Many enabling formulations give rise to supersaturated solutions wherein the solute possesses higher thermodynamic activity gradients than the solute in a saturated solution. Since flux across a membrane is driven by solute activity rather than concentration, understanding how solute thermodynamic activity varies with solution composition, particularly in the presence of solubilizing additives, is important in the context of passive absorption.

PURPOSE:Highly supersaturated aqueous solutions of poorly soluble compounds can undergo liquid-liquid phase separation (LLPS) when the concentration exceeds the "amorphous solubility". This phenomenon has been widely observed during high throughput screening of new molecular entities as well as during the dissolution of amorphous solid dispersions. In this study, we have evaluated the use of environment-sensitive fluorescence probes to investigate the formation and properties of the non-crystalline drug-rich aggregates formed in aqueous solutions as a result of LLPS.METHODS:Six different environment-sensitive fluorophores were employed to study LLPS in highly supersaturated solutions of several model compounds, all dihydropyridine derivatives.RESULTS:Each fluoroprobe exhibited a large hypsochromic shift with decreasing environment polarity. Upon drug aggregate formation, the probes partitioned into the drug-rich phase and exhibited changes in emission wavelength and intensity consistent with sensing a lower polarity environment. The LLPS onset concentrations determined using the fluorescence measurements were in good agreement with light scattering measurements as well as theoretically estimated amorphous solubility values.CONCLUSIONS:Environment-sensitive fluorescence probes are useful to help understand the phase behavior of highly supersaturated aqueous solutions, which in turn is important in the context of developing enabling formulations for poorly soluble compounds.

Amorphous materials are high-energy solids that can potentially enhance the bioavailability of poorly soluble compounds. A major impediment to their widespread use as a formulation platform is the tendency of amorphous materials to crystallize. The aim of this study was to evaluate the relative crystallization tendency of six structural analogues belonging to the dihydropyridine class, in an aqueous environment in the absence and presence of polymers, using wide-angle X-ray scattering synchrotron radiation and polarized light microscopy. The crystallization behavior of precipitates generated from supersaturated solutions of the active pharmaceutical ingredients was found to be highly variable ranging from immediate to several hours in the absence of polymers. Polymers with intermediate hydrophilicity/hydrophobicity were found to substantially delay crystallization, whereas strongly hydrophilic or hydrophobic polymers were largely ineffective. Nuclear magnetic resonance spectroscopy experiments supported the supposition that polymers need to have affinity for both the drug-rich precipitate and the aqueous phase in order to be effective crystallization inhibitors. This study highlights the variability in the crystallization tendency of different compounds and provides insight into the mechanism of inhibition by polymeric additives.

The commercial and clinical success of amorphous solid dispersions (ASD) in overcoming the low bioavailability of poorly soluble molecules has generated momentum among pharmaceutical scientists to advance the fundamental understanding of these complex systems. A major limitation of these formulations stems from the propensity of amorphous solids to crystallize upon exposure to aqueous media. This study was specifically focused on developing analytical techniques to evaluate the impact of polymers on the crystallization behavior during dissolution, which is critical in designing effective amorphous formulations. In the study, the crystallization and polymorphic conversions of a model compound, nifedipine, were explored in the absence and presence of polyvinylpyrrolidone (PVP), hydroxypropylmethyl cellulose (HPMC), and HPMC-acetate succinate (HPMC-AS). A combination of analytical approaches including Raman spectroscopy, polarized light microscopy, and chemometric techniques such as multivariate curve resolution (MCR) were used to evaluate the kinetics of crystallization and polymorphic transitions as well as to identify the primary route of crystallization, i.e., whether crystallization took place in the dissolving solid matrix or from the supersaturated solutions generated during dissolution. Pure amorphous nifedipine, when exposed to aqueous media, was found to crystallize rapidly from the amorphous matrix, even when polymers were present in the dissolution medium. Matrix crystallization was avoided when amorphous solid dispersions were prepared, however, crystallization from the solution phase was rapid. MCR was found to be an excellent data processing technique to deconvolute the complex phase transition behavior of nifedipine.

Amorphous solid dispersions (ASDs) give rise to supersaturated solutions (solution concentration greater than equilibrium crystalline solubility). We have recently found that supersaturating dosage forms can exhibit the phenomenon of liquid-liquid phase separation (LLPS). Thus, the high supersaturation generated by dissolving ASDs can lead to a two-phase system wherein one phase is an initially nanodimensioned and drug-rich phase and the other is a drug-lean continuous aqueous phase. Herein, the membrane transport of supersaturated solutions, at concentrations above and below the LLPS concentration has been evaluated using a side-by-side diffusion cell. Measurements of solution concentration with time in the receiver cell yield the flux, which reflects the solute thermodynamic activity in the donor cell. As the nominal concentration of solute in the donor cell increases, a linear increase in flux was observed up to the concentration where LLPS occurred. Thereafter, the flux remained essentially constant. Both nifedipine and felodipine solutions exhibit such behavior as long as crystallization is absent. This suggests that there is an upper limit in passive membrane transport that is dictated by the LLPS concentration. These results have several important implications for drug delivery, especially for poorly soluble compounds requiring enabling formulation technologies.

The goal of this study was to investigate the influence of particle size on the crystallization kinetics of amorphous felodipine powders stored below the glass transition temperature and to evaluate the role of surface versus bulk crystallization in influencing the kinetic profiles. Raman spectroscopy and powder X-ray diffraction (PXRD) were used to monitor the crystallization of different particle size fractions of pure amorphous felodipine and solid dispersions containing 3 wt.% polyvinyl pyrrolidone (PVP) stored at 30 °C. Optical microscopy was employed to measure surface and bulk growth rates of felodipine in the absence and presence of PVP at 30 °C. Solution concentration-time profiles for the various samples prior to and after crystallization were also measured. The growth rate of felodipine from the free surface was approximately 6 times faster than from the bulk in the absence of any polymer while the ratio of the surface to bulk growth rates was 23 in the presence of PVP. The overall crystallization rates of the amorphous powders were particle size dependent with smaller particle sizes crystallizing faster. Felodipine alone crystallized within 7 days. However, in the presence of the polymer, crystallization was retarded and was incomplete after 6 months. For the polymer-containing powders, biphasic crystallization was observed whereby rapid initial crystallization (50–60 days) was followed by a much slower rate over the remaining time period. The initial rapid crystallization was attributed to a faster rate of surface growth. The dissolution profiles of the different powders were dependent on both the particle size and the extent of crystallinity, with the level of supersaturation achieved varying considerably.

The use of amorphous drugs to generate supersaturated solutions that have the potential to enhance oral drug delivery is currently an area of intense interest. From an in vivo performance standpoint, inhibiting crystallization from these supersaturated systems is extremely important. In this study the ability of a polymer, hydroxypropylmethyl cellulose (HPMC), to inhibit nucleation and crystal growth of felodipine from supersaturated solutions was investigated. Nucleation and bulk crystal growth rates, in the absence and presence of seed crystals, were estimated from de-supersaturation curves. It was found that the presence of ppm levels of predissolved HPMC could inhibit both nucleation and growth of felodipine crystals. Empirical and mechanistic models were used to quantify the magnitude of inhibition. Crystal growth shifted toward an integration-controlled mechanism in the presence of HPMC where the overall impact on the growth rate was found to be strongly dependent on the extent of supersaturation. As predicted by theory, the polymer became less effective as a growth inhibitor with increases in supersaturation. The nucleation rate at similar supersaturations was significantly reduced comparison of the impact of HPMC on nucleation and growth demonstrated that delaying the stabilization of a supersaturated solution than hindering crystal growth. in the presence of HPMC. A direct nucleation was much more crucial to

Amorphous solid dispersions (ASDs) are widely utilized in the pharmaceutical industry for bioavailability enhancement of low solubility drugs. The important factors governing the dissolution behavior of these systems are still far from adequately understood. As a consequence, it is of interest to investigate the behavior of these systems during the dissolution process. The purpose of this research was twofold. First, the degree of supersaturation generated upon dissolution as a function of drug-polymer composition was investigated. Second, an investigation was conducted to correlate physical behavior upon dissolution with polymer loading. Felodipine and indomethacin were selected as model drugs and hydroxypropylmethylcellulose (HPMC) and polyvinylpyrrolidone (PVP) were used to form the dispersions. Diffusion and nuclear magnetic resonance spectroscopy experiments revealed that the extent of bulk supersaturation generated on dissolution of the ASD did not depend on the drug-polymer ratio. Interestingly, the maximum supersaturation generated was similar to the predicted amorphous solubility advantage. However, dynamic light scattering measurements revealed that particles on the submicron scale were generated during dissolution of the solid dispersions containing 90% polymer, whereas solid dispersions at a 50% polymer loading did not yield these nanoparticles. The nanoparticles were found to result in anomalous concentration measurements when using in situ ultraviolet spectroscopy. The supersaturation generated upon dissolution of the solid dispersions was maintained for biologically relevant timeframes for the HPMC dispersions, whereas PVP appeared to be a less effective crystallization inhibitor.

To critically evaluate the effect of submicron and micron-sized organic particulates on the ultraviolet (UV) absorption spectra of aqueous systems and assess the applicability of UV/Vis fiber-optic probes for in-situ concentration monitoring in the presence of particles of different sizes.

To investigate the underlying physical processes taking place during dissolution of amorphous pharmaceuticals and correlate them to the observed solution concentration-time profiles. Felodipine and indomethacin were used as model hydrophobic compounds.

To evaluate drug-polymer miscibility behavior in four different drug-polymer amorphous solid dispersion systems, namely felodipine-poly(vinyl pyrrolidone) (PVP), nifedipine-PVP, ketoconazole-PVP, and felodipine-poly(acrylic acid) (PAA).

Amorphous solid dispersions are used as a strategy to improve the bioavailability of poorly water-soluble compounds. When formulating with a polymer, it is important not only for the polymer to stabilize against crystallization in the solid state, but also to improve the dissolution profile through inhibiting crystallization from the supersaturated solution generated by dissolution of the amorphous material. In this study, the dissolution profiles of solid dispersions of felodipine formulated with poly(vinylpyrrolidone) (PVP), hydroxypropyl methylcellulose (HPMC) or hydroxypropyl methylcellulose acetate succinate (HPMCAS) were compared. In addition, concentration versus time profiles were evaluated for the supersaturated solutions of felodipine in the presence and absence of the polymers. HPMCAS was found to maintain the highest level of supersaturation for the greatest length of time for both the dissolution and solution crystallization experiments, whereas PVP was found to be the least effective crystallization inhibitor. All polymers appeared to reduce the crystal growth rates of felodipine at an equivalent supersaturation and this mechanism most likely contributes to the enhanced solution concentration values observed during dissolution of the amorphous solid dispersions.