Rottendorf Pharma GmbH

Amino groups derived from naturally abundant amino acids or (di)amines can be used as “shuttles” in nature for oxygen transfer to provide intermediates or products comprising N-O functional groups such as N-hydroxy, oxazine, isoxazolidine, nitro, nitrone, oxime, C-, S-, or N-nitroso, and azoxy units. To this end, molecular oxygen is activated by flavin, heme, or metal cofactor-containing enzymes and transferred to initially obtain N-hydroxy compounds, which can be further functionalized. In this review, we focus on flavin-dependent N-hydroxylating enzymes, which play a major role in the production of secondary metabolites, such as siderophores or antimicrobial agents. Flavoprotein monooxygenases of higher organisms (among others, in humans) can interact with nitrogen-bearing secondary metabolites or are relevant with respect to detoxification metabolism and are thus of importance to understand potential medical applications. Many enzymes that catalyze N-hydroxylation reactions have specific substrate scopes and others are rather relaxed. The subsequent conversion towards various N-O or N-N comprising molecules is also described. Overall, flavin-dependent N-hydroxylating enzymes can accept amines, diamines, amino acids, amino sugars, and amino aromatic compounds and thus provide access to versatile families of compounds containing the N-O motif. Natural roles as well as synthetic applications are highlighted.Key points• N-O and N-N comprising natural and (semi)synthetic products are highlighted.• Flavin-based NMOs with respect to mechanism, structure, and phylogeny are reviewed.• Applications in natural product formation and synthetic approaches are provided.

Incorporating poorly soluble drugs into polymeric nanoparticles is a widely investigated approach to improve their biopharmaceutical performance. Poly(DL-lactide-co-glycolide) (PLGA) nanoparticle formulations have previously been tested and recommended as drug carriers for peroral administration of poorly soluble porphyrin derivatives intended for photodynamical therapy. Based on those PLGA formulations the present study investigates conventional techniques like fluid bed granulation and tableting for conversion of such polymeric nanoparticle suspensions into solid dosage forms. Analytical methods like asymmetrical flow field-flow fractionation (AF4) and photon correlation spectroscopy (PCS) were used to assess changes of the nanoparticle properties during processing and the recovery after redispersion of the solid dosage forms. Preliminary experiments were conducted to demonstrate the feasibility of the granulation and tableting strategy. Afterwards, design of experiments (DoE) was used to determine formulation and process parameters with critical influence on several properties of the solid forms, in particular the recovery of nanoparticles during dissolution testing. Fluid bed granulation with aqueous PLGA nanoparticle suspensions and soluble carriers was shown to be a simple and high yield process for drying of the nanoparticles. The nanoparticle concentration of the granulation suspension and the ratio of the spraying rate and the atomization air pressure were critical for the physicochemical characteristics of the granules like density and particle size distribution (PSD) as well as for the redispersibility to nanoparticle suspensions of original properties. The granules were compressed to tablets without impairing the nanoparticle diameter and the recovery when an adequate level of filler and low compression forces were used.

Microcrystalline cellulose (MCC) is the most important pelletization aid in extrusion/spheronization. Because of known disadvantages, the search for substitutes is ongoing. In this context, crospovidone has proven to offer substantial advantages as pelletization aid because of its ability to turn low-soluble active ingredients into fast-dissolving stable pellets.

Pellets from crospovidone with different amounts of paracetamol, hydrochlorothiazide, and spironolactone as model drugs were prepared by extrusion/spheronization. For comparison, pellets with MCC as extrusion aid were also produced. The pellets of different formulations were evaluated in terms of yield, aspect ratio, mean Feret diameter, 10% interval fraction, tensile strength, disintegration, and drug release profile.

Only crospovidone types exhibiting small particle sizes are suitable as pelletization aid. While maintaining the pharmaceutical quality aspects, it was possible to incorporate up to 60% (w/w) active pharmaceutical ingredients (API) into pellets with crospovidone. The most distinguished differences between pellets based on crospovidone and MCC are the disintegration and drug release behavior. The pellets containing binary mixtures of the low-soluble APIs and crospovidone resulted in fast release in contrast to the pellets with MCC as pelletization aid, which exhibited a slow release.

Crospovidone shows an excellent behavior as pelletization aid and produces fast-releasing pellets even with low-soluble APIs.