A substantial change in the thermal activity was observed between prednisone/DCPD two-layer preparations (Fig. ) and the 1:1 ratio blended mixtures (Fig. ). The prednisone/DCPD two-layer preparation showed a latent solid-state reaction occurring, which was represented by the slow endothermic heat flow (Fig. ). This reaction is mostly limited by the small surface shared between prednisone and DCPD particles. However, mixing prednisone with DCPD for 30 min provided enough contact surfaces shared between the two materials, boosting the solid-state reaction to a visible peak. Mixing did not affect the prednisone/MCC preparations as the thermal activity of the two-layer and mixed preparation of prednisone and MCC were identical (Fig. ), exhibiting no heat flow. Therefore, the solid-state reaction existed only between prednisone and DCPD, but not between prednisone and MCC. Since one excipient triggered a solid-state reaction and the other did not, our interest was to investigate how the blending sequences might affect the observed solid-state reaction and ultimately the release profile of prednisone/DCPD/MCC powder blends and tablets.
In an industrial scale, larger amounts of material are mixed in different sized blenders. Thus, the amount of friction and the heat resulted during the blending process might not be comparable with the gram scale that was used during this study. Therefore, the study was designed to include an extra time of incubation during powder preparation to compensate for such effects (Fig. ). This incubation was carried out in the ITMC channels in an isothermal environment at 37°C. The powder mixtures were incubated until the ITMC recorded zero heat exchange, indicating the end of any reactions.
Even though IA/IB mixtures were prepared using different blending sequences (Fig. ), DSC and dissolution tests showed similar results (Fig. ). This can be explained by the lack of heat and presumably time required to initiate a solid-state reaction between prednisone and DCPD. In other mixtures, a longer incubation was used to see the effect of that reaction.
In an industrial scale, similar mixtures to IA/IB may happen after brief mixing process. This might be preferable to eliminate any solid-state reaction; however, brief mixing will lead to uneven distribution of prednisone in the final mixture that may react upon storage. Although IA/IB mixtures were prepared without incubation, both mixtures produced a shift in DCPD melting point from 123.4°C to192.7°C, similar to all other mixtures (Fig. ). Compared with other tablets, IA/IB showed higher dissolution rates (Fig. , IA/B). This indicated that the reaction responsible for the shifting DCPD melting point has no effect on the dissolution behavior of the tablets.
The appearance of the new peak at 222°C in the DSC of IIB mixture (Fig. ) confirmed the observation made by ITMC about having an extra thermal activity in the prednisone/DCPD powder mixture. The peak at 222°C did not appear in the DCS of the IIA in which prednisone was mixed and incubated in the first stage with MCC. Comparing the dissolution profiles of IIA and IIB tablets revealed a significant difference between the tablets with a dissimilarity factor of 41. 2 and failing similarity with a F2 of 33.2 (Fig. , IIA/B). This proves that the extra thermal activity detected by ITMC in IIB mixture was associated with different prednisone dissolution behavior.
The difference in the thermal activity between IIIA and IIIB mixtures further emphasized the effect of the blending sequences on the solid-state reaction. Although both mixtures showed endothermic thermal activity, the one associated with mixture IIIA was faster compared to IIIB (IIIA Tmax
24 days, IIIB Tmax
19 days) and had a larger amount of heat exchanged (223 mJ for IIIA and 456 mJ for IIIB, respectively). IIIB mixture preparation was initiated from a reacted IIB mixture, and MCC was not added until the thermal activity associated with prednisone/DCPD mixture was almost zero, indicating the end of the solid-state reaction. Therefore, it was expected that IIIB will not exhibit any extra thermal activity after adding MCC and mixing it for 30 min. The ITMC results showed the opposite, indicating that adding and mixing an inert material, like MCC, to an already reacted mixture will provoke the reaction again. This is most probably due to blending which will provide a new interactive surface between the two materials.
This can be explained by the fact that blending might create new surfaces between the reacted materials. On the other hand, the slow reaction associated with IIIA mixture indicates that mixing and incubating prednisone with MCC before adding DCPD had a protective effect on the prednisone/DCPD reaction (Fig. ), presumably by the coating effect of MCC on the prednisone particles. DSC of the IIIB mixture showed the appearance of a new peak, indicating a similar reaction to what was seen in the IIB mixture (Fig. ). The absence of the extra peak in the DSC of the IIIA mixtures indicates that an additional reaction is going on in IIIB mixture, but not in IIIA mixture.
As ITMC is a universal tool with the ability to monitor the total heat exchange, it shows the total heat exchange over time without differentiating between different reactions happening simultaneously, or forming any new products. This suggests that the blending sequences of IIB and IIIB mixtures, in which DCPD was added and mixed with prednisone then incubated, might provoke a new reaction to happen and resulted in the appearance of the new peaks in the DSC.
The behavior of IVA/IVB mixtures was surprising. The extensive blending of prednisone with one material for a longer time before and after adding the complementary excipient resulted in two mixtures with identical thermal heat flow and similar dissolution rates regardless of the sequence of excipient blending. ITMC showed a very slow heat exchange (Fig. ) and no extra peaks on the DSC runs (data not shown); the DSC was identical to what seen in IA/IB mixtures (data not shown). The absence of the new peaks in the DSC runs of IVA/IVB indicates that the extra reactions associated with mixtures IIB/IIIB was not happening with IVA/IVB mixtures. Both IVA/IVB showed similar dissolution behavior as F2
73.8 (Fig. , IVA/B). Although both the IVA/IVB tablets showed a lower release pattern compared to mixture I A/IB, the difference was not significant as indicated by borderline F2
values: 55 and 52 for IVA and IVB, respectively.