XRD Investigation and Refinement of Acetaminophen

X-ray diffraction is an established procedure employed in the investigation of pharmaceutical compounds and formulations, within both manufacturing and academic contexts. FDA regulations mandate that an Active Pharmaceutical Ingredients (API) examination is supplemented with XRD data. Due to the growing sophistication required of contemporary APIs to participate in a competitive market focused on maintaining societal health, there is an associated demand for increasingly versatile X-ray diffractometers. These are required to maintain research and validation levels.

APIs and other compounds are obliged to satisfy stringent screening criteria, such as salt, co-crystal, polymorphism, throughout research, production and QA/QC. These steps can be expediently overcome with the assistance of powder X-ray diffraction, which possesses an intrinsic sensitivity and is capable of differentiating multiple crystallographic structures.

Moreover, the performance of dynamic studies is achievable, and it is also possible to monitor the crystallization behavior of compounds in various solvents, or alternative crystallization scenarios. There is even the scope to habitually extrapolate the crystal structure of new compounds from powder data. Finally, X-ray diffraction enables the researcher to refine processes through the tracking of impurities during synthesis.

Instrument

The Thermo Scientific™ ARL™ EQUINOX 100 utilizes a bespoke Cu (50 W) or Co (15 W) high-brilliance micro-focus tube supported by mirror optics. The minimal power expended by the instrument, which negates the requirement for an external water chiller, enables it to be completely portable. This portability therefore permits convenient inter-laboratory transportation, for which specific infrastructure is no longer required.

The ARL EQUINOX 100 offers extremely rapid data acquisition rates in comparison to competing diffractometers as a result of its special curved position sensitive detector (CPS). This calculates all diffraction peaks simultaneously, and in real time, and is consequently ideally suited for both reflection and transmission calculations (Figure 1).

Figure 1. ARL EQUINOX 100 X-ray diffractometer

Experimental

Brand name acetaminophen was examined by granulating the samples and inserting them in reflection sample holders. A sample was also studied in transmission mode with the assistance of a capillary attachment. With the samples revolving throughout the analysis, an examination was performed under Cu Kα (1.541874 Å) radiation for five minutes.

Figure 2. Brand name raw data in reflection mode

Figure 3. Brand name raw data in capillary transmission mode

Raw data determination was undertaken with I_MAD (Figures 2 and 3). MDI JADE 2010, furnished with the Crystallographic Open Database (COD) for qualitative and quantitative phase analysis, enabled the execution of data processing and evaluation, comprising whole pattern fitting Rietveld refinement (WPF).

Moreover, the utilization of EXPO2014, with direct methods, permitted the determination of a crystal structure solution for the sample. Following the location of a suitable solution, the crystal structure was optimized via the implementation of additional Rietveld calibrations.

Results

Acetaminophen products comprise the API alongside an assortment of compounds which typically vary from vendor to vendor. By examining the samples utilizing XRD, the explicit differentiation of the crystalline phases in such mixtures becomes feasible. It is similarly possible to undertake a number of other experimental determinations, including crystallinity proportion, structure solution and refinement, crystallite size analysis, as well as others. The data for both samples, and their associated analyses, is exhibited below.

Figure 4. Diffraction pattern of brand name sample in reflection geometry

The brand-name sample is constituted by a singular crystalline phase, acetaminophen, coupled with an amorphous element (Figure 3). The crystallinity proportion of the sample is 60.71%. The same sample was inserted into a glass capillary (Figures 5 and 6), placed onto a goniometer head, and examined in transmission mode utilizing the capillary attachment (Figure 7).

Figure 5. Brand name sample in glass capillary attachment

Figure 6. Capillary attachment shown on alignment tool

Figure 7. Diffraction pattern of brand name sample in a capillary

The examination of samples in a capillary permits the observation of meta-stable phases, materials in the mother liquor, small sample volumes, and materials which are disposed to preferred orientation, as well as other properties.

Implementing the program EXPO2014 with direct methods enables the determination of a structural solution on the reflection geometry sample. The software is capable of deciphering crystal structures by powder diffraction data, through the use of thermal annealing, or alternatively with direct methods.

It implements the complete solution process pathway: indexing, space group ascertainment, evaluation of the integrated intensities, ab initio and a priori structure solution, and Rietveld refinement. The consequent Rwp = 6.981 for the refined structure, with a unit cell of a = 12.92452, b = 9.41834, c =7.11006 and β = 115.762, with cell volume = 779.47, and SG = P2₁/a (Figure 8).

Figure 8. Crystal structure of acetaminophen from reflection sample

The atomic fractional coordinates are provided in the following table.

Table 1. Atomic fractional coordinates of Acetaminophen

Conclusion

The resolution and speed of the ARL EQUINOX 100 enable the ability to clearly characterize phases in pharmaceutical compounds. A five minute calculation time is adequate to execute WPF quantitative phase analysis, crystallinity proportion measurements, and even, using direct methods, a structure solution of the crystalline phase. As a result, the ARL EQUINOX 100 is a highly practicable instrument for all components of pharmaceutical research and production, spanning pre-formulation research and development through to QA/QC of the final drug product.

This information has been sourced, reviewed and adapted from materials provided by Thermo Fisher Scientific - Elemental Analyzers.

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