Development of a multiparticulate drug delivery system for in situ amorphisation

In the current study, the concept of multiparticulate drug delivery systems (MDDS) was applied to tablets intended for the amorphisation of supersaturated granular ASDs in situ, i.e. amorphisation within the final dosage form by microwave irradiation. The MDDS concept was hypothesised to ensure geometric and structural stability of the dosage form and to improve the in vitro disintegration and dissolution characteristics. Granules were prepared in two sizes (small and large) containing the crystalline drug celecoxib (CCX) and polyvinylpyrrolidone/vinyl acetate copolymer (PVP/VA) at a 50 % w/w drug load as well as sodium dihydrogen phosphate monohydrate as the microwave absorbing excipient. The granules were subsequently embedded in an extra-granular tablet phase composed of either the filler microcrystalline cellulose (MCC) or mannitol (MAN), as well as the disintegrant crospovidone and the lubricant magnesium stearate. The tensile strength and disintegration time were investigated prior to and after 10 min of microwave irradiation (800 and 1000 W) and the formed ASDs were characterised by X-ray powder diffraction and modulated differential scanning calorimetry. Additionally, the internal structure was elucidated by X-ray micro-Computed Tomography (XµCT) and, finally, the dissolution performance of selected tablets was investigated. The MDDS tablets displayed no geometrical changes after microwave irradiation, however, the tensile strength and disintegration time generally increased. Complete amorphisation of CCX was achieved only for the MCC-based tablets at a power input of 1000 W, while MAN-based tablets displayed partial amorphisation independent of power input. The complete amorphisation of CCX was associated with the fusion of individual ASD granules within the tablets, which negatively impacted the subsequent disintegration and dissolution performance. For these tablets, supersaturation was only observed after 60 min. On the other hand, the partially amorphised MDDS tablets displayed complete disintegration during the dissolution experiments, resulting in a fast onset of supersaturation within 5 min and an approx. 3.5-fold degree of supersaturation within the experimental timeframe (3 h). Overall, the MDDS concept was shown to potentially be a feasible dosage form for in situ amorphisation, however, there is still room for improvement to obtain a both fully amorphous and disintegrating system

Comparative study of different methods for the prediction of drug-polymer solubility

YesIn this study, a comparison of different methods to predict drug−polymer solubility was carried out on binary systems consisting of five model drugs (paracetamol, chloramphenicol, celecoxib, indomethacin, and felodipine) and polyvinylpyrrolidone/vinyl acetate copolymers (PVP/VA) of different monomer weight ratios. The drug−polymer solubility at 25 °C was predicted using the Flory−Huggins model, from data obtained at elevated temperature using thermal analysis methods based on the recrystallization of a supersaturated amorphous solid dispersion and two variations of the melting point depression method. These predictions were compared with the solubility in the low molecular weight liquid analogues of the PVP/VA copolymer (N-vinylpyrrolidone and vinyl acetate). The predicted solubilities at 25 °C varied considerably depending on the method used. However, the three thermal analysis methods ranked the predicted solubilities in the same order, except for the felodipine−PVP system. Furthermore, the magnitude of the predicted solubilities from the recrystallization method and melting point depression method correlated well with the estimates based on the solubility in the liquid analogues, which suggests that this method can be used as an initial screening tool if a liquid analogue is available. The learnings of this important comparative study provided general guidance for the selection of the most suitable method(s) for the screening of drug−polymer solubility.The Irish Research Council and Eli Lilly S.A. through an Irish Research Council Enterprise Partnership Scholarship for C.M.B., in part by The Royal Society in the form of Industrial Fellowship awarded to G.A., and in part by a research grant from Science Foundation Ireland (SFI) under Grant Number SFI/12/RC/2275 (for A.M.H., L.T., K.P., and A.K.)

Development of predictive tools for amorphous solid dosage forms

The application of amorphous solid dosage forms is one of the most promising formulation strategies to overcome the limited oral bioavailability of poorly soluble drugs. However, despite the increased interest in amorphous solid dispersions in academic and industrial research, the commercial application of this formulation strategy is still limited. This situation is mainly due to an insufficient understanding of the basic properties of amorphous solid dispersions such as their physical stability and the lack of predictive in vitro models. Therefore, the aim of the present dissertation was to contribute to the understanding and development of predictive tools for amorphous solid dispersions. The physical stability of an amorphous solid dispersion can only be fully ensured by dissolving the drug in the polymer below its equilibrium solubility (i.e. by forming a glass solution). Several methods to predict the drug–polymer solubility at room temperature have been proposed and the majority of these are based on data obtained at elevated temperature using differential scanning calorimetry (DSC) followed by extrapolation to room temperature using the Flory-Huggins model. In order to enable a rational comparison of the solubility predictions, the confidence of the extrapolation by means of a prediction interval was introduced for the solubility curve through formal statistical analysis. This approach allowed for a range of interesting studies including a large comparative study that showed that the predicted drug-polymer solubility at room temperature is significantly influenced by the method used to obtain the solubility data at elevated temperature. In order to overcome the uncertainty associated with the temperature extrapolation performed in the established methods, a new methodology to estimate drug–polymer solubility was also developed. The method is based on the solubility of a drug in a polymer dissolved in a solvent at room temperature using a simple shake-flask approach. This new method has the potential to provide faster and possibly more precise solubility estimates than the established methods, which can save valuable time in the early drug development phase. Besides contributing to an increased understanding of the stability of amorphous solid dispersions, different polymer properties responsible for improving both in vitro and in vivo performance were also identified. Even though the dissolution rate was found to decrease with increasing polymer molecular weight and hydrophobicity, the polymer that performed the best both in vitro and in vivo was neither the polymer with the highest or lowest molecular weight nor the most or least hydrophobic polymer. This indicates that for a given drug there is a molecular weight and hydrophobicity of a polymer where the balance between dissolution rate-enhancing and precipitation inhibiting factors is optimal. Furthermore, as the thermodynamic driving force for crystallization increased with increasing degree of supersaturation, it could be shown that both the in vitro and in vivo performance of amorphous solid dispersions were significantly influenced by the drug dose. In conclusion, this dissertation has contributed to the understanding of the thermodynamics behind amorphous solid dispersions and demonstrated that this formulation strategy presents an exciting possibility for oral delivery of poorly water-soluble drugs.Die Anwendung amorpher fester Arzneiformen ist eine der vielversprechendsten Formulierungsstrategien um die begrenzte orale Bioverfügbarkeit schlecht wasserlöslicher Arzneistoffe zu überwinden. Jedoch ist trotz des gestiegenen Interesses an amorphen Feststoffdispersionen, sowohl in akademischer als auch in industrieller Forschung, die kommerzielle Anwendung dieser Formulierungsstrategie nach wie vor begrenzt. Diese Situation ist in erster Linie auf ein unzureichendes Verständnis der grundlegenden Eigenschaften von amorphen Feststoffdispersionen, zum Beispiel ihrer physikalischen Stabilität, sowie auf das Fehlen von prädiktiven in vitro Modellen, zurückzuführen. Daher war es das Ziel der vorliegenden Arbeit, zum Verständnis und zur Entwicklung prädiktiver Methoden für amorphe Feststoffdispersionen beizutragen. Die physikalische Stabilität einer amorphen Feststoffdispersion kann nur dann vollständig gewährleistet werden, wenn der Arzneistoff unterhalb seiner Gleichgewichtslöslichkeit in Polymer gelöst vorliegt (d.h. durch Bildung einer Glaslösung). Mehrere Methoden wurden vorgeschlagen, um die Arzneimittel-Polymer-Löslichkeit bei Raumtemperatur vorherzusagen und die meisten dieser Methoden beruhen auf Daten, die bei erhöhten Temperaturen mittels der Dynamischen Differenzkalorimetrie erhalten werden, mit nachfolgender Extrapolation auf Raumtemperatur unter Verwendung des Flory-Huggins-Modells. Um einen rationalen Vergleich der Löslichkeitsvorhersagen zu ermöglichen, wurde durch die Einführung des Konfidenzintervalls in die Löslichkeitskurve eine formale statistische Analyse ermöglicht. Dieser Ansatz erlaubte die Durchführung einer Reihe von interessanten Studien, einschließlich einer großen vergleichenden Studie. Diese zeigten, dass die vorhergesagte Wirkstoff-Polymer-Löslichkeit bei Raumtemperatur signifikant von der verwendeten Methode beeinflusst wird, welche verwendet wird um die Löslichkeitsdaten bei erhöhter Temperatur zu erhalten. Um die Unsicherheit, die mit der Temperaturextrapolation in den etablierten Methoden einhergeht, zu überwinden, wurde eine neue Methode zur Abschätzung der Wirkstoff-Polymer-Löslichkeit entwickelt. Dieses neue Verfahren basiert auf der Ermittlung der Löslichkeit eines Arzneistoffs in einer organischen Polymerlösung bei Raumtemperatur, mittels eines einfachen Schüttelkolbenversuchsansatzes. Diese neue Methode hat das Potenzial, schnellere und möglicherweise genauere Löslichkeitsabschätzungen als die etablierten Verfahren zu ermöglichen, und daher wertvolle Zeit in der frühen Wirkstoffentwicklungsphase einzusparen. Neben den Beiträgen zum verbesserten Verständnis der Stabilität amorphen Feststoffdispersionen, wurden verschiedene Polymereigenschaften identifiziert, die für die Verbesserung sowohl der in vitro als auch der in vivo Performance verantwortlich sind. Obwohl mit steigendem Molekulargewicht und erhöhter Hydrophobizität des Polymers eine Verringerung der Auflösungsgeschwindigkeit festgestellt wurde, war das Polymer, das die beste in vitro und in vivo Performance zeigte, weder das Polymer mit dem höchsten oder niedrigsten Molekulargewicht, noch das am stärksten oder am schwächsten hydrophobe Polymer. Dies zeigt, dass es für einen gegebenen Arzneistoff ein Molekulargewicht und eine Hydrophobizität des Polymers gibt, bei der das Gleichgewicht zwischen auflösungsgeschwindigkeitssteigernden und präzipitationshemmenden Faktoren optimal ist. Da die thermodynamische Triebkraft zur Kristallisation mit zunehmendem Grad der Übersättigung erhöht wird, konnte darüber hinaus gezeigt werden, dass sowohl die in vitro als auch die in vivo Performance amorpher Feststoffdispersionen signifikant von der Arzneistoffdosis beeinflusst wird. Zusammenfassend hat diese Dissertation zum Verständnis der Thermodynamik amorpher Feststoffdispersionen beigetragen und gezeigt, dass diese Formulierungsstrategie spannende Möglichkeiten zur oralen Verabreichung schlecht wasserlöslicher Arzneistoffe bietet