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Drug development, pre-formulation and formulation in depth

CubiX³ Pharma, PANalytical

Drug development, pre-formulation and formulation

Many X-ray analysis tools have earned their place in today’s pharmaceutical development laboratories, especially in the areas of pre-formulation and formulation of solids. The non-destructive character of the analyses often allows a multitude of process steps to be performed on the same sample without destroying its original structure. For the full characterization of API’s, incl. co-crystals, and excipients in the drug development stages several important X-ray solutions are highlighted here.

Polymorph screening: XRPD is the recognized technique to uniquely identify polymorphs. High Throughput polymorph and salt screening, supported by automatic full pattern cluster analysis allows rapid sorting of large amounts of samples.

Crystallization studies and scale-up: in situ crystallization studies can be performed by the use of a slurry flow cell. The investigation of the parameters influencing the crystallization process and the study of reaction intermediates and hemihydrates is a valuable tool for understanding the crystallization process in a Quality by Design (QbD) approach.

Amorphous versus crystalline determination: XRPD is used in the determination of percent crystallinity where the volume concentration of, for example, amorphous filler to crystalline active matrix, is measured within a drug's dosage form. In addition, small-angle X-ray scattering (SAXS) permits researchers to identify nanomaterial particle size, shape and quantify surface-area of a compound.

Investigation of amorphous and nano-crystalline compounds: The pair distribution function (PDF) analysis gives information on the local structure (short range order) of a compound. It allows to not only investigate crystalline, but also nanocrystalline and amorphous phases as well as crystallization processes of unstable compounds.

Stability studies: XRPD can provide unambiguous information about the formation of polymorphs or hydrates under a variety of different environmental conditions through non-ambient diffraction experiments (Temperature and/or Humidity).

Compatibility studies: XRPD is an ideal tool for systematic drug-excipient compatibility studies in pre-formulation. Careful selection of excipients, and the systematic evaluation of drug-excipient interactions, is essential to achieve consistent release and bioavailability data.

Formulation optimization: XRPD can also be extended to provide a full quantitative phase analysis. The latter is of particular value in optimizing pharmaceutical formulations. Formulation morphology, such as the tablet granularity, distribution of multi-unit pallet systems inside a tablet or coating homogeneity can be visualized by Computed Tomography (CT).

Elemental analysis: XRF spectroscopy detects and quantifies major and minor elements in fillers, lubricants, coatings and other excipients down to sub-ppm levels. XRF can also be applied to the high precision quantification of catalyst residues present in active ingredients or final drug products. Fingerprinting in addition allows rapid scan based identification of all materials including excipients, APIs and raw materials.

X-ray Diffraction - Instrumentation

Empyrean
Typical uses include:
• Crystal structure determination enhanced when coupled with High Throughput stage for automated use with well plate investigations
• Crystalline impurity quantification, % crystallinity/amorphous ratio and crystallite size
• Polymorhs, co-crystal (hemi)hydrates formation and identification
• Full non-ambient experiments
• API quantification and final dose forms(s)
• Real time (in situ) crystallization studies when coupled with the Slurry Flow Cell
• Nanomaterial investigations – enhanced when coupled with ScatterX78
• Pair Distribution Function determination for near neighbor distance determinations
• Tablet granularity studies when combined with the CT module

X’Pert³ Powder
Typical uses include:
• Crystal structure determination
• API crystal morphology monitoring
• API quantification and final dose forms(s)
• % crystallinity quantification

CubiX³ Pharma
Typical uses include:
• API crystal morphology monitoring
• API quantification and final dose forms(s)

X-ray Fluorescence - Instrumentation

Epsilon 3X(LE) (energy dispersive XRF)
Typical uses include:
• Elemental and trace heavy metal screening
• Rapid identification of raw materials when combined with FingerPrint

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