A. F. Achkasov

Following the products of mechanochemical synthesis step by step

We describe an experiment in a special device, which permits to quantify the energy input into a solid sample and to follow the products of mechanochemical synthesis step by step. The application of the device is tested on the “glycine–oxalic acid dihydrate” system, in which two products are formed concomitantly on co-grinding.

The effect of carboxylic acids on glycine polymorphism, salt and co-crystal formation. A comparison of different crystallisation techniques

The effect of carboxylic acids on glycine polymorphism, salt and co-crystal formation was compared for slow evaporation of solutions at ambient conditions, spray drying, “fast” and “slow” anti-solvent crystallisation and dry co-grinding. Different phases were found to crystallise from the same starting components, depending on the preparative technique. Small amounts of most carboxylic acids (glutaric acid being the only exception) promoted crystallisation of the γ-polymorph in solution and as a result of co-grinding. When added in equimolar quantities, the same carboxylic acids formed salts with glycine (addition of glutaric acid resulted in co-crystal formation) on slow evaporation of solutions and on co-grinding. Neither succinic nor L-malic acids produced glycine salts, but instead promoted formation of γ-glycine when present in any amount. Anti-solvent crystallisation and spray drying of solutions containing small or large amounts of carboxylic acids produced a variety of glycine polymorphs as both pure phases and their mixtures, whereas only oxalic acid yielded salts. The ability to synthesise glycinium semi-oxalate form II by spray drying was demonstrated.

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.

About the possibilities to detect intermediate stages in mechanochemical synthesis of molecular complexes

We have developed a device to carry out mechanochemical reactions, which allows us to detect the intermediate products during the reaction and to stop mechanical treatment after they have been formed.

Different effects of α- and γ-polymorphs of glycine on behavior of GC rats predisposed to catalepsy

1 The amino acid glycine is currently widely used in medicine. Medicines containing glycine can reduce the psychoemotional stress and aggression, raise social adaptation, normalize sleep and enhance mental per� formance, reduce the severity of brain disorders in ischemic stroke, and reduce the toxic effect of alcohol [1–3]. In the United States, drugs containing glycine have been approved for the treatment of negative symptoms in patients with schizophrenia [4]. Usually glycine is administrated as sublingual pills. It was found that the solution of glycine is less effective than the dry form [5]. Hence we can assume that the biolog� ical activity of glycine is associated not only with its chemical formula per se, but with the characteristics of the solid, such as its crystal structure (polymorphs). When glycine is used in formulations, its activity may also depend on the structure and properties of supramolecular complexes with excipients. Despite the fact that glycine can exist as several polymorphs [6], the influence of the crystal structure on the biolog� ical activity was not investigated. Neither catalogs nor packages of reagents and drugs containing glycine (as a pure substance or as a part of multicomponent pills) provide information on which polymorph(s) of glycine are present in the sample. In the publications devoted to the therapeutic use of glycine, there is no informa� 1 The article was translated by the authors. tion on which polymorph(s) of glycine have been used. 2 The aim of this work was to compare the effect of α and γ polymorphs of glycine on behavior of GK rats with a genetic predisposition to catalepsy. As a result, it was shown that γ�polymorph of glycine has a higher biological activity than the α�form. This effect was very unusual because both forms of glycine have almost the same kinetics of dissolution and their mol� ecules have the same conformation. An interpretation of the difference in the biological activity of two poly� morphs of glycine can be sought in the different struc� tures of molecular associates that enter the body when the two forms of drug have been taken orally. Glycine bought from Soyuzkhimreaktiv (Russia) contained a mixture of α and γ polymorphs; it was recrystallized to obtain pure α and γ polymorphs. The

A compact device for loading diamond anvil cells with low‐boiling pressure‐transmitting media

A new compact laboratory device for loading diamond anvil cells with low-boiling pressure-transmitting media is described. This device allows, in particular, the easy loading of diamond anvil cells with pentane–isopentane (1:1) mixture at environmental temperatures up to 303 K and relative humidity at least up to 75–80%. The relatively simple design, the easy availability of materials used for the device and the application of liquid nitrogen as cooling agent allow the manufacture of such a device in a short time at almost any laboratory.

Effect of α- and γ-polymorphs of glycine on the intranasal delivery of manganese hydroxide nanoparticles into brain structures

6 Glycine is the simplest amino acid produced by the body during metabolism. Glycine is classified with biotics—substances that, when administered into the body exogenously even in small amounts, can enter the biochemical structures and systems and not only participate in physiological processes but also normal ize them [1]. Glycine is widely used because it acti vates the processes of defensive inhibition in the cen tral nervous system, reduces emotional stress, and improves mental performance [2]. All currently known pharmaceuticals contain glycine in the α poly morphic modification. The biological effect of another, γ polymorph of glycine, was first studied in the strains of rat with genetic predisposition to cata lepsy [3, 4]. These rats are used as a biological model for studying certain forms of pathological behavior, which are characteristic, in particular, for the negative symptoms in schizophrenic patients. Administration of γ glycine sharply reduced the duration of cataleptic reactions, decreased the fear response when getting into a new environment, and strengthened the explor atory motivation. Glycine was administered to the ani mals in the crystalline form with food [3, 4]. In further studies, the biological effects of glycine solutions rather than its crystalline modifications on the aber rant activity caused by the imbalance of the excitatory and inhibitory neuronal activity of CA1 pyramidal neurons in hippocampal sections of ICR mice were compared [5]. The difference in the dynamics of action of two polymorphic modifications of glycine was shown: when glycine forms were applied directly on the hippocampal cells, the modulating effect of γ glycine developed more slowly [5]. The observed effect was explained by the peculiarities of interaction of the polymorphic modifications of glycine with the receptors of this inhibitory neurotransmitter of hip pocampal neurons [6].

A new method for obtaining fine powders of paracetamol for compression without excipients

Paracetamol (N(phydroxyphenyl)acetamide) is a widely used nonnarcotic analgesic having also anti inflammatory and antipyretic action. Several crystalline polymorphs of paracetamol are known. One of these (monoclinic form I) is thermodynamically stable and is readily prepared but cannot be compressed to tablets without excipients (fillers). Another polymorph (orthorhombic form II) can be readily compressed to tablets without excipients [1, 2] and is better soluble but its formation as a pure phase is not reproducible, and, what is worse, it is metastable and is spontaneously converted to the monoclinic form on storage [1]. The idea of obtaining compressible forms of paracetamol that would be stable on storage attracts considerable attention of the scientific community and pharmaceutical companies. For solving this problem, it has been proposed to use, instead of pure paracetamol, its mixtures with polyvinylpyrrolidone [3], carbohydrates [4], chitosan and sodium alginate [5] or mixed crystals based on oxalic acid, naphthalene and other compounds [6] or the inclusion compounds with hydroxypropylβcyclodextrin [7].

Application of physical methods of pharmacy to improve the properties of dosage forms

It has been shown on the examples of paracetamol, ibuprofen, and salbutamol that the use of mixed water-organic solvents, which are capable of clathrate formation, enables one to obtain high-disperse drug powders that are weakly soluble in water via sublimation drying of frozen solutions. The prepared powders are applicable for direct compression to pellets, have a higher rate of passing into solution for drug compared to initial substances, and can be used to prepare the suspensions for children’s preparations and dosage forms as freon-free aerosols for pulmonary administration.

Difference of shear and impact treatment for mechanochemical co-cristallization.

Currently one of the most popular methods to obtain various molecular co-crystals is mechanochemical synthesis, i.e. mechanical treatment of a mixture of powder reactants. Traditional approach for mechanical treatment is milling in a ball mill or grinding in a mortar. However, using these methods causes a number of problems related to investigation of the reaction’s mechanism. For instance, ball mill produces impact treatment and shear treatment simultaneously and it is almost impossible to separate these two types of mechanical treatment. So, if detailed analysis of reaction is required, alternative methods of mechanical treatment are necessary. This study describes how mechanochemical co-crystallization of piroxicam and succinic acid has been investigated by using special model devices constructed for separated impact and shear mechanical treatment. Such devices allowed us to perform controlled impact or shear mechanical treatment, what was necessary for detailed investigation of mechanochemical processes for molecular crystals, based on the X-ray powder diffraction analysis. We could change and control energy and frequency of mechanical pulses in the impact model device and average velocity and pressure in the shear model device. For some other systems applying controlled impact treatment allowed us to detect the intermediate products of the mechanochemical synthesis of molecular complexes [1-2]. As for ‘piroxicam – succinic acid” system, a comparison of impact and shear mechanical treatment had lead to opposite results for mechanochemical reactions – shear treatment appeared to disintegrate co-crystal obtained by impact mechanical treatment. Acknowledgements This work was supported by grants from RFBR (No. 11-03-00684, 12-03-31663, 13-03-00795, 13-0392704) and Ministry of Education and Science Agreement (No. 14.B37.21.1093).