1.

DISCUSS THE SOURCES OF IMPURITIES IN PHARMACEUTICAL CHEMICALS

RAW MATERIALS

Impurities known to be associated with these chemicals may be carried through the process
and contaminate the final product. For example, rock salt contains small amounts of calcium
sulphate and magnesium chloride. The sodium chloride prepared from rock salt will have traces
of calcium and magnesium compounds. Heavy metals such as lead and arsenic may be present
in raw materials and hence may also be found in final product thus pure chemicals and
substances should be used in the manufacturing process.

MANUFUCTURING PROCESS

Many drugs and chemicals are manufactured from different raw materials by using different
methods or processes. Some impurities are incorporated into the materials during the
manufacturing process. The type and amount of impurity present in drug greatly varies. In
certain drugs, a multi step synthesis procedure is used which produces intermediate
compounds whose purification is needed otherwise will lead to presence of impurities in the
final product

STARTING MATERIALS.

Impurities known to be associated with these chemicals may be carried through the process
and contaminate the final product. Heavy metals such as lead and arsenic may be present in
raw materials and hence may also be found in final product thus pure chemicals and substances
should be used in the manufacturing process. . In certain drugs, a multi step synthesis
procedure is used which produces intermediate compounds whose purification is needed
otherwise will lead to presence of impurities in the final product. For example, potassium iodide
is prepared by reacting iodine with potassium hydroxide. In this process is potassium iodate
formed as an intermediate is not completely converted to KI then it may be present in final
product as an impurity.

REAGENTS AND SOLVENTS

Reagents employed in the manufacturing process and reagents added to remove other
impurities may be used as sources of impurities. As for reagents employed in the manufacturing
process, for example, soluble alkali in calcium carbonate arises from sodium carbonate used in
the process. Calcium carbonate is obtained by interaction of a soluble calcium salt and a soluble
carbonate and therefore the product will contain traces of soluble alkali which the washing

1. DESCRIBE PHYSICAL AND CHEMICAL INSTABILITY

The pharmaceutical properties of a drug, such as solubility, dissolution, and toxicology, can
change dramatically when a drug undergoes chemical or physical degradation, limiting the
drug's efficacy and safety. Therefore, the evaluation of drug stability becomes part of the
development process as early as candidate selection and continues for the lifetime of the
product. With a molecular understanding of the degradation pathways, whether chemical or
physical, we can rationally design a strategy to stabilize the compound. Chemical stability refers
to the resistance of a chemical to change in a chemical reaction. Some chemicals, like gold, are
very stable and resistant to change; but sodium is unstable and corrodes rapidly in the presence
of air. Development of a robust biologic drug product is accomplished by extensive formulation
and process development screening studies; however, even in the most optimal formulation,

a protein can undergo spontaneous degradation during manufacture, storage, and clinical use.
Chemical changes to amino acid residues, such as oxidation of methionine or tryptophan, or
changes in charge such as deamidation or carbonylation, can induce conformational changes in
the overall protein structure, potentially leading to changes in physical – in addition to chemical
– stability. Oxidation is often caused by light exposure or the presence of metal ions or
peroxides. Asparagine deamidation is more likely to occur at higher pH and/or elevated
temperature. Mechanical and interfacial stresses during manufacturing can lead to physical
instabilities (i.e. various forms of aggregation). A well-defined manufacturing process and
effective in-process controls are essential in minimizing chemical and physical instabilities,
enabling robust production and distribution of a safe and efficacious drug product. In this work,
the authors provide a review of developments in these areas over.

2. LIMIT TESTS

The following factors affect limit tests

i. Specificity of test
ii. Sensitivity
iii. Analytical errors
iv. Tests where there is no physical reaction
v. Quantitative determination

GENERAL LIMIT TESTS FOR NON SPECIFIC IMPURITY

Limit test is defined as quantitative or semi quantitative test designed to identify and control
small quantities of impurity which is likely to be present in the substance. Limit test is generally
carried out to determine the inorganic impurities present in compound. In short, limit test is
nothing but to identify the impurities present in the substance and compare it with standard.
Importance of Limit tests include to find out the harmful amount of impurities and to find out
the avoidable/unavoidable amount of impurities. It covers impurities or degradation products.

4.DISCUSS ASH VALUES

Ash values are helpful in determining the quality and purity of crude drugs, especially in powder
form. The objective of ashing vegetable drugs is to remove all traces of organic matter, which
may otherwise interfere in an analytical determination. On incineration, crude drugs normally
leave an ash usually consisting of carbonates, phosphates and silicates of sodium, potassium,
calcium and magnesium.

TOTAL ASH
The total ash is the residue remaining after incineration. Total ash value is useful for detecting
the following

i. low grade products

ii. exhausted products
iii. excess of sandy matter
iv. earthly matter within the drug

Take about 2 or 3 g, accurately weighed, of the ground drug in a tarred platinum or silica dish
previously ignited and weighed. Scatter the ground drug in a fine even layer on the bottom of
the dish. Incarnated by gradually increasing the heat-not exceeding dull red heat- until free
from carbon, cool and weigh. If a carbon free ash cannot be obtained in this way, exhaust the
charred mass with hot water, collect the residue on an ash less filter paper, increate the residue
and filter paper, add the filtrate, evaporate to dryness and ignite at low temperature. Calculate
the percentage of ash with reference to the air-dried drug.

ACID- INSOLUBLE ASH

The acid insoluble ash is the part of the total ash which is insoluble in diluted hydrochloric acid.
Acid insoluble ash is used for the following :

i. Determination of earthly matter present in roots, rhizomes and leaves

ii. Crude drugs that contain calcium oxalate crystals that may vary depending on
environmental conditions

Boil the total ash with for five minutes with 25 ml of dilute hydrochloric acid, collect the
insoluble matter in a Gooch crucible or on an ash less filter paper, wash with hot water, ignite,
and weigh. Calculate the percentage of acid- insoluble ash with reference to the air dried drug.

WATER- SOLUBLE ASH

It is used to detect materials exhausted by water or not for example tea leaves, ginger
Boil the total ash for 5 minutes with 25 ml of water; collect the insoluble matter in a Gooch
crucible or on an ash less filter paper, wash with hot water, and ignite to constant weight at a
low temperature. Subtract the weight of insoluble matter from the weight of the ash; the
difference in weight represents the water- soluble ash. Calculate the percentage of water-
soluble ash with reference to the air-dried drug.

SULPHATED ASH

It is used to get the following

i. Used for detection of low-grade products

A silica crucible was heated to redness for 10 minutes, allowed to cool in desiccators and
weighed. 1 g of substance was accurately weighed and transferred to the crucible. It was
ignited gently at first, until the substance was thoroughly charred. Then the residue was cooled
and moistened with 1 ml concentrated sulfuric acid, heated gently until white fumes are no
longer evolved and ignited at 800° ± 25°C until all black particles have disappeared. The ignition
was conducted in a place protected from air currents. The crucible was allowed to cool, and a
few drops of concentrated sulfuric acid were added and heated. Ignited as before, allowed to
cool, and weighed. The operation was repeated until two successive weighing does not differ by
more than 0.5 mg. calculate the percentage of Sulphated ash with reference to the air dried
drug.

REFERENCES

Ashutosh Kar, Pharmaceutical Drug Analysis, New Age International Publishers