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On review of Tab. 4.5, one can speculate that the profitability of a 10-mg tablet
selling at ten cents per tablet would not affect the drug seller’s profitability in any
way, even if the API content cost doubles. It is important to recognize and under-
stand that the selling prices of the tablets are independent of API manufacturing
costs or their selling price.
The API manufacturer/seller has to carefully evaluate its own effort for any cost
reduction. Each API producer has to justify its own return on investment for such
investment. Due to limited patent life, brand API producers do not want to invest in
any cost reduction efforts. For such an effort, they may have to get regulatory ap-
proval, which costs additional money, too. Simi larly, every generic API producer
will evaluate cost reduction advantage of its patent-protected process and compli-
ance costs. Table 4.6 illustrates the value of such effort.
All of the above that has been discussed applies to branded and generic products. It
is well known that almost all branded products move to generic produ cts. Safety
and consistent product quality from the very beginning are the price drivers.
The following are brief reviews of some selected products. Review of these patents
suggests that inventors of the processes have progressively improved and simplified
processesandmadeeffortstoreducemanufacturing cost, using improved chemistries
and processes, and reduce use and production of toxic chemicals in the chemistries.
The purpose of this is to emphasize that significant chemistry and processing
information is available that can be used t o create better chemistries/processes at
lower costs.
4.2.1 Mycophenolate mofetil
Mycophenolate mofetil is sold under the brand name Cellcept. Once it became ge-
neric, many companies filed patents for it. USP 7019133 B2 [32] and US 2010/029560
A1 [33] are two alternate methods of manufacture of mycophenolate mofetil.
Tab. 4.6: Months for return and revenue.
API volume (kg/
year/site)
API factory selling price
($/kg)
API revenue ($) Savings % Savings ($) Return
months
, $. $,. $. $,.
, $. $,. $. $,.
, $. $,. $. $,.
, $. $,,. $. $,.
Arbitrary R&D effort cost, $,
96 Chapter 4 Pharma chemistry/chemical development
It is important that the chemist and chemical engineer in the process develop-
ment be familiar with chemical and physical properties of each chemical (Tab. 4.7)
involved and produced. These are not only needed for safe process design but are
also used in manipulating and improving productivity, and can be used in lowering
of cost of each product.
In USP 7019133 B2 [32], mycophenolate mofetil is manufactured by transesterifica-
tion of methyl mycophenolate in the presence of a catalyst. In US 2010/0298560 A1
[33], mycophenolic acid is reacted with an aliphatic or aromatic amine to produce
an amine salt. Amine salt is halogenated to an acid halide, which is esterified to
produce the desired product.
Syntheses in the above patents are the inventors’ perspective and their attempt
to simplify manufacture, using the mutual behavior of each chemical used and pro-
duced. Tables 4.8 and 4.9 illustrate manufacturing costs of two different chemistries
[32, 33] of mycophenolate mofetil. S&E (service and expense) costs relate to conver-
sion costs, which include hourly and salaried labor, utilities, deprecia tion, and
other fixed and variable charges that companies allocate to each product. Most
companies use their own ways to calculate factory cost of each product.
Tab. 4.7: Physical and chemical properties of reactants used in USP 7019133 B2 [32] and US 2010/
0298560 A1 [33].
Chemical CAS # Formula Mol. wt Melting point (°C) Boiling point (°C)
Methyl mycophenolate ,-- C
H
O
-Morpholinoethanol -- C
H
NO
−
Dibutyltin oxide -- C
H
OSn .
Toluene -- C
H
.
Ethyl acetate -- C
H
O
− .
Hydrochloric acid -- HCl . −
Caustic soda -- NaOH
Mycophenolic acid ,-- C
H
O
Thionyl chloride -- SOCl
−
Triethylamine -- C
H
N −
MMF -- C
H
NO
The corresponding chemical and physical properties of intermediates can be gathered from the
literature and Chemical Abstract Services once the compounds are defined.
4.2 Chemical synthesis product/processes/development 97
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Tables 4.8 and 4.9 are an illustration of a product cost using USP 7109133 [32]
and US 2010/0298560 A1 [33]. These costs are based on synthesis examples from
respective patents and are not optimized.
Process for the manufacture of mycophenolate mofetil described in US 2010/
0298560 A1 [33] can be further simplified and improved, and the global API need
can be produced in a single plant. It is currently produced by 41 producers and sold
at $232/kg [34]. Factory cost of mycophenolate mofetil based on USP 7019133 B2 [32]
(Tab. 4.2) is about $165.09/kg and per US 2010/0298560 A1 [33] is about $133.31/kg.
Each cost was calculated by getting the prices of each raw material from their ven-
dors. Both processes are not optimized. In addition, cost of solvents used in the pro-
cess is not included.
In the above cost estimates, S&E (service and expense) charge of 30% of the
raw material cost is used. S&E is, essentially, conversion cost to cover hourly, sala-
ried labor, utility cost, maintenance charges, depreciation, etc. This number could
be considere d a low number, by some. If the process is complex, S&E can be in-
creased, based on each company’s norms.
Costing of products from the paper chemistry stage to the laboratory chemistry
stage is necessary. Such an exercise makes the chemistry developers aware of how
the complexity of process can impact the factory cost. It gives them an opportunity
to improve processing. Brand and generic API developers can create excellent pro-
cesses, as they progress. Costing would include material recovery and disposal cost
of toxic and nontoxic materials. These are also reviewed in Chapter 5.
Other APIs and fine/specialty chemicals are also reviewed. The purpose is to
emphasize that significant processing and chemistry information, along with physi-
cal properties, can be used to develop excellent processes at lower costs.
+
Fig. 4.3: Mycophenolate mofetil USP 7109133 B2 [32].
98 Chapter 4 Pharma chemistry/chemical development
+
Fig. 4.4: Mycophenolate mofetil US 2010/0298560 A1 [32] [33].
4.2 Chemical synthesis product/processes/development 99
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Tab. 4.9: Factory cost of mycophenolate mofetil US 2010/0298560 A1 [33].
US / A [] CAS # Mol. wt Kilogram Cost ($/kg) $, total
Mycophenolic acid -- . . .
Thionyl chloride -- . . .
Triethylamine -- . . .
-Morpholinoethanol -- . . .
Ethyl acetate -- . .
Hydrochloric acid --.. . .
Caustic soda -- . . .
MMF -- ,.
Yield .% $/kg .
S&E .
Factory cost $/kg .
Tab. 4.8: Mycophenolate mofetil factory costs USP 7109133 B2 [32].
USP B [] CAS # Mol. wt Kilogram Cost ($/kg) $
Methyl mycophenolate ,-- . . ,.
-Morpholinoethanol -- . . .
Dibutyltin oxide -- . . .
Toluene -- . .
Ethyl acetate -- . .
Hydrochloric acid --.. . .
Caustic soda -- . . .
MMF -- ,.
Yield .% .
S&E .
Factory cost $/kilo .
100 Chapter 4 Pharma chemistry/chemical development
4.2.2 Nevirapine
The following patents discuss the manufacture of Nevirapine. These patents give a
telltale story of how process developers recognize complexities of preceding synthe-
sis and toxicity of the chemicals used and produced.
1. USP 5366972 (1994) Boehringer Ingelheim [35]
2. USP 5569760 (1996) Boehringer Ingelheim [36]
3. USP 6680383 (2004) and EP 1 519 936 B1 (2008) Boehringer Ingelheim [37]
4. WO 2007/010352 A1 (2007) Emcure Pharmaceuticals [38]
5. WO 2012/168949 A2 (2012) Laurus Labs [39]
6. USP 8212025 [40]
Figure 4.5 is illustration of USP 5366972 [35] for the preparation of nevirapine.
The process described in USP 5366972 [35] is complex. It would have low pro-
ductivity if commercialized as developed in the laboratory. The overall yield of the
four steps in Example 1 is about 40%. The shortcomings of this patent are acknowl-
edged in subsequent patents. If this process is commercialized as is, most likely,
the processing costs to recover solvents and disposal of waste would be as much as,
or more than, the actual product cost from this step. This would also be due to low
productivity of the process. Example 1 of USP 5366972 [35] is as follows.
Example 1
5,11-Dihydro-6H-dipyrido[3,2-b:2ʹ,3ʹ-e][1,4]diazepin-6-one (Nevirapine)
There are four steps. The overall yield of the following is about 40%.
Fig. 4.5: Nevirapine synthesis in USP 5366972 [35].
4.2 Chemical synthesis product/processes/development 101
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Step a) 2-Chloro-N-(2-chloro-3-pyridinyl)-3-pyridinecarboxamide
In a three-necked round-bottomed flask, fitted with an efficient reflux condenser, mechanical stirrer
and dropping funnel were placed 215 g (1.672 mol) of 3-amino-2-chloropyridine dissolved in a mix-
ture of 400 mL dioxane, 500 mL cyclohexane, and 130 mL pyridine. The solution of 299.2 g
(1.7 mol) of freshly prepared 2-chloro-3-pyridinecarboxylic acid chloride in 200 mL dioxane was
added at such a rate as to keep the vigorous reaction under control. Thereafter, the reaction mix-
ture was allowed to cool to room temperature, and the resulting crystalline precipitate was filtered
off and washed successively with cyclohexane and ether.
The dark brown product was dissolved in 5 L of a 3% aqueous solution of sodium hydroxide. The
resulting solution was treated with charcoal, suction filtered, and the filtrate was acidified by addi-
tion of 50% aqueous acetic acid. The resulting precipitate was collected by filtration and thoroughly
washed with water. After being dried overnight in a stream of nitrogen at room temperature, the al-
most colorless product had an m.p. of 156–159 °C and was sufficiently pure for further reactions. The
yield was 376.0 g (84% of theory).
Step b) N-(2-Chloro-3-pyridinyl)-2-[[(4-methoxyphenyl)methyl]amino]-3-pyridinecarb oxamide
13.4 g (0.05 mol) of the product obtained in step a) was dissolved in 20 mL of xylene, and the re-
sulting solution was admixed with 13.8 g (0.1 mol) of p-methoxybenzylamine. Thereafter, the mix-
ture was refluxed for 2 h. The reaction mixture was then evaporated in vacuo, and the residue was
purified by column chromatography on silica gel (0.2–0.5 mm), using dichloromethane/ethyl ace-
tate 10/1 (v/v) as an eluent. Concentration afforded colorless crystals, melting at 122–124 °C (after
recrystallization from acetonitrile). The yield was 17.2 g (93% of theory).
Step c) 5,11-Dihydro-11-[(4-methoxyphenyl)methyl]-6H-dipyrido[3,2-b:2ʹ,3ʹ-e][1,4]d iazepin-6-one
16.7 g (0.0453 mol) of the product obtained in step b) was dissolved in 150 mL of absolute dioxane,
and the resulting solution was admixed with 6.7 g (0.14 mol) of a 50% dispersion of sodium hydride
in mineral oil. Thereafter, the mixture – while protected against the external atmosphere by a low flow
of nitrogen – was refluxed until no starting material could be detected by TLC. The surplus of sodium
hydride was decomposed by cautious addition of 10 mL of a mixture of methanol and tetrahydrofuran
(50/50 v/v). The reaction mixture was neutralized by addition of acetic acid and then was evaporated
in vacuo. The residue was purified by column chromatography on silica gel (0.2–0.5 mm), using suc-
cessively dichloromethane/ethyl acetate 10/1 (v/v) and dichloromethane/ethyl acetate 1/1 (v/v) as
eluents. The crystalline product obtained by evaporation of suitable fractions was recrystallized from
acetonitrile and 2-propanol. The product had an m.p. of 213–215 °C and was identified as 5,11-dihydro
-11-[(4-methoxyphenyl)-methyl]-6H-dipyrido[3,2-b:2ʹ,3ʹ-e][1,4]diazepin-6-one. The yield was 10.3 g
(68% of theory).
Step d) 5,11-Dihydro-6H-dipyrido[3,2-b:2ʹ,3ʹ-e][1,4]diazepin-6-one
10.0 g (0.3 mol) of the product obtained in step c) was dissolved in 50 mL of trifluoroacetic acid,
whereby the mixture became slightly warm. Thereafter, the reaction mixture was stirred at 60 °C
for 1 h. No starting material could be detected by TLC at that time. The mixture was then evaporated
in vacuo. The residue thus obtained was thoroughly stirred with 0.5% aqueous ammonia and then,
was filtered by suction. The raw product was recrystallized from 150 ml of dimethyl sulfoxide to
provide colorless crystals of m.p. >340 °C. The yield was 4.8 g (75% of theory). The product was
identified as 5,11-dihydro-6H-dipyrido[3,2-b:2ʹ,3ʹ-e][1,4]diazepin-6-one.
Patentee in its USP 5569760 [36] acknowledges complexities of USP 5366972 [35].
If the process of ’760 [36] is commercialized as is, most likely, the processing costs
to recover solvents and disposal of waste would be as much as, or more than, the ac-
tual product from this step. This would also be due to low productivity of the process.
102 Chapter 4 Pharma chemistry/chemical development
Table 4.10 is an illustration of Step 1 of Example 1 of USP 5366972 [35]. Similar
information must be generated for each reaction step. This process step uses multi-
ple solvents and the solid concentration is less than 30%. Such an exercise might
look unnecessary and complicated, but it is needed, as it would lead to the develop-
ment of an economic process that will produce a quality product from the get go.
Table 4.10 does not illustrate stoichiometry. It is discussed later in this chapter.
WO 2007/010352 A1 [38] very well reviews scheme 1 and the shortcomings of the
USP 5366972 [35] for the preparation of nevirapine.
– Reduction of 2-chloro-4-methyl-3-nitro pyridine with stannic chloride, employ-
ing acetic acid as a solvent to give 3-amino-2-chloro-4-methyl pyridine. The re-
action is characterized by long reaction times of at least about 12 h and utilizes
a hazardous reagent like stannic chloride, which is difficult to handle on an in-
dustrial scale due to its fuming and corrosive nature. Further, the process is not
environment friendly, since there is considerable load on the effluent treatment
plant for removal of sludge material formed during work up. The preparation of
3-amino-2-chloro-4-methyl pyridine is the first step of the reaction. This has to
be prepared in large quantity, and this proportionately creates a large volume
of the sludge, which becomes difficult to remove on a commercial scale.
– Acylation of 3-amino-2-chloro-4-methyl pyridine with 2-chlor onicotinoyl chlo-
ride in the presence of a base like pyridine, and in a mixture of solvents like
cyclohexane and dioxane to yield 2-chloro-N-(2-chloro-4-methyl-3-pyridinyl)-3-
pyridine carboxamide. The reaction employs a solvent like dioxane, which is
highly toxic for inhalation, an d hence, cannot be utilized on an industrial
scale. Further, dioxane needs elaborate safety precautions during storage and
handling in view of its explosive nature. Further, the yield of the compound of
formula obtained is only about 10%, which is very low for commercial utiliza-
tion. Also, dioxane solvent present in the effluent, if released into soil, is diffi-
cult to remove, as dioxane is not biodegradable.
Tab. 4.10: Step 1 of Example 1 of USP 5366972 [35].
CAS Formula Mol. wt Melting
point (°C)
Boiling point
(°C)
-Amino--chloropyridine -- C
H
Cl
N
–
Cyclohexane -- C
H
..
Pyridine -- C
H
N − .
-Chloro--pyridinecarboxylic acid
chloride
-- C
H
Cl
NO
Dioxane -- C
H
O
.
4.2 Chemical synthesis product/processes/development 103
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– Reaction of 2-chloro-N-(2-chloro-4-methyl-3-pyridinyl)-3 -pyridine carboxamide
with cyclopropyl amine to give 2-N’-cyclopropyl amino-N-(2-chloro-4-methyl- 3-
ρyridinyi)-3-pyridine carboxamide.
– Cyclization of 2-N’-cyclopropylamino-N-(2-chloro-4-methyl-3-pyridinyl)-3-pyridine
carboxamide of formula by employing a strong base like sodium hydride in di-
methyl formamide as solvent, to give nevirapine. Further, this method mentions
that isolation of nevirapine involves quenching with water, which is quite danger-
ous, especially when a reagent like sodium hydride is used, as sodium hydride
reacts violently and explosively with water and is highly flammable.
WO 2007/010352 [38] also reviews USP ‘760 [36]. It suggests that USP ‘760 [36] is a
time-consuming, complex process requiring multiple reactors. It discloses an improved
method for preparing 2-N‘-cyclopropylamino-N-(2-chloro -4-methyl-3- pyridinyl)-3-
pyridine carboxamide, where in the reaction of 2-chloro-N-(2-chloro-4-methyl-3-
pyridinyl)-3-pyridine carboxamide with cyclopropyl amine is carried out in the
presence of an oxide or hydroxide of an element of the second group of the peri-
odic table, with diglyme as solvent. Further, 2-N’-cyclopropylamino-N-(2-chloro-4-
methyl-3-pyridinyl)-3-pyridine carboxamide, thus formed i s not isolated but is
converted after removal of the inorganic base to nevirapine.
According to the inventors of WO 2007/010352 [38], USP ‘760 [36] suffers from
the following drawbacks:
– 2-N’-Cyclopropylamino-N-(2-chloro-4-methyl-3-pyridinyl)-3-pyridine carboxa-
mide formed by reaction with cyclopropyl amine is not isolated; therefore, it is
very likely that an impurity of formula (VIII) disclosed in US 5569760 [36] and
likely to be formed in this reaction will be carried forward to the final stage and
would be isolated along with nevirapine, thereby affecting its purity profile.
– Uses a strong base like sodium hydride, which is difficult to handle on an in-
dustrial scale and also requires stringent conditions such as careful quenching
with water.
Figure 4.6 describes Scheme-II of US 6680383 [37] for the preparation of nevirapine.
This process utilizes a costly base such as sodi um hexamethyl disilazane (HMDS)
for the production of nevirapine.
The method disclosed in Scheme-II USP ‘383 [37] is slightly different from that
disclosed in Scheme-I of USP 5366972 [35], but this route also utilizes a fuming and
costly base such as sodium hexamethyl disilazane in the final step, for preparation
of nevirapine.
In addition, USP 6680383 [37] utilizes a very toxic and hazardous raw material
like 2-halo-3-cyano pyridine, compound IX (Fig. 4.6), which is difficult to handle on
a large scale due to its high toxicity, since compound IX contains a cyano func-
tional group.
104 Chapter 4 Pharma chemistry/chemical development
In view of the above shortcomings, there is a need for a method for preparing
nevirapine, which would not only make the process safe and environment friendly,
but would also be simple and cost-effective for commercial utilization.
Patent WO 2007/010352 [38] describes its process in Fig. 4.7. It claims the
following:
Fig. 4.6: Scheme-ll: Method for the preparation of nevirapine USP 6680383 [37].
Fig. 4.7: Method of preparation of nevirapine per patent WO 2007/010352 [38].
4.2 Chemical synthesis product/processes/development 105
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