Understanding the dehydration of levofloxacin hemihydrate

Levofloxacin is a broad-spectrum antibiotic that exists as a hemihydrate under ambient conditions. In addition to the hemihydrate, there are three known crystalline anhydrate forms, denoted as α, β, and γ. In this study, differential scanning calorimetry (DSC), thermogravimetric analysis, Raman spectroscopy, single-crystal and powder X-ray diffraction, and solid-state NMR spectroscopy were used to investigate the transitions that occurred upon dehydration to the anhydrate as well as additional transitions that occurred to the anhydrous material upon heating/cooling. An enantiotropic conversion was observed in the DSC around 54°C corresponding to the conversion of the γ form to a new form, denoted as the δ form. Raman spectroscopy, powder X-ray diffraction, and solid-state NMR spectroscopy confirmed that a new crystalline form was being produced.     

Conformational polymorphism on imatinib mesylate: grinding effects

Crystal structures of polymorphs α and β of imatinib mesylate were obtained. Thermal behavior and grinding effects were studied by X-ray powder diffraction and differential scanning calorimetry techniques. Molecules in forms α and β exhibit significant conformational differences due to dissimilar intramolecular interactions, which stabilize their molecular conformations. In spite of that, both crystal structures present a dimer-chain arrangement. Dimers are mainly determined by hydrogen bonding interactions and some weak π-π interactions. Connections between dimers are provided by mesylate ions to determine chains of dimers. Neighboring chains are linked by very weak interactions: C-H···π interactions in form α and π-π interactions in form β. At room temperature, thermal disorder was observed in the mesylate ion in form α, which could be removed at low temperatures (-123°C). Form β was found to be the more stable form at room temperature. Both polymorphs exhibit a tendency to generate amorphous material by grinding, which can be converted to a crystalline phase by either temperature or aging. When amorphous crystallization is kinetically studied at room temperature, form β is obtained after a week. Conversely, when the crystallization is activated by temperature, the final obtained crystal form depends on the starting material, proving the importance of seeding.     

Solid-state studies on the hemihydrate and the anhydrous forms of flunisolide

Flunisolide exists in at least two different anhydrous crystalline forms (I and II) and in a hemihydrate form with distinctly different physico-chemical properties. Modification II and the hemihydrate form are the commercial products. Form I was obtained by heating all other forms above 230 degrees C. The different crystalline forms of flunisolide were investigated by FTIR spectroscopy, X-ray powder diffractometry, differential scanning calorimetry (DSC), thermogravimetric analysis and thermomicroscopy both coupled with FTIR spectroscopy (TG-FTIR and FTIR thermomicroscopy). The three forms were easily differentiated by their IR spectra, X-ray powder diffraction patterns and thermal behaviour. Their stability was investigated under different experimental conditions to verify the tendency to solid solid transition and to study the existence range of the three forms. The relationship among the two anhydrous polymorphs and the hemihydrate form and their equilibrium solubilities in water at 20 degrees C were also investigated.     

Synthesis of γ Phase and Amorphous Solid Dispersion of Glycine from α-Glycine During the Solvent-Free Ball Milling Process

Nano α-glycine crystals, γ-glycine crystals, and amorphous solid dispersion (ASD) of glycine were prepared through solvent-free ball milling of commercial α-glycine. The solid-state polymorph conversion of glycine from α to γ was completely realized by ball milling with 0.2 wt.% NaCl for 1 h or by ball milling with 0.02 wt.% NaCl for 1 h with subsequent storage for one week. The ASD of glycine was prepared by ball milling α-glycine with an equal amount of CaCl₂ for 1 h. We studied the effect of inorganic salt types and their concentrations on the extent of polymorph conversion and amorphization of glycine in our experiments. This solvent-free ball milling method could be used for the synthesis of polymorphs and amorphous phase of drugs and other organic materials.     

氯苄律定的结构表征

目的研究氯苄律定的结构与晶型。方法采用卡氏水分滴定法, 傅立叶变换红外光谱法, 热分析, 单晶和粉末X射线衍射法对氯苄律定的结构及晶型进行了研究。结果氯苄律定及其非对映异构体可用不同的熔点来区分。氯苄律定晶型A为三斜晶系，空间群为P-1, 每个晶胞中有两个互为镜象的分子，为一水合物。并对氯苄律定的两种晶型进行了鉴定。结论对氯苄律定的结构及晶型进行的研究对于其临床研究及重结晶工艺的选择均是十分有用的。     

Investigating the hydrate conversion propensity of different etoricoxib lots

The physical stability of bulk active pharmaceutical ingredients (API) is of significant scientific and regulatory concern. Carrying out physical stability testing on lots with varying rates of hydrate conversion can potentially lead to erroneous conclusions if these rate differences remain unknown and unstudied. The lot dependency of etoricoxib's rate of hemihydrate conversion was investigated and a quick discriminatory technique was developed to qualitatively assess relatively slow to rapidly converting lots. This novel technique was also used to screen potential parameters affecting the hydrate conversion rate such as particle size/surface area, amorphous content, and initial hemihydrate content. Based on qualitative X-ray powder diffraction (XRPD) and quantitative Raman data, significant effects on the rate of hydration were observed with the addition of small amounts of amorphous etoricoxib. Furthermore, it was found that the presence of hemihydrate also increased the rate of conversion by seeding anhydrous etoricoxib. This suggests that the initial presence of the hydrate form can cooperatively accelerate conversion. A better understanding of the factors affecting hydrate conversion rates resulted in the appropriate selection of storage conditions for both the bulk API and the formulated product.     

A Structural Powder Diffraction Study of Two Polymorphic Forms of Nortriptyline Hydrochloride

Nortriptyline hydrochloride, a tricyclic antidepressant, appears in two different polymorphic forms, only one of which (hereafter, form β) has been previously characterized by single‐crystal analysis. Form β is monoclinic, P2₁/c, with a = 5.070(2), b = 34.088(5), c = 9.976(1) Å, and β = 90.74(2)°. A second crystalline form (the α form) has now been characterized by structural powder diffraction methods (using both laboratory and synchrotron radiation diffraction data). Form α crystallizes in the monoclinic P2/c space group, a = 9.99126(6), b = 5.10021(3), c = 34.1636(1) Å, and β = 98.684(6)°. The thermodynamic relationship between the two forms has been determined by differential scanning calorimetry analysis and variable‐temperature thermodiffractometric experiments, revealing that the two forms are monotropically related and form α is more stable. Both phases are characterized by a sequence of hydrogen‐bonded N‐protonated molecules, which, in the two crystalline environments, adopt the same conformation. The difference between the two crystals can be traced back to the supramolecular arrangement characterized by one‐dimensional chains, built by homochiral molecules (for conformationally driven chirality) in the α form, and by enantiomeric ones in the β form. This observation nicely explains why, upon heating, solid‐solid interconversion between the two forms does not occur.     

Ab initio structure determination of anhydrous sodium alendronate from laboratory powder X-ray diffraction data

Sodium alendronate, a member of bisphosphonate class of compounds commonly used for treatment of generalized bone disorders, exists in various hydrated forms. Dehydration of sodium alendronate trihydrate has been studied using variable temperature X-ray powder diffraction technique. The crystal structure of anhydrous sodium alendronate, prepared by heating the trihydrate sodium alendronate at 150 degrees C, has been determined from X-ray powder data using direct space global optimization technique for structure solution, followed by the Rietveld refinement. The structure of the anhydrous form of sodium alendronate is compared with that of the trihydrate form, which was determined previously from single crystal X-ray diffraction data. Both anhydrous and trihydrate sodium alendronate crystallize in monoclinic system with space group P2(1)/n. The crystal structure of the anhydrous sodium alendronate is built by edge-sharing of NaO(6) octahedra into a two-dimensional molecular sheet in the (011) plane, whereas in the trihydrate compound, one-dimensional chain along the (010) direction is generated by corner sharing of NaO(6) octahedra.     

Polysorbate 80 coated poly (ɛ-caprolactone)-poly (ethylene glycol)-poly (ɛ-caprolactone) micelles for paclitaxel delivery

Physicochemical properties of two anhydrates (α-form and β-form) and three hydrates (hemihydrate, monohydrate and sesquihydrate) of sitafloxacin (STFX), a novel fluoroquinolone antibiotic, were investigated and correlated with the crystal structure of each crystalline form. STFX sesquihydrate showed larger weight change between 1% and 95% relative humidities (RHs) than other crystalline forms. In the crystal of sesquihydrate, STFX molecules form a channel structure where water molecules exist. Contrary to sesquihydrate, water molecules in a monohydrate are located in well-defined and isolated crystallographic sites. The β-form exhibited the worst photostability than any other forms under the irradiation of a D65 lamp. The intramolecular hydrogen bonding in the β-form caused a red shift on the solid-state UV spectrum by prolonging the conjugation system of the quinolone ring, resulting in greater absorption of photoenergy and consequent degradation. Solubility is also affected by the crystalline structure. Standard free energy of the formation of STFX molecule in each crystalline form and/or lattice energy binding STFX molecules to retain the crystal structure might cause a difference in solubility.     

Characterizing the conversion kinetics of carbamazepine polymorphs to the dihydrate in aqueous suspension using Raman spectroscopy

In an aqueous environment, polymorphic forms I-III of carbamazepine all convert to the dihydrate. This study investigated the conversion of each polymorphic form individually and of a mixture of forms III and I to the dihydrate. Two batches of form I with different crystal morphology were used. Samples were dispersed independently in water at 23+/-1 degrees C and recovered at various timepoints varying from 10 to 210 min. Scanning electron microscopy, X-ray powder diffraction and Raman spectroscopy were used to characterize the initial polymorphic forms and the recovered samples after 210 min. Raman spectroscopy combined with partial least squares analysis was used to generate quantitative models of binary and ternary mixtures of the different polymorphic forms with the dihydrate. On the basis of these models the conversion kinetics of the polymorphic forms I-III were characterized. First-order kinetics with an unconverted portion were used to model the data (R2> or =0.95). The unconverted portions ranged from 16 to 51% after dispersion for 210 min. The conversion kinetics were similar between polymorphic forms with comparable crystal morphology, but differed significantly between batches of the same polymorph (form I) with different crystal morphology. Furthermore, the conversion of forms III and I in the aqueous suspension was not influenced by the presence of the other polymorph when dispersed together.     

Physical characterization of two oxyphenbutazone pseudopolymorphs

Two pseudopolymorphic forms of oxyphenbutazone, a benzene solvate (Solvate B) and a cyclohexane solvate (Solvate C), were prepared by recrystallization from benzene and cyclohexane, respectively. The forms were characterized by means of differential scanning calorimetry, thermogravimetry, infrared spectrophotometry, X-ray powder diffraction, and thermomicroscopy, as well as powder and intrinsic dissolution rates. The dissolution rates of the two pseudopolymorphs were shown to be superior to those of the anhydrate, hemihydrate, and monohydrate which were previously reported. A brief stability report is included.     

Two new polymorphs and one dihydrate of lenalidomide: solid-state characterization study

Purpose: Lenalidomide (LDM) is a blockbuster drug for multiple myeloma and non-Hodgkin’s lymphoma, and contributed $ 6.974 billion in sales for Celgene in 2016. The aim of this research is to expand the crystal form landscape, characterize the physicochemical properties and thoroughly investigate the potential solid forms transformation for this famous drug.

Materials and methods: In this study, a comprehensive solid-state screening was carried out. The physicochemical properties, stability and phase transformation were fully investigated using powder X-ray diffraction (PXRD), thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), solid state nuclear magnetic resonance (solid state NMR) and Infrared Spectroscopic Analysis (IR). Finally the differences of dissolution behavior were compared through powder dissolution test.

Results: Two new anhydrous forms (α and β) and one new dihydrate form (DH) of LDM were discovered through a comprehensive solid-state screening experiment. The new discovered DH showed better stability under accelerated storage condition (40 °C/75% RH) and in most organic solvents than other forms. The new discovered form α exhibited faster dissolution rate in the early phase and larger apparent solubility than the currently marketed form.

Conclusions: These new forms exhibit a new chance for drug development in view of their pharmaceutical properties and intellectual property.     

Physicochemical Stability of Phenobarbital Polymorphs at Various Levels of Humidity and Temperature

The physicochemical stability of six phenobarbital modifications [forms A, B, C (monohydrate), D (dioxane solvate), E (hemihydrate), and F] at various levels of humidity and temperature were measured using X-ray diffractometry and differential scanning calorimetry. Form D was identified as a new crystalline form (dioxane solvate). Polymorphic transformations of the modifications were investigated by the Kissinger method under nonisothermal conditions. Change of polymorphic content of phenobarbital modifications under various humidity levels at 45°C was evaluated by X-ray powder diffraction. The polymorphic stability under isothermal conditions was estimated kinetically, based upon the Jander equation. Forms A, B, and F were stable at 0 and 75% RH and 45°C for 3 months. On the contrary, forms C, D, and E transformed during storage. The transformation rates of form D were larger than that of forms C and E.     

Polymorphism and pseudopolymorphism of salicaine and salicaine hydrochloride crystal polymorphism of local anaesthetic drugs, part V

The local anaesthetic drug salicaine hydrochloride (hydroxytetracaine hydrochloride, 4-butylamino-2-hydroxybenzoic acid 2-dimethylaminoethyl ester hydrochloride, SLCHC) and the free-base salicaine (SLC) were characterized by thermal analysis, vibrational and solid-state NMR-spectroscopy, X-ray powder diffraction, X-ray single crystal structure analysis, and water vapor sorption analysis. Additionally, the crystal structures of the anhydrate mod. II degrees (monoclinic, space group P2(1)/n), the hydrated mod. I (triclinic, space group P(bar)1), and of the free base (SLC) in the form of the hemihydrate (triclinic, space group P(bar)1 are discussed. Mod. II degrees of the polymorphic SLCHC is the thermodynamically stable form at room temperature and is present in commercial products mostly contaminated with a hydrated form that is isomorphic with mod. I. Mod. II degrees crystallizes from most organic solvents and from the melt below 110 degrees C. Mod. I crystallizes from the melt at temperatures above 110 degrees C, and additionally appears on dehydration of the hydrated mod. I. A third polymorph monotropically related to mod. II degrees was found by freeze-drying. The free-base SLC was found to crystallize from ethanol/water as a triclinic hemihydrate.     

X-ray crystallographic characterization of nilvadipine monohydrate and its phase transition behavior.

Crystals of nilvadipine monohydrate were obtained from aqueous acetonitrile solution and characterized by powder and single crystal X-ray crystallography and thermal analysis. Water molecules of crystallization exist in nilvadipine monohydrate crystals in a molar ratio of 1:1 (drug-to-water) and were fixed by three hydrogen bonds with two carbonyl groups of the methyl and isopropyl esters, respectively, and one imino group of neighboring nilvadipine molecules. The conformation of the methyl and isopropyl esters in the monohydrate crystal was the reversal of that in the anhydrate crystal due to the presence of hydrogen bonds with water in the former crystal. The monohydrate crystal was slowly converted to the dehydrate at low humidity, and the latter rapidly converted to the former at high humidity. Powder X-ray diffraction studies indicated that the dehydrate retains the original structure of the monohydrate, i.e., a layer structure stacked on the ac plane perpendicular to the b-axis The solubility of the monohydrate in water was lower than that of the dehydrate and anhydrate forms, although the initial dissolution rate of the monohydrate was faster than that of the anhydrate. The present results indicated that the conformation of 1, 4-dihydropyridine-type calcium channel antagonists such as nilvadipine is easily changed by hydrogen bonds with water molecules of crystallization, and the water molecules are mobile through the void spaces formed between the layers in crystals.     

Studies on mechanism of thermal crystal transformation of sitafloxacin hydrates through melting and recrystallization, yielding different anhydrates depending on initial crystalline forms

The polymorphic and pseudopolymorphic forms of sitafloxacin, a novel fluoroquinolone antibiotic, were characterized by infrared spectroscopy, X-ray diffractometry, and thermal analysis. Hydrates of sitafloxacin underwent thermal transformation during the course of heating to 300°C. Monohydrate melted at 130°C and crystallized at 147°C to yield α-form (anhydrate) while sesquihydrate melted at 127°C and crystallized at 146°C to yield β-form (anhydrate). The crystal structural analysis revealed that monohydrate and sesquihydrate had opposite torsion at quinolone ring and the conformation of quinolone ring tended to be retained during hydrates to anhydrates crystal conversion. The infrared spectroscopy showed that hydrates and anhydrate α-from exists in zwitterion while β-from is consist of neutral molecule. Detail investigation of thermal behavior of hydrates suggested that water vapor also affected anhydrous crystal forms obtained by heating hydrates, though promoting ionization at carboxyl group and amine group.     

Solid state characterization and crystal structure from X-ray powder diffraction of two polymorphic forms of ranitidine base

Ranitidine hydrochloride (RAN-HCl), a known anti-ulcer drug, is the product of reaction between HCl and ranitidine base (RAN-B). RAN-HCl has been extensively studied; however this is not the case of the RAN-B. The solid state characterization of RAN-B polymorphs has been carried out using different analytical techniques (microscopy, thermal analysis, Fourier transform infrared spectrometry in the attenuated total reflection mode, (13)C-CPMAS-NMR spectroscopy and X-ray powder diffraction). The crystal structures of RAN-B form I and form II have been determined using conventional X-ray powder diffraction in combination with simulated annealing and whole profile pattern matching, and refined using rigid-body Rietveld refinement. RAN-B form I is a monoclinic polymorph with cell parameters: a = 7.317(2), b = 9.021(2), c = 25.098(6) A, beta = 95.690(1) degrees and space group P2(1)/c. The form II is orthorhombic: a = 31.252(4), b = 13.052(2), c = 8.0892(11) A with space group Pbca. In RAN-B polymorphs, the nitro group is involved in a strong intramolecular hydrogen bond responsible for the existence of a Z configuration in the enamine portion of the molecules. A tail to tail packing motif can be denoted via intermolecular hydrogen bonds. The crystal structures of RAN-B forms are compared to those of RAN-HCl polymorphs. RAN-B polymorphs are monotropic polymorphic pairs.     

Structural determination of the stable and meta-stable forms of atomoxetine HCl using single crystal and powder X-ray diffraction methods

Stratteratrade mark is the first FDA-approved nonstimulant medication for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) in children, adolescents, and adults. Two polymorphic forms and an amorphous form of the active pharmaceutical ingredient, atomoxetine HCl, were discovered during drug development. The thermodynamically stable polymorphic form was selected for the commercial product. The stable form readily grows as crystals suitable for single crystal diffraction. The meta-stable crystal form is isolated by rapid crystallization, providing crystals that are too small for routine single crystal methods; consequently its structure was determined by X-ray powder diffraction.     

Characterization and crystal structure of D-mannitol hemihydrate

The objectives of this study were (i) to isolate and characterize mannitol hydrate, and (ii) to solve its crystal structure from high-resolution synchrotron X-ray powder diffraction data. Mannitol hydrate was prepared by freeze-drying aqueous mannitol solutions (5% w/v) under controlled conditions. X-ray powder diffractometry, differential scanning calorimetry, and thermogravimetric analyses indicated that mannitol exists as a hemihydrate (C(6)H(14)O(6) . 0.5H(2)O). Synchrotron data were collected on the X3B1 beamline at the National Synchrotron Light Source. The simulated annealing program PSSP was used to solve the structure, which was subsequently refined by Rietveld analysis using the program package GSAS. The compound crystallizes in space group P1, with a = 9.8963 A, b = 10.5424 A, c = 4.7860 A, alpha = 102.589 degrees , beta = 86.092 degrees , and gamma = 116.079 degrees . The unit cell contains two dissimilar D-mannitol molecules and one water molecule, forming a hydrogen bonding pattern significantly different from that seen in the anhydrous polymorphs.     

The effect of crystal morphology and mill type on milling induced crystal disorder.

Milling is a key process in the preparation of many solid dosage forms. One possible milling induced change is the production of small levels of disorder or amorphous material found predominantly at the surface of a powder, which could lead to significant chemical and physical instability. The influence of crystal habit on this change was investigated using beta-succinic acid, in plate like and needle like morphologies. beta-Succinic acid crystals with these habits were processed in a ball mill and a jet mill. SEM images indicated jet milled material was finer than the ball milled product. Powder X-ray diffraction of the milled powders revealed an amorphous halo at lower angles and peak broadening suggesting disorder though this could not be quantified accurately. In addition, a partial conversion during milling to the alpha form was noted. Quantitation of the alpha form in the milled powders indicated it was present at <2% (w/w). Plate and needle shaped particles had similar heats of solution pre-milling, however, all milled powders had lower heats of solution compared to the unmilled powers. The contribution of the alpha polymorph to the lower heats of solution was calculated to be insignificant. Therefore, the reduced heat of solution is attributed to a loss in crystallinity. The largest decreases were seen in the plate like morphology. These findings suggest that beta-succinic acid crystals with plate like morphology are more prone to crystallinity loss on milling compared to the needle like morphology. The mill type has also been shown to influence the final crystallinity.