Clathrate Hydrates of Organic Solvents as Auxiliary Intermediates in Pharmaceutical Research and Development: Improving Dissolution Behaviour of a New Anti-Tuberculosis Drug, Perchlozon.

There is an urgent need for new drugs to overcome the challenge of the ever-growing drug resistance towards tuberculosis. A new, highly efficient anti-tuberculosis drug, Perchlozone (thioureidoiminomethylpyridinium perchlorate, Pz), is only available in an oral dosage form, though injectable forms and inhalation solutions could be better alternatives, offering higher bioavailability. To produce such forms, nano- and micro-particles of APIs would need to be prepared as dispersions with carriers. We use this case study to illustrate the principles of selecting solvents and excipients when preparing such formulations. We justify the choice of water-THF (19.1 wt % THF) as solvent and mannitol as carrier to prepare formulations of Pz-a poorly soluble compound-that are suitable for injection or inhalation. The formulations could be prepared by conventional freeze-drying in vials, making the proposed method suitable for industrial scaling. A similar strategy for selecting the organic solvent and the excipient can be applied to other compounds with low water solubility.

Tribochemistry, Mechanical Alloying, Mechanochemistry: What is in a Name?

Over the decades, the application of mechanical force to influence chemical reactions has been called by various names: mechanochemistry, tribochemistry, mechanical alloying, to name but a few. The evolution of these terms has largely mirrored the understanding of the field. But what is meant by these terms, why have they evolved, and does it really matter how a process is called? Which parameters should be defined to describe unambiguously the experimental conditions such that others can reproduce the results, or to allow a meaningful comparison between processes explored under different conditions? Can the information on the process be encoded in a clear, concise, and self-explanatory way? We address these questions in this Opinion contribution, which we hope will spark timely and constructive discussion across the international mechanochemical community.

Supramolecular architecture of betulin diacetate complexes with arabinogalactan from Larix sibirica.

Supramolecular ensembles of arabinogalactan (AG) and its complexes with betulin diacetate (BDA) were studied in water and dimethyl sulfoxide (DMSO) using ablation, induced by submillimeter radiation from the free electron laser. Solutions of 1wt% AG resulted in formation of aerosol particles with a maximum size of 60-70nm. In contrast, with DMSO as the solvent, the majority of particles were significantly smaller. Nevertheless, the addition of water shifted the particle size distribution to a larger size, suggesting the cross-linking of AG chains due to hydrogen bonding through water molecules. The ensembles of molecules were larger in solutions of the AG-BDA complex as compared to pure AG aqueous solution, and the distribution was narrow. The role of side chain interactions in the formation of AG-BDA complexes in aqueous solutions was confirmed by NMR.

A new method of producing monoclinic paracetamol suitable for direct compression.

PURPOSE: To develop a technique of obtaining monoclinic polymorph of paracetamol suitable for direct compression without excipients. METHODS: Preparation of spongy monoclinic paracetamol was based on quench-cooling of paracetamol solutions in water-acetone mixtures sprayed into a vessel with liquid nitrogen followed by removal of solvents by freeze-drying. X-ray powder diffraction was used to study annealing of quench-cooled solutions in "paracetamol-acetone-water" and "acetone-water" systems and to find optimum conditions for obtaining fine particles of pure monoclinic paracetamol. Samples were characterized by electron microscopy; compression properties were measured. RESULTS: The preparation technique gave fine monoclinic paracetamol powder containing agglomerates (30-200 µm) composed of flat particles (linear sizes 1-10 µm, the thickness 60-150 nm). The spongy sample was suitable for direct compression without excipients, stable on storage, and mechanically robust. Mechanically stable tablets pressed from the spongy sample were better soluble in water than commercially available tablets of paracetamol with excipients. CONCLUSIONS: The proposed method gave spongy monoclinic paracetamol samples with improved properties. For inexpensive paracetamol, the method may not yield economic advantage. However, the same method based on freeze-drying solutions in mixed aqueous-organic solvents can be used to prepare new improved forms of other molecular solids for pharmaceutical applications.

Effects of the alpha- and gamma-polymorphs of glycine on the behavior of catalepsy prone rats.

Glycine is used to treat various health problems and is efficient in the treatment of the negative symptoms of schizophrenia. Since glycine exists as a few polymorphs, the aim of this work is to compare the effects of the alpha- and gamma-forms of glycine on the behavior of the genetic catalepsy (GC) strain of rats. Both polymorphs of glycine have been administered to rats orally as pure solid chemicals, and cataleptic behavior and behaviors in the open-field, elevated plus-maze, and light-dark box tests were studied. Both the alpha- and gamma-polymorphs of glycine increased exploratory activity in the open-field test, but only the gamma-polymorph had beneficial effects on catalepsy and exploratory activity in the light-dark box and reduced anxiety in the elevated plus-maze.

Analgesic effect from Ibuprofen nanoparticles inhaled by male mice.

BACKGROUND: Aerosol lung administration is a convenient way to deliver water-insoluble or poorly soluble drugs, provided that small-sized particles are generated. Here, for the outbred male mice, we show that the pulmonary administration of ibuprofen nanoparticles requires a dose that is three to five orders of magnitude less than that for the orally delivered particles at the same analgesic effect. METHOD: The aerosol evaporation-condensation generator consisted of a horizontal cylindrical quartz tube with an outer heater. Argon flow was supplied to the inlet and aerosol was formed at the outlet. The particle mean diameter and number concentration varied from 10 to 100 nm and 10(3)-10(7) cm(-)3, respectively. The analgesic action and side pulmonary effects caused by the inhalation of ibuprofen nanoparticles were investigated. RESULTS: The chemical composition of aerosol particles was shown to be identical with the maternal drug. Using the nose-only exposure chambers, the mice lung deposition efficiency was evaluated as a function of the particle diameter. CONCLUSIONS: The dose-dependent analgesic effect of aerosolized ibuprofen was studied in comparison with the oral treatment. It was found that the dose for aerosol treatment is three to five orders of magnitude less than that required for oral treatment at the same analgesic effect. Accompanying effects were moderate venous hyperemia and some emphysematous signs.

Anti-inflammatory effect from indomethacin nanoparticles inhaled by male mice.

The respiratory system provides entry for drug nanoparticles to cure systemic diseases. The modern devices that are available on the market of therapeutic aerosol delivery systems have a number of disadvantages. There remains a need for an alternative means that is low cost, convenient, and capable of producing small-sized particles. On the other hand, one-third of the modern drugs are poorly water soluble. Many currently available injectable formulations of such drugs can cause side effects that originate from detergents and other agents used for their solubilization. The aerosol lung administration may by a good way for delivery of the water-insoluble drugs. We present here a new way for the generation of drug nanoparticles suitable for many water insoluble substances based on the evaporation-condensation route. In this paper the indomethacin nanoaerosol formation was studied and its anti-inflammatory effect to the outbred male mice was examined. The evaporation-condensation aerosol generator consisted of a horizontal cylindrical quartz tube with an outer heater. Argon flow was supplied to the inlet and the aerosol was formed at the outlet. The particle mean diameter and number concentration were varied in the ranges 3 to 200 nm and 10(3) to 10(7) cm(-3), respectively. The liquid chromatography and X-ray diffraction methods have shown the nanoparticles consist of the amorphous phase indomethacin. The aerosol lung administration experiments were carried out in the whole-body exposure chamber. Both the lung deposited dose and the particle deposition efficiency were determined as a function of the mean particle diameter for mice being housed into the nose-only exposure chambers. The anti-inflammatory action and side pulmonary effects caused by the inhalation of indomethacin nanoparticles were investigated. It was found that the aerosol administration was much more effective than the peroral treatment. The aerosol route required a therapeutic dose six orders of magnitude less than that for peroral administration.