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7.4.11 Ammonia
7.4.12 Hydrochloric acid
7.5 Section 4: process chemistry and heat balance
7.5.1 Process chemistry
In this section, the chemistry of the process is described. Metformin hydrochloride
chemistry is used as an example. It is necessary to outline the chemistry and its ra-
tionale, as it is used for the process design. Of the three potential processes sche-
matically shown earlier, a batch process (Fig. 7.6) [20] is used.
Tab. 7.18: Physical properties of ammonia [42].
Ammonia NH
Boiling point (°C) −.
Density, liquid at − °F/–. °C ( atm., kg/m
)
Density, liquid at °F/. °C (kg/m
) .
Heat (enthalpy) of evaporation, ΔH
v
, at boiling point
(kJ/kg)
.
Heat(enthalpy) of formation, ΔH
f
(gas) (kJ kg) −,
Heat (enthalpy) of fusion/melting, ΔH (m, kJ/kg) .
Melting (freezing) point (°C ) −.
Molecular weight
Specific heat, C
p
(gas) (kJ/kg K) .
Specific heat, C
p
(liquid) (kJ/kg K) .
Tab. 7.19: Physical properties of hydrochloric acid [43, 44].
Hydrochloric acid HCl, Be
CAS --
Mol. wt .
Melting point (°C) −
Boiling point (°C)
236 Chapter 7 Process documentation and operating strategies
Hydrochloric acid is charged to the designated reactor and then, the desired
amount of DMA gas is bubbled into the hydrochloric acid. Reaction temperature is con-
trolled. After the desired residence time, the batch is transferred to the next reactor,
which is used as a centrifuge feed tank. The filtrate is recycled, if necessary, to ensure
that there is no unreacted dimethyl amine. Wet dimethyl amine hydrochloride is dried.
In Reactor 3, the desired amount of xylene is charged, and desired amounts of
dimethylamine hydrochloride and dicyandiamide are charged. The reaction mass is
heated, and the desired temperature is maintained. Evaporated xylene is condensed
and recycled. The reaction mass is transferred to Reactor 4, where carbon is added
to decolorize the metformin hydrochloride solution. The reaction mass temperature
is maintained to ensure that metformin hydrochloride is dissolved in xylene. After a
designated time to ensure that the solution has met the color specifications, the re-
action mass is transferred to a reactor where the reaction mass is cooled to precipi-
tate all of the metformin hydrochloride, which is centrifuged and dried.
7.5.2 Heat and mass balance
Table 7.20 is a typical heat and mass balance sheet for a batch process. It is ex-
tremely important that the physical properties of each process stream are included,
as they are needed to design every part of the process, e.g., piping, pumps, heat ex-
changers, and other material handling equipment. Details of properties and flow
rate at the operating temperature are critical to design the process.
All the streams and those that include recovery and disposal have to b e in-
cluded. In this exam ple, to protect the confidentiality of the process, components
have not been defined. However, a chemist and/or a chemical engineer will fully
understand the value of such mass balance.
Since mass balance and processing conditions for most batch processes are dif-
ferent, it is necessary to know that proper equipment is used for an efficient pro-
cess. However, that is normally not the case. Mostly, the equipment that is available
on site is used [8, 9]. They generally lead to prolonged batch cycle times, inefficient
process, and lower-than-desired yields. This has been discussed in earlier chapters.
Fig. 7.12 is an illustration of a continuous process. Heat and mass balances for a
continuous process are similar to batch process heat and mass balance. In this ex-
ample, Table 7.21, to protect proprietary information, components have not been
defined. However, chemists and chemical engineers will understand the value of
such information. Additional properties and other relevant information that are
necessary for equipment design should be included.
In every chemical process, design, reactors, heat exchangers and pumps are in-
volved. Other specialized equipment might be needed. Using the process operating
parameters, design rationale of each equipment becomes critical. This is important
for every continuous process.
7.5 Section 4: process chemistry and heat balance 237
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Tab. 7.20: Heat and mass balance of a batch process.
Mix Rx 1 Filter
10
96
7
8
5
4
1
2
3
5000
1248
1248
2496
B
A
Component
Stream Number
C
D
E
F
Total
Teemo °C
Pressure
Specific gravity
Viscosity, Pascal second
Sp. Heat, cal/kgC
pH
1.232 1.525
0.783 1
1
25 47
23821
5360
5360
1.334 1.525
1184
592
420
85 80
80
20 29925
19754
592
0.0017
0.38
16325
16325
34 5 6 78910
50
5000
12
238 Chapter 7 Process documentation and operating strategies
Fig. 7.12: Process flow diagram of a continuous process.
7.5 Section 4: process chemistry and heat balance 239
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However for batch processes, the equipment is not necessarily designed for a
specific product. Documentation of the process and other details mentioned in
Tab. 7.2 can be a challenge. In these circumstances, extra care and scrutiny are
needed at the start of each batch campaign. Product quality becomes pa ramount,
in such cases.
7.6 Section 5: process equipment
For the manufacture of APIs as mentioned earlier, batch or continuous process are
the two choices. However, based on the total global volume of each API, many
plants produce the same API [45]. This suggests that each company could produce
the API using their own process, chemistry, and equipment, which could be dissim-
ilar to those of the next company or their own site. If the company outsources the
API to a CMO (contract manufacturing organization), their equipment and methods
could be different, too.
The manufacturer’s approved API ANDA would be based on the equipment that
is available at their site and is used for commercial production. It is expected that
the process engineers would design a process that fits like a glove in new or existing
equipment. Documentation of the process design and its rationale is critical for con-
sistent product quality. It is important for each producing company to know the
characteristics of each piece of equipment, so that the selected equipment and the
process produce the desired quality product, from the onset.
If the same equipment is not available for routine product campaigns on an on-
going basis, it is very likely that the product profile could be different for each
batch in each campaign. It is possible that the operating parameters and the operat-
ing procedures might have to be altered to assure quality. Thus, the documented
information can be used to troubleshoot the process, if there is need. In addition,
some of the “in-process” analysis can be minimized if every nuance of the reaction
operating parameter and equipment performance is understood and is accounted
for, in the operating procedure.
The basis of equipment selection and design criteria for the reactors, pumps,
heat exchangers, centrifuge, and distillation unit have to be documented in the
technical manual. Though the practice of documenting the design details might be
considered obsolete, without the documentation of “why and what” of the process,
no one will understand the rationale for the equipment design and its operations.
Considering job reassignments, retirement, and job changes of operating produc-
tion staff, such documentation is critical.
Process operating instructions are written on the basis of process chemistry and
equipment design and authenticated. But if they are not practiced batch after batch
or for the continuous process, it is very likely that the product will have batch-to-
240 Chapter 7 Process documentation and operating strategies
Tab. 7.21: Heat and mass balance of a continuous process.
7.6 Section 5: process equipment 241
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batch or lot-to-lot product quality variation. This cannot be tolerated, as it will result
in lesser product quality and recalls. Thus, it is necessary that the equipment used is
operated as close as possible to the process design criterion documented in the prod-
uct’s process operating manual. Process performance cannot deviate from the estab-
lished process.
It is importan t that the functionality of the process equipment used for each
processing step be described in the manual. If any equipment is specially designed
and/or fabricated for use in the process, its description should be included. Agitated
tanks that are used for holding materials need to be included. If a gravity-based de-
canter is used for ph ase separation, its de sign and process ope rating parameters
need to be included. Basically, the rationale for use of each equipment design has to
be described,
If a product requires use of a centrifuge or any filter or a crystallizer, their de-
sign basis and their suggested operating procedure need to be included.
Some examples of the equipment information, for example, heat exchangers
(Fig. 7.13, 7.14), centrifugal pumps (Fig. 7.15, 7.16, 7.17, 7.18), and reactor (7.19)
need to be included in the “Process Design and Technical Manual” are illustrated.
All of the necessary design basis and calculations for each process equipment have
to be included. This section would also include design basis information for the
process controllers. Process control logic has to be included.
It is necessary that the process control design basis and the logic have to be
included in the manual. The process control logic might have to be modified if dif-
ferent equipment than the original design is used in the manufacture of APIs.
In a batch or a continuous process, as has been discussed throughout the book,
total command of the process is a must. This especially applies to the meters and
valve that are used for the flow control of liquids and solids. They have to perform
at their optimum continuously, when they are being used. The workmanship of the
meters and control valves, over the years, have been perfected to precisely deliver
the materials at the desired rates. However, they are machines that on occasions
will not perform optimally. Thus, it is essential that they are calibrated on a planned
schedule. Some might consider this an unnecessary perturbation, but experienced
chemists and chemical engineers will understand the value of such an exercise. It
will save the headaches of dealing with less-than-expected yield and off- specifica-
tion product, which translate to financial loss.
242 Chapter 7 Process documentation and operating strategies
Fig. 7.13: Shell and tube heat exchanger data sheet [46].
7.6 Section 5: process equipment 243
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Fig. 7.14: Shell and tube heat exchanger data sheet [47].
244 Chapter 7 Process documentation and operating strategies
Fig. 7.15: Centrifugal pump data sheet [48].
7.6 Section 5: process equipment 245
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