Tecastemizole, an active metabolite of the histamine H 1 -receptor antagonist Astemizole (Hismanal), crystallizes out in two polymorphic forms (form A and form B). Thermodynamic stability screening results show that form A is more stable and form B is kinetically favorable (metastable) in the temperature range of process interest. A process design switch from a seed controlled growth approach to a solvent mediated interconversion based approach was adopted for reasons of simplicity and robustness during early Phase II development. The effects of dissolution, mass transfer, and surface-controlled growth on the observed interconversion rate were studied under well-defined seeding conditions. The experimental results show a significant effect of operating temperature on the interconversion rate and also show that the rate-limiting step is the growth of form A. Growth controlled kinetic parameters were estimated and are reported here. A nonlinear cooling profile was developed to take advantage of the temperature rate effect on form interconversion. Scale-up of the modified procedure was performed at both pilot and full-scale manufacturing, and the results confirmed the laboratory findings.
By the application of a compliance technique the fatigue crack closure behavior of surface cracks in British Standard or Low Alloy Steels, Composition and Properties (BS) 4360-50D structural steel was investigated under pure bending. Crack closure at the vicinity of surface intersection points was monitored by use of an Elber type gage, whereas the overall closure behavior was determined by means of a standard clip gage situated at the notch mouth. Under constant amplitude loading the crack opening load was larger around the surface intersection points than the overall opening load. For the range of ΔK that was considered, Kop increased with Kmax and the variation was dependent on the applied stress ratio. A comparison of the results of this study with those in the literature showed that the closure response of surface cracks under bending was less significant than that observed from the through thickness crack geometries. The closure parameter U showed an increasing trend with ΔK. However, for a low stress ratio the influence of closure was much more pronounced at small ΔK values. Presentation of the crack growth data of the surface intersection points in terms of ΔKeff produced well correlated data without any mean stress effect being observed in the mid-range regime.
Drug powders with improved flow were found to exhibit low dilation and low impedance values. A common linear correlation between flow index and impedance and also between dilation and impedance was observed for all three APIs, indicating that electric properties play a substantial role in the cohesivity of all three APIs, and suggesting the presence of a common mechanism for the emergence (and mitigation) of cohesive phenomena.
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