When seeking to confirm that a new solid phase had been produced, XRPD was used

Question

When seeking to confirm that a new solid phase had been produced, XRPD was used to examine the two solid phases. The result of XRPD is shown in Figure 3 below: T-258% a) phase 1 D) phase a 5 10 15 20 25 30 35 4045 50 20(. Question for Figure 1. What two things do the XRPD patterns tell us about the two samples that we are comparing? 2. What would the XRPD of a glass or liquid look like? 3. What would be the expected solubility, rate of dissolution and bioavailability of an ibuprofen formulation using the new crystalline phase? What problems would you foresee in formulating phase II? 4.

Explanation / Answer

The reference X-ray powder diffraction pattern of the conventional crystalline Ibuprofen recorded at 258 K is reported on Figure with clear, intense and sharp Bragg peaks can be seen Their positions are in agreement with the diffraction pattern of the racemic form whose structure has been determined as belonging to the monoclinic P21/c space group by McConnel & Shankland The new polymorphic variety can be obtained by imposing the following thermal history to the sample. The crystalline powder, enclosed in the X-ray capillary, is melted (heating to 373 K), then cooled at 6 K/min till 143 K where it is annealed for 1 hour. The sample is then heated to 258 K (with a heating rate of 6 K/min) and held at this temperature for ta=15 hours. A X-ray diffraction pattern is recorded every hour. On the first recording, a halo characteristic of an amorphous phase is observed on the obtained pattern and no Bragg peak can be seen: after the cooling to 143 K and the heating to 258 K, the Ibuprofen sample is still amorphous. After one hour at 258 K, some Bragg peaks appear and their magnitude increases upon further annealing: the sample slowly crystallizes. After 5 hours, intense and thin peaks can be seen and no evolution is noted for the 10 following hours. The diffraction pattern obtained after the 15 hours annealing is reported on the Fig. 3b. The comparison of the diffraction patterns of the initial crystal state and of the amorphous sample re-crystallized at 258 K (Fig. 3a and b) clearly indicates that the two crystalline phases are different. It should be noted that the diffraction pattern does not correspond either to the S(+)-Ibuprofen As a consequence of the specific treatment, a new crystalline form of Ibuprofen has thus appeared at 258 K. It can be observed that, at wide angles, the peaks of the new form are clearly less intense than those of the conventional form. This leads us to suspect that the new crystalline form is more disordered. However, since the Bragg peaks are sharp, such a disorder should be compatible with a great crystallographic perfection, as it is the case for example for crystals with huge thermal agitation or for rotator crystalline phases (so-called plastic crystals) In the following, for sake of clarity, the conventional crystalline phase can be called “phase I” and the new crystalline form, “phase II”

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