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Application Note - Magnetic Resonance

Time Domain-NMR Effectively Distinguishes Between Crystalline and Amorphous States in Powdered Tablet Formulations

“Our findings led us to conclude that TD-NMR is a novel approach for the evaluation of the crystalline state of APIs”

“Our findings led us to conclude that TD-NMR is a novel approach for the evaluation of the crystalline state of APIs”

The easiest way to administer medication is orally. It is most convenient for the patient and does not require sterile measures or healthcare resources. For this reason, oral drug formulations are used wherever possible. The feasibility of such an approach however relies on the solubility of the drug. The bioavailability of a drug administered as a solid dosage form depends heavily on its dissolution rate in the gastrointestinal tract.

Recent advances in drug development have resulted in an increasing number of active pharmaceutical ingredients (APIs) that have poor water-solubility.  It has been estimated that 70% of drug candidates identified in screening programs have low solubility and 40% of immediate-release oral formulation APIs launched recently are classified as insoluble. The oral absorption of these poorly water-soluble APIs (≤100 μg/mL) is substantially limited by their low dissolution in gastrointestinal fluids, resulting in low bioavailability. Despite this, these drugs are available as oral formulations. Rather than having to resort to a less convenient mode of administration, a variety of strategies are employed to improve API solubility.

One of the most common methods used to improve solubility is to change the crystalline form of the API.  Much data exists showing that solubility is substantially increased by amorphization using a solid dispersion technique. However, maintaining the amorphous state of the API for the duration of its shelf-life period remains a great challenge. It is therefore desirable to be able to readily investigate the crystalline state of an API.

Information concerning the crystalline state of a compound can be obtained using a range of techniques, such as powder X-ray diffraction, differential scanning calorimetry and various types of spectroscopy. Solid-state NMR (SSNMR) spectroscopy is particularly useful in this regard but its use for determining crystalline state is limited due to the high running costs and time-consuming measurements.

Recently, it was shown that a more viable technique for evaluating crystalline state with the same level of detail is time domain NMR (TD-NMR). This can be performed using a benchtop NMR spectrometer to rapidly and easily to measure the T1 and T2 relaxation times of both solid and liquid samples. TD-NMR is already widely used in the pharmaceutical industry to evaluate the molecular mobility of hydration water in APIs.

The use of TD-NMR for identifying the amorphous and crystalline forms of APIs was recently investigated. Two APIs with poor water solubility, carbamazepine and indomethacin, were studied by powder X-ray diffraction using a Bruker D8 DISCOVER and by TD-NMR using a Bruker Minispec mq20.

The data obtained showed that the T1 relaxation time measured by TD-NMR effectively distinguished between crystalline and amorphous states of the powdered APIs.  This was confirmed in continuous monitoring of the crystalline state of the APIs incorporated into physical mixtures during the thermal stress test. The conversion of the API to crystalline forms of the APIs was successfully reflected in the T1 relaxation behavior recorded by TD-NMR.

The authors concluded that their findings support the use of TD-NMR as a useful new approach for evaluating the crystalline state of APIs.


Okada K, et al. 1H NMR Relaxation Study to Evaluate the Crystalline State of Active Pharmaceutical Ingredients Containing Solid Dosage Forms Using Time Domain NMR. Journal of Pharmaceutical Sciences 2019;108(1):451–456.