The present thesis deals with crystallisation and co-crystallisation of small and rigid organic molecules. The main focus was set on the two molecules benzoic acid (HBz) and benzamide. HBz and its corresponding alkali metal salts (sodium benzoate (NaBz) and potassium benzoate (KBz)) are commonly used as preservatives in the food industry. Substituted derivatives of benzamide are used in the pharmaceutical industry. Therefore both molecules are ideal model systems for studying both, polymorphism and crystallisation of active pharmaceutical ingredients (APIs). Two features are of eminent importance for the pharmaceutical industry. APIs must meet on the one hand the desired/required physico-chemical properties (solubility and stability) and on the other hand the marketed (patented) form must be phase pure.
In the HBz system two polymorphic co-crystals with sodium benzoate (2 HBz ∙ 1 NaBz (two parts HBz and one part NaBz)) could be structurally characterised. Additionally the thermodynamic relationship could be determined: form A (thermodynamically stable at room temperature) converts enantiotropically into form B (metastable at room temperature) upon heating. For several reasons this result is quite interesting. On the one hand up to now only very few polymorphic co-crystals could be structurally characterised. On the other hand the new co-crystals contribute to an answer for a general dilemma from which many pharmaceutical salts suffer. In order to realise the common 6-fold coordination for sodium, the coordination polyhedra would have to be connected by heavily shared edges and corners, even if the carboxylate group would act as bidentate ligand. The high connectivity is, however, difficult to realise due to the relatively small size of the sodium cation compared to the benzoate anion and the related steric requirements. In consequence, NaBz as marketed is a semi-crystalline material and no crystal structure could be determined until now. Lots of APIs, which often have much bigger organic anions, are suffering from the same problem. One way out of this “coordination dilemma” is co-crystallisation. The neutral HBz delivers additional coordination sites for the cation allowing for crystallisation of phase pure products. The number of additional ligands is crucially influenced be the volume ratio between the cation and the anion. Consequently, along with changes in size and coordination of the inorganic cation, stoichiometry and modes of joining polyhedra vary. Thus, for the co-crystal between HBz and lithium benzoate (LiBz) the stoichiometric ratio was determined to be 1:1 (1 HBz ∙ 1 LiBz). The reason for this can be found in the preferred 4-fold coordination of lithium. All new co-crystals were further compared to the already characterised co-crystal between HBz and potassium benzoate (KBz) (1 HBz 1 KBz) , where octahedral coordination is realized but with increased condensation of polyhedra as compared to 2 HBz ∙ 1 NaBz. In conclusion of the systematic study, the formation of these co-crystals is governed by the following factors: a) cation size, b) ratio of HBz : benzoate (stoichiometry), c) mode of coordination of the carboxylic groups (mono- or bidentate), d) connectivity (edge- or corner-sharing) and degree of condensation between neighbouring polyhedra.
By laborious optimising the conditions for crystal growth we finally also succeeded to obtain crystals of sufficient quality for crystal structure determination of the pure benzoate salts, NaBz and KBz, as well. In both of these food additives a kind of micro phase separation is realised, a phenomenon which is well known for surfactants and block copolymers. The reason for this behaviour can be traced to the amphiphilic character of the benzoate molecule. For NaBz a kind of hexagonal tube packing, while in the case of KBz a lamellar arrangement is realised.
In the second model system, benzamide, another approach was followed to optimise the solubility and therefore bioavailability. Metastable polymorphs are more soluble than thermodynamically stable forms, because of their higher Gibbs free enthalpy. Until now, however, it is still not possible to crystallise metastable polymorphs systematically and phase pure. Following Ostwald’s step rule chances to crystallise a metastable form improve when applying higher degrees of supersaturation at nucleation. This also applies to metastable form III of benzamide which was already described by Wöhler and Liebig. So far, however, only microcrystalline powders of form III in mixture with form I could be obtained. By optimising the conditions of crystal growth, now sufficiently large crystals could be obtained to allow for mechanical separation of the biphasic mixture of form I and III. Hence a phase pure sample of metastable form III could be thoroughly characterised for the first time. Comparing the results from differential scanning calorimetry (DSC) measurements of both forms, form I surprisingly showed an additional endothermic event prior to melting. Applying molecular dynamics (MD)-simulations this endothermic event could be related to the formation of metastable molecular defects, which appear before the melting point. The experimental evidence of these effects could be affirmed by 1H-SS-NMR spectroscopy measurements. The role of such defects in the course of phase transitions have long be discussed, but this is the first time that experimental evidence could be produced for molecular solids.
This work is a cumulative dissertation which describes the results explicitly in the attached publications.
|Commitee:||Senker, Jürgen , Breuning, Matthias , Papastavrou, Georg|
|School:||Universitaet Bayreuth (Germany)|
|Source:||DAI-C 81/4(E), Dissertation Abstracts International|
|Subjects:||Materials science, Chemical engineering|
|Keywords:||Crystal engineering, Molecular solid|
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