Informatic Calibration of a Materials Properties Database for Predictive Assessment of Mechanically Activated Disordering Potential for Small Molecule Organic Solids

Formation, Physical Stability, and Quantification of Process-Induced Disorder in Cryomilled Samples of a Model Polymorphic Drug

“…The latter is expected to be directly related to lattice energy. 13 47 Recent work has suggested that fully amorphous sulfathiazole was difficult to obtain either by extended milling times at room temperature or by spray drying methods. The material produced also showed very high instability and rapid recrystallization.…”

“…The RMSEC and RMSEP values were 1.58 and 1.22 % for the determination of amorphous content in amorphous / form I mixtures and 1.39 and 1.38% for the 13 determination of amorphous content in amorphous / form III mixtures. In both cases just one PLS factor was required.…”

“…12 This process represents an effective method of reducing the risk of recrystallisation of any amorphous materials produced due to the lower process temperatures involved compared to milling at ambient or higher temperatures, and it is often a more efficient way to prepare an amorphous API for those compounds which are disordered by milling. [13][14][15][16][17] Amorphous drugs are important as their greater surface area and surface activity can lead to higher bioavailability 18,19 and attempts have also been made to use the amorphous form of a drug to circumvent patents which apply to a crystalline form. 20 However, due to the metastable nature of amorphous drugs, the amorphous regions or crystal defects created by milling are unstable and under a range of circumstances such as elevated temperature or relative humidity, they undergo structural changes or revert to the original form or to other stable crystalline forms.…”

“…35,45 Recently, the preparation of amorphous sulfathiazole by cryo-milling has been reported but no stability testing of the amorphous phase was described. 13 In this paper we describe a detailed study of the effect of cryo-milling on two sulfathiazole polymorphic forms I and III. The physical stability of the amorphous 5 forms produced under different storage conditions has been investigated and the quantitative analysis of binary mixtures of amorphous sulfathiazole with crystalline forms I and III is also constructed to quantify the process induced crystalline disorder in the cryo-milled samples.…”

Investigation of the Capacity of Low Glass Transition Temperature Excipients to Minimize Amorphization of Sulfadimidine on Comilling

“…5 The general agreement between the four methods gave a reliable indicator of the amorphous content in the milled API and provided a basis on which to compare the effects of co-milling with the selected dicarboxylic acids. The dicarboxylic acids investigated are crystalline in nature and, except for malic acid, were resistant to amorphisation when milled, spray dried or melt quenched alone (Figure 1 45 The Tg values for SDM and excipients are displayed in Table 3.…”