessel
adhering particles that are not removable by a stream of water from the wash bottle. A policeman should never be used as a
stirring rod or allowed to remain analytical solutions.

Reagents
Must be pure. “Analyzed” or “Reagent” grade meet the specifications of American Chemical Society.

Materials Required
All reagent materials should meet the official requirements of purity and strength.

SAMPLING
The first important consideration in an analysis is the securing of a representative sample, a consideration too frequently
ignored by analysts. Fixed rules cannot be laid down in sampling, for much depends on the nature of the material and the
quantity from which the representative sample is to be taken. Whenever possible, a sample from each package should be
examined separately. When a single package s sampled, the contents should be mixed or samples should be taken from
different parts of the container and mixed, and then a portion of this mixture should be taken for analysis.

CALCULATIONS OF RESULTS AND ERRORS


Source and Nature of Errors
It is only in rare cases that the numerical value of an experimental result be directly determined.

There are two types of errors:


Indeterminate errors- manifest themselves by slight variations in a series of observations made by the same observer
under identical conditions. Causes difficult to detect, such as differences in the judgment and skill of the analyst. Generally
intangible and their elimination is impossible.
Determinate errors- recur in a constant manner in each of a series of determination. Causes such as
(1) personal errors made by the individual analyst, e.g. inability to judge color sharply, resulting in habitual reading of end
points in titration too late.
(2) errors of method caused by faulty procedure, e.g. incorrect sampling, contamination of precipitates, and improper
selection of indicators.
(3) apparatus errors 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, and incorrect weights.
Errors of this type are usually detectable and so may be eliminated to a large extent.

Accuracy and Precision

Accuracy is used to denote the agreement of an experimental result or the agreement of the mean value X of a series of
experimental results with the true value, and is usually expressed in terms of error.

Absolute error the difference between the mean and the true value.

Relative error is found by dividing the absolute error by the true value. Usually reported on a percentage basis. PPH or PPT

Precision is a measure of reproducibility of data within a series of results.

Average deviation d is calculated by finding the differences between the individual results and the mean, regardless the
sign, adding these differences and dividing by the number of determinations.
Relative Average Deviation is found by dividing the average deviation by the mean. Expressed in PPT.

Standard Deviation s is calculates using the equation found in S…….. and is the preferred measure of precision.
Relative Standard Deviation, sometimes called the coefficient of variation, is found by dividing the standard deviation by
the mean and multiplying by 100.

Range is the difference between the largest and smallest results in a series of measurements.

Significant Figures
Significant figures in a number are defined as all certain digits of a measurement plus one doubtful digit.

General operations

Crucibles
A variety of crucibles is used in quantitative analysis. Those most common employed are made of high-grade porcelain. They
withstand high temperature and are suitable for use in the ignition of most drugs and precipitates. Not suitable for fusions.
Fused silica, alundum, nickel, and platinum.

The Gooch Filtration Crucible

The gooch filtration crucible is designed for the separation of precipitates by suction filtration. Bedded with Asbestos, thus
making it possible to collect, wash, dry, and weigh a precipitate in the same crucible.

Fritted-Glass Crucibles
Fritted-glass crucibles have fused-in sintered or fritted-glass bottoms and are supplied in various porosities such as medium
and fine.

Filtration and Washing Precipitates


The most usual and efficient method of washing a precipitate is by the process of decantation. This process is repeated 3-4
times. Then policeman. It should be borne in mind that it is better to wash a precipitate a comparatively large number of
times with small portions of liquid than only a few times with large portions, and that each portion of wash liquid should be
removed as completely as practicable before the next portion is added.

Colloidal and Fine-grained Precipitates


Colloidal precipitates, some of them gelatinous, some of them finely divided given by the most insoluble substances, such as
sulfides, hydroxides, elemental sulfur, etc.

Evaporation of Liquids
The evaporation of liquids is best carried out in porcelain dishes constructed for that purpose, which expose a large surface
of liquid to the air.

Transfer of Liquids
As few transfers of liquid as possible should be made, since each is possible source of error. When transfers are necessary,
they must be made quantitatively, washing the original container with successive small portions of wash liquid.

Drying and Ignition of Samples and Precipitates


Many substances are directed to be dried under specified conditions before analysis to correct for absorbed moisture.
Precipitates must be dried previous to ignition.

Constant Weight
Dried to constant weight means that two consecutive weighings do not differ by more than 0.5 mg/g of substance taken for
determination, the second weighing following an additional hour of drying.

Use of Dessicators
Dessicators are a special form of glass vessel, rendered airtight by means of ground contact surfaces, used to maintain a
dry atmosphere for objects that might be affected by moisture or carbon dioxide.

The Analytical Balance


Rules for the Use and Care of the Balance
1. Use the balance assigned by the instructor.
2. Adopt an attitude of personal responsibility.
3. Brush the pan and floor of the balance
4. Adjustment of the balance before each weighing
5. Do not attempt to adjust the balance.
6. No sample should ever be placed directly upon the balance pan.
7. Hot objects must be allowed to cool to room temperature before placed inside the balance case.
8. Material spilled on the balance pan or floor must be brushed up at once.
9. To avoid damaging the balance, all levers and knobs must be turned slowly and carefully.

Weighing Procedures
1. Before Weighing
2. Zero the balance
3. Preweigh
4. Weigh
5. Final Step

Weights
Should meet standards.
Quality Control (Week 1)

Volumetric Analysis
Titration, Titrant and Analyte

Analytical Chemistry- branch of chemistry which provides information relative to its composition of matter. AKA
Pharmaceutical Chemistry.

Pharmaceutical Chemistry
1. Qualitative Method of Analysis- the process of determining the elements or compounds present in the give sample.
2. Quantitative Analysis- the process of determining the proportions in which the various elements or compounds are
present.

Quality- is the combination of attributes or characteristics of a product which, when compared to a standard, serves as a
basis for measuring the uniformity of the product and determines its degree of acceptability.

Official Compendia- approved sources of guidelines for drug quality required by certain practitioners or agency.
USP, NF, British Formulary

The complete MONOGRAPH of a raw material or finished dosage form includes the following information:
a. chemical structure
b. chemical name
c. Purity rubric
d. Packaging and Storage
e. Reference Standard
f. Identification Test
g. Corresponding tests for chemical and physical constants such as melting-range, rotary power, refractive index.
h. water content
i. Assay procedure

Control- refers to the measure or step that is used to prevent or eliminate drug risks/hazards to make it safe and
effective.

Quality Control- is a tool, which gives the assurance that a product conforms to standards and specifications through the
system of inspection, analysis and action. Assures that a drug product is safe, pure and effective. Is product oriented and
focuses on defect, identification.

Quality Assurance- the sum total of the organized activities performed. Focuses on defect prevention.

Quality Control Guarantees that the drug product is:


- Free from impurities
- Physically and chemically stable
- Right Amount of Active Ingredient
- Delivers the right therapeutic action upon administration

Types of Qualitative Analysis


A. Volumetric analysis (mL)
Analysis involving the measurement of volume of a solution of known concentration required to react with the
desired constituent.
Divisions of volumetric analysis
- Neutralization
- Precipitation
- Compleximetry
- Oxidation-reduction
 Permanganate
 Ceric Sulfate
 Iodometry
 Iodimetry
 Bromine
 Potassium Iodate
 Diazotization assay with nitrite
B. Gravimetric Analysis (g)
Involving accurate measurement of weights.

C. Special Methods
Analysis which require a distinct type of technique such as analysis of crude drugs, assay of fats and fixed oil,
assay of volatile oils and assay of alkaloids.

D. Physico-chemical Methods
Analysis based on some specific physical and chemical property or properties of the substance being analyzed with
the use of instrument such as:
- Spectrophotometer
- Chromatograph Unit
- Polarographer
- Polarimeter
- Fluorometer- Fluoride Content

Control Functions
- May appear varied and never quite identical in any way.
1. MONITOR FUNCTION- is to assure that even though production personnel have primary responsibility for control over
their processes, these processes are maintained and that any deviation for specified requirements is reported. Conducts
environmental monitoring. This is to control the microbial and particulate matter content of environmental air in areas where
pharmaceuticals such as parenterals are processed.

2. ANALYSIS FUNCTION- Conducts testing not only on the raw materials and packaging components but also on the bulk
product during processing and after packaging prior to its release to the market and continues even after distribution to the
end user when selected lots are subjected to shelf life studies to confirm the expiration period of the finished product.

3.RECORD, REVIEW AND RELEASE FUNCTION- to determine accuracy and completeness of all records generated during
the cause of production prior to the release of each lot finished product to the market.
A detailed checklist is frequently employed by the employer.

4. AUDIT FUNCTION- to train employees to comply with the SOP’s and to understand why and how these SOP’s are to be
followed. Quality audit is designed to detect areas where the established SOP’s are not being followed and to these findings
to the supervisor for appropriate action.

Benefits derived from a QC Systems


1. Minimize or eliminates the risk of marketing unsafe products.
2. Guarantees conformance to regulatory requirements.
3. Guarantees product efficacy.
4. Reduces operating costs.
5. Reduces operating losses.
6. Produce higher employee morale
7. Motivates the pharmaceutical/medical professional to prescribe the product.

QC and Pharmacist
Pharmacist must have working knowledge if they are to advise medical practitioners on drug quality. Is responsible for
initiating steps to determine if a product is defective. He is also responsible for solving problems related to drug quality.

Methods of Analysis
Sampling- process of removing an appropriate number of items from a population in order to make influences to the entire
population.
Population- is the totaling of all actual or conceivable items of a certain class under consideration.
Sample- is a finite number of subjects selected from a population.
Random sample- is a sample chosen in such a manner that one object has a good chance of being selected as another.

Assay- process of determining the potency, strength, or percentage purity of a drug or preparation.

Classification of Analysis

I. Based on sample size


Ultra-microanalysis <1mg
Micro-analysis 1mg-10mg
Semi-microanalysis 10 mg-100 mg
Macro-analysis 100mg- 1g

II. Based on the extent of determination


Proximate analysis- total amount of class of active principles in a given sample.
Ex. Alkaloid
Ultimate Analysis- Amount of specific constituent or a single chemical species present in the
sample.
Ex. Caffeine in coffee

III. Based on Nature of Methods


Classical Method
Also known as General/ Chemical/ Wet/ Stoichiometric Method
Ex. Titrimetric
Instrumental Method
More accurate
Ex. Spectrometry
Miscellaneous Special Methods
Involves the crude drugs and other natural products.
Ex. Water Content

IV. Based on Materials Used


Chemical- Titrimetric methods
Physical- instrument and special apparatus
Biological- use of microorganisms and animals

Absolute error- Difference between the mean value and the true value
E. Absolute= Mean Value- True Value
Relative Error- Absolute error divided by true value.
E. Relative= E. Absolute/ True Value

Outline:
- Volumetric Analysis
-Neutralization reaction
- Indicators that can be used in neutralization reaction
- Types of Titration
- Modern Theories for Acid and Base

Volumetric Analysis
- Also known as TITRIMETRIC METHOD
- A solution of known concentration is added to solution of analyte until the reaction is judged complete.
- The experimental way of determining when equivalent amounts have reacted.