Mechanochemical Synthesis of Multicomponent Crystals: One Liquid for One Polymorph? A Myth to Dispel

Identifying as many polymorphs as possible for a molecular compound is important in the design of materials with desired properties. In this paper we demonstrate, using a simple experimental procedure, how the amount of liquid present during liquid-assisted mechanochemical reactions can be used to rapidly explore polymorph diversity. Through detailed experimental evidence it is concluded that for the specific (multicomponent) crystal system investigated (caffeine−anthranilic acid) the commonly accepted rule “one liquid for one specific polymorph” is not correct. Additionally we demonstrate that through modification of the amount of added liquid it is possible to form a polymorph previously obtained only by a desolvation reaction. We believe that while the results raise many mechanistic questions the approach is advantageous as a means of rapidly screening for polymorph diversity as well as being a simple screening methodology. While we focus here on a cocrystal system, we believe a similar approach will be advantageous for single component systems.This is the final version of the article. It first appeared from the American Chemical Society via http://dx.doi.org/10.1021/acs.cgd.6b0068

Dissolution of an ensemble of differently shaped poly-dispersed drug particles undergoing solubility reduction: mathematical modelling

The aim of this theoretical paper is to develop a mathematical model for describing the dissolution process, in a finite liquid environment, of an ensemble of poly-dispersed drug particles, in form of sphere, cylinder and parallelepiped that can undergo solubility reduction due to phase transition induced by dissolution. The main result of this work consists in its simplicity as, whatever the particular particles size distribution, only two ordinary differential equations are needed to describe the dissolution process. This, in turn, reflects in a very powerful and agile theoretical tool that can be easily implemented in electronic sheets, a widespread tool among the research community. Another model advantage lies on the possibility of determining its parameters by means of common independent techniques thus enabling the evaluation of the importance of solid wettability on the dissolution process.</p

Modulating Thermal Properties of Polymers through Crystal Engineering

Crystal engineering has exclusively focused on the development of advanced materials based on small organic molecules. We now demonstrate how the cocrystallization of a polymer yields a material with significantly enhanced thermal stability but equivalent mechanical flexibility. Isomorphous replacement of one of the cocrystal components enables the formation of solid solutions with melting points that can be readily fine-tuned over a usefully wide temperature range. The results of this study credibly extend the scope of crystal engineering and cocrystallization from small molecules to polymers

Mechanochemical Formation of Racemic Praziquantel Hemihydrate with Improved Biopharmaceutical Properties.

Praziquantel (PZQ) is the first-line drug used against schistosomiasis, one of the most common parasitic diseases in the world. A series of crystalline structures including two new polymorphs of the pure drug and a series of cocrystals of PZQ have been discovered and deposited in the Cambridge Structural Database (CSD). This work adds to the list of multicomponent forms of PZQ a relevant example of a racemic hemihydrate (PZQ-HH), obtainable from commercial PZQ (polymorphic Form A) through mechanochemistry. Noteworthy, the formation of the new hemihydrate strongly depends on the initial polymorphic form of PZQ and on the experimental conditions used. The new PZQ-HH has been fully characterized by means of HPLC, Differential Scanning Calorimetry (DSC), Thermogravimetric Analysis (TGA), Hot-Stage Microscopy (SEM), Powder X-Ray Diffraction (PXRD), Scanning Electron Microscopy (SEM), FT-IR, polarimetry, solid-state NMR (SS-NMR), solubility and intrinsic dissolution rate (IDR), and in vitro tests on Schistosoma mansoni adults. The crystal structure was solved from the powder X-ray diffraction pattern and validated by periodic-DFT calculations. The new bioactive hemihydrate was physically stable for three months and showed peculiar biopharmaceutical features including enhanced solubility and a double intrinsic dissolution rate in water in comparison to the commercially available PZQ Form A

Mechanochemical Synthesis and Physicochemical Characterization of Previously Unreported Praziquantel Solvates with 2-Pyrrolidone and Acetic Acid.

Two new solvates of the widely used anthelminthic Praziquantel (PZQ) were obtained through mechanochemical screening with different liquid additives. Specifically, 2-pyrrolidone and acetic acid gave solvates with 1:1 stoichiometry (PZQ-AA and PZQ-2P, respectively). A wide-ranging characterization of the new solid forms was carried out by means of powder X-ray diffraction, differential scanning calorimetry, FT-IR, solid-state NMR and biopharmaceutical analyses (solubility and intrinsic dissolution studies). Besides, the crystal structures of the two new solvates were solved from their Synchrotron-PXRD pattern: the solvates are isostructural, with equivalent triclinic packing. In both structures acetic acid and 2-pyrrolidone showed a strong interaction with the PZQ molecule via hydrogen bond. Even though previous studies have shown that PZQ is conformationally flexible, the same syn conformation as the PZQ Form A of the C=O groups of the piperazinone-cyclohexylcarbonyl segment is involved in these two new solid forms. In terms of biopharmaceutical properties, PZQ-AA and PZQ-2P exhibited water solubility and intrinsic dissolution rate much greater than those of anhydrous Form A

New resveratrol analogues for potential use in diabetes and cancer.

open access journalResveratrol is a well notorious compound that may play a role in the prevention of diabetes complications and different cancers. Along, resveratrol, a naturally occurring phytoalexin, is known to exert numerous beneficial effects in the organism. Isolation of resveratrol from plants, however, has been proved being difficult. Importantly, the bioavailability in the body is poor therefore capability is reduced and not enough resveratrol reaches the target organ. In this study we generated different methoxylated resveratrol analogues using Wittig reaction. Trans stilbene obtained was 0.08 g and the cis one was 0.01 g. Additionally with the Horner-Witting method a yield of 0.15 g trans stilbene was obtained. By substituting the hydroxyl group with methoxy group at different positions on the aromatic rings, we could increase the efficacy and bioavailability of the Trans form of resveratrol

3D human foreskin model for testing topical formulations of sildenafil citrate

: Sildenafil citrate is an approved drug used for the treatment of erectile dysfunction and premature ejaculation. Despite a widespread application, sildenafil citrate shows numerous adverse cardiovascular effects in high-risk patients. Local transdermal drug delivery of this drug is therefore being explored as an interesting and noninvasive alternative administration method that avoids adverse effects arised from peak plasma drug concentrations. Although human and animal skin represents the most reliable models to perform penetration studies, they involve a series of ethical issues and restrictions. For these reasons new in vitro approaches based on artificially reconstructed human skin or "human skin equivalents" are being developed as possible alternatives for transdermal testing. There is little information, however, on the efficiency of such new in vitro methods on cutaneous penetration of active ingredients. The objective of the current study was to investigate the sildenafil citrate loaded in three commercial transdermal vehicles using 3D full-thickness skin equivalent and compare the results with the permeability experiments using porcine skin. Our results demonstrated that, while the formulation plays an imperative role in an appropriate dermal uptake of sildenafil citrate, the D coefficient results obtained by using the 3D skin equivalent are comparable to those obtained by using the porcine skin when a simple drug suspension is applied (1.17&nbsp;×&nbsp;10-10&nbsp;±&nbsp;0.92&nbsp;×&nbsp;10-10 cm2/s vs 3.5&nbsp;×&nbsp;102&nbsp;±&nbsp;3.3&nbsp;×&nbsp;102 cm2/s), suggesting that in such case, this 3D skin model can be a valid alternative for ex-vivo skin absorption experiments

Enhanced Oral Bioavailability of Vinpocetine Through Mechanochemical Salt Formation: Physico-Chemical Characterization and In Vivo Studies

The file attached to this record is the author's final peer reviewed version. The Publisher's final version can be found by following the DOI link.Purpose Enhancing oral bioavailability of vinpocetine by forming its amorphous citrate salt through a solvent-free mechanochemical process, in presence of micronised crospovidone and citric acid. Methods The impact of formulation and process variables (amount of polymer and citric acid, and milling time) on vinpocetine solubilization kinetics from the coground was studied through an experimental design. The best performing samples were characterized by employing a multidisciplinary approach, involving Differential scanning calorimetry, X-ray diffraction, Raman imaging/spectroscopy, X-ray photoelectron spectroscopy, solid-state NMR spectroscopy, porosimetry and in vivo studies on rats to ascertain the salt formation, their solidstate characteristics and oral bioavailability in comparison to vinpocetine citrate salt (Oxopocetine®). Results The analyses attested that the mechanochemical process is a viable way to produce in absence of solvents vinpocetine citrate salt in an amorphous state. Conclusion From the in vivo studies on rats the obtained salt was four times more bioavailable than its physical mixture and bioequivalent to the commercial salt produced by conventional synthetic process implying the use of solvent

Melt extruded helical waxy matrices as a new sustained drug delivery system

The file attached to this record is the author's final peer reviewed version. The Publisher's final version can be found by following the DOI link.The aim of this research was to prepare helical and cylindrical extrudates by melt extrusion and to evaluate their potential as sustained release dosage form. The systems contained theophylline as water-soluble model drug and microcrystalline wax as thermoplastic binder. The temperature suitable to ensure a successful extrusion process of formulations containing the wax in three different percentages was found to be below the melting point of the excipient. After the production of the extrudates in three different helical shapes (having 2, 3 and 4 blades) and a classical cylindrical shape, the systems were studied by means of X-ray powder diffraction and differential scanning calorimetry to check possible variations of the solid state of the drug during the thermal process. The morphology and chemical composition of the surface of the extrudates were examined by Scanning Electron Microscopy/Energy Dispersive X-ray Microanalysis to evaluate the presence of the drug on the surface of the extrudates and to monitor changes on the aspect of the waxy matrix during dissolution. Then, the different systems were analysed from the in vitro dissolution point of view to study the influence of the shape and of the composition on the drug release. An in vivo pilot study on the best performing system (helix with 3 blades) was carried out on five healthy volunteers and monitoring the intestinal transit by X-ray images. The resulting plasma profiles were analysed by means of a suitable pharmacokinetic analysis. Finally, an ad hoc mathematical model was developed to perform an accurate description of the in vitro release and in vivo performance of the 3-blades helical system