Libmonster ID: EE-321
Author(s) of the publication: Elena BOLDYREVA

by Elena BOLDYREVA, Dr. Sc. (Chem.), Head of the Chair of Chemistry of Solids at the Novosibirsk State University and Chief Researcher of the Group of Reactivity of Solids at the Institute of Chemistry of Solids and Mechanical Chemistry, RAS Siberian Branch

Development of new efficient drugs is a long and labor-consuming process. It involves long-term efforts both of scientists and engineers including specialists in physical pharmacy which is based largely on the achievements in solid state chemistry, physical chemistry and crystallography.

Compounds or drugs?"--this is a question on the cover of the October 2011 issue of Chemistry and Engineering News published by the American Chemical Society. Pharmaceutical compounds, whether synthesized artificially or extracted from a natural raw material, are powders or liquids, which are in most cases not yet suitable to be used as drugs. To become a drug, a pharmaceutical compound must be a component of a solution for injections, a tablet, a syrup, an ointment, a spray, a plaster, or even of a chewing gum or a candy. Pharmaceutical formulations contain also a considerable share of auxiliary inert substances, fillers or, as they are also called--excipients. They are added to simplify the process of preparation of a drug, to increase its shelf-life, ease of use, bioavailability or bioactivity. For example, the following properties can be improved: compressability and mechanical strength of tablets, their hygroscopicity (susceptibility to humidity), rate of dissolution, target delivery to appropriate organs or even cells (for example, cancer cells), taste, smell and color. Different pharmaceutical formulations can contain substances of the same chemical composition but with a different crystal structure (polymorphs), or amorphous, can differ in size and shape of the particles, they can be classified chemically as salts, multi-component crystals (cocrystals, solvates, molecular complexes), mechanical mixtures or composite materials.

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Research fields necessary for drug development. Gray-coded segments are related to production of solid substances. Color code intensity depends on the amount of a drug.

NEW, EFFICIENT, OR OLD, TESTED?

The route from a pharmaceutical substance to a drug takes years and even decades. The main time and resource expenses are related to preclinical and clinical trials including toxicity test, selection of optimum and critical doses and also to the development of production technology, selection of the most acceptable forms, and licensing.

Of primary importance are careful complex safety testing of new drugs and the studies of side effects of their usage; side effects are often revealed only many years later and sometimes even in the next generations. In this regard old substances already proved by decades and sometimes even centuries of usage have a number of advantages; in particular, they do not require long-term pharmacological and toxicological tests, though their efficiency is not always as high as one would like it to be. Therefore the problem of development of more effective dosage forms based on the known substances is quite important, as it can provide much faster return of spent research funds, as compared with investing into development of drugs based on absolutely new substances.

It should be noted that generics occupy a large proportion of the pharmaceutical market. They contain a pharmaceutical substance of the original preparation (brand) patented by any company but produced in another form, which allows to leave the field protected by the patent. As analogs are much cheaper than the original, their production increases, particularly after expiration of the brand patent. Not only small companies in countries with low-profit population but also large transnational pharmaceutical corporations show considerable interest in generics. The

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expenses invested in their development are rapidly growing. For example, if in 2005 about 20 percent of funds invested in the development of drugs in the world were allocated for these purposes, by 2015 it is planned to allocate already 50 percent of such funds. In order to get a generic, which is by no means inferior by its therapeutic effect to the patented preparation, one should be able not only to synthesize substances or check their chemical and stereochemical purity, but also produce high-quality drug formulations.

Even small companies can compete with large ones if they launch production of generics. They can patent their new products and methods of producing them, thus protecting themselves from large companies. Moreover, the designers often change the composition of exipents, delivery means and ways of a pharmaceutical substance to the body, introduce additional active pharmaceutical ingredients to the pharmaceutical formulation, prepare salts, mixed crystals or composites on their basis and create new polymorphs and amorphous forms.

SOLUBILITY-PERMEABILITY CONFLICT

Irrespective of whether a pharmaceutical substance is completely new or well-known, it is necessary to solve the same set of problems in the development of drug formulations (brands or generics), namely, solubilization (colloid dissolution), permeability of biological barriers (transdermal or hematoencephalic*), target delivery, control of the rates of delivery to the body and of the excretion of decomposition products, reduction of toxicity, and the search of optimum delivery methods. Some problems deal with production, transportation and storage of pharmaceutical preparations. Finally, it is important to create one's

*Hematoencephalic barrier regulates transport of biologically active substances and metabolites from blood to brain thus preventing penetration to the central nervous system of alien substances, microorganisms, toxins, etc., transported by blood.---Ed.

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own or to overcome foreign patent protection. To solve most of these problems, it is necessary to change not the chemical composition of a pharmaceutical, but its state, i.e. to prepare it in the form of particles of a certain size and shape, of different crystalline structure or amorphous, in the form of complexes or mechanical mixtures with other components. Physical pharmacy is designed to solve all these problems.

At least 40 percent of the pharmaceutical substances sold in the market are poorly soluble in biological liquids. Out of the whole amount of new substances suggested for use as drugs, about 90 percent are poorly soluble. The problem is further complicated by the fact that solubility and permeability are not usually in conflict, i.e. substances which easily pass through cell membranes (which is important for their action) are as a rule poorly soluble. Unfortunately, good solubility and hereby good permeability are rather rare. Poorly soluble and poorly permeable substances are hopeless for potential applications as drugs. It is extremely important to reveal them timely among new synthesized preparations in order to save time and funds of designers.

There are many methods of affecting properties of dosage forms (without changing their chemical composition) such as variation of particle size or form, modification of the method of organizing an appropriate mix, changes in the structure, preparation of salts, solvents, molecular complexes, cocrystals, etc.

When changing a particle size from millimeters to nanometers solubility can increase several times. It is important to keep in mind that for pharmaceutical applications such "moderate" growth is better than increasing solubility orders of magnitude. Too high a supersaturation preserved for a short period can cause precipitation of pharmaceutical substances in kidneys, liver, muscles; too high concentration in biological liquids (blood, lymph, gastric juice) can exceed toxicity threshold. Increased solubility through formation of complexes will cause not an increase but a decrease of their bioavailability if a complex turns out to be so stable that it will not be destroyed in a human organism, it will be excreted without being assimilated.

SMALL BUT PRECIOUS

Small particles not only dissolve better but often also possess a higher antibacterial activity in respect of pathogenic microorganisms. In order to avoid agglomeration of nanoparticles resulting in the loss of their unique properties, they must be incorporated into a matrix or a carrier (fluoropolymer, silica gel). Sometimes production of nanoparticles and their dispersion in an inert stabilizing matrix are performed in the same process. For example, our colleagues

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have developed a method which provides formation of microspheres from nanoparticles of a pharmaceutical substance in a combination with a mono- or multi-component carrier in the course of solid-phase reactions. Using multi-component carriers makes it possible "to reconcile the irreconcilable", i.e. to produce powders of substances easily soluble in biological liquids and at the same time capable to penetrate through biological membranes, which is important, for instance, for anticancer drugs. Moreover, the obtained dispersed samples can be compressed much better even without additives (starch, cellulose, and talc) and also used as powders for inhalation without freon. The carrier itself is not only harmless in this case but, on the contrary, improves the therapeutic properties, as, for example, in the compositions of salbutamol (medication arresting bronchial asthma bouts) with glycine.

For per-nasal delivery of the dispersed particles of pharmaceutical substances it is important to prepare fractions of a well-defined size. Depending on the size, the inhaled particles get into nasopharynx, central or peripheral respiratory tract, bronchial tubes, lungs and also the brain. Besides, some nanoparticles

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(for example, of glycine) can block penetration of other nanoparticles (for example, of metal oxides or hydroxides) into brain during inhalation, which is important for safety of those who are forced to contact with nanoparticles in the air.

Another opportunity which appears due to reduction of a particle size is an increase of particle stability with respect to structural transformations, for example, on transportation or on storage. Thus, an amino acid DL-cystein undergoes a phase transition at about 15 °C below zero (real winter temperature for Russia and some other countries), if particles are larger than 10 mkm, but becomes stable when their size is in the range from 1 to 10 mkm.

There are different methods of obtaining particles of controlled size and shape: very quick crystallization from solution, mechanical or ultrasound processing, dehydration or desolvation of large particles, and polymorphic transformations in large particles, when as a result a crystal is destroyed to small fragments, and finally, solid-state reactions, for example, of decomposition or exchange accompanied by fragmentation of the samples.

One of the promising methods is fast freezing of solutions of pharmaceutical compounds in mixed water-organic solvents followed by vacuum drying. When a solution freezes, solid clathrates (i.e. crystalline complexes of the molecules of an organic solvent and water, or so-called "mixed ices") are formed. The pharmaceutical substance "is pressed out" from the clathrate and forms globules consisting of very small particles. Small particles of a pharmaceutical substance can be preserved and used later on, if clathrate evaporates under necessary drying conditions and forms no intermediate liquid phases. Otherwise, they recrystallyze from the formed liquid and grow larger, so that their consumer properties deteriorate.

IMPORTANCE OF SHAPE AND STRUCTURE

The particle size is not the only parameter affecting its properties. Another important characteristic is its shape (a needle, a platelet, or a polyhedron with different ratio of the surface areas of different faces). It affects the technological stages (filtration, tabletting) and also the penetration of particals into brain via respiratory tract, dissolution and penetration through biological membranes. For example, needles can pass through channels, whereas flat platelets cannot. It is also possible to change sorption capacity and even chemical stability in reactions of "solid + gas" type, or decomposition (respectively), varying the relative areas of selected faces. Properties of different faces of many molecular crystals differ so much that, for example, one face can be hydrophilic and easily wet-table with water and another one--hydrophobic, one face can be oxidized easily, whereas another one remains inert under the same conditions.

The crystal form affects essentially the dissolution rate of ibuprofen (anti-inflammatory drug), trimethoprim (bacteriostatic antibiotic) and a number of other compounds. The following main methods can be used to change the shape of particles: varying of the supersaturation of solution, cooling and mixing rates, crystallization from different solvents, adding impurities, surfactants, for example, soap to the solution or melt, using of substrates, crystallizing under confined conditions (for instance, in nanoporous ceramics).

The structure is a very important characteristic of a solid substance along with its chemical composition. One and the same substance can form different crystal structures (for example, diamond and graphite). This phenomenon is termed polymorphism. Polymorphism is very common among molecular crystals. The ability to predict existence of all possible polymorphs for any substance, to develop the methods of reliable and reproducible production of the desirable polymorphs, and also to prevent their uncontrolled transformation to other forms is important for pharmaceutical industry.

There are many types of polymorphism of molecular crystals. If molecules are rigid, crystal structures can differ in packing. As examples, one can mention the polymorphs of the simplest amino acid, glycine or of the anti-inflammatory drug paracetamol. Larger molecules can differ also in their conformations in the crystal structures thus causing conformational polymorphism. As examples, one can refer to the antidiabetic drugs--chlorpropamide, tolbutamide, many anti-inflammatory drugs, amino acids serine and cysteine. Finally, polymorphism can be accompanied by a significant redistribution of electron density and charge causing tautomeric transitions (hydrogen atom moves from one group to another inside a molecule), zwitterionic isomerization (the molecule is neutral in general but its ends bear negative and positive charges, respectively). As examples, one can mention anti-inflammatory drugs piroxicam and indometacin.

The importance of polymorphism of pharmaceutical substances and excipents for pharmaceutical

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industry cannot be overestimated. Different polymorphs have different properties, this may have a significant effect on manufacturing, biological effect, storage, and can be used to improve the dosage forms. On the other hand, polymorphs may form beyond the control unexpectedly in the course of manufacturing or on storage, which has a negative action on the quality and patent protection. It is not accidental that thousands of papers and dozens of monographs are devoted to the problem of polymorphism of molecular crystals in general and of pharmaceuticals in particular.

Glycine serves as an interesting example of how different polymorphs can differ in their biological activity. Glycine is manufactured and sold by many companies, but in all the formulations available at the market glycine is present as the same polymorph, i.e. alpha-form. We have obtained several patents for the methods of reliable and reproducible production of another polymorph i.e. gamma-form, and studied its biological activity in vivo and in vitro. The activity of gamma-glycine and its influence on the electrical activity of neurons was shown to be several times higher than that of alpha-glycine.

If undesirable polymorphs are formed in a sample during manufacturing or on storage, this can result in enormous losses due to the forced phasing out of the drug. Ritonavir, a drug for treatment of HIV disease produced by the American Abbott Chemico-Pharmaceutical Corporation, can serve as a striking example. After several years of successful production, a stable and inactive crystalline modification started crystallizing spontaneously under the same operating conditions, instead of the soluble metastable form. The company failed to solve this problem because of non-adequate actions. Instead of localizing the problem and cutting-off the "infected" production place from any contacts with the outside world the company carried out numerous inspections and meetings all over the world. Finally, the seeds of the undesired more stable form appeared to be spread everywhere, and in their presence a less stable form could no longer be obtained. The forced suspension of production and the replacement of the drug with another form took a long time and resulted in a loss of US$ 500 mln by the company.

After this sensational event the new rules of certifying pharmaceuticals were introduced which made it obligatory to give information on all the existing polymorphs and solvates for each pharmaceutical substance. It is necessary to make a search for all possible polymorphs, to solve their structures, to study thermal stability and possible transformations on storage and at different stages of the technological process.

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POLYMORPHISM AND MECHANICAL EFFECTS

New polymorphs can be obtained by different methods, such as variation of crystallization conditions or storage, temperature and pressure, solid-phase transformations, i.e. phase transitions and chemical reactions, and also as a result of mechanical action.

In the course of production solid pharmaceutical substances are repeatedly subjected to shearing and impact actions, as well as to uniaxial or hydrostatic compression. In many crystals polymorphic transitions can be initiated just by their indenting, or touching, as well as during mechanical processing in a mill. New forms are metastable under normal conditions and are often soluble much better than the stable forms, but they cannot be stored for a long time. If a pharmaceutical solid is processed together with excipients, the polymorphic transitions under mechanical action proceed more completely, metastable forms "live" longer, a year or more, therefore they can be used as part of pharmaceutical formulations.

In order to achieve the desired effect, it is often necessary to combine several types of action. For example, mechanical processing of some antidiabetic drugs at room temperature does not cause any substantial changes in the samples. Their cooling with subsequent heating to room temperature also gives no tangible result. However, if the same samples are cooled at the moment of mechanical action, one can observe polymorphic transformations. Cooling results in a change of molecular conformation which is reversible in the absence of mechanical action, but can cause a change of molecular packing in the crystal, if cooling is accompanied by processing in a mill. On the contrary, sometimes a transformation requires to combine mechanical processing and heating. Different types of mechanical action, such as impact, shear, compression, stretching, can bring different results. For example, impact and shear can cause quite different types of transformations. Therefore, it is necessary to choose a proper treatment and sometimes even to design special devices for different transformations.

Application of hydrostatic high pressure is being used to modify pharmaceutical substances since relatively recently. It was first used at the end of the 1990s to obtain a new polymorph of paracetamol. Three polymorphs are known for this compound. One of them (the stable form at ambient conditions) is less active and is difficult to compact into tablets without using special additives. It transforms into a more active and easily compressed form at high pressure. However, a reverse process takes place during processing in the mill or manual grinding in a mortar.

Transformation of paracetamol into a new form initiated by pressure proceeds incompletely in the solid phase despite the fact that the new polymorph is thermodynamically more stable at high pressure. All molecules in a crystal of the "ambient-pressure" form are linked via a network of hydrogen to form two-dimensional layers. To rearrange this network one would need to break many bonds, and therefore this process is kinetically hindered. If we prepare a solution of the same drug and grow crystals under high pressure, the structure of the high-pressure polymorph is formed, in which all the molecules are also linked in layers by multiple hydrogen bonds. As a result, the transformation of the high-pressure polymorph back to the ambient-pressure form on decompression is also hindered, and it can be preserved as a metastable form for an indefinitely long time. Crystallization at high pressure from solutions with subsequent "quenching" on decompression can be used to obtain new polymorphs of many other pharmaceutical solids including antibiotics. Reproducible high-pressure crystallization of even small quantities of polymorphs, which are metastable under normal conditions, allows to use them further as seeds for subsequent mass crystallization already at ambient conditions.

Polymorphism can manifest itself quite unexpectedly. For example, a sample can transform irreversibly or with a very large hysteresis (temperature difference between direct and reverse transition) into another form when transported from one building to another (in winter), when delivered by air-mail or stored in a refrigerator or deep-freezer. Polymorphic transitions can be also affected by the particle size, or by the residual inclusions of mother liquor in a sample. Sometimes such a transition can be provoked by cyclic changes of temperature--from ambient to low temperature and vice versa. Contrary to the "common sense", not all medicines can or should be stored in a refrigerator!

When the crystal structure is disturbed so much that a long-range order disappears (regular arrangement of atoms and molecules preserved at indefinitely large distances from each other), the sample becomes amorphous. In this case the particle size can either decrease, or remain the same. Amorphization is one of the most common methods of producing soluble forms of drugs. To transform a solid into an amorphous state and to preserve this state for a rather long time, it is often necessary to apply mechanical treat-

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Patents received by Novosibirsk scientists for new drugs obtained from industrial wastes (betulin, serotonin, galokatechine, etc.). Photo, O. Lomovsky

ment of the solid together with an excipient. As an example, a very interesting achievement of the researchers from Izhevsk (Udmurtia) can be mentioned. Amorphous calcium gluconate possesses quite unique properties in a comparison with the crystalline form of the same compound. When administered, it gives calcium in the form that can be built into the bone tissue thus assisting in healing damaged bones and gristles, the treatment of osteoporosis and elimination of serious injuries.

COCRYSTALS AS A FRESH IDEA IN PHARMACY

Design and development of the pharmaceutical multicomponent crystals, mixed crystals or, as they are called in contemporary literature, cocrystals is a new trend in pharmaceutical science and technology. In cocrystals the molecules of different types alternate regularly, so that the crystal structure can be described by an elementary cell in which different molecules occupy strictly defined positions. Some-

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times such structures can be also regarded as nanocomposites, in which the nanometer layers and chains of components alternate to form a regular pattern. Including one or more pharmaceutical substances into a cocrystal allows one to modify such practically important properties of drugs as solubility and a dissolution rate, hygroscopicity, shelf-life, etc.

Cocrystals can be produced by crystallization from solution or from the melt, and also by co-grinding of several solid components. For example, meloxicam-- an important drug which is very poorly soluble in water--was transformed into a significantly more soluble form by co-crystallizing it with pharmaceutically allowed dicarbonic acids using co-grinding. The properties of the new cocrystals could be correlated nicely with their crystal structures. The second component added to the crystal structure breaks the centrosymmetric dimers of meloxicam molecules, and this facilitates access to meloxicam by solvent molecules on dissolution, making transition of meloxicam molecules into solution easier. As a result, much higher concentrations of meloxicam in solution can be achieved, and this supersaturation is preserved for a long time (a day and more), which is sufficient for therapy.

SYNTHETIC OR "NATURAL" SUBSTANCES?

Quite often we can hear or read in advertisements: "No chemistry, everything natural!" As a matter of fact, proper "chemical", i.e. artificially synthesized substances, are not worse than the same compounds isolated from natural materials. So why do pharmaceuticals "of natural origin" sometimes indeed appear to be more efficient as compared to synthetic analogues? The reason is that the formulations produced from a natural raw material usually include more than one component which form not a mechanical mixture, but a complex multicomponent structure, i.e. a composite. Already in prehistoric and ancient times people knew that in order to use medicinal plants it was not necessary to isolate pure substances from them. On the contrary, it is more efficient to use the whole plant just processing it properly, for example, mechanically grinding between stones.

Having passed through the "passion for chemistry" period, when extraction of pure pharmaceutical substances from natural materials by different solvents was considered a must, the Mankind turns back to original natural resources. First, the technological processes including many stages of repeated extraction using tons of expensive and toxic organic solvents and water, were replaced by mechanochemical technologies with "dry" extraction, which were less harmful for the environment and more economical. A more recent trend is to avoid the extraction of pure substances completely. Instead, the conditions of mechanical processing were found under which cell membranes of plant tissues are damaged making active substances from the cells bioavailable, the pharmaceutically valuable components remaining intact. The plant polymer fibers and other compounds remaining in such an "activated" sample do not hinder the action of biologically active compounds; on the contrary, they improve the characteristics of the drug, playing the same role as synthetic excipients in the tablets do. An advantage is that there is no need to add the excipients to the tablet---they are already included in the mechanical composite as prepared from a natural material. This is a very promising new approach. It combines the experience of etno-medicine with modern pharmaceutical technologies and allows to use efficiently natural resources. Quite often parts of plants remaining as tons of industrial or agricultural wastes, such as bark and sawdust of larch, birch, cedar, rice hulls, etc. can be used to produce valuable pharmaceuticals, including antitumor, immunomodulating and many other agents. In the South-East Asia investments in the new "dry" mechanical biotechnologies are enormous, also since these technologies make it possible to get rid of tons of wastes.

To conclude, I would emphasize that the times when producing pharmaceuticals using "recipes" or "trial and error methods" are over. To get a high quality dosage form, one needs multi-disciplinary fundamental research. Design, screening and optimizing of the dosage forms are no less important than screening and synthesis of drug substances. The work in this direction is carried on all over the world. In Novosibirsk we have a Research and Education Center "Molecular Design and Environmentally Safe Technologies" of the Novosibirsk State University. Our research is recognized by leading experts from many countries. Numerous guests coming to us to research and study from many countries, including Great Britain, Italy, Austria, the USA, Switzerland, Germany and Canada serve as true evidence of this.


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