Preparation and formulation of progesterone para-aminobenzoic acid co-crystals with improved dissolution and stability.

The crystal structure of a new Progesterone (PROG) co-crystal with para-aminobenzoic acid (PABA) showing enhanced solution properties is reported. PROG-PABA co-crystal was first identified though an in silico coformer screening process using the CSD Co-crystal deign function, then confirmed through a solution evaporation crystallisation experiment. The resulting co-crystal was characterized using single crystal X-ray diffraction, differential scanning calorimetry and Fourier-transform infrared spectroscopy. Liquid assisted grinding was selected as a suitable scale up method compared to spray drying and antisolvent methods due to minimal starting material phases in the final product. Following scale up, aqueous solubility, stability and dissolution measurements were carried out. PROG-PABA showed increased distinct aqueous solubility and dissolution compared to PROG starting material and was shown to be stable at 75 % relative humidity for 3 months. Tablets containing co-crystal were produced then compared to the Utrogestan® soft gel capsule formulation through a dissolution experiment. PROG-PABA tablets showed a substantial increase in dissolution over the course of the experiment with over 30× the amount of PROG dissolved at the 3-hour time point. This co-crystal shows positive implications for developing an improved oral PROG formulation.

Spray dried progesterone formulations for carrier free dry powder inhalation.

Low oral absorption and extensive first pass metabolism of progesterone is reported for many oral formulations which warrants investigation into other routes of administration. It is the aim of this study to investigate the generation of inhaled formulations of progesterone though a spray drying approach with a focus on how spray drying impacts the physicochemical properties of progesterone. Formulations of progesterone with L-leucine and hydroxypropyl methylcellulose acetate succinate (HPMCAS) are reported to this aim. X-ray diffraction, spectroscopy and thermal analysis were used to characterise these formulations and confirmed that progesterone crystallises as the Form II polymorph during spray drying regardless of the solvent used. The resultant formulations showed higher aqueous solubility than progesterone Form I starting material and the addition of HPMCAS was shown to temporarily enable a supersaturated state. Thermal analysis was used to show that the Form II polymorph was sensitive to transformation to Form I during heating. The addition of L-leucine to the formulations reduced the temperature for the polymorphic transformation by âˆ¼ 10 °C. However, when HPMCAS was added to the formulation, the Form II polymorph was prevented from transforming to the Form I polymorph. Cascade impaction was used to determine the aerosol performance of the spray dried powders and showed promising lung deposition profiles (mass median aerodynamic diameter 5 µm) with significant variation depending on the organic solvent used and the ratio of organic to aqueous phase in the feedstock. However, further optimisation of formulations was required to direct more progesterone into the alveolar regions. The addition of HPMCAS was seen to increase the alveolar deposition and therefore formed a formulation with a lower fine particle fraction and mass median aerodynamic diameter. The most suitable formulation for inhalation was formed from a 50:50 acetone:water mixture and showed an ED, FPF and FPD of 81.7%, 44.5% and 7.3 mg respectively. Therefore, HPMCAS is suggested as a suitable excipient to increase solubility, prevent polymorphic transformation and improve inhalation properties of spray dried progesterone formulations. This study highlights the use of spray drying to form inhalable progesterone powders with higher solubility which may broaden the application of this medicine.

Crystal Structure and NMR of an α,δ-Peptide Foldamer Helix Shows Side-Chains are Well Placed for Bifunctional Catalysis: Application as a Minimalist Aldolase Mimic.

We report the first NMR and X-ray diffraction (XRD) structures of an unusual 13/11-helix (alternating i, i+1 {NH-O=C} and i, i+3 {C=O-H-N} H-bonds) formed by a heteromeric 1 : 1 sequence of α- and δ-amino acids, and demonstrate the application of this framework towards catalysis. Whilst intramolecular hydrogen bonds (IMHBs) are the clear driver of helix formation in this system, we also observe an apolar interaction between the ethyl residue of one δ-amino acid and the cyclohexyl group of the next δ-residue in the sequence that seems to stabilize one type of helix over another. To the best of our knowledge this type of additional stabilization leading to a specific helical preference has not been observed before. Critically, the helix type realized places the α-residue functionalities in positions proximal enough to engage in bifunctional catalysis as demonstrated in the application of our system as a minimalist aldolase mimic.

Preparation and Physiochemical Analysis of Novel Ciprofloxacin / Dicarboxylic Acid Salts.

The crystal structures of four novel dicarboxylic acid salts of ciprofloxacin (CFX) with modified physicochemical properties, prepared by mechanochemical synthesis and solvent crystallization, are reported. A series of dicarboxylic acids of increasing molecular weight was chosen, predicted to interact via a carboxylic acid:secondary amine synthon. These were succinic (SA), glutaric (GA), adipic (AA) and pimelic (PA) acids (4, 5, 6, 7 carbon atoms respectively). Characterized by single crystal and powder X-ray diffraction, Fourier-Transform Infrared Spectroscopy, thermogravimetric analysis, differential scanning calorimetry, scanning electron microscopy and aqueous solubility measurements, these salts showed distinct physicochemical properties relative to ciprofloxacin base. Searches of the Cambridge Structural Database (CSD) confirmed CFX-SA, CFX-GA, CFX-AA and CFX-PA to be novel crystal structures. Furthermore, the GA salt has substantially higher solubility than the widely available hydrochloride monohydrate salt (CFX-HCl·H2O). CFX-SA, CFX-GA and CFX-AA showed minimum inhibitory concentration (MIC) of 0.008 g/L and CFX-PA showed MIC of 0.004 g/L. The prepared CFX salts retained antibacterial activity exhibiting equivalent antimicrobial activity to CFX-HCl·H2O. These salts have positive implications for increasing the application of CFX beyond conventional oral formulations and highlight mechanochemical activation as suitable production method.

Crystal Structure and NMR of an α,δ-Peptide Foldamer Helix Shows Side-Chains are Well Placed for Bifunctional Catalysis: Application as a Minimalist Aldolase Mimic.

We report the first NMR and X-ray diffraction (XRD) structures of an unusual 13/11-helix (alternating i, i+1 {NH-O=C} and i, i+3 {C=O-H-N} H-bonds) formed by a heteromeric 1 : 1 sequence of α- and δ-amino acids, and demonstrate the application of this framework towards catalysis. Whilst intramolecular hydrogen bonds (IMHBs) are the clear driver of helix formation in this system, we also observe an apolar interaction between the ethyl residue of one δ-amino acid and the cyclohexyl group of the next δ-residue in the sequence that seems to stabilize one type of helix over another. To the best of our knowledge this type of additional stabilization leading to a specific helical preference has not been observed before. Critically, the helix type realized places the α-residue functionalities in positions proximal enough to engage in bifunctional catalysis as demonstrated in the application of our system as a minimalist aldolase mimic.

Regio- and Stereoselectivity of the Norrish-Yang Photocyclization of Dialkyl 1,2-Diketones: Solution versus Solid State Photochemistry of Two Polymorphs.

As shown by X-ray crystallography, crystals of 3ß-acetoxy-16,17-seco-17,20-dioxopregn-5-ene-16-nitrile are dimorphic. The regioselectivity of the Norrish-Yang type II photocyclization under visible light of this steroidal 1,2-diketone, which bears primary, secondary, and tertiary nonequivalent abstractable γ-hydrogens, dramatically increases in the crystalline state of both polymorphs. X-ray crystallography and molecular mechanics calculations reveal crystal structure-solid state photochemistry relationships.

Enantioselective Organocatalytic Synthesis of Bicyclic Resorcinols via an Intramolecular Friedel-Crafts-Type 1,4-Addition: Access to Cannabidiol Analogues.

The organocatalytic transformation of resorcinols is extremely rare. In this article, we report a highly enantioselective, organocatalytic intramolecular cyclization of these systems by a Friedel-Crafts-type 1,4-addition using a Jørgensen-Hayashi-like organocatalyst with a large silyl protecting group, and show that heat improves reaction yield with virtually no detriment to enantioselectivity. A variety of bicyclic resorcinols were obtained with excellent enantioselectivities (up to 94%). To show the utility of these constructs, and as part of a wider project involving the synthesis of cannabinoid-like compounds, the resorcinol formed was used to generate both 'normal' and 'abnormal' cannabidiol (CBD) derivatives which were shown to have anticonvulsant activity.

Insights into the Mechanochemical Synthesis of MOF-74.

Mechanochemical synthesis has recently emerged as a scalable "green" approach for the preparation of MOFs, but current understanding of the underlying reaction mechanisms is limited. In this work, an investigation of the reaction pathway of the mechanochemical synthesis of MOF-74 from ZnO and 2,5-dihydroxyterephthalic acid (H4HDTA), using DMF as a liquid additive, is presented. The complex reaction pathway involves the formation of four short-lived intermediate phases, prior to the crystallization of MOF-74. The crystal structures of three of these intermediates have been determined using a combination of single-crystal and powder X-ray diffraction methods and are described here. The initial stages of the reaction are very fast, with a DMF solvate of H4HDTA forming after only 2 min of milling. This is followed by crystallization, after only 4 min of milling, of a triclinic one-dimensional coordination polymer, Zn(H2DHTA)(DMF)2(H2O)2, which converts into a monoclinic polymorph on additional milling. Highly crystalline MOF-74 appears after prolonged milling, for at least 70 min.

Structure and spectroscopy of methionyl-methionine for aquaculture.

The amino acid L-methionine is an essential amino acid and is commonly used as a feed supplement in terrestrial animals. It is less suitable for marine organisms because it is readily excreted. It is also highly water soluble and this results in loss of the feed and eutrophication of the water. To address these problems, the dipeptide DL-methionyl-DL-methionine (trade name: AQUAVI Met-Met) has been developed as a dedicated methionine source for aquaculture. The commercial product is a mixture of a racemic crystal form of D-methionyl-D-methionine/L-methionyl-L-methionine and a racemic crystal form of D-methionyl-L-methionine/L-methionyl-D-methionine. In this work, we have computationally, structurally, spectroscopically and by electron microscopy characterised these materials. The microscopy and spectroscopy demonstrate that there is no interaction between the DD-LL and DL-LD racemates on any length scale from the macroscopic to the nanoscale.

Highly Enantioselective, Organocatalytic, and Scalable Synthesis of a Rare cis,cis-Tricyclic Diterpenoid.

A highly enantioselective, organocatalytic, and scalable synthesis of a very unusual cis-decalin-cis-hydrindane tricyclic diterpenoid system has been achieved. Despite the prevalent pharmacological space that the related trans,trans and trans,cis-systems occupy, there have been no reports of an asymmetric synthesis of the cis,cis systems in the literature until now. We demonstrate the flexibility of our approach not only through access to a diverse range of products, all of which are attained in exceptionally high selectivities, but also by showing their easy conversion to the corresponding trans,cis-system and other derivatives.

Organocatalytic Access to a cis-Cyclopentyl-γ-amino Acid: An Intriguing Model of Selectivity and Formation of a Stable 10/12-Helix from the Corresponding γ/α-Peptide.

In this study, we have developed a highly enantioselective organocatalytic route to the (1S,2R)-2-(aminomethyl)cyclopentane-1-carboxylic acid monomer precursor, which has a cis-configuration between the C- and N-termini around the cyclopentane core. Kinetic measurements show that the product distribution changes over time due to epimerization of the C1 center. Computations suggest the cis-selectivity is a result of selective C-C bond formation, while subsequent steps appear to influence the selectivity at higher temperature. The resulting γ-amino acid residue was incorporated into a novel γ/α-peptide, which forms a well-ordered 10/12-helix with alternate H-bond directionality in spite of the smallest value of the ζ-angle yet observed for a helix of this type. This highly defined structure is also a result of the narrow range of potential ζ-angles in our monomer. In contrast, the larger range of potential ζ-values observed for the corresponding trans-system can be fulfilled by several competing helical structures.

Chasing the "Killer" Phonon Mode for the Rational Design of Low-Disorder, High-Mobility Molecular Semiconductors.

Molecular vibrations play a critical role in the charge transport properties of weakly van der Waals bonded organic semiconductors. To understand which specific phonon modes contribute most strongly to the electron-phonon coupling and ensuing thermal energetic disorder in some of the most widely studied high-mobility molecular semiconductors, state-of-the-art quantum mechanical simulations of the vibrational modes and the ensuing electron-phonon coupling constants are combined with experimental measurements of the low-frequency vibrations using inelastic neutron scattering and terahertz time-domain spectroscopy. In this way, the long-axis sliding motion is identified as a "killer" phonon mode, which in some molecules contributes more than 80% to the total thermal disorder. Based on this insight, a way to rationalize mobility trends between different materials and derive important molecular design guidelines for new high-mobility molecular semiconductors is suggested.

A new crystalline form of αß-D-lactose prepared by oven drying a concentrated aqueous solution of D-lactose.

A new crystalline form of αß-D-lactose (C12H22O11) has been prepared by the rapid drying of an approximately 40% w/v syrup of D-lactose. Initially identified from its novel powder X-ray diffraction pattern, the monoclinic crystal structure was solved from a microcrystal recovered from the generally polycrystalline mixed-phase residue obtained at the end of the drying step. This is the second crystalline form of αß-D-lactose to be identified and it has a high degree of structural three-dimensional similarity to the previously identified triclinic form.

High potency of lipid conjugated TLR7 agonist requires nanoparticulate or liposomal formulation.

Conjugation of small molecule agonists of Toll-like receptor 7 (TLR7) to proteins, lipids, or polymers is known to modulate potency, and the physical form or formulation of these conjugates is likely to have a major effect on their immunostimulatory activity. Here, we studied the effect of formulation on potency of a 1,2­di­(9Z­octadecenoyl)­sn­glycero­3­phosphoethanolamine (DOPE) conjugated TLR7 agonist (DOPE-TLR7a) alongside assessing physical form using Dynamic Light Scattering (DLS), Nanosight Particle Tracking (NTA) analysis and Small Angle X-ray Scattering (SAXS). A very high potency of DOPE-TLR7a conjugate (EC50 around 9 nM) was observed either when prepared by direct dilution from DMSO or when formulated into 400-700 nm large multilamella liposomes containing dimethyldioctadecylammonium bromide salt (DDA) and DOPE. When prepared by dissolution in DMSO followed by dilution in aqueous culture medium, 93 ±â€¯5 nm nanoparticles were formed. Without dilution from solution in DMSO, no nanoparticles were observed and no immunostimulatory activity could be detected without this formulation step. SAXS analysis of the conjugate after DMSO dissolution/water dilution revealed a lamellar order with a layer spacing of 68.7 Å, which correlates with arrangement in groups of 3 bilayers. The addition of another immunostimulatory glycolipid, trehalose­6,6­dibehenate (TDB), to DOPE:DDA liposomes gave no further increase in immunostimulatory activity beyond that provided by incorporating DOPE-TLR7a. Given the importance of nanoparticle or liposomal formulation for activity, we conclude that the major mechanism for increased potency when TLR7 agonists are conjugated to macromolecules is through alteration of physical form.

Pushing the Limits of Molecular Crystal Structure Determination From Powder Diffraction Data in High-Throughput Chemical Environments.

Crystal structure determination from powder diffraction data (SDPD) using the DASH software package is evaluated for data recorded using transmission capillary, transmission flat plate, and reflection flat plate geometries on a selection of pharmaceutical compounds. We show that transmission capillary geometry remains the best option when crystal structure determination is the primary consideration and, as expected, reflection flat plate geometry is not recommended for SDPD because of preferred orientation effects. However, the quality of crystal structures obtained from transmission plate instruments can be excellent, and the convenience factor for sample preparation, throughput, and retrieval is higher than that of transmission capillary instruments. Indeed, it is possible to solve crystal structures within an hour of a polycrystalline sample arriving in the laboratory, which has clear implications for making small-molecule crystal structures more routinely available to the practicing laboratory medicinal chemist. With appropriate modifications to crystal structure determination software, it can be imagined that SDPD could become a rapid turn-around walk-up analytical service in high-throughput chemical environments.

Elucidating an Amorphous Form Stabilization Mechanism for Tenapanor Hydrochloride: Crystal Structure Analysis Using X-ray Diffraction, NMR Crystallography, and Molecular Modeling.

By the combined use of powder and single-crystal X-ray diffraction, solid-state NMR, and molecular modeling, the crystal structures of two systems containing the unusually large tenapanor drug molecule have been determined: the free form, ANHY, and a dihydrochloride salt form, 2HCl. Dynamic nuclear polarization (DNP) assisted solid-state NMR (SSNMR) crystallography investigations were found essential for the final assignment and were used to validate the crystal structure of ANHY. From a structural informatics analysis of ANHY and 2HCl, conformational ring differences in one part of the molecule were observed which influence the relative orientation of a methyl group on a ring nitrogen and thereby impact the crystallizability of the dihydrochloride salt. From quantum chemistry calculations, the dynamics between different ring conformations in tenapanor is predicted to be fast. Addition of HCl to tenapanor results in general in a mixture of protonated ring conformers and hence a statistical mix of diastereoisomers which builds up the amorphous form, a-2HCl. This was qualitatively verified by 13C CP/MAS NMR investigations of the amorphous form. Thus, to form any significant amount of the crystalline material 2HCl, which originates from the minor (i.e., energetically less stable) ring conformations, one needs to involve nitrogen deprotonation to allow exchange between the minor and major conformations of ANHY in solution. Thus, by controlling the solution pH value to well below the p Ka of ANHY, the equilibrium between ANHY and 2HCl can be controlled and by this mechanism the crystallization of 2HCl can be avoided and the amorphous form of the dichloride salt can therefore be stabilized.

Development of a Zeolite Filter for Removing Polycyclic Aromatic Hydrocarbons (PAHs) from Smoke and Smoked Ingredients while Retaining the Smoky Flavor.

The popularity of smoked foodstuffs such as sauces, marinades, and rubs is on the rise. However, during the traditional smoking process, in addition to the desirable smoky aroma compounds, harmful polycyclic aromatic hydrocarbons (PAHs) are also generated. In this work, a selective filter was developed that reduces PAH concentrations in a smoke by up to 90% while maintaining a desirable smoky flavor. Preliminary studies using a cocktail of 12 PAHs stirred with a zeolite showed the potential for this zeolite to selectively remove PAHs from a simple solution. However, pretreatment of the smoke prior to application removed the PAHs more efficiently and is more widely applicable to a range of food ingredients. Although volatile analysis showed that there was a concomitant reduction in the concentration of the smoky compounds such as 2-methoxyphenol (guaiacol), 2-methylphenol ( o-cresol), and the isoeugenols, sensory profiling showed that the difference in perception of flavor was minimal.

Ruthenium-conjugated chrysin analogues modulate platelet activity, thrombus formation and haemostasis with enhanced efficacy.

The constant increase in cardiovascular disease rate coupled with significant drawbacks of existing therapies emphasise the necessity to improve therapeutic strategies. Natural flavonoids exert innumerable pharmacological effects in humans. Here, we demonstrate the effects of chrysin, a natural flavonoid found largely in honey and passionflower on the modulation of platelet function, haemostasis and thrombosis. Chrysin displayed significant inhibitory effects on isolated platelets, however, its activity was substantially reduced under physiological conditions. In order to increase the efficacy of chrysin, a sulfur derivative (thio-chrysin), and ruthenium-complexes (Ru-chrysin and Ru-thio-chrysin) were synthesised and their effects on the modulation of platelet function were evaluated. Indeed, Ru-thio-chrysin displayed a 4-fold greater inhibition of platelet function and thrombus formation in vitro than chrysin under physiologically relevant conditions such as in platelet-rich plasma and whole blood. Notably, Ru-thio-chrysin exhibited similar efficacy to chrysin in the modulation of haemostasis in mice. Increased bioavailability and cell permeability of Ru-thio-chrysin compared to chrysin were found to be the basis for its enhanced activity. Together, these results demonstrate that Ru-thio-coupled natural compounds such as chrysin may serve as promising templates for the development of novel anti-thrombotic agents.

Asymmetric cyclopropanation of conjugated cyanosulfones using a novel cupreine organocatalyst: rapid access to δ(3)-amino acids.

An organocatalytic asymmetric synthesis of a novel, highly functionalised cyclopropane system furnished with versatile substituents and containing a quaternary centre is described. The process utilises a new bifunctional catalyst based on the cinchona alkaloid framework and the products made using this catalyst were obtained as single diastereoisomers, with very high enantioselectivities (up to 96% ee). We have also demonstrated that these resulting cyclopropanes are very useful synthetic intermediates to interesting products, such as the difficult to access δ(3)-amino acids.

Detection of nitroaromatic vapours with diketopyrrolopyrrole thin films: exploring the role of structural order and morphology on thin film properties and fluorescence quenching efficiency.

Sensitive optical detection of nitroaromatic vapours with diketopyrrolopyrrole thin films is reported for the first time and the impact of thin film crystal structure and morphology on fluorescence quenching behaviour demonstrated.