Simultaneous Differential Scanning Calorimetry-Synchrotron X-ray Powder Diffraction: A Powerful Technique for Physical Form Characterization in Pharmaceutical Materials

Abstract

We report a powerful new technique: hyphenating synchrotron X-ray powder diffraction (XRD) with differential scanning calorimetry (DSC). This is achieved with a simple modification to a standard laboratory DSC instrument, in contrast to previous reports which have involved extensive and complex modifications to a DSC to mount it in the synchrotron beam. The high-energy X-rays of the synchrotron permit the recording of powder diffraction patterns in as little as 2 s, meaning that thermally induced phase changes can be accurately quantified and additional insight on the nature of phase transitions obtained. Such detailed knowledge cannot be gained from existing laboratory XRD instruments, since much longer collection times are required. We demonstrate the power of our approach with two model systems, glutaric acid and sulfathiazole, both of which show enantiotropic polymorphism. The phase transformations between the low and high temperature polymorphs are revealed to be direct solid-solid processes, and sequential refinement against the diffraction patterns obtained permits phase fractions at each temperature to be calculated and unit cell parameters to be accurately quantified as a function of temperature. The combination of XRD and DSC has further allowed us to identify mixtures of phases which appeared phase-pure by DSC.

Polymorphic Phase Transitions in Carbamazepine and 10,11‐Dihydrocarbamazepine

“…DSC Measurements were performed with modified TA 2010 or Q20 instruments (TAI nstruments LLC), with holes drilled in the furnace to permit the passage of the X-ray beam as detailed in our previous study. [3] Calibration was performed with ac ertified indium standard according to the manufacturer's instructions. Samples of all materials (5-20 mg) were held in Tzero aluminium pans and heated at 10 8Cmin À1 from ambient to 220 8C.…”

“…Differences in sample sizes between XRD and DSC instruments can also affect the nature of the events observed . We recently demonstrated that a simple modification to a standard lab DSC instrument permits it to be mounted on a synchrotron X‐ray source, such that diffraction patterns can be obtained in as little as 2 s, as the instrument records thermal data in real‐time . This allowed us to perform simultaneous DSC–XRD, and collect large amounts of XRD data of a quality suitable for Rietveld refinement during heating at standard DSC rates (10 °C min −1 ).…”

“…This allowed us to perform simultaneous DSC–XRD, and collect large amounts of XRD data of a quality suitable for Rietveld refinement during heating at standard DSC rates (10 °C min −1 ). As a result, we could accurately explore and obtain new insights into phase transformations of several pharmaceutical active ingredients, including sulfathiazole, glutaric acid and paracetamol …”

“…[2] We recently demonstrated that asimple modification to astandardl ab DSCinstrument permits it to be mounted on as ynchrotron X-ray source, such that diffraction patterns can be obtained in as little as 2s, as the instrumentr ecordst hermal data in real-time. [3] Thisa llowed us to perform simultaneous DSC-XRD, and collectl arge amountso fX RD data of aq uality suitable for Rietveld refinement during heatinga ts tandard DSC rates (10 8Cmin À1 ). As a result, we could accurately explore and obtain new insights into phase transformationso fs everal pharmaceutical active ingredients, including sulfathiazole, glutaric acid and paracetamol.…”

“…As a result, we could accurately explore and obtain new insights into phase transformationso fs everal pharmaceutical active ingredients, including sulfathiazole, glutaric acid and paracetamol. [3,4] Carbamazepine (CBZ) (Figure 1) is an anticonvulsant commonly used to treat epilepsy and trigeminal neuralgia. [5] It has extremelyp oors olubility in water [6] and is therefore an ideal candidate to screen for metastable polymorphs,s ince these will have higher solubility and more rapid dissolution rates than the thermodynamically most stable form.…”