Phenobarbital and its Sodium Salt - IARC Monographs on the ...

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1.2 Production
<strong>IARC</strong> MONOGRAPHS VOLUME 79
The introduction of barbital in 1903 <strong>and</strong> phenobarbital in 1912 initiated the
predominance of barbiturates, <strong>and</strong> for over half a century they reigned as the preeminent
sedative-hypnotic agents. Although several so-called ‘non-barbiturates’ were
introduced to displace barbiturates from time to time, it was not until chlordiazepoxide
was marketed in 1961 that their position was challenged seriously. During the ensuing
quarter of a century, the benzodiazepines displaced the barbiturates as the sedativehypnotics
of choice (Hardman et al., 1996).
Two general methods of synthesis have been used for phenobarbital. The first is
based on condensation of α-ethylbenzenepropanedioic acid ester (methyl or ethyl ester)
with urea in the presence of sodium ethoxide. The second comprises condensation of
benzeneacetonitrile with diethyl carbonate in ether solution to form α-cyanobenzeneacetic
ester, followed by ethylation of this ester to α-cyano-α-ethylbenzeneacetic acid
ester, which is further condensed with urea to yield iminobarbituric acid, <strong>and</strong> hydrolysis
of iminobarbituric acid to phenobarbital (Chao et al., 1978).
<strong>Sodium</strong> phenobarbital is obtained by dissolving phenobarbital in an ethanolic
solution of an equivalent quantity of sodium hydroxide <strong>and</strong> evaporating at low temperature
(Gennaro, 1995).
Information available in 2000 indicated that phenobarbital was manufactured by
three companies each in China <strong>and</strong> India, by two companies in the Russian Federation
<strong>and</strong> by one company each in Armenia, Germany, Hungary, Latvia, Switzerl<strong>and</strong> <strong>and</strong> the
USA (CIS Information Services, 2000a).
Information available in 2000 indicated that phenobarbital <strong>and</strong> <strong>its</strong> salts (unspecified)
were formulated as a pharmaceutical by 31 companies in India, 18 companies in France,
12 companies in the USA, 11 companies each in Chile <strong>and</strong> South Africa, 10 companies
each in Taiwan, Turkey <strong>and</strong> the United Kingdom, nine companies in Argentina, eight
companies each in Brazil, Italy <strong>and</strong> Spain, six companies each in China <strong>and</strong> Pol<strong>and</strong>, five
companies each in Hungary <strong>and</strong> Japan, four companies each in Canada, Germany, the
Islamic Republic of Iran, Portugal, the Republic of Korea <strong>and</strong> Switzerl<strong>and</strong>, three
companies each in Australia, Belgium, Bulgaria, Ecuador, Greece, Peru <strong>and</strong> Venezuela,
two companies each in the Czech Republic, Egypt, Lithuania, Mexico, Romania, the
Russian Federation, Thail<strong>and</strong> <strong>and</strong> Viet Nam <strong>and</strong> one company each in Hong Kong,
Indonesia, Irel<strong>and</strong>, Malta, Norway, the Philippines, Singapore, the Slovak Republic,
Surinam, Sweden, the Ukraine <strong>and</strong> Yugoslavia (CIS Information Services, 2000b).
Information available in 2000 indicated that sodium phenobarbital was manufactured
by one company each in China, Germany, Hungary, Latvia <strong>and</strong> the United
Kingdom (CIS Information Services, 2000a) <strong>and</strong> that it was formulated as a pharmaceutical
by seven companies in India, four companies in Italy, two companies each in
Argentina, Australia, Chile, Ecuador, France, the United Kingdom <strong>and</strong> the USA <strong>and</strong>
one company each in Belgium, Bulgaria, Germany, Hungary, Indonesia, the Islamic