The document discusses various organic solvents that are commonly used in the pharmaceutical industry, including alcohols, ketones, halogenated solvents, and others. It provides tables with information on these solvents such as their Hansen solubility parameter values, boiling points, densities, and acceptable daily exposure limits. The document also notes that residual solvents are not desirable in final drug products, so various drying and analytical methods are used to ensure solvent levels meet safety guidelines.

1. Assignment
Solvents Used in Pharmacy
Submitted
To
Dr. Usman Paracha
By
Zulcaif Ahmad (696)
Pharm-D
Submission Date: 30th January 2013
1|Page Assignment Solvents used in Pharmacy

2. Table of Contents
Solvent used in Pharmacy ............................................................................................................... 3
Solvent:- ...................................................................................................................................... 3
Abstract:...................................................................................................................................... 3
Organic solvents in the pharmaceutical industry ............................................................................ 3
Alcohols Ketones Halogenated solvents ............................................. 5
Amide Ethers Sulfur containing.................................................... 5
Amine Nitriles Esters ......................................................... 5
Hansen solubility parameter values (HSPiP) ................................................................................. 5
Boiling point ............................................................................................................................... 7
Density ........................................................................................................................................ 8
2|Page Assignment Solvents used in Pharmacy

3. Solvent used in Pharmacy
Solvent:-
A solvent is a substance that dissolves a solute (a chemically different liquid, solid or gas),
resulting in a solution. A solvent is usually a liquid but can also be a solid or a gas. The
maximum quantity of solute that can dissolve in a specific volume of solvent varies with
temperature.
Abstract:
Organic solvents are commonly used in the pharmaceutical industry as reaction media, in
separation and purification of synthesis products and also for cleaning of equipment. This paper
presents some aspects of organic solvents utilization in an active pharmaceutical ingredient and
a drug product manufacturing process. As residual solvents are not desirable substances in a final
product, different methods for their removal may be used, provided they fulfill safety criteria.
After the drying process, analyses need to be performed to check if amounts of solvents used
at any step of the production do not exceed acceptable limits (taken from ICH
Guideline or from pharmacopoeias). Also new solvents like supercritical fluids or ionic liquids
are developed to replace ìtraditionalî organic solvents in the pharmaceutical production
processes.
Organic solvents in the pharmaceutical industry
Solvents PDE (mg/day) Concentration limit (ppm)
Acetonitrile 4.1 410
Chlorobenzene 3.6 360
Chloroform 0.6 60
Cyclohexane 38.8 3880
1,2-Dichloroethene 18.7 1870
Dichloromethane 6.0 600
1,2-Dimethoxyethane 1.0 100
N,N-Dimethylacetamide 10.9 1090
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4. N,N-Dimethylformamide 8.8 880
1,4-Dioxane 3.8 380
2-Ethoxyethanol 1.6 160
Ethylene glycol 6.2 620
Formamide 2.2 220
Hexane 2.9 290
Methanol 20.0 2000
2-Methoxyethanol 0.5 50
Methylbutylketone 0.5 50
Methylcyclohexane 11.8 1180
Nñmethylpyrrolidone 48.4 4840
Nitromethane 0.5 50
Pyridine 2.0 200
Sulfolane 1.6 160
Tetralin 1.0 100
Toluene 8.9 890
1,1,2-Trichloroethylene 0.8 80
Xylene 21.7 2170
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5. Alcohols Ketones Halogenated solvents
Ethanol Ethylene bromide
Butanol Acetone Chloroform
2-Ethylhexanol Methyl ethyl ketone Ethylene chloride
Isobutanol Methyl isobutyl ketone Dichloromethane
Isopropanol Methyl isopropyl ketone Tetrachloroethylene
Methanol Mesityl oxide Carbon tetrachloride
Propanol Trichloroethylene
Propylene glycol
Amide Ethers Sulfur containing
Dimethylformamide 1,4-Dioxane Dimethyl sulfoxide
Butyl ether
Ethyl ether
Diisopropyl ether
Tetrahydrofuran
tert-Butyl methyl ether
Amine Nitriles Esters
Pyridyne Acetonitrile Ethyl acetate
Aliphatic hydrocarbons Water Aromatic hydrocarbons
Cyclohexane Toluene
Hexane Xylene
Hansen solubility parameter values (HSPiP)
There's another powerful way to look at these same solvents. By knowing their Hansen solubility
parameter values, which are based on δD=dispersion bonds, δP=polar bonds and δH=hydrogen
bonds, you know important things about their inter-molecular interactions with other solvents
and also with polymers, pigments, nanoparticles etc. so you can do two things. First, you can
create rational formulations knowing, for example, that there is a good HSP match between a
solvent and a polymer. Second, you can make rational substitutions for "good" solvents (they
dissolve things well) that are "bad" (for the environment, for health, for cost etc.). The following
table shows that the intuitions from "non-polar", "polar aprotic" and "polar protic" are put
numerically – the "polar" molecules have higher levels of δP and the protic solvents have higher
levels of δH. Because numerical values are used, comparisons can be made rationally by
5|Page Assignment Solvents used in Pharmacy

6. comparing numbers. So acetonitrile is much more polar than acetone but slightly less hydrogen
bonding.
δD δP δH Hydrogen
Solvent Chemical formula
Dispersion Polar bonding
Non-polar solvents
CH3-CH2-CH2-CH2-
Hexane 14.9 0.0 0.0
CH2-CH3
Benzene C6H6 18.4 0.0 2.0
Toluene C6H5-CH3 18.0 1.4 2.0
Diethyl ether CH3CH2-O-CH2-CH3 14.5 2.9 4.6
Chloroform CHCl3 17.8 3.1 5.7
/-CH2-CH2-O-CH2-
1,4-Dioxane 17.5 1.8 9.0
CH2-O-
Polar aprotic solvents
CH3-C(=O)-O-CH2-
Ethyl acetate 15.8 5.3 7.2
CH3
/-CH2-CH2-O-CH2-
Tetrahydrofuran (THF) 16.8 5.7 8.0
CH2-
Dichloromethane CH2Cl2 17.0 7.3 7.1
Acetone CH3-C(=O)-CH3 15.5 10.4 7.0
Acetonitrile (MeCN) CH3-C≡N 15.3 18.0 6.1
Dimethylformamide
H-C(=O)N(CH3)2 17.4 13.7 11.3
(DMF)
Dimethyl sulfoxide
CH3-S(=O)-CH3 18.4 16.4 10.2
(DMSO)
Polar protic solvents
Acetic acid CH3-C(=O)OH 14.5 8.0 13.5
CH3-CH2-CH2-CH2-
n-Butanol 16.0 5.7 15.8
OH
Isopropanol CH3-CH(-OH)-CH3 15.8 6.1 16.4
n-Propanol CH3-CH2-CH2-OH 16.0 6.8 17.4
6|Page Assignment Solvents used in Pharmacy

7. Ethanol CH3-CH2-OH 15.8 8.8 19.4
Methanol CH3-OH 14.7 12.3 22.3
Formic acid H-C(=O)OH 14.6 10.0 14.0
Water H-O-H 15.5 16.0 42.3
Consider a simple example of rational substitution. Suppose for environmental reasons we
needed to replace the chlorinated solvent, chloroform, with a solvent (blend) of equal solvency
using a mixture of two non-chlorinated solvents from this table. Via trial-and-error, a spreadsheet
or some software such as HSPiP we find that a 50:50 mix of toluene and 1,4 dioxane is a close
match. The δD of the mixture is the average of 18.0 and 17.5 = 17.8. The δP of the mixture is the
average of 1.4 and 1.8 = 1.6 and the δH of the mixture is the average of 2.0 and 9.0 = 5.5. So the
mixture is 17.8, 1.6, 5.5 compared to Chloroform at 17.8, 3.1, 5.7. Because Toluene itself has
many health issues, other mixtures of solvents can be found using a full Hansen solubility
parameter dataset.
Boiling point
Solvent Boiling point (°C)
ethylene dichloride 83.48
pyridine 115.25
methyl isobutyl ketone 116.5
methylene chloride 39.75
isooctane 99.24
carbon disulfide 46.3
carbon tetrachloride 76.75
o-xylene 144.42
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8. An important property of solvents is the boiling point. This also determines the speed of
evaporation. Small amounts of low-boiling-point solvents like diethyl ether, dichloromethane, or
acetone will evaporate in seconds at room temperature, while high-boiling-point solvents like
water or dimethyl sulfoxide need higher temperatures, an air flow, or the application of vacuum
for fast evaporation.
Low boilers: boiling point below 100 °C (boiling point of water)
Medium boilers: between 100 °C and 150 °C
High boilers: above 150 °C
Density
Most organic solvents have a lower density than water, which means they are lighter and will
form a separate layer on top of water. An important exception: most of the halogenated solvents
like dichloromethane or chloroform will sink to the bottom of a container, leaving water as the
top layer. This is important to remember when partitioning compounds between solvents and
water in a separatory funnel during chemical syntheses.
Often, specific gravity is cited in place of density. Specific gravity is defined as the density of the
solvent divided by the density of water at the same temperature. As such, specific gravity is a
unitless value. It readily communicates whether a water-insoluble solvent will float (SG < 1.0) or
sink (SG > 1.0) when mixed with water.
Solvent Specific gravity
Pentane 0.626
Petroleum ether 0.656
Hexane 0.659
Heptane 0.684
Diethyl amine 0.707
Diethyl ether 0.713
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9. Triethyl amine 0.728
Tert-butyl methyl ether 0.741
Cyclohexane 0.779
Tert-butyl alcohol 0.781
Isopropanol 0.785
Acetonitrile 0.786
Ethanol 0.789
Acetone 0.790
Methanol 0.791
Methyl isobutyl ketone 0.798
Isobutyl alcohol 0.802
1-Propanol 0.803
Methyl ethyl ketone 0.805
2-Butanol 0.808
Isoamyl alcohol 0.809
9|Page Assignment Solvents used in Pharmacy

10. 1-Butanol 0.810
Diethyl ketone 0.814
1-Octanol 0.826
p-Xylene 0.861
m-Xylene 0.864
Toluene 0.867
Dimethoxyethane 0.868
Benzene 0.879
Butyl acetate 0.882
1-Chlorobutane 0.886
Tetrahydrofuran 0.889
Ethyl acetate 0.895
o-Xylene 0.897
Hexamethylphosphorus triamide 0.898
2-Ethoxyethyl ether 0.909
10 | P a g e Assignment Solvents used in Pharmacy

11. N,N-Dimethylacetamide 0.937
Diethylene glycol dimethyl ether 0.943
N,N-Dimethylformamide 0.944
2-Methoxyethanol 0.965
Pyridine 0.982
Propanoic acid 0.993
Water 1.000
2-Methoxyethyl acetate 1.009
Benzonitrile 1.01
1-Methyl-2-pyrrolidinone 1.028
Hexamethylphosphoramide 1.03
1,4-Dioxane 1.033
Acetic acid 1.049
Acetic anhydride 1.08
Dimethyl sulfoxide 1.092
11 | P a g e Assignment Solvents used in Pharmacy

12. Chlorobenzene 1.1066
Deuterium oxide 1.107
Ethylene glycol 1.115
Diethylene glycol 1.118
Propylene carbonate 1.21
Formic acid 1.22
1,2-Dichloroethane 1.245
Glycerin 1.261
Carbon disulfide 1.263
1,2-Dichlorobenzene 1.306
Methylene chloride 1.325
Nitromethane 1.382
2,2,2-Trifluoroethanol 1.393
Chloroform 1.498
1,1,2-Trichlorotrifluoroethane 1.575
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13. Carbon tetrachloride 1.594
Tetrachloroethylene 1.623
Refrences:-
http://books.google.com.pk/books?id=NFGSSSbaWjwC&pg=PA746&lpg=PA746&dq=solvents
+used+in+pharmacy&source=bl&ots=V70YLhiqvs&sig=elXvBTB33Ps2xo-
14BL4yoQvoFA&hl=en&sa=X&ei=kF0DUezJAdS50QGN3oGACw&ved=0CDcQ6AEwAg#v
=onepage&q=solvents%20used%20in%20pharmacy&f=false
http://www.chem.ubc.ca/research-services/stores/solvent-dispensing
http://journal.pda.org/content/54/6/456.abstract
http://onlinelibrary.wiley.com/doi/10.1002/jps.3080070208/abstract
http://en.wikipedia.org/wiki/Solvent
http://emedicine.medscape.com/article/1174981-overview
13 | P a g e Assignment Solvents used in Pharmacy