Analysis and stability of polymorphs in tablets: The case of Risperidone

Identification of the crystal phase of an active pharmaceutical ingredient (API) in a pharmaceutical tablet is of outmost importance since different polymorphs exhibit different physicochemical properties. Furthermore, some of the crystal phases are protected by patents. Identification of Risperidone polymorph A in film coated commercial tablets was attempted using IR spectroscopy, Raman spectroscopy and X-ray powder diffraction (XRPD). The stability of this polymorph through time and during the manufacturing process was also examined. The inability of IR and Raman techniques to identify the presence of polymorph A in the tablets, despite their lower detection limits for Risperidone, left the XRPD as the only technique that could be used for identifying the presence of Risperidone A against the other crystal phases in the presence of the excipients. Polymorph A was proved to be stable during the manufacturing process and after a storage period of 2 years.     

Qualitative Discrimination Between Paracetamol Tablets Made by Near Infrared Spectroscopy and Chemometrics With Regard to Polymorphism

Polymorphism is an important characteristic of pharmaceutical products because different polymorphs exhibit different physicochemical stabilities, dissolution rates, etc., which makes them different in therapeutic efficiency. Thus, it is important to control the polymorphic structure of pharmaceutical products. A spectroscopy method based on Fourier transform near infrared (FT-NIR) spectroscopy and chemometric techniques is introduced to classify paracetamol preparations according to polymorphic changes. X-ray diffraction (XRD) and FT-NIR studies were carried out on standard samples, paracetamol preparations (acetaminophen tablet), and also the additives. A direct comparison was performed between the spectroscopic data and those obtained by XRD. The NIR and XRD analyses of paracetamol preparations show some distinct differences, particularly in the Iranian tablet. These differences are found to be related to polymorphism and paracetamol purity. The cluster analysis (CA) and principal component analysis (PCA) were utilized to classify the paracetamol preparations. FT-NIR spectroscopy provides a simple, rapid and accurate qualitative analysis method for the identification of paracetamol polymorphs.     

Polymorphism in crystalline cinchomeronic acid

The structural relationship between the two crystal forms of cinchomeronic acid (CA 3,4-dicarboxypyridine) has been investigated by single crystal X-ray diffraction, IR and Raman spectroscopy and solid state NMR spectroscopy, showing that the two polymorphs form a monotropic system, with the orthorhombic form I being the thermodynamically stable form, while the monoclinic form II is unstable. In both forms CA crystallizes as a zwitterion and decomposes before melting. The crystal structure and spectroscopic analysis indicate that the difference in stability can be ascribed to the strength of the hydrogen-bonding patterns established by the protonated N-atom and the carboxylic/carboxylate O-atoms.     

New applications of electron diffraction in the pharmaceutical industry: polymorph determination by using a combination of electron diffraction and synchrotron X-ray powder diffraction techniques.

Electron diffraction has been recently used in the pharmaceutical industry to study the polymorphism in crystalline drug substances. While conventional X-ray diffraction patterns could not be used to determine the cell parameters of two forms of the microcrystalline GP IIb/IIIa receptor antagonist roxifiban, a combination of electron single-crystal and synchrotron powder diffraction techniques were able to clearly distinguish the two polymorphs. The unit-cell parameters of the two polymorphs were ultimately determined using new software routines designed to take advantage of each technique's unique capabilities. The combined use of transmission electron microscopy (TEM) and synchrotron patterns appears to be a good general approach for characterizing complex (low-symmetry, large-unit-cell, micron-sized) polymorphic pharmaceutical compounds.     

Quantification of flupirtine maleate polymorphs using X-ray powder diffraction

Flupirtine maleate,a pharmaceutical compound for treating psychotic disease in clinics,has seven polymorphs.Form A,with better crystal stability and bioavailability,has been widely used as the pharmaceutical crystal form.Unfortunately,it is usually found in a polymorphic mixture with form B.In this study,pure crystal forms of A and B were prepared and characterized by X-ray powder diffraction (XRPD),Fourier transform infrared spectroscopy (FT-IR) and thermal analysis.An XRPD-based method for the quantitative determination of the amount of the flupirtine maleate polymorphs form A and form B was also established through a systematic optimization of instrumental parameters.The results of the analytical methodology validation showed that the XPRD method had a broad quantitative range of 0-100%(w/w),good linear relationship,with R²=0.999,excellent repeatability and precision and low limits of detection (LoD) of 0.15%(w/w) and quantification (LoQ) of 0.5%(w/w).The results also showed that the single-peak method was not as good as the whole pattern in reducing the influence of the preferred orientation,but this can be compensated for by a systematic optimization of instrumental parameters and validating the analytical methodology to reduce errors and obtain a good,repeatable,sensitive,and accurate method.This XRPD method can be used to analyze mixtures of flupirtine maleate polymorphs (forms A and B) quantitatively and control the quality of the bulk drug.     

Near infrared spectroscopy in the study of polymorphic transformations

The potential of near infrared (NIR) spectroscopy for the characterization of polymorphs in the active principle of a commercial formulation prior to and after the manufacturing process was assessed. Polymorphism in active principles is extremely significant to the pharmaceutical industry. Polymorphic changes during the production of commercial pharmaceutical formulations can alter some properties of the resulting end-products. Multivariate curve resolution-alternating least squares (MCR-ALS) methodology was used to obtain the “pure” NIR spectrum for the active principle without the need to pretreat samples. This methodology exposed the polymorphic transformation of Dexketoprofen Trometamol (DKP) in both laboratory and production samples obtained by wet granulation. No polymorphic transformation, however, was observed in samples obtained by direct compaction. These results were confirmed using by X-ray powder diffractometry (XRD) and differential scanning calorimetry (DSC) measurements. Pure crystalline polymorphs of DKP were available in the laboratory but amorphous form was not, nevertheless the developed methodology allows the identification of amorphous and crystal forms in spite of the lack of pure DKP.     

Synergistic effect of crystal and electronic structures on the visible-light-driven photocatalytic performances of Bi(2)O(3) polymorphs

Three polymorphs of Bi(2)O(3) were selectively synthesized via solution-based methods. The phase structures of the as-prepared samples were confirmed by X-ray powder diffraction (XRD) and X-ray photoelectron spectroscopy (XPS). UV-vis diffuse reflectance spectroscopy was employed to study the optical properties of Bi(2)O(3) polymorphs, and the band gaps were estimated to be 2.80, 2.48, and 3.01 eV for α-Bi(2)O(3), β-Bi(2)O(3), and δ-Bi(2)O(3), respectively. The photocatalytic performances of the oxides were investigated by decomposing methyl orange and 4-chlorophenol under visible irradiation at room temperature. It was observed that β-Bi(2)O(3) displayed much higher photocatalytic performance than N-doped P25. Among the three polymorphs of Bi(2)O(3), the photocatalytic activities followed the order: β-Bi(2)O(3) > α-Bi(2)O(3) > δ-Bi(2)O(3), which was in good accordance with the photoluminescence spectra measurement results. The synergistic effect of the crystal and electronic structures on the photocatalytic performances of Bi(2)O(3) polymorphs was investigated. The much better photocatalytic activity of β-Bi(2)O(3) was considered to be closely related to its smaller band gap, higher crystallinity and unique tunnel structure.     

Determination of indomethacin polymorphic contents by chemometric near-infrared spectroscopy and conventional powder X-ray diffractometry

A chemoinfometric method for the quantitative determination of the crystal content of indomethacin (IMC) polymorphs, based on Fourier-transform near-infrared (FT-NIR) spectroscopy, was established. A direct comparison of the data with those collected using the conventional powder X-ray diffraction method was performed. Pure alpha and gamma forms of IMC were prepared using published methods. Powder X-ray diffraction profiles and NIR spectra were recorded for six kinds of standard material with various contents of the gamma form of IMC. Principal component regression (PCR) analyses were performed on the basis of the normalized NIR spectral sets of standard samples with known contents of the gamma form of IMC. A calibration equation was determined to minimize the root mean square error of the prediction. The predicted gamma form contents were reproducible and had a relatively small standard deviation. The values of the gamma form contents predicted by the two methods were in close agreement. The results indicated that NIR spectroscopy provides an accurate quantitative analysis of crystallinity in polymorphs compared with the results obtained by conventional powder X-ray diffractometry.     

Differentiating calcium carbonate polymorphs by surface analysis techniques—an XPS and TOF‐SIMS study

Calcium carbonate has evoked interest owing to its use as a biomaterial, and for its potential in biomineralization. Three polymorphs of calcium carbonate, i.e. calcite, aragonite, and vaterite were synthesized. Three conventional bulk analysis techniques, Fourier transform infrared (FTIR), X‐ray diffraction (XRD), and SEM, were used to confirm the crystal phase of each polymorphic calcium carbonate. Two surface analysis techniques, X‐ray photoelectron spectroscopy (XPS) and time‐of‐flight secondary ion mass spectroscopy (TOF‐SIMS), were used to differentiate the surfaces of these three polymorphs of calcium carbonate. XPS results clearly demonstrate that the surfaces of these three polymorphs are different as seen in the Ca(2p) and O(1s) core‐level spectra. The different atomic arrangement in the crystal lattice, which provides for a different chemical environment, can explain this surface difference. Principal component analysis (PCA) was used to analyze the TOF‐SIMS data. Three polymorphs of calcium carbonate cluster into three different groups by PCA scores. This suggests that surface analysis techniques are as powerful as conventional bulk analysis to discriminate calcium carbonate polymorphs. Copyright © 2008 John Wiley & Sons, Ltd.     

Low-temperature synthesis and microstructural control of titania nano-particles

Nanocrystalline titania powders were synthesized at low temperature (⩽100°C) by a sol–gel method that achieved fine control of particle size and polymorph fraction. X-ray diffraction (XRD), transmission electron microscopy (TEM) and UV–Vis spectroscopy were used to characterize the phase assemblages, crystal size and band gap of the powders. It was demonstrated that larger, well-ordered titania crystals can be obtained by increasing aging temperature and time. These processing parameters can be adjusted to select specific polymorphs from the gel precursors with particular size and shape. The quantum size effect was observed in the size-controlled nanocrystalline titania particles, leading to a blue shift in UV absorption with decreasing in particle size. The anatase to rutile transformation, which may proceed with brookite as a transition phase, is dependent on both particle size and surface structure of the nascent crystals.     

Structural study of α-lactose monohydrate subjected to microwave irradiation

The aim of this work was to investigate the influence of different levels of microwave irradiation on the structure and particle size characteristics of α-lactose monohydrate. The structural study of the samples was carried out by XRD, the presence of lactose polymorphs in the test samples was determined by DSC and the particle size distribution was measured by laser diffraction. The samples subjected to microwave irradiation retained their original X-ray patterns. No significant differences in thermal transition characteristics and particle size were observed. Hence, neither the occurrence of crystalline-amorphous transition resulted by microwave irradiation nor the presence of lactose polymorphs in the test samples can be assumed. The unmodified properties can be attributed to the fact that the water of crystallization is very difficult to remove from the crystal structure and is not free to move during microwave treatment, which results in stability to microwaves.     

Evaluation of solvents’ effect on solubility,intermolecular interaction energies and habit of ascorbic acid crystals

Solubility of active pharmaceutical ingredient (API) in solvents is very important for drug development and manufacturing. Solubility data may provide further information such as thermochemical properties and intermolecular interactions that may lead to a better understanding of the formation of API crystals. In this study, solubility of ascorbic acid was determined by gravimetric method in four different commonly used polar protic solvents: water, methanol, ethanol and 2-propanol. The solubility of ascorbic acid crystal was also predicted using Conductor-like Screening Model – Realistic Solvent (COSMO-RS) approach. In this computational analysis, the generated ΔG values are based on the solubilities that were experimentally obtained to simulate the intermolecular forces. The intermolecular interaction data from COSMO-RS provide an insight into the relationship between the intermolecular interactions and its crystal habit across four different polar protic solvents. The habit of the crystals was then determined using light microscopy and scanning electron microscopy techniques, while the polymorphic form of the crystals was identified by X-ray powder diffraction and single X-ray diffraction techniques. The solubility and characterization data showed that the solvents with high polarity increased the solubility of ascorbic acid. The data also showed that different solvent polarity influenced the crystal habit, but did not change the crystal structure to form a new polymorph.     

Characterization of calcium carbonate polymorphs with Ca K edge X-ray absorption fine structure spectroscopy

Ca K edge X-ray absorption fine structure (XAFS) spectroscopy was utilized for the characterization and quantification of calcium carbonate polymorphs and their mixtures. The advantage of the XAFS is the small sample quantity required for measurements, and a flexible sample environment. The near-edge XAFS spectra of calcite, aragonite and vaterite were measured with the conversion electron yield (CEY) method, and the obtained spectra showed characteristic features that can be utilized as fingerprints. The quantification of mixed polymorphs was examined by using a linear combination fitting of reference XAFS spectra. Though the quality of the fits was satisfactory, discrepancies in the evaluated values were observed between those with X-ray diffraction (XRD) and XAFS. The nonuniformity of samples may be enhanced by the surface sensitivity of the CEY method.     

A tale of two polymorphic pharmaceuticals: pyrithyldione and propyphenazone and their 1937 co-crystal patent

A co-crystal of two polymorphic active pharmaceutical ingredients (APIs), first reported and patented in 1937, has been prepared and thoroughly characterised, including crystal structure analysis. The existence of four crystal forms of one of the APIs, the sedative and hypnotic active pharmaceutical ingredient 3,3-diethyl-2,4(1H,3H)-pyridinedione, pyrithyldione (PYR), and of three crystal forms of the co-crystal-forming second API, the non-steroidal anti-inflammatory drug 1,2-dihydro-1,5-dimethyl-4-(1-methylethyl)-2-phenyl-3H-pyrazol-3-one, propyphenazone (PROP), has been reported previously, but they have only been partly characterised. For both compounds, none of the metastable forms exist at room temperature. DSC, hot-stage microscopy, X-ray diffraction and powder synchrotron X-ray diffraction were employed to characterise the polymorphic forms and to determine the crystal structures of forms I-III of PYR and forms I and II of PROP.     

Polymorphic Characterization and Bioavailability of Nomegestrol Acetate

Polymorph screening is currently one of the most important strategies of innovators and generic companies from both pharmaceutical and intellectual property rights perspectives. Different polymorphs may have varying physicochemical properties which influence the bioavailability. The purpose of this study was to investigate the crystal structures and physicochemical properties of Nomegestrol acetate(NOMAC) polymorphs. Forms I and II(dioxane solvate) were isolated and prepared by systemic crystallization screening in this study, and the forms are reported for the first time. A structural analysis and comparison of all the forms are presented. This study was also the first time to apply a rapid and feasible ultra-highperformance-liquid chromatography(UHPLC)-electrospray ionization(ESI)-tandem mass spectrometry(MS) method to determine plasma levels of NOMAC within 3.0 mins. And this study demonstrated that the optimal crystal Form I displayed higher bioavailability than API indicating that Form I could be an alternative solid form that needs further research.     

N-(1-萘基)-琥珀酰亚胺化合物晶体结构的理论预测

用Materials Studio软件对N-(1-萘基)-琥珀酰亚胺多晶粉末的X射线衍射数据进行衍射峰指标化、晶胞参数优化和空间群搜索等理论计算, 可以确定晶体结构所属的晶系和空间群, 并初步给出和多晶粉末衍射数据相近的晶胞参数; 在已确定空间群范围内, 以密度泛函理论计算得到的最低能量构象作为初始分子结构, 对N-(1-萘基)-琥珀酰亚胺多晶进行晶体结构理论预测, 给出一系列假定的晶胞参数, 从中可以找到和经上述计算给出的晶胞参数一致的晶体结构；对其进行晶胞参数优化后, 得到晶体结构具有和多晶粉末X射线衍射数据相近的衍射曲线, 并与已有的单晶数据相吻合.     

非负载和氧化铝负载的纳米CeO2-ZrO2和CeO2-We2O3固溶体催化CO氧化

Ceria-zirconia(CZ)and ceria-terbia(CT)and alumina-supported ceria-zirconia(CZA)and ceria-terbia(CTA)solid solutions were synthesized by coprecipitation and deposition precipitation methods,respectively.Structural characteristics and catalytic activity of the synthesized samples have been investigated using X-ray diffraction(XRD),high resolution transmission electron microscopy(HRTEM),X-ray photoelectron spectroscopy(XPS),Raman spectroscopy(RS),and Brunauer-Emmett-Teller(BET)surface area measurements.To evaluate the catalytic properties,total oxygen storage capacity and CO oxidation activity measurements were carried out.The XRD analyses revealed the formation of Ce0.75Zr0.25O2 phase for CZ and Ce0.5Zr0.5O2 and Ce0.6Zr0.4O2 phases for CZA samples,respectively.While the formation of only Ce0.8Tb0.2O2-δphase was noted for both CT and CTA samples.All the supported and unsupported samples adopted a fluorite-type structure and exhibited cell parameters with respect to Vegard’s rule.The HRTEM results indicated well-dispersed particles of the size around 5 nm.The RS measurements suggested the presence of oxygen vacancies due to defective structure formation.The XPS studies revealed the presence of cerium in both Ce 4+ and Ce 3+ oxidation states in different proportions.It was found that CO oxidation for CTA occurs at very much lower temperature than CT,CZ,and CZA samples.Details of these findings by correlating with the structural characterization studies are consolidated.     

Cu、Ag、Au掺杂BiVO_4可见光催化剂的制备及性能研究

水热法制备了币族金属(Cu、Ag和Au)掺杂的BiVO4可见光催化剂,借助X-射线衍射(XRD)、X-射线光电子能谱(XPS)、紫外-可见漫反射光谱(DRS)和扫描电子显微镜(SEM)对其进行表征.XRD分析显示所有催化剂都呈现单斜结构.XPS结果显示掺杂元素均以其稳定氧化态形式存在与催化剂表面.DRS谱中掺杂样品的吸收边界比纯BiVO4都有不同程度的红移.以甲基橙的可见光催化降解反应为探针,研究了催化剂的可见光催化性能.结果表明,经币族金属掺杂改性的催化剂催化能力比纯BiVO4有所提高.对其掺杂增强催化能力的可能原因进行了分析讨论.     

Structural characterization of ammonium molybdophosphate with different amount of cesium adsorption

Powdered crystal AMP was synthesized by precipitation method and different Cs-loading AMP samples were prepared in this work. They were studied by modern methods of X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FT-IR) and thermogravimetric analysis (TGA) to gain a better understanding of the ion exchange mechanism of ammonium molybdophosphate (AMP). The XRD patterns combined with the FT-IR analysis indicate that the Keggin structure is retained after Cs adsorption, while the changes of certain characteristic diffraction peaks show crystal lattice distortion caused by the mismatching sizes of Cs⁺ and [NH₄]⁺. The TGA showed that the weight percent of H₂O and [NH₄]⁺ decreases as the amount of Cs adsorbed onto AMP increases, which corresponds with the theory of isomorphous exchange.     

Growth and characterization of 2-hydroxy-4-methoxybenzophenone single crystal using modified vertical Bridgman technique

The 2-hydroxy-4-methoxybenzophenone single crystal has been grown by the modified vertical Bridgman technique using the double wall ampoule. The grown crystal was confirmed by single and powder X-ray diffraction (XRD) and Fourier transform infrared (FTIR) spectroscopy analyses. High resolution X-ray diffraction (HRXRD) analysis indicates the crystalline perfection of the grown crystal. The cutoff wavelength of the grown crystal was analyzed by optical studies. The dielectric measurements were carried out and the results indicate an increase in dielectric and conductivity parameters with the increase of temperature at all frequencies. The thermal property of the grown crystal was studied by thermo gravimetric (TG) and differential thermal analyses (DTA).