Mechanochemical synthesis and physicochemical characterization of isoniazid and pyrazinamide co-crystals with Glutaric acid

The present work reports two novel pharmaceutical co-crystals; 2:1 isoniazid-glutaric acid (INHGA) and 2:1 pyrazinamide-glutaric acid (PGA). Isoniazid and pyrazinamide are key first-line drugs used for the treatment of tuberculosis. The co-crystals were produced via solid-state and solvent assisted grinding methods. Thermal characteristics of the samples were obtained using the differential scanning calorimetry, hot stage microscopy, and thermogravimetric analyses. The morphology of the powder samples by scanning electron microscopy, structural analysis by Fourier transform infrared spectroscopy and powder X-rays diffraction ensured co-crystal formation. Thermal analyses confirmed the co-crystals with new melting transitions ranging between their respective starting materials. Unique morphologies of the co-crystal particles were clear in SEM micrographs. The formation of intermolecular interactions with the co-crystal former was confirmed by the FT-IR spectral band shifting and was supported by distinct PXRD patterns of co-crystals thereby authenticating the successful co-crystal formation. In vitro solubility evaluation of the synthesized co-crystals by HPLC suggested a remarkable increase in solubility of both INH and PZA in their respective co-crystals

Assessment of the tableting properties of chitosan through wet granulation and direct compression formulations

Thesis (M.Sc. (Pharmaceutics))--North-West University, Potchefstroom Campus, 2005.Chitosan is a natural polysaccharide that is obtained by the partial deacetylation of chitin, the second most abundant natural polymer. Chitosan is currently extensively utilised in various pharmaceutical and non-pharmaceutical preparations. It has found wide applicability in conventional pharmaceutical devices as a potential formulation excipient. As a pharmaceutical excipient, its main contribution seems to be as an absorption enhancer of large molecule drugs from the gastro-intestinal tract (through "tight junctions") and as a fat absorber in dietary products. Although it is present in various tablet preparations, little if any is known about the tablet ability of this versatile polymer. Characterisation of chitosan raw material revealed poor flowability, a large partide size distribution and poor compressibility. These properties provided the challenges circumvented in this study. The direct compression of chitosan indicated that the flowabillity and compressibility of the polymer were insufficient to produce acceptable tablets comprising of pure chitosan raw material. Therefore, chitosan was combined with Avicelp PH200 and Prosolvp SMCCm 90 respectively. The properties of tablets comprising of chitosan and these directly compressible fillers were compared in terms of filler concentration and mixing time. It was found that Avicelp PH200 proved to be most effective at a concentration of 30% (w/w). Furthermore, a mixing time of 10 minutes produced optimal results for all the chitosan / filler combinations. The inclusion of single dry binders was investigated to assess the suitability of dry binders as enhancers of the binding properties of chitosan raw material. Kollidon" VA-64 (co-polyvidone) and Methocep K100M hydroxypropylmethylcellulose) were combined respectively with chitosan raw material in concentrations of 4, 5, 7, 10, 15 or 20% w/w. It was evident that chitosan exhibited a significantly higher sensitivity for Kollidon' VA-64 than for Methocelp K100M. A log-linear relation between the Kollidon" VA-64 concentration and crushing strength was identified. This could be considered a significant attribute of the chitosan / Kollidon' VA-64 combination, since this correlation could be utilised to predict the crushing strength of tablets comprising of chitosan and Kollion' VA-64 at any given concentration of the binder. In comparison with the combinations containing the directly compressible fillers the formulation comprising of 20% w/w Kollidong VA-64 produced superior crushing strength and friability. Conversely, the chitosan / Methocel' K100M mixtures revealed erratic and relatively unacceptable results in terms of crushing strength and friability. However, the presence of Methocep K100M in the formulations seemed advantageous to tablet disintegration. Therefore, the combination of both binders in different concentration ratios were investigated to determine whether a combination of the dry binders would result in potentiation of the binding effect during compression and furthermore if the presence of Methocelp K100M would enhance the disintegration of the tablets. Concentration ratios of 1:1; 3:1 and 1:3 (Kollidon~ VA-64 : MethocelP K100M) were utilised during these experiments. The formulations comprising of single dry binders produced superior results compared to the formulations containing the dry binder combinations. Furthermore, it was evident that the binder combinations did not result in the potentiation of the binding effect nor did it prove advantageous in terms of tablet disintegration. Since the characterisation of chitosan raw material proved that this polymer exhibited poor flowability, the subsequent wet granulation of chitosan was investigated utilising low and high speed granulation. kollidon" VA-64 (co-polyvidone) and Methocelp K100M (hydroxypropylmethylcellulose) were the two binders utilised in concentrations of 3% and 5% w/w respectively during granulation. Wet granulation of the polymer did improve the flowabillity, however, the inherent characteristics of chitosan still affected the tabletability of the material. Therefore, the inclusion of extragranular binder was necessitated to improve the binding of chitosan granules during compression. Kollidon" VA-64 and Methocelp K100M were utilised as external binders in concentrations of 3,5,7 and 10% w/w. Generally, the granulation processes overall improved the tabletability of the polymer since it was possible to compress larger quantities of chitosan with the aid of selected binders. Kollidon~ VA-64 posed to be better suited as a granulation binder for chitosan, compared to Methocelp K100M. Dissolution studies provided a method to determine the effect(s) of chitosan as well as the included binders on drug release. Furosemide was included in selected formulations as a tracer drug. The gel-forming ability of chitosan in acidic pH evidently decreased the release rate of the incorporated drug. Dissolution profiles of all the formulations containing chitosan granules and extragranular binder indicated sustained release of furosemide (24 hour period). Since Methocelp K100M also possesses the ability to form a gel layer on contact with water or biological fluid, the production of matrix tablets was a possibility. However, it was clear that a total concentration of 15% w/w Methocel-P K100M was insufficient to achieve matrix-like dissolution profiles. The combination of chitosan and Methocel℗ KIOOM proved to be advantageous in the formulation of sustained release dosage forms. Short-term stability testing of chitosan raw material proved that the exposure of chitosan to elevated temperatures had a detrimental effect on the tabletability of the polymer. Furthermore, it was evident that lower moisture content (sorbed water) detrimentally affected the compressibility of chitosan raw material. Long-term stability testing indicated that ambient conditions could have pronounced effects on the physical properties of the raw material, chitosan tablets as well as the granules. Furthermore, the tablets comprising of Methocelp K100M revealed the most significant deterioration in terms of crushing strength and friability. In contradiction, the tablets containing Avicep PH200 revealed the most acceptable results, confirming that direct compression produced the optimal system in terms of product stability. However, the combination of chitosan with binders allows the exclusion of Avicelp PH200. However, the formulations containing binders (granulate) revealed poor stability. It could be concluded that the storage of chitosan raw material, tablets or granules should be ensured at temperatures lower that 25 "C and relative humidity not exceeding 60%. The optimisation of chitosan raw material for utilisation in tablet formulations as well as its applicability as pharmaceutical excipient was pertinently illustrated.Master

Different amorphous solid-state forms of roxithromycin: a thermodynamic and morphological study

The striking impact that different preparation methods have on the characteristics of amorphous solidstate forms has attracted considerable attention during the last two decades. The pursuit of more extensive knowledge regarding polyamorphism therefore continues. The aim of this study was firstly, to investigate the influence of different preparation techniques to obtain amorphous solid-state forms for the same active pharmaceutical ingredient, namely roxithromycin. The preparation techniques also report on a method utilizing hot air, which although it is based on a melt intermediary step, is considered a novel preparation method. Secondly, to conduct an in-depth investigation into any physico-chemical differences between the resulting amorphous forms and thirdly, to bring our findings into context with that of previous work done, whilst simultaneously discussing a well-defined interpretation for the term polyamorphism and propose a discernment between true polyamorphism and pseudo-polyamorphism/ atypical-polyamorphism. The preparation techniques included melt, solution, and a combination of solution-mechanical disruption as intermediary steps. The resulting amorphous forms were investigated using differential scanning calorimetry, X-ray powder diffraction, hot-stage microscopy, scanning electron microscopy, and vapor sorption. Clear and significant thermodynamic differences were determined between the four amorphous forms. It was also deduced from this study that different preparation techniques have a mentionable impact on the morphological properties of the resulting amorphous roxithromycin powders. Thermodynamic properties as well as the physical characteristics of the amorphous forms greatly governed other physico-chemical properties i.e. solubility and dissolutionNational Research Foundation (NRF) of South Africa(Grant no.: TTK13020718661); Centre of Excellence for Pharmaceutical Sciences (Pharmacen) at the North-West Univer- sity Potchefstroom, South Afric