Physicochemical characterization and solubility analysis of thalidomide and its N-alkyl analogs

Article abstract of DOI:10.1023/A:1013643013244

Purpose. The present study was primarily aimed at exploring the feasibility of improving percutaneous delivery via chemical manipulation of the thalidomide molecule to form analogs with improved physicochemical properties. N-Alkyl analogs were synthesized with the belief that these would be suitably hydrophobic and far less crystalline than the reference compound. This article presents their physicochemical properties. Methods. Thalidomide and three of its N-alkyl analogs were synthesized. Identification and levels of purity (>96%) were assured through element analysis, fast atom-bombardment mass spectrometry, nuclear magnetic resonance spectroscopy, and high-performance liquid chromatography. N-Octanol/water partition cohigh efficients were determined at pH 6.4. Solubilities in water and a series of n-alkanols were obtained. Best-fit solubility parameters were determined from the solubilities of the respective compounds in London solvents and were also calculated from respective hexane solubilities, melting points and heats of fusion. Results. Methylation of the thalidomide molecule at its acidic nitrogen led to an aqueous solubility about 6-fold higher than thalidomide but, because the alkyl chain length was further extended from methyl to pentyl, aqueous solubilities decreased essentially exponentially. The destabilization of the crystalline structure with increasing alkyl chain length led to an increased solubility in nonpolar media. The log partition coefficient increased linearly with increasing alkyl chain length and the solubility parameters declined systematically through this series. By adding a methyl group to the thalidomide structure, the melting point dropped by more than 100°C. Adding to the alkyl chain length led to further, more modest decreases. Heats of fusion decreased dramatically upon thalidomide's alkylation as well. Conclusion. Alkylation of the thalidomide molecule resulted in compounds with physicochemical properties that appear to be markedly better suited for percutaneous delivery.

Full text of DOI:10.1023/A:1013643013244

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Pharmaceutical Research, Vol. 19, No. 1, January 2002 (© 2002)
Research Paper
and hypnotic drug. Soon after, it came into use as a tranquil-
izer and anti-emetic for pregnant women. Tragically, it was
soon found to be teratogenic and had to be withdrawn from
the market. However, it remained available in certain coun-
tries for research purposes. In 1964, Sheskin discovered that
thalidomide was beneficial in the treatment of erythema no-
dosum leprosum (1). Clinical and immunologic similarities
between the leprotic reaction of erythema nodosum leprosum
and diffuse connective tissue diseases, particularly rheuma-
toid arthritis (RA), have been observed (2). Gutie´rrez–
Rodríguez (3) proved that the systemic administration of tha-
lidomide to patients with RA results in rapid clinical improve-
ment, although unacceptable side effects were observed. The
action has been linked to the ability of thalidomide to sup-
press the synthesis of tumor necrosis factor alpha (TNF␣). An
alternative means of delivering thalidomide to minimize some
of its adverse effects would be desirable. We reasoned that
percutaneous delivery might allow the drug to be delivered
into the joints and other affected areas of the extremities
without raising systemic levels to a worrisome point.
Physicochemical Characterization and
Solubility Analysis of Thalidomide
and Its N-Alkyl Analogs
Colleen Goosen,1,3,6 Timothy J. Laing,4
Jeanetta du Plessis,1 Theunis C. Goosen,2,5 and
Gordon L. Flynn3
Received April 10, 2001; accepted September 27, 2001
Purpose. The present study was primarily aimed at exploring the
feasibility of improving percutaneous delivery via chemical manipu-
lation of the thalidomide molecule to form analogs with improved
physicochemical properties. N-Alkyl analogs were synthesized with
the belief that these would be suitably hydrophobic and far less crys-
talline than the reference compound. This article presents their phys-
icochemical properties.
For a drug to be taken seriously as a candidate for per-
cutaneous delivery, it must have suitable physicochemical
properties, particularly with respect to its absolute and rela-
tive solubilities and related partitioning tendencies (4,5).
Based on thalidomide’s physicochemical properties (high
melting point and low lipophilicity), it appeared unlikely that
it would be delivered percutaneously in amounts required for
arresting the symptoms of RA. Given the potential clinical
efficacy of TNF␣ inhibitors such as thalidomide in a wide
range of immunologic disorders (1,6–8), especially RA (9), it
seemed worthwhile to investigate what changes in thalido-
mide’s structure might produce an active compound suitable
for skin transport. It is for this reason that we have embraced
the idea of synthesizing N-alkyl analogs of thalidomide (Fig.
1), which should exhibit decreased crystallinity and increased
lipophilicity. Therefore, the solubilities and lipophilicities of
thalidomide and several N-alkyl analogs were determined.
Methods. Thalidomide and three of its N-alkyl analogs were synthe-
sized. Identification and levels of purity (>96%) were assured
through element analysis, fast atom-bombardment mass spectrom-
etry, nuclear magnetic resonance spectroscopy, and high-
performance liquid chromatography. N-Octanol/water partition co-
efficients were determined at pH 6.4. Solubilities in water and a series
of n-alkanols were obtained. Best-fit solubility parameters were de-
termined from the solubilities of the respective compounds in Lon-
don solvents and were also calculated from respective hexane solu-
bilities, melting points and heats of fusion.
Results. Methylation of the thalidomide molecule at its acidic nitro-
gen led to an aqueous solubility about 6-fold higher than thalidomide
but, because the alkyl chain length was further extended from methyl
to pentyl, aqueous solubilities decreased essentially exponentially.
The destabilization of the crystalline structure with increasing alkyl
chain length led to an increased solubility in nonpolar media. The log
partition coefficient increased linearly with increasing alkyl chain
length and the solubility parameters declined systematically through
this series. By adding a methyl group to the thalidomide structure, the
melting point dropped by more than 100°C. Adding to the alkyl chain
length led to further, more modest decreases. Heats of fusion de-
creased dramatically upon thalidomide’s alkylation as well.
Conclusion. Alkylation of the thalidomide molecule resulted in com-
pounds with physicochemical properties that appear to be markedly
better suited for percutaneous delivery.
MATERIALS AND METHODS
For the synthesis of thalidomide and its N-alkyl analogs,
N-phthaloyl-DL-glutamic anhydride and urea were obtained
from Aldrich (Milwaukee, WI) and methylamine, propyl-
amine, and n-amylamine were obtained from Sigma Chemical
Co. (St. Louis, MO). For solubility studies, reagent-grade or-
ganic solvents (Aldrich, Milwaukee, WI) were used as re-
ceived. High-performance liquid chromatography (HPLC)
grade acetonitrile and methanol (Fisher Scientific, Pittsburgh,
PA) were used for the chomatography procedure and to di-
lute samples in preparation for HPLC analysis, respectively.
Thalidomide and its analogs were synthesized according to
literature methods (10,11) but with modification of the pub-
lished purification procedures. Identification and levels of pu-
rity (>96%) were assured through element analysis, fast
atom-bombardment mass spectrometry, nuclear magnetic
resonance (1H-NMR and 13C-NMR) spectroscopy, HPLC,
KEY WORDS: thalidomide; N-alkyl analogs; solubility parameter;
lipophilicity; solubility.
INTRODUCTION
Synthesized in Germany in 1954, thalidomide was intro-
duced into the pharmaceutical market in 1956 as a sedative
1 Department of Pharmaceutics, School of Pharmacy, Potchefstroom,
University for Christian Higher Education, Potchefstroom, 2520,
Republic of South Africa.
2 Department of Pharmacology, School of Pharmacy, Potchefstroom,
University for Christian Higher Education, Potchefstroom, 2520,
Republic of South Africa.
3 College of Pharmacy, University of Michigan, Ann Arbor, Michigan
48109.
5 Department of Pharmacology, University of Michigan, Ann Arbor,
Michigan 48109.
6
4 Department of Rheumatology, University of Michigan, Ann Arbor,
Michigan 48109.
To whom correspondence should be addressed. (e-mail:
fmscg@puknet.puk.ac.za)
13
0724-8741/02/0100-0013/0 © 2002 Plenum Publishing Corporation

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14
Goosen et al.
analysis and the sharpness of the melting point, a high purity
(Ն98%) was obtained for N-methyl thalidomide. Anal
(C14H12N2O4) calc. C 61.82% N 10.30% H 4.45%, found C
1
61.82% N 10.26 H 4.50%. H-NMR (DMSO-d6) ␦: 7.85 (m,
4H, aromatic protons), 5.18 (1H, dd, J ס 5.4, 12.8, H-1Ј), 2.95,
2.75, 2.55, and 2.05 (4×m, 2×CH2 of piperidinedione ring),
3.05 (3H, s, CH3); 13C-NMR (DMSO-d6) ␦: 172.48, 170.48,
and 168.03 (4×CO), 135.81, 132.11, and 124.36 (aromatic car-
bon atoms), 50.44 (C-1Ј), 31.97 (C-5Ј), 22.05 (C-6Ј), 27.50
(CH3); m/z 272 (M+, 53), 186 (8), 162 (100), 154 (41), 137 (40),
and 107 (15).
N-Propyl Thalidomide (Racemic Mixture)
One mol of N-phthaloyl-DL-glutamic anhydride and 1.2
mol of 99% propylamine were heated in an oil bath at 200°C
for 8 h. After cooling, the crude imide was purified by recrys-
tallization from ethanol (95%). The crude imide was dis-
solved in ethanol, heated to 60°C and then cooled at −20°C.
This recrystallization process was repeated five times. The
final product was an off-white powder with a melting point of
136°C and yields of 50–60%. A 66–68°C melting point was
previously reported for the compound by De and Pal (11).
Anal (C16H16N2O4) calc. C 64.06% N 9.34% H 5.38, found C
Fig. 1. Structures of thalidomide and its N-alkyl analogs.
and by the sharpness of melting points. Fast atom-bombard-
ment mass spectra were recorded using xenon13 as the bom-
bardment gas (8 kV, 1 mA). The mass spectrometer was op-
erated at 6 kV, and the magnetic analyser scanned at a rate of
5 s per decade over a mass range of 50–500 Da. These oper-
ating parameters applied to both positive- and negative-ion
analysis. Samples were directly dissolved in the matrix and
ionized on stainless steel targets at room temperature. 1H-
and 13C-NMR spectra were performed at 30°C on a Varian
Gemini-300 spectrometer operating at 400.08 and 75.46 MHz,
respectively, using DMSO as a reference.
1
64.09% N 9.31% H 5.56%. H-NMR (DMSO-d6) ␦: 7.92 (m,
4H, aromatic protons), 5.25 (1H, dd, J ס 5.4, 12.8, H-1Ј), 3.63
(m, 2H, N-CH2), 2.96, 2.78, 2.54 and 2.09 (4×m, 2×CH2 of
piperidinedione ring), 1.45 (m, 2H, CH2), 0.83 (3H, t, CH3);
13C-NMR (DMSO-d6) ␦: 172.46, 170.28, 168.02 (4×CO),
135.79, 132.11, 124.33 (aromatic carbon atoms), 50.47 (C-1Ј),
31.99 (C-5Ј), 22.19 (C-6Ј), 41.88 and 22.18 (2×CH2 of propyl
group), 11.97 (CH3); m/z 300 (M+, 100), 273 (6), 186 (38), 154
(23), 137 (28), and 126 (22).
Synthesis Method
Thalidomide (Racemic Mixture)
One mol of N-phthaloyl-DL-glutamic anhydride was
melted with 2 mol of urea in an oil bath at 170–180°C for 45
min. After cooling, the crude thalidomide was dissolved in 60
mL of ethanol (95%), heated to 60°C, and cooled. The crys-
tallization was repeated three more times. Thalidomide was
obtained as an almost white powder, with a melting point of
275°C and a yield of 70–75%. Anal (C13H10N2O4) calc. C
60.52% N 10.86% H 3.91%, found C 60.48% N 10.96% H
N-Pentyl Thalidomide (Racemic Mixture)
One mol of N-phthaloyl-DL-glutamic anhydride was
heated with 1.2 mol of N-amylamine (99%) in an oil bath at
200°C for 8 h. After unsuccessful attempts at distillation, the
crude N-pentyl thalidomide was purified by silica gel column
chomatography (diethyl either:hexane) using a stepwise gra-
dient (10:90, 20:80, 30:70, 40:60; and 45:55). The volume of
each mobile phase used was two times the column volume
and N-pentyl thalidomide was collected during the 45% di-
ethyl ether mobile phase elution. It was dried in vacuo and
recrystallized once from diethyl ether, yielding white crystals
of N-pentyl thalidomide and yields of 40–60%. According to
the literature (11), N-pentyl thalidomide can be purified by
distillation in vacuo and a 19–21°C melting point was re-
ported. A melting point of 105°C was determined for N-
1
3.97%. H-NMR (DMSO-d6) ␦: 7.89 (m, 4H, aromatic pro-
tons), 5.16 (1H, dd, J ס 5.4, 12.8, H-1Ј), 2.08, 2.57, and 2.90
(3×m, 2×CH2 of piperidinedione ring), 11.00 (1H, brs, NH);
13C-NMR (DMSO-d6) ␦: 172.92, 170.00 and 167.33 (4×CO),
134.96, 131.35 and 123.49 (aromatic carbon atoms), 49.02 (C-
1Ј), 30.91 (C-5Ј), 21.95 (C-6Ј), m/z 259 (M+ + 1, 50), 154 (100),
136 (75), 120 (16), and 107 (27).
N-Methyl Thalidomide (Racemic Mixture)
One mol of N-phthaloyl-DL-glutamic anhydride and 1.2 pentyl thalidomide. Anal (C18N20N2O4) calc. C 65.91% N
mol of a 2 M methylamine solution in methyl alcohol were 8.54% H 6.15%, found C 65.55% N 8.45% H 6.08%. 1H-
heated in an oil bath at 200°C for 8 h. After cooling, the crude NMR (DMSO-d6) ␦: 7.90 (m, 4H, aromatic protons), 5.22
imide was purified by recrystallization from 95% ethanol. The (1H, dd, J ס 5.4, 12.8, H-1Ј), 3.63 (m, 2H, N-CH2), 2.98, 2.74,
crude imide was dissolved in ethanol, heated to 60°C and then 2.50, and 2.07 (4×m, 2×CH2 of piperidinedione ring), 1.40 and
cooled at 4°C. This recrystallization process was repeated 5 1.22 (2×m, 2H and 4H, 3×CH2), 0.83 (3H, t, CH3); 13C-NMR
times. De and Pal (11) purified N-methyl thalidomide by sub- (DMSO-d6) ␦: 171.67, 169.47 and 167.30 (4×CO), 134.90,
limation and a melting point of 131–133°C was reported. In 131.35 and 123.51 (aromatic carbon atoms), 49.61 (C-1Ј),
this study, N-methyl thalidomide was purified by recrystalli- 39.42, 28.27, 26.87, and 21.24 (4×CH2 of pentyl chain), 13.64
zation from 95% ethanol and a melting point of 159°C was (CH3), 31.09 (C-5Ј) and 21.66 (C-6Ј); m/z 328 (M+, 100), 301
obtained and yields of 60–70%. According to HPLC, element (6), 186 (44), 173 (5), 154 (16), and 130 (5).

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Thalidomide and Its N-Alkyl Analogs
15
Chromatographic Procedure
Elmer DSC7 Differential Scanning Calorimeter (DSC). Heat-
ing curves were recorded at 10°C/min. All tracings were re-
peated four times. There were no appreciable differences
( 4%) in the thermograms for any compound from run to
run.
The HPLC system consisted of a Beckman 114M solvent
delivery system and a Spectraflow 783 variable wavelength
ultraviolet detector, operated at 220 nm and a flow rate of 1.2
mL/min. A Perkin–Elmer ISS-100 autoinjector was used to
inject samples (20 ␮L) onto a Spheri-5 (RP-8, 5 ␮m, 220 × 4.6
mm) column (Alltech Associates, Inc., Deerfield, IL) and a
NewGuard precolumn (RP-18, 7 ␮, 15 × 3 mm) insert was
Melting Point Determination
The melting points of thalidomide and its N-alkyl analogs
used. The mobile phase comprised of acetonitrile:water (25% were determined by two methods: (1) differential thermal
acetonitrile for thalidomide and N-methyl thalidomide and analysis (as described above) and (2) controlled-heating ther-
35% and 45% for N-propyl and N-pentyl thalidomide, respec- mal microscopy (Mettler Hot Stage with FPS Temperature
tively). The pH was adjusted to 2 with ortho-phosphoric acid Regulator and a Zeiss Standard Microscope). The heating
(Fluka Chemical Co., Ronkonkoma, NY). Calibration curves rate for both methods was 10°C/min.
established that excellent linearity existed over the entire con-
centration range from 0.01 ␮g/mL to 10 ␮g/mL.
Partition Coefficient Determination
Solutions of each compound in this study were prepared
with phosphate buffer (pH 6.4)-saturated octanol and trans-
Solubility Determination
The 25°C solubilities of thalidomide and its N-alkyl ana- ferred to assay tubes containing equal volumes of phosphate
logs in hexane, cyclohexane, carbon tetrachloride, toluene, buffer. These mixtures were agitated for 2 h and after cen-
benzene and phosphate buffer (pH 6.4) and the 32°C solu- trifugation at 2000 g for 10 min, the n-octanol and buffer
bilities in phosphate buffer (pH 6.4) and an extended series of phases were analyzed by HPLC. Partition coefficients (Koct
)
n-alkanols were obtained by equilibrating excess amounts of were calculated as the ratio of drug concentration in the n-
each of the compounds with these solvents. Samples were octanol phase to that in the buffer phase.
filtered (PTFE filter media with Polypropylene housing, 0.45-
␮m pore size, Whatman Inc., Haverhill, MA) and measured
with respect to volume. The solvent from each individual
sample was then evaporated and reconstructed in an appro-
priate amount of methanol or directly diluted with methanol
and assayed by HPLC.
RESULTS
Table I summarizes the physicochemical properties of
thalidomide and its N-alkyl analogs. Enthalpies of fusion,
⌬Hf, and entropies of fusion, ⌬Sf, are also shown in Table I.
Thalidomide, N-propyl thalidomide and N-pentyl thalido-
mide exhibited only one thermal transition each. The endo-
therms at 275, 136, and 105°C, correspond to the melting of
Differential Thermal Analysis
The heat (⌬Hf) and entropy (⌬Sf) of fusion of thalido- these crystals, respectively. N-Methyl thalidomide showed a
mide and its N-alkyl analogs were determined with a Perkin– major endotherm at 159°C and a small endotherm at 165°C.
Table I. Physicochemical Properties of Thalidomide and Its N-alkyl Analogs
N-Methyl
N-Propyl
N-Pentyl
Physical parameter
Thalidomide
thalidomide
thalidomide
thalidomide
Molecular weight
(g/mol)
258
272
300
328
Crystalline density
(g/mL)
1.48
1.43
1.35
1.28
Molar volume, V2
(mL/mol)
174
191
223
255
Melting Temperature,
Tf(°C) SD
Heat of fusion, ⌬Hf
(kcal/mol) SD
Entropy of fusion, ⌬Sf
(cal/mol/K)
275 0.11
8.61 0.27
15.71
159 0.11
4.33 0.06
10.02
136 0.90
6.52 0.25
15.94
105 0.26
5.73 0.08
15.16
Activity of solid phase
as2, ␦Cp ס 0*
1.29 × 10−3
8.07 × 10−3
13.2
1.03 × 10−1
1.54 × 10−1
12.2
5.18 × 10−2
7.89 × 10−2
11.4
1.29 × 10−1
1.64 × 10−1
11.2
Activity of solid phase
as2, ␦Cp ס ⌬Sp*
Solubility parameter, ␦2
(cal/cm3)1/2, ␦Cp ס 0
Solubility parameter, ␦2
(cal/cm3)1/2, ␦Cp ס ⌬Sp
Ln X2, ideal (⌬Cp ס 0)
Ln X2, ideal (⌬Cp ס ⌬Sp)
13.7
−6.65
−4.82
12.3
−2.27
−1.87
11.5
−2.96
−2.54
11.2
−2.05
−1.81
* Ideal activity of solid phase, as2 estimated from Eq. 1 (15) with one or the other assumption.

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16
Goosen et al.
The endotherm at 159°C corresponds to the melting point of at ␦ 7.89. The signal from H-1Ј appears as a doublet of dou-
N-methyl thalidomide, suggesting that the small subsequent blets (J 5.4 and 12.8) at ␦ 5.16. The remaining four protons on
energy absorption involved relaxation of structure in the liq- the piperidinedione ring appear as three sets of multiplets at
uid state. Melted samples of all the compounds, assayed by ␦ 2.08, 2.57, and 2.90. The amine proton resonates as a broad
HPLC showed only trace amounts (less than 0.5%) of decom- singlet at ca. ␦ 11.00. In the 13C-NMR spectrum of thalido-
position, and it was assumed that the endotherms primarily mide three signals at ␦ 172.92, 170.00, and 167.33 attributable
represent energy consumed on melting.
to the four carbonyl carbon atoms and three signals at 134.96,
A physical parameter that is necessary for solubility 131.35, and 123.49 attributable to the six aromatic carbon
analysis is the molar volume of liquid solute. The molar vol- atoms are clearly discernable. The three remaining carbon
ume, V2, of thalidomide was determined from its molecular atoms of the piperidinedione ring resonate at 49.02 (C-1Ј),
weight divided by its crystalline density (12). Because the 30.91 (C-5Ј), and 21.95 (C-6Ј), respectively.
crystalline densities of the N-alkyl analogs were not known,
their molar volumes were estimated, starting with thalido-
mide’s true molar volume, by summation and subtraction of
functional-group molar volumes that distinguish the indi-
vidual compounds from thalidomide (13). The essentials of
estimation of the molar volumes for the N-alkyl analogs are
presented in Table II.
N-Methyl Thalidomide
The 1H-NMR spectrum of N-methyl thalidomide is iden-
tical to that of thalidomide except for the signal from the
methyl group at ␦ 3.05 in the 1H-NMR spectrum and at ␦
27.50 in the 13C-NMR spectrum.
The aqueous and hexane solubilities of thalidomide and
its N-alkyl analogs are listed in Table III along with their
octanol/water partition coefficients (Koct). The solubilities of
these compounds in a series of n-alkanols are summarized in
Table IV on a molar scale. It can be seen that for every solute
the molar solubilities across the homologous series of solvents
decrease systematically with increasing alkanol chain length.
The hexane solubilities of the compounds can be seen in
Table III. The assumption that the volume fraction of hexane
in the saturated solutions (␾1), is unity, was made (14). Using
this surmise, the solubility parameters for all the solutes were
calculated according to Eq. 3 (15) and the assumption that
⌬Cp ס 0 or ⌬Cp ס ⌬Sf. The mol fraction solubilities (ln X)
of thalidomide and its N-alkyl analogs in several organic sol-
vents at 25°C are listed in Table V, as well as the values of the
solubility parameters of the solvents. To show the extent to
which thalidomide’s and the analogs’ solubility behavior
might conform to regular solution behavior, the regular solu-
tion solubility parabolas for all four compounds were calcu-
lated according to Roy and Flynn (15) (Eq. 3) (with the as-
sumption, ⌬Cp ס ⌬Sf and ⌬Cp ס 0) where in each case the
solutions are considered ideal (Fig. 2 A–D).
N-Propyl Thalidomide
The 1H-NMR spectrum of the N-propyl analog shows in
addition to the signals of the thalidomide nucleus a multiplet
at each of ␦ 3.63 and 1.45 due to the methylene protons and
a triplet at ␦ 0.83 due to the methyl group of the propyl
moiety. In addition to the signals of the thalidomide nucleus
the 13C-NMR spectrum of the N-propyl analog shows signals
at ␦ 41.88 and 21.53 due to the methylene carbon atoms and
11.97 arising from the methyl group of the propyl moiety.
N-Pentyl Thalidomide
1
The H-NMR spectrum of the N-pentyl analog shows in
addition to the signals of the thalidomide nucleus a multiplet
at ␦ 3.63 and 1.40 for the terminal methylene groups of the
pentyl moiety whereas the signal from the two central meth-
ylene groups appears as a multiplet at ␦ 1.22 and the methyl
group resonate as a triplet at ␦ 0.83. In addition to the signals
from the thalidomide nucleus the 13C-NMR spectrum of the
N-pentyl analog shows signals due to methylene carbon atoms
at ␦ 39.42, 28.27, 26.87, and 21.24 whereas the methyl group
resonates at ␦ 13.64.
DISCUSSION
Physicochemical Properties
Structures of Thalidomide and Its N-Alkyl Analogs
N-Alkylation of the glutarimide ring in the thalidomide
molecule replaces the imido hydrogen atom, which is respon-
sible for strong hydrogen and dipolar bonding within the crys-
Thalidomide
1
In the H-NMR spectrum of thalidomide, the four pro- talline state. The melting points for the N-alkyl analogs in this
tons of the aromatic ring resonate as a symmetrical multiplet series are all at least 100°C lower than thalidomide’s melting
Table II. Estimation of Molar Volumes for the N-Alkyl Analogs
Partial molar
volume
Functional
group or atom
contribution per
group (mL/mol)
N-Methyl
thalidomide
N-Propyl
thalidomide
N-Pentyl
thalidomide
Thalidomide
H
CH2
CH3
174.33
3.1
16.2
19.3
174.33
−3.1
—
+19.3
191
174.33
−3.1
+32.4
+19.3
223
174.33
−3.1
+64.8
+19.3
255
Estimated molar volume (mL/mol)