Thesis (MSc)--Stellenbosch University, 2014. / ENGLISH ABSTRACT: A theoretical and experimental study was performed in order to identify factors that influence the propensity of compounds containing anionic functional groups that are commonly found on pharmaceutical drug compounds to form hydrates. A Cambridge Structural Database (CSD) survey was initially undertaken to determine the propensity of different pharmaceutically acceptable anions to form hydrates. The results showed that hydrate formation will take place more regularly when the polarity of the functional group increases. Furthermore, if the charge distribution is very concentrated over the polar groups, hydrate formation will occur more readily. This observation was further investigated by performing a series of potential energy surface (PES) scans for the hydrogen bond (H-bond) in the structure of N-(aminoiminomethyl)-N-methylglycine monohydrate (creatine monohydrate) with various Density Functional Theory (DFT) and Wave Functional Theory (WFT) methods. WFT is often also referred to as ab initio, which refers to the construction of the wave function from first principles when this theory is applied. The scans revealed that several strong and directional H-bonds with different geometrical parameters between the carboxylate group and the water molecule are possible, which suggests that the H-bond plays an important role in driving the formation of pharmaceutical hydrates.
A total of 44 hydrate structures were identified that have pharmaceutically acceptable functional groups. Optimisations in the gas phase and in an implicit solvent polarisable continuum solvent model with a variety of solvents showed that there is a significant dependence of the H-bond interaction energy on the anionic group as well as the steric density of surrounding substituents. It was found that the M06-2X method utilising the 6-311++G(d,p) basis set outperformed the other methods that were tested when compared to optimisations performed with the benchmark MP2/aug-cc-pVTZ level of theory. Furthermore, the strength of the H-bond was measured in the 44 experimentally determined structures by using a total of five generalized gradient approximation (GGA) methods, of which two methods contained the DFT-D3 correction. The results of these DFT methods were subsequently compared to results obtained at the benchmark MP2/aug-cc-pVTZ level of theory. The M06-2X method was identified as the most economical method to calculate H-bond energies. It was also found that the H-bond interaction energy shows a substantial dependence on the electrostatic environment. This was observed by a significant decrease in H-bond strength as the relative permittivity of the solvent increases. The effect of steric density on the H-bond interaction energy was investigated by performing hydrogen bond propensity calculations. These values were then compared to the interaction energies of each structure and the results showed that the presence of large bulky substituents can lead to an increase in bond energy by forcing the anionic functional group closer to the water molecule. Contrastingly, the bulky group can also push the anionic group away from the water molecule and result in a decrease in bond energy. Approximate values for the amount of stabilisation offered to the H-bonding system by the surrounding crystalline environment were calculated by optimising the H-bond geometrical parameters of selected compounds with a combination of the M06-2X and MP2 methods utilising the 6-311++G(d,p) basis set. The H-bond interaction energies were then calculated at the M06-2X/6-311++G(d,p) level of theory and compared to the H-bond interaction energies in geometries that have been fully optimised. After these energies were compared and the crystal packing of each structure was investigated, it was found that the packing of some structures within the crystalline environment limits the number of H-bonds that can be formed between the water and the compound of interest. Full optimisation calculations result in structures with cooperative stabilisation, such that more than one H-bond is found between the two fragments.
The effect of substituents on H-bond interaction energy was investigated by the addition of six electron-donating and electron-withdrawing groups on four aromatic compounds with different anionic functional groups, namely carboxylate, nitrogen dioxide, sulfonate and phosphonate. It should also be mentioned that the nitrogen dioxide is not an anionic functional group, but it was included as it is a neutral radical that often forms hydrogen bonds.
A total of 80 structures were optimised with a combination of the M06-2X and MP2 methods utilising the 6-311++G(d,p) basis set. This was followed by counterpoise corrected single point calculations at the M06-2X/6-311++G(d,p) level of theory. The results showed that the H-bond interaction energy bears no relationship to the inductive strength or the inductive ability of the substituents, but rather the ability of these substituents to rotate the anionic functional group and allow cooperative stabilisation of the H-bond. Furthermore, AIM analysis was performed for the substituted H-bonded aromatic structure. The results showed that electron-donating groups that are placed at the para position yield stronger H-bonds, which is once again accompanied by cooperative stabilisation. Electron-withdrawing groups with sufficient inductive effects can result in a weaker H-bond when placed at the meta position. The effect of water activity (aw) on the hydrate crystal formation was investigated experimentally by performing a series of crystallisations in various solvent mixtures. These mixtures consisted of water mixed with acetone, ethanol and ethyl acetate. A total of three organic acids were used in crystal formation, namely pyridine-4-carboxylic acid (isonicotinic acid), N-amino-iminomethyl-N-methylglycine (creatine) and benzene-1,3,5-tricarboxylic acid. It was found that water activity affects the formation of the hydrate as well as the anhydrous product. Additionally, nucleation and super saturation plays a large role in crystal formation and can serve as an effective technique when the formation of crystals of an appropriate shape and size is required for further analysis. / AFRIKAANSE OPSOMMING: 'n Teoretiese en eksperimentele studie was uitgevoer om faktore te identifiseer wat die geneigdheid van verbindings met anioniese funksionele groepe wat algemeen gevind word op farmaseutiese dwelm verbindings om die hidraat produk te vorm, affekteer. 'n Opname van strukture in die Cambridge Strukturele Databasis (CSD) is onderneem om die geneigdheid van verskillende farmaseutiese aanvaarbare anione om hidrate te vorm te bepaal. Die resultate het getoon dat hidraatvorming meer gereeld plaasvind indien die polariteit van die funksionele groepe toeneem. Verder is daar ook opgemerk dat 'n gekonsentreerde ladingsverspreiding op die polêre groepe ook tot 'n toename in hidraat vorming sal lei. Hierdie waarneming is verder ondersoek deur 'n reeks potensiële energie oppervlak (PES) skanderings van die waterstof binding (H-binding) vir die struktuur van N-amino-iminometiel-N-metielglisien monohidraat (kreatien monohidraat) met verskeie Digtheids-Funksionele Teorie (DFT) en Golffunksie Teorie (WFT) metodes uit te voer. Die skanderings het getoon dat verskeie sterk, gerigte H-bindings met verskillende geometriese parameters tussen die karboksilaatgroep en die watermolekule kan vorm. Hierdie bevindinge lê klem op die belangrike rol wat H-bindings in die vorming van farmaseutiese koolhidrate speel. 'n Totaal van 44 hidraat strukture met farmaseutiese aanvaarbare funksionele groepe was geïdentifiseer. Optimaliserings is in die gas fase asook in 'n implisiete kontinuum polariseerbare oplosmiddel model met 'n verskeidenheid oplosmiddels uitgevoer. Die resultate het 'n beduidende afhanklikheid van die H-binding interaksie-energie op die anioniese groep asook die steriese afkskerming van omringende groepe getoon. Daar is bepaal dat die M06-2X metode wat saam met die 6-311++G(d,p) basisstel die mees akkuraatste resultate gelewer het in vergelyking met die ander DFT metodes asook die MP2/aug-cc-pVTZ maatstaf. Die H-binding se sterkte is vir hierdie strukture bereken deur vyf GGA metodes te gebruik, waarvan twee metodes van die DFT-D3 korreksie gebruik maak. Die resultate van die berekeninge met hierdie DFT metodes is daarna vergelyk met resultate verkry met die MP2/aug-cc-pVTZ maatstaf. Daar is gevolglik bepaal dat die M06-2X metode die mees ekonomiese metode is om H-binding energië te bereken. Die H-binding interaksie energie toon 'n aansienlike afhanklikheid op die diëlektriese konstante van die oplosmiddel aan. Hierdie waarneming is op grond van 'n beduidende afname in die H-binding interaksie-energie indien die relatiewe permittiwiteit van die oplosmiddel verhoog word gemaak. Die effek van steriese digtheid is ondersoek deur waterstofbindinggeneigdheid waardes te bereken. Hierdie waardes is met die interaksie-energië van elke struktuur vergelyk. Die resultate dui daarop dat steries digte groepe tot 'n toename in interaksie energie kan lei wanneer die anioniese funksionele groep nader aan die water molekule gestoot word. Verder is dit ook moontlik vir hierdie steries digte groepe om die anioniese groep weg van die water molekule te stoot en gevolglik 'n afname in interaksie energie te veroorsaak. Benaderde waardes vir die hoeveelheid stabilisering wat die omringende kristallyne omgewing aan die H-binding bied is bereken deur die H-binding geometriese parameters van geselekteerde verbindings met die M06-2X en MP2 metodes en die 6-311++G (d,p) basisstel te optimaliseer. Die H-binding interaksie-energië is gevolglik by die M06-2X/6-311++G(d,p) vlak van teorie bereken en met die H-binding energië in strukture wat volledige optimaliseer is vergelyk. Nadat hierdie waardes vergelyk is, is daar gevind dat die pakking van strukture in the kristallyne omgewing verhoed dat sekere H-bindings tussen die water molekule en die verbinding van belang kan vorm. Strukture wat volledig optimaliseer is, lei tot strukture wat in staat is om koöperatiewe stabilisering te ondergaan. Koöperatiewe stabilisering word gekenmerk deur die vorming van meer as een H-binding tussen twee fragmente. Die effek van substituente op die H-binding interaksie energie is ondersoek deur die bevoeging van ses elektrondonor- en elektronontrekkendegroepe op vier aromatiese verbindings, naamlike die karboksilaatgroep , stikstofdioksied , sulfonaat en fosfonaat. Dit moet ook genoem word dat stikstofdioksied nie 'n anioniese funksionele groep is nie, maar dit was wel ingesluit omdat dit ‘n neutrale radikaal groep is wat dikwels waterstofbindings vorm.
'n Totaal van 80 strukture optimiserings was uitgevoer met 'n kombinasie van die M06-2X en MP2 metodes wat gebruik maak van die 6-311++G(d,p) basisstel. Dit is gevolg deur interaksie-energie berekeninge op die M06-2X/6-311++G(d,p) vlak van teorie. Die resultate het getoon dat daar geen verband tussen die induktiewe vermoë van die substituente en die sterkte van die H-binding is nie, dit is eerder die vermoë van hierdie substituente om die anioniese funksionele groep te laat roteer wat toelaat dat koöperatiewe stabilisering van die H-binding kan geskied. Die AIM analise is op 'n gesubstitueerde H-binding struktuur toegepas. Die resultate het getoon dat elektrondonorgroepe wat by die para posisie geplaas word tot sterker H-bindings sal lei, wat weereens met koöperatiewe stabilisering vergesel word. Elektrononttrekkendegroepe met sterk induktiewe effekte kan tot 'n swakker H-binding lei indien hulle by die meta posisie geplaas word. Die effek van water aktiwiteit (𝑎w) op hidraatkristalvorming is deur die uitvoering van 'n reeks kristallisasies in verskeie oplosmiddelmengsels ondersoek. Hierdie oplosmiddel mengsels bestaan uit water met asetoon, etanol of etielasetaat gemeng. Kristallisasies is vir drie organiese sure, naamlik piridien-4-karboksielsuur, N-amino-iminometiel-N-metielglisien monohidraat en 1,3,5-benseen tri-karboksielsuur uitgevoer. Daar is gevind dat water aktiwiteit 'n invloed op die vorming van die hidraat en watervrye produkte kan hê. Daarbenewens, speel water aktiwiteit 'n belangrike rol in die nukleasie fase van kristalvorming en kan as 'n effektiewe tegniek dien om kristalle van 'n toepaslike vorm en grootte vir verdere analise te verkry.
| Identifer | oai:union.ndltd.org:netd.ac.za/oai:union.ndltd.org:sun/oai:scholar.sun.ac.za:10019.1/95979 |
| Date | 12 1900 |
| Creators | Dippenaar, Alwyn Bernard |
| Contributors | Esterhuysen, Catharine, Haynes, Delia Ann, Stellenbosch University.Faculty of Science. Dept. of Chemistry and Polymer Science. |
| Publisher | Stellenbosch : Stellenbosch University |
| Source Sets | South African National ETD Portal |
| Language | en_ZA |
| Detected Language | English |
| Type | Thesis |
| Format | 147 p. : ill. (some col.) |
| Rights | Stellenbosch University |
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