Anhydrous Form Research Articles

Oral solid dosage form using alternate crystalline neratinib maleate anhydrous form: Pharmaceutical, bioequivalent, and clinical perspectives.

Neratinib (an active pharmaceutical ingredient [API]) is an irreversible pan-human epidermal growth factor receptor (HER) inhibitor used to treat HER2-positive breast cancer. The dosage form (marketed in the United States, China, Europe, and other regions) is a tablet for oral administration, and the brand product (NERLYNX) has patent protection for the crystalline neratinib maleate monohydrate form. This paper describes the product development using stable crystalline neratinib maleate anhydrous form, stability study, bioequivalence (BE) study of the products, and discussion of the adverse effects observed in the clinical study.

Novel Crystalline Salts of 4-Piperidyl- and 4-Pyridylmethylamines Prepared by Catalytic Hydrogenation of 4-Pyridinecarbonitrile: Crystallographic Unit Cells Based on Powder XRD Patterns by Using the DASH Program Package

Structures of some hydrogenated products and intermediates, prepared by a heterogeneous Pd/C or Ru/C catalyst starting from 4-pyridinecarbonitrile (4PN), in water and in the presence of an acidic additive (HCl or H2SO4), were confirmed in various salt forms of 4-piperidylmethylamine (4PIPA) and 4-pyridylmethylamine (4PA). Crystallographic unit cell structure of the completely hydrogenated product salts (4PIPA·H2SO4 and 4PIPA·2HCl) showed a common double-protonated [4PIPA+2H]2+ divalent cation structure, also proved by FT-IR, and that of the 4PA·H2SO4 intermediate salt was also indexed and modeled by means of powder X-ray diffraction, applying the DASH 4.0 software package and crystal coordinates coming from former single-crystal X-ray structure determination. Formations of the anhydrous and hydrated forms of 4PA·0.5H2SO4·xH2O (x = 0 or x = 0.5, hemisulfates) were also studied by powder XRD and FT-IR spectroscopy for comparing these crystal structures.

Are caffeine effects equivalent between different modes of administration: the acute effects of 3 mg.kg-1 caffeine on the muscular strength and power of male university Rugby Union players.

There is growing interest in the potential of alternative modes of caffeine administration for enhancing sports performance. Given that alternative modes may evoke improved physical performance via distinct mechanisms, effects may not be comparable and studies directly comparing the erogenicity of alternative modes of caffeine administration are lacking. To address this knowledge gap, the present study evaluated the effect of 3 mg·kg-1 caffeine delivered in anhydrous form via capsule ingestion, chewing gum or mouth rinsing on measures of muscular strength, power, and strength endurance in male Rugby Union players. Twenty-seven participants completed the study (Mean ± SD: Age 20 ± 2 yrs; daily caffeine consumption 188 ± 88 mg). Following assessments and reassessment of chest press (CP), shoulder press (SP), Deadlift (DL), and Squat (SQ) 1-repetition maximum (1RM) and familiarization to the experimental procedures, participants completed six experimental trials where they were administered 3 mg.kg-1 caffeine (Caff) or placebo (Plac) capsule(CAP), chewing gum(GUM) or mouth rinse(RINSE) in a randomized, double-blind and counterbalanced fashion prior to force platform assessment of countermovement jump, drop jump and isometric mid-thigh pull performance. Strength endurance was measured across two sets of CP, SP, DL, and SQ at 70% 1RM until failure. Pre-exercise perceptions of motivation and arousal were also determined. Caffeine increased perceived readiness to invest mental effort (p = .038; ηp2=.156), countermovement jump height (p = .035; ηp2=.160) and SQ repetitions until failure in the first set (p < .001; d = .481), but there was no effect of delivery mode (p > .687; ηp2<.015). Readiness to invest physical effort, felt arousal, drop jump height, countermovement jump, drop jump and isometric mid-thigh pull ground reaction force-time characteristics and repetitions until failure in CP, SP and DL were not affected by caffeine administration or mode of caffeine delivery (p > .0.052; ηp2< .136). 3 mg.kg-1 caffeine administered via capsule, gum or mouth rinse had limited effects on muscular strength, power, and strength endurance. Small effects of caffeine on CMJ height could not be explained by changes in specific ground reaction force-time characteristics and were not transferable to DJ performance, and effects specific to the SQ RTP exercise underpin the complexity in understanding effects of caffeine on muscular function. Novel modes of caffeine administration proposed to evoke benefits via distinct mechanisms did not offer unique effects, and the small number of effects demonstrated may have little translation to a single performance trial when data examining direct comparison of each caffeine vehicle compared against a mode matched placebo is considered.

Micronization of ciprofloxacin by the Supercritical Antisolvent (SAS) Technique

Ciprofloxacin is a broad-spectrum antibiotic that is proposed for pulmonary administration. In this work micronization of ciprofloxacin was performed by the Supercritical Antisolvent Technique (SAS) using ciprofloxacin base (CIP) in ethanol/acetic acid and ciprofloxacin hydrochloride salt (CIP·HCl) in methanol at 40–60 ºC and 100–150 bar. Yields ranged from 40 % to 90 %. CIP precipitated incorporating acetate whilst CIP·HCl precipitated as the AH1 anhydrous form. CIP and CIP·HCl particles exhibited an acicular morphology (0.2–0.9 μm wide × 1–4 μm long). Micronization adding lactose, PVP K-10 and K-30 modified the precipitate morphology. CIP·HCl:lactose and CIP·HCl:PVP K-30 at a 4:1 drug:excipient mass ratio precipitated like flakes. CIP·HCl:PVP K-10 precipitated as submicron globular particles suitable for oral formulation. Increasing the PVP content, the morphology changed to sheets and flakes, which could be used for pulmonary administration. The antibacterial activity of the samples for Staphylococcus epidermidis was confirmed.

Liquid-liquid equilibrium of binary ethanol–polyisobutene and ternary ethanol–water–polyisobutene systems under low- and high-pressure conditions: An assessment using the PC-SAFT equation of state

Sugarcane bioethanol in either anhydrous or hydrous forms stands out as an economically viable bioproduct that can be used as a fuel or feedstock in various innovative applications, reducing human-generated greenhouse gas emissions. Low-molar-mass polyisobutene (PiB) is used as a lubricant in sugarcane-processing plants and is a possible contaminant of sugarcane bioethanol. Understanding the liquid–liquid equilibrium (LLE) of ethanol–PiB binary systems and ethanol–water–PiB ternary systems is essential to avoid undesired phase separation at high-pressure engine conditions and other potential innovative applications. However, the experimental investigation of these systems is significantly hampered by very low polymer solubilities in aqueous ethanol. The LLE of ethanol-PiB and ethanol–water–PiB mixtures was qualitatively investigated using the PC-SAFT equation of state through the development and implementation of extrapolation strategies allowing to estimate ethanol–PiB and water–PiB binary parameters using experimental data obtained for other systems containing lighter alkanes. Phase diagrams were calculated considering temperatures ranging from 298.15 K to 350 K and pressures ranging from 1 bar to 200 bar. It was shown that lower pressures, higher temperatures, lower PiB molar masses, and lower water contents increase the polymer solubility in the solvents. Thus, the risk of liquid–liquid separation can be mitigated by correctly managing such operational parameters. The obtained phase diagrams may present significant quantitative deviations from reality because of the model’s sensitivity to the estimated binary parameters. Thus, they should be interpreted as general qualitative guidelines to avoid and manage undesired phase separation in industrial processes and engines rather than phase equilibrium predictions.

Crystal structures and properties of derivatives of the alkaloid matrine: salts and hydrate forms.

We report the crystal structures of three matrine derivatives, namely, the salts (1R,2R,9S,17S)-6-oxo-7,13-diazatetracyclo[7.7.1.02,7.013,17]heptadecan-13-ium (2E)-3-(3,4-dihydroxyphenyl)prop-2-enoate (matrine caffeinate) sesquihydrate, C15H25N2O+·C9H7O4-·1.5H2O (Matrine-CA), and the 2-hydroxybenzoate (salicylate) monohydrate, C15H25N2O+·C7H5O3-·H2O (Matrine-SA), as well as the 1.75-hydrate form, (1R,2R,9S,17S)-7,13-diazatetracyclo[7.7.1.02,7.013,17]heptadecan-6-one 1.75-hydrate, C15H24N2O·1.75H2O (Matrine-H). Each derivative exhibited a consistent molecular conformation for the matrine core, which is notably distinct from that of the anhydrous form. Notably, both salts crystallized in the orthorhombic space group P212121, with an asymmetric unit featuring one cation and one anion. Within the two salt structures, intermolecular proton transfer between matrine and the acid is observed, culminating in the formation of a matrine cation protonated at the tertiary amine N site. The Matrine-CA crystal packing is manifested as a three-dimensional (3D) network arising from one-dimensional (1D) supramolecular helical chains, stabilized by N-H...O and O-H...O hydrogen bonds. In the case of Matrine-SA, the matrine cation is interconnected via hydrogen bonds with salicylate anions and water molecules, also forming a 1D helical motif. The structure of the hydrate form, Matrine-H, is reported again with the disordered solvent molecules accurately located. To further elucidate the structural attributes, Hirshfeld surface analysis and fingerprint plots are employed, offering a nuanced perspective on the intermolecular contacts and interactions within these crystalline forms.

Growth, Characterizations of Aspartame-ASP Crystals for Mechano, Spectral, Photonic, Opto-Electronic and Sensor Applications

The organic crystal has prevalent outcome and Aspartame-ASP crystal which is in anhydrate form is of 160–200 times sweeter than the sucrose and the single crystalline X-ray diffraction (XRD) data for ASP are a, b, c in Å as 19.4077, 4.9604, 15.6547, and alpha and gamma as 90°, beta as 94.877° and system is monoclinic, the space group is P21. The XRD reveals the monoclinic arrangement of the ASP crystal, the UV effect with Tauc’s plot for lower frequency cut off at 295 nm and band gap as 4.203 eV, morphology by scanning electron microscopy study in μm scaling, Vicker’s proviso by hardness profile, basic functional groups by Fourier transform infrared and basic examinations, excitation—emission by PhotoLuminescence-PL peak at 513 nm, electronic sort of ASP filters in 4.3275 microns, electric depiction by dielectric study and mechano use by hardness profile of ASP are studied and reported. Hardness coefficient by Vicker’s intended for ASP with n as 2.91. The NLO-SHG is of 1.76 times KDP with phase matched effect of ASP is reported. Also, the room-temperature sensor study of ASP is measured and compliance by red light-emitting diode source.

Hydrometallurgical Technology for Producing Rhenium(VII) and Cobalt(II) from Waste

This paper presents a method for obtaining cobalt(II) perrhenate from waste derived from two types of materials, i.e., Li-ion battery scrap, or more precisely, battery mass, and superalloy scrap. Both of the above-mentioned materials are a source of Co. However, a source of rhenium is perrhenic acid produced from ammonium perrhenate (recycled) by the ion exchange method using resins. Co(OH)2 can be precipitated from solutions resulting from the leaching of Li-ion battery mass, sludge from the Zn-Pb industry and superalloy scrap. The compound, after proper purification, can be used in a reaction with perrhenic acid to form Co(ReO4)2. The reaction should be conducted under the following conditions: time 1 h, room temperature, 30% excess of cobalt(II) hydroxide, and rhenium concentration in HReO4 from about 20 g/dm3 to 300 g/dm3. This work shows that with the use of Co(OH)2, obtained from waste, an anhydrous form of cobalt(II) perrhenate can be obtained, containing &lt; 1000 ppm of the cumulative metal impurities.

Recovery of Zinc and Rhenium for the Production of Zinc Perrhenates

This study outlines findings from an investigation into the development of a hydrometallurgical process for manufacturing various forms of zinc perrhenate, entirely from waste from recycling and from the Zn–Pb industry. Scraps of Re-bearing Ni-based superalloys and acidic waste, circulating zinc solutions generated during the production of Zn by the electrolytic method and which contain &gt;45 g/dm3 of Zn, Na, Mn, and Mg, were used in the research. In the publication, the conditions for the production of three types of zinc perrhenate, i.e., Zn(ReO4)2·4H2O, Zn(ReO4)2, and Zn(ReO4)2·2H2O, are presented. As a result of the analysis of the obtained results, it was concluded that to obtain the above-mentioned forms of zinc perrhenate, zinc carbonate can be used, precipitated from acidic, waste, and multi-component solutions after their prior neutralization to pH 4.0 and partial purification from Mn, Mg, and Na using metallurgical zinc oxide. Zinc carbonate should be precipitated using Na2CO3 at pH 6.3 and subsequently purified from other impurities, i.e., Mg, Na, and Mn, using aqueous ammonia solutions. As a result, zinc carbonate was obtained, which was used in a reaction with an aqueous solution of HReO4 to produce zinc perrhenate. The precipitated forms of Zn(ReO4)2 were obtained by appropriately drying the crude and hydrated Zn(ReO4)2 to obtain its tetrahydrate, dihydrate, and anhydrous forms, respectively, using drying temperatures of 55, 135, and 185 °C. The developed technology has been submitted for a patent and is an example of a technology founded on the principles of sustainable development, with a particular emphasis on the minimalization of loss of rhenium and zinc at all stages of its realization.

Quantification of Gypsum in Soils via Portable X-ray Fluorescence Spectrometry

Abstract This study explores the potential of X-ray fluorescence (XRF) as a rapid, nondestructive, and cost-effective technique for in situ sulfate quantification. Gypsum, the main source of sulfate in soils, reacts with calcium-based stabilizers to form expansive minerals, which reduces the long-term strength of the treated soil. Therefore, accurate detection of sulfate content prior to employing calcium-based chemical stabilization is important to mitigate the possibility of expansive mineral formation and ensure acceptable engineering behavior of the stabilized soil. Portable handheld XRF (PXRF) has shown the ability to estimate gypsum content accurately, utilizing calcium as a proxy. However, detecting sulfur, in the form of sulfite or sulfate remains challenging due to device sensitivity limitations. This research aims to address this limitation and develop a method for direct sulfur detection, enhancing the utility of PXRF for in situ sulfate quantification. Laboratory standards were created with known amounts of gypsum and portions were sent to a commercial laboratory for whole rock analysis. The remainder of the reference standards were used to calibrate several soil library standards within the PXRF. The calibrated PXRF was able to accurately detect the anhydrous form of gypsum, anhydrite (CaSO4), in these reference standards for contents ranging from 0 to 8 %. The proposed XRF-based approach offers the potential to revolutionize sulfate detection in soils, providing a rapid and reliable tool for assessing soil stability and optimizing chemical stabilization efforts. By enabling real-time, on-site analysis, this method holds promise for improving construction practices and reducing the risk of structural damage associated with soils containing sulfate-bearing minerals.

Influence of the preparation method (thermal quench, ball-milling, dehydration and freeze-drying) on the dynamical properties of glassy trehalose

Dielectric relaxation measurements have been performed on the glassy states of trehalose reached using different routes of amorphisation: thermal quench of the liquid state, milling of the anhydrous crystalline form, freeze-drying and dehydration of the dihydrate crystalline form. This study has revealed that all the glassy states are characterized by two relaxation processes respectively attributed to the slow Johari-Goldstein mode and to fast secondary intramolecular relaxations. These sub-Tg secondary relaxations are however strikingly different in the four glassy states revealing different energy landscape topologies.

Eutectic mixtures containing the active pharmaceutical ingredient ezetimibe: Phase diagrams, solid state characterization and dissolution profiles

Cardiovascular disease represents the leading cause of death worldwide, according to the World Health Organization (WHO) report. One of the treatment strategies is the use of the drug ezetimibe (EZT). This drug is a cholesterol absorption inhibitor with low aqueous solubility, which affects its therapeutic efficacy. The purpose of this paper was to obtain eutectic materials of EZT with methylparaben (MPB), salicylic acid (SCA) and nicotinamide (NTM) coformers, and to study their phase diagrams, dissolution properties and hygroscopicity to assess possible enhancements. Phase and Tamman diagrams were constructed using differential scanning calorimetry (DSC) results. The eutectic materials were characterized by powder X-ray diffraction (PXRD) and polarized light optical microscopy (OM). The hygroscopicity of the materials was assessed at different relative humidities (RH) through dynamic vapor sorption (DVS). The dissolution study was conducted with the materials in powder form, with paddle dissolution, rotating at 50 rpm, in 900 mL of aqueous buffer solution at pH 6.8 and 37 °C. The phase diagrams demonstrated that EZT formed eutectic systems with eutectic molar fractions of 0.59, 0.67 and 0.69 for EZT-SCA, EZT-NTM and EZT-MPB, respectively. The three eutectic materials are characterized as microcrystalline conglomerates of their components. In terms of the hygroscopic behavior of EZT at different RHs, eutectic materials demonstrated lower susceptibility to monohydrate formation compared to the anhydrous form. In dissolution studies, EZT-SCA and EZT-MPB solubilized EZT in amounts 22 % higher than the pure drug in 15 min. On the other hand, EZT-NTM eutectic suppressed the dissolution of EZT down to 56 % at the same time. The results indicated the possibility of obtaining materials with enhanced properties using eutectic mixtures, with improved dissolution rates and hygroscopic stability.

Structural characterization and comparative analysis of polymorphic forms of psilocin (4-hydroxy-N,N-dimethyltryptamine)

The title compound, C12H16N2O, is a hydroxy-substituted monoamine alkaloid, and the primary metabolite of the naturally occurring psychedelic compound psilocybin. Crystalline forms of psilocin are known, but their characterization by single-crystal structure analysis is limited. Herein, two anhydrous polymorphic forms (I and II) of psilocin are described. The crystal structure of polymorphic Form I, in space group P21/c, was first reported in 1974. Along with the redetermination to modern standards and unambiguous location of the acidic H atom and variable-temperature single-crystal unit-cell determinations for Form I, the Form II polymorph of the title compound, which crystallizes in the monoclinic space group P21/n, is described for the first time. The psilocin molecules are present in both forms in their phenol–amine tautomeric forms (not resolved in the 1974 report). The molecules in Forms I and II, however, feature different conformations of their N,N-dimethyl ethylene substituent, with the N—C—C—C link in Form I being trans and in Form II being gauche, allowing the latter to bend back to the hydroxyl group of the same molecule, leading to the formation of a strong intramolecular O—H...N hydrogen bond between the hydroxyl moiety and ethylamino-nitrogen group. In the extended structure of Form II, the molecules form one-dimensional strands through N—H...O hydrogen bonds from the indole group to the oxygen atom of the hydroxyl moiety of an adjacent molecule. Form II exhibits whole-molecule disorder due to a pseudo-mirror operation, with an occupancy ratio of 0.689 (5):0.311 (5) for the two components. In contrast, Form I does not feature intramolecular hydrogen bonds but forms a layered structure through intermolecular N—H...O and O—H...N hydrogen bonds.

Eight anhydrous organic salt forms of 2-amino-4,6-dimethoxypyrimidine and organic acids: Preparation, structure, characterizations, synthons diversity, and hirshfeld surface analysis

The intricate part of the non-covalent associates in numerous realms covering from chemistry, biology, catalysis, material science, to medicinal chemistry inspires a continuous motivation towards the discovery of new synthons that stabilize the supramolecular systems. In this work the co-crystallization between 2-amino-4,6-dimethoxypyrimidine (admpym) and eight organic acids resulted in the manufacturing of eight new crystalline salts, which were further fully characterized via the single crystal X-ray diffraction (SCXRD), spectroscopic (FT-IR) and elemental analysis methods. Their melting points were also measured. All the fabricated salts exhibited the identical stoichiometry regarding the number of the acidic unit and the admpym, namely with the 1:1 ratio at the monacids and 2 : 1 ratio in the diacids.Among the eight crystals, the H-shift from the acid to pyrimidine ring N atom has occurred, yet the NH2 group was not protonated ever. In all the crystals, the respective molecular fragments are permanently tethered to each other via the energetic H-bonds as the Npyrimidinium-Ophenolate/carboxylate type. The various weaker intermolecular linkages, embodying CH···O/CH3···O, CH···CH, CH3···N, CH···Br, CH3···CH, CH3···Cl, Cl···O, CH···π/CH3···π, C···π, O···π and π···π also contributed to the stabilization of the crystal structures in the respective conglomerates. The percentage contribution of the significant non-covalent contacts were calculated via the Hirshfeld surface analysis. The R22(8) graph was enclosed in all the systems when an acid pairs with an admpym. The job ensures that there engender both principle contact modes between the admpym and the acids, which appear in the relative higher frequency, linear heterotetramer (LHT), and cyclic heterotetramer (CHT). LHT is dominant as it appears in 5 cases, CHT in 2 ones, with the rest one structure building a rare heterodimer. The heterotrimer (HT) was never occurred here.

Low temperature heat capacities and magnetic properties of anhydrous and hydrated forms of manganous sulfate (MnSO4)

Manganese (II) sulfate (MnSO4), also known as manganous sulfate, has gained attention due to its low temperature magnetic properties. Following a study of its magnetic structure, manganese sulfate was proposed as being the first orthorhombic compound to have a spiral magnetic structure. It was predicted to have a three-step magnetic transition at low temperatures, which neutron diffraction studies have since confirmed. This work represents the first time that heat capacity data has been collected on MnSO4 and MnSO4 0.984(H2O) at low temperatures, which we report from 1.8 K to 300 K and comment on the presentation of the magnetic transition in the low temperature heat capacity region. Previous studies report the heat capacity of the anhydrous form above 50 K, and the data collected herein is compared with those previously published results. Theoretical fits of the heat capacity data are used to calculate the smoothed thermodynamic data, including Cp,m°, Δ0TSm°, Δ0THm°, andΦm°.

An Evaluation of Wet Granulation Process Selection for API Prone to Polymorphic Form Conversion in the Presence of Moisture and Heat.

Wet granulation (WG) is one of the most versatile processes to improve blend properties for processing. However, due to its need for moisture and heat, it is often considered not amenable to active pharmaceutical ingredients (APIs) prone to forming hydrates. Despite this claim, little literature exists evaluating the extent to which polymorphic form conversions occur for such API when processed with WG. This work sets out to explore two common WG methods, high-shear (HSG) and fluid-bed (FBG), and two drying processes, tray-drying (TD) and fluid-bed drying (FBD), and evaluate the risk they pose to hydrate form conversion. The progression of anhydrous to hydrate form conversion of two model compounds with vastly different solubilities, fexofenadine hydrochloride and carbamazepine, was monitored throughout the various processes using powder X-ray diffraction. The resultant granules were characterized using thermogravimetric analysis, differential scanning calorimetry, BET adsorption, and sieve analysis. FBG and FBD processing resulted in the preservation of the original form of both APIs, while HSG+TD resulted in the complete conversion of the API. The FBD of fexofenadine and carbamazepine granules prepared with HSG resulted in partial and complete re-conversion back to the original anhydrous forms, respectively. The drying process is a critical factor in anhydrous form conservation. FBG and FBD yielded better preservation of the initial anhydrous forms. HSG could be an acceptable granulation method for API susceptible to hydrate formation if the API solubility is low. Selecting an FBG+FBD process minimizes API hydrate formation and preserves the original anhydrous form.

Effect of Hydration Forms and Polymer Grades on Theophylline Controlled-Release Tablet: An Assessment and Evaluation.

Drug release from controlled release delivery systems is influenced by various factors, including the polymer's grade and the drug's hydration form. This study aimed to investigate the impact of these factors on the controlled release of theophylline (THN). This research compares the monohydrate form found in branded products with the anhydrous form in generic equivalents, each formulated with different polymer grades. Quality control assessment was conducted alongside in vitro evaluation, complemented by various analytical techniques such as X-ray diffraction (XRD) and scanning electron microscopy (SEM). Additionally, thermal analyses using differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) were employed. Quality control assessments demonstrated that the generic tablets exhibited lower average weight and resistance force compared to the branded ones. In vitro tests revealed that generic tablets released contents within 120 min, compared to 720 min for the branded counterpart. Characterization using XRD and SEM identified disparities in crystallinity and particle distribution between the three samples. Additionally, the thermal analysis indicated consistent endothermic peaks across all samples, albeit with minor variations in heat flow and decomposition temperatures between the two products. This study demonstrated that variations in polymer grade and hydration form significantly impact THN release.

Terminal crystalline solid solutions, solubility enhancements and T-X phase diagram of salicylic acid - 4-hydroxybenzoic acid.

The binary T-X phase diagram of salicylic acid (SA) and 4-hydroxybenzoic acid (4HBA) has been constructed from 20 °C to melting, revealing a partially miscible system with an eutectic composition of 27.3 mol% 4HBA in SA. Terminal crystalline solid solutions were obtained at the extremes of the phase diagram with solid-state miscibility limits below 0.4% at 20 °C. The limited phase boundaries could be captured experimentally by both DSC analyses at around melting temperature and solid-liquid equilibria studies at 20 °C in two solvent systems. The NRTL model was applied to regress phase boundaries and generate the final binary T-X phase diagram. The NRTL model was also used to regress solubility data, and reproduce the ternary SA/4HBA/solvent phase diagram at 20 °C and 1 atm. 4HBA was obtained as two crystal forms, viz. anhydrate and monohydrate. It is shown how the monohydrate of 4HBA is less miscible with SA in the solid state than the anhydrous form of 4HBA. As compared to pure SA and 4HBA, the crystalline solid solutions exhibited significant changes in physical properties that are relevant for organic and pharmaceutical materials in the context of impurity effects. A lattice incorporation of just 0.2 mol% 4HBA in SA caused a 10% reduction in melting enthalpy and a 66% solubility increase in 40 wt% MeOH in H2O. The reasons for this thermodynamic effect are discussed.

Structural analysis of anti-retroviral drug raltegravir and its potential impurity C: investigation of solubility and stability

An anhydrous form of raltegravir and two crystalline phases of its impurity C were obtained during solid form screening and their crystal structures are reported with variable conformations.

Solid-State Phase Transformation of Monohydrate and Anhydrous Form II of Sitagliptin Phosphate into a Novel Anhydrous Form IV – Solvent-Driven, Temperature-Induced and Stress Testings

The solid form landscape of sitagliptin phosphate was systematically evaluated by differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), Fourier transform infrared spectroscopy (FTIR), Raman spectroscopy and X-ray powder diffraction (XRPD), supported by a plethora of auxiliary analytical techniques. The preformulation experiments resulted in the transition of sitagliptin phosphate monohydrate into a new anhydrous form (designated as form IV), obtained after recrystallization from absolute ethanol. The anhydrous form IV remained stable under stressed conditions (1 month at 25 °C/60 %RH and 40 °C/75 %RH). On the other hand, thermal heating (dehydration) of sitagliptin phosphate monohydrate resulted in conversion into another anhydrous form II. Form II was found to be metastable, because after melting, under exposure at 40 °C/75 %RH for 1 month, or when dissolved in absolute ethanol converted to the stable anhydrous form IV of sitagliptin phosphate. A monotropic relationship was found between both studied anhydrous forms. Intrinsic dissolution tests revealed differences in the dissolution rates between the monohydrate and the anhydrous forms of sitagliptin phosphate. This research corrects the record with an accurate chemical composition of the anhydrous form IV of sitagliptin phosphate that was previously regarded as a hemiethanolate. In addition, the crystal structure of anhydrous form II of sitagliptin phosphate has been solved and reported for the first time.