Structure determination of the theophylline-nicotinamide cocrystal: A combined powder XRD, 1D solid-state NMR, and theoretical calculation study

Article abstract of DOI:10.1039/c4ce00012a

The crystal structure of a powder pharmaceutical cocrystal, theophylline-nicotinamide (1:1) crystal complex, is determined for the first time by using a combination of X-ray powder diffraction (XRPD), 1D solid state NMR, as well as density functional theory (DFT) calculations. With the aid of solid state NMR spectroscopy, a candidate structure can be determined from XRPD data by Rietveld refinement with acceptable residual variances. The structure was subjected to periodic geometry optimization, followed by NMR parameter calculations. The agreement between experimental and computed ¹³C and ¹⁵N NMR chemical shift values validates the refined structure as an accurate representation of the actual cocrystal structure. Intermolecular interactions existing in the cocrystal are further confirmed by the commonly used vibrational spectra. This study confirms that the straightforward synergistic approach offers a simple and credible way to solve the crystal structure of powder cocrystal samples. the Partner Organisations 2014.

Full text of DOI:10.1039/c4ce00012a

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Journal Name
RSCPublishing
ARTICLE
Structure Determination of Theophylline-
Nicotinamide Cocrystal: A Combined Powder
XRD, 1D Solid-State NMR, and Theoretical
Calculation Study
Cite this: DOI: 10.1039/x0xx00000x
Received 00th January 2012,
Accepted 00th January 2012
Ping Li,a,b,§ Yueying Chu,c, § LinWang,a Robert M. Wenslow Jr.,d Kaichao Yu,b
Hailu Zhang*a and Zongwu Denga
DOI: 10.1039/x0xx00000x
www.rsc.org/
The crystal structure of a powder pharmaceutical cocrystal, theophyllineꢀnicotinamide (1:1)
crystal complex, is solved for the first time by using a combination of Xꢀray powder diffraction
(XRPD), 1D solid state NMR, as well as density functional theory (DFT) calculations. With
the aid of solid state NMR spectroscopy, a candidate structure can be determined from XRPD
data by Rietveld refinement with acceptable residual variances. The structure was subjected to
periodic geometry optimization, followed by NMR parameter calculations. The agreement
between experimental and computed 13C and 15N NMR chemical shift values validates the
refined structure as an accurate representation of the actual cocrystal structure. Intermolecular
interactions existing in the cocrystal are further confirmed by the commonly used vibrational
spectra. This study confirms the straightforward synergistic approach offers a simple and
credible way to solve the crystal structure of powder cocrystal samples.
from the powder sample. Fortunately, the development of Xꢀray
powder diffraction (XRPD) equipment and structure solving
Introduction
A cocrystal is a structurally homogeneous crystalline complex,
simultaneously containing two or more components that are
solids at ambient condition in a wellꢀdefined stoichiometry,
where at least one cocrystal former is in an unꢀionized state.1ꢀ3
In recent years, cocrystals have been widely used as means to
improve and tailor the physicochemical properties of active
pharmaceutical ingredients (APIs), such as thermal stability,
algorithms make it possible to extract crystal structure from the
XRPD pattern.12,15 However, due to the highly overlapped
Bragg peaks and limited data, the structural information
extracted from XRPD pattern is often not a true representation
of actual structure. Thus, it is further necessary to confirm the
refined result via other methods. Solid state NMR spectroscopy
(ssNMR), which provides information concerning the chemical
environment of organic nuclei (e.g. 1H, 13C, 14/15N, 19F, 31P), can
provide this supplementary structure information. The
combination of XRPD and ssNMR to solve structure of
pharmaceutical crystals can be found in several reports which
mainly focus on pure API.16,17 Recently, peers also introduced
such a protocol into the cocrystal field.18
mechanical
properties,
dissolution
rate,
solubility,
hygroscopicity, and chiral resolution.4ꢀ9 For pharmaceutical
cocrystals, studies reveal that some physicochemical properties
(e.g. solubility, tabletting properties, thermal and hydration
stability) can be readily predicted by crystal structures in
addition to corresponding properties of the constituents.10,11
Thus, the understanding of structureꢀproperty relationships is
necessary as research strives towards synthesis by design.
C5
N4H
O3
C13
For structure investigations, qualified single crystals are
typically desired. However, the preparation of satisfactory
single crystal samples of cocrystals is often restricted by many
factors, i.e. the different solubilities of the cocrystal formers
during the most prevalent solution cocrystallisation processes.12
In comparison, it is more efficient and convenient for
researchers to obtain cocrystal powder samples by various
routes including neat grinding13 and solventꢀdrop grinding14.
These methods would then require obtaining a crystal structure
N3
C3
O1
C10
N5
C4
N2
C2
N1
C9
C8
C11
C12
N6H2
H37C
C1
O2
C6H3
(a)
(b)
Scheme 1 Molecular structures of TP (a) and NCT (b).
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DOI: 10.1039/C4CE00012A
X-ray powder diffraction
XRPD data were collected on a PANalytical X’Pert Pro Xꢀray
powder diffractometer (PANalytical B.V., Almelo, The
Netherlands) equipped with X’Celerator Real Time MutilꢀStrip
detector. A Cu Kα radiation was used at 45 kV and 40 mA.
Samples were wrapped in two pieces of Mylar film and scanned
in the transmission mode. The scan range, step size, and time
per step were 2
respectively.
θ = 3.0 to 40.0°, 0.0167113°, and 30 s,
Vibrational (Raman and FTIR) spectroscopy
Raman analyses were performed by using a LabRam HR 800
confocal Raman system (HORIBA, Ltd., Lille, France) in the
spectral range of 400–4000 cmꢀ1. The excitation of Raman
scattering was operated by a He−Ne laser at 632.81 nm.
Samples were placed on glass with acquisition time of 20 s.
FTIR spectra were collected on a ThermoꢀNicolet 6700 IR
spectrometer (Thermo Fisher Scientific, Waltham, MA).
Samples were compressed into disks with KBr and analyzed
over the wavenumber range of 400–4000 cm–1 with 100 scans
at a resolution of 4 cm–1.
Scheme 2 Two proposed heterosynthons between TP and NCT.
In this study, the crystal structure of
a
powder
pharmaceutical cocrystal of theophylline (TP) and nicotinamide
(NCT) (Scheme 1) is determined by a combination of XRPD,
1D ssNMR, and density functional theory (DFT) calculations.
The preparation of 1:1 TPꢀNCT cocrystal was first reported by
Lu and Rohani with improved physicochemical properities.19
Solid-state NMR (13C NMR and 15N NMR)
2
Solidꢀstate 13C and 15N crossꢀpolarization magic angle
spinning (CP/MAS) spectra were acquired using a Bruker
AVANCE IIIꢀ500 spectrometer (Bruker BioSpin, Karlsruhe,
Germany) operating at a magnetic field strength of 11.7 T,
equipped with a 4 mm doubleꢀresonance MAS probe. A total of
sideband suppression (TOSS) frame was embedded into the
conventional CrossꢀPolarization (CP) pulse sequence, which
was used to acquire the 13C and 15N CP/MAS spectra. The
HartmannꢀHahn conditions of the CP/MAS TOSS experiment
for acquiring 13C and 15N spectra were optimized by using
adamantane and glycine, respectively. 13C NMR spectra were
obtained at an 8 kHz MAS spinning speed with a contact time
of 2 ms. 15N NMR spectra were obtained at an 8 kHz MAS
spinning speed with a contact time of 3.5 ms. Recycle delay
times for TP, NCT, and cocrystal are 10 s, 200 s, and 10 s,
respectively. In order to make a distinction between protonated
carbon atoms and quaternary carbon atoms, the nonꢀquaternary
carbon suppression (13C NQS) experiment of cocrystal was also
performed. 13C, 15N chemical shifts were externally referenced
According to the Raman data, an R2 (7) supramolecular
synthon (Scheme 2a) was proposed existing in the cocrystal,
where intermolecular hydrogen bondings occur between N3,
C5−H of TP and amide of NCT.19 A similar R2 (7) graph set
2
can be observed when caffeine (structural analogue of TP)
cocrystallized with some organic carboxylic acids.8 According
to the hydrogenꢀbond rules for organic compounds,20 the
primary synthons always formed between best acceptor and
2
best donor. Hence, R2 (9) synthon shown in Scheme 2b is
expected to be established between TP and NCT molecules.
2
Such R2 (9) graph set (or its analogues) can be observed when
TP cocrystallized with urea,21 organic carboxylic acids,22ꢀ25 and
other molecules26. Additionally, dimeric interactions formed
between two TP molecules (an analogue of Scheme 2b) may
also exist.27ꢀ29 It is critical to ensure which kind of
supramolecular synthon exists in the TPꢀNCT cocrystal, and
whether novel supramolecular synthon can be found.
Experimental
to adamantane (
respectively.
δ = 29.5 ppm) and Lꢀglycine (δ = −347.0 ppm),
Materials and sample preparation
TP (≥99%, Adamas Reagent Co., Ltd., China), NCT (≥98.5%,
Sinopharm Chemical Reagent Co., Ltd., China) and EtOH
(≥99.7%, Sinopharm Chemical Reagent Co., Ltd., China) were
purchased and used as received. In order to obtain the TPꢀ
NCT cocrystal, 72 mg TP was ground with 48.8 mg NCT (in a
molar ratio of 1:1) in a pestle and mortar for 10 min followed
by addition of one drop of EtOH, then the resulting mixture was
further ground for 20 min. Single crystal growth was also
attempted by using solution methods, but no sample with
appropriate size and quality was obtained for further singleꢀ
crystal Xꢀray diffraction analysis.
Computation methods
All the computational tasks were performed using Accelrys
Materials studio (MS) software. The cocrystal structure
refinement from XRPD was carried out using MS Reflex
program. After completing pattern processing, the diffraction
pattern was first indexed by using the TREOR90 algorithm30.
Next, Pawley refinement31 of the peak profiles was performed
until the figure of merit reached a good quality of fit (Rwp
3.01%, Rp = 2.28%). Subsequently, a couple of TP and NCT
molecules were introduced into the empty unit cell determined
=
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by the Pawley refinement. This structure model was subjected collected (Supporting Information: Figure S3). The resonance
to preliminary crystal structure solution using a directꢀspace peaks of cocrystal sample can be readily assigned by referring
method based on the Simulated Annealing algorithm. The best to that of the input materials.40
fit between the simulated and experimented powder patterns
was obtained with Rwp = 7.25% (Rp = 5.32%). The obtained
structure model was used for the final Rietveld refinement.32
The TP (CSD refcode: BAPLOT01)33, NCT (CSD refcode:
NICOAM02)34, and refined cocrystal structures were subjected
to firstꢀprinciples geometry optimization to obtain
configurations with minimum energy by keeping the unit cell
parameters fixed while allowing the positions of all atoms to be
relax freely. Such optimization can help to obtain more accurate
atomic coordinates in the crystal cell, from which more
accurate chemical shift values can be derived.35,36
Optimizations were performed by using the MS CASTEP
program which implements density functional theory within a
generalized gradient approximation (GGA) and the planewave
pseudopotential approach.37 Calculations were carried out by
using PerdewꢀBurkeꢀErnzerhof (PBE) functional, ultrasoft
1
2
4
(d)
1,12
13
8
5
10
2
(c)
(b)
8
12
11
9
10
6,7
3
5
21 4
(a)
pseudopotential, medium planewave cutoff energy (300 eV) 180 160 140 120 100 80 60 40 20
and Kꢀpoint as default setting in MS package. NMR shielding
δ(
13C)
calculations were performed with MS CASTEPꢀNMR code,
using periodic gauge including projector augmented waves
(GIPAW) method at the GGA/PBE level. A fine Kꢀpoint and
cutꢀoff energy of 550 eV were employed, combining with coreꢀ
valance interactions described by ultrasoft pseudopotential
generated onꢀtheꢀfly.
Figure 1 13C CP/MAS TOSS NMR spectra of TP (a), NCT (b), cocrystal (c) and
13C NQS NMR spectrum of cocrystal (d).
Results and discussion
Cocrystal characterization
The preparation of 1:1 TPꢀNCT cocrystal was first reported
by Lu and Rohani.19 The TPꢀNCT sample obtained in this study
was first characterized by XRPD and differential scanning
calorimetry. The resulting XRPD pattern and melting point
agree well with the reference (Supporting Information: Figure
S1&S2),19 indicating successful synthesis of the target product.
The cocrystal was further characterized by 13C CP/MAS
TOSS NMR (Fig. 1c). 13C chemical shifts of TP and NCT (Fig.
1a and 1b) can be clearly assigned according to ref. [38] and
[39]. The TPꢀNCT sample shows slight changes in 13C
chemical shifts with respect to the spectra of input materials,
which is ascribed to the altered chemical environments
associated with the formation of a new phase. Chemical shifts
of C3, C5, C6, C7, C9, C10, C11, and C13 in the new phase
can be assigned directly by referring to the spectra of TP and
NCT. The remaining peaks are assigned with the help of NQS
data (Figure 1d). Each chemically distinct carbon in the
cocrystal molecule is represented by single resonance, and no
peaks of phase impurities can be found in the 13C spectrum.
Thus, it’s easy to realize the resulting phase is not a physical
mixture of input materials, nor does it contain impurities at
detectable concentrations, and the number of molecules per
asymmetric unit (Z’) should be equal to 1 for the cocrystal. 15N
solid state NMR spectra of TP, NCT, and cocrystal were also
5
10
15
20
25
30
35
40
2 Theta (degree)
Figure 2 Restrained Rietveld fitting of the TPꢀNCT XRPD data, where the
measured pattern is represented with the black line (top), the simulated pattern
with the red line (middle), and the difference pattern with the blue line (bottom),
respectively.
Structure determination from XRPD
Formation of cocrystals is dependent on the establishment of
favorable nonꢀcovalent intermolecular interactions. As
mentioned in the introduction section, there may be multiple
2
possibilities, though the R2 (9) heterosynthon (Scheme 2b) is
most favorable. With the assistance of solid state NMR
spectroscopy (Z’ = 1), one cocrystal structure was determined
from the XRPD data by Rietveld refinement with favorable
residual variances (Figure 2, Rwp = 3.38%, Rp = 2.49%).
Crystallographic details of the refined structure are presented in
Table 1 and Table 2.
As shown in Figure 3 and Table 2, the refined structure
mainly adopts the R2 (9) heterosynthon (Scheme 2b) with a
2
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TP/NCT ratio of 1:1. The TPꢀNCT cocrystal crystallizes in the
monoclinic unit cell where each unit cell is comprised of four
TP molecules and four NCT molecules. C2=O1 and N4−H of
TP connect with amide group of NCT, forming a intermolecular
hydrogen bonding pair, the surplus N6−H proton is further
hydrogen bonded with the C1=O2 group of another TP
molecule. Additionally, very weak dimeric interaction occurs
between two NCT molecules via C8−H and N5 atoms, and N3
of TP is weakly interacted with C10−H of NCT.
Table 1 Crystallographic details of the refined cocrystal structure.
Name
Formula
Molecular weight
Crystal system
Space group
a (Å)
TPꢀNCT cocrystal
C13H14N6O3
302.30
monoclinic
P1 21/C1
3.8669
b (Å)
16.6497
21.7468
90
c (Å)
α (º )
β (º )
99.5215
90
γ (º )
Volume (Å3)
Z/Z’
1380.830
4/1
Rwp
3.38%
Figure 3 Packing diagram of refined cocrystal structure viewed along [100] face.
Rp
2.49%
Table 2 Intermolecular hydrogen bonds in TPꢀNCT cocrystal
D−HꢁꢁꢁA
N4−HꢁꢁꢁO3
N6−HꢁꢁꢁO1
N6−HꢁꢁꢁO2
C8−HꢁꢁꢁN5
C10−HꢁꢁꢁN3
D−H/Å
HꢁꢁꢁA/Å
DꢁꢁꢁA/Å
D−HꢁꢁꢁA/deg
1.063(1.061a)
1.034(1.035)
1.029(1.028)
1.093(1.093)
1.091(1.090)
1.774(1.704)
2.004(1.922)
1.922(1.987)
2.545(2.476)
2.412(2.511)
2.835(2.760)
3.032(2.946)
2.918(2.991)
3.427(3.428)
3.463(3.572)
176.032(173.786)
172.473(169.584)
161.687(164.600)
137.049(144.706)
161.009(163.962)
a the parameters after geometry optimization are shown in the brackets; TPꢀNCT structure after geometry optimization (in CIF format) can be found in
Supporting Information.
Table 3 Experimental and calculateda 13C/15N chemical shifts of TP, NCT, and cocrystal.
exp
TP
cal
TP
exp
TPꢀNCT
cal
TPꢀNCT
exp
NCT
cal
NCT
exp
TPꢀNCT
cal
TPꢀNCT
Position
Position
δ
δ
δ
δ
δ
δ
δ
δ
C1
N1
C2
C3
C4
N2
N3
C5
N4
C6
C7
150.8
−226.6
155.1
149.5
−222.8
153.7
152.7
153.5
C8
C9
149.2
122.9
137.9
129.3
−77.6c
152.0
169.3
−275.8
152.6
124.1
138.5
131.3
−77.4
155.2
171.3
−276.5
149.1
121.7
138.6
126.8
−66.5
152.7
170.5
149.5
120.1
136.1
127.8
−67.0
151.2
171.6
−230.8
155.4
106.4
148.3
−264.7
−145.5
141.5
−218.8
29.1
−229.3
156.0
107.2
147.9
−263.3
−146.7
141.9
−222.8
25.1
C10
C11
N5
105.9
106.8
146.1
145.4
−269.0
−162.3
140.9
−265.8
−167.6
140.5
C12
C13
N6
−274.4
−277.4
−218.1
−219.2
30.0
25.3b
31.4
26.2
a the calculated 13C/15N chemical shifts δcal = − (σcal − σref), where σcal is the calculated 13C/15N shielding value, σref = 168.0 ppm (for 13C) and −165.2 ppm (for
15N), respectively; b average chemical shift value of C6&C7; c from ref.[45].
DFT calculations
Though the structure refinement is regarded as a routine
practice,41,42 it remains a trialꢀandꢀerror approach. A solution
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with acceptable XRPD feature of merit (Rwp and Rp) can not atoms but not carbon atoms are often directly involved in the
always ensure the correctness of the obtained structure. intermolecular interaction changes. For the cocrystal sample,
Following the recent examples,16ꢀ18,43,44 NMR parameters are the calculated 13C and 15N chemical shifts (especially for 15N
used to evaluate the rationality of the refined TPꢀNCT structure. spins) all agree well with the experimental values, indicating
Experimental and calculated 13C and 15N chemical shift data the refined structure is the accurate representation of actual
of cocrystal and two input materials are summarized in Table 3. cocrystal structure.
For TP and NCT, the maximal chemical shift difference
between the experimental and calculated values is ca. 5 ppm,
which is within the level of calculating error and confirms the
Further checking the intermolecular interactions
For N3 and N5 spins, the 15N chemical shifts are displaced by
availability of current computational accuracy. After the 16.8 and 11.1 ppm after cocrystal formation, respectively.
cocrystal formation, the experimental chemical shift changes of Significant differences of intermolecular interactions between
13C spins are all less than 2.5 ppm, while for some nitrogen the original materials and cocrystal sample on these sites are
atoms (N3 and N5), significant experimental chemical shift believed to be the major contributor of these large chemical
changes are observed. It’s a normal phenomenon for nitrogen shift variations.
Figure 4 Intermolecular hydrogen bonds in TP (a), NCT (b), and TPꢀNCT cocrystal (c). The relevant interꢀatomic distances are in Å.
Figure 4 displays the crystal fragments of TP, NCT, and weak48 (Figure 5b), and therefore a clear assignment in the
cocrystal after periodic structure optimization. In TP crystal, N3 spectrum of cocrystal sample is difficult. In the high
is involved in a strong hydrogen bond (1.710 Å) with N4−H of wavenumber range (> 2750 cm−1), Raman spectra only show
another TP molecule. In the cocrystal, O3 plays the role of the activity of C−H stretching47,48
proton acceptor as N3 does in TP crystal. While, N3 is only concerning N−H stretching is absent.
very weakly (2.511 Å) interacted with C10−H in the cocrystal
,
while information
form, leading to a significant deꢀshielding effect on the nuclear
and hence a significant downfield 15N chemical shift value.46
1673
N5 in the NCT molecule encounters a similar situation
compared to N3. Such qualitative analysis displays consistency
of intermolecular interaction changes and characteristic
chemical shifts, further confirming the correctness of the
obtained structure.
1251
1715
(c)
(b)
Once the crystal structure was confirmed, the commonly used
Raman19 and FTIR data should be investigated to check for
consistency. RAMAN spectra of TP, NCT, and cocrystal are
shown in Figure 5. The obvious changes (~10 cm−1) of the C=O
stretching frequency of TP47 (from 1706&1664 to 1715&1673
cm−1) suggest the carbonyl groups should be involved in
hydrogen bonding in the cocrystal (Figure 4). For NCT, the
change on its C=O stretching frequency48 is inconspicuous
(from 1677 to 1673 cm−1), indicating the C13=O3 involved
hydrogen bonding still exists in the cocrystal (Figure 4). For
N4−H group of TP, Raman data only show there is no obvious
alterations on its inꢀplane deformation mode (from 1249 to
1251 cm−1)47. The N6H2 rocking frequency of NCT is very
1677
C-H
NH2 rocking
1664
1706
1249
C-H
C-H
(a)
3500
3000
1500
1000
500
Wavenumber (cmꢀ1)
Figure 5 RAMAN spectra of TP (a), NCT (b), and TPꢀNCT (c).
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This study further confirms that supramolecular synthon
approach affords a feasible way to design, develop and analyze
new pharmaceutical cocrystals, and synergistic approach offers
a simple and credible way to solve the crystal structure of
powder cocrystal samples.
(c)
3214
3159
3059
3400
1712
1652 (C=O&ring stretching)
(b)
Acknowledgements
This work was supported by the Natural Science Foundation of
China (No. 21205129, 21073226), and Jiangsu Provincial Fund
for Natural Sciences (No. BK2012191). The NMR system used
in this study was funded through the key scientific equipment
plan of the Chinese Academy of Sciences (CAS). Authors also
thank FUNSOM, Soochow University, for the calculation
supporting.
3366
1679
(a)
3059
1717
1668
Notes and references
a
Laboratory of Magnetic Resonance Spectroscopy and Imaging, Suzhou
3500 3000 2500 2000 1500 1000 500
Wavenumber (cmꢀ1)
Institute of Nanoꢀtech and nanoꢀbionics, Chinese Academia of Sciences,
Suzhou 215123, P.R. China. Tel: +86ꢀ512ꢀ62872713; Fax: +86ꢀ512ꢀ
62603079; Eꢀmail: hlzhang2008@sinano.ac.cn.
Figure 6 FTIR spectra of TP (a), NCT (b), and TPꢀNCT (c).
b
School of Chemistry and Chemical Engineering, Huazhong University
FTIR spectra (Figure 6) show more information about NH
and NH2 groups. After cocrystal formation, the stretching
vibration frequency of N4−H remains unchanged47 (3059
cm−1), indicating the N4−H involved hydrogen bonding does
not change significantly (Figure 4). For NCT, asymmetric and
symmetric stretching vibrations48,49 of the N6H2 group at 3366
and 3159 cm–1 are blueꢀshifted to 3407 and 3228 cm–1 in the
cocrystal, respectively. Such large frequency changes must
origin from marked hydrogen bonding structure changes on
N6H2 group (Figure 4).
of Science and Technology, Wuhan 430074, P.R. China.
c
State Key Laboratory of Magnetic Resonance and Atomic and
Molecular Physics, Wuhan Institute of Physics and Mathematics, Chinese
Academia of Sciences, Wuhan 430071, P.R. China.
d Crystal Pharmatech, Suzhou Industrial Park, Suzhou 215123, P.R. China.
§ These two authors made equal contributions.
†
Electronic Supplementary Information (ESI) available: [XRPD
patterns, DSC curves, 15N CP/MAS NMR spectra of TP, NCT, and TPꢀ
NCT cocrystal. TPꢀNCT structure after geometry optimization (in CIF
format)]. See DOI: 10.1039/b000000x/
Interpretation of the vibrational data is not straightforward if
the crystal structure is not solved. For example, the shifts of the
stretching vibrations of N6H2 group should originate from the
hydrogen bonding structure changes, rather than the
formation/disappearance of hydrogen bonding. Thus, to obtain
detailed intermolecular interactions of a powder cocrystal
sample, it’s more convincing to solve out the crystal structure
with credible method, if possible. Several XRPD refined
cocrystal structures, such as acyclovirꢀtartaric acid and adefovir
dipivoxilꢀnicotinamide complexes, have been reported
recently.18,50ꢀ52 For the synergistic approach, it was only
adopted by Harris for the structure determination of
indomethacinꢀnicotinamide cocrystal.18 Thus, there must be
large space for its wide application in the pharmaceutical
crystallography research field.
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Table of Contents Graphic
Crystal structure of theophyllineꢀnicotinamide cocrystal is solved for the first time by using a
combined multiꢀtechnique approach.
8 | J. Name., 2012, 00, 1-3
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