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A new type of hybrid compound, combining properties of MOFs and borohydrides, was synthesized solvothermally using Mg(BH4)2 and imidazole as precursors. Material in the form of acetonitrile solvate with formula [Mg3{(Im)BH2(Im)}6(ImH)6] ·CH3CN crystallizes in the space group R¯3, having the unit cell parameters a = 15.1942(2)˚A and c = 28.3157(3)˚A as determined by single crystal X-ray diffraction. The structure was further investigated by solid state NMR and DFT quantum chemical calculations. The main feature of the structure, reported here for the first time, is a linear trinuclear complex, where octahedrally nitrogen-coordinated Mg2+ ions are bridged with {(Im)BH2(Im)}– units, forming inside voids of 4.6˚A in diameter between the magnesium ions. Polar intermolecular interactions hold the molecules in a dense 1 Page 1 of 32 ACS Paragon Plus Environment Submitted to Inorganic Chemistry 123456789 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 rhombohedral stacking, where a disordered acetonitrile molecule plays a cohesive role. The compound is stable in air and upon heating to about 160 ◦C. Using an alternative synthesis method from imidazole melt, an imidazole solvate with the formula [Mg3{(Im)BH2(Im)}6(ImH)6] ·ImH and a very similar crystal structure to acetonitrile solvate was prepared. It is stable up to 220 ◦C. Upon further heating, it transformed into a layered structure with the formula Mg(Im3BH)2, space group P¯31c, and unit cell parameters a = 8.7442(4)˚A, c = 17.643(2)˚A determined by synchrotron powder diffraction. Besides its structural novelty, two types of potentially reactive hydrogens, bonded to boron and nitrogen in the same molecule, make the material highly interesting for future investigations in the fields of energy storage applications.

Izvēlētu farmaceitiski aktīvo vielu cieto šķīdumu veidošanās iespējas un analīze. Saršūns K., darba vadītājs Dr. Chem. Bērziņš A. Bakalaura darbs, 76 lappuses, 43 attēli, 28 tabulas, 6 pielikumi, 55 literatūras avoti. Latviešu valodā. Bakalaura darba ietvaros ir apkopota informācija par farmaceitiski aktīvajām vielām - benperidolu un droperidolu, kā arī par barbitūrskābi un tiobarbitūrskābi, vispārīgs preparātu raksturojums, polimorfisma parādība, kristalizācijas process, cieto šķīdumu raksturojums, papildus tam arī par rentgendifraktometriju, diferenciālo skenējošo kalorimetriju, termogravimetriju un 1H-KMR spektroskopiju, kā par fizikālajām cietfāžu pētīšanas metodēm, kas tika izmantotas pētījumos. Eksperimentālajā daļā ir veikta benperidola – droperidola un barbitūrskābes – tiobarbitūrskābes vielu maisījumu pārkristalizēšana no dažādiem šķīdinātājiem un tā rezultātā – dažādu cieto šķīdumu iegūšana. Ar pulvera rentgendifraktometru identificētas eksperimentāli iegūtās kristāliskās fāzes, kā arī, apvienojot to ar termiskās analīzes metodēm, pētītas kristālisko formu un solvātu (t.sk. arī hidrātu) pārvērtības, fāžu pārejas desolvatācijas laikā un identificēti tās rezultātā radušies produkti. Papildus tam noteikti izvēlētu iegūto cieto šķīdumu kristālisko režģu parametri, izmantojot eksperimentāli iegūtos pulvera rentgendifraktometrijas datus, kā arī starpmolekulāro mijiedarbību enerģiju vērtības, un izmantojot iegūtos kodolmagnētiskās rezonanses spektrus, iegūta informācija par benperidola – droperidola attiecību kristalizācijas produktos., Preparation and formation analysis of solid solutions of a selected pharmaceutical active substances. Saršūns K., supervisor Dr. Chem. Bērziņš A. Bachelor thesis, 76 pages, 43 figures, 28 tables, 6 supplements, 55 references. In Latvian. This bachelor thesis contains information about pharmaceutical active substances - benperidol and droperidol, as well as barbituric acid and thiobarbituric acid, general characterization of preparations, polymorphism, crystallization process, description of solid solutions, in addition about X-ray powder diffraction, differential scanning calorimetry, thermogravimetric analysis and nuclear magnetic resonance as physical solid-phase methods that have been employed in this research. Experimental part includes benperidol – droperidol and barbituric acid – thiobarbituric acid mixture of substances recrystallization from different solvents, and as a result – various solid solutions. Crystalline phases that were obtained during the work were identified using X-ray powder diffraction. Studies about crystaline forms and solvates (including hydrates) transformations, phase transitions in desolvation process and identifying of desolvation products were realised by combining X-ray powder diffraction with a thermal analysis methods. Crystalline lattice parameters of a selected solid solutions obtained were determined by using the experimentally obtained X-ray powder diffractometry pattern, as well as energy values of intermolecular interactions, and using the resulting nuclear magnetic resonance spectrum, obtained information about the ratio of benperidol – droperidol in crystallization products.

2-metil-4-nitrobenzoskābes un 2-fluor-4-nitrobenzoskābes solvātu un polimorfu iegūšana un raksturošana. Jarmuts A., darba vadītājs vadošais pētnieks Dr. chem. Agris Bērziņš. Bakalaura darbs. 73 lappuses, 66 attēli, 8 tabulas, 3 pielikumi, 50 literatūras avoti. Latviešu valodā. Bakalaura darbā ir aprakstīti divi nitrobenzoskābes izomēri: 2-metil-4-nitrobenzoskābe un 2-fluor-4-nitrobenzoskābe. Tika atrasta un apkopota informācija par pētītajām vielām, cietvielu kristāliskām formām, polimorfismu un solvātiem. Darbā tika izmantotās šādas fizikālās pētīšanas metodes: pulvera rentgendifraktometrija, diferenciālā skenējošā kalorimetrija (DSK), termogravimetrija (TG), kodolmagnētiskās rezonanses spektroskopija un augsttemperatūras rentgendifraktometrija. Eksperimentālajā daļā tika sintizēta 2-fluor-4-nitrobenzoskābe no 2-fluor-4-nitrotoluola, iegūtā viela (kopā ar 2-metil-4-nitrobenzoskābi) bija pārkristalizēta no vairākiem šķīdinātājiem. Iegūtās kristāliskās formas identificētas ar pulvera rentgendifraktometru un analizētas, izmantojot iepriekšminētās fizikālās pētīšanas metodes. Izmantojot eksperimentāli iegūtos pulvera rentgendifraktometrijas datus tika noteiktas kristālisko režģu parametri un 2-metil-4-nitrobenzoskābes polimorfu I un II kristāliskā struktūra. 2-METIL-4-NITROBENZOSKĀBE, SOLVĀTI, 2-FLUOR-4-NITROBENZOSKĀBE, SOLVATĀCIJA, KOFORMĒRI, POLIMORFISMS, STRUKTŪRFORMULU NOTEIKŠANA, Preparation and characterization of 2-methyl-4-nitrobenzoic and 2-fluor-4-nitrobenzoic acid solvates and polymorphs. Jarmuts A, supervisor senior researcher Dr. Chem. Agris Bērziņš. Term paper consists of 73 pages, 66 pictures, 8 tables, 50 literature references. Written in latvian. This bachelor thesis contains information about two nitrobenzoic acid isomers: 2-methyl-4-nitrobenzoic acid and 2-fluor-4-nitrobenzoic acid. The information about crystalline polymorphism and solvates was found and gathered. The following physical research methods were used in the work: X-ray powder diffraction, differential scanning calorimetry (DSC), thermogravimetry (TG), solid-state nuclear magnetic resonance spectroscopy, and high-temperature chamber. Experimental part involves the synthesis of 2-fluor-4-nitrobenzoic acid from 2-fluoro-4-nitrotoluene. The resulting substance (as well as 2-methyl-4-nitrobenzoic acid) was recrystallized from several solvents. The obtained crystalline forms were identified by X-ray powder diffraction and analyzed using the above-mentioned methods. Using experimentally obtained X-ray powder diffraction data, crystalline lattice parameters and 2-methyl-4-benzoic acid I un II polymorph forms crystal structure were determined. 2-METHYL-4-NITROBENZOIC, SOLVATES, 2-FLUOR-4-NITROBENZOIC ACID, SOLVATION, CONFORMERS, POLYMORFISM, STRUCTURE DETERMINATION

Bikarfēna un ivabradīna kristālisko formu izpēte. Borisova A., zinātniskais vadītājs Dr. ķīm., prof. Andris Actiņš. Maģistra darbs, 60 lpp., 19 attēli, 7 tabulas, 46 literatūras avoti, 2 pielikumi. Latviešu valodā Darbs ir veltīts farmaceitisko vielu bikarfēna un ivabradīna kristālisko formu izpētei. Bikarfēna A formas paraugs tika pārkristalizēts no 25 šķīdinātājiem, ir iegūti 14 bikarfēna solvāti. Tika pārbaudīta solvātu stabilitāte paaugstinātā temperatūrā. Ivabradīna 10 kristālisko formu iegūšana bija veikta, pamatojoties uz pēdējo gadu patentos norādītām metodikām., Research of Bicarphen and Ivabradine crystalline forms. Borisova A., supervisor Dr. Chem., prof. Andris Actiņš. Master’s thesis, 60 pages, 19 figures, 7 tables, 46 literature references, 2 appendices. In Latvian. Solid forms of pharmaceutical substances bicarphen and ivabradine were studied. In experiments with 25 solvents were obtained 14 solvates of bicarphen. Stability of solvates were tested. Experiments were taken to find 10 crystalline forms of Ivabradine. Those experiments were based on last years patents

2-hlor-4-nitrobenzoskābes un tās izomēru solvātu un polimorfu iegūšana unraksturošana. Bogdanova E., darba vadītājs Dr. Chem. Bērziņš A. Bakalaura darbs. 74 lappuses,40 attēli, 9 tabulas, 5 pielikumi, 48 literatūras avoti. Latviešu valodā. Bakalaura darba ietvaros ir apkopota informācija par 2-hlor-4-nitrobenzoskābi, tāsizomēriem, polimorfisma parādību, solvātiem, kā arī par rentgendifraktometriju,termogravimetriju, diferenciālo skenējošo kalorimetriju, diferenciāli termisko analīzi un kodolmagnētisko rezonansi, kā par metodēm, kas tika izmantotas pētījumos. Eksperimentālajā daļā ir veikta CNBA jeb hlornitrobenzoskābes izomēru pārkristalizēšana no 27 dažādiem šķīdinātājiem un tā rezultātā – polimorfo modifikāciju un dažādu solvātu iegūšana. Ar pulvera rentgendifraktometru identificētas eksperimentāli iegūtās kristāliskās formas, kā arī, apvienojot to ar termisko analīzi un kodolmagnētisko rezonanses spektrometriju, pētītas solvātu pārvērtības, fāžu pārejas desolvatācijas laikā un identificēti tās rezultātā radušies produkti. Līdz šim literatūras avotos neaprakstītajiem hlornitrobenzoskābes izomēriem tika noteiktas struktūrformulas, kristālisko režģu parametri, kā arī starpmolekulāro mijiedarbibu enerģiju vērtības, izmantojot eksperimentāli iegūtos pulvera rentgendifraktometrijas datus., Preparation and characterization of 2-chloro-4nitrobenzoic acid and its isomers’ solvates and polymorphs. Bogdanova E., supervisor Dr. Chem. Bērziņš A. Bachelor thesis.74 pages, 40 figures, 9 tables, 5 supplements, 48 references. In Latvian. This bachelor thesis contains information about 2-chloro-4-nitrobenzoic acid, itsisomers, polymorphism, solvates as well as about X-ray powder diffraction, thermogravimetricanalysis, differential scanning calorimetry, differential thermal analysis and nuclear magneticresonance as methods that have been employed in this research. Experimental part includes crystallisaton of chloronitrobenzoic acid’s isomers from 27 different solvents and as a result –preparation of polymorphic modifications and solvates. Crystalline forms that were obtainedduring the work were identified using X – ray powder diffraction. Studies about solvate, transformations, phase transitions in desolvation process and identifying of desolvationproducts were realised by combining XRD with a thermal analysis methods and nuclear magnetic resonance spectrometry. Crystalline lattice parameters, structures as well as energy of intermolecular interactions of chloronitrobenzoic acid’s isomers that weren’t explored before, were determinated using experimental X – ray powder diffraction pattern.

Holskābes metilestera solvātu desolvatācija. Trimdale A., darba vadītājs Dr. Chem. Bērziņš A. Bakalaura darbs, 64 lappuses, 41 attēls, 4 tabulas, 7 pielikumi, 36 literatūras avoti. Latviešu valodā. Darbā apkopota informācija par holskābes metilesteri, polimorfismu, solvātiem un pētījumos izmantotajām metodēm: pulvera rentgendifraktometriju, termiskajām analīzes metodēm un IS spektroskopiju. Eksperimentālajā daļā veikta dažādu holskābes metilestera solvātu iegūšana. Ar pulvera rentgendifraktometru gan tradicionālā režīmā, gan aprīkotu ar karsēšanas un klimatisko apstākļu kameru, kā arī ar derivatogrāfiju pētīts un noskaidrots iegūto solvātu desolvatācijas mehānisms un identificēti desolvatācijas produkti. Jauniegūtajām holskābes metilestera polimorfajām formām un dažiem solvātiem no to pulvera rentgendifraktogrammām noteikti kristāliskā režģa parametri, kā arī IV polimorfajai formai un dihlormetāna solvātam noteikta to kristāliskā struktūra., Desolvation of methyl cholate solvates. Trimdale A., supervisor Dr. Chem. Bērziņš A. Bachelor thesis. 64 pages, 41 figures, 4 tables, 36 references. In Latvian. This work contains information about methyl cholate, polymorphism, solvates and used methods: X – ray powder diffraction, thermal analysis and IR spectroscopy. In the experimental part various solvates of methyl cholate were prepared. X – ray powder diffractometer in conventional mode and equipped with heating stage or environmental chamber, as well as thermal analysis were employed to analyze and clarify desolvation mechanism and identify products of desolvatation. Lattice parameteres of the discovered methyl cholate polymorphs and some of the solvates were determined from X – ray powder diffraction data. Also, crystal structure of polymorph IV and dichlormethane solvate was determined.

Dasatiniba solvātu iegūšana un raksturošana. Čerņavska K., Darba vadītājs vadošā pētniece Dr. chem. Orola L., Maģistra darbs, 51 lappuses, 24 attēli, 18 tabulas, 71 literatūras avoti. Latviešu valodā. Darbā ir veikta dasatiniba solvātu iegūšana ar sekojošiem šķīdinātājiem: acetonitrilu, nitrometānu, etilacetātu, acetonu, 1,4-dioksānu, 1,3-dioksalānu, butilacetātu, tetrahidrofurānu, izopropilalkoholu, metiletilketonu, metilacetātu, n-propanolu, izobutanolu, n-butanolu, izopropilacetātu, etanolu, toluolu un dimetilsulfoksīdu. Iegūtie solvāti tika analizēti ar pulvera rentgendifraktometrijas metodi un diferenciālās termiskās analīzes/termogravimetrijas (DTA/TG) metodi. Iegūtajiem solvātiem tika veikta stabilitātes noteikšana 24 °C un 100 °C temperatūrā. Izmantojot suspendēšanas metodi divu šķīdinātāju maisījumā, dasatiniba solvātiem tika veikta veidošanas priekšrokas pārbaude., Preparation and characterization of dasatinib solvates. Čerņavska K., Supervisor senior researcher Dr. chem. Orola L., Master thesis, 51 pages, 24 images, 18 tables, 71 literature references. In Latvian. In this study dasatinib solvates with acetonitrile, nitromethane, ethyl acetate, acetone, 1,4-dioxane, 1,3-dioxolane, butyl acetate, tetrahydrofuran, isopropyl alcohol, methyl ethyl ketone, methyl acetate, n-propanol, isobutanol, n-butanol, isopropyl acetate, ethanol, toluene and dimethyl sulfoxide were prepared. Powder X-ray diffractometry, differential thermal analysis and thermogravimetry were used for the analysis of these compounds. Desolvation of dasatinib solvates was carried out at 24 °C and 100 °C temperatures. In addition, the formation relationships in 2-solvent mixture between different dasatinib solvate were determined by slurring. DASATINIB, SOLVATES, SLURRING, DESOLVATION, POWDER X-RAY DIFFRACTOMETRY, THERMAL ANALYSIS.

Holskābes un tās atvasinājumu solvātu veidošanās un desolvatācijas mehānisms. Zvaniņa D., darba vadītāji prof. Actiņš A., Mg.Chem. Bērziņs A. Maģistra darbs, 60 lappuses, 27 attēli, 6 tabulas, 47 literatūras avoti, 3 pielikumi. Latviešu valodā. Darbā tika pagatavots holskābes metilestera dimetilformamīda solvāts un, kristalizējot holskābes metilesteri no izo-propanola, n-propanola un izo-butilspirta, iegūta holskābes metilestera I polimorfā forma. Kristalizējot holskābi, henodeoksiholskābi un ursodeoksiholskābi no dažādiem organiskajiem šķīdinātājiem, tika iegūti holskābes etanola, metanola un acetonitrila solvāti un henodeoksiholskābes nitrometāna solvāts. Iegūtās cietās fāzes tika pārbaudītas ar pulvera rentgendifraktometru. Ar pulvera rentgendifraktometru un derivatogrāfu tika pētīta iegūto solvātu desolvatācijas mehānisms un desolvatācjias produkti. Darbā mēģināts izprast un izskaidrot atšķirības novērotajā holskābes, henodeoksiholskābes, ursodeoksiholskābes un holskābes metilesterao solvātu veidošanās daudzveidībā, analizējot šo savienojumu kristāliskās struktūras. Lai to izskaidrotu, veica šo savienojumu polimorfu struktūru kvantitatīvu analīzi datorprogrammā PIXEL, ar datorprogrammu Gaussian 09 analizēja enerģijas, kas saistītas ar holskābes un holskābes metilestera iespējamo konformāciju to kristāliskajās struktūrās, kā arī salīdzināja stipro ūdeņraža saišu veidošanās efektivitāti visās pieejamajās pētīto vielu kristāliskajās struktūrās., Formation and desolvation mechanism of cholic acid and its derivatives. Zvaniņa D., supervisors prof. Actiņš A, Mg.Chem. Bērziņš A. Master thesis, 60 pages, 27 figures, 6 tables, 47 references, 3 appendix. In Latvian. In this work methyl cholate dimethylformamide solvate was prepared, whereas crystallization of the methyl cholate from iso-propanol, n-propanol and izo-butanol produced methyl cholate polymorph I. Crystallization of cholic acid, chenodeoxycholic acid and ursodeoxycholic acid from various organis solvents produced cholic acid ethanol, methanol, and acetonitrile solvates as well as chenodeoxycholic acid nitromethane solvates. The obtained solid phases were identified using X-ray powder diffraction. The desolvation mechanism and desolvation products of the obtained solvates were analyzed using X-ray powder diffraction and thermal analysis. In this work it was tried to understand and explain the observed differences in the diversity of the solvate formation of cgolic acid, chenodeoxycholic acid, ursodeoxycholic acid, and methyl cholate by analyzing the crystalline structures formed by these compounds. To explain this quantitative analysis of the crystal structures of the mentioned compound polymorphs was performed with computer program PIXEL, the energy associated with the potential conformations of cholic acid and methyl cholate in the crystalline structures was analyzed with computer program Gaussian 09, and the efficient of the strong hydrogen bonding formation was compared in all accessible crystal structures of the studied compounds.

Na primjeru odabranih modelnih supstancija razrađena je metodologija pretraživanja i karakterizacije čvrstif formi, koja je primijenjena na odabranim djelatnim tvarima, sildenafilu i flurirtinu. Pretraživanjem čvrstih formi sildenafila pripravljeno je 9 novih soli u obliku 14 anhidro formi, 7 solvata i 4 hidrata. Dodatno je priređen jedan kokristal te jedna sol- kokristal. Proučavanjem svojstava novopripravljenih čvrstih formi odabran je čitav niz kandidata za razvoj novih, poboljšanih finalnih dorirnih oblika. Poswbno zanimljiv slučaj formiranja kokristala sildenafila i acetilsalicilne kiseline te soli-kokristala sildenafil-acetilsalicilata sa salicilnom kiselinom je detaljno istražen. Konstruiran je trofazni dijagram priprave te su za obje specije određene krivulje topljivosti u odabranim otapalima. Pretraživanjem čvrstih formi flupirtina pripravljeno je 14 novih soli, koje su podvrgnute detaljnoj karakterizaciji te proučavanju svojstava. Kao rezultat odabrane su 3 soli kao kandidati za razvoj finalnog dozirnog oblika poboljšanih svojstava. Za jednu od odabranih soli određene su krivulje topljivosti u odabranim otapalima te je pomoću njih razvijen postupak prekristalizacije.

Solvati nastaju kada tvar kristalizira iz otopine tako da u kristalnu strukturu ulazi i molekule otapala (solventa). Farmakološki aktivne tvari su tvari koje utječu na ljudski organizam. Svaki solvat može imati različit utjecaj na ljudski organizam. Svojstva solvata koja se najviše razlikuju su brzina otapanja, konstanta topljivosti i bioraspoloživost. Vrsta solvata može imati drastičan utjecaj na fizikalna svojstva lijeka, razvoj sinteze, oblika doziranja i u konačnici skladištenje lijeka. Razlikuju se u svojim svojstvima stoga je proizvodnja točnog solvata bitna u raznim granama industrije, a posebno u farmaceutskoj industriji. Budući da je voda najneotrovnije i najneutralnije otapalo, u farmaceutskoj industriji su najčešći solvati hidrati. Agencije za nadzor lijekova kao što su Europska agencija za lijekove (EMA) ili američka Agencija za nadzor hrane i lijekova (FDA) sa zadrškom uzimaju u obzir ostale solvate farmakoloških aktivnih tvari. Ukoliko otapalo u solvatu aktivne tvari nije voda, prolazi puno veće procedura i opširnija istraživanja nego u slučaju hidrata. Upravo se zbog toga farmaceutske tvrtke odlučuju prije na razvoj hidrata nego drugih solvata.

The variety of crystal forms that may be associated with one specific molecule of interest can be extremely large: in addition to polymorphs, all sorts of crystalline solids can be obtained, from molecular and ionic co-crystals to hydrates/solvates, to, needless to say, polymorphs of all these new crystal forms. Lack of predictability of crystallization experiments, far from representing a failure or a nuisance, should encourage in the crystal maker the same attitude shown by the three princes of Serendip (who were making unexpected discoveries by virtue of their “sagacity and readiness of mind”) to be ready to pick new avenues as the crystal experiments will yield something unplanned for.