Techniques of analysis, Sources of Impurities

1. DIFFERENT
TECHNIQUES OF
ANALYSIS, SOURCES
OF IMPURITIES IN
MEDICINAL AGENTS
Nidhi Sharma

2. Different techniques of analysis
• Proximal analysis- In this analysis the amount of each element in a
sample is determined with no concert as to the actual compound
precent.
• Partial analysis- The selected constituent in a sample is
determined by partial analysis.
• Trace constituent analysis- The very minute quantity of a
specified component in a sample is determined by this method.
• Complete analysis- The proportion of each component of the
sample is determined by complete analysis.
The main technique employed in quantitative analysis are based upon-

3. a. The quantitative performance of suitable chemical reactions & either
measuring the amount of reagent needed to complete the reaction or
ascertaining the amount of reaction product.
b. Appropriate electrical measurement.
c. The measurement of certain optical property.
The quantitative chemical analysis are of basically three type.
1. Gravimetry
2. Titrimetry
3. Volumetry
1. Gravimetry- Gravimetry analysis involves the separation of the constituent to
be estimated in the form of an insoluble compound of known composition.

4. 2. Titrimetry- A quantitative method of analysis dealing with the volumes of
solution and measurement is termed as titrimetric analysis.
The substance to be determined is allowed to react with an appropriate reagent
added as a standard solution needed for complete reaction is determined
The common type of reaction which are used in titrimetry are-
• Neutralization (acid- base) reaction
• Complex forming reaction
• Precipitation reaction
• Oxidation- Reduction reaction.
3. Volumetry- It is concerned with measuring the volume of gas evolved or
absorbed in a chemical reactions.

5. Special technique in quantitative analysis-
1. Electrical method of analysis-These involve the measurement of
current voltage or resistance in relation to the concentration of a
certain species in a solution.
These methods are of following type-
1. Volumetry
2.Coulometry
3.Potentiometry
4.Conductometry.

6. 2. Optical method of analysis- The optical method of
analysis are dependent either upon-
1.Measurement of the amount of radiation energy of
a particular wavelength absorbed by the sample.
2.The emission of radiant energy & measurement of
the amount of energy of a particular wavelength
emitted.

7. Several analytical techniques have been developed which
involve the measurement of radiant energy. They are-
1.Emission spectroscopy.
2.Colorimetry
3.Fluorimetry
4.Turbidimetry & Nephelometry
5.Spectrophotometry
6.Flame photometry
7.Atomic absorption spectroscopy
8.Polarimetry

8. 3. Chromatography- It is a separative process which is very
useful for separating molecular mixture.
4. Radioactivity- It involves the measurement of intensity
of radiation from a naturally radioactivity material.

9. SOURCES OF IMPURITIES IN MEDICINALAGENTS-
Impurities are chemical substances inside a confined amount of liquid,
gas, or solid, which differ from the chemical composition of the
material or compound.
Impurities are either naturally occurring or added during synthesis
of a chemical or commercial product.
Source of Impurities-
1. Inorganic impurities
2. Organic impurities (Process and Drug-related)
3. Residual solvents

10. 1. ORGANIC IMPURITIES-
Organic impurities may arise during the manufacturing process and/or storage of the drug substance.
They may be identified or unidentified, volatile or non-volatile, and include the following.
A. Starting materials or intermediates- These are the most common impurities found in every API unless
a proper care is taken in every step involved throughout the multi-step synthesis.
Although the end products are always washed with solvents, there are always chances of having the
residual unreacted starting materials may remain unless the manufacturers are very careful about the
impurities.
In paracetamol bulk, there is a limit test for p-aminophenol, which could be a starting material for some
one manufacturer or be an intermediate for another.
By-products- In synthetic organic chemistry, getting a single end product with 100% yield is very rare;
there is always a chance of having by-products.
In the case of paracetamol bulk, diacetylated paracetamol may form as a by-product.

11. B. Degradation products- Impurities can also be formed by degradation of the end product during
manufacturing of bulk drugs.
However, degradation products resulting from storage or formulation to different dosage forms or aging
are common impurities in the medicines.
C. Reagents, ligands, and catalysts- These chemicals are less commonly found in APIs, however, in some
cases they may pose a problem as impurities.
In general, an individual API may contain all of the above mentioned types of organic impurities at levels
varying from negligible to significant.
As the organic impurities are the most common product as well as process related impurities, it is the
responsibility of both the manufacturers of APIs and the users (ie, formulators) to take care of these
impurities according to ICH guidelines or compendia.
In addition, for an optically active single isomer drug there could be enantiomeric impurities present in
the API.

12. D. Enantiomeric impurities - The single enantiomeric form of a chiral drug is now considered as
an improved chemical entity that may offer a better pharmacological profile and an increased
therapeutic index with a more favorable adverse reaction profile.
2. INORGANIC IMPURITIES-
Inorganic impurities may also derive from the manufacturing processes used for bulk drugs.
They are normally known and identified and include the following
A. Reagents, ligands, and catalysts- The chances of having these impurities are rare.
however, in some processes, these could create a problem unless the manufacturers take
proper care during production.
B. Heavy metals- The main sources of heavy metals are the water used in the processes and
the reactors (if stainless steel reactors are used), where acidification or acid hydrolysis takes
place. These impurities of heavy metals can easily be avoided using demineralized water and
glass-lined reactors.
C. Other materials (Eg- filter aids, charcoal)- The filters or filtering aids such as
centrifuge bags are routinely used in the bulk drugs manufacturing plants, and, in many cases,
activated carbon is also used. The regular monitoring of fibers and black particles in the bulk
drugs is essential to avoid these contaminations.

13. 3. RESIDUAL SOLVENT:
Residual solvents are organic volatile chemicals used during the
manufacturing process or generated during the production.
It is very difficult to remove these solvents completely by the
work-up process, however efforts should be taken to the extent
possible to meet the safety data.
Some solvents that are known to cause toxicity should be avoided
in the production of bulk drugs.

14. Depending on the possible risk to human health, residual solvents are
divided into 3 classes.
Class I Solvents- Benzene (2 ppm limit) and carbon tetrachloride
(4 ppm limit) are to be avoided.
Class II Solvents- Methylene chloride (600 ppm), methanol (3000
ppm), pyridine (200 ppm), toluene (890 ppm), N, N-
dimethylformamide (880 ppm), and acetonitrile (410 ppm) are most
commonly used solvents.
Class III solvents- Acetic acid, acetone, isopropyl alcohol, butanol,
ethanol, and ethyl acetate have permitted daily exposures of 50 mg
or less per day.

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