Development and evaluation of nano-formulations for immediate release oral dosage forms of poorly soluble drugs

Inaugural-Dissertation to obtain the academic degree Doctor rerum naturalium (Dr. rer. nat.) submitted to the Department of Biology, Chemistry, Pharmacy of Freie Universität Berlin by Zun Huang

Solubility and dissolution rate are essential for the oral absorption and thus bioavailability of poorly soluble drugs. Currently, there are various formulation approaches available to overcome issues in solubility and dissolution rate. However, single formulation approach always has its drawback. The purpose of this work was to explore the nano-cocrystal formulation by combining cocrystal and nanocrystal formulation technologies and to optimize the formulation by investigating its dissolution mechanism. A downstream process investigation was also explored to transform the nano-cocrystal formulation into a final oral solid dosage form. Preparation and optimization of nanocrystal formulations with different lab-scale wet milling methods Different laboratory-scale nanocrystal preparation methods were compared as milling efficiency and process attributes. Dual centrifugation milling was considered the most promising method with higher milling efficiency, formulation screening efficiency, and broader controllable process attributes. Applying the dual centrifugation milling method to efficiently screen stabilizers and adjust process parameters, optimized itraconazole nanocrystal stabilized by poloxamer 407 was produced with a mean particle size of 200 nm and PDI 0.2. The nanosuspension was physically stable at 4, 25 and 40 °C for one month. The optimized nanocrystal formulation exhibited a faster dissolution rate than the physical mixture and raw drug under sink or non-sink conditions in in vitro dissolution study. While compared with commercial product Sporanox®, nanocrystal formulation exhibited faster drug release under sink conditions but lower and limited solubility increment under non-sink conditions. Itraconazole nanocrystal formulation might not exhibit advantageous in vivo behavior compared to the commercial product. A selection of a suitable in vitro dissolution test to evaluate nanocrystal formulation was crucial. In addition, nanocrystalline formulation significantly improved the dissolution rate of poorly soluble APIs, while its increases in solubility were limited. Finally, some other solubilization methods like cocrystal or amorphization could be combined with the nanocrystal approach and utilized to offer a practical approach for delivering orally poorly soluble drugs. Combination of cocrystal and nanocrystal techniques to improve the solubility and dissolution rate of poorly soluble drugs Four itraconazole and indomethacin nano-cocrystals with mean particle diameters of around 450 nm were successfully prepared. Solid-state characterization suggested that by transforming raw drug powder into its cocrystal form is a new strategy for the preparation of nano-formulations which are physically or chemically unstable during wet milling. Furthermore, in situ solubility studies indicated that nano-cocrystals showed remarkably higher solubility and dissolution rate compared to nanocrystals and cocrystals. The maximum kinetic solubility of nano-cocrystals increased with excess conditions until reaches a plateau. The highest increase was obtained with itraconazole-succinic acid nano-cocrystals with a solubility of 263.5 ± 3.9 µg/mL which is 51.5 and 6.6 times higher than the solubility of itraconazole crystalline and itraconazole-succinic acid cocrystal. The combination of cocrystals and nanocrystals could potentially overcome the limitation of nanocrystals in solubility improvement and the limitation of cocrystal in dissolution rate improvement. Nanocrystal technique efficiently promotes the potential of cocrystal solubilization effect by its superior dissolution rate. This nano-cocrystal formulation expands the drug development strategies of poorly soluble drugs. Itraconazole-succinic acid nano-cocrystals: Kinetic solubility improvement and influence of polymers on controlled supersaturation A systematic experimental investigation was conducted to explore the precipitation inhibition capacity of a range of commonly used precipitation inhibitors (HPMC E5, HPMC E50, HPMCAS, HPC-SSL, PVPK30 and PVPVA64) in itraconazole-succinic acid nano-cocrystal formulation. HPMC E5 achieved greatest extended nano-cocrystals dissolution and maintenance of supersaturation based on specific drug/polymer intermolecular interaction. Dissolved polymer not only increased maximum achievable supersaturation, but also maintained supersaturation for prolonged times, resulting in significantly broadened AUC maxima. The maximum achievable supersaturation was proportional to the dissolution rate which can be modulated by the rate of supersaturation generation (i.e., addition rate or dose). Supersaturation could be prolonged significantly resulting in 2-5-fold increased area under the dissolution curves compared to nano-cocrystals alone. This effect was however limited by a critical excess of undissolved particles with high specific surface area which acted as crystallization seeds resulting in faster precipitation. To achieve higher and sustained supersaturation from nano-cocrystal formulation during dissolution, faster dissolution rate and proper application of precipitation inhibitors were two driving factors. The relationship between particle size, dose and polymer ratio and their synergic impact on the supersaturation must be considered. Generally, these insights and findings would contribute to the design of optimally performing oral solid dosage formulations with incorporated nano-cocrystals. Incorporation of itraconazole nano-cocrystal into granulated or bead-layered solid dosage forms Three downstream processes (wet granulation, spray granulation, and bead layering) were evaluated on the performance of itraconazole-succinic acid nano-cocrystal suspension. Limited by low drug loading and slow dissolution profile, traditional wet granulation was not suitable for downstream processing of nano-cocrystal formulation. Spray granulation and bead layering could increase the drug loading without significantly compromising the rapid dissolution behavior of nano-cocrystal. However, the type of substrate used for spray granulation impacted the dissolution performance from the granules containing nano-cocrystals. Faster dissolution profiles and higher maximum solubility were obtained when the water-soluble substrate was used. While the type of substrate has no impact on the dissolution behavior of beads layered with nano-cocrystals. Furthermore, during the accelerated stability studies, the nano-cocrystal processed by spray granulation was less stable than nano-cocrystal processed by bead layering upon 3 months storage at 40 °C/75% RH in non-blistered condition. Overall, bead layering was the most suitable method for the downstream process of nano-cocrystal suspensions with the overall performance of a solid product.

In conclusion, this entire work indicated that the combination of cocrystals and nanocrystals could potentially overcome the limitation of nanocrystals in solubility improvement and the limitation of cocrystal in dissolution rate improvement. Nano-cocrystal formulations could be optimized with adding specific precipitation inhibitor. Bead layering was a superior downstream process approach for incorporating nano-cocrystals into an oral solid dosage form without compromising release.

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Materials
Drugs: Itraconazole (BASF AG, Ludwigshafen, Germany), Sporanox® 100 mg capsules (Janssen GmbH, Neuss, Germany), indomethacin (Fluka Chemie AG, Buchs, Switzerland)

Stabilizers: Poloxamer 188, poloxamer 407, Tween 80, D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) (BASF SE, Ludwigshafen, Germany), sodium dodecyl sulfate (SDS) (Carl Roth GmbH & Co., Karlsruhe, Germany)

Polymers: hydroxypropyl methylcellulose E5/E50 (HPMC E5/E50), hydroxypropylmethylcellulose acetate succinate (HPMCAS) (Colorcon Ltd., Dartford Kent, UK), hydroxypropyl cellulose (HPC-SSL) (Nisso Chemical Europe, Düsseldorf, Germany), polyvinyl pyrrolidone (PVP K30), polyvinyl pyrrolidone vinyl acetate copolymer (PVPVA64) (BASF SE, Ludwigshafen, Germany)

Solvents: Methanol, ethanol, chloroform, tetrahydrofuran, ethyl acetate, dimethyl sulfoxide (DMSO) (Carl Roth GmbH & Co., Karlsruhe, Germany), ultrapurified water purified by a Milli-Q-apparatus (Millipore GmbH, Darmstadt, Germany)

Other chemicals: Fumaric acid, succinic acid, saccharin, nicotinamide (Merck KGaA, Darmstadt, Germany), lactose (Granulac® 200, Meggle AG, Wasserburg, Germany), microcrystalline cellulose (Avicel® PH102, FMC BioPolymers, Philadelphia, USA)), sugar beads (Suglets® 25-30 mesh, 600–710 μm diameter, NP Pharm S.A., Bazainville, France), MCC beads (Celphere® CP-507 grade, 500-710 μm diameter, Asahi Kasei Chemicals Corporation, Tokyo, Japan), hydrochloride (HCl), sodium hydroxide (NaOH), sodium chloride (NaCl) (Sigma Aldrich Chemie GmbH, Steinheim, Germany)