Chemistry Reference
In-Depth Information
Organic impurities can come from the chemical process or can arise during stor-
age [7]. These impurities may include starting materials, by-products, intermedi-
ates, degradation products, reagents, ligands, and catalysts. These may or may not
be identified, may or may not be volatile, and may or may not have UV absorption
properties similar to the API. Because many organic impurities found in APIs are
amenable to HPLC analysis, many impurity methods utilize this technique coupled
with UV detection. Because impurities and APIs do not all absorb UV light equally,
selection of detection wavelength is important, and an understanding of the UV
light absorptive properties of the organic impurities and the API is very helpful.
Some organic impurities or APIs, however, do not appreciably absorb UV light. In
such cases, HPLC coupled with alternate methods of detection should be employed.
Techniques are available such as evaporative light scattering, refractive index, mass
spectrometric, and fluorescence detection, and various other element-specific detec-
tors. Each detection technique has its own advantages and limitations. Knowledge of
the nature of the API and its impurities is very helpful when selecting the appropri-
ate impurity analytical technique. Application of this sort of knowledge will better
ensure the development of precise and accurate impurity methods.
When the API is produced as a salt and the counterion is inorganic, the major
inorganic component of the batch is the counterion; however, minor inorganic impu-
rities are typically present in APIs and must also be controlled. Inorganic impurities
that can result from the manufacturing process are typically known and identified.
They include reagents, ligands, catalysts, heavy or other residual metals, inorganic
salts, and other materials such as filter aids. Inorganic impurities are normally
detected using procedures found in pharmacopeia or other standard references [6].
Alternative procedures used for the detection of inorganic impurities not listed in the
foregoing general literature should always be validated. Based on knowledge of the
manufacturing process, one can determine which inorganic impurities may be pres-
ent in the API. Known metals, used as catalysts, for example, should be controlled
during the manufacturing process, if possible. If the desired degree of removal is not
achieved prior to API isolation, then metal levels in the API must be determined.
Typical techniques for this include atomic absorption spectroscopy and inductively
coupled plasma emission spectroscopy. To quantify levels of other inorganic impu-
rities in the API of unknown nature, typically a residue on ignition technique is
utilized [8].
Finally, API batches are typically harvested or isolated from a solvent or a mix-
ture of solvents. Solvents used in the API synthesis are generally of known toxicity,
and capillary gas chromatography is typically used to quantify levels of residual
solvents in APIs [3]. Residual solvents are considered impurities and are listed
in three classifications: 1, 2, and 3. Class 1 solvents should be avoided. They are
known (or strongly suspected) human carcinogens and environmental hazards such
as carbon tetrachloride and benzene. Class 2 solvents should be limited; they are
not genotoxic carcinogens but possibly cause irreversible toxicities such as neuro-
toxicity and teratogenicity. For example, acetonitrile and methylene chloride are
class 2 solvents. Class 3 solvents have low toxic potential and include substances
such as ethanol, whose permissible daily limit (PDL) allows for APIs containing
0.5% ethanol.
