S. A. Myz

How good are the crystallisation methods for co-crystals? A comparative study of piroxicam

Co-crystallisation of two components into one crystal form can enhance the solid-state properties of drug compounds. A plethora of crystallisation methods has been applied to co-crystallisation and the reported study compares the three most common ones (crystallisation from the melt, from solution and solvent-drop grinding) with respect to their applicability and necessity for a co-crystal screening. Piroxicam, a non-steroidal anti-inflammatory drug, was chosen as a model system and submitted to an extensive co-crystal screening using twenty different acids as co-crystal formers, six crystallisation techniques and five solvents. A total of 46 co-crystal forms were obtained, 38 of which are novel. Solvent-drop grinding showed the highest absolute number of experiments resulting in co-crystals, while crystallisation from the melt yielded the highest number of co-crystal formation when crystalline material was obtained. Evaporation resulted in a high number of crystalline products but many of those were binary and ternary mixtures of crystal forms. Cooling and precipitation techniques gave only poor results. Acetone and THF showed the highest number of crystalline products while chloroform gave the highest relative yield of co-crystals. Ethanol and acetonitrile showed extensive hydrate formation. No influence of the co-crystal former on the co-crystal formation could be detected.

Are meloxicam dimers really the structure-forming units in the ‘meloxicam–carboxylic acid’ co-crystals family? Relation between crystal structures and dissolution behaviour

We compare the packing of meloxicam in all the meloxicam-containing crystal structures known up to now, with a special emphasis on meloxicam and its co-crystals with carboxylic acids, two of which, with adipic and terephthalic acids, have not been reported before. We argue that it is not the meloxicam dimers, as was claimed in Cheney et al., Cryst. Growth Des. 2010, 10, 4401–4413, but a fragment containing two molecules of meloxicam linked via a carboxylic acid molecule that is the primary structure-forming element in all the known 2 : 1 meloxicam : carboxylic acid co-crystals. Meloxicam molecules form H-bonded dimers in the crystals of meloxicam, but these dimers are no longer present in any of the known meloxicam co-crystals. The molecules of meloxicam in some of its co-crystal structures can be occasionally close to each other as a consequence of a certain steric relation defined by the size of the carboxylic acid molecules. However, these molecular pairs termed “dimers” by Cheney et al. are different from the dimers in the crystals of meloxicam and can be held together by weak H-bonds only (if any), therefore they can hardly be considered as a structure-forming unit. An improved dissolution of meloxicam co-crystals as compared to poorly soluble meloxicam is supposed to be related to the presence of meloxicam dimers linked by relatively strong H-bonds in the crystals of meloxicam and to the absence of these dimers in its co-crystals.

Mechanochemical Synthesis of Nanocomposites of Drugs with Inorganic Oxides

The nanocomposites of piroxicam and indomethacin with fine porous inorganic oxides, alumina, silica, and magnesia, were obtained by high energy ball milling. Except for the piroxicam–alumina system, the composites revealed higher dissolution rate and solubility of the drugs as compared to the initial ones. The changes in the IR spectra suggested the interaction of the components during ball milling. It was assumed that the formation of new bonds at the contacts of particles in the composite resulted in stabilization of drugs in a metastable state inhibiting their transition into the initial crystalline form.

Preparation and studies of the co-crystals of meloxicam with carboxylic acids

Mechanical treatment with addition of some liquid, crystallization from solutions, and heating of the mixture components preliminary subjected to mechanical treatment were the methods used for the preparation of the co-crystals of 4-hydroxy-2-methyl-N-(5-methylthiazol-2-yl)-2H-1,2-benzothiazin-3-carboxamide 1,1-dioxide (meloxicam) with carboxylic acids. It was shown that preliminary mechanical treatment plays significant role for the synthesis, whereas the addition of small amounts of solvents accelerates the process. The co-crystals were obtained for 17 mixtures of meloxicam—carboxylic acid. The use of the co-crystals of meloxicam in the compositions of improved pharmaceutical forms was found promising, which was attributable to the fact that the dissolution rate and the solubility of the co-crystals of meloxicam with the carboxylic acids under study are higher than those for meloxicam itself.

Large porous particles for respiratory drug delivery. Glycine-based formulations

Abstract Large porous particles are becoming increasingly popular as carriers for pulmonary drug delivery with both local and systemic applications. These particles have high geometric diameters (5–30 &mgr;m) but low bulk density (˜ 0.1 g/cm3 or less) such that the aerodynamic diameter remains low (1–5 &mgr;m). In this study salbutamol and budesonide serve as model inhalable drugs with poor water solubility. A novel method is proposed for the production of dry powder inhaler formulations with enhanced aerosol performance (e.g. for salbutamol‐glycine formulation the fine particle fraction (FPF ≤ 4.7 &mgr;m) value is 67.0 ± 1.3%) from substances that are poorly soluble in water. To overcome the problems related to extremely poor aqueous solubility of the APIs, not individual solvents are used for spray freeze‐drying of API solutions, but organic‐water mixtures, which can form clathrate hydrates at low temperatures and release APIs or their complexes as fine powders, which form large porous particles after the clathrates are removed by sublimation. Zwitterionic glycine has been used as an additive to API directly in solutions prior to spray freeze‐drying, in order to prevent aggregation of powders, to enhance their dispersibility and improve air‐flow properties. The clathrate‐forming spray freeze‐drying process in the multi‐component system was optimized using low‐temperature powder X‐ray diffraction and thermal analysis. Graphical abstract Figure. No Caption available.

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.

Using SEM to design a new generation of drug forms

Detailed study and understanding of the processes that occur during the cooling and subsequent annealing of frozen solutions of drugs in two-component systems of low boiling point liquids and water with clathrate formation requires the active involvement of scanning electron microscopy (SEM) to select the optimum conditions for freeze drying and comparative analysis of samples, forms of dosage, and initial substances. A new way of creating ultrafine forms of drugs and pharmaceutical compositions by freeze drying that can easily be extended to almost all modern low-dosage drugs to improve their pharmacokinetic profile and technological properties is developed.

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).

In situ X-ray diffraction study of the processes that occur upon annealing frozen solutions in systems with clathrate formation, aimed at developing new forms of medicinal substances with improved properties

The use of in situ powder diffraction for investigating processes that occur upon the annealing of frozen solutions in binary clathrate-forming low-boiling liquid-water systems allows us to propose a new method for preparing ultrafine medicinal substances by freeze-drying. This approach is of a universal nature and can easily be applied to virtually all of today’s low-dosage medicinal substances to improve their pharmacokinetic profiles and processibility.