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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5994_Библиотеки_им_академика_М_И_Перельмана
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Due to lack of economies of scale, most of these plants, compared to high yearly pro-
duction rate plants (they could be two or three continuous process plants), will be inef-
ficient and have their own waste.
For the synthesis of metoprolol, due to the simplicity of the chemistry and so
much idle equipment at most sites, it should not be difficult for a company to repur-
pose the available equipment to create and commercialize a simple continuous
manufacturing process. Thus, investment for a dedicated new equipment might not
be needed. Such repurposing opportunities are reviewed.
Simplicity of chemistry and the estimated demand suggests that between one or
two continuous plants can easily fulfill the global demand at 100–200 kg/h rate and
operating about 7,500 h/year. Such plant/s, due to economies of scale, would have
an efficient process and, most likely, will have about 30% of the waste generated by
the 51 plants. The continuous process factory manufacturing cost will be significantly
lower than the batch process. This would come through from economies of scale, pur-
chasing power of the raw materials, inventory management (cash flow), and efficient
manufacturing plant/s. In addition to fulfilling the global demand, the production
rate can be modulated in a continuous plant to meet the changing API demand.
Figure 6.9 is a schematic of the metoprolol reaction and reviews the process
equipment options that are a combination of the available conventional equipment
and the equipment that is conventionally not used in the chemical industry. Due to
the smaller size of the pilot plant equipment, the concept of solvent reduction can
also be tested.
In Fig. 6.9, Rx1 and Rx2 are electrically heated tube heat exchangers [40] that
can be used for the reaction process. These would be used as modular reactors and
can be used for the synthesis of other products also. If electrically heated tube heat
exchangers are not available, use of smaller, between 75 and 150 L or smaller jack-
eted reactors, could be evaluated. The idea is to minimize the solvent use by mini-
mizing the reaction mass fluid. In addition, the heat flux to the liquid has to be
maximized. This can hasten reaction times and reduce the batch cycle times, if
batch process is selected for manufacturing.
The following are some of the design considerations for the modular metoprolol
process. This process, if properly designed, can significantly reduce solvent use. It
is highly possible that a properly designed process could be operated as a continu-
ous process to fulfill the global metoprolol API demand. A solvent would be needed
and it can be selected by experimentation. It would be necessary to generate solu-
bility data for the selected solvent.
196 Chapter 6 Active pharmaceutical ingredients (API)
1. Due to the low melting point of p-(2-methoxyethyel) phenol, it can be used as a
melt; thereby reducing/minimizing the need for a solvent. Liquid phenol will
react with caustic to produce the corresponding sodium phenolate, which can
be further reacted with epichlorohydrin in an electrically temperature-controlled
tubular heat exchanger to act as a reactor. The resulting product can similarly be
reacted with isopropylamine in an electrically heat-controlled tube heat ex-
changer, acting as a reactor. Since the intermediates are low melting point mate-
rials, an opportunity to minimize the solvent use exists and needs to be explored.
Temperature/solubility relationship of each step’s reaction product will have to
be generated. Similarly, reaction and the solubility parameters for the epichloro-
hydrin derivative will also have to be generated, and the properties used in the
reaction process.
2. Since solvent use can be minimized, the reaction can be carri ed out at high
temperatures. This would result in a zero-order reaction, thereby minimizing
the reactor volume needed. Safety cannot be compromised. Instead of using a
conventional reactor, an electrical heat-controlled tubular heat exchanger [40]
can act as the reaction space. Use of an electric tubular heat exchanger, as a
reactor, minimizes the large reactor space that, in conventional reactors, has to
be filled with a solvent for proper mixing and heat transfer. If such heat ex-
changers are not available, small jacketed reactors need to be evaluated. Reac-
tion residence time will determine heat exchanger configuration.
3. Isopropyl amine has a low boiling point and it can be used to improve mixing,
thereby improving the reaction rate.
4. A water/toluene mix and a subsequent decanter [46] use will simplify the pro-
cess further.
5. In the patents reviewed, intermediates are purified. That may be an acceptable
practice for the laboratory process develo pment, as their property information
is an indicator of the in-process quality. This can be used to optimize the pro-
cess and is necessary for an economic and viable process. Such pro cesses, if
commercialized, would have a low “E-factor.”
Fig. 6.9: Metoprolol simplified manufacturing process schematic.
6.6 API examples 197
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Depending on the production capacity, p-(2-methoxyethyl) phenol for the metopro-
lol process has three feed options.
1. p-(2-Methoxyethyl) phenol could be received as liquid in a tank truck.
2. p-(2-Methoxyethyl) phenol, received as solid, could be f ed using options sug-
gested in Fig. 6.3 or 6.5.
6.6.2 Hydrochlorothiazide (HCTZ)
Synthesis of hydrochlorothiazide, Fig. 6.9, is another classic text book chemistry.
With its estimated global need of about 0.7 million kg/year [53], its production at
about 50 plants [54] suggests that the processes have been fitted in the existing plants
[16, 17]. This, most likely, has happened not due to the capabilities of the chemists
and chemical engineers but due to business model of the different companies and
the lack of processing options available.
Following are the steps outlined in the USP 2965675 [56].
Step 1: m-Chloroaniline (64 g, 0.5) is added dropwise, with stirring, to 375 mL
chlorosulfonic acid in a 3 L, round bottom, three-necked flask, cooled in ice bath.
Sodium chloride (350 g) is added, portion–wise, over a period of 1–2 h and the mix-
ture is then heated gradually in an oil batch to 150 °C. After 3 h, at 150–160 °C, the
flask is cooled thoroughly in an ice bath and the contents treated with a liter of cold
water. The product is extracted with ether, and the extract washed with water and
dried over sodium sulfate. After removal of ether on the steam bath, the residual
5-chloroaniline-2,4-sulfonyl chloride is crystallized from benzene–hexane, MP
130–132 °C.
Fig. 6.10: Synthesis of hydrochlorothiazide [55].
198 Chapter 6 Active pharmaceutical ingredients (API)
Step 2: The product from step 1 is cooled in an ice bath, treated with 150 mL of
28% ammonium hydroxide solution, and the mixture is heated to produce 4-amino
-6-chlorobenzene-1,3-disulfonamide. It is crystallized.
Step 3: 88 g of 4-amino-6-chlorobenzene-1,3-disulfonamide is treated with 1.1 liter
of formic acid, under reflux, to produce 6-chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine
-7-sulfonamide 1,1-dioxide (HCTZ). HCTZ would then be crystallized.
In other patents [57, 58], formaldehyde is added, twice, to complete the reac-
tion. These syntheses are developed in the laboratory to show feasibility. Such in-
termittent additions are di sruptive to the actual plant manufacturing process, if
commercialized. They also prolong the batch cycle time, and also lead to frequent
sampling of in-process material to check intermediate product quality and the reac-
tion progress. These have to be minimized and avoided.
HCTZ chemistry needs to be streamlined and revised for a viable and economic
commercial process. Information from the patents [55– 58]andTab.6.9[59]canbe
used to develop and define the operating con ditions. The following need to be
considered.
1. Operating conditions and methods mentioned in the patent show the feasibility
of the chemistry, but they may not be the optimum processing conditions for
the equipment to be used. They will have to be validated and refined for the
operating conditions.
2. Laboratory operating conditions andprocesswouldhavetobetestedinthe
equipment to be used, to assure that the process uses minimum and safe sol-
vent, which can be easily recycled. Solubility data would have to be generated
for the selected solvent.
3. How can the solvent use be minimized and kept to a single solvent?
4. Stoichiometry suggested in the USP 2965675 [56] needs to be reviewed, as it sug-
gests excessive amount of chlorosulfonic acid. Excess will have to be neutralized
and disposed as waste.
5. Depending on the volume of the product to be produced at a site, equipment
selection becomes critical.
6. Purification process would need to be developed and tested.
Physical properties Tab. 6.7 give clues about the process simplification.
Figure 6.12 is a suggested simple process schematic for the production of HCTZ.
Reaction products after each step are solids at room temperature. Solvent selection
and reaction conditions need to be defined.
It may be possible to carry out the first reaction step as a melt and maintain the
temperature at about 135 °C to keep the reaction mass liquid. Use of sodium chlo-
ride, USP 2965675 [56], suggests that the inventors were trying to use the melting
point of the disulfonyl dichloride as the reaction media. Preferably, a single solvent
of high boiling point, instead, could be used as a solvent for the whole reaction. It
would be added to the liquid from the first reaction step to assure a fluid mass
6.6 API examples 199
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when liquid ammonia is added to the process, to produce 4-amino-6-chlorobenzene
-1,3-disulfonamide, which is a high melting point solid.
For amination, the use of liquid ammonia will significantly improve the reac-
tion rate. It will also free up the reactor volume that would have been occupied by
water if ammonium hydroxide solution is used. Ammonia addition rate can be used
to control the heat of exotherm. Sulfonamide, from step two, reacts with formalde-
hyde to produce HCTZ, a solid at room temperature. Formaldehyde reaction can
also use an electrical heat exchanger, reviewed earlier [40], with proper residence
time as a reactor.
An experienced chemist and chemical engineer will totally understand the reac-
tion mechanics and would do everything possible to have a simple process, similar
to the one illustrated in Fig. 6.12. Purification process for HCTZ would have to be
developed and tested.
Tab. 6.9: Physical properties of chemicals for hydrochlorothiazide [59].
Chemical CAS Chemical formula Mol. wt MP (°C) BP (°C)
-Chloroaniline -- C
H
ClN . −.–
Chloro sulfonic acid -- ClHO
S . − –
-Amino--chlorobenzene
-, disulfonyl dichloride
-- C
H
Cl
NO
S
. –
Ammonia -- NH
− −
-Amino--chlorobenzene
-,-disulfonamide
-- C
H
ClN
O
S
. –
p-Formaldehyde -- OH(CH
O)
n
H
(n = –)
Hydrochlorothiazide -- C
H
ClN
O
S
.
Fig. 6.11: Process for HCTZ manufacture.
200 Chapter 6 Active pharmaceutical ingredients (API)
Laboratory equipment can be used to test each individual step of the process
concept outlined above. It will also allow the development of processing conditions
that would need to be tested and improved.
Use of pilot plant would be necessary to authenticate the above outlined con-
cept. Some of the equipment that have been discussed earlier should be considered
to reduce the solvent use. Kinetics of each reaction step can be managed using elec-
trically heated tubular heat exchanger or small jacketed reactors. These could sig-
nificantly reduce the total volume of the reaction space if the product can be
campaigned or produced continuously using modular equipment. Reduced reaction
space would translate to reduction in solvent use.
Modular equipment shou ld be considered for commercial production. If such
equipment is not available, consider ation should be give n to using pilot plant
equipment that is much smaller compared to traditional reactors, as modular reac-
tors/equipment. Its use would reduce the solvent needed for the process. It might
lead to a continuous process to produce the global demand at a single site. Multiple
formulation lines would be needed to produce different dose tablets.
6.6.3 Dimethyl fumarate
Commercial production of dimethyl fumarate , like other fine/specialty chemicals,
presents an opportunity to improve and simplify its manufacturing process. The
processing parameters that are explored in the laboratory show the pathway, but
need to be reviewed for a commercial operation. Figure 6.12 is the chemical synthe-
sis for the reaction.
Using maleic anhydride, various syntheses processes have been presented [60–63].
In these, anhydride is reacted with methanol using different catalysts (e.g., H
2
SO
4
,
thiourea, AlCl
3,
acetyl chloride, etc.) to produce mono methyl fumarate, which is
then converted to dimethyl fumarate.
Dimethyl fumarate can also be produced from fumaric acid. However, this
route, as explained in Chapter 5, based on the price difference of maleic anhydride
versus fumaric acid, is not only more expensive but also produces additional water
as a by-product, which increases the waste handling load.
Fig. 6.12: Maleic anhydride route.
6.6 API examples 201
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Processing conditions for the maleic anhydride route, which includes the catalyst,
need to be defined. References [60–63] indicate the conversion from maleic anhydride
to be a two-step process route, suggested in Fig. 6.13, which is very viable. Smaller
pilot plant reactors or modular reactors or electrically heated heat exchangers [35, 40]
can be used for the process. Processing conditions for either of the process routes will
need to be defined and optimized. Since the process can use alternate smaller-sized
equipment, the solvent used in the process would be considerably reduced.
6.6.4 Omeprazole
Omeprazole is a large-volume drug [64] used for acid reflux treatment. Its levo-
enantiomer, sold under the Nexium name, is also a high-volume drug. Omeprazole,
due to its high volume, most likely, would be produced in conventional-sized reac-
tors that are used in the fine/specialty chemical industry. This is due to the similarity
of manufacturing methods. As we all know, small-molecule active pharmaceutical in-
gredients are fine/specialty chemicals that have healthcare value. Otherwise, the
chemistry and manufacturing methods are the same and similar.
A simplified block process diagram or similar diagram, illustrated in Fig. 5.23
[65–67], would, most likely, be used by most companies. However, the chemistry
and the manufacturing process can be further improved if an attempt is made to
minimize the solvent in the chemistry that would be commercialized using conven-
tional processing equipment.
A review of the chemistry and various patents suggests the use of toluene as a
solvent. Developers have done an excellent job of using the recovered wet toluene.
It improves the yield and drivestheprocesstoloweringits“E-factor” [6]. Since solvents
form a large volume of the reaction mass, their use can be reduced and the chemistry
can be practiced using the pilot plant size or modular reactors as schematically shown
Fig. 6.13: Dimethyl fumarate process flow diagram.
202 Chapter 6 Active pharmaceutical ingredients (API)
in Fig. 6.14. The process can be operated in batch or continuo us mode. It is very
likely that the manufacturing company will adopt the continuous operation mode,
once they have realized the value of benefits of capitalizing on the physical proper-
ties of the reactants.
For the continuous process, instead of using conventional large reactors, it is possi-
ble to use small reactors (75–150 L) or back mix plug flow reactors [68] that have
been used in the fine/specialty chemical manufacturing. The produced product can
be crystallized [69] continuously using the established criterion. Chemical engi-
neers, who are familiar with process designs, would not have any problem commer-
cializing such a process.
6.6.5 Modafinil
Synthesis of modafinil is another example of classical chemistry that can let an
imaginative and creative chemist/chemical engineer, through exploita tion of the
physical and chemical properties and by selection of proper equipment, to commer-
cialize a process that can have a significantly lower “E Factor” than the current
practices.
Using the modafinil chemistry [70] (Fig. 6.15), a simplified process and flow dia-
gram is explored in Figs. 6.16 and 6.17 [71].
Conventional reactors and equi pment would be used for production. Conse-
quently, they will have a high “E-factor.” Based on modafinil’s global demand, all of
the needed API, using a continuous process, can be produced at a single plant [72].
However, multiple formulation plants would be required.
Fig. 6.14: Batch/continuous process for omeprazole.
6.6 API examples 203
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Equipment and concepts, reviewed earlier in this chapter, in combination with
modular reactors and smaller reactors versus conventional large reactors can be
creatively used to significantly lower the solvent use.
As said earlier, each of the potential processing methods and equipment used
has to be tested in laboratories and/or pilot plants. Chemical engineers and chemists,
Fig. 6.15: Modafinil chemistry [70].
Fig. 6.16: Version ONE simplified modafinil process flow diagram [71].
204 Chapter 6 Active pharmaceutical ingredients (API)
who are well versed, can emulate, create, and test. They have to incorporate and ex-
ploit the physical properties to their advantage. It is necessary to emphasize that the
solvent use has to be limited to one additional solvent, besides water, and volume
use has to be minimized. Simple and efficient processes that will produce the highest
quality product with best economics can be commercialized.
6.7 Pharma’s continuous improvement process and why it has
lagged
Having discussed the alternate equipment and methods that can be used to exploit
manufacturing, an opportunity exists to lower the “E-factor” for the pharmaceutical in-
dustry Tab. 6.1. By definition, “continuous improvement” requires companies to put in
an ongoing effort to improve their manufacturing technologies and processes. Unless the
regulatory agencies facilitate such a change [5] and companies are held accountable for
their product’s performance, such an effort has not and will not be forthcoming.
The laws imposed by regulatory agencies, such as the FDA in the US, present sub-
stantial barriers to “continuous improvement” in the pharmaceutical industry. It is
not possible for a manufacturer to implement any process change without a regulatory
agency review. Regulatory agency review costs time and money; hence, there is no or
little motivation for a manufacturer to engage in “continuous improvement.” It is pos-
sible that more monies may be spent in a re-approval than the monies spent in im-
proving the process.
Companies do make an effort. Sildenafil and Lyrica [74, 75], ibuprofen [75, 76] are
excellent examples. Their “E-factor” numbers were lowered only after their patents
Fig. 6.17: Version TWO simplified modafinil process flow diagram [71].
6.7 Pharma’s continuous improvement process and why it has lagged 205
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