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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5716_Библиотеки_им_академика_М_И_Перельмана
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Tab. 7.4: Stage 1 crop of metformin process [20].
Stage : first crop No. of batches: per day
Input (kg) Output (kg)
DMA HCl Metformin hydrochloride ,
Dicyanodiamide Loss on drying
Xylene Recovery
Charcoal Xylene
Water (recycle) ,. Xylene loss
Recycle water ,.
Purge ML for second crop
Residue
Solid waste (charcoal)
,. Total output ,.
Tab. 7.5: Second crop of metformin process [20].
Stage II: second crop Batches per month
Input (kg) Output (kg)
Purge mother liquor , Product, wet second crop
Methanol Recycle water ,
Mother liquor for MeOH recycle and third crop ,
Total input , Total output ,
Tab. 7.6: Third crop of metformin process [20].
Stage II: Third crop Batches per month
Input (kg) Output (kg)
Purge mother liquor , Product, wet third crop
Recycle water
Recovered methanol
Residue solid waste
Total input , Total output ,
226 Chapter 7 Process documentation and operating strategies
Fig. 7.9: Stage 1 crop of metformin process [20].
7.3 Section 2: process charge and recovery 227
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Fig. 7.10: Second and third crop of metformin process [20].
228 Chapter 7 Process documentation and operating strategies
Tab. 7.7: Purification of second and third metformin crop [20].
Purification of second and third crop Batches per month:
Input (kg) Output (kg)
Product
Metformin second and third crop , Metformin HCl
Methanol Loss on drying .
Freshwater , Recycle water ,
Charcoal Recovery
Methanol mother liquor for second crop ,
Solid waste (charcoal) .
Total input , Total output ,
Fig. 7.11: Purification of second and third metformin crop [20].
7.3 Section 2: process charge and recovery 229
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7.4 Section 3: raw material specifications/properties
Generally, at the start of detailed process development, as reviewed in earlier chapters,
the chemistry of the reaction is detailed and the process is tested for feasibility and
economics. Once the feasibility is proven, the real process development begins, in ear-
nest. It is necessary that the API laboratory process development and manufacturing
be based on commercially available raw materials. This will assist in developing the
best process. In addition, this facilitates the API manufacturers to develop relation-
ships with suppliers. For commercial production, unless the specialty supply houses/
companies are as competitive as the commercial suppliers, it is important not to source
raw materials from them as, most likely, they have a limited supply chain. Their
materials are expensive and do not represent the reality, as they have very little
semblance to commercially available materials.
Sourcing of commercially available raw materials can be a challenge. This can be
due to multiple reasons. To have raw material specifications as part of the Technical
Manual spells out every rationale and reason for the selection. The following are some
examples. These are accessed from different suppliers online technical data sheets.
Compiling physical properties, for example, viscosities, heat of formation, solu-
bilities, heat of reaction, etc. of raw materials and intermediates can be a significant
challenge. In the middle of the twentieth century, vendors shared many of the prop-
erties of the key starting raw materials.
In theory, the internet should be able to provide rudimentary physical and chem-
ical properties [22] of products supplied by vendors. Most vendors have engaged a
data mining strategy on information gathered from inquiries for their own marketing
benefit. Often, vendors ask questions that either cannot be answered at the moment
or are considered proprietary to the manufacturer. This approach can be an impedi-
ment to process innovation and can significantly extend process development time.
Some of the starting raw m aterials for many of the APIs are fine/specialty
chemicals that are strictly used for pharma. Since their sales volumes are not
large, producing companies do not spend time on developing and studying every
property or their solubilities in different solvents. With the challenges of accessing
many of the physical properties, user companies might have to generate their
properties and solubility data. They may have to develop temperature/property re-
lationships. Correlations for solubility predictions have been published. They will
have to be verified and improved in the laboratory and used in process design
[23–25]. Published solubility data for different chemical compounds is available
and is useful [26, 27]. Some of the properties for different chemicals, that are avail-
able, are shared. Tables 7.8, 7.9, 7.10, 7.11,7.12,7.13,7.14,7.15,7.16,7.17,7.18and
7.19 are examples of raw material specifications of some of the chemicals used in
different processes. Physical properties of these chemicals used in each reaction
need to be acquired so that they can facilitate proce ss desig n.
230 Chapter 7 Process documentation and operating strategies
7.4.1 4-(2-Methoxyethyl)phenol
7.4.2 Epichlorohydrin
7.4.3 Sodium hydroxide
Tab. 7.8: Physical properties of p-(2-methoxyethyl) phenol [28].
-(-Methoxyethyl)phenol
C
H
O
CAS --
Mol. wt .
B.P. (°C) –
Solubility Methanol
Tab. 7.9: Physical properties of epichlorohydrin [29].
Epichlorohydrin
C
H
ClO
CAS --
Epichlorohydrin is a colorless, volatile, and flammable liquid with an irritating, chloroform-like
odor, which emits toxic fumes when heated to decomposition. It is only slightly soluble in water
but is soluble in many organic solvents.
Mol. wt .
Sp. gr. kg/m
@ °C .
Boiling point (°C) .
Melting point (°C) −
Tab. 7.10: Physical properties of sodium hydroxide [30, 31].
Chemical formula NaOH
CAS --
Molar mass .
Density (kg/m
) .
Melting point (°C) −
Boiling point (°C)
7.4 Section 3: raw material specifications/properties 231
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7.4.4 Ammonia
7.4.5 Methanol
7.4.6 Maleic anhydride
Tab. 7.11: Physical properties of ammonia [32].
Ammonia NH
CAS --
Molecular weight .
Density (kg/m
) .
Boiling point (°C) −.
Melting point (°C) −.
Tab. 7.12: Physical properties of methyl alcohol [33].
Methanol (methyl alcohol)
CH
OH
CAS --
Mol. wt
Sp. gr. kg/m
@ °C
Boiling point (°C)
Melting point (°C) −.
Tab. 7.13: Physical properties of maleic anhydride [34].
Maleic anhydride
C
H
O
CAS --
Mol. wt .
Sp. gr. kg/m
.
Boiling point (°C)
232 Chapter 7 Process documentation and operating strategies
7.4.7 Thiourea
Tab. 7.13 (continued)
Maleic anhydride
C
H
O
Melting point (°C) –
Appearance: Maleic anhydride, +%; maleic
anhydride, +%; colorless needles, white lumps, or
pellets with an irritating, choking odor; colorless or
white solid with an acrid odor.
Tab. 7.14: Physical properties of thiourea [26, 35, 36].
Thiourea
Chemical formula CH
N
S
CAS --
Molar mass . g/mol
Appearance White crystalline solid
Density , kg/m
Melting point °C
Boiling point Decomposes
Solubility in water . g/ ml ( °C). g/ ml ( °C)
Solubility Reacts with acids soluble in ethanol and methanol.Almost insoluble
in diethyl ether and hexane
Solubility in ethanol kg/m
( °C) kg/m
(. °C) kg/m
( °C) kg/m
( °
C) kg/m
(. °C)
Solubility in methanol kg/m
( °C) kg/m
(. °C) kg/m
(. °C) kg/m
(. °C)
7.4 Section 3: raw material specifications/properties 233
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7.4.8 Toluene
Azeotropic properties can be selectively used to improve manufacturing processes.
Use of toluene azeotrope has been reviewed in this chapter and earlier chapters.
Toluene azeotropes with water and has about 0.06% moisture. Use of wet toluene
improves the first-step conversion in the manufacture of Omeprazole [18]. Proper-
ties of other chemicals can be explored and exploited to simplify processes.
7.4.9 Xylene
Tab. 7.15: Physical properties of toluene [37].
Synonym Methylbenzene
CAS number --
H
CH
Molecular weight .
Density
Boiling point (kg/m
) – °C
Melting point − °C
Flash point . °C
Viscosity (kg/m s) .
Toluene and water form a minimum boiling azeotrope
(.% water @ °C) []
Tab. 7.16: Physical properties of xylene [39].
Molecular formula
C
H
CAS no. --
Molecular weight . g/mol
Density (kg/m
)
234 Chapter 7 Process documentation and operating strategies
Similarly, azeotropic property of xylene/water can be us ed for the production
of metformin hydrochloride. In this process, dimethyl amine is reacted with com-
mercially available hydrochloric acid, with xylene as the solvent. This has been re-
viewed in this Chapter 5.
7.4.10 Dimethyl amine
Dimethyl amine, being a gas at room temperature, is commercially available as a
40% solution and 100% liquid. Both forms can be used in a reaction, and their use
has been reviewed earlier in this chapter. E conomics and availability will help
make a decision.
Dimethylamine hydrochloride is miscible in water, and this property can be of
value in the production of metformin hydrochloride.
Tab. 7.16 (continued)
Molecular formula
C
H
Boiling point (°C) .
Melting point (°C) −. (meta)
Water/xylene azeotrope Temp. (°C) [] .
Tab. 7.17: Physical properties of dimethyl amine [40, 41].
Molecular formula
C
H
N
CAS no. --
Molecular weight .
Density (kg/m
)
Boiling point (°C) .
Melting point (°C) −.
7.4 Section 3: raw material specifications/properties 235
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