Polymorphism of phenylpyruvic acid studied by IR, Raman and solid state C NMR spectroscopy

Polymorphs I and II of phenylpyruvic acid are obtained as mixtures of both crystal forms or relatively pure crystals, from different solvents. Polymorph I is more stable than polymorph II at room temperature. Spectral characteristics of these polymorphs are discussed on the basis of IR, Raman and solid state ¹³C NMR spectra. Also, the assignment of the IR features observed in the 1600–1700 cm⁻¹ region is re-investigated by referring to the spectra of heavy-atom substituted derivatives. It is suggested that the C=O stretching band is split by the crystal field for both polymorphs.     

Polymorphs of Aspirin – Solid-state IR-LD spectroscopic and quantitative determination in solid mixtures

Solid-state linear-dichroic infrared (IR-LD) spectroscopy, using an orientation technique as a suspension in nematic liquid crystal, has been carried out of Aspirin polymorphs (forms I and II). Reducing-difference procedure for polarized IR-spectra interpretation has been applied for structural analysis of both modifications and the data have been compared with known crystallographic ones. A vibration assignment of forms I and II has been included and on this basis, a quantitative determination by FT-IR spectra for form I in mixtures with second one has been presented, using intensity ratio of 1606 cm⁻¹ peak (characteristic for both forms) to 599 cm⁻¹ one (attributed to form I). The obtained reliability is 99.78%.     

尼群地平晶型转变条件及其影响因素的确定

根据熔化数据推算相变稳定性理论计算了尼群地平不同晶型之间的相变温度, 并分别考察了高温、高温和高湿及高压条件下的晶型转变. 理论推导尼群地平I与II, 尼群地平I与III, 尼群地平II与III的转化温度分别为158.88, 160.50和158.65 ℃, 三者均为单变关系, 且在高温条件下尼群地平II, III都转变为尼群地平I, 在高压条件下, II易转变为I. 试验结果表明室温下尼群地平I为稳定型, II和III为亚稳定型, 3种晶型稳定性顺序为尼群地平I＞II＞III.     

Recognition of the syndiotactic polypropylene polymorphs via dynamic-mechanical analysis

Three syndiotactic polypropylene samples were crystallized under different conditions in order to obtain different polymorphs. A first sample was crystallized at high temperature, obtaining the helical form I; a second was crystallized from the melt at 0°C for many days obtaining the trans-planar mesophase; a third sample was obtained by solvent induced crystallization followed by annaeling of the trans-planar mesophase, leading to a mixture of both the helical forms I and II. In the dynamic-mechanical analysis the helical form I showed only one peak of tan δ corresponding to the amorphous glass transition. The other polymorphs also showed this transition centered at about the same temperature. Beside the peak corresponding to the Tg, the trans-planar mesophase was characterized by a peak appearing at 70°C, and the helical form II by a peak at 100°C. These peaks, unambiguously associated to transitions of the different forms, can be considered a distinctive evidence for the polymorphs obtained in different processing conditions.     

Effect of High Pressure on the Polymorphs of Paracetamol

Effect of hydrostatic pressure on the two (I – monoclinic and II – orthorhombic) polymorphs of paracetamol was studied by X-ray diffraction in the diamond anvil cell at pressures up to 4.5 GPa (for the monoclinic form) and up to 5.5 GPa (for the orthorhombic form). The two groups of phenomena were studied: (i) the anisotropic structural distortion of the same polymorph, (ii) transitions between the polymorphs induced by pressure. The anisotropy of structural distortion of polymorphs I and II was well reproducible from sample to sample, also from powder samples to single crystals. The bulk compressibility of the two forms was shown to be practically the same. However, a noticeable qualitative difference in the anisotropy of structural distortion was observed: with increasing pressure the structure of polymorph II contracted in all the directions showing isotropic compression in the planes of hydrogen-bonded molecular layers, whereas the layers in the structure of the polymorph I expanded in some directions. Maximum compression in both polymorphs I and II was observed in the directions normal to the molecular layers. The transitions between the polymorphs induced by pressure were poorly reproducible and depended strongly on the sample and on the procedure of increasing/decreasing pressure. No phase transitions were induced in the single crystals of the monoclinic polymorph at pressures at least up to 4GPa, although a partial transformation of polymorph I into polymorph II was observed at increased pressure in powder samples. Polymorph II transformed partly into the polymorph I during grinding. The transformation could be hindered if grinding was carried out in CCl₄. This revised version was published online in August 2006 with corrections to the Cover Date.     

Evaluation of the physical stability and local crystallization of amorphous terfenadine using XRD-DSC and micro-TA

It is very difficult to follow rapid changes in polymorphic transformation and crystallization and to estimate the species recrystallized from the amorphous form. The aim of this study was to clarify the structural changes of amorphous terfenadine and to evaluate the polymorphs crystallized from amorphous samples using XRD-DSC and an atomic force microscope with a thermal probe (micro-TA). Amorphous samples were prepared by grinding or rapid cooling of the melt. The rapid structural transitions of samples were followed by the XRD-DSC system. On the DSC trace of the quenched terfenadine, two exotherms were observed, while only one exothermic peak was observed in the DSC scan of a ground sample. From the in situ data obtained by the XRD-DSC system, the stable form of terfenadine was recrystallized during heating of the ground amorphous sample, whereas the metastable form was recrystallized from the quenched amorphous sample and the crystallized polymorph changed to the stable form. Obtained data suggested that recrystallized species could be related to the homogeneity of samples. When the stored sample surface was scanned by atomic force microscopy (AFM), heterogeneous crystallization was observed. By using micro-TA, melting temperatures at various points were measured, and polymorph forms I and II were crystallized in each region. The percentages of the crystallized form I stored at 120 and 135 °C were 47 and 79%, respectively. This result suggested that increasing the storage temperature increased the crystallization of form I, the stable form, confirming the temperature dependency of the crystallized form. The crystallization behavior of amorphous drug was affected by the annealing temperature. Micro-TA would be useful for detecting the inhomogeneities in polymorphs crystallized from amorphous drug.     

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.     

Mechanism of polymorph selection during crystallization of random butene-1/ethylene copolymer

Starting from an initial sample of butene-1/ethylene copolymer with stable form I’, we examined the nucleation of different crystalline polymorphs (here metastable form II and stable form I’) at different isothermal crystallization temperatures after being melted at different melt temperature (T _melt). When T _melt was just above the melting temperature (T _m) of the crystallites, self-seeding took place. There, residue crystallites served as nuclei leading to the crystallization of the same crystalline phase. When T _melt was a few degrees above the T _m, self-seeding was disabled due to complete melting of the initial crystals. Upon crystallization, the selection of the different polymorphs in this random copolymer was found to depend on an interplay between the domain size of segregated long crystallizable sequences and the size and energy barrier of the critical nucleus of the respective crystalline forms. Our results provide a clear understanding of the polymorphs selection during crystallization of a random copolymer as well as homo-polymers under confinement.     

Visible spectrophotometric and first-derivative UV spectrophotometric determination of rifampicin and isoniazid in pharmaceutical preparations

Two methods are described for the determination of rifampicin and isoniazid in mixtures by visible spectrophotometry and first-derivative ultraviolet spectrophotometry. The absorbance at 475 nm in buffer solution pH 7.4 was employed to determine rifampicin after applying the three-point correction technique between 420 and 520 nm, while the amplitude of the first-derivative spectrophotometric spectrum at 257 nm in HCl 0.012 M was selected for the determination of isoniazid. The methods are rapid, simple and do not require any separation step. The recovery average was 99.03% for rifampicin and 100.01% for isoniazid. The methods were applied to determine the two compounds in commercial capsules and compared with the official method of the USP XXIII with good agreement between the results.     

Polymorphic Characterization,Pharmacokinetics, and Anti-Inflammatory Activity of Ginsenoside Compound K Polymorphs

Polymorphism exhibits different physicochemical properties, which can impact the bioavailability and bioactivity of solid drugs. This study focused on identifying the polymorphs of ginsenoside compound K (CK) and studying their different behaviors in pharmacokinetics (PK) and pharmacodynamics (PD). Four CK polymorphs (form I, II, III, and IV) from organic solvents were characterized by scanning electron microscope (SEM), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), Fourier transform infrared spectroscopy (FTIR), and powder X-ray diffraction (PXRD). A feasible LC-MS/MS method was exploited to determine the PK parameters. Form II displayed the most exposure, followed by form I, III, and IV. Notably, all forms showed sex dimorphism, and the bioavailability in the female group was about two-fold higher than in the male group. The PD properties were investigated in carrageenan-induced acute paw inflammation, and form II at 20 mg/kg showed significant inhibition of edema by 42.7%. This study clarified the polymorphic, PK, and PD characters of four crystal forms of CK, and the data suggested that form II had the best efficacy for drug development.     

Characterization and quantitation of clarithromycin polymorphs by powder X-ray diffractometry and solid-state NMR spectroscopy

Characterization of clarithromycin polymorph was performed by solid-state cross polarization and magic angle spinning (CP/MAS) 13C-NMR spectroscopy. Two polymorphs, form II and form I, of clarithromycins indicated characteristic resonances of C1 carbonyl carbon at 176.2 and 175.2 ppm, respectively. Since each peak of C1 carbon was well separated in the spectrum of the two polymorphs, we performed quantitative analysis of the polymorphic fraction from the peak area of these peaks. The peak area of form I was found to linearly increase with an increase of its content, with a correlation coefficient of above 0.99. Solid-state NMR was found to be a useful technique to determine the characteristics of the polymorphic forms.     

Crystal polymorphism of local anaesthetic drugs

Crystal polymorphs of pramocaine hydrochloride (PRCNC) and pramocaine (PRCN) free base were produced and characterized by means of thermomicroscopy, differential scanning calorimetry (DSC), FTIR- and FT-Raman-spectroscopy as well as X-ray-powder diffractometry. The relative thermodynamic stabilities of all forms were determined and are represented in semi-schematic energy/temperature diagrams. PRCN, which is a viscous liquid at room temperature and insoluble in water, was found to exist in two different crystal forms with the melting points 23.5°C (mod. I°) and 12.5°C (mod. II). The water-soluble PRCNC crystallizes in three different crystal modifications. Mod. II° is the thermodynamically stable form at room temperature and is present in commercial products. This form is obtained by crystallization from solvents and transforms on heating at about 95°C into the high temperature form mod. I which melts at 171.0°C. Both compounds show conformational polymorphism with forms of low kinetic stability. This revised version was published online in July 2006 with corrections to the Cover Date.     

Wettability of paracetamol polymorphic forms I and II

It is well known that different forms of solid-state polymorphic materials exhibit diverse physicochemical properties. The variations in the wetting and surface energetics of a pair of organic polymorphic solids are reported in detail here for the first time. The growth of macroscopic single crystals (facet area >1 cm(2)) of paracetamol has enabled for the first time the direct measurement of advancing contact angles, theta(A) for water and diiodomethane on a range of specific facets for two polymorphs; forms I and II. Not only was the wetting behavior found to be anisotropic, as has been recently reported, but the differing polymorphic forms exhibited significant variations in their wetting behavior for the same Miller indexed faces. The (001), (010), and (110) faces were studied, and the observed wettability data differed confirming the independence of facet wettability and Miller indices for both polymorphs. theta(A) was found to be very sensitive to the local surface chemistry for each facet examined, which in turn is a direct consequence of the molecular packing and structure within the crystal lattice. On the basis of the theta(A) value of water, the hydrophilicity rankings for the facet surfaces of form II examined is: (010) approximately (110) > (001). This experimental study highlights complex surface chemistry of polymorphic solids in which anisotropic surface energies were observed for both forms of paracetamol, strongly suggesting that such anisotropic wetting behavior is the norm for organic crystalline solids. Furthermore, the same Miller indexed facets for forms I and II exhibited very different surface chemical behavior, such that it was not possible to infer understanding about one form based upon knowledge of another form.     

Time-resolved synchrotron X-ray study of crystalline phase transition in poly(aryl ether ketone ketone) containing alternated terephthalic/isophthalic moieties

Unique crystallization and melting behavior in poly(aryl ether ketone ketone) containing alternated terephthalic and isophthalic moieties were studied by time-resolved synchrotron x-ray methods. Recently, this material has been shown to exhibit three polymorphs (forms I, II, and III). In this work, we further investigated their distinctive thermal properties and found that form I is the dominating and the most thermally stable phase while form II is favored by fast nucleation conditions and is the least stable phase. On the other hand, form III represents a minor intermediate phase that usually coexists with form I and can be transferred from form II and to form I. Structural and morphological changes in form I have been followed by simultaneous wide-angle x-ray diffraction (WAXD)/small-angle x-ray scattering (SAXS) measurements during cold- or melt-crystallization and subsequent melting. In all cases, a larger dimensional change was found in the crystallographic a-axis than the b-axis during heating and cooling. This may be due to the greater lateral stress variation with respect to temperature along the a direction of the primary lamellae which is induced by either the formation of secondary lamellae or the preferential chain-folding direction in poly(aryl ether ketone ketone)s. During the phase transitions of form II ← III in the cold-crystallized specimen and form III ← I in the melt-crystallized samples, lamellar variables (long period, lamellar thickness, and invariant) obtained from SAXS remain almost constant. This indicates that the density distribution in the long spacing is independent of the melting in form II or III. For melt-crystallization, the corresponding changes in unit-cell dimensions and lamellar morphology during the annealing-induced low endotherm are most consistent with the argument that these changes are due to the melting of thin lamellar population. © 1995 John Wiley & Sons, Inc.     

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.     

以Cu(II)为光谱探针离子分光光度法测定异烟肼的新方法

以Cu(II)为光谱探针建立了一种高选择性、高灵敏度测定异烟肼的新方法。试验表明：在pH 6.0时，Cu(II)可被异烟肼还原生成Cu(I)，反应生成的Cu(I) 与SCN-反应生成CuSCN白色乳状沉淀，在硝酸钠的存在下该沉淀可被浮选至水相表面。通过测定水相中剩余Cu(II)的量，可以间接测定异烟肼的含量。已反应Cu(II) 的量与异烟肼的浓度呈良好的线性关系，线性范围为0.050-4.50 µg mL-1，检出限为0.048 µg mL-1。该法已经成功的用于药物样品和病人尿液样品中异烟肼含量的测定。     

Vibrational study of tamoxifen citrate polymorphism

The trans isomer of (Z)-2-[p-(1,2-diphenyl-butenyl)phenoxy]-N,N-dimethyletylamine (tamoxifen) is well known for its endocrine activity as an antiestrogenic agent. Its citrate salt, a widely used pharmaceutical agent, appears in three main polymorphic forms, two of which are well known (I and II) and another form not yet well evidenced.

A vibrational study has been conducted for identifying the two known polymorphic forms of tamoxifen citrate (I and II) and for characterising the other form (form III) examined in this study.

Other techniques for the characterization of the different polymorphs, such as XRDP, have been used.     

Polymorphic forms of bisoprolol fumarate

Bisoprolol fumarate is a beta blocker-type drug substance which has been well known for several decades. However, no relevant data can be found in the literature about its crystal polymorphism. The purpose of this paper was to present two anhydrous forms (Form I and Form II) and a hydrate of bisoprolol fumarate substance. Crystalline forms were studied by various solid-state analytical methods: Fourier transform infrared (FT-IR) spectroscopy, X-ray powder diffraction (XRPD), dynamic vapor sorption (DVS) and thermoanalytical methods (thermogravimetry and differential scanning calorimetry). Thermodynamic stability and solubility of the presented polymorphs were also investigated. Both FT-IR and XRPD methods were found to be suitable for the characterization of the different crystal structures. Thermoanalytical measurements showed that (1) Form I and Form II own clearly different melting points and (2) both Form II and hydrate forms can transform into Form I at higher temperature values. Results of the DVS measurements prove that both Form I and Form II became metastable under extremely humid conditions (>?80% RH) and converted into the hydrate. Thermodynamic stability studies showed that Form I and Form II polymorphs are in enantiotropic relationship with an enantiotropic point at about 40–45 °C. Solubility studies indicated that all of the prepared forms are highly soluble, and no difference was found between them. Considering the recommendations of the corresponding International Conference of Harmonization guideline, it can be stated that no specification is required for crystal polymorphism in case of this substance.

     

The Richest Collection of Tautomeric Polymorphs: The Case of 2‐Thiobarbituric Acid

Five new polymorphs and one hydrated form of 2‐thiobarbituric acid have been isolated and characterised by solid‐state methods. In both the crystalline form II and in the hydrate form, the 2‐thiobarbituric molecules are present in the enol form, whereas only the keto isomer is present in crystalline forms I (reported in 1967 by Calas and Martinex), III , V and VI . In form IV , on the other hand, a 50:50 ordered mixture of enol/keto molecules is present. All new forms have been characterised by single‐crystal X‐ray diffraction, 1D and 2D (¹H, ¹³C, and ¹⁵N) solid‐state NMR spectroscopy, Raman spectroscopy and X‐ray powder diffraction at variable temperature. It has been possible to induce keto–enol conversion between the forms by mechanical methods. The role of hydrogen‐bond interactions in determining the relative stability of the polymorphs and as a driving force in the conversions has been ascertained. To the best of the authors’ knowledge, the 2‐thiobarbituric family of crystal forms represents the richest collection of examples of tautomeric polymorphism so far reported in the literature.     

Two polymorphs of N1,N4‐bis(5‐hydroxypenta‐1,3‐diynyl)‐N1,N4‐diphenylbenzene‐1,4‐diamine

The title compound, C₂₈H₂₀N₂O₂, forms two conformational polymorphs, (I) and (II), where the molecular structures are similar except for the orientation of the two hydroxy groups. In (I), which was obtained by slow evaporation from chloroform, the two hydroxy groups have an anti conformation. The molecules form a sheet structure within the ac plane, where the hydroxy groups form zigzag hydrogen bonds. In (II), which was obtained by slow evaporation from acetonitrile, the two hydroxy groups have a syn conformation. The molecules form a double‐sheet structure within the ab plane, where the hydroxy groups form 4‐helix hydrogen bonds.