We offer multiple XRPD methods for the characterization of active pharmaceutical ingredients (APIs), intermediates and finished drug products. XRPD methods for the characterization of pharmaceuticals are referred to in chapter <941> of USP and Ph.Eur.2.9.33 chapter.
At DANNALAB we can quantify polymorphic impurities down to a very low LOQ (limit of quantification), in some cases as low as 0.1% wt of pure API.
Why is this important? XRPD is a method specifically for the identification of polymorphs. The investigation of polymorphs (chemically identical substances in different crystallographic forms) is a key step in drug product development. Since polymorphic forms differ in their solid-state structure, they can have different aqueous solubilities and dissolution rates. XRPD patterns are directly related to the crystalline structure of a material. Therefore, XRPD is considered the “gold standard” for identification of different crystalline phases, polymorphs, hydrates or solvates according to their unique diffraction patterns at different stages of drug development. It is therefore crucial to be able to detect and quantify polymorphic impurities down to very low concentration levels throughout all development and production steps. Presence of minor traces of polymorphic impurity may have significant IP implications as well.
In some cases we are able to validate LOD level down to 0.17% and LOQs as low as 0.5% wt from total.
XRPD allows for the analysis of actual percentages of an API in formulation and in the final dosage form of a drug. XRPD therefore serves as a powerful tool for detecting the polymorph transformations in a pharmaceutical formulation. XRPD quantification of active pharmaceutical substances is also used during stability studies and batch quality control (QC) testing. Each quantification method is developed and validated following the cGMP and ICH guidelines.
To confirm the identity of a pharmaceutical in comparison to a reference, in most cases it is sufficient to prove that there is a match between the XRPD peak positions to the reference values. Our instrumentation allows us to achieve a bandwidth of as low as 0.02 degrees between the reference and the measured peak positions, while for example Ph.Eur.2.9.33 allows a 10x higher bandwidth.
Since the physico-chemical properties of pharmaceuticals are influenced by their solid-state forms, the crystallinity of an active ingredient has a profound impact on both processing behavior (compressibility, compactibility and hygroscopicity) and the bioavailability of the active ingredient in the finished product. Due to its better stability, the desired solid-state form for an active pharmaceutical ingredient (API) is usually crystalline. However, the amorphous state is sometimes required to achieve sufficient efficacy for low soluble active ingredients. During the production or processing of pharmaceutical solids, certain procedures, such as milling, spray drying or lyophilization, can disrupt the crystalline structure and lead to the formation of amorphous regions. On the other hand, undesirable recrystallization can take place within amorphous formulations, driven by thermodynamic or physico-chemical factors. To establish the integrity of the finished product it is important, therefore, to be able to determine the existence and amount of amorphous material within a crystalline matrix or crystalline material in an amorphous matrix. XRPD is successfully used for the determination of crystallinity, both for small crystalline contents in an amorphous matrix and vice versa. An approximate LOQ of 1% wt is achievable for the quantification of crystalline material in amorphous matrices. Note that in some cases the combination of XRPD with additional SAXS characterization may reveal important information about the mesostructure of an API, such as the value of a specific surface, with direct implications for its dissolution profile.
The Rietveld method is a full-pattern fitting method in which a calculated profile is fitted to a measured pattern by varying a range of crystallographic parameters. It is used for atomic structure refinement and for precise determination of the characteristics of a unit cell. The method derives crystallographic parameters, such as lattice constants, atom coordinates within the unit cell, site occupancy and preferred orientation. In addition, Rietveld refinement can be used to reveal the quantitative composition of multiphase mixtures.
The XRPD pattern of a crystalline phase is directly related to its crystalline structure, and an XRPD pattern of a compound mixture is generally the sum of the XRPD patterns of the single compounds. XRPD pattern decomposition often serves as the preliminary step before the subsequent identification of unknown compounds in a mixture by comparison with the available databases. Phase analysis using XRPD is ideal for the analysis of polymorphic mixtures, investigations of phase transformations in compatibility studies, and optimization and quality control of the final formulation. In addition, XRPD full-pattern analysis allows for the (semi-)quantitative analysis of amorphous compounds in the formulation.