Effect of coating excipients on chemical stability of active coated tablets.

The objective of this study was to understand the impact of coating excipients on the chemical stability of active pan coated peliglitazar, which was prone to acid as well as base-catalyzed degradation. Four different coating formulations containing either polyvinyl alcohol (PVA) or hydroxypropyl methylcellulose (HPMC) as a coating polymer and triacetin (glycerol triacetate) or polyethylene glycol (PEG) as a plasticizer/detackifier were used for coating of peliglitazar in a perforated pan coater. Tablets of one-milligram strength were manufactured by suspending the drug in the coating suspension and spray coating onto inert core tablets. The active coated tablets were placed on stability (40 °C/75% RH) in high-density polyethylene (HDPE) bottles in closed condition with desiccants or in open condition. Tablet samples were withdrawn and analyzed for degradants using a stability-indicating HPLC method. The overall stability for the film-forming polymer-plasticizer/detackifier combination showed the rank order: HPMC-triacetin > PVA-triacetin > HPMC-PEG > PVA-PEG. Higher stability of triacetin systems over PEG systems was attributed to lower solubility of peliglitazar in triacetin coating systems. For the same plasticizer/detackifier, higher stability of HPMC over PVA-based formulations was attributed to lower solubility and mobility of peliglitazar in HPMC compared with the PVA-based coating.

Congruent Release of Drug and Polymer from Amorphous Solid Dispersions: Insights into the Role of Drug-Polymer Hydrogen Bonding, Surface Crystallization, and Glass Transition.

Drug loading is an important parameter known to impact the release rate of a poorly soluble drug from an amorphous solid dispersion (ASD). Recent studies have shown that small increases in drug loading can dramatically reduce the drug release rate from ASDs prepared with poly(vinylpyrrolidone-co-vinyl acetate) (PVPVA). However, the link between drug physicochemical properties and the drug loading where the release is abruptly compromised is not well understood. This study probes the role of different factors on the relative dissolution rates of drug and polymer from PVPVA-based ASDs as a function of drug loading: (1) the impact of drug-polymer hydrogen bonding interactions on the initial dissolution rate of ASDs, investigated using two structural analogues, indomethacin (IND) and indomethacin methyl ester (INDester), (2) the influence of surface drug crystallization, observed for INDester ASDs, and (3) by changing temperature, the impact of the "wet" glass transition temperature (Tg). Scanning electron microscopy (SEM), with or without energy dispersive X-ray (EDX) analysis, Fourier transform infrared spectroscopy (FTIR), and powder X-ray diffraction (PXRD) were utilized to study the solid-state phase behavior and/or drug enrichment on the partially dissolved ASD tablet surfaces. Nanoparticle tracking analysis (NTA) was utilized to study the solution-state phase behavior. It was found that, contrary to expectations, ASDs with drug-polymer hydrogen bonding exhibited poorer initial release at moderate drug loadings (15-25%) as compared to the non-hydrogen bonding analogue ASDs. Surface crystallization led to the deterioration of dissolution performance. Lastly, Tg relative to experimental temperatures also appeared to play a role in the observed dissolution behavior as a function of drug loading. These findings shed light on potential mechanisms governing ASD dissolution performance and will aid in the development of optimized ASD formulations with enhanced dissolution performance.

Impact of moisture and magnesium stearate functionality on manufacturability of wet granulated metformin tablets.

During the development of a wet granulated 850 mg metformin hydrochloride tablet formulation, the tablets exhibited high friability (>3% w/w) irrespective of the source of extra-granular magnesium stearate (MgSt). High friability values indicated that an anti-bonding effect of MgSt was too high to be overcome by 3.3% w/w povidone as a binder in the formulation with 1.5% w/w residual granule moisture. Increasing the povidone concentration up to 7% w/w showed limited improvement in friability, with tablets showing variable friability depending on MgSt source. Characterization of MgSt indicated differences in crystallinity, surface area and particle morphology between different vendors. In addition, a new bulk yield strength test, which determines the MgSt fragmentation tendency, was found to be indicative of the MgSt performance in the tablet formulation. To improve bonding properties of granules, residual granule moisture was increased to 2% w/w at different povidone concentrations. At 2% w/w residual granule moisture content, regardless of MgSt source, the tablets showed significant improvement in friability (∼0.6% w/w) even at the lowest povidone concentration (3.3% w/w). The bonding power of higher residual granule moisture had a greater impact than higher povidone concentration in overcoming the anti-bonding effects of magnesium stearate.

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.

Characterization of Supersaturated Danazol Solutions - Impact of Polymers on Solution Properties and Phase Transitions.

PURPOSE: Excipients are essential for solubility enhancing formulations. Hence it is important to understand how additives impact key solution properties, particularly when supersaturated solutions are generated by dissolution of the solubility enhancing formulation. Herein, the impact of different concentrations of dissolved polymers on the thermodynamic and kinetic properties of supersaturated solutions of danazol were investigated. METHODS: A variety of experimental techniques was used, including nanoparticle tracking analysis, fluorescence and ultraviolet spectroscopy and flux measurements to characterize the solution phase behavior. RESULTS: Neither the crystalline nor amorphous solubility of danazol was impacted by common amorphous solid dispersion polymers, polyvinylpyrrolidone, hydroxypropylmethyl cellulose (HPMC) or HPMC-acetate succinate. Consequently, the maximum membrane transport rate was limited only by the amorphous solubility, and not by the presence of the polymers. The polymers were able to inhibit crystallization to some extent at concentrations as low as 1 µg/mL, with the maximum effectiveness being reached at 10 µg/mL. Aqueous danazol solutions formed a drug-rich phase with a mean size of 250 nm when the concentration exceeded the amorphous solubility, and the polymers modified the surface properties of this drug-rich phase. CONCLUSIONS: The phase behavior of supersaturated solutions is complex and the kinetics of phase transformations can be substantially modified by polymeric additives present at low concentrations. However, fortunately, these additives do not appear to impact the bulk thermodynamic properties of the solution, thus enabling supersaturated solutions, which provide enhanced membrane transport relative to saturated solutions to be generated.

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.

Strategies for Managing Solid Form Transformation Risk in Drug Product.

The International Conference of Harmonization (ICH) Q6A document provides guidance on setting specifications for new drug substances and drug products.1 In this paper we focus on decision trees 4 (#1) to (#3) in the guidance related to solid-state form transformation. Form transformation could occur from use of high energy forms to overcome solubility challenges or stresses from manufacturing processes. The decision trees provide guidance on when and how polymorphic form changes should be monitored and controlled. However, guidance is high level and does not capture aspects related to assessments needed to understand if there is a risk of transformation or tools that can be integrated to understand the severity of bioavailability impact at different stages of development. The objective of this paper is therefore to provide comprehensive chemistry manufacturing and controls (CMC) and regulatory strategies to manage the risk of form transformation. This includes practical workflows for form transformation risk assessment, analytical tools to detect and quantify the transformation including their shortcomings, biopharmaceutical tools to understand the severity of transformation risk and if needed justify the limits based on clinical relevance. Finally, a few case studies are discussed that capture how the workflow can be used to manage transformation risk.

Exploring the Role of Surfactants in Enhancing Drug Release from Amorphous Solid Dispersions at Higher Drug Loadings.

To reduce the dosage size of amorphous solid dispersion (ASD)-based formulations, it is of interest to devise formulation strategies that allow increased drug loading (DL) without compromising dissolution performance. The aim of this study was to explore how surfactant addition impacts drug release as a function of drug loading from a ternary ASD, using felodipine as a model poorly soluble compound. The addition of 5% TPGS (d-α-tocopheryl polyethylene glycol 1000 succinate, a surfactant) to felodipine-polyvinylpyrrolidone/vinyl acetate ASDs was found to facilitate rapid and congruent (i.e., simultaneous) release of drug and polymer at higher DLs relative to binary ASDs (drug and polymer only). For binary ASDs, good release was observed for DLs up to <20% DL; this increased to 35% DL with surfactant. Microstructure evolution in ASD films following exposure to 100% relative humidity was studied using atomic force microscopy coupled with nanoscale infrared imaging. The formation of discrete, spherical drug-rich domains in the presence of surfactant appeared to be linked to systems showing congruent and rapid release of drug and polymer. In contrast, a contiguous drug-rich phase was formed for systems without surfactant at higher DLs. This study supports the addition of surfactant to ASD formulations as a strategy to increase DL without compromising release. Furthermore, insights into the potential role of surfactant in altering ASD release mechanisms are provided.

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.

Patterns of drug release as a function of drug loading from amorphous solid dispersions: A comparison of five different polymers.

To reduce the pill burden associated with amorphous solid dispersions (ASDs), which arises from the large quantity of polymer used in the formulation, it is of interest to understand the relationship between drug loading and release properties. The aim of this study was to comprehensively evaluate drug release mechanisms from ASDs with polymers of varying hydrophobicity as a function of drug loading. Surface normalized dissolution rates of drug and polymer were studied for felodipine ASDs with polyvinylpyrrolidone (PVP), polyvinylpyrrolidone/vinyl acetate (PVPVA), EudragitⓇ S 100 (EUDS), hydroxypropylmethylcellulose (HPMC), and hydroxypropylmethylcellulose acetate succinate (HPMCAS), as a function of drug loading. The water sorption profiles and water contact angle measurements suggested the following rank order for hydrophobicity of the different polymers: HPMCAS  ≃  EUDS > HPMC > PVPVA > PVP. For ASDs with relatively hydrophilic polymers (PVP, PVPVA and HPMC), drug release rates were polymer-controlled at low drug loadings (≤15%), whereas at higher drug loadings, release rates were more similar to that of the amorphous drug. The sudden decline in the release performance of ASDs with hydrophilic polymers when a certain drug loading was reached, was attributed to water-induced phase separation. For ASDs with more hydrophobic polymers (HPMCAS and EUDS), the dissolution rate of both drug and polymer was polymer-controlled for drug loadings as high as 50%, with a more gradual decline in drug release rate at higher drug loadings. Notably, at low drug loadings and across the different polymers, when the polymer dictated the drug release rate, ASDs prepared with the most hydrophilic polymers showed the fastest drug release. This suggested a 'trade-off' in choosing between higher release rates with more hydrophilic polymers at low drug loadings and higher drug loadings achievable with more hydrophobic polymers at the expense of lowered release rates. The findings described herein have significant implications for rational selection of polymers for formulation of ASDs with high drug loading and enhanced dissolution performance.

Congruent release of drug and polymer: A "sweet spot" in the dissolution of amorphous solid dispersions.

Liquid-liquid phase separation (LLPS) occurs following amorphous solid dispersion (ASD) dissolution when the drug concentration exceeds the "amorphous solubility", and is emerging as an important characteristic of formulations that may enhance the oral bioavailability of poorly soluble drugs. The purpose of this research was to identify criteria that impact the rate and extent of drug release and hence the occurrence or not of LLPS upon ASD dissolution. Specifically, the effect of drug log P, phase behavior of the hydrated but undissolved ASD matrix and the relative dissolution rates of drug and polymer were studied as a function of drug loading, using nilvadipine (Nil) (ClogP = 3.04) and cilnidipine (Cil) (ClogP = 5.54) as model drugs. The model polymer was poly (vinylpyrrolidone-co-vinyl acetate) (PVPVA). Nil-PVPVA and Cil-PVPVA ASDs with different drug loadings were prepared. Surface area normalized dissolution rates of both the drug and the polymer from ASD tablets were studied. At a similar and relatively low drug loading (<20% w/w drug), dissolution of both Nil-PVPVA and Cil-PVPVA ASDs was found to switch from rapid, congruent (i.e., simultaneous) release of drug and polymer to incongruent release with slow release of drug. Only ASDs showing congruent release underwent LLPS, with the formation of amorphous drug-rich aggregates (~300nm). Scanning electron microscopy (SEM) and micro-computed tomography (micro-CT) showed the presence of characteristic "pits" on the surface of partially dissolved, incongruently releasing ASD tablets. These most likely arise due to faster polymer release in comparison to drug, whereby the drug-rich composition around these pits was confirmed by energy-dispersive X-ray (EDX) analysis and the surface drug enrichment on the compacts was confirmed by X-ray photoelectron spectroscopy (XPS). This study demonstrates two important findings, firstly, a link between congruent release of drug and polymer and the occurrence of LLPS and secondly, the switch between congruent and incongruent release of drug and polymer is a result of competitive kinetics between phase separation and the release rate of ASD components with minimal influence from drug hydrophobicity for two structural analogues.

Food Effect in Humans: Predicting the Risk Through In Vitro Dissolution and In Vivo Pharmacokinetic Models.

In vitro and in vivo experimental models are frequently used to assess a new chemical entity's (NCE) biopharmaceutical performance risk for food effect (FE) in humans. Their ability to predict human FE hinges on replicating key features of clinical FE studies and building an in vitro-in vivo relationship (IVIVR). In this study, 22 compounds that span a wide range of physicochemical properties, Biopharmaceutics Classification System (BCS) classes, and food sensitivity were evaluated for biorelevant dissolution in fasted- and fed-state intestinal media and the dog fed/fasted-state pharmacokinetic model. Using the area under the curve (AUC) as a performance measure, the ratio of the fed-to-fasted AUC (FE ratio) was used to correlate each experimental model to FE ratio in humans. A linear correlation was observed for the in vitro dissolution-human IVIVR (R (2) = 0.66, % mean square error 20.7%). Similarly, the dog FE ratio correlated linearly with the FE ratio in humans (R (2) = 0.74, % mean square error 16.25%) for 15 compounds. Data points near the correlation line indicate dissolution-driven mechanism for food effect, while deviations from the correlation line shed light on unique mechanisms that can come into play such as GI physiology or unusual physicochemical properties. In summary, fed/fasted dissolution studies and dog PK studies show a reasonable correlation to human FE, hence are useful tools to flag high-risk NCEs entering clinical development. Combining kinetic dissolution, dog FE model and in silico modeling one can study FE mechanism and formulation strategies to mitigate the FE risk.

Controlling the chemical stability of a moisture-sensitive drug product through monitoring and identification of coating process microenvironment.

The objective of this work was to monitor and identify the impact of coating microenvironment, as measured by PyroButtons(®) data loggers, on the chemical stability of a moisture-sensitive drug molecule brivanib alaninate (BA). BA tablets were coated at two different scales (15 and 24 in pan). PyroButtons(®) data loggers were allowed to move freely within the tablet bed to record the temperature and relative humidity conditions of the tablet bed. The tablet moisture content at the end of the coating runs, and the rate of hydrolysis of the BA tablets based on HPLC analysis was found to be a function of the coating thermodynamic microenvironment. Wetter coating conditions resulted in tablets with higher water content and showed greater degradation upon storage. The coating process which yielded acceptable stability in a 15 in coater was transferred to a 24 in coater by maintaining similar tablet-bed relative humidity and temperature conditions. This was compared to a traditional scale-up approach where the environmental equivalency factor (EEF) was matched between scales during coating. The moisture content observed across the two scales indicated that maintaining a similar tablet-bed microenvironment ensured consistent results between scales.

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.

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.

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.

Interfacially assembled carbohydrate nanocapsules: a hydrophilic macromolecule delivery platform.

A prospective approach was used to synthesize carbohydrate nanocapsules with a macromolecule payload and suitable interfacial properties for in vivo systemic circulation. Spatially directed carbohydrate assembly and polymerization resulted in structured hydrophilic vesicles with diameters of 200-300 nm. Mononucleated dispersions with monodisperse distributions were demonstrated in aqueous vehicles. The effects of pH, buffer capacity and reaction time on the molar degree of substitution of terephthaloyl chloride, trimesoyl chloride, and diethylmalonyl chloride were evaluated. The delivery of a test protein, lysozyme showed continuous release for 7 days. Immobilization of lysozyme caused by co-polymerization was 20% based on asymptotic recovery of released lysozyme. A theoretical shell thickness of 9.5 nm was estimated from a relative core volume of 80% and the average vesicle size.

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.