Chemical Impurities

Inorganic Pharmacy-I (PHR 101)

Asef Raj
Lecturer
School of Pharmacy
BRAC University
[Link]@[Link]
+8801843749110
Pure substance and mixtures

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 Chemical Purity
▪ Chemical purity is the degree to which a substance is undiluted or unmixed
with extraneous material. It is typically expressed as a percentage (%).
▪ Purity is very important for pharmaceutical products where impurities could
have dangerous effects in a drug or medicine.
▪ However in any chemical process it is almost impossible to get 100% purity
and so samples are always analyzed in industry to monitor the quality of
the product.

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 Pharmaceuticals Impurities
• “Pharmaceuticals impurities are the unwanted
chemicals that remain with active pharmaceutical
ingredients (API) or drug product formulations”.
• The impurities observed in drug substances may arise

during synthesis or may be derived from sources such as

starting materials, intermediates, reagents, solvents,
catalysts, and reaction by-products.

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 Pharmaceuticals Impurities
▪ During drug product development, impurities may be formed as a result of the inherent
instability of drug substances, may be due to incompatibility with added excipients, or
may appear as the result of interactions with packaging materials.

2 NaHCO3 Na2CO3 + H2CO3

H2CO3 H2O + CO2

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 Pharmaceuticals Impurities (cont.)
▪ The amount of various impurities found in drug substances will determine
the ultimate safety of the final pharmaceutical product.
▪ Therefore, the identification, quantitation, and control of impurities are
now a critical part of the drug development process.

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The sources of impurities in pharmaceutical
products
▪ Raw materials
▪ The manufacturing process
▪ Chemical instability
▪ Reaction with container elements
▪ Manufacturing hazards
▪ Particulate contamination
▪ Cross contamination
▪ Microbial contamination

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 The sources of impurities in pharmaceutical
products (cont.)
1. Raw Materials
API
Excipients

These may arise from the

following:
(a) The starting material and its
impurities
(b) Intermediates
(c) Reagents, and catalysts used
in the process
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 The sources of impurities in pharmaceutical
products (cont.)
2. The manufacturing process
(a)From the environment
(b)From the machine and apparatus
(c)From the personnel
The majority of modern pharmaceutical chemicals are prepared by organic
synthesis from starting materials which are, themselves, either synthetic
organic chemicals or natural products. The process itself may, therefore,
introduce impurities into the final product.
These may arise from the following:
▪ The starting material and its impurities
▪ Intermediates
▪ Reagents, and catalysts used in the process
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 The sources of impurities in pharmaceutical
products (cont.)
3. Chemical Instability
▪ A number of pharmaceutically important substances are known to undergo
chemical decomposition when stored under non-ideal conditions.
▪ The nature of the decomposition, which is often catalyzed by light, acid or
alkali, air oxidation, water vapor, carbon dioxide and metallic ions, can
frequently be predicted from a knowledge of the chemical properties of the
substance.
▪ Liquid dosage forms provide a typical example of oxidative degradation with
loss of potency which can occur under inadequate storage conditions.

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 The sources of impurities in pharmaceutical
products (cont.)
4. Reaction with Container Materials
▪ Certain creams and ointments are likely to react with metal surfaces. For
example, salicylic acid ointment must not be packed in metal tubes.
▪ Aqueous injectable solutions must be packed in containers consisting of glass of
either Type I (Borosilicate glass) or Type II (soda-lime-silica glass). Type III
(Regular soda lime glass) glass may be used for non-aqueous solutions or oral
liquid dosage form which are stable in this standard of glass.
▪ Plastic containers and closures require careful evaluation because of the
tendency to produce undesirable chemicals.

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 The sources of impurities in pharmaceutical
products (cont.)
5. Manufacturing Hazards
▪ Considerable attention to the design of buildings and manufacturing areas,
cleanliness and production procedures is also essential if the highest standards are
to be achieved.

6. Particulate Contamination
• The presence of unwanted particulate matter can arise in a number of ways. These
include:
▪ Accidental inclusion of atmospheric pollutants, such as aluminium oxide, silica,
sulphur.
▪ Metallic and plastic fragments from sieves, granulating, tableting and filling
machines, or even from product containers.
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 The sources of impurities in pharmaceutical
products (cont.)
7. Cross-contamination
▪ Contamination of one product by any others is known as cross contamination. e.g.
Paracetamol tablet is contaminated by cefuroxime antibiotic.
▪ It has substantial adverse effect on antimicrobial resistance or drug resistance.
▪ The handling of powders, granules and tablets in large bulk frequently creates a
considerable amount of air-borne dust, which, if not controlled, can lead to cross-
contamination of products.
▪ Area segregation, air flow control in the machines and production area and proper
design of HVAC (Heating, ventilation and air conditioning system) can reduce this
incidence.
▪ Precautions, such as the use of face-masks and special extraction equipment, used
to protect operators from undesirable effects of certain drugs, are also suitable for
more general use to limit cross-contamination. 16
 The sources of impurities in pharmaceutical
products (cont.)

8. Microbial Contamination
▪ The pharmacopoeial requirement of sterility tests for all products
intended for parenteral administration and ophthalmic preparations,
regardless of whether they are prepared by end-sterilisation processes or
produced under aseptic conditions, provides an adequate level of control
for such preparations.

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 Standardization

Standardization of pharmaceutical chemicals and formulated products:

A. Qualitative analysis
B. Quantitative analysis

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 Identification/Qualitative analysis
▪ The purpose of identification tests is ensuring that materials have been
correctly labeled.

▪ Principle of Identification: Select and ensure the specific chemical or

physical property(/ies) that or those is/are identical for specific compound.
▪ Identification is usually achieved by a combination of simple chemical tests
and/or measurement of appropriate physical parameters.

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 Identification/Qualitative analysis (cont.)

Measurement of physical constants:

▪ Melting point
▪ Solubility
▪ Density
▪ Specific gravity
▪ Relative density
▪ Refractive index

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 Identification/Qualitative analysis (cont.)

Measurement of Absorption of Electromagnetic Radiation

▪ Measurement of radiation absorption in the IR, visible and/or ultraviolet range is now
widely used as a means of identification.
▪ Because of the high structural specificity of infrared (IR) absorption spectroscopy, this
technique now forms the basis of most identification procedures. Comparison of the
infrared absorption spectrum with that of an authentic reference compound (BP
Chemical Reference Substances, EP Chemical Reference Substances and USP Reference
Standards) has been widely used.
▪ Infrared absorption spectroscopy is also useful for recognizing differences in
polymorphism.

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 Identification/Qualitative analysis (cont.)
Light absorption
▪ Measurement of light absorption in the visible and ultraviolet range is now
widely used as a means of identification.
▪ In some cases, the absorbance at specified wavelengths is used as the basis
of limit tests to exclude undesirable impurities.

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 Identification/Qualitative analysis (cont.)

Optical rotation
▪ Measurement of the optical rotation chemically in homogeneous liquids such as castor
oil assists both identification and maintenance of quality.
▪ Additionally, the specific optical rotation of optically active compounds provides a
valuable means of controlling the purity of pharmaceutical chemicals, in which
pharmacological activity is highly correlated with molecular configuration.
▪ Rotation measurements are also used as an assay to control the content.

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 Identification/Qualitative analysis (cont.)

Some Other Methods for Identification

▪ Thin-layer chromatography (TLC) can be used for identification.

▪ High pressure liquid chromatography (HPLC) is one of the convenient
and reliable tools for both identification and quantification.

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 Assay for Quantitative Analysis
▪ The purpose of quantitative analysis is ensuring that desired or right
materials remain in accurate or labeled amount and free from impurities
or impurities remain in certain level.
▪ Principle: Basic principle of quantification of any compound is related to the
comparison of any one of some reproducible inherent properties of that
compound with the standard one which potency is known.
▪ Principle of chemical quantification: A substance will react with specific
reagents in a fixed ratio under certain conditions.

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 Ways of Quantification
▪ By chemical method
▪ By spectroscopic method
▪ By chromatographic method

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 Quantitative Determinations
Different types of quantitative analysis have to confirm for the purity and
safety of products:
▪ Insoluble matter
▪ Moisture
▪ Volatile matter
▪ Residue on ignition
▪ Loss on ignition
▪ Heavy metals

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 Heavy metals
Heavy metal Source Adverse effect

Arsenic Contaminated soil and water Promotes tumor growth, promotes

cancer

Lead Wall paints

Mercury Electrical devices, wood processing, Damages GIT, CNS and kidneys;
preservatives promotes cancer

Iron Equipment, iron salts in colouring Damages heart, liver, CNS;

agents promotes; can cause vomiting and
bleeding by damaging GIT

Copper Electrical devices, equipment Anemia, jaundice

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 Heavy metals
Arsenic Dimercaprol
Treatment:
• Chelating agents Lead Dimercaprol, calcium di sodium
versanate

Mercury Dimercaprol

Iron Deferoxamine

Copper D-Penicillamine

• New chelating agents such as meso-2,3-dimercaptosuccinic acid (DMSA) and 2,3-

dimercapto-propanesulphonate (DMPS) can effectively mobilize deposits of
mercury as well as of lead into the urine.
• Whole-bowel irrigation with polyethylene glycol solution is used in acute toxicity.
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Thank You

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