a. Faculty of Chemistry, University of Latvia, Kr. Valdemara 48, Riga 1013, Latvia

b. Formulation and Drug Delivery Research Group, School of Pharmacy and Biomolecular Sciences, Liverpool John Moores University, Liverpool, United Kingdom

This paper describes a study of the solvent-mediated polymorphic transformation (SMPT) of the metastable α tegafur to the thermodynamically stable β tegafur in several solvents. Phase transformation in acetone, ethanol, i-propanol, toluene, and water at 22 °C was described using the solid-state kinetic model P2; the rate constants for this process were in the range from 0.028 min-1 to 0.0056 min-1. In all of the employed solvents, an induction time was observed. Kinetic, solubility and scanning electron microscopy data indicated that nucleation kinetics corresponded to a second-order power function and according to the kinetic model, the nuclei growth rate was constant in the examined SMPT. Surface nucleation was observed, and the possible nucleation mechanism was given. The phase transition rate depended linearly on the difference between the equilibrium solubilities of α and β tegafur in the respective solvent, i.e. supersaturation.

a. Faculty of Chemistry, University of Latvia, Kr. Valdemara 48, Riga 1013, Latvia

An experimental and theoretical investigation of protonation effects on the UV/Vis absorption spectra of imatinib showed systematic changes of absorption depending on the pH, and a new absorption band appeared below pH 2. These changes in the UV/Vis absorption spectra were interpreted using quantum chemical calculations. The geometry of various imatinib cations in the gas phase and in ethanol solution was optimized with the DFT/B3LYP method. The resultant geometries were compared to the experimentally determined crystal structures of imatinib salts. The semi-empirical ZINDO-CI method was employed to calculate the absorption lines and electronic transitions. Our study suggests that the formation of the extra near-UV absorption band resulted from an increase of imatinib trication concentration in the solution, while the rapid increase of the first absorption maximum could be attributed to both the formation of imatinib trication and tetracation.

a. Faculty of Chemistry, University of Latvia, Kr. Valdemara 48, Riga 1013, Latvia

This paper reports an investigation of a complex solid state phase transition where two inter-converting polymorphs (X and A) of the pharmaceutical molecule xylazine hydrochloride formed and transformed during and after the dehydration of its monohydrate (H). The crystal structures of all three forms were compared. During the investigation of this solid state phase transition it was determined that the dehydration of H produced either a pure X form, or a mixture of the X and A forms. The phase composition depended on the sample preparation procedure and the experimental conditions. It was found that grinding of the hydrate enhanced the formation of polymorph X as a product of dehydration, whereas higher humidity, temperature, or mechanical compression enhanced the formation of polymorph A. The transition mechanism of this complex process was analysed and explained by taking into account the crystal structures of these three forms.

a. Faculty of Chemistry, University of Latvia, Kr. Valdemara 48, Riga 1013, Latvia

In order to find a tool for comparison of solvate stability and to rationalize their relative stability, droperidol nonstoichiometric isostructural solvates were characterized experimentally and computationally. For the experimental evaluation of stability, three comparison tools were considered: thermal stability characterized by the desolvation rate, desolvation activation energy, and solvent sorption-desorption isotherms. It was found that the desolvation process was limited by diffusion, and the same activation energy values were obtained for all of the characterized solvates, while the solvent content in the sorption isotherm was determined by the steric factors. Therefore, the only criterion characterizing the solvate stability in this particular system was the thermal stability. It was found that computationally obtained solvent-droperidol and solvent-solvent interaction energies could be used for the rationalization of the isostructural solvate stability in this system and that the solvent-solvent interaction energy has a crucial role in determining the stability of solvates.

a. Faculty of Chemistry, University of Latvia, Kr. Valdemara 48, Riga 1013, Latvia

The dehydration of mildronate dihydrate (3-(1,1,1-trimethylhydrazin-1-ium- 2-yl)propionate dihydrate) was investigated by powder X-ray diffraction, thermal analysis, hot-stage microscopy, water sorption-desorption studies and dehydration kinetic studies. It was determined that mildronate dihydrate dehydrated in a single step, directly transforming into the anhydrous form. In order to understand the reasons for a one step dehydration mechanism, crystal structures of dihydrate, monohydrate and anhydrous forms were compared, proving the similarity of the dihydrate and anhydrous forms. In order to understand the reasons for molecule reorganization during dehydration, the energy of the anhydrous form was compared with that of a theoretical dihydrate structure without water molecules. It was proven that the experimentally observed anhydrous phase AP was thermodynamically more stable. By analyzing the effect of the particle size and sample weight on the dehydration kinetic parameters it was determined that besides the main rate limiting step, phase boundary advancement, contribution from the water diffusion outside the crystal and the water diffusion outside the powdered sample also appeared to affect the dehydration kinetics and contribution from these processes could be changed by changing the aforementioned factors.

a. Faculty of Chemistry, University of Latvia, Kr. Valdemara 48, Riga 1013, Latvia

A solvate screening and characterization of the obtained solvates was performed to rationalize and understand the solvate formation of active pharamaceutical ingredient droperidol. The solvate screening revealed that droperidol can form 11 different solvates. The analysis of the crystal structures and molecular properties revealed that droperidol solvate formation is mainly driven by the inability of droperidol molecules to pack efficiently. The obtained droperidol solvates were characterized by X-ray diffraction and thermal analysis. It was found that droperidol forms seven nonstoichiometric isostructural solvates, and the crystal structures were determined for five of these solvates. To better understand the structure of these five solvates, their solvent sorption-desorption isotherms were recorded, and lattice parameter dependence on the solvent content was determined. This revealed a different behavior of the nonstoichiometic hydrate, which was explained by the simultaneous insertion of two hydrogen-bonded water molecules. Isostructural solvates were formed with sufficiently small solvent molecules providing effective intermolecular interactions, and solvate formation was rationalized based on already presented solvent classification. The lack of solvent specificity in isostructural solvates was explained by the very effective interactions between droperidol molecules. Desolvation of stoichiometric droperidol solvates produced one of the four droperidol polymorphs, whereas that of nonstoichiometic solvates produced an isostructural desolvate.

a. Faculty of Chemistry, University of Latvia, Kr. Valdemara 48, Riga 1013, Latvia

The control of inorganic contaminants in active pharmaceutical ingredients has a significant role in the quality control of drug products. The concentration limits for metal residues in drug products have been defined by various regulatory guidelines. Laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS) is a powerful and fast analytical technique for multi-elemental analysis. A disadvantage in using LA-ICP-MS method is the lack of matrix reference materials for validation and calibration purposes. This article focuses on the handling strategy of laboratory-made matrix calibration standards for the quantification of elemental impurities in an active pharmaceutical ingredient by LA-ICP-MS.

a. Faculty of Chemistry, University of Latvia, Kr. Valdemara 48, Riga 1013, Latvia

The kinetics of the solid-state phase transformation of xylazine hydrochloride form X to A has been investigated using powder X-ray diffraction and differential thermal analysis. Three different kinetic models have been used to describe transition kinetics: the Avrami-Erofeev equation, the Cardew equation, and the methodology for simulation of solid-state phase transition kinetics by the combination of nucleation and nuclei growth processes. The latter has been recently developed and has been tested in this paper for the case of a real solid-state transition. The relative humidity, mechanical pressure, temperature, and sample-preparation effect on phase-transition kinetics have been investigated, and rate constant changes have been analyzed.

a. Faculty of Chemistry, University of Latvia, Kr. Valdemara 48, Riga 1013, Latvia

b. Latvia Institute of Organic Synthesis, Aizkraukles 21, Riga 1006, Latvia

Flecainide base is pharmaceutically active substance used for production of flecainide acetate which is known in market as Tambacor, Almarytm, Apocard, Ecrinal or Flecaine. It is determined that flecainide base forms four polymorphic forms abbreviated as Ib, IIb, IIIb and IVb. Flecainide base form Ib is thermodynamically stable form at laboratory temperature while form IIIb is stable at higher temperatures. Flecainide form Ib absorbs water in its structure between layers and forms non-stoichiometric hydrate. Flecainide base binds with organic solvents and form monosolvates. Flecainide base form Ib crystallizes in orthorhombic crystals with lattice parameters a=27.88Å, b=13.78Å, c=9.98Å and two independent molecules in unit cell (Z =2; Z=8). Molecule arrangement in flecainide base form Ib structure is not dense and it forms a channel-type structure, where molecules of water and alcohols are placed.

a. Faculty of Chemistry, University of Latvia, Kr. Valdemara 48, Riga 1013, Latvia

b. Faculty of Natural Sciences and Mathematics, Daugavpils University, Daugavpils, Latvia

Flecainide base is pharmaceutically active substance used for production of flecainide acetate which is known in market as Tambacor, Almarytm, Apocard, Ecrinal or Flecaine. It is determined that flecainide base forms four polymorphic forms abbreviated as Ib, IIb, IIIb and IVb. Flecainide base form Ib is thermodynamically stable form at laboratory temperature while form IIIb is stable at higher temperatures. Flecainide form Ib absorbs water in its structure between layers and forms non-stoichiometric hydrate. Flecainide base binds with organic solvents and form monosolvates. Flecainide base form Ib crystallizes in orthorhombic crystals with lattice parameters a=27.88Å, b=13.78Å, c=9.98Å and two independent molecules in unit cell (Z =2; Z=8). Molecule arrangement in flecainide base form Ib structure is not dense and it forms a channel-type structure, where molecules of water and alcohols are placed.

a. Faculty of Chemistry, University of Latvia, Kr. Valdemara 48, Riga 1013, Latvia

b. Latvia Institute of Organic Synthesis, Aizkraukles 21, Riga 1006, Latvia

The umifenovir salts of maleic, salicylic, glutaric, and gentisic acid as well as the chloroform solvate of the salicylate were prepared. Single crystals of the five compounds were obtained and their molecular and crystal structures determined by X-ray diffraction. In each structure the conformation of phenyl ring with respect to the indole group of the umifenovir moiety is different. The water solubility and melting points of the studied umifenovir salts have been determined.

a. Faculty of Chemistry, University of Latvia, Kr. Valdemara 48, Riga 1013, Latvia

b. Latvia Institute of Organic Synthesis, Aizkraukles 21, Riga 1006, Latvia

A new polymorph of the cinnamic acid-isoniazid cocrystal has been prepared by slow evaporation, namely cinnamic acid-pyridine-4-carbohydrazide (1/1), C9H8O2•C6H7N 3O. The crystal structure is characterized by a hydrogen-bonded tetrameric arrangement of two molecules of isoniazid and two of cinnamic acid. Possible modification of the hydrogen bonding was investigated by changing the hydrazide group of isoniazid via an in situ reaction with acetone and cocrystallization with cinnamic acid. In the structure of cinnamic acid-N'-(propan-2-ylidene)isonicotinohydrazide (1/1), C9H 8O2•C9H11N3O, carboxylic acid-pyridine O - H⋯N and hydrazide-hydrazide N - H⋯O hydrogen bonds are formed.

a. Faculty of Chemistry, University of Latvia, Kr. Valdemara 48, Riga 1013, Latvia

The dehydration kinetics of mildronate dihydrate [3-(1,1,1- trimethylhydrazin-1-ium-2-yl)propionate dihydrate] was analyzed in isothermal and nonisothermal modes. The particle size, sample preparation and storage, sample weight, nitrogen flow rate, relative humidity, and sample history were varied in order to evaluate the effect of these factors and to more accurately interpret the data obtained from such analysis. It was determined that comparable kinetic parameters can be obtained in both isothermal and nonisothermal mode. However, dehydration activation energy values obtained in nonisothermal mode showed variation with conversion degree because of different rate-limiting step energy at higher temperature. Moreover, carrying out experiments in this mode required consideration of additional experimental complications. Our study of the different sample and experimental factor effect revealed information about changes of the dehydration rate-limiting step energy, variable contribution from different rate limiting steps, as well as clarified the dehydration mechanism. Procedures for convenient and fast determination of dehydration kinetic parameters were offered.