X-ray Powder Diffraction

X-ray powder diffraction (XRPD) is one of the most powerful methods for the study of crystalline and partially crystalline solid-state materials. Each crystalline form has a unique powder diffraction fingerprint that can be used to identify the presence of that form within a sample. SSCI has extensive experience in the interpretation of powder diffraction patterns and has developed unique methodologies for fully automated recognition of crystalline forms.

As a crystalline form becomes disordered it may pass through micro-crystalline and nano-crystalline forms before reaching a final amorphous or random form. Like the crystalline form, each of these disordered forms has a unique diffraction fingerprint which can be extracted by SSCI’s proprietary pattern recognition software, enabling each form’s identification within a sample. The relative amounts of each of these unique diffraction patterns can be used to quantify sample composition, with the use of the appropriate quantitative model. SSCI has a range of controlled humidity and non-ambient chambers where the thermodynamics of these various crystalline and disordered forms can be studied in-situ and in real time.

SSCI has developed various sample presentation methods allowing samples to be studied in solid, powder, suspension, cream, or melt form. Special approaches have been developed to overcome common sample limitations such as inhomogeneity, preferred orientation, and particle statistics and extremely small amounts of material can be analyzed using particular techniques.

Indexing

X-Ray Powder Diffraction pattern indexing is the first step in the solution of a crystal structure from powder data but in addition can be used to determine if a given pattern represents a pure solid phase. The latter information is often sufficient to assure product homogeneity if a crystal structure is unavailable. Learn more about SSCI’s XRPD indexing tools to confirm crystalline phase purity in our KnowledgeBase.

Single Crystal X-ray

An unequivocal method of solid form identification, and one preferred by the FDA when possible, is Single Crystal X-ray Structure Determination. An attempt should be made to obtain a single-crystal structure on all suitably crystalline new drug candidates. SSCI’s scientists have the most modern methods at their disposal, including a state-of-the-art Rigaku SuperNova diffractometer equipped with a micro-focus x-ray source and HPAD detector. This allows the determination of structures using smaller crystals than are required for conventional equipment.

Calculation of Powder Patterns

Calculation of an X-ray powder diffraction pattern from single crystal data provides important information about the homogeneity of a crystalline solid, as well as an unequivocal pattern for use as a standard. SSCI uses multiple software methods to calculate powder patterns from crystal coordinate files.

Once the crystal structure of a material has been determined, a calculated XRPD pattern can be created. A calculated powder pattern is important because it provides information about homogeneity of the crystalline phase and serves as an unequivocal pattern for use as a standard for polymorph screening or quantitative analysis of multi-phase samples. Parameters such as crystallite size, morphology, and preferred orientation can be built into the pattern calculation, providing insight into the microstructure of single-phase samples. Micro-structural parameters often play a significant role in the physical and chemical properties of a sample.

One of the more powerful features of pattern calculation is the ability to study disordering processes to identify relationships between crystalline phases and micro-crystalline/amorphous phases. The subsequent calculated amorphous patterns can be used for precise crystallinity analysis if pure amorphous forms of the material are not available for measurement. SSCI has a wide range of tools at it disposal for the calculation of powder patterns starting from crystal coordinate files, D and I files, or reference patterns.

Rietveld Analysis

The Rietveld method is a computational treatment of diffraction data that separates overlapping data from a typical powder x-ray diffraction pattern and allows accurate determination of the structure of a compound. SSCI uses this method to address various problems including quantitation using XRPD patterns with high degrees of overlap.

Crystal Structure Determination from Powder X-ray Diffraction

On occasion, despite significant efforts, suitable single crystals cannot be grown for a given molecule or particular solid form thereof.  If a good quality powder sample is available, it is often possible to determine the crystal structure using computational methods.

 

 

 

 

 

Hydrogen bonding motif in the Ketoconazole:Succinic Acid Cocrystal as determined from powder X-ray diffraction data.

SSCI has a track record of solving structures from powder data. Although we have experience with synchrotron data, in most cases good results can be obtained using our in-house high resolution XRPD data.

The structure solution is performed by a computational method called simulated annealing in which the molecular structure is used as the input model and the conformation, orientation, and position of the molecule is varied until a plausible solution is found. Larger, flexible molecules and multi-component crystals require more computational time. SSCI has a parallel implementation for structure solution. The more complicated ketoconazole cocrystals showcased in the application note were solved in overnight calculations.

The major caveat, in comparison to structure determination from single crystals, is that the absolute configuration cannot be determined from powder data due to the overlap of the Friedel pair intensities needed for that analysis. SSCI recommends performing additional experimental testing to confirm the molecular structure and the composition in case of solvated crystals using vibrational spectroscopy.

 

 

 

 

 

 

 

 

Final Rietveld refinement result for the Ketoconazole:Succinic Acid Cocrystal.