Non-destructive evaluation of pseudo-polymorphic impurities in a drug tablet

In the tableting process of a pharmaceutical product, the drug sometimes reacts with excipients (inactive substances used as carriers for the drug) such as sugar and starch, or the process induces a dehydration reaction or a polymorphic transition. Scientists involved in the pharmaceutical industry need to determine—as quickly as possible—whether a drug of interest maintains its original crystalline system during the tableting process or if polymorphic impurities are produced.

A model sample was created in which a part of the original drug substance was converted in to a polymorphic impurity when making tablets. Theophilline anhydride, a tracheal relaxant, was combined with theophilline monohydrate as a pseudo-polymorphic impurity. A double-weight standard excipient (a mixture of lactose and starch) was added and the resulting powder was cast into a tablet 6 mm in diameter and 3 mm thick.

The tablet was measured just as it is without destroying it, using a TTRAX III θ/θ rotating anode XRD system. By combining the parallel beam and transmission techniques available in Rigaku's Cross Beam Optics system, precise diffraction profiles can be obtained independent of the sample shape. This makes it possible to detect and use the diffraction lines from both the outside and the inside of the tablet.

As shown in Figure 1, even when the polymorphic impurity in the original drug substance is as low as 1 wt% (0.3 wt% for the total weight of the tablet), it can be detected with a measurement of about 10 minutes.

Evaluation of the pseudo-polymorphic impurity

Figure 1: 1 Evaluation of the pseudo-polymorphic impurity in the drug tablet

A calibration curve, Figure 2, that has a high correlation with the original drug substance was obtained.

Calibration curvs

Figure 2: Correlation of the original drug substance and the pseudo-polymorphic impurity in the tablet

Samples provided by Professor Katsuhide Terada, Pharmaceutical sciences, TOHO University