International Journal of Trend in Scientific Research and Development (IJTSRD)

Volume 6 Issue 5, July-August 2022 Available Online: www.ijtsrd.com e-ISSN: 2456 – 6470

Residual Solvents, Their Limits and PDE: A Review

Nitin Thorat1, Prof. Santosh Waghmare2, Dr. Hemant Kamble3
1
Student, Department of Pharmaceutics, 2Professor, Department of Pharmacy, 3Principle,
1, 2, 3
Lokanete Shri Dada Patil Pharate College of Pharmacy, Mandavgan Pharate, Shirur, Maharashtra, India

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INTRODUCTION GENERAL PRINCIPLES

#The objective of this Review Paper is to recommend Classification of Residual Solvents by Risk
acceptable amounts for residual solvents in Assessment The term "tolerable daily intake" (TDI) is
pharmaceuticals for the safety of the patient. The used by the International Program on Chemical
Review Paper recommends use of less toxic solvents Safety (IPCS) to describe exposure limits of toxic
and describes levels considered to be toxicologically chemicals and "acceptable daily intake" (ADI) is used
acceptable for some residual solvents. Residual by the World Health Organization (WHO) and other
solvents in pharmaceuticals are defined here as national and international health authorities and
organic volatile chemicals that are used or produced institutes. The new term "permitted daily exposure"
in the manufacture of drug substances or excipients, (PDE) is defined in the present guideline as a
or in the preparation of drug products. The solvents pharmaceutically acceptable intake of residual
are not completely removed by practical solvents to avoid confusion of differing values for
manufacturing techniques. ADI's of the same substance
Appropriate selection of the solvent for the synthesis Class 1 solvents: Solvents to be avoided Known
of drug substance may enhance the yield, or human carcinogens, strongly suspected human
determine characteristics such as crystal form, purity, carcinogens, and environmental hazards.
and solubility. Therefore, the solvent may sometimes
Class 2 solvents: Solvents to be limited Non-
be a critical parameter in the synthetic process. This
genotoxic animal carcinogens or possible causative
Review Paper does not address solvents deliberately
agents of other irreversible toxicity such as
used as excipients nor does it address solvates.
neurotoxicity or teratogenicity. Solvents suspected of
However, the content of solvents in such products
other significant but reversible toxicities.
should be evaluated and justified. Since there is no
therapeutic benefit from residual solvents, all residual Class 3 solvents: Solvents with low toxic potential
solvents should be removed to the extent possible to Solvents with low toxic potential to man; no health-
meet product specifications, good manufacturing based exposure limit is needed. Class 3 solvents have
practices, or other quality-based requirements. Drug PDEs of 50 mg or more per day.
products should contain no higher levels of residual 1. Solvents to Be Avoided
solvents than can be supported by safety data. Some Solvents in Class 1 should not be employed in the
solvents that are known to cause unacceptable manufacture of drug substances, excipients, and drug
toxicities (Class 1, Table 1) should be avoided in the products because of their unacceptable toxicity or
production of drug substances, excipients, or drug their deleterious environmental effect. However, if
products unless their use can be strongly justified in a their use is unavoidable in order to produce a drug
risk-benefit assessment. Some solvents associated product with a significant therapeutic advance, then
with less severe toxicity (Class 2, Table 2) should be their levels should be restricted as shown in Table 1,
limited in order to protect patients from potential unless otherwise justified. 1,1,1-Trichloroethane is
adverse effects. Ideally, less toxic solvents (Class 3, included in Table 1 because it is an environmental
Table 3) should be used where practical. hazard. The stated limit of 1500 ppm is based on a
review of the safety data.

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TABLE 1 Class 1 solvents in pharmaceutical TABLE 3 Class 3 solvents which should be
products (solvents that should be avoided). limited by GMP or other quality-based
Concentration requirements.
solvents concern
Limits (ppm) Acetic Acid 1-butanol Heptane
Benzene 2 Carcinogen Acetone 2-butanol Isobutyl Acetate
Toxic and Anisole Butyl Acetate Methyl Acetate
Carbon
4 environmental PDE FOR TRIETHYLAMINE
tetrachloride
hazard
TRIETHYLAMINE
1,2-
5 Toxic Introduction
Dichloroethane
Triethylamine (TEA) is used as catalytic solvent in
1,1- chemical synthesis (1,2). It is a colourless liquid that
8 Toxic
Dichloroethene is soluble in water, ethanol, carbon tetrachloride, and
1,1,1- Environmental ethyl ether, and very soluble in acetone, benzene, and
1500
Trichloroethane Hazards chloroform. TEA has a vapour pressure of 54 mmHg
2. Solvents to Be Limited (20°C), and has been reported to be irritating to the
Solvents in Table 2 should be limited in lung and nasal passage with strong ammoniac odour
pharmaceutical products because of their inherent (2,3). Data from human studies show that TEA is
toxicity. PDEs are given to the nearest 0.1 mg/day, easily absorbed via the oral or inhalation route and is
and concentrations are given to the nearest 10 ppm. rapidly excreted, mainly in the urine, as the parent
The stated values do not reflect the necessary compound and/or its N-oxide (4-6). In studies in
analytical precision of determination. Precision human volunteers, exposures of more than 2.5 ppm
should be determined as part of the validation of the (10 mg/m3) caused transient visual disturbance (4,7)
method. due to a locally induced cornea swelling; no systemic
effects were observed at the exposures which showed
TABLE 2 Class 2 solvents in pharmaceutical
the cornea effect. The odour thresholds ranged from
Product
0.0022 to 0.48 mg/m3 (8-10).
PDE Concentration
Solvent Genotoxicity
(mg/day) limit (ppm)
Acetonitrile 4.1 410 In an Ames test TEA did not induce mutations in
Chlorobenzene 3.6 360 standard Salmonella strains with or without metabolic
Chloroform 0.6 60 activation (11). TEA did not induce sister chromatid
Cumene 0.7 70 exchanges in Chinese hamster ovary cells with or
Cyclohexane 38.8 3880 without metabolic activation (12). In an in vivo study,
1,2 Dichloroethane 18.7 1870 TEA induced aneuploidy but was not clastogenic in
N, N Dimethyl the bone marrow of rats exposed to 1 mg/m3 (0.25
10.9 1090 ppm) and 10 mg/m3 (2.5 ppm) TEA via continuous
Acetamide
inhalation for 30 or 90 days (13). The weak aneugenic
3. Solvents with Low Toxic Potential effect was observed at the low dose and early time
Solvents in Class 3 (shown in Table 3) may be point only; due to study deficiencies the relevance of
regarded as less toxic and of lower risk to human this finding is highly questionable. Overall, the
health. Class 3 includes no solvent known as a human available data do not provide evidence for a relevant
health hazard at levels normally accepted in genotoxic potential of TEA.
pharmaceuticals. However, there are no long-term
toxicity or carcinogenicity studies for many of the Carcinogenicity
solvents in Class 3. Available data indicate that they No data available.
are less toxic in acute or short-term studies and Reproductive toxicity
negative in genotoxicity studies. It is considered that No reliable information about reproductive toxicity is
amounts of these residual solvents of 50 mg per day available. A three-generation reproductive study in
or less (corresponding to 5000 ppm or 0.5% under which rats (10/sex/group) were administered 0, 2, or
Option 1) would be acceptable without justification. 200 ppm (c.a. 0, 0.14 or 14 mg/kg/day) TEA in
Higher amounts may also be acceptable provided they drinking water was cited in the United States
are realistic in relation to manufacturing capability Environmental Protection Agency (US EPA)
and good manufacturing practice. Integrated Risk Information System assessment
review (14). The high dose was increased to 500 ppm
in the third generation due to a lack of observed

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symptoms. No apparent effects occurred at 200 ppm triethylamine-N-oxide in man. Toxicol Appl
through two generations. However, due to Pharmacol 1989; 100:529-38.
deficiencies in end-points measured the study data [6] Akesson B, Skerfving S, Stahlbom B, Lundh T.
were disregarded from determining a Permitted Daily Metabolism of triethylamine in polyurethane
Exposure (PDE). foam manufacturing workers. Am J Ind Med
Repeated dose toxicity 1989; 16:255-65.
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most relevant published animal study for deriving a
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whole body inhalation at concentrations of 0, 25, or chemical safety: Odor thresholds compared
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Since the proposed PDE is greater than 50 mg/day it
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(“solvents with low toxic potential”) in Table 3 in the Mortelmans K, Speck W. Salmonella
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