Drug Release and Nanodroplet Formation from Amorphous Solid Dispersions: Insight into the Roles of Drug Physicochemical Properties and Polymer Selection.

Dissolution of amorphous solid dispersions (ASD) can lead to the formation of amorphous drug-rich nano species (nanodroplets) via liquid-liquid phase separation or glass-liquid phase separation when the drug concentration exceeds the amorphous solubility. These nanodroplets have been shown to be beneficial for ASD performance both in vitro and in vivo. Thus, understanding the generation and stability of nanodroplets from ASD formulations is important. In this study, the impacts of polymer selection and active pharmaceutical ingredient (API) physicochemical properties (wet glass transition temperature (Tg) and log P) on nanodroplet release were studied. Six APIs with different physicochemical properties were formulated as ASDs with two polymers, polyvinylpyrrolidone/vinyl acetate (PVPVA) and hydroxypropyl methylcellulose acetate succinate (HPMCAS). Their release performance was evaluated using both powder and surface normalized dissolution of compacts. In general, HPMCAS-based dispersions resulted in higher drug release compared to PVPVA-based dispersions. The two polymers also exhibited different trends in nanodroplet formation as a function of drug loading (DL). PVPVA ASDs exhibited a "falling-off-the-cliff" effect, with a dramatic decline in release performance with a small increase in drug loading, while HPMCAS ASDs exhibited a negative "slope" in the release rate as a function of drug loading. For both polymers, low Tg compounds achieved higher levels of nanodroplet formation compared to high Tg compounds. The nanodroplets generated from ASD dissolution were also monitored with dynamic light scattering, and HPMCAS was found to be more effective at stabilizing nanodroplets against size increase. Insights from this study may be used to guide formulation design and selection of excipients based on API physicochemical properties.

In situ analytical characterization and chemical imaging of tablet coatings using laser induced breakdown spectroscopy (LIBS).

Laser induced breakdown spectroscopy (LIBS) has emerged as an innovative tool for quantitative and qualitative elemental analysis in pharmaceutical research. Herein, the potential use of LIBS for rapid characterization of tablet coatings is illustrated, including the investigation of coating thickness, coating uniformity and localized coating contamination. The laser shot number required for penetrating the coating correlates well with coating thickness determined from traditional scanning electron microscopy measurements. Each laser shot represents a 2.58 µm coating thickness. The inter-tablet coating uniformity was directly visualized using LIBS-based 3D chemical imaging, and the intra-tablet coating uniformity was quantitatively investigated. To our knowledge, this is the first report of 3D LIBS-based chemical imaging being utilized for quantitative analysis of pharmaceutical tablet coatings. In addition to elemental information, the accurate location of contaminants on the tablet coating was rapidly identified using 2D imaging. These results pave the way for LIBS to be a valuable technique for the analysis of pharmaceutical tablet coatings.

Insights into Nano- and Micron-Scale Phase Separation in Amorphous Solid Dispersions Using Fluorescence-Based Techniques in Combination with Solid State Nuclear Magnetic Resonance Spectroscopy.

PURPOSE: Miscibility between the drug and the polymer in an amorphous solid dispersion (ASD) is considered to be one of the most important factors impacting the solid state stability and dissolution performance of the active pharmaceutical ingredient (API). The research described herein utilizes emerging fluorescence-based methodologies to probe (im)miscibility of itraconazole (ITZ)-hydroxypropyl methylcellulose (HPMC) ASDs. METHODS: The ASDs were prepared by solvent evaporation with varying evaporation rates and were characterized by steady-state fluorescence spectroscopy, confocal imaging, differential scanning calorimetry (DSC), and solid state nuclear magnetic resonance (ssNMR) spectroscopy. RESULTS: The size of the phase separated domains for the ITZ-HPMC ASDs was affected by the solvent evaporation rate. Smaller domains (<10 nm) were observed in spray-dried ASDs, whereas larger domains (>30 nm) were found in ASDs prepared using slower evaporation rates. Confocal imaging provided visual confirmation of phase separation along with chemical specificity, achieved by selectively staining drug-rich and polymer-rich phases. ssNMR confirmed the results of fluorescence-based techniques and provided information on the size of phase separated domains. CONCLUSIONS: The fluorescence-based methodologies proved to be sensitive and rapid in detecting phase separation, even at the nanoscale, in the ITZ-HPMC ASDs. Fluorescence-based methods thus show promise for miscibility evaluation of spray-dried ASDs.

Leaching of Lopinavir Amorphous Solid Dispersions in Acidic Media.

PURPOSE: Amorphous solid dispersions (ASDs) formulated with acid-insoluble (enteric) polymers form suspensions in acidic media where the polymer is largely insoluble. However, a small amount of drug can dissolve and a supersaturated solution may be generated. The goal of this study was to gain insight into the leaching mechanisms of both drug and polymer from the suspended particles, studying the impact of solution additives such as surfactants. METHODS: ASDs were prepared by spray drying lopinavir (LPV) with an enteric polymer, either hydroxypropylmethylcellulose acetate succinate (HPMCAS) or hydroxypropylmethylcellulose phthalate (HPMCP). Four surfactants and a suspending agent were added to the liquid media to evaluate the effect of these excipients on leaching. pH 3 and pH 5 buffers were used to investigate the effect of pH. RESULTS: The extent of drug leaching from the amorphous formulation was proportional to the crystalline solubility of the drug in the same medium. All surfactants promoted solubilization of LPV with the exception of poloxamer and sodium dodecyl sulfate-HPMCP combinations. A small amount of polymer ionization significantly enhanced LPV leaching in solutions containing an ionic surfactant. CONCLUSIONS: The mechanism of enhanced leaching appeared to be solubilization, with the apparent supersaturation remaining the same for systems containing the same polymer.

Impact of surfactants on the crystallization of aqueous suspensions of celecoxib amorphous solid dispersion spray dried particles.

Amorphous solid dispersions are frequently prepared by spray drying. It is important that the resultant spray dried particles do not crystallize during formulation, storage, and upon administration. The goal of the current study was to evaluate the impact of surfactants on the crystallization of celecoxib amorphous solid dispersions (ASD), suspended in aqueous media. Solid dispersions of celecoxib with hydroxypropylmethylcellulose acetate succinate were manufactured by spray drying, and aqueous suspensions were prepared by adding the particles to acidified media containing various surfactants. Nucleation induction times were evaluated for celecoxib in the presence and absence of surfactants. The impact of the surfactants on drug and polymer leaching from the solid dispersion particles was also evaluated. Sodium dodecyl sulfate and Polysorbate 80 were found to promote crystallization from the ASD suspensions, while other surfactants including sodium taurocholate and Triton X100 were found to inhibit crystallization. The promotion or inhibition of crystallization was found to be related to the impact of the surfactant on the nucleation behavior of celecoxib, as well as the tendency to promote leaching of the drug from the ASD particle into the suspending medium. It was concluded that surfactant choice is critical to avoid failure of amorphous solid dispersions through crystallization of the drug.

Design of experiments utilization to map the processing capabilities of a micro-spray dryer: particle design and throughput optimization in support of drug discovery.

There has been a growing interest in amorphous solid dispersions for bioavailability enhancement in drug discovery. Spray drying, as shown in this study, is well suited to produce prototype amorphous dispersions in the Candidate Selection stage where drug supply is limited. This investigation mapped the processing window of a micro-spray dryer to achieve desired particle characteristics and optimize throughput/yield. Effects of processing variables on the properties of hypromellose acetate succinate were evaluated by a fractional factorial design of experiments. Parameters studied include solid loading, atomization, nozzle size, and spray rate. Response variables include particle size, morphology and yield. Unlike most other commercial small-scale spray dryers, the ProCepT was capable of producing particles with a relatively wide mean particle size, ca. 2-35 µm, allowing material properties to be tailored to support various applications. In addition, an optimized throughput of 35 g/hour with a yield of 75-95% was achieved, which affords to support studies from Lead-identification/Lead-optimization to early safety studies. A regression model was constructed to quantify the relationship between processing parameters and the response variables. The response surface curves provide a useful tool to design processing conditions, leading to a reduction in development time and drug usage to support drug discovery.

Direct visualization of the drug release process of non-conductive polymeric implants via molecular imaging.

Long-acting parenteral (LAP) implant has garnered the attraction as a drug delivery technique in recent years. Understanding the drug release process is critical for the study of underlying release mechanism. In this paper, we present a novel application of matrix-assisted laser desorption/ionization-mass spectrometry imaging (MADLI-MSI) for the direct visualization of the drug release process from non-conductive polymeric based LAP implants at molecular level. Custom-made sample holders were designed for LAP sample introduction in place of traditional conductive glass slides. The main technical obstacles of applying MALDI-MSI to study non-conductive materials are surface conductivity which can lead to charge build-up. In order to obtain homogeneous imaging of non-conductive sample surfaces, we developed a new sample surface treatment procedure, which is a critical control step to ensure the data reliability and accuracy in understanding kinetics of drug release process of LAP. Overall, this is the first comprehensive report of a sample preparation methodology tailored for imaging LAP at molecular level, allowing for the direct chemical identification and 2D mapping of an active pharmaceutical ingredient (API) distribution during LAP release process. Furthermore, this work has established the foundation to apply MALDI-MSI to the understanding of LAP implant formulation homogeneity, chemical composition, and degradation. More importantly, this work enabled the extension of MALDI-MSI technique to study a wide range of non-conductive materials.

How broadly can poly(urethane)-based implants be applied to drugs of varied properties?

Implants offer the opportunity to improve patient adherence and real-world outcomes. However, most polymers used today are hydrophobic and limit drug properties suitable for development. Thermoplastic poly(urethanes) (TPUs) form pores upon hydration and may facilitate the development of implants containing drugs exhibiting broadly different properties. We sought to investigate the effect of drug physicochemical properties on permeability through membranes of varying TPU mixture composition; leverage imaging to visualize microstructural changes to the membrane across the TPU mixture composition range; and quantitatively characterize the membrane microstructure using equivalent pore analysis. We observed a correlation between drug hydrophobicity and its permeability through hydrophobic-rich TPU membranes. Conversely, all compounds diffused through hydrophilic-rich TPU membranes at similar rates, regardless of drug properties. Imaging revealed significant microstructure differences between hydrophobic-rich and hydrophilic-rich TPU membranes, supporting hypotheses proposed in our previous study. The hydrated hydrophilic TPU membrane pore area was determined to be 0.583% and its equivalent pore radius was found to be 128 nm, suggesting that hydrophilic TPU membranes may be used to modify the release of small molecular weight drugs and macromolecules. These findings highlight the benefits of hydrophilic TPUs as rate-controlling membranes to modulate the release rate of drugs with varying physicochemical properties.