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Fig. 5.14: Omeprazole synthesis.
Tab. 5.12: Properties of the chemicals involved in the production of omeprazole.
Chemical CAS no. Chemical formula Mol. wt MP (°C) BP (°C)
Pyrmethyl alcohol -- C
H
NO
. −
Thionyl chloride -- SOCl
−..
Toluene -- C
H
− .
Pyrmethyl chloride -- C
H
NOCl
–
Caustic % -- NaOH
Metmercazole -- C
H
N
OS – .
Pyrmetazole -- C
H
N
O
S Solid @ RT
m-Chloroperoxybenzoic acid -- C
H
ClO
.–
Omeprazole -- C
H
N
O
S
146 Chapter 5 Manufacturing process development and case studies
use batch processes even when the demand is high enough (Tab. 5.13) to produce it
using a continuous process.
If the global demand for Nexium (esomeprazole sodium, the s-enantiomer of
omeprazole) is included with omeprazole demand, the overall demand for omepra-
zole far exceeds the demand illustrated in Tab. 5.13. Concept and process scheme of
a continuous omeprazole process are reviewed [82].
A well-trained chemical engineer or chemist can take teachings of the referenced pat-
ents [67–76, 83] and physical and chemical properties to create an excellent continu-
ous process. However, most likely they may use traditional design of new reactors
ranging from 1,500 to 5,000 L and/or most likely use existing reactors to their process
in the available equipment [15, 16]. There are alternate manufacturing technologies
and strategies that are available but have not been considered for commercial pro-
duction. They are discussed later in this chapter.
5.8 Metoprolol
Metoprolol is another drug that makes the top 20 drug list [37]. Using US demand,
this drug ’ s global demand is extrapolated. With one prescription per person about
20% of the US population [84] uses this drug. This number cannot be applied to the
global population, and it is assumed that only 1% the global population uses this
drug at 50 mg per day [Tab. 5.14].
API metoprolol’s global demand [Tab. 5.14] is large enough to have a very effi-
cient continuous process. Synthesis of metoprolol is a classical fine/specialty chemis-
try that is simple and can be easily executed. Figure 5.15 is the illustration of the
chemical reaction.
Manufacturing process of metoprolol [85] is revie wed further. Tab. 5.15 lists
physical properties of the chemicals involved in Metoprolol synthesis.
1-(2,3-Epoxypropoxy)-4-(2-methoxyethyl) benzene p-(2-methoxyethyl)phenol
(A, ~ 6.6 mol), epichlorohydrin (B, 1.45 equiv.), and water (~2 kg) were combined and
the mixture is heated to ~ 50 °C.
Tab. 5.13: Global annual omeprazole API demand.
Global population ,,,
Population in need of omeprazole %
Dose, mg/day ,,,
@ Days per patient, total milligrams ,,,,
API, kg ,,
5.8 Metoprolol 147
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Sodium hydroxide solution (50%; 1.4 equiv.) was added during 3 h and the tem-
perature was elevated to reach approximately 60 °C. during the addition. Formation
of the title compound occurred during this period.
The batch was stirred for another hour at approximately 60 °C, then cooled to
approximately 50 °C, and the phases were separated and the product washed with
water.
Tab. 5.14: Global metoprolol API demand.
Global population ,,,
% using metoprolol %
Dose, mg/day
Days/year
API needed kg/year ,,
Fig. 5.15: Metoprolol synthesis.
Tab. 5.15: Physical and chemical properties of metoprolol chemicals.
Chemical CAS no. Chemical
formula
Mol.
wt
MP (°C) BP (°C)
p-(-Methoxyethyl) phenol ,-- C
H
O
@
mm Hg
Epichlorohydrin -- C
H
ClO . −.
Caustic, % -- NaOH
[-(-Methoxyethyl)phenoxy]methyl]oxirane ,-- C
H
O
Isopropyl amine -- C
H
N −
Metoprolol [-[-(-methoxyethyl)-phenoxy]
--(isopropylamino)--propanol]
,-- C
H
NO
148 Chapter 5 Manufacturing process development and case studies
The residue was distilled at ≤190 °C, and a pressure of ≤20 mm Hg and the dis-
tillate was collected. The yield of the title compound was 80% of theory and t he
purity was 98% according to GC analysis.
1-(2,3-Epoxypropoxy)-4-(2-methoxyethyl)benzene (1 kg, 4.8 mol), isopr opyl al-
cohol (~0.9 kg), and isopropylamine (0.8–1.7 kg, 3–6 equiv.) were mixed and re-
acted for 2–5 h at reflux. Formation of metoprolol base occurred during this period.
The reaction mixture was then concentrated at atmospheric pressure until the
inner temperature reached ~100 °C. Water was added to the batch and then distilled
off in vacuo until the inner temperature reached ~100 °C to form a concentrate.
The resulting concentrate was diluted with isobutyl methyl ketone (~0.6 kg) and
water (~2.2 kg), and concentrated sulfuric acid was added to adjust the pH to 4–6.
After separation, isobutyl methyl ketone (~1 kg) was added to the water layer,
and concentrated sodium hydroxide solution was added to adjust the pH to 13.
The organic layer was concentrated in vacuo at ≤80 °C, until distillation ceased,
and the concentrated batch was redissolved in acetone (~1.6 kg) and filtered, to
yield metoprolol base solution. The assay of metoprolol base in the solution was
determined by titration. Yield: ~1.2 kg metoprolol base (100%) ~95% of theory. The
purity of the metoprolol base was 96%.
In this process, reactants are added sequentially per the reaction mechanism to
create a good process. This has to be translated to a commercial process similarly.
Additional optimization and improvements are possible. No suggestions are made as
they can be best reviewed and implemented by the scale-up team. Table 5.16 reviews
the theoretical and patent-suggested stoichiometry. In the patent compared to a
molar need for isopropyl amine, a large excess is used.
Theoretically, 1 mol of p-(2-methoxyethyl) phenol is reacted with a mole of alkali to
produce the sodium salt which is then reacted with epichlorohydrin. The resulting
oxirane compound is reacted with isopropyl amine to produce the desired product.
Schematically, Fig. 5.16 is an illustration of the reaction and its mechanism.
Tab. 5.16: Theoretical and actual mole ratio comparison.
Patent US / A []
Chemical Theoretical Actual
p-(-Methoxyethyl) phenol ..
Epichlorohydrin ..
KOH ..
Isopropyl amine ..
5.8 Metoprolol 149
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There are other synthesis methods disclosed [86–88]. They can be reviewed
and their teachings used to design and commercialize excellent process.
Traditionally, manufacturing of metoprolol like other fine/specialty chemicals
is produced in commercially available equipment. Due to the simplicity and the vol-
ume of the needed product, this can also be produced using a continuous process.
This is reviewed later in the chapter.
5.9 Modafinil
Modafinil synthesis is reviewed here. It was a blockbuster drug in around 2010–2012. It
was categorized that way due to its yearly sales being over 1 billion dollar per year
rather than high consumption. Five million patients using the drug are estimated at
0.06% of the global population (Tab. 5.17). Thiscouldbeconsideredasaconservative
number.
Its process chemistry [89, 90] is a classical organic chemistry tha t is illustrated in
Fig. 5.17. Many other patents have been filed for modafinil manufacturing processes
[91–101]. Additional synthesis methods have also been published [102–105]. These
Fig. 5.16: Metoprolol reaction mechanism.
Tab. 5.17: Global modafinil API need, kg/year.
Global population ,,,
% Global patients .%
Patients number ,,
Dose, mg/day
Days/year
Yearly API need, kg ,
150 Chapter 5 Manufacturing process development and case studies
teach different approaches and synthesis methods and are of value. Figure 5.17
illustrates the theoretical reaction chemistry.
Purpose of this discussion is to review how the nuances of the reaction mechanism,
chemistry and physical and chemical properties of a synthesis can be exploited to
create a simple manufacturing process. It is difficult to say if these are exploited to
the fullest with the current manufacturing practices. Since it is being produced at
multiple sites [106], most likely they are not. Companies are also not able to capitalize
on economies of scale and the product is being produced using existing process
equipment [15, 16] that is too large for the process. This is generally the case when a
process is fitted in the existing equipment.
Table 5.18 illustrates some of the chemical and physical properties of the reac-
tion components.
Benzhydrol + Thiourea + HBr S-benzhydrylthiouronium bromide + H
2
O
S-benzhydrylthiouronium bromide + KOH Benzhydrylthiol + Potassium bromide +Urea
Benzhydrylthiol + chloroacetamide 2-diphenylmethyl thio acetamide + HCl
2-(benzhydrylthiol) acetamide + Acetic acid +H
2
O
2
2
-[(Diphenylmethyl)sulfinyl]-acetamide [Modafinil]
Fig. 5.17: Modafinil chemistry.
5.9 Modafinil 151
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An example of laboratory modafinil synthesis outlined in USP ‘893 [89] is as
follows and is analyzed further.
To a suspension of benzhydrol (35.00 g,0.188mol,1equiv.)andthiourea
(17.40 g, 0.226 mol, 1.20 equiv.) in tetrahydrofuran (THF)/water (35.5 mL/52.5 mL),
an aqueous 48% HBr solution (25.3 mL, 0.226 mol, 1.2 equiv.) over a 10 min period
was added. During the addition, the reaction mixture is heated to 70 °C. After 3 h
stirring at 70 °C, the uronium intermediate was hydrolyzed by addition of an aque-
ous 9.3 N potassium hydroxide solution (58 mL, 0.542 mol, 2.88 equiv.) over a
55 min period. After 1.5 h stirring at 70 °C, chloroacetamide (26.6 g, 0.282 mol, 1.5
equiv.) in a THF/water (80 mL/79 mL) solution was added over 15 min. After 1 h
stirring at 70 °C, the reaction mixture was cooled down to 55 °C and the stirring was
stopped. The lower aqueous phase was removed, and the reaction mixture was
again stirred. Acetic acid (34.7 mL, 0.601 mol, 3.2 equiv.) was added. Hydrogen per-
oxide 30% (38.4 mL, 0.376 mol, 2 equiv.) was slowly added over 30 min. After 1 h
stirring, the reaction mixture was cooled to 20 °C and water (263 mL) was added.
The resultant suspension was stirred at 0 °C overnight. The suspension was then
filtered, and the solid was washed with water and dried to yield modafinil (47.9 g,
80.4%). The crude modafinil was purified by recrystallization in methanol.
Table 5.19 compares the theoretical and laboratory mole ratios. Such comparison
and review is of value and indicates the potential for process optimization. THF/
water mix is used as a solvent. Sodium hydroxide can be an alternate for KOH [94].
Modafinil reaction chemistry and physical properties offer opportunities to ex-
ploit and simplify the process. Benzhydrol is solid at room temperature. By tradition,
Tab. 5.18: Physical and chemical properties of modafinil reactants.
Chemical Formula CAS no. Mol. wt MP (°C) BP (°C)
Benzhydrol C
H
O --
Hydrobromic acid HBr ,-- −
Bromodiphenylmethane C
H
Br -- ~ ºC ( mm Hg)
Tetrahydrofuran (CH
)
O -- −
Thiourea CH
N
S --
KOH KOH -- −
Diphenylmethanethiol C
H
S --
Chloroacetamide C
H
ClNO --.
Acetic acid CH₃COOH --
Hydrogen peroxide H
O
-- −. .
Modafinil C
H
NO
S ,--
152 Chapter 5 Manufacturing process development and case studies
a solvent is used in the laboratory to facilitate the reaction. This is an acceptable
practice. This would also be followed in scale-up in a pilot plant and on a commercial
scale. Generally, between 25% and 40% solvent is used if a solid reactant is involved.
This is also necessary for 1,500 L or above volume reactors. Solvent facilitates mixing
and heat transfer but contributes to lower productivity. For higher productivity, their
use has to be minimized.
In step 1 of Modafinil synthesis, a slurry of benzhydrol and urea in THF/water
and hydrobromic acid are heated to 70 °C. An alternate [97] could be solubilizing
thiourea in an appropriate solvent [35, 107, 108] with hydrobromic acid and reacting
the mixture with be nzhydrol to produce S-benzhydrylthiouronium bromide which
is processed further to produce the modafinil.
Another alternate for step 1 (Fig. 5.18) is reacting benzhydrol as a melt with hydrobro-
mic acid to produce bromodiphenyl methane which is reacted with thiourea to produce
Tab. 5.19: Modafinil stoichiometry comparison.
Chemical Theoretical Actual
Benzhydrol .
Thio urea ..
KOH ..
Chloroacetamide ..
Acetic acid ..
H
O
..
Fig. 5.18: Step 1 alternate process.
5.9 Modafinil 153
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S-benzhydrylthiouronium bromide (Fig. 5.18). Since bromodiphenyl methane’smelting
point is about 35 °C, this can be used as a fluid in the process to reduce or minimize
the use of THF/water or any other solvent in this step. Formation of bromodiphenyl
methane also generates a mole of water. Thus, the solvent use can be reduced.
Reviewed alternates could significantly reduce the reactor size. The overall re-
action time can be reduced if the reaction temperature is raised. In the annals of
chemistry this is well known that raising the reaction temperature by 10 °C doubles
the reaction rate [109].
5.10 Levothyroxine
Levothyroxine is an important drug for hypothyroidism. It is estimated that there
are approximately 1 billion users globally. An average use of 112 µg/day per person
would require about 41,000 kg to satisfy the global need. USP ‘295 [110] is reviewed.
This chemistry is an application of iodization processes developed using bleach
and sodium iodide [111–113].
Step 1 of Example 1 of USP ‘295 [110] is as follows.
3,5-Diiodo thyronine (50 g, 0.095 mol) was added in methanolic methyl amine
(250mL)at20–30 °C followed by addition of sodium iodide (49.99 g, 0.333 mol),
and reaction mixture was stirred to get a clear solution. Aqueous solution of sodium
hypochlorite [preparation: sodium hypochlorite (464 mL, 0.333 mol) in w ater
(193 mL)] was slowly added in the reaction mixture and the mixture was stirred for
2–4 h. After completion of the reaction, the mixture was cooled at 5–10 °C and acidi-
fied to pH 4.0–5.0 using 50% hydrochloric acid (~22 mL). The reaction mixture was
stirred for 30 min at 25–30 °C. The resultant solid was filtered and spray washed
with methanol (50 mL). The obtained solid was dried at 50 °C under reduce d pres-
sure to get title compound (weight: 72 g, yield 97%).
In this step, it would be worth reviewing the sequence of addition of sodium
iodide and bleach. It could improve the reaction and reduce the excessive use of
iodide and bleach.
Fig. 5.19: Levothyroxine synthesis USP ‘295 [110].
154 Chapter 5 Manufacturing process development and case studies
5.11 Status of the current manufacturing technologies
The history of pharmaceuticals discussed in Chapter 1 indicates that the development
and commercialization of many small-molecule drugs had their origin in the late nine-
teenth and early twentieth centuries at fine/specialty chemical companies. Since there
were/are chemistry and manufacturing similarities, equipment available at these com-
panies was used to manufacture these APIs. The need to change manufacturing prac-
tices has not been considered necessary. As a result, manufacturing technologies
between API and fine/specialty chemical manufact uring practices besides quality
considerations have not changed much in over 100 years.
Another factor influencing lack of innovation is the price differential between
API manufacturing cost and sale price illustrated in Tab. 5.20 and the drug selling
price (Tab. 5.1). Innovation might be beneficial to the API manufacturers resulting
in cost reduction: however, the average patient will never see any impact.
With many companies producing the same API at low volumes, there is lack of
economies of scale. This prevents innovation [114].
The resulting lack of economies of scale benefits neither manufacturer nor user.
Despite the lack of economies of scale and production inefficiencies, profits from API
sales remain high compared to “average” fine/specialty chemical (~$2–10/kg ). In-
deed, so high that there is no driver for innovation in many/most cases.
Under the current business scenario, brand API manufacturers have no price bench-
mark for their new molecules. Their drug selling prices are set to maximize their prof-
its. The API price component of the drug selling remains low (Tab. 5.1). Thus, having
efficient chemistry and excellent manufacturing technology does not matter to an
average patient. It is up to each company to optimize the chemistry and commer-
cialize the most economic manufacturing. Getting the product approved and to
the market is the highest priority. Due to availability of the equipment and com-
pany’s ability to fit the process in the existing equipment [15, 16], a need for inno-
vation does not arise.
Generic API producers attempt to develop better chemistries and manufacturing
technologies than the brand API. They have the time and they must compete against
other generic companies. This is evident by many patents that are filed by the generic
Tab. 5.20: Factory cost and selling price of selected APIs.
API Factory cost ($/kg) Selling price ($/kg)
Mycophenolate mofetil []
Dimethyl fumarate (Tecfidera) . (Tab. .) []
Modafinil . [] []
5.11 Status of the current manufacturing technologies 155
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