Investigation of the formation of drug-drug cocrystals and coamorphous systems of the antidiabetic drug gliclazide.

The antidiabetic drug gliclazide (GLZ) has a slow absorption rate and a low bioavailability due to its poor solubility. GLZ is often prescribed along with an antihypertensive, as many diabetic patients have coexistent hypertension. Cocrystallization and coamorphization are attractive strategies to enhance dissolution rates and to reduce the number of medications a patient has to take. In this work the formation of cocrystals and coamorphous systems of GLZ with various antihypertensive drugs was studied, namely chlorothiazide (CTZ), hydrochlorothiazide (HTZ), indapamide (IND), triamterene (TRI) and nifedipine (NIF) as well as benzamidine (BZA) as a model for the amidine pharmacophore. TRI, IND and HTZ were found to form coamorphous systems with GLZ that are stable for at least six months at 22 ±â€¯2 °C and 56% relative humidity. Coamorphous GLZ-TRI is also stable in dissolution medium. Coamorphization of GLZ-TRI with 15% sodium taurocholate gave a viable coamorphous formulation with an enhanced dissolution rate. Comilling of GLZ with BZA and cocrystallization from solution gave the amorphous and crystalline salt, respectively and the X-ray structure is reported. During attempts to obtain X-ray suitable cocrystals crystals of Na+GLZ- and IND 0.5H2O were obtained. Redetermination of the published structure of IND 0.5H2O revealed a unit cell with the length of the a axis doubled, a different space group and no disorder. Liquid-assisted grinding of a 1:1 mixture of GLZ and IND indicated the transformation of IND to a new solid-state form, while GLZ remained unaltered. Milling- and heating-induced solid-state transformations of IND are discussed.

The natural bile acid surfactant sodium taurocholate (NaTC) as a coformer in coamorphous systems: Enhanced physical stability and dissolution behavior of coamorphous drug-NaTc systems.

The amorphization of 18 different drugs on milling with one mole equivalent sodium taurocholate (NaTC) was investigated. In all cases the X-ray powder pattern showed an amorphous halo after milling at room temperature or after cryomilling and 14 of the 18 coamorphous drug-NaTC systems were physically stable for between one to eleven months under ambient storage conditions. In three cases, namely carbamazepine-NaTC, indomethacin-NaTC and mefenamic acid-NaTC, significant dissolution advantages over the crystalline drugs were observed, both for the freshly prepared samples and after storage for seven months. To understand the increased physical stability, infrared-, near-infrared and Raman spectroscopic studies were carried out. The effectiveness of NaTC as a coformer in a diverse range of coamorphous systems is attributed to its awkward molecular shape that hampers recrystallization and phase separation and its propensity to form a range of similar, yet different drug-coformer hydrogen bonding arrangements.

Effects of ball-milling and cryomilling on sulfamerazine polymorphs: a quantitative study.

The effects of ball-milling and cryomilling on sulfamerazine forms I and II (SMZ FI, FII) were investigated using X-ray powder diffraction, infrared and near-infrared (NIR) spectroscopy. Cryomilling resulted in a 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, whereas samples milled for more than 60 min crystallized to pure FII. The effect of comilling SMZ with stoichiometric amounts of additives was investigated. SMZ formed amorphous materials with oxalic, dl-tartaric, and citric acids that were more stable toward recrystallization than FA. Amorphous SMZ/oxalic acid was found to recrystallize to a 2:1 cocrystal during storage.

Formation, physical stability, and quantification of process-induced disorder in cryomilled samples of a model polymorphic drug.

The formation and physical stability of amorphous sulfathiazole obtained from polymorphic forms I and III by cryomilling was investigated by X-ray powder diffraction (XRPD) and near-infrared (NIR) spectroscopy. Principal component analysis was applied to the NIR data to monitor the generation of crystalline disorder with milling time and to study subsequent recrystallization under different storage conditions. Complete conversion into the amorphous phase was observed for both forms after 45 (form I) and 150 min (form III) milling time. Upon storage under vacuum over silica gel for 14 days at 4°C, amorphous samples remained amorphous. However, under the same conditions at ambient temperature, recrystallization occurred. Amorphous samples obtained from form I had crystallized back to the original polymorph, whereas those prepared from form III had partially crystallized to mixtures of polymorphs. Amorphous samples stored at ambient temperature and humidity absorbed moisture, which facilitated crystallization to a mixture of polymorphs in both cases. Quantitative analyses of amorphous content in binary mixtures with forms I and III were carried out by XRPD and NIR spectroscopy combined with partial least squares regression. The calibration models had root mean square error of prediction values of <2.0% and were applied to quantify the extent of crystalline disorder during cryomilling.