Crystal Growth & Design
Article
calculated X-ray lines from the single crystal structure were compared
to confirm the purity of the bulk phase using Powder Cell.29
Thermal Analysis. DSC and TGA were performed on a Mettler
Toledo DSC 822e module and a Mettler Toledo TGA/SDTA 851e
module, respectively. Samples were placed in open alumina pans for
TGA and in crimped but vented aluminum sample pans for DSC.
A typical sample size is 4−6 mg for DSC and 9−12 mg for TGA.
The temperature range was 30−250 °C at 2 K min−1 for DSC and
10 K min−1 for TGA. Samples were purged with a stream of dry N2
flowing at 150 mL min−1 for DSC and 50 mL min−1 for TGA.
Vibrational Spectroscopy. A Thermo-Nicolet 6700 FT-IR
spectrometer (Waltham, MA, USA) with a NXR FT-Raman Module
(Nd:YAG laser source, 1064 nm wavelength) was used to record IR
and Raman spectra. IR spectra were recorded on samples dispersed in
KBr pellets. Raman spectra were recorded on samples contained
in standard NMR diameter tubes or on compressed samples contained
in a gold-coated sample holder.
were carried out in distilled water and absorbance was measured at
318 nm in a UV−vis spectrophotometer.
ASSOCIATED CONTENT
* Supporting Information
■
S
Crystallographic information files; Refcodes of cocrystals and
salts of piperazine (Table S1) and piperazinium dications
with carboxylate anions (Table S2); 13C solid-state NMR of
piperazinium meclofenamate salts compared to values for the
pure coformers (Table S3); ORTEP diagrams (Figure S1);
TGA results (Figure S2); PXRD results (Figures S3, S6, S7);
comparison of calculated X-ray diffraction lines of monoclinic
and orthorhombic forms of piperazinium meclofenamate (1:1)
salts (Figure S4); DSC endotherm (Figure S5); DSC and TGA
thermograms (Figure S8). This material is available free of
Solid-State NMR Spectroscopy. Solid-state 13C NMR (ss-NMR)
spectroscopy provides structural information about differences in
hydrogen bonding, molecular conformations, and molecular mobility
in the solid state. The solid-state 13C NMR spectra were obtained on
a Bruker Ultrashield 400 spectrometer (Bruker BioSpin, Karlsruhe,
Germany) utilizing a 13C resonant frequency of 100 MHz (magnetic
field strength of 9.39 T). Approximately 100 mg of crystalline sample
was lightly packed into a zirconium rotor with a Kel-F cap. The cross-
polarization, magic angle spinning (CP-MAS) pulse sequence was used
for spectral acquisition. Each sample was spun at a frequency of 5.0
0.01 kHz and the magic angle setting was calibrated by the KBr
method. Each data set was subjected to a 5.0 Hz line broadening factor
and subsequently Fourier transformed and phase corrected to produce
a frequency domain spectrum. The chemical shifts were referenced to
TMS using glycine (δglycine = 43.3 ppm) as an external secondary
standard.
Dissolution and Solubility Measurements. Intrinsic dissolution
rate (IDR) and solubility measurements were carried out on a USP-
certified Electrolab TDT-08 L Dissolution Tester (Electrolab, Mumbai,
MH, India). A calibration curve was obtained for all the new solid
phases including MFA by plotting absorbance vs concentration UV−vis
spectra curves on a Thermo Scientific Evolution EV300 UV−vis spec-
trometer (Waltham, MA, USA) for known concentration solutions in
50% EtOH−water medium. The mixed solvent system (EtOH−water)
was selected for its higher solubility of MFA in this medium. The slope
of the plot from the standard curve gave the molar extinction coeffi-
cient (ε) by applying the Beer−Lambert’s law. Equilibrium solubility
was determined in 50% EtOH−water medium using the shake-flask
method.27 To obtain the equilibrium solubility, 100 mg of each solid
material was stirred for 24 h in 5 mL of 50% EtOH−water at 37 °C,
and the absorbance was measured at 318 nm. The concentration of the
saturated solution was calculated at 24 h, which is referred to as the
equilibrium solubility of the stable solid form.
100 mg of the solid (drug, cocrystal, salt) was taken in the intrinsic
attachment and compressed to a 0.5 cm2 pellet using a hydraulic press
at a pressure of 2.5 ton/inch2 for 2 min. The pellet was compressed to
provide a flat surface on one side and the other side was sealed. Then
the pellet was dipped into 900 mL of 50% EtOH−water medium at
37 °C with the paddle rotating at 150 rpm. At a regular interval of 5−
10 min, 5 mL of the dissolution medium was withdrawn and replaced
by an equal volume of fresh medium to maintain a constant volume.
Samples were filtered through 0.2 μm nylon filter and assayed for drug
content spectrophotometrically at 318 nm on a Thermo-Nicolet
EV300 UV−vis spectrometer. There was no interference to MFA
UV−vis maxima at 318 nm by coformers INA and bipyridine which
absorb strongly at 250−270 nm. Piperazine is UV−vis inactive. The
amount of drug dissolved in each time interval was calculated using the
calibration curve. The linear region of the dissolution profile was used
to determine the intrinsic dissolution rate (IDR) of the compound
(= slope of the curve, that is, the amount of drug dissolved divided by
the surface area of the disk (0.5 cm2) per minute). The dissolution
rates for MFA, its cocrystals, and salts were computed from their IDR
values. Similarly IDR experiments of MFA−PPZ-M and MFA-SS salts
AUTHOR INFORMATION
Corresponding Author
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the DST (SR/S1/OC-67/2006), JC Bose fellowship
(SR/S2/JCB-06/2009), and CSIR (01(2410)/10/EMR-II) for
research funding, and DST (IRPHA) and UGC (PURSE grant)
for providing instrumentation and infrastructure facilities. P.S.
and G.B. thank the UGC for fellowship. We thank Dr. Naba
Kamal Nath for his assistance to resolve disorder issues in
crystal structure refinement of MFA.
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dx.doi.org/10.1021/cg300002p | Cryst. Growth Des. 2012, 12, 2023−2036