Umesh S. Kestur

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

The physical stability of amorphous molecular level solid dispersions will be influenced by the miscibility of the components. The goal of this work was to understand the effects of temperature and relative humidity on the miscibility of a model amorphous solid dispersion. Infrared spectroscopy was used to evaluate drug-polymer hydrogen bonding interactions in amorphous solid dispersions of felodipine and poly(vinyl pyrrolidone) (PVP). Samples were analyzed under stressed conditions: high temperature and high relative humidity. The glass transition temperature (T(g)) of select systems was studied using differential scanning calorimetry (DSC). Atomic force microscopy (AFM) and transmission electron microscopy (TEM) were used to further investigate moisture-induced changes in solid dispersions. Felodipine-PVP solid dispersions showed evidence of adhesive hydrogen bonding interactions at all compositions studied. The drug-polymer intermolecular interactions were weakened and/or less numerous on increasing the temperature, but persisted up to the melting temperature of the drug. Changes in the hydrogen bonding interactions were found to be reversible with changes in temperature. In contrast, the introduction of water into amorphous molecular level solid dispersions at room temperature irreversibly disrupted interactions between the drug and the polymer resulting in amorphous-amorphous phase separation followed by crystallization. DSC, AFM, and TEM results provided further evidence for the occurrence of moisture induced immiscibility. In conclusion, it appears that felodipine-PVP solid dispersions are susceptible to moisture-induced immiscibility when stored at a relative humidity >or=75%. In contrast, the solid dispersions remained miscible on heating.

Role of polymer chemistry in influencing crystal growth rates from amorphous felodipine

The inhibition of crystallization from organic amorphous solids is currently of great interest in the pharmaceutical field, since the amorphous form of the drug can enhance drug delivery. Polymers have been found to be effective crystallization inhibitors for many organic glasses and supercooled liquids. The objective of this study was to investigate potential correlations between drug–polymer hydrogen bonding and crystal growth inhibition. Quench cooled samples of a model hydrophobic drug, felodipine, were prepared with various polymers: poly(vinylpyrrolidone) (PVP), hydroxypropyl methylcellulose acetate succinate (HPMCAS), poly(vinylpyrrolidone)/vinyl acetate (PVP/VA) and poly(vinyl acetate) (PVAc). Crystal growth rates as a function of temperature (70–110 °C) were measured using optical microscopy, in the presence and absence of 3% w/w polymer. Differential scanning calorimetry (DSC) was used to evaluate glass transition temperatures (Tg) and melting points. Infrared (IR) spectroscopy was used to probe drug–polymer hydrogen bonding interactions. The various polymers were found to inhibit the crystal growth to different degrees. The order of inhibition effectiveness was PVP > PVP/VA > HPMCAS > PVAc with PVP being the best inhibitor among the polymers used. The growth rates in the presence of the polymers were similar to those of the drug alone at high temperatures but showed a significant reduction as the temperature was reduced. The Tgs of the drug–polymer dispersions were not significantly different from that of the pure drug. The order of the strength/extent of drug–polymer hydrogen bonding interactions was PVP > PVP/VA > HPMCAS ≥ PVAc. Hence polymers which can form stronger/more extensive hydrogen bonds with the drug appear to be better crystallization inhibitors.

Selective Detection and Quantitation of Organic Molecule Crystallization by Second Harmonic Generation Microscopy

Second order nonlinear optical imaging of chiral crystals (SONICC) was applied to selectively detect crystal formation at early stages and characterize the kinetics of nucleation and growth. SONICC relies on second harmonic generation (SHG), a nonlinear optical effect that only arises from noncentosymmetric ordered domain structures, which include crystals of chiral molecules. The model systems studied include pharmaceutically relevant compounds: griseofulvin and chlorpropamide. SONICC demonstrates low detection limits producing an 8 order of magnitude improvement relative to macroscopic average techniques and 5 order of magnitude improvement relative to optical microscopy. SONICC was also applied to examine the kinetics of crystallization in amorphous griseofulvin. The results show that SONICC enables simultaneous monitoring of individual crystal growth, nucleation rate, and macroscopic crystallization kinetics.

Dissolution of Danazol Amorphous Solid Dispersions: Supersaturation and Phase Behavior as a Function of Drug Loading and Polymer Type

Amorphous solid dispersions (ASDs) are of great interest as enabling formulations because of their ability to increase the bioavailability of poorly soluble drugs. However, the dissolution of these formulations under nonsink dissolution conditions results in highly supersaturated drug solutions that can undergo different types of phase transitions. The purpose of this study was to characterize the phase behavior of solutions resulting from the dissolution of model ASDs as well as the degree of supersaturation attained. Danazol was chosen as a poorly water-soluble model drug, and three polymers were used to form the dispersions: polyvinylpyrrolidone (PVP), hydroxypropylmethyl cellulose (HPMC), and hydroxypropylmethyl cellulose acetate succinate (HPMCAS). Dissolution studies were carried out under nonsink conditions, and solution phase behavior was characterized using several orthogonal techniques. It was found that liquid-liquid phase separation (LLPS) occurred following dissolution and prior to crystallization for most of the dispersions. Using flux measurements, it was further observed that the maximum attainable supersaturation following dissolution was equivalent to the amorphous solubility. The dissolution of the ASDs led to sustained supersaturation, the duration of which varied depending on the drug loading and the type of polymer used in the formulation. The overall supersaturation profile observed thus depended on a complex interplay between dissolution rate, polymer type, drug loading, and the kinetics of crystallization.

Factors influencing crystal growth rates from undercooled liquids of pharmaceutical compounds.

Amorphous forms of drugs are increasingly being used to deliver poorly water-soluble compounds. Therefore, understanding the magnitude and origin of differences in crystallization kinetics is highly important. The goal of this study was to better understand the factors that influence crystal growth rates from pharmaceutically relevant undercooled liquids and to evaluate the range of growth rates observed. The crystal growth rates of 31 drugs were determined using an optical microscope in the temperature region between the glass transition temperature (Tg) and the melting temperature (Tm). Thermodynamic parameters such as Tm, melting enthalpy, and Tg were determined using a differential scanning calorimeter (DSC). Selected viscosity values for the undercooled liquid were taken from the literature. The growth rates of the different compounds were found to be very different from each other with a variation of about 5 orders of magnitude between the fastest growing compounds and the slowest growing compounds. A comparison of the physicochemical properties showed that compounds that had fast crystal growth rates had smaller molecular weights, higher melting temperatures, lower melt entropies, lower melt viscosities, and higher crystal densities. Variations in the growth rates of the compounds could be rationalized to a large extent by considering the thermodynamic driving force for crystallization, the viscosity, and the entropy difference between the melt and undercooled liquid. This study therefore provides important insight into factors that may compromise the stability of amorphous pharmaceuticals.

Impact of Polymers on the Precipitation Behavior of Highly Supersaturated Aqueous Danazol Solutions

The phase behavior of supersaturated solutions of a relatively hydrophobic drug, danazol, was studied in the absence and presence of polymeric additives. To differentiate between phase separation to a noncrystalline phase and phase separation to a crystalline phase, an environmentally sensitive fluorescent probe was employed. Induction times for crystallization in the presence and absence of polymeric additives were studied using a combination of ultraviolet and fluorescence spectroscopy. It was found that, when danazol was added to aqueous media at concentrations above the amorphous solubility, liquid-liquid phase separation was briefly observed prior to crystallization, resulting in a short-lived, drug-rich noncrystalline danazol phase with an initial size of around 500 nm. The addition of polymers was found to greatly extend the lifetime of the supersaturated two phase system, delaying the onset of crystallization from a few minutes to a few hours. Below a certain threshold danazol concentration, found to represent the amorphous solubility, only crystallization was observed. Thus, although the addition of polymers was unable to prevent danazol from precipitating once a threshold concentration was exceeded, they did inhibit crystallization, leading to a solution with prolonged supersaturation. This observation highlights the need to determine the structure of the precipitating phase, since it is linked to the resultant solution concentration time profile.

Single Particle Nonlinear Optical Imaging of Trace Crystallinity in an Organic Powder

Microscopic characterization of crystallinity in powders can reveal information lost in ensemble-averaged measurements. Nonlinear optical imaging based on second harmonic generation (SHG) provides rapid and highly selective detection of individual chiral microcrystals, enabling insights into the fundamental mechanism of action for the observed crystallinity loss of an organic powder induced by mechanical grinding. Using griseofulvin as the model compound, the results from second order nonlinear optical imaging of chiral crystals (SONICC) compared favorably with those of powder X-ray diffraction (PXRD) over the linear dynamic range of the PXRD measurements. However, the SHG measurements demonstrated three decade improvements in linear dynamic range. The detection limit of SHG was estimated to be 4 ppm crystallinity in the powder. The rate of crystallinity loss induced by milling followed a first order process with a half-life of 15 ± 1 min. Recrystallization of cryomilled powder is ~40 times faster than that prepared by melt-quenched powder, suggesting that the disordered state obtained by exhaustive cryomilling appears to contain ordered domains that are larger than the critical nucleation size, but below the detection limit of SONICC. The presence of such domains provides a barrier-less nucleation source resulting in rapid crystallization, the kinetics of which depends only on crystal growth.

Nonlinear optical imaging for sensitive detection of crystals in bulk amorphous powders

The primary aim of this study was to evaluate the utility of second-order nonlinear imaging of chiral crystals (SONICC) to quantify crystallinity in drug-polymer blends, including solid dispersions. Second harmonic generation (SHG) can potentially exhibit scaling with crystallinity between linear and quadratic depending on the nature of the source, and thus, it is important to determine the response of pharmaceutical powders. Physical mixtures containing different proportions of crystalline naproxen and hydroxyl propyl methyl cellulose acetate succinate (HPMCAS) were prepared by blending and a dispersion was produced by solvent evaporation. A custom-built SONICC instrument was used to characterize the SHG intensity as a function of the crystalline drug fraction in the various samples. Powder X-ray diffraction (PXRD) and Raman spectroscopy were used as complementary methods known to exhibit linear scaling. SONICC was able to detect crystalline drug even in the presence of 99.9 wt % HPMCAS in the binary mixtures. The calibration curve revealed a linear dynamic range with a R(2) value of 0.99 spanning the range from 0.1 to 100 wt % naproxen with a root mean square error of prediction of 2.7%. Using the calibration curve, the errors in the validation samples were in the range of 5%-10%. Analysis of a 75 wt % HPMCAS-naproxen solid dispersion with SONICC revealed the presence of crystallites at an earlier time point than could be detected with PXRD and Raman spectroscopy. In addition, results from the crystallization kinetics experiment using SONICC were in good agreement with Raman spectroscopy and PXRD. In conclusion, SONICC has been found to be a sensitive technique for detecting low levels (0.1% or lower) of crystallinity, even in the presence of large quantities of a polymer.

Influence of polymer chemistry on crystal growth inhibition of two chemically diverse organic molecules

The purpose of this study was to understand how different polymers affect the crystal growth rates of two chemically diverse organic drug molecules (bifonazole and nimesulide) from the undercooled melt regime close to the glass transition temperature. Bifonazole is an antifungal drug that contains no traditional hydrogen bond donors, only acceptors. In contrast, nimesulide contains both hydrogen bond donor and acceptor groups. Therefore, the potential hydrogen bonding interactions with polymers vary between the two compounds. For bifonazole, poly(vinylpyrrolidone) (PVP), hydroxypropyl methylcellulose acetate succinate (HPMCAS), poly(vinylpyrrolidone-vinyl acetate) (PVP/VA) and poly(acrylic acid) (PAA) were investigated, while for nimesulide, PVP, PVP/VA and poly(vinyl acetate) (PVAc) were probed. Polymers were incorporated at a level of 5%w/w by cryomilling followed by melt quenching. Linear crystal growth rates in the presence and absence of polymers were measured as a function of temperature (18–100 °C for bifonazole and 18–80 °C for nimesulide) using optical microscopy. Differential scanning calorimetry (DSC) and infrared spectroscopy were performed for further characterization. All of the polymers decreased the growth rates of both drugs, however large differences could be observed between polymers in terms of the extent of crystal growth inhibition. For bifonazole, PAA was a notably better crystal growth inhibitor compared to the other polymers. This may be related to formation of specific interactions between the drug and the polymer. For nimesulide, the order of effectiveness was PVP∼PVP/VA>PVAc and, compared to bifonazole, differences seen between polymers were more modest. Infrared (IR) spectroscopy and density functional calculations strongly suggested that amorphous nimesulide formed an intramolecular hydrogen bond. IR spectroscopy showed that drug-polymer intermolecular hydrogen bonding did occur, but was hampered by the partial loss of the hydrogen bond donor to the intramolecular hydrogen bond. Hence the effectiveness of a polymer appears to depend not only on the chemistry of the drug, but also on the availability of hydrogen bonding groups.

Interaction of Environmental Moisture with Powdered Green Tea Formulations: Relationship between Catechin Stability and Moisture-Induced Phase Transformations

This study investigated the effect of phase transformations of amorphous and deliquescent ingredients on catechin stability in green tea powder formulations. Blends of amorphous green tea and crystalline sucrose, citric acid, and/or ascorbic acid were analyzed by X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), dynamic water vapor sorption, water activity measurements, and high-performance liquid chromatography (HPLC) after storage for up to 12 weeks at 0-75% relative humidity (RH) and 22 degrees C. The glass transition temperature (T(g)) of green tea was reduced to below room temperature (<22 degrees C) at 68% RH. Dissolution of deliquescent ingredients commenced at RH values below deliquescence points in blends with amorphous green tea, and these blends had greater water uptake than predicted by an additive model of individual ingredient moisture sorption. Catechin degradation was affected by T(g) of green tea powder and both dissolution and deliquescence of citric and ascorbic acids.