Apremilast Amorphous Solid Dispersions: Formulation Optimization using QbD and Comprehensive In vitro-In silico Assessment

In vitro-in silico evaluation of Apremilast solid dispersions prepared via Corotating Twin Screw Extruder

The overall aim of the thesis was to introduce new analytical techniques to characterize solid dispersion formulations. Solid dispersion formulations are employed to enhance the dissolution behavior and apparent solubility of poorly soluble compounds. This formulation strategy uses typically an amorphous physical form of a poorly soluble drug and combines it with a carrier for stabilization. The amorphous form presents higher free energy compared to a crystalline drug form thereby yielding a higher dissolution rate and possibly more complete oral absorption as well as bioavailability. The selection of appropriate excipients is crucial to guarantee the formulation performance and stability during the shelf life of the final product. To investigate drug formulation characteristics and predict their performance, different analytical techniques are needed. Along with the classical characterization techniques, novel approaches such as fluorescence spectroscopy and diffusing wave spectroscopy are introduced in the present thesis. The chapters 1 and 2 of this thesis cover fundamental aspects of poorly soluble drugs: an overview is given on amorphous solid dispersion (ASD) manufacturing technologies and characteristics of polymers and surfactants used in ASD. Moreover, analytical tools to characterize solid dispersions are presented. Among them, special emphasis is given to novel approaches such as Diffusing Wave Spectroscopy (DWS) and Fluorescence Spectroscopy. As for the selection of excipients, drug polymer miscibility is a crucial requisite for the performance of an ASD formulation. One of the methods to predict drug-polymer miscibility is to employ solubility parameter approach; its application in solid dispersion formulations is outlined in the Chapter 3. The first study introduces a novel fluorescence quenching approach together with size exclusion chromatography to study drug-polymer interactions that emerge from ASDs drug release in an aqueous medium. Celecoxib was combined with different pharmaceutical polymers and the resulted solid dispersion was evaluated by the (modified) Stern-Volmer model. Drug accessibility by the quencher and its affinity to the drug were compared in physical mixtures as well as within the ASDs using different polymer types. It was possible to gain knowledge about specific drug-polymer interactions and the amount of drug embedded in the evolving drug-polymer aggregates upon formulation dispersion and drug dissolution. More research in the future will show how such in vitro findings translate into performance of an ASD in vivo. The second study of this thesis has also a biopharmaceutical focus and investigates formulation differences from a microrheological perspective by considering further an in vitro absorption sink using a biphasic dissolution equipment. Indeed, biphasic dissolution testing can simulate an intestinal absorption from dispersed formulation by using an organic layer. This study employed ketoconazole, a poorly soluble drug, together with different grades of HPMCAS and formulations were produced by hot melt extrusion (HME). Diffusing wave spectroscopy highlighted microrheological differences among the different polymer grades and plasticizers in the aqueous phase. These differences were found to influence drug release and finally the uptake in the organic layer that was intended to mirror the absorption process. There is surely more research needed before final conclusions can be drawn but the obtained findings point already to an important contribution of microrheological differences that evolved upon formulation dispersion. The third study also emphasized microrheology but with a focus on non-dispersed solid dispersions. It was aimed to investigate microstructuring during phase transitions in drug-polymer solid dispersions. This formulation microstructuring is critical for the physicochemical properties such as stability of the final dosage form. In this study, eutectic mixtures of polyethylene glycol (PEG) were investigated using two drugs: fenofibrate and flurbiprofen. Unlike fenofibrate, the drug flurbiprofen was strongly interacting with the polymer and this was also confirmed by the rheological characterization. Therefore, broadband DWS provided valuable mechanistic information on the drug-polymer interactions and macromolecular structuring during the cooling of the eutectic melts.

Preparation of amorphous solid dispersions using polymers is a commonly used formulation strategy for enhancing the solubility of poorly water-soluble drugs. However, often a single polymer may not bring about a significant enhancement in solubility or amorphous stability of a poorly water-soluble drug. This study describes application of a unique and novel binary polymeric blend in preparation of solid dispersions. The objective of this study was to investigate amorphous solid dispersions of glipizide, a BCS class II model drug, in a binary polymeric system of polyvinyl acetate phthalate (PVAP) and hypromellose (hydroxypropyl methylcellulose, HPMC). The solid dispersions were prepared using two different solvent methods: rotary evaporation (rotavap) and fluid bed drug layering on sugar spheres. The performance and physical stability of the dispersions were evaluated with non-sink dissolution testing, powder X-ray diffraction (PXRD), and modulated differential scanning calorimetry (mDSC). PXRD analysis demonstrated an amorphous state for glipizide, and mDSC showed no evidence of phase separation. Non-sink dissolution testing in pH 7.5 phosphate buffer indicated more than twofold increase in apparent solubility of the drug with PVAP-HPMC system. The glipizide solid dispersions demonstrated a high glass transition temperature (Tg) and acceptable chemical and physical stability during the stability period irrespective of the manufacturing process. In conclusion, the polymeric blend of PVAP-HPMC offers a unique formulation approach for developing amorphous solid dispersions with the flexibility towards the use of these polymers in different ratios and combined quantities depending on drug properties.

Formulation and delivery of improved amorphous fenofibrate solid dispersions prepared by thin film freezing

The objective of this study was to investigate the phase behavior of amorphous solid dispersions composed of a hydrophobic drug and a hydrophilic polymer following exposure to elevated relative humidity. Infrared (IR) spectroscopy, differential scanning calorimetry (DSC) and moisture sorption analysis were performed on five model systems (nifedipine-poly(vinylpyrrolidone) (PVP), indomethacin-PVP, ketoprofen-PVP, droperidol-PVP, and pimozide-PVP) immediately after production of the amorphous solid dispersions and following storage at room temperature and elevated relative humidity. Complete miscibility between the drug and the polymer immediately after solid dispersion formation was confirmed by the presence of specific drug-polymer interactions and a single glass transition (T(g)) event. Following storage at elevated relative humidity (75-94% RH), nifedipine-PVP, droperidol-PVP, and pimozide-PVP dispersions formed drug-rich and polymer-rich amorphous phases prior to crystallization of the drug, while indomethacin-PVP and ketoprofen-PVP dispersions did not. Drug crystallization in systems exhibiting amorphous-amorphous phase separation initiated earlier (<6 days at 94% RH) when compared to systems that remained miscible (>or=46 days at 94% RH). Evidence of moisture-induced amorphous-amorphous phase separation was observed following storage at as low as 54% RH for the pimozide-PVP system. It was concluded that, when an amorphous molecular level solid dispersion containing a hydrophobic drug and hydrophilic polymer is subjected to moisture, drug crystallization can occur via one of two routes: crystallization from the plasticized one-phase solid dispersion, or crystallization from a plasticized drug-rich amorphous phase in a two-phase solid dispersion. In the former case, the polymer is still present in the same phase as the drug, and can inhibit crystallization to a greater extent than the latter scenario, where the polymer concentration in the drug phase is reduced as a result of the amorphous-amorphous phase separation. The strength of drug-polymer interactions appears to be important in influencing the phase behavior.

In this work, an amorphous solid dispersion (ASD) formulation was systematically developed to simultaneously enhance bioavailability and mitigate the mechanical instability risk of the selected crystalline form of a development drug candidate, GDC-0334. The amorphous solubility advantage calculation was applied to understand the solubility enhancement potential by an amorphous formulation for GDC-0334, which showed 2.7 times theoretical amorphous solubility advantage. This agreed reasonably well with the experimental solubility ratio between amorphous GDC-0334 and its crystalline counterpart (∼2 times) in buffers of a wide pH range. Guided by the amorphous solubility advantage, ASD screening was then carried out, focusing on supersaturation maintenance and dissolution performance. It was found that although the type of polymer carrier did not impact ASD performance, the addition of 5% (w/w) sodium dodecyl sulfate (SDS) significantly improved the GDC-0334 ASD dissolution rate. After ASD composition screening, stability studies were conducted on selected ASD powders and their hypothetical tablet formulations. Excellent stability of the selected ASD prototypes with or without tablet excipients was observed. Subsequently, ASD tablets were prepared, followed by in vitro and in vivo evaluations. Similar to the effect of facilitating the dissolution of ASD powders, the added SDS improved the disintegration and dissolution of ASD tablets. Finally, a dog pharmacokinetic study confirmed 1.8 to 2.5-fold enhancement of exposure by the developed ASD tablet over the GDC-0334 crystalline form, consistent with the amorphous solubility advantage of GDC-0334. A workflow of developing an ASD formulation for actual pharmaceutical application was proposed according to the practice of this work, which could provide potential guidance for ASD formulation development in general for other new chemical entities.

Structural and Dynamic Properties of Amorphous Solid Dispersions: The Role of Solid-State Nuclear Magnetic Resonance Spectroscopy and Relaxometry

Numerous amorphous solid dispersion (ASD) formulations of celecoxib (CEL) have been attempted for enhancing the solubility, dissolution rate, and in vivo pharmacokinetics via high drug loading, polymer combination, or by surfactant addition. However, physical stability for long-term shelf life and desired in vivo pharmacokinetics remains elusive. Therefore, newer formulation strategies are always warranted to address poor aqueous solubility and oral bioavailability with extended shelf life. The present investigation elaborates a combined strategy of amorphization and salt formation for CEL, providing the benefits of enhanced solubility, dissolution rate, in vivo pharmacokinetics, and physical stability. We generated amorphous salts solid dispersion (ASSD) formulations of CEL via an in situ acid-base reaction involving counterions (Na+ and K+) and a polymer (Soluplus) using the spray-drying technique. The generated CEL-Na and CEL-K salts were homogeneously and molecularly dispersed in the matrix of Soluplus polymer. The characterization of generated ASSDs by differential scanning calorimetry revealed a much higher glass-transition temperature (Tg) than the pure amorphous CEL, confirming the salt formation of CEL in solid dispersions. The micro-Raman and proton nuclear magnetic resonance spectroscopy further confirmed the formation of salt at the -S═O position in the CEL molecules. CEL-Na-Soluplus ASSD exhibited a synergistic enhancement in the aqueous solubility (332.82-fold) and in vivo pharmacokinetics (9.83-fold enhancement in the blood plasma concentration) than the crystalline CEL. Furthermore, ASSD formulations were physically stable for nearly 1 year (352 days) in long-term stability studies at ambient conditions. Hence, we concluded that the ASSD is a promising strategy for CEL in improving the physicochemical properties and biopharmaceutical performance.

Abiraterone acetate (ABTA) is used as a primary treatment for metastatic castration-resistant prostate cancer. Its low aqueous solubility results in inadequate dissolution and poor oral bioavailability (<10%), necessitating the consumption of large doses of ABTA (1000 mg per day) for desired efficacy. The aim of this study is to enhance the solubility, dissolution, and bioavailability of ABTA through amorphous solid dispersions (SDs). ABTA-SD was prepared via a solvent granulation method with different grades of hydroxypropyl methylcellulose acetate succinate (HPMCAS 716 and 912). The theoretical solubility parameter between ABTA and HPMCAS was below 7 MPa1/2, indicating miscibility between the drug and the polymer according to the Hansen solubility parameter. HPMCAS showed a remarkable recrystallization inhibition of up to 180 min compared to the free drug (10 min), maintaining the soluble drug in supersaturation state and exhibiting the "spring and parachute" phenomenon. ABTA-SD exhibited a higher solubility (1.16-fold to 52-fold) in different media than free ABTA. The results of DSC, PXRD, ATR-FTIR, and FE-SEM indicated that the crystallinity of ABTA was completely transformed to an amorphous form and maintained in the SD formulation. In vitro and bio-relevant dissolution behavior of ABTA was studied in various dissolution media, indicating the higher dissolution of ABTA-SD than that of free ABTA. The pharmacokinetic study conducted in Wistar rats revealed that C max and AUC0-t of the optimized ABTA-SD formulation were significantly enhanced by 1.92-fold and 2.87-fold, respectively, compared to those of free ABTA.

Effect of temperature and moisture on the miscibility of amorphous dispersions of felodipine and poly(vinyl pyrrolidone)

Amorphous solid dispersion (ASD) formulations are routinely used to enable the delivery of poorly soluble compounds. This type of formulations can enhance bioavailability due to higher kinetic solubility of the drug substance and increased dissolution rate of the formulation, by the virtue of the fact that the drug molecule exists in the formulation in a high energy amorphous state. In this article we report the application of physiologically based absorption models to mechanistically understand the clinical pharmacokinetics of solid dispersion formulations. Three case studies are shown here to cover a wide range of ASD bioperformance in human and modeling to retrospectively understand their in vivo behavior. Case study 1 is an example of fairly linear PK observed with dose escalation and the use of amorphous solubility to predict bioperformance. Case study 2 demonstrates the development of a model that was able to accurately predict the decrease in fraction absorbed (%Fa) with dose escalation thus demonstrating that such model can be used to predict the clinical bioperformance in the scenario where saturation of absorption is observed. Finally, case study 3 shows the development of an absorption model with the intent to describe the observed incomplete and low absorption in clinic with dose escalation. These case studies highlight the utility of physiologically based absorption modeling in gaining a thorough understanding of ASD performance and the critical factors impacting performance to drive design of a robust drug product that would deliver the optimal benefit to the patients.

Continuous production of itraconazole-based solid dispersions by hot melt extrusion: Preformulation, optimization and design space determination

The objective of this study was to develop a solid dispersion based controlled release system for drug substances that are poorly soluble in water. A wax-based disintegration mediated controlled release system was designed based on the fact that an amorphous drug can crystallize out from hydrophilic matrices. For this study, cilostazol (CIL) was selected as the model drug, as it exhibits poor aqueous solubility. An amorphous solid dispersion was prepared to assist the drug to attain a supersaturated state. Povidone was used as carrier for solid dispersion (spray drying technique), hydrogenated vegetable oil (HVO) as wax matrix former, and sodium carboxymethyl cellulose (NaCMC) as a disintegrant. The extreme vertices mixture design (EVMD) was applied to optimize the designed and developed composition. The optimized formulation provided a dissolution pattern which was equivalent to the predicted curve, ascertaining that the optimal formulation could be accomplished with EVMD. The release profile of CIL was described by the Higuchi's model better than zero-order, first-order, and Hixson-Crowell's model, which indicated that the supersaturation state of CIL dominated to allow drug release by diffusion rather than disintegration regulated release as is generally observed by Hixson-Crowell's model. The optimized composition was evaluated for disintegration, dissolution, XRD, and stability studies. It was found that the amorphous state as well as the dissolution profile of CIL was maintained under the accelerated conditions of 40°C/75% RH for 6 months.

Barrier Coated Drug Layered Particles for Enhanced Performance of Amorphous Solid Dispersion Dosage Form

Preparation, characterization and in vivo studies of amorphous solid dispersion of berberine with hydrogenated phosphatidylcholine