Solvent inclusion properties of triamterene crystal forms and solubility differences between roxithromycin polymorphic forms

Abstract

Polymorphism is very common among drug substances. Differences in the physical properties of a solid form may impact largely on the processing of a drug substance, while differences in solubility may impact on the absorption of the active drug from its dosage form, by affecting the dissolution rate and possibly the mass transport of the molecules. Changes in the crystal form at any stage of the production process can alter the bioavailability of the drug. With this theory in mind, the following objectives were identified with respect to triamterene and roxithromycin, two active pharmaceutical ingredients that are known for their poor water solubility: a) The preparation of different polymorphic and / or pseudopolymorphic forms of triamterene and roxithromycin, in an attempt to isolate a more water-soluble form; b) The investigation of the physical properties (i.e. solubility, stability, crystal morphology and thermal properties) of the different forms being prepared; c) To identify those polymorphic forms of roxithromycin that are the most amorphous; and d) To investigate the respective solubility profiles of the various polymorphs of triamterene and roxithromycin, and to determine the influence of their crystal morphology on solubility. Characterisations of these different crystal forms are important when considering the development of solid dosage forms. Various methods of analysis include microscopy, crystallography, thermal analysis, molecular motion, solubility, and Karl Fischer titrations. These methods were combined in this study for the identification and characterisation of triamterene and roxithromycin crystals. Triamterene is insoluble in water, most of the organic solutions, but is more soluble in acids, such as formic acid. In this study triamterene was recrystallised from various organic solvents, i.e. acids, DMF and DMF:water mixtures, and alcohols. From the data being generated during this study it was concluded that: a) The recrystallisation products from the three acid solvents produced disolvates, i.e. novel pseudopolymorphic forms of triamterene; b) The 2-butanol recrystallisation products were either hydrates, solvates, or hydrated solvates; c) DMF and DMF:water mixtures only yielded solvates. Recrystallisation of triamterene was unfortunately hampered by low solubility and hence crystal yield, which made it impossible to obtain enough crystals on which to perform solubility studies. This was unfortunate, since it was reported in the literature that active pharmaceutical ingredients (APl's) with low solubilities, such as mebendazole, showed significant differences in solubilities between the different polymorphic forms. Roxithromycin is very slightly soluble in water, slightly soluble in diluted hydrochloric acid, and freely soluble in acetone, alcohol and dichloromethane. It was reported that some of the roxithromycin polymorphic forms gave problems during a powder dissolution study, due to poor wettability in the dissolution medium. Furthermore, prior to the dissolution, during vortexing of the powder, a gel formed, which complicated the quantitative transfer of the samples into the dissolution vessels, hence resulting in poor dissolution results. The aim of this investigation thus was to prepare different crystal forms of roxithromycin, and, instead of performing powder dissolution studies, to determine the solubility thereof, which would arguably be a better method of discriminating between the solubilities of the different forms. The different recrystallisation products that were obtained from the different solvents during this study were classified as: a) A ethyl acetate hemi-solvate (would require confirmation with single X-ray crystallography); b) A meta-stable lower melting point form recrystallised from acetonitrile; c) A dichloromethane hemi-solvate (would require confirmation with single X-ray crystallography); and d) An amorphous chloroform solvate. The ethyl acetate hemi-solvate proved to be the only form with a significantly better solubility profile in all three media tested, than that of the raw material. These results have created new questions regarding the morphology and differences in crystal forms of roxithromycin. It should be challenging to prepare quality crystals, suitable for single X-ray crystallography, in order to clarify the actual crystal forms of this complex antibiotic, since all the recrystallisation products tended to be more amorphous, having low peak intensity counts (XRPD). Furthermore, the fact that roxithromycin has no free hydroxyl groups, explains the poor wettability and the hydrophobicity, hence its poor solubility in water. The outcomes of this study, however, raised the question as to why the solubility of the prepared ethyl acetate crystal form differed so much from the other prepared forms, especially with regards to its higher solubility in water. This finding, especially, has therefore created the need for further investigation and it is anticipated that such further studies would solve the solubility problems of roxithromycin in aqueous media.