Recrystallization Inside Amorphous Solid Dispersions as a Problem in Improving the Solubility of an API

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.

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

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

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

Synergistic approach of salt formation and polymer-mediated stabilization to enhance the biopharmaceutical performance of Mebendazole.

Amorphization of crystalline active pharmaceutical ingredients via formulation technologies

Objective: This study aimed to evaluate kinetic solubility advantage of amorphous etoricoxib solid dispersions prepared with three water soluble polymers and correlate it with solid state and supersaturated drug solution stabilization potential of these polymers.Methods: Amorphous solid dispersions (ASDs) of etoricoxib were prepared with polyvinyl alcohol (PVA), polyvinyl pyrrolidone (PVP) and hydroxyethyl cellulose (HEC) at 70:30w/w ratio and characterized for glass transition temperature (Tg), miscibility and intermolecular interactions. Kinetic solubility profiles of amorphous etoricoxib and its ASDs were determined in water at 37 °C. Solid-state stability was assessed by enthalpy relaxation studies at a common degree of undercooling of around 19.0 °C at 0% RH. Recrystallization behavior of supersaturated drug solution was evaluated in the absence and presence of pre-dissolved polymer at 37 °C.Results: Amorphous etoricoxib exhibited rapid solid-to-solid transition to yield a solubility advantage of merely 1.5-fold in water. Among the ASDs, etoricoxib-PVP dispersion exhibited maximal “peak” (2-fold) and “plateau” (1.8-fold) solubility enhancement, while etoricoxib-PVA dispersion could only sustain the “peak” solubility achieved by amorphous etoricoxib. In contrast, etoricoxib-HEC dispersion displayed no solubility advantage. The rank order for solid state and supersaturated solution stabilization followed a similar trend of amorphous etoricoxib < HEC < PVA < PVP.Conclusion: Dissolution behavior of ASDs is influenced by concomitantly occurring solid phase changes, thus understanding these processes independently can enable assessment of the predominant route of drug crystallization and stabilization by the polymer.

To explore in-situ forming cocrystal as a single-step, efficient method to significantly depress the processing temperature and thus minimize the thermal degradation of heat-sensitive drug in preparation of solid dispersions by melting method (MM) and hot melt extrusion (HME). Carbamazepine (CBZ)-nicotinamide (NIC) cocrystal solid dispersions were prepared with polymer carriers PVP/VA, SOLUPLUS and HPMC by MM and/or HME. The formation of cocrystal was investigated by differential scanning calorimetry and hot stage polarized optical microscopy. State of CBZ in solid dispersion was characterized by X-ray powder diffraction and optical microscopy. Interactions between CBZ, NIC and polymers were investigated by FTIR. Dissolution behaviors of solid dispersions were compared with that of pure CBZ. CBZ-NIC cocrystal with melting point of 160°C was formed in polymer carriers during heating process, and the preparation temperature of amorphous CBZ solid dispersion was therefore depressed to 160°C. The dissolution rate of CBZ-NIC cocrystal solid dispersion was significantly increased. By in-situ forming cocrystal, chemically stable amorphous solid dispersions were prepared by MM and HME at a depressed processing temperature. This method provides an attractive opportunity for HME of heat-sensitive drugs.

Stability and solubility enhancement of ellagic acid in cellulose ester solid dispersions

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

The formulation of BCS Class II drugs as amorphous solid dispersions has been shown to provide advantages with respect to improving the aqueous solubility of these compounds. While hot melt extrusion (HME) and spray drying (SD) are among the most common methods for the production of amorphous solid dispersions (ASDs), the high temperatures often required for HME can restrict the processing of thermally labile drugs, while the use of toxic organic solvents during SD can impact on end-product toxicity. In this study, we investigated the potential of supercritical fluid impregnation (SFI) using carbon dioxide as an alternative process for ASD production of a model poorly water-soluble drug, indomethacin (INM). In doing so, we produced ASDs without the use of organic solvents and at temperatures considerably lower than those required for HME. Previous studies have concentrated on the characterization of ASDs produced using HME or SFI but have not considered both processes together. Dispersions were manufactured using two different polymers, Soluplus and polyvinylpyrrolidone K15 using both SFI and HME and characterized for drug morphology, homogeneity, presence of drug-polymer interactions, glass transition temperature, amorphous stability of the drug within the formulation, and nonsink drug release to measure the ability of each formulation to create a supersaturated drug solution. Fully amorphous dispersions were successfully produced at 50% w/w drug loading using HME and 30% w/w drug loading using SFI. For both polymers, formulations containing 50% w/w INM, manufactured via SFI, contained the drug in the γ-crystalline form. Interestingly, there were lower levels of crystallinity in PVP dispersions relative to SOL. FTIR was used to probe for the presence of drug-polymer interactions within both polymer systems. For PVP systems, the nature of these interactions depended upon processing method; however, for Soluplus formulations this was not the case. The area under the dissolution curve (AUC) was used as a measure of the time during which a supersaturated concentration could be maintained, and for all systems, SFI formulations performed better than similar HME formulations.

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

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.

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.

With the advent of combinatorial chemistry and high throughput screening of drug molecules, poorly water soluble molecules have been entering the development stage as new drug candidates. The poor aqueous solubility of these molecules is one of the limiting factors for them to succeed as a new drug product. This had led to converting these drugs in most cases are crystalline to amorphous solid dispersion with use of amorphous polymers to improve the solubility. Although amorphous solid dispersion of a poorly water drug can improve the solubility, careful selection of polymer is a necessity in order to stabilize the high energy nature of the amorphous solid dispersion. Miscibility of a drug and a polymer is important. With specific interaction between the drug and the polymer, the dispersion can remain miscible much longer. Another factor that needs to be considered when formulating an amorphous solid dispersion is the amount of drug that is incorporated into the polymer. Over saturating the polymer with the drug can cause instability of the dispersion and crystallization may occur which will lead to reduced solubility. In this work, effects of processing method, polymer selection and the drug concentrations for the preparation of amorphous solid dispersion as well as prediction of drug-polymer miscibility have been studied. Hot melt extrusion (HME), rotary evaporation (Rot) and spray drying (SD) processing methods used in the study with Eudragit E 100 (EPO), HPMCAS LF and PVPVA 64 polymers. Drug concentration was another factor that was explored. The objective of this dissertation were: (1) to prepare amorphous solid dispersion of nifedipine with polymers (2) to characterize the solid dispersions (3) to determine the factors which contributes to successful amorphous solid dispersion (4) to evaluate prediction methods used to study drug and polymer miscibility and solubility (5) to use a thermodynamic prediction model to determine solubility of nifedipine at room temperature. In the first manuscript, amorphous solid dispersions of nifedipine and polymers were prepared. Physical and chemical characterizations of the solid dispersions indicated solid dispersions prepared with EPO polymer were unstable although intrinsic dissolution rates (IDR) of those samples had higher rates than those prepared with HPMCAS LF or PVPVA 64 polymers. The instability was explained by the lack of specific hydrogen bond interaction while the high IDR was explained by the low glass transition temperature (Tg) of the polymer. With lower Tg, molecular mobility would be higher and therefore the drug could