The relative stabilities of crystalline polymorphs are an important aspect of the manufacturing and effective utilization of pharmaceuticals. These stabilities are driven by both molecular conformational energy within the solid-state components and cohesive binding energy of the crystalline arrangement. The combined approach of experimental vibrational terahertz spectroscopy with solid-state density functional theory provides a powerful tool to study such properties and is applied here in the analysis of conformational polymorphism in crystalline aripiprazole. The low-frequency (<95 cm–1) terahertz vibrations of several aripiprazole polymorphs were measured, revealing distinct spectral features that uniquely identify each form. Solid-state density functional theory was employed to interpret the experimental terahertz spectra, correlating the observed spectral features to specific atomic motions within the crystalline lattice. The computational analysis provides insight into the formation and stability of the polymorphs by revealing the balance between the external binding forces and internal molecular forces that is ultimately responsible for the physical characteristics of the numerous crystalline polymorphs of aripiprazole.
A method using Raman spectroscopy was recently developed for the determination of the degree of acetylation in modified wheat starch. In this article, we show that the method can be generalized to a wide range of starches of different botanical origin and amylose content. Calibration sets were used to develop regression equations for 11 types of acetylated starches, including cereal (rice, maize, wheat) and noncereal (potato and sweetpotato) sources. The calibration lines were then used to predict the level of acetylation of starch samples with unknown level of acetylation using their Raman spectra. In each case, R2 > 0.98 for linear regression of Raman vs. titrimetric determination of acetylation. The Raman‐based calibration curves allow fast and nondestructive determination of the degree of acetylation for different types of starches.
The characterization of crystalline polymorphs of drug molecules is an area of great interest since these variations in solid-state structure directly influence the physical properties of such substances. Terahertz spectroscopy provides a powerful analytical tool for these investigations and has been used here to study tautomeric polymorphism and conformational disorder in crystallized irbesartan, an antihypertensive medication. The low-frequency (<90 cm −1 ) terahertz spectra of both irbesartan Form A and Form B were measured and interpreted using solid-state density functional theory. The spectra reveal distinct identifying features for each polymorph and are indicative of the variations in the packing arrangements of the solids. The computational analyses of the solid-state forms also provide new insights into the origins and temperature dependence of the conformational disorder found in Form B. The results indicate that the disorder present in this crystal structure arises from a competition between internal conformational strain and external cohesive binding.
A generalized screening approach, applying isothermal calorimetry at 37 °C 100% RH, to formulations of spray dried dispersions (SDDs) for two active pharmaceutical ingredients (APIs) (BMS-903452 and BMS-986034) is demonstrated. APIs 452 and 034, with similar chemotypes, were synthesized and promoted during development for oral dosing. Both APIs were formulated as SDDs for animal exposure studies using the polymer hydroxypropylmethlycellulose acetyl succinate M grade (HPMCAS-M). 452 formulated at 30% (wt/wt %) was an extremely robust SDD that was able to withstand 40 °C 75% RH open storage conditions for 6 months with no physical evidence of crystallization or loss of dissolution performance. Though 034 was a chemical analogue with similar physical chemical properties to 452, a physically stable SDD of 034 could not be formulated in HPMCAS-M at any of the drug loads attempted. This study was used to develop experience with specific physical characterization laboratory techniques to evaluate the physical stability of SDDs and to characterize the propensity of SDDs to phase separate and possibly crystallize. The screening strategy adopted was to stress the formulated SDDs with a temperature humidity screen, within the calorimeter, and to apply orthogonal analytical techniques to gain a more informed understanding of why these SDDs formulated with HPMCAS-M demonstrated such different physical stability. Isothermal calorimetry (thermal activity monitor, TAM) was employed as a primary stress screen wherein the SDD formulations were monitored for 3 days at 37 °C 100% RH for signs of phase separation and possible crystallization of API. Powder X-ray diffraction (pXRD), modulated differential scanning calorimetry (mDSC), Fourier transform infrared spectroscopy (FTIR), and solid state nuclear magnetic resonance (ssNMR) were all used to examine formulated SDDs and neat amorphous drug. 452 SDDs formulated at 30% (wt/wt %) or less did not show phase separation behavior upon exposure to 37 °C 100% RH for 3 days. 034 SDD formulations from 10 through 50% (wt/wt %) all demonstrated thermal traces consistent with exothermic phase separation events over 3 days at 37 °C 100% RH in the TAM. However, only the 15, 30, and 50% containing 034 samples showed pXRD patterns consistent with crystalline material in post-TAM samples. Isothermal calorimetry is a useful screening tool to probe robust SDD physical performance and help investigate the level of drug polymer miscibility under a humid stress. Orthogonal analytical techniques such as pXRD, ssNMR, and FTIR were key in this SDD formulation screening to gain physical understanding and confirm or refute whether physical changes occur during the observed thermal events characterized by the calorimetric screening experiments.
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