Continuous Monitoring of Pseudopolymorphic Transition in Ezetimibe Using T1 Relaxation with Time-Domain NMR.

The purpose of this study was to continuously monitor the pseudopolymorphic transition from anhydrate to monohydrate by measuring the NMR relaxation using time-domain NMR (TD-NMR). Taking advantage of the simplicity of the low-field NMR instrument configuration, which is an advantage of TD-NMR, the NMR instrument was connected to a humidity controller to monitor the pseudopolymorphic transition. First, ezetimibe (EZT) monohydrate was prepared from its anhydrate using a saturated salt solution method, and T1 relaxation of EZT monohydrate and anhydrate was measured without a humidity controller. The T1 relaxation results confirmed that EZT anhydrate and monohydrate could be distinguished using T1 relaxation measurement. Next, continuous monitoring was conducted by TD-NMR and connected to a humidity controller. Anhydrous EZT was placed in an NMR glass tube and the T1 relaxation measurement was repeated while maintaining the humidity on the side entering the NMR tube at 80% relative humidity. The T1 relaxation became gradually faster from the initial to middle monitoring phases. The final T1 relaxation was then recovered fully and these T1 relaxation times were the same as the T1 relaxation of EZT monohydrate. This study successfully monitored the pseudopolymorphic transition from EZT anhydrate to monohydrate via NMR relaxation.

Mechanistic Insight of Polymer Effects on the Kinetic of Solution-Mediated Phase Transformation of Nitrofurantoin Anhydrate to Monohydrate.

PURPOSE: Nitrofurantoin is an effective antibacterial drug for the treatment of lower urinary tract infection. However, the anhydrate form can easily transform to the less soluble hydrate form (monohydrate) during dissolution, resulting in a reduction of dissolution rate and oral bioavailability. Therefore, inhibition of phase transformation is vital to stabilize the quality of drugs. METHODS: In this work, the potential of polyethylene glycol (PEG 8000), polyvinyl pyrrolidone (PVP K30), poloxamer 188 and hydroxypropyl methylcellulose (HPMC) to inhibit the hydration of nitrofurantoin during dissolution was investigated by experimental and simulation approaches. RESULTS: The rates of phase transformation were decreased in the presence of PEG 8000 and poloxamer 188, and PVP K30 and HPMC completely inhibited the phase transformation of anhydrate. The abundant hydrogen bond donor and acceptor groups of PVP and HPMC may easily establish intermolecular interactions with nitrofurantoin molecules, accounting for stronger inhibition of nucleation. Besides, the molecular dynamic simulation further indicated the formation of more extensive interactions between PVP K30 (or HPMC) and the (111) face of monohydrate, suggesting that the strong absorption of polymers on the surface and thus block the sites for incorporation of new growth. CONCLUSION: This study provides a mechanistic insight into the inhibition of nitrofurantoin hydration by polymeric additives, which helps design formulations and improve the physical stability of anhydrate.

The effect of combination treatment of CO2-laser irradiation and tetracalcium phosphate/dicalcium phosphate anhydrate on dentinal tubules blockage: an in vitro study.

The aim of this study was the evaluation of the in vitro efficacy of a carbon dioxide (CO2) laser, a tetracalcium phosphate/dicalcium phosphate anhydrate (TP/DP) desensitizer and the combination of the desensitizer and additional CO2 laser irradiation as a treatment modality for cervical dentin hypersensitivity. A total of 48 dental specimens, prepared from extracted human premolars and molars, were divided into four groups: a control group, a TP/DP desensitizer paste group, a CO2 laser (10.600-nm wavelength) group, and a paste and laser group. The specimens were coated with nail varnish except in the marked area and were then immersed in 2% methylene blue dye for 1 h. The specimens were then washed, dried, and cut longitudinally. Thereafter, photos of 40 dentin specimens were taken and evaluated. The area of penetration was assessed and reported as percentage of the dentin surface area. Additionally eight dental specimens were examined with the aid of a scanning electron microscope and evaluated. Significant differences in the penetration depth were found for all experimental groups compared to the control group. The lowest penetration area was detected in the paste-laser group (16.5%), followed by the laser (23.7%), the paste (48.5%), and the control group (86.2%). The combined treatment of the CO2 laser and a TP/DP desensitizer was efficient in sealing the dentinal surface and could be a treatment option for cervical dentin hypersensitivity.

Dynamic Semicrystalline Networks of Polypropylene with Thiol-Anhydride Exchangeable Crosslinks.

Thermoplastic polyolefins (TPOs) crosslinked by dynamic covalent bonds (xTPOs) have the potential to be the most utilized class of polymer in the world, with applications ranging from household and automotive to biomedical devices and additive manufacturing. xTPO combines the benefits of thermoplastics and thermosets in a "single material" and potentially avoids their shortcomings. Here, we describe a new two-stage reaction extrusion strategy of TPOs with a backbone consisting of inert C-C bonds (polypropylene, PP), and thiol-anhydride, to dynamically crosslink PP through thiol-thioester bond exchange. The degree of PP crosslinking determines the rubber plateau modulus above the melting point of the plastic: the modulus at 200 °C increases from zero in the melt to 23 kPa at 6% crosslinking, to 60 kPa at 20%, to 105 kPa at 40%. The overall mechanical strength of the solid xTPO plastic is 25% higher compared to the original PP, and the gel fraction of xTPO reaches 55%. Finally, we demonstrate that the crosslinked xTPO material is readily reprocessable (recycled, remolded, rewelded, and 3D printed).

Terahertz signatures and quantitative analysis of glucose anhydrate and monohydrate mixture.

Glucose, as the main energy carrier and significant source of nutrition, generally comes in two available forms of anhydrate and monohydrate in commercial production. Considering their respective application occasions, proper identification of glucose in single composition or binary-mixture and quantification of the mixture are crucial in industry monitoring to guarantee merchandise quality. Simultaneously, public confusions of glucose are rather ubiquitous partly due to anhydrate and monohydrate with identical white crystalline appearance. In this paper, utilizing the molecular fingerprints of terahertz (THz) technology that are corresponding to structural characteristics of anhydrous and hydrated form, THz signatures of glucose anhydrate, monohydrate and their mixture, as well as THz spectral transformation from monohydrate to anhydrate with the dehydrating process are systematically studied. Some visible peaks of monohydrate were noted at 1.82 and 1.99 THz signifying the presence of hydrated structure. However, with the dehydrating process, the peaks related to the hydrated structure are not very apparent when the peaks at 1.44 and 2.08 THz appear due to changes in the molecular structure of anhydrate, which provide clear indication for hydrogen-bond network reconstruction at the micro level. Furthermore, characteristic peaks at 1.44 and 1.82 THz can be specified as the main quantitative indicators for quantitative detection. The linear relationships between the amplitudes of characteristic peaks and the percentage compositions of anhydrate and monohydrate are revealed. Three commercially available brands of edible glucose powder A, B, C were effectively identified by THz signatures. While powder C was recognized as binary-mixture and the proportion of anhydrate and monohydrate was further quantified. THz spectroscopy technology has advantages of direct recognition, simple quantitative model based on THz absorption peaks, and no need for complicated chemical treatment. It may be potentially shed light on industrial monitoring of glucose production and other related mixture in the future.

Mechanochemical Synthesis and Structure of the Tetrahydrate and Mesoporous Anhydrous Metforminium(2+)-N,N'-1,4-Phenylenedioxalamic Acid (1:2) Salt: The Role of Hydrogen Bonding and n→π * Charge Assisted Interactions.

A new organic salt of metformin, an antidiabetic drug, and N,N'-(1,4-phenylene)dioxalamic acid, was mechanochemically synthesized, purified by crystallization from solution and characterized by single X-ray crystallography. The structure revealed a salt-type crystal hydrate composed of one dicationic metformin unit, two monoanionic units of the acid and four water molecules, namely H2Mf(HpOXA)2∙4H2O. X-ray powder, IR, 13C-CPMAS, thermal and BET adsorption-desorption analyses were performed to elucidate the structure of the molecular and supramolecular structure of the anhydrous microcrystalline mesoporous solid H2Mf(HpOXA)2. The results suggest that their structures, conformation and hydrogen bonding schemes are very similar. To the best of our knowledge, the selective formation of the monoanion HpOXA-, as well as its structure in the solid, is herein reported for the first time. Regular O(δ-)∙∙∙C(δ), O(δ-)∙∙∙N+ and bifacial O(δ-)∙∙∙C(δ)∙∙∙O(δ-) of n→π * charge-assisted interactions are herein described in H2MfA organic salts which could be responsible of the interactions of metformin in biologic systems. The results support the participation of n→π * charge-assisted interactions independently, and not just as a short contact imposed by the geometric constraint due to the hydrogen bonding patterns.

The effective volumes of waters of crystallization: general organic solids.

Using a list of compatible hydrate/anhydrate pairs prepared by van de Streek and Motherwell [CrystEngComm (2007), 9, 55-64], we have examined the effective volume per water of crystallization for 179 pairs of organic solids using current data from the Cambridge Crystallographic Structural Database (CSD). The effective volume is the difference per water molecule between the asymmetric unit volumes of the hydrate and parent anhydrate, and has the mean value 24 Å3. The conformational changes in the reference molecule between the hydrate and its anhydrate are shown in two figures: one for a relatively rigid standard organic molecule and (in the supplementary file) one for a more flexible linear molecule. Using data from Nyman and Day [Phys. Chem. Chem. Phys. (2016), 18, 31132-31143], we have also established a generic volumetric coefficient of thermal expansion of organic solids with a value of 147 ± 56 × 10-6 K-1. There is a significant number of outliers to the data, negative, near zero, and large and positive. Some explanation for the existence of these outliers is attempted.

Islatravir Case Study for Enhanced Screening of Thermodynamically Stable Crystalline Anhydrate Phases in Pharmaceutical Process Development by Hot Melt Extrusion.

The emergence of new active pharmaceutical ingredient (API) polymorphs in pharmaceutical development presents significant risks. Even with thorough polymorph screening, new pathways toward alternate crystal phases can present themselves over the course of formulation development; thus, further improvements in phase screening methods are needed. Herein, a case study is presented of a thermodynamically stable crystalline phase of the HIV drug Islatravir (MK-8591, EFdA) that was not isolated from initial pharmaceutical polymorph screening. In total, five Islatravir phases are identified: one monohydrate and four anhydrate phases. The new phase, anhydrate form IV, was unexpectedly discovered during hot melt extrusion (HME) process development of polymeric implant drug product formulations while probing extreme manufacturing process conditions (elevated shear forces). X-ray diffraction (XRD), differential scanning calorimetry (DSC), and solid-state nuclear magnetic resonance (ssNMR) were utilized as principal tools to identify the new polymorph. The result suggests that HME introduces conditions that may allow a thermodynamically stable crystalline phase to form and these conditions are not necessarily captured by routine pharmaceutical polymorph screening. Subsequent investigations identified procedures to generate the new anhydrate phase without HME equipment by the use of special thermal procedures. It is found that for a crystalline hydrate phase the rate of water loss as well as water entrapment in a heating vessel play a crucial role in phase conversions into different anhydrate polymorphs. Further, the polymer involved in the HME manufacturing process also plays a critical role in the phase conversion, likely by coating the API microparticles and thereby altering the phase conversion kinetics. Strategies presented herein to mimic phase changes during formulation manufacture hold promise for the identification of thermodynamically stable anhydrate forms in earlier stages of pharmaceutical development.

Relative humidity-temperature transition boundaries for anhydrous ß-caffeine and caffeine hydrate crystalline forms.

Caffeine is a hydrate-forming polymorphic crystalline compound that can exist in α, ß, and hydrate forms. Phase transitions between hydrate and anhydrous forms of a crystalline ingredient, and related water migration, can create product quality challenges. The objective of this study was to determine the relative humidity (RH)-temperature phase boundary between anhydrous ß-caffeine and caffeine hydrate. The ß-caffeine→caffeine hydrate and caffeine hydrate→ß-caffeine RH-temperature transition boundaries were determined from 20 to 45 °C using a combination of water activity (aw ) controlled solution and vapor-mediated equilibration, moisture sorption, powder X-ray diffraction, and Fourier-transform infrared spectroscopy techniques. Two transition boundaries were measured: the ß-caffeine→caffeine hydrate transition boundary (0.835 ± 0.027 aw at 25 °C) was higher than the caffeine hydrate→ß-caffeine transition boundary (0.625 ± 0.003 aw at 25 °C). Moisture sorption rates for ß-caffeine, even at high RHs (>84% RH), were slow. However, caffeine hydrate rapidly dehydrated at low RHs (<30% RH) into a metastable transitional anhydrous state with a similar X-ray diffraction pattern to metastable α-caffeine. Exposing this dehydrated hydrate to higher RHs (>65% RH) at lower temperatures (20 to 30 °C) resulted in full restoration to a 4/5 caffeine hydrate. This transitional anhydrous state was unstable and converted to a less hygroscopic state after annealing at 50 °C and 0% RH for 1 day. It was postulated that the caffeine hydrate→ß-caffeine was the true ß-caffeine↔caffeine hydrate phase boundary and that ß-caffeine could be metastable above the caffeine hydrate→ß-caffeine transition boundary. These caffeine RH-temperature transition boundaries could be used for selecting formulation and storage conditions to maintain the desired caffeine crystalline form. PRACTICAL APPLICATION: Caffeine can exist as either an anhydrous (without water) or hydrate (internalized water) crystalline state. The stability of each caffeine crystalline form is dictated by humidity (or water activity) and temperature, and these environmental stability boundaries for the caffeine crystalline forms are reported in this manuscript. Conversions between the two crystalline states can lead to deleterious effects; for example, the presence of caffeine hydrate crystals in a low water activity food (e.g., powder) could lead to the relocation of the water in caffeine to other ingredients in the food system, leading to unwanted water-solid interactions that could cause clumping and/or degradation.

Influence of Carbamazepine Dihydrate on the Preparation of Amorphous Solid Dispersions by Hot Melt Extrusion.

Amorphous solid dispersions (ASDs) are commonly used in the pharmaceutical industry to improve the dissolution and bioavailability of poorly water-soluble drugs. Hot melt extrusion (HME) has been employed to prepare ASD based products. However, due to the narrow processing window of HME, ASDs are normally obtained with high processing temperatures and mechanical stress. Interestingly, one-third of pharmaceutical compounds reportedly exist in hydrate forms. In this study, we selected carbamazepine (CBZ) dihydrate to investigate its solid-state changes during the dehydration process and the impact of the dehydration on the preparation of CBZ ASDs using a Leistritz micro-18 extruder. Various characterization techniques were used to study the dehydration kinetics of CBZ dihydrate under different conditions. We designed the extrusion runs and demonstrated that: 1) the dehydration of CBZ dihydrate resulted in a disordered state of the drug molecule; 2) the resulted higher energy state CBZ facilitated the drug solubilization and mixing with the polymer matrix during the HME process, which significantly decreased the required extrusion temperature from 140 to 60 °C for CBZ ASDs manufacturing compared to directly processing anhydrous crystalline CBZ. This work illustrated that the proper utilization of drug hydrates can significantly improve the processability of HME for preparing ASDs.

RH-temperature stability diagram of α- and ß-anhydrous and monohydrate lactose crystalline forms.

Lactose crystals exhibit polymorphic, deliquescent, and hydrate-forming traits and can exist in monohydrate, ß-anhydrate, stable α-anhydrate, and hygroscopic α-anhydrate (isomorphic desolvate) forms. The objective of this study was to identify the relative humidity (RH) and temperature boundaries at which anhydrate-hydrate transitions and deliquescence occur for these lactose crystal forms. The deliquescence point (RH0) of lactose monohydrate was determined by measuring the water activity (aw) of a saturated solution, and the RH0s of the anhydrates were determined using dynamic vapor sorption measurement techniques. Increasing temperatures from 20 to 50 °C resulted in decreases in RH0 from 99 to 98% RH for the monohydrate, 89 to 82% RH for the ß-anhydrate, and 87 to 82% RH for the stable α-anhydrate. The effects of temperature on the anhydrate-hydrate RH boundaries were determined using a combination of controlled aw equilibration, powder X-ray diffraction, and Fourier-transform infrared spectroscopy techniques. Increasing temperature from 20 to 50 °C resulted in increasing RHs of the anhydrate-to-hydrate boundaries: the ß-anhydrate-to-monohydrate boundary increased from 77 to 79% RH, the stable α-anhydrate-to-monohydrate from 63 to 79% RH, and the unstable α-anhydrate-to-monohydrate from 10 to 13% RH. This is the first report of an RH-temperature stability map for lactose crystalline forms.

Crystal structure of strontium perchlorate anhydrate, Sr(ClO4)2, from laboratory powder X-ray diffraction data.

The crystal structure of strontium perchlorate anhydrate, Sr(ClO4)2, was determined and refined from laboratory powder X-ray diffraction data. The material was obtained by dehydration of Sr(ClO4)2·3H2O at 523 K for two weeks. It crystallizes in the ortho-rhom-bic space group Pbca and is isotypic with Ca(AlD4)2 and Ca(ClO4)2. The asymmetric unit contains one Sr, two Cl and eight O sites, all on general positions (Wyckoff position 8c). The crystal structure consists of Sr2+ cations and isolated ClO4 - tetra-hedra. The Sr2+ cation is coordinated by eight O atoms from eight ClO4 - tetra-hedra. The validity of the crystal structure model for Sr(ClO4)2 anhydrate was confirmed by the bond valence method.

RH-Temperature Stability Diagram of the Dihydrate, ß-Anhydrate, and α-Anhydrate Forms of Crystalline Trehalose.

Trehalose crystals exhibit polymorphic, deliquescent, and hydrate-forming traits and can exist in dihydrate, ß-anhydrate, or α-anhydrate (isomorphic desolvate) forms. The objective of this study was to identify the relative humidity (RH) and temperature boundaries for phase changes of these different trehalose crystal forms. The deliquescence points (RH0 s) of the anhydrate and dihydrate trehalose crystals were determined from 20 to 50 °C using a combination of water activity and dynamic vapor sorption measurement techniques. Increasing temperatures from 20 to 50 °C resulted in decreases in RH0 from 95.5% to 90.9% RH for the dihydrate and 69.9% to 62.0% RH for the ß-anhydrate. The effects of temperature on the anhydrate-hydrate RH boundaries were also determined, using a combination of equilibration in controlled water activity solutions, powder X-ray diffraction, and Fourier-transform infrared spectroscopy techniques. Increasing temperatures resulted in increases in the anhydrate-hydrate RH boundaries. The irreversible ß-anhydrate to dihydrate boundary increased from 44.9% to 57.8% RH, and the reversible α-anhydrate to dihydrate boundary increased from 10% to 25% RH, as temperature increased from 20 to 50 °C. This is the first report of an RH-temperautre stability map for crystalline trehalose. PRACTICAL APPLICATION: The manuscript addresses the issue of the physical stability and phase transformations of crystalline trehalose stored in different temperature and relative humidity environments. Unwanted hydrate formation or dehydration of crystal hydrates can lead to other undesirable water-solid interactions and/or physical modifications that have the potential to influence product quality and delivery traits. Therefore, this study identified relative humidity and temperature stability boundaries of the different trehalose crystal forms, using a variety of established and novel techniques to create a relative humidity-temperature stability map of crystalline trehalose from 20 to 50 °C.

Crystal structure of calcium perchlorate anhydrate, Ca(ClO4)2, from laboratory powder X-ray diffraction data.

The crystal structure of calcium perchlorate anhydrate was determined from laboratory X-ray powder diffraction data. The title compound was obtained by heating hydrated calcium perchlorate [Ca(ClO4)2·xH2O] at 623 K in air for 12 h. It crystallizes in the ortho-rhom-bic space group Pbca and is isotypic with Ca(AlD4)2. The asymmetric unit contains one Ca, two Cl and eight O sites, all on general sites (Wyckoff position 8c). The crystal structure consists of isolated ClO4- tetra-hedra and Ca2+ cations. The Ca2+ cation is coordinated by eight O atoms of eight symmetry-related ClO4- tetra-hedra within a distorted square-anti-prismatic environment.

Capturing and concentrating adenovirus using magnetic anionic nanobeads.

We recently demonstrated how various enveloped viruses can be efficiently concentrated using magnetic beads coated with an anionic polymer, poly(methyl vinyl ether-maleic anhydrate). However, the exact mechanism of interaction between the virus particles and anionic beads remains unclear. To further investigate whether these magnetic anionic beads specifically bind to the viral envelope, we examined their potential interaction with a nonenveloped virus (adenovirus). The beads were incubated with either adenovirus-infected cell culture medium or nasal aspirates from adenovirus-infected individuals and then separated from the supernatant by applying a magnetic field. After thoroughly washing the beads, adsorption of adenovirus was confirmed by a variety of techniques, including immunochromatography, polymerase chain reaction, Western blotting, and cell culture infection assays. These detection methods positively identified the hexon and penton capsid proteins of adenovirus along with the viral genome on the magnetic beads. Furthermore, various types of adenovirus including Types 5, 6, 11, 19, and 41 were captured using the magnetic bead procedure. Our bead capture method was also found to increase the sensitivity of viral detection. Adenovirus below the detectable limit for immunochromatography was efficiently concentrated using the magnetic bead procedure, allowing the virus to be successfully detected using this methodology. Moreover, these findings clearly demonstrate that a viral envelope is not required for binding to the anionic magnetic beads. Taken together, our results show that this capture procedure increases the sensitivity of detection of adenovirus and would, therefore, be a valuable tool for analyzing both clinical and experimental samples.

Predictive evaluation of pharmaceutical properties of direct compression tablets containing theophylline anhydrate during storage at high humidity by near-infrared spectroscopy.

BACKGROUND: Theophylline anhydrate (TA) in tablet formulation is transformed into monohydrate (TH) at high humidity and the phase transformation affected dissolution behavior. OBJECTIVE: Near-infrared spectroscopic (NIR) method is applied to predict the change of pharmaceutical properties of TA tablets during storage at high humidity. METHODS: The tablet formulation containing TA, lactose, crystalline cellulose and magnesium stearate was compressed at 4.8 kN. Pharmaceutical properties of TA tables were measured by NIR, X-ray diffraction analysis, dissolution test and tablet hardness. RESULTS: TA tablet was almost 100% transformed into TH after 24 hours at RH 96%. The pharmaceutical properties of TA tablets, such as tablet hardness, 20 min dissolution amount (D20) and increase of tablet weight (TW), changed with the degree of hydration. Calibration models for TW, tablet hardness and D20 to predict the pharmaceutical properties at high-humidity conditions were developed on the basis of the NIR spectra by partial least squares regression analysis. The relationships between predicted and actual measured values for TW, tablet hardness and D20 had straight lines, respectively. CONCLUSIONS: From the results of NIR-chemometrics, it was confirmed that these predicted models had high accuracy to monitor the tablet properties during storage at high humidity.

Crystal structure of barium perchlorate anhydrate, Ba(ClO4)2, from laboratory X-ray powder data.

The previously unknown crystal structure of barium perchlorate anhydrate, determined and refined from laboratory X-ray powder diffraction data, represents a new structure type. The title compound was obtained by heating hydrated barium perchlorate [Ba(ClO4)2·xH2O] at 423 K in vacuo for 6 h. It crystallizes in the ortho-rhom-bic space group Fddd. The asymmetric unit contains one Ba (site symmetry 222 on special position 8a), one Cl (site symmetry 2 on special position 16f) and two O sites (on general positions 32h). The structure can be described as a three-dimensional polyhedral network resulting from the corner- and edge-sharing of BaO12 polyhedra and ClO4 tetra-hedra. Each BaO12 polyhedron shares corners with eight ClO4 tetra-hedra, and edges with two ClO4 tetra-hedra. Each ClO4 tetra-hedron shares corners with four BaO12 polyhedra, and an edge with the other BaO12 polyhedron.

Composite scaffolds of dicalcium phosphate anhydrate /multi-(amino acid) copolymer: in vitro degradability and osteoblast biocompatibility.

This study aims to evaluate in vitro degradability and osteoblast biocompatibility of dicalcium phosphate anhydrate/multi-(amino acid) (DCPA/MAA) composites prepared by in situ polymerization method. The results revealed that the composites could be slowly degraded in PBS solution, with weight loss of 9.5 ± 0.2 wt.% compared with 12.2 ± 0.2 wt.% of MAA copolymer after eight weeks, and the changes of pH value were in the range of 7.18-7.4 and stabilized at 7.24. In addition, the compressive strength of the composite decreased from 98 to 62 MPa while that of MAA copolymer from 117 to 86 MPa. Furthermore, with non-toxicity demonstrated by 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl-tetrazolium bromide assay, the addition of DCPA to the MAA copolymer evidenced an enhancement of osteoblast differentiation and attachment compared with pure MAA materials regarding to alkaline phosphatase activity as well as initial cell adhesion. The results indicated that the DCPA/MAA scaffolds with good osteoblast biocompatibility, degradability, and sufficient strength had promising potential application in bone tissue engineering.

Physicochemical and crystal structure analysis of pranlukast pseudo-polymorphs I: anhydrates and hydrate.

Pranlukast (PRS) is a leukotriene receptor antagonist for the treatment of bronchial asthma. Pranlukast is formulated as a hemihydrate (HH) form in the drug product. Here, we report three new anhydrate forms of PRS (AH, form I-III). These polymorphs and PRS HH were characterized by PXRD, TG-DTA, simultaneous PXRD-DSC and vapor sorption analysis. In addition, the crystal structures of HH and AH-I were determined by single crystal X-ray structure analysis for the first time. HH transformed to AH-I, AH-II and AH-III as the temperature was increased from 25°C to 210°C. At 25°C, AH-I transformed to HH at above 5%RH. HH and AH-I possessed similar crystal packing patterns and molecular structures.

Nitrofurantoin enteric pellets with high bioavailability based on aciform crystalline formation by wet milling.

The aim of the present study was to grind nitrofurantoin (NF) with HPMC solution and to determine the dissolution and bioavailability of the enteric pellets prepared with the NF cogrounds and other excipients. During milling, crystalline transformation occurred--the aciform microcrystalline monohydrate II replaced the coarse crystal anhydrate ß and the particle size markedly reduced. In vitro test demonstrated that the enteric pellets prepared with NF cogrounds (4 h) revealed a faster dissolution than the commercial tablet and 50% was released within 30 min in the basic medium. Finally, an in vivo test was conducted in beagle dogs. The Cmax and AUC(0 → 24) of the pellets were 2.19 ± 0.74 µg/ml and 6.73 ± 4.71 µg/ml h, respectively, while the corresponding values were 0.49 ± 0.42 µg/ml and 1.38 ± 1.17 µg/ml h for the tablet. Thus, the bioavailability of the pellets was increased significantly. In conclusion, the wet grinding that reduced the particle size and created the microcrystalline played a major role in the acceleration of the dissolution of NF and, consequently, enhanced the bioavailability, and the wet grinding process offers an alternative approach to improve the dissolution and bioavailability of drugs with poor aqueous solubility.