Variable Temperature 13 C CP MAS Solid-State NMR

Experiments

Experiments on ibuprofen were performed using a Bruker Avance III 500 spectrometer, operating at Larmor frequencies of 500.1 MHz for 1H and 125.8 MHz for 13C. All experiments were 13C CP MAS (8 kHz), with transverse magnetisation transferred from 1H using a 1 ms contact pulse, ramped from 50% to 100% power on the 1H channel. During the 39.9 ms acquisition time, SPINAL-64 decoupling was applied on the 1H channel at an rf frequency of 100 kHz and with a pulse duration of 4.6 µs. Unless otherwise stated, 256 transients were recorded and co-added. A 3 s recycle delay was used, resulting in a total acquisition time of approximately thirteen minutes. Preparation of the sample in such a way that it would be possible to follow the

7.2. EXPERIMENTAL AND COMPUTATIONAL DETAILS 129

emergence of the crystalline form II from the amorphous form by solid-state NMR required the following pre-experiment set-up procedure. Powdered form I ibuprofen was packed into a standard Bruker 4mm MAS zirconia rotor, which was fitted with a boron nitride cap to ensure that the variations in temperature required to produce form II did not result in the rotor and cap becoming separated. The rotor was then placed in an oven and heated to (355 ± 1) K (above the melting point of 349 K) and held at that temperature for several minutes, to ensure a complete melt of the sample within the rotor. The rotor was then removed from the oven and quenched in liquid nitrogen (77 K) to rapidly solidify the sample. Meanwhile, a Bruker 4mm triple resonance probe, operating in double-resonance mode and tuned to1H and13C, was cooled using a Bruker BVT3000 variable temperature unit and a Bruker BCU-Xtreme refrigeration unit, using a cooling gas temperature of 258 K. The rotor was removed from the liquid nitrogen and inserted directly into the probe using the insert-eject mechanism.

In order to start magic angle spinning, it was necessary to interrupt the flow of cool- ing gas to the probe. The rotor was spun up to 4 kHz before resuming cooling, during which time the temperature measured inside the probe rose due to the application of room temperature bearing and drive gas flows and absence of cooling gas. During this interval the probe temperature did not rise above 272 K. Once the MAS frequency had reached 4 kHz, the cooling gas flow was resumed and the temperature measured inside the probe returned to 258 K. The MAS rate was then increased gradually, in steps of 500 Hz, up to the final frequency of 8 kHz. During this second phase of spin rate increase, the probe temperature remained in the range 258±1 K.

Fifty 13C CP MAS experiments were performed, using the parameters described previously in this chapter, while the cooling gas temperature was maintained at 258 K (above the reported glass transition temperature of 228±1 K [151]). In order to follow the conversion of form I to form II as the temperature increased, a further two 13C CP MAS experiments were then performed. Firstly after the cooling gas temperature had increased first to 273 K, then the cooling gas flow was switched off and the final 13C experiment was performed after the sample had reached room temperature.

The discussion of the temperature throughout refers to the temperature of the cooling gas measured inside the probe. The temperature of the sample will differ from this value due to frictional heating caused by magic angle spinning. However, in this

(a) (b)

Figure 7.2: Ibuprofen form II structures. (a) Before (blue) and after (red) geometry optimisation. (b) The geometry optimised structures of form II(a) (green) and form II(b) (orange).

case due to the relatively low spinning frequency of 8 kHz, this heating effect is likely to be relatively small (<10 K).

7.2.2 Computational Details

First-principles density functional theory (DFT) calculations were performed using CASTEP [48] version 4.3. Structural files for ibuprofen forms I and II were obtained from the Chemical Database Service CrystalWeb database (refcodes COTYOA for form I and IBPRAC04 for form II).

For each structure, a geometry optimisation calculation was performed, and the resulting structure was then used as input for a calculation using the GIPAW [50, 51] (Gauge-Including Projector Augmented-Wave) method to obtain the NMR chemical shielding parameters. Both stages of the calculation used a cut-off energy of 1100 eV. A Monkhurst-Pack grid with a k-point spacing of 0.1 ˚A−1 was used for the geometry optimisation stage, and with a spacing of 0.05 ˚A−1 for the NMR calculation. The PBE exchange-function correlational and ultrasoft pseudopotentials were used in all calculations. During the geometry optimisation stage of the calculation, the positions of all atoms were optimised. The importance of fully optimising the structure, rather than just the proton positions is shown in figure 7.2(a), which shows significant differences in the positions of carbon and oxygen atoms in the overlayed unit cells of form II before and after geometry optimisation. The geometry optimisation and NMR calculations for form II were performed on two different structures. The first, referred to as form II

7.3. RESULTS AND DISCUSSION 131 18 3. 0 0 20 40 60 80 100 120 140 160 180 200 15 .2 21 .8 24 .9 32 .4 44 .0 45 .8 12 6. 7 12 8. 8 13 0. 6 13 2. 2 13 7. 1 14 2. 0 δ13_{C / ppm} Figure 7.3: 13C (125 MHz) CP MAS (8 kHz) spectrum of ibuprofen form I as received, as recorded at room temperature. Spinning sidebands are marked with an asterisk. (a), is the (geometry optimised) published [152] structure. The second, referred to as form II (b), is the published structure with the carboxyl group rotated through 180◦ about the axis defined by the C7–C9 bond, as illustrated in the overlayed (geometry optimised) unit cells of form II(a) and form II(b) in figure 7.2(b). For form II(b), the carboxyl group was rotated before the geometry optimisation.

Following geometry optimisation, the average forces acting on each atomic species (in units of eV/˚A) for each structure were: 0.015(H), 0.019(C) and 0.020(O) for form I; 0.013(H), 0.021(C) and 0.026(O) for form II(a); and 0.014(H), 0.023(C) and 0.024(O) for form II(b).

7.3

Results and Discussion