For 40% of currently discovered drugs which are poorly water soluble, engineering amorphous nanoparticles with rapid dissolution and enhanced solubility can improve their absorption. Antisolvent precipitation by mixing organic drug solutions with aqueous solutions produced sub-300 nm amorphous nanoparticle dispersions. Polymeric stabilizers increased the nucleation rate by lowering the interfacial tension and adsorbed to particle surfaces to inhibit growth by condensation and coagulation. An increase in the stabilizer concentration decreased the average particle size until reaching a threshold where the particles were < 300 nm for the poorly water soluble drug, itraconazole. The amorphous itraconazole nanoparticle dispersions dissolved at pH 1.2 to produce high supersaturation levels up to 90-times the equilibrium solubility. The supersaturation increased with particle curvature, as described qualitatively by the Kelvin equation. A thermodynamic analysis indicated the stabilizer maintained amorphous ITZ in the solid phase with a fugacity 90-times the crystalline value, while it did not influence the activity coefficient of ITZ in the aqueous phase. Recovery of the amorphous nanoparticles from water was achieved by adding salt to desolvate the polymeric stabilizers and flocculate the particles, which could then be rapidly filtered. The flocculation under constant particle volume fraction produced open flocs which were redispersible in water to their original ~300 nm size, after filtration and drying. Amorphous particles were preserved, as flocs were formed below the drug's glass transition temperature. After flocculation/filtration, medium surface area (2-5 m²/g) particles dissolved rapidly in pH 6.8 buffer with 0.17% surfactant to an unusually large supersaturation up to 17, comparable to that for high surface area (13-36 m²/g) particles. However, the decay in supersaturation was much slower for the medium surface area particles, as the smaller excess surface area of undissolved particles produced slower nucleation and growth from solution. In contrast, the maximum supersaturation was far lower for more conventional low surface area solid dispersions of drug in polymers, because of crystallization of undissolved solid during slow dissolution. The ability to design the particle morphology to manipulate the level in supersaturation in pH 6.8 media, offers new opportunities in raising bioavailability in gastrointestinal delivery. / text

In most cases, organic materials exist in the solid phase as polymorphs, solvatomorphs or amorphous forms. Physico-chemical properties in the solid-state are all affected primarily in terms of dissolution, solubility, bioavailability, stability and processability. Therefore investigation into the polymorphic behaviour of APIs has become a mandatory part of drug characterisation studies by pharmaceutical companies (Giron, 2001). The influence polymorphism has on bioavailability and the need for the development of drugs in the amorphous form have instigated regulatory bodies such as the FDA to require solid-state characterisation of pharmaceuticals (Strachan et al., 2005). Subsequently a study was conducted to determine the physico-chemical properties of two poorly watersoluble macrolides; clarithromycin and spiramycin. Characterisation methods included: XRPD, IR, TGA, DSC, SEM, Karl Fischer titration, solubility and stability studies. Recrystallisations of spiramycin from various solvents indicated that this API mainly exists in the amorphous form. The DSC proved to be of little value in the characterisation of this particular macromolecular antibiotic, since wide inter-sample variations were mostly obtained. TGA results showed higher solvent uptake than expected. This was ascribed to the amorphous, sponge-like character of this drug. For the sake of reproducibility and quality of the results, characterisation of spiramycin was more reliant on spectroscopic and crystallographic methods. Samples generated from 2- butanol, chloroform, ethyl acetate, 1.4-dioxane, methanol, n-propanol, iso-propanol and tetrahydrofuran showed characteristic peaks in the range of 2000-2400 cm-1 that were not present in the IR spectrum of the raw material. Conversely, the XRPD patterns were all identical, exhibiting a characteristic “halo” pattern with no detectable Bragg diffraction peaks. A solubility assessment showed no significant differences between the raw material and the recrystallisation products. In fact the raw material seemed to be the form with the highest solubility, albeit it only by a small margin. According to the literature, clarithromycin exists in five forms. Form 0 exists as a solvate, form I is a metastable form, form II is the stable form (Liu & Riley 1998; Deshpande et al., 2006), form III is a solvate of acetonitrile (Liu et al., 2003; Liang & Yao, 2008) and form IV is a hydrate (Avrutov et al., 2003). The stable form II is used in formulations currently on the market. A follow-up study was done relating to a study performed by De Jager (2005). The raw material (form II) was recrystallised from acetonitrile, chloroform and ethyl acetate. Two new crystal forms were prepared from chloroform and acetonitrile. With the necessary driving force, both of these crystals forms are able to convert to the thermodynamically stable form II. In addition, a solvate recrystallised from chloroform together with its corresponding desolvate, showed a 4 and 1.5 fold respective increase in solubility when compared to the raw material. The recrystallisations from ethyl acetate delivered crystals with an XRPD pattern similar to form II. This proved that clarithromycin can be recrystallised directly from this solvent without the need of an additional conversion step, as was the case in the study done by De Jager (2005). / MSc (Pharmaceutics), North-West University, Potchefstroom Campus, 2013

Roxithromycin is a semi-synthetic, macrolide antibiotic, derived from erythromycin A. It acts as a bacteriostatic drug at low concentrations and a bactericidal drug at high concentrations. It binds to the 50S subunit of the 70S ribosome, which causes the reversible inhibition of RNA-dependent bacterial protein synthesis. It is well known that active pharmaceutical ingredients (APIs) may exist in numerous solid states. Differences in the solid state significantly influence the physical and chemical properties of an API. The in vivo performance of a dosage form will also be influenced by the solid state properties of a given pharmaceutical active. The amorphous characteristics of APIs have a significant impact on their performance and thus offer the potential for exciting new pharmaceuticals. Whilst amorphous forms of poorly soluble APIs are more soluble than their crystalline counterparts, they tend to be physically unstable, which makes their formulation into solid dosage forms quite challenging. Roxithromycin has only 50% oral bioavailability due to its poor aqueous solubility and for this reason, its potential for optimal therapeutic effect are limited. Poor solubility is thus an important obstacle in formulation development. During this study, amorphous forms of roxithromycin were prepared via quench cooling, and desolvation of chloroform- and ethyl acetate solvates. These amorphous forms were characterised by means of several techniques, whilst their solubilities and stabilities were also investigated. The outcomes of the solubility studies illustrated the complexity of this API and its amorphous forms with regards to their interactions with water. Solubility studies confirmed the superior solubility of the roxithromycin glass (prepared through quench cooling) and amorphous forms (desolvation of solvates) over the roxithromycin monohydrate in water. The solubility in water improved in the order of roxithromycin monohydrate < roxithromycin glass < roxithromycin glass powder < amorphous chloroform desolvate. The roxithromycin monohydrate, as well as the amorphous forms of roxithromycin demonstrated stability over a one-month period of exposure 40°C and relative humidity (RH) of 75%. The roxithromycin glass powder tended to revert to the more stable crystalline monohydrate after week 3 of stability testing. The roxithromycin glass at lower temperatures of 25°C and 30°C (both at 75% RH) tended to transform into the more crystalline form at week 4 of the study. These transformations were, however, not as significant as during the 40°C / 75% RH study. The conclusion could therefore be made that this transformation into the crystalline form was more temperature – than moisture dependant. At a higher temperature (at identical humidity conditions), the transformation into the crystalline form was much faster. Stability studies on the two roxithromycin desolvates were also performed in order to determine whether these amorphous forms, would differ, with regards to their stability, from the glass prepared through heating and cooling. It was determined that the desolvates were more stable than the roxithromycin glass. / Thesis (MSc (Pharmaceutics))--North-West University, Potchefstroom Campus, 2012