Co-Crystalline Solid Solution Affords a High-Soluble and Fast-Absorbing Form of Praziquantel.

Praziquantel (PZQ) is a chiral class-II drug, and it is used as a racemate for the treatment of schistosomiasis. The knowledge of several cocrystals with dicarboxylic acids has prompted the realization of solid solutions of PZQ with both enantiomers of malic acid and tartaric acid. Here, the solid form landscape of such a six-component system has been investigated. In the process, two new cocrystals were structural-characterized and three non-stoichiometric, mixed crystal forms identified and isolated. Thermal and solubility analysis indicates a fourfold solubility advantage for the newly prepared solid solutions over the pure drug. In addition, a pharmacokinetic study was conducted in rats, which involved innovative mini-capsules for the oral administration of the solid samples. The available data indicate that the faster dissolution rate of the solid solutions translates in faster absorption of the drug and helps maintain a constant steady-state concentration.

Combining Mechanochemistry and Spray Congealing for New Praziquantel Pediatric Formulations in Schistosomiasis Treatment.

Praziquantel (PZQ) is the first line drug for the treatment of schistosome infections and is included in the WHO Model List of Essential Medicines for Children. In this study, the association of mechanochemical activation (MA) and the spray congealing (SC) technology was evaluated for developing a child-friendly PZQ dosage form, with better product handling and biopharmaceutical properties, compared to MA materials. A 1:1 by wt PZQ-Povidone coground-was prepared in a vibrational mill under cryogenic conditions, for favoring amorphization. PZQ was neat ground to obtain its polymorphic form (Form B), which has an improved solubility and bioactivity. Then, activated PZQ powders were loaded into microparticles (MPs) by the SC technology, using the self-emulsifying agent Gelucire® 50/13 as a carrier. Both, the activated powders and the corresponding loaded MPs were characterized for morphology, wettability, solubility, dissolution behavior, drug content, and drug solid state (Hot Stage Microscopy (HSM), Differential Scanning Calorimetry (DSC), X-Ray Powder Diffraction Studies (PXRD), and FT-IR). Samples were also in vitro tested for a comparison with PZQ against Schistosoma mansoni newly transformed schistosomula (NTS) and adults. MPs containing both MA systems showed a further increase of biopharmaceutical properties, compared to the milled powders, while maintaining PZQ bioactivity. MPs containing PZQ Form B represented the most promising product for designing a new PZQ formulation.

Natural Deep Eutectic Solvents (NADES) to Enhance Berberine Absorption: An In Vivo Pharmacokinetic Study.

In the present study results related to the in vivo administration of Natural Deep Eutectic Solvents (NADES)-solubilized berberine are reported for the first time. NADES are mixtures of small natural compounds having a melting point significantly lower than that of any individual component. Such solvents have gained much attention of the scientific community in the green chemistry area, being considered useful alternatives to common organic solvents. NADES can be used also as administration vehicles, and this can be attractive for nutraceutical products when eutectics are formed with food grade ingredients. In this work, different NADES were prepared using mainly food grade constituents and were tested as solvents for the alkaloid berberine. Three selected NADES/berberine solutions and an aqueous suspension were orally administered to mice with in dose of 50 mg/Kg. Blood levels of berberine were measured by a LC-MS/MS method. The pharmacokinetic analysis revealed a 2-20 fold increase in blood concentration of NADES/berberine with significant changes in pharmacokinetic profile. Natural Deep Eutectic Solvents may thus be considered attractive solubilizing agents and may also play a role in the increase of absorption of poorly bioavailable natural products such as berberine.

Nanostructured Drugs Embedded into a Polymeric Matrix: Vinpocetine/PVP Hybrids Investigated by Debye Function Analysis.

Microcrystalline vinpocetine, coground with cross-linked polyvinylpyrrolidone, affords hybrids containing nanosized drug nanocrystals, the size and size distributions of which depend on milling times and drug-to-polymer weight ratios. Using an innovative approach to microstructural characterization, we analyzed wide-angle X-ray total scattering data by the Debye function analysis and demonstrated the possibility to characterize pharmaceutical solid dispersions obtaining a reliable quantitative view of the physicochemical status of the drug dispersed in an amorphous carrier. The microstructural properties derived therefrom have been successfully employed in reconciling the enigmatic difference in behavior between in vitro and in vivo solubility tests performed on nanosized vinpocetine embedded in a polymeric matrix.

Natural Deep Eutectic Solvents (NADES) as a Tool for Bioavailability Improvement: Pharmacokinetics of Rutin Dissolved in Proline/Glycine after Oral Administration in Rats: Possible Application in Nutraceuticals.

There is a need for innovation in plant-derived pharmaceuticals, food supplements and nutraceutical products regarding the use of more eco-sustainable solvents for their extraction. Furthermore, the poor oral bioavailability of several phytochemicals with health promoting effects stimulates the research in the field of pharmaceutical formulations. Natural Deep Eutectic Solvents (NADES) are formed by natural compounds, and can be considered as future solvents being especially useful for the preparation of nutraceuticals and food-grade extracts. In this paper various NADES were prepared using sugars, aminoacids and organic acids. Rutin (quercetin-3-O-α-l-rhamnopyranosyl-(1→6))-ß-d-glucopyranose) was used as a model compound to study NADES. Moreover, the effect of various eutectic mixtures on rutin's water solubility was studied. Proline/glutamic acid (2:1) and proline/choline chloride (1:1) mixtures have a solubility comparable to ethanol. The proline/glutamic acid (2:1) eutectic containing rutin was used in a pharmacokinetic study in Balb/c mice while bioavailability was compared to oral dosing of water suspension. Plasmatic levels of rutin were measured by HPLC-MS/MS showing increased levels and longer period of rutin permanence in plasma of NADES treated animals. This paper reports the possible use of non-toxic NADES for pharmaceutical and nutraceutical preparations.

Enantiospecific crystallisation behaviour of malic acid in mechanochemical reactions with vinpocetine.

We report an intriguing example of enantioselectivity in the formation of new multicomponent crystalline solid containing vinpocetine and malic acid. Several experimental data sets confirmed that the multicomponent system presents a clear enantiospecific crystallisation behaviour both in the solid-state and in solution: only the system consisting of vinpocetine and L-malic acid produces a free-flowing solid consisting of a new crystalline form, while the experiments with D-malic acid produced an amorphous and often deliquescent material. The new vinpocetine-L-malic system crystallizes in the monoclinic space group of P21 and in a 1:1 molar ratio, where the two molecules are linked through intermolecular hydrogen bonds in the asymmetric unit. The vinpocetine-DL-malic system was partially crystalline (with also traces of unreacted vinpocetine) with diffraction peaks corresponding to those of vinpocetine-L-malic acid. Solid-state NMR experiments revealed strong ionic interactions in all the three systems. However, while vinpocetine-L-malic acid system was a pure and crystalline phase, the other two systems persistently showed the presence of unreacted vinpocetine. This resulted in a significant worsening of the dissolution profile with respect to the pure vinpocetine-L-malic crystalline salt, whose dissolution kinetics appeared superior.

Supramolecular eutectogel as new oral paediatric delivery system to enhance benznidazole bioavailability.

Benznidazole (BNZ) serves as the primary drug for treating Chagas Disease and is listed in the WHO Model List of Essential Medicines for Children. Herein, a new child-friendly oral BNZ delivery platform is developed in the form of supramolecular eutectogels (EGs). EGs address BNZ's poor oral bioavailability and provide a flexible twice-daily dose in stick-pack format. This green and sustainable formulation strategy relies on the gelation of drug-loaded Natural Deep Eutectic Solvents (NaDES) with xanthan gum (XG) and water. Specifically, choline chloride-based NaDES form stable and biocompatible 5 mg/mL BNZ-loaded EGs. Rheological and Low-field NMR investigations indicate that EGs are viscoelastic materials comprised of two co-existing regions in the XG network generated by different crosslink distributions between the biopolymer, NaDES and water. Remarkably, the shear modulus and relaxation spectrum of EGs remain unaffected by temperature variations. Upon dilution with simulated gastrointestinal fluids, EGs results in BNZ supersaturation, serving as the primary driving force for its absorption. Interestingly, after oral administration of EGs to rats, drug bioavailability increases by 2.6-fold, with a similar increase detected in their cerebrospinal fluid. The noteworthy correlation between in vivo results and in vitro release profiles confirms the efficacy of EGs in enhancing both peripheral and central BNZ oral bioavailability.

Shifting the Focus from Dissolution to Permeation: Introducing the Meso-fluidic Chip for Permeability Assessment (MCPA).

In response to the growing ethical and environmental concerns associated with animal testing, numerous in vitro tools of varying complexity and biorelevance have been developed and adopted in pharmaceutical research and development. In this work, we present one of these tools, i.e., the Meso-fluidic Chip for Permeability Assessment (MCPA), for the first time. The MCPA combines an artificial barrier (PermeaPad®) with an organ-on-chip device (MIVO®) and real-time automated concentration measurements, to yield a sustainable, yet effortless method for permeation testing. The system offers three major physiological aspects, i.e., a biomimetic membrane, an optimal membrane interfacial area-to-donor-volume-ratio (A/V) and a physiological flow on the acceptor/basolateral side, which makes the MPCA an ideal candidate for mechanistic studies and excellent in vivo bioavailability predictions. We validated the method with a handful of assorted drug compounds in unstirred and stirred donor conditions, before exploring its applicability as a tool for dissolution/permeation testing on a BCS class III/I drug (pyrazinamide) crystalline adducts and BCS class II/IV (hydrocortisone) amorphous solid dispersions. The results were highly reproducible and clearly displayed the method's potential for evaluating the performance of enabling formulations, and possibly even predicting in vivo performance. We believe that, upon further development, the MCPA will serve as a useful in vitro tool that could push sustainability into pharmaceutics by refining, reducing and replacing animal testing in early-stage drug development.

Drug salt formation via mechanochemistry: the case study of vincamine.

In the present research a salt of vincamine, a poorly bioavailable indole alkaloid derived from the leaves of Vinca minor L., was synthesized in the solid state by means of a mechanochemical process employing citric acid as a reagent. The mechanochemical process was adopted as a solvent-free alternative to classical citrate synthetic route that involves the use of solvents. Since the mechanochemical salification is little studied to date and presents the disadvantage of offering a low yield, in this work, the influence of three process and formulation variables on the percentage of vincamine citrate was studied. In particular, the time of mechanical treatment (in planetary mill Fritsch P5) and the amount of citric acid were varied in order to evaluate their effect on the yield of the process, and the introduction of a solid solvent, a common pharmaceutical excipient (sodium carboxymethylcellulose, NaCMC), was considered. Due to the complexity of the resulting samples' matrix, an appropriate experimental design was employed to project the experimental trials and the influence of the three variables on the experimental response was estimated with the help of a statistical analysis. The experimental response, that is, the yield of the process corresponding to the percentage of vincamine in the protonated form, was unconventionally calculated by means of X-ray photoelectron spectroscopy analysis (XPS). Out of 16 samples, the one with the highest yield was the coground sample containing vincamine and citric acid in a 1:2 molar ratio, treated for 60 min in the presence of NaCMC. Under the above conditions the salification reaction was completed highlighting the importance of a proper selection of process and formulation variables of the mechanochemical salification, and emphasizing the crucial role of the solid solvent in facilitating the salification. The second step of the research encompassed the characterization of the citrate salt obtained by solid excipient assisted mechanochemical salification (SEAMS) in comparison with the vincamine citrate obtained by classical synthetic route. The samples were characterized by, besides XPS, high resolution transmission electron microscopy (HRTEM), X-ray powder diffraction (XRPD), in vitro solubilization kinetics and in vivo oral pilot study in rats. Finally, in order to monitor over time possible disproportionation phenomena, stability studies have been performed by repeating XPS analysis after 8 months. As expected, the the SEAMS-vincamine salt consisted of particles both crystalline and amorphous. The solubilization kinetics was superior to the corresponding salt probably thanks to the favorable presence of the hydrophilic excipient although the two salts were bioequivalent in rats after oral administration. Furthermore, no evidence of disporportionation phenomena in the SEAMS-vincamine salt was found after storage. In conclusion, in the case of forming salts of poorly soluble drugs, the SEAMS process may be an interesting alternative to both classical synthetic routes, eliminating the need for solvent removal, and simple neat mechanochemical salification, overcoming the problem of limited process yield.

Praziquantel Fifty Years on: A Comprehensive Overview of Its Solid State.

This review discusses the entire progress made on the anthelmintic drug praziquantel, focusing on the solid state and, therefore, on anhydrous crystalline polymorphs, amorphous forms, and multicomponent systems (i.e., hydrates, solvates, and cocrystals). Despite having been extensively studied over the last 50 years, new polymorphs and the greater part of their cocrystals have only been identified in the past decade. Progress in crystal engineering science (e.g., the use of mechanochemistry as a solid form screening tool and more strategic structure-based methods), along with the development of analytical techniques, including Synchrotron X-ray analyses, spectroscopy, and microscopy, have furthered the identification of unknown crystal structures of the drug. Also, computational modeling has significantly contributed to the prediction and design of new cocrystals by considering structural conformations and interactions energy. Whilst the insights on praziquantel polymorphs discussed in the present review will give a significant contribution to controlling their formation during manufacturing and drug formulation, the detailed multicomponent forms will help in designing and implementing future praziquantel-based functional materials. The latter will hopefully overcome praziquantel's numerous drawbacks and exploit its potential in the field of neglected tropical diseases.

Praziquantel meets Niclosamide: A dual-drug Antiparasitic Cocrystal.

In this paper we report a successful example of combining drugs through cocrystallization. Specifically, the novel solid is formed by two anthelminthic drugs, namely praziquantel (PZQ) and niclosamide (NCM) in a 1:3 molar ratio, and it can be obtained through a sustainable one-step mechanochemical process in the presence of micromolar amounts of methanol. The novel solid phase crystallizes in the monoclinic space group of P21/c, showing one PZQ and three NCM molecules linked through homo- and heteromolecular hydrogen bonds in the asymmetric unit, as also attested by SSNMR and FT-IR results. A plate-like habitus is evident from scanning electron microscopy analysis with a melting point of 202.89 °C, which is intermediate to those of the parent compounds. The supramolecular interactions confer favorable properties to the cocrystal, preventing NCM transformation into the insoluble monohydrate both in the solid state and in aqueous solution. Remarkably, the PZQ - NCM cocrystal exhibits higher anthelmintic activity against in vitro S. mansoni models than corresponding physical mixture of the APIs. Finally, due to in vitro promising results, in vivo preliminary tests on mice were also performed through the administration of minicapsules size M.

Better and greener: sustainable pharmaceutical manufacturing technologies for highly bioavailable solid dosage forms.

In the last decades, Green Chemistry has been gaining widespread attention within the pharmaceutical field. It is thus very important to bring more sustainable approaches into the design and manufacture of effective oral drug delivery systems. This review focuses on spray congealing and mechanochemical activation, two technologies endorsing different principles of green chemistry, and at the same time, addressing some of the challenges related to the transformation of poorly water-soluble drugs in highly bioavailable solid dosage forms. We therefore present an overview of the basic principles, equipment, and application of these particle-engineering technologies, with specific attention to case studies carried out by the groups working in Italian Universities.

Overcoming the Drawbacks of Sulpiride by Means of New Crystal Forms.

This study aims at developing new multicomponent crystal forms of sulpiride, an antipsychotic drug. The main goal was to improve its solubility since it belongs to class IV of the BCS. Nine new adducts were obtained by combining the active pharmaceutical ingredient with acid coformers: a salt cocrystal and eight molecular salts. In addition, three novel co-drugs, of which two are molecular salts and one is a cocrystal, were also achieved. All samples were characterized in the solid state by complementary techniques (i.e., infrared spectroscopy, powder X-ray diffraction and solid-state NMR). For systems for which it was possible to obtain good-quality single crystals, the structure was solved by single crystal X-ray diffraction (SCXRD). SCXRD combined with solid-state NMR were used to evaluate the ionic or neutral character of the adducts. In vitro dissolution tests of the new crystal forms were performed and all the adducts display remarkable dissolution properties with respect to pure sulpiride.

Validation and testing of a new artificial biomimetic barrier for estimation of transdermal drug absorption.

Human skin remains the most reliable model for studying the transdermal permeation of active compounds. Due to the limited source, porcine skin has been used extensively for performing penetration tests. Performing penetration studies by using human and animal skin, however, would also involve a series of ethical issues and restrictions. For these reasons, new biomimetic artificial barriers are being developed as possible alternatives for transdermal testing. If appropriately optimized, such products can be cost-effective, easily standardized across laboratories, precisely controlled in specific experimental conditions, or even present additional properties compared to the human and animal skin models such as negligible variability between replicates. In this current work we use the skin mimicking barrier (SMB) for drug permeability tests. The aim was to evaluate the suitability of the new barrier for studying the percutaneous absorption of the lipophilic extract of the plant Zingiber officinale Roscoe in vitro and compare its permeability ability with the artificial membrane Permeapad® and porcine skin. Our results showed that the permeability values obtained through the SMB are comparable are comparable to those obtained by using the porcine skin, suggesting that the new barrier may be an acceptable in vitro model for conducting percutaneous penetration experiments.

Enhanced oral bioavailability of vinpocetine through mechanochemical salt formation: physico-chemical characterization and in vivo studies.

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 solid-state 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.

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.

Simultaneous release and ADME processes of poorly water-soluble drugs: mathematical modeling.

The importance of studying oral drug absorption is well recognized by both research facilities/institutions and the pharmaceutical industry. The use of mathematical models can represent a very profitable and indispensable tool to understand oral drug absorption. Indeed, mathematical models can verify the correctness of the mechanisms proposed to describe drug release, absorption, distribution and elimination thus reducing the number of expensive and time-consuming experiments. In this paper we develop a mathematical approach able to model both the polymeric particle mediated delivery and the gastrointestinal absorption-metabolism-excretion (ADME) of a given drug. As a model drug a poorly water-soluble drug (vinpocetine) in both the amorphous and nanocrystalline state is considered. The delivery system is obtained by drug cogrinding with a polymer (cross-linked polyvinilpyrrolidone). As the proposed mathematical model can properly fit the in vivo data on the basis of information obtained in vitro, it represents a powerful theoretical tool connecting in vitro and in vivo behavior.

Echinacea angustifolia DC. Lipophilic Extract Patch for Skin Application: Preparation, In Vitro and In Vivo Studies.

Dodeca-2E,4E,8Z,10E/Z-tetraenoic isobutylamide (tetraene) is the main component of Echinacea angustifolia DC. lipophilic extract, the bioavailability and immunomodulatory effect after oral administration in soft gel capsules in healthy volunteers of which we have already demonstrated. In the present work, we assessed the transdermal administration as an alternative route of administration of such an alkamide. The first step, therefore, encompassed the preparation of a drug-in-adhesive patch with an area of 868 mm2 and containing a dose of 0.64 mg of tetraene. In vitro skin permeation studies in Franz-type diffusion chambers resulted in a tetraene flux of (103 ± 10) ng × cm-2 × h-1 with a very good linearity (r = 0.99). The relatively low lag time of just 13 min indicates low binding and the accumulation of tetraene in the skin. Finally, the patch was administered to six healthy volunteers, and the pharmacokinetic analysis was performed by nonlinear mixed effects modelling with soft gel oral capsules serving as the reference formulation. The in vivo results correlated well with the in vitro permeation and indicated an initial burst tetraene absorption from the patch that was in parallel with the zero-order kinetics of absorption. The rate of the latter process was in good agreement with the one estimated in vitro. The tetraene absorption rate was therefore slow and prolonged with time, resulting in a bioavailability of 39% relative to the soft gel capsules and a very flat plasma concentration profile.

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.

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.