Yun Hu

A comparative study of the use of powder X-ray diffraction, Raman and near infrared spectroscopy for quantification of binary polymorphic mixtures of piracetam

Diffraction and spectroscopic methods were evaluated for quantitative analysis of binary powder mixtures of FII(6.403) and FIII(6.525) piracetam. The two polymorphs of piracetam could be distinguished using powder X-ray diffraction (PXRD), Raman and near-infrared (NIR) spectroscopy. The results demonstrated that Raman and NIR spectroscopy are most suitable for quantitative analysis of this polymorphic mixture. When the spectra are treated with the combination of multiplicative scatter correction (MSC) and second derivative data pretreatments, the partial least squared (PLS) regression model gave a root mean square error of calibration (RMSEC) of 0.94 and 0.99%, respectively. FIII(6.525) demonstrated some preferred orientation in PXRD analysis, making PXRD the least preferred method of quantification.

Predicting and understanding crystal morphology: the morphology of benzoic acid and the polymorphs of sulfathiazole

Crystals of benzoic acid grown from dichloromethane and acetonitrile are greatly extended along the b-axis. The enhanced growth is not related to hydrogen bonding as benzoic acid is respectively dimeric and monomeric in these solvents. A mechanism is suggested for enhanced growth in the π-stacking direction for flat π-stacking systems. Facilities have been added to the Oscail software package which provide attachment energy calculations, crystal surface analysis and crystal visualization. Crystal surface analysis can be used to find the π-stacking direction and to identify the density of available hydrogen bond donors and acceptors on crystal faces. Observed and calculated morphologies for crystals of sulfathiazole form 2 grown from ethanol are in good agreement. Differences in the observed and calculated shapes of sulfathiazole forms 1, 3, 4 and 5 are attributed to solvent effects which correlate with the density of available hydrogen bond acceptors on crystal faces.

Investigation of the capacity of low glass transition temperature excipients to minimize amorphization of sulfadimidine on comilling.

The coprocessing of active pharmaceutical ingredient (API) with an excipient which has a high glass transition temperature (T(g)) is a recognized strategy to stabilize the amorphous form of a drug. This work investigates whether coprocessing a model API, sulfadimidine (SDM) with a series of low T(g) excipients, prevents or reduces amorphization of the crystalline drug. It was hypothesized that these excipients could exert a T(g) lowering effect, resulting in composite T(g) values lower than that of the API alone and promote crystallization of the drug. Milled SDM and comilled SDM with glutaric acid (GA), adipic acid (AA), succinic acid (SA), and malic acid (MA) were characterized with respect to their thermal, X-ray diffraction, spectroscopic, and vapor sorption properties. SDM was predominantly amorphous when milled alone, with an amorphous content of 82%. No amorphous content was detected by dynamic vapor sorption (DVS) on comilling SDM with 50% w/w GA, and amorphous content of the API was reduced by almost 30%, relative to the API milled alone, on comilling with 50% w/w AA. In contrast, amorphization of SDM was promoted on comilling with 50% w/w SA and MA, as indicated by near-infrared (NIR) spectroscopy. Results indicated that the API was completely amorphized in the SDM:MA comilled composite. The saturated solubility of GA and AA in the amorphous API was estimated by thermal methods. It was observed that the T(g) of the comelt quenched composites reached a minimum and leveled out at this solubility concentration. Maximum crystallinity of API on comilling was reached at excipient concentrations comparable to the saturated concentration solubility of excipient in the API. Moreover, the closer the Hildebrand solubility parameter of the excipient to the API, the greater the inhibition of API amorphization on comilling. The results reported here indicate that an excipient with a low T(g) coupled with high solubility in the API can prevent or reduce the generation of an amorphous phase on comilling.

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.

A Comprehensive near Infrared Spectroscopic Study of the Limits of Quantitative Analysis of Sulfathiazole Polymorphism

A comprehensive study on the quantification of sulfathiazole polymorphs by near infrared (NIR) spectroscopy combined with multivariate analysis is reported. Calibration models were developed for each of the sulfathiazole polymorphs that can be obtained as polymorphically pure samples, sulfathiazole forms I, III and V, in binary mixtures in the 0–15% concentration range. Partial least squares regression (PLS) was employed and different spectral pre-treatment algorithms including, multiplicative scatter correction (MSC), standard normal variate (SNV) transformation, 1st derivative calculations and SNV combined with 1st derivative were applied to the data. The NIR method was compared with X-ray powder diffraction (XRPD) and was found to give more accurate results in all cases except one where XPRD was more accurate. For the NIR method, limits of detection were <0.5% except for form V in l/V mixtures where the limit of detection was 1.5%. Limits of quantification ranged from 1.1% to 4.6%. When quantities of forms II and IV were added to samples which were analysed using the model developed for form III in I, their presence was detected by very large prediction errors. A comparison of multivariate and univariate analysis of the NIR data demonstrated that, in general, multivariate methods were superior.