The anhydrous solvent-free mechanochemical reaction of sulfathiazole, STZ, polymorphs I, III, and V with 10 carboxylic acids was monitored by powder X-ray diffraction (PXRD), attenuated total reflectance infrared (ATR-IR), and near-infrared (NIR) spectroscopy. A 1:1 cocrystal was observed with glutaric acid and the strongest acid, oxalic acid, gave a 1:1 salt. A principal components analysis of the glutaric acid NIR data showed that forms I and V proceeded to the cocrystal, but that form III transformed to form IV before cocrystal formation. The oxalic acid salt was formed via complete amorphization. The crystal structures of the cocrystal and the salt were determined. Sulfathiazole comilled with l-tartaric and citric acids gave coamorphous systems that were stable at 10% RH for up to 28 days. Comilling sulfathiazole with dl-malic acid gave mixtures of form V and the amorphous form.

The effects of ball-milling and cryomilling on sulfamerazine forms I and II (SMZ FI, FII) were investigated using X-ray powder diffraction, IR and NIR spectroscopy. Cryomilling resulted in the complete amorphization of both polymorphs. Milling at room temperature gave mixtures of amorphous SMZ (FA) and FII. Calibration models were developed for the quantitative analysis of binary (FI/FII, FI/FA and FII/FA) and ternary (FI/FII/FA) mixtures using NIR spectroscopy combined with partial least-squares (PLS) regression. The PLS models for binary (0 -100 %), ternary (0 -100 %) and low level (0 -10 %) binary mixtures had root-mean-square errors of prediction of 1.8, 5.1 and 0.80 %, respectively. The calibration models were used to obtain a detailed quantitative picture of solid-state transformations during milling and any subsequent recrystallizations. FA prepared by cryomilling FI for less than 60 min. recrystallized to mixtures of FI and FII, while samples milled for more than 60 min. crystallized to pure FII. The effect of co-milling SMZ with stoichiometric amounts of additives was investigated. SMZ formed amorphous materials with oxalic, DL-tartaric and citric acids that were more stable towards recrystallization than FA.Amorphous SMZ/oxalic acid was found to recrystallize to a 2:1 co-crystal during storage.

No abstract

Milling is an important secondary processing technique in the manufacture of pharmaceuticals, primarily used as a particle size reduction process. Para-, meta-and ortho-aminobenzoic acid (PABA, MABA, OABA) and carbamazepine (CBZ) are pharmaceutically relevant compounds that can exist in different polymorphic forms with distinct packing motifs and thus different physicochemical properties. A comprehensive study of the effect of milling on the polymorphism of PABA, MABA, OABA and CBZ was carried out. Milling PABA in the presence of catalytic amounts of valeric acid or methanol yielded the -polymorph which is otherwise difficult to obtain in bulk quantities. Milling also proved to be a more convenient method for producing MABA form IV compared to previously reported procedures. Principal component analysis of the pair distribution function transformed X-ray powder diffraction spectra of ball-milled CBZ samples showed that the milling-induced polymorphic transformation strongly depends on the ball-to-powder ratio. Elusive CBZ form IV could be obtained in pure form by optimizing the milling conditions.

A comprehensive study on the dissolution properties of three co-amorphous sulfamerazine/excipient systems, namely sulfamerazine/deoxycholic acid, sulfamerazine/citric acid and sulfamerazine/sodium taurocholate (SMZ/DA, SMZ/CA and SMZ/NaTC; 1:1 molar ratio), is reported. While all three co-formers stabilize the amorphous state during storage, only coamorphization with NaTC provides a dissolution advantage over crystalline SMZ and the reasons for this were analyzed. In the case of SMZ/DA extensive gelation of DA protects the amorphous phase from crystallization upon contact with buffer, but at the same time prevents the release of SMZ into solution. Disk dissolution studies showed an improved dissolution behavior of SMZ/CA compared to crystalline SMZ. However, enhanced dissolution properties were not seen in powder dissolution testing due to poor dispersibility. Co-amorphization of SMZ and NaTC resulted in a significant increase in dissolution rate, both in powder and disk dissolution studies.