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Lynne S Taylor - One of the best experts on this subject based on the ideXlab platform.
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Physical Stability and Dissolution of Lumefantrine Amorphous Solid Dispersions Produced by Spray Anti-Solvent Precipitation.
Journal of pharmaceutical sciences, 2020Co-Authors: Sonal Bhujbal, Lynne S Taylor, Vaibhav Pathak, Dmitry Zemlyanov, Qi Tony ZhouAbstract:This study aims to develop Amorphous Solid dispersion (ASD) of lumefantrine with a cost-effective approach of spray anti-solvent precipitation. Four acidic polymers, hydroxypropylmethylcellulose phthalate (HPMCP), hydroxypropylmethylcellulose acetate succinate (HPMCAS), poly(methacrylic acid-ethyl acrylate) (EL100) and cellulose acetate phthalate (CAP) were studied as excipients at various drug-polymer ratios. Of the studied polymers, satisfactory physical stability was demonstrated for HPMCP- and HPMCAS-based ASDs with no observed powder X-ray diffraction peaks for up to 3 months of storage at 40°C/75% RH. HPMCP and HPMCAS ASDs also achieved greater drug release levels in the dissolution study than other polymers. The HPMCP-based ASDs with a drug:polymer ratio of 2:8 exhibited a maximum drug release of 140 μg/mL for up to 2 hours, which is significantly higher than the currently marketed formulation of Coartem® (
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congruent release of drug and polymer a sweet spot in the dissolution of Amorphous Solid dispersions
Journal of Controlled Release, 2019Co-Authors: Sugandha Saboo, Dmitry Zemlyanov, Naila A Mugheirbi, Umesh S Kestur, Lynne S TaylorAbstract:Abstract 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 (
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the application of temperature composition phase diagrams for hot melt extrusion processing of Amorphous Solid dispersions to prevent residual crystallinity
International Journal of Pharmaceutics, 2018Co-Authors: Dana E Moseson, Lynne S TaylorAbstract:Hot melt extrusion (HME) can be used to produce Amorphous Solid dispersions (ASDs) at temperatures below the drug's melting point if the drug and polymer exhibit melting point depression. However, the risk of residual crystallinity becomes significant. The purpose of this study was to apply the temperature-composition phase diagram to the HME process, correlating process conditions to ASD residual crystallinity, and identifying the formulation critical temperature, which defines the theoretical minimum processing temperature. The phase diagram of indomethacin (IDM) and polyvinylpyrrolidone/vinyl acetate copolymer (PVPVA) was generated using melting point depression measurements coupled with Flory-Huggins theory. Extrudates were manufactured above, at, and below the formulation critical temperature (Tc) as identified from the phase diagram, with a range of residence times, and characterized for crystallinity. Below the Tc, a fully Amorphous sample could not be prepared. Above Tc, sufficient residence time led to Amorphous samples. A processing operating design space diagram with three regimes was generated to correlate temperature and residence time factors with process outcome. In conclusion, phase diagrams provide a rational basis for designing hot melt extrusion processes of Amorphous Solid dispersions to minimize residual crystalline content, delineating the minimum processing temperature based on thermodynamic considerations.
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tailoring supersaturation from Amorphous Solid dispersions
Journal of Controlled Release, 2018Co-Authors: Lynne S TaylorAbstract:The maximum achievable concentration of a drug in solution is dictated by the chemical potential of the Solid form. Because an Amorphous Solid has a higher chemical potential than the corresponding crystal form, in the absence of phase transformations, a higher transient solubility is expected. However, the chemical potential of an Amorphous drug can be reduced by mixing with another component. Therefore, upon mixing with a polymer to form an Amorphous Solid dispersion (ASD), the maximum solution concentration achieved can be potentially altered, in particular if the polymer is poorly soluble in the dissolution medium. Such changes in the chemical potential of the drug may be a critical factor in determining the maximum achievable solution concentration, and could alter the crystallization driving force of the drug. Therefore, the aim of this study was to gain insights into the impact of poorly soluble polymers on the "Amorphous solubility" of drugs formulated as Amorphous Solid dispersions. Lopinavir was selected as a model drug with a low crystallization tendency, enabling determination of the Amorphous solubility as a function of ASD composition. Model polymers included cellulose acetate (CA), CA phthalate (CAP), ethylcellulose (EC), Eudragit® RL PO (EUD), hydroxypropylmethylcellulose (HPMC), HPMC acetate succinate (HPMCAS), and HPMC phthalate (HPMCP). The "Amorphous solubility" of the drug alone was determined and then the changes in maximum achievable concentration were measured as a function of drug loading. Drug-polymer interactions were characterized using infrared spectroscopy (IR), differential scanning calorimetry (DSC) and moisture sorption analysis. The results showed that the maximum achievable concentration ("Amorphous solubility") of lopinavir varied with the extent of drug-polymer interactions, as well as the drug weight fraction in the ASD. This information is of great value when evaluating the maximum achievable concentration of Amorphous systems formulated with pH responsive polymers, and should contribute to a broader understanding of drug phase behavior in the context of ASDs.
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cellulose based Amorphous Solid dispersions enhance rifapentine delivery characteristics in vitro
Carbohydrate Polymers, 2018Co-Authors: Christopher J Winslow, Lynne S Taylor, Brittany L B Nichols, Diana C Novo, Laura I Mosqueragiraldo, Kevin J Edgar, Andrew P NeilsonAbstract:The efficacy of rifapentine, an oral antibiotic used to treat tuberculosis, may be reduced due to degradation at gastric pH and low solubility at intestinal pH. We hypothesized that delivery properties would be improved in vitro by incorporating rifapentine into pH-responsive Amorphous Solid dispersions (ASDs) with cellulose derivatives including: hydroxypropylmethylcellulose acetate succinate (HPMCAS), cellulose acetate suberate (CASub), and 5-carboxypentyl hydroxypropyl cellulose (CHC). ASDs generally reduced rifapentine release at gastric pH, with CASub affording >31-fold decrease in area under the curve (AUC) compared to rifapentine alone. Critically, reduced gastric dissolution was accompanied by reduced degradation to 3-formylrifamycin. Certain ASDs also enhanced apparent solubility and stabilization of supersaturated solutions at intestinal pH, with HPMCAS providing nearly 4-fold increase in total AUC vs. rifapentine alone. These results suggest that rifapentine delivery via ASD with these cellulosic polymers may improve bioavailability in vivo.
Adam J Matzger - One of the best experts on this subject based on the ideXlab platform.
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effect of polymer hydrophobicity on the stability of Amorphous Solid dispersions and supersaturated solutions of a hydrophobic pharmaceutical
Molecular Pharmaceutics, 2019Co-Authors: Derek S Frank, Adam J MatzgerAbstract:Amorphous Solid dispersions of pharmaceuticals often show improved solubility over crystalline forms. However, the crystallization of Amorphous Solid dispersions during storage, or from elevated supersaturation once dissolved, compromise the solubility advantage of delivery in the Amorphous phase. To combat this phenomenon, polymer additives are often included in Solid dispersions to inhibit crystallization; however, the optimal properties for polymer to stabilize against crystallization are not fully understood, and furthermore, it is not known how inhibition of precipitation from solution is related to the propensity of a polymer to inhibit crystallization from the Amorphous phase. Here, polymers of varied hydrophobicity are employed as crystallization inhibitors in supersaturated solutions and Amorphous Solid dispersions of the BCS Class II pharmaceutical ethenzamide to investigate the chemical features of polymer that lead to long-term stability for a hydrophobic pharmaceutical. A postpolymerization functionalization strategy was employed to alter the hydrophobicity of poly( N-hydroxyethyl acrylamide) without changing physical properties such as number-average chain length. It was found that supersaturation maintenance for ethenzamide is improved by increasing the hydrophobicity of dissolved polymer in aqueous solution. Furthermore, Amorphous Solid dispersions of ethenzamide containing a more hydrophobic polymer showed superior stability compared to those containing a less hydrophobic polymer. This trend of increasing polymer hydrophobicity leading to improved Amorphous stability is interpreted by parsing the effects of water absorption in Amorphous Solid dispersions using intermolecular interaction strengths derived from global structural analysis. By comparing the structure-function relationships, which dictate stability in solution and Amorphous Solid dispersions, the effect of hydrophobicity can be broadly understood for the design of polymers to impart stability throughout the application of Amorphous Solid dispersions.
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effect of polymer hydrophobicity on the stability of Amorphous Solid dispersions and supersaturated solutions of a hydrophobic pharmaceutical
Molecular Pharmaceutics, 2019Co-Authors: Derek S Frank, Adam J MatzgerAbstract:Amorphous Solid dispersions of pharmaceuticals often show improved solubility over crystalline forms. However, the crystallization of Amorphous Solid dispersions during storage, or from elevated su...
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Effect of Polymer Hydrophobicity on the Stability of Amorphous Solid Dispersions and Supersaturated Solutions of a Hydrophobic Pharmaceutical
2019Co-Authors: Derek S. Frank, Adam J MatzgerAbstract:Amorphous Solid dispersions of pharmaceuticals often show improved solubility over crystalline forms. However, the crystallization of Amorphous Solid dispersions during storage, or from elevated supersaturation once dissolved, compromise the solubility advantage of delivery in the Amorphous phase. To combat this phenomenon, polymer additives are often included in Solid dispersions to inhibit crystallization; however, the optimal properties for polymer to stabilize against crystallization are not fully understood, and furthermore, it is not known how inhibition of precipitation from solution is related to the propensity of a polymer to inhibit crystallization from the Amorphous phase. Here, polymers of varied hydrophobicity are employed as crystallization inhibitors in supersaturated solutions and Amorphous Solid dispersions of the BCS Class II pharmaceutical ethenzamide to investigate the chemical features of polymer that lead to long-term stability for a hydrophobic pharmaceutical. A postpolymerization functionalization strategy was employed to alter the hydrophobicity of poly(N-hydroxyethyl acrylamide) without changing physical properties such as number-average chain length. It was found that supersaturation maintenance for ethenzamide is improved by increasing the hydrophobicity of dissolved polymer in aqueous solution. Furthermore, Amorphous Solid dispersions of ethenzamide containing a more hydrophobic polymer showed superior stability compared to those containing a less hydrophobic polymer. This trend of increasing polymer hydrophobicity leading to improved Amorphous stability is interpreted by parsing the effects of water absorption in Amorphous Solid dispersions using intermolecular interaction strengths derived from global structural analysis. By comparing the structure–function relationships, which dictate stability in solution and Amorphous Solid dispersions, the effect of hydrophobicity can be broadly understood for the design of polymers to impart stability throughout the application of Amorphous Solid dispersions
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probing the interplay between Amorphous Solid dispersion stability and polymer functionality
Molecular Pharmaceutics, 2018Co-Authors: Derek S Frank, Adam J MatzgerAbstract:Amorphous Solid dispersions containing a polymeric component often impart improved stability against crystallization for a small molecule relative to the pure Amorphous form. However, the relationship between side chain functionalities on a polymer and the ability of a polymer to stabilize against crystallization is not well understood. To shed light on this relationship, a series of polymers were functionalized from a parent batch of poly(chloromethylstyrene-co-styrene) to investigate the effect of functionality on the stability in Amorphous Solid dispersions without altering the physical parameters of polymers, such as the average molecular weight or backbone chain chemistry. The kinetics of the crystallization of the nonsteroidal anti-inflammatory drug nabumetone from Amorphous Solid dispersions containing each functionalized polymer were interpreted on the basis of two interactions: hydrogen bonding between the drug and the polymer and the solubility of the polymer in the Amorphous drug. It was found ...
Kevin J Edgar - One of the best experts on this subject based on the ideXlab platform.
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cellulose based Amorphous Solid dispersions enhance rifapentine delivery characteristics in vitro
Carbohydrate Polymers, 2018Co-Authors: Christopher J Winslow, Lynne S Taylor, Brittany L B Nichols, Diana C Novo, Laura I Mosqueragiraldo, Kevin J Edgar, Andrew P NeilsonAbstract:The efficacy of rifapentine, an oral antibiotic used to treat tuberculosis, may be reduced due to degradation at gastric pH and low solubility at intestinal pH. We hypothesized that delivery properties would be improved in vitro by incorporating rifapentine into pH-responsive Amorphous Solid dispersions (ASDs) with cellulose derivatives including: hydroxypropylmethylcellulose acetate succinate (HPMCAS), cellulose acetate suberate (CASub), and 5-carboxypentyl hydroxypropyl cellulose (CHC). ASDs generally reduced rifapentine release at gastric pH, with CASub affording >31-fold decrease in area under the curve (AUC) compared to rifapentine alone. Critically, reduced gastric dissolution was accompanied by reduced degradation to 3-formylrifamycin. Certain ASDs also enhanced apparent solubility and stabilization of supersaturated solutions at intestinal pH, with HPMCAS providing nearly 4-fold increase in total AUC vs. rifapentine alone. These results suggest that rifapentine delivery via ASD with these cellulosic polymers may improve bioavailability in vivo.
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novel cellulose based Amorphous Solid dispersions enhance quercetin solution concentrations in vitro
Carbohydrate Polymers, 2017Co-Authors: Andrew Gilley, Lynne S Taylor, Brittany L B Nichols, Laura I Mosqueragiraldo, Kevin J Edgar, Hale Cigdem Arca, Andrew P NeilsonAbstract:Quercetin (Q) is a bioactive flavonol with potential to benefit human health. However, Q bioavailability is relatively low, due to its poor aqueous solubility and extensive phase-II metabolism. Strategies to increase solution concentrations in the small intestinal lumen have the potential to substantially increase Q bioavailability, and by extension, efficacy. We aimed to achieve this by incorporating Q into Amorphous Solid dispersions (ASDs) with cellulose derivatives. Q was dispersed in matrices of cellulose esters including 6-carboxycellulose acetate butyrate (CCAB), hydroxypropylmethylcellulose acetate succinate (HPMCAS) and cellulose acetate suberate (CASub) to afford ASDs that provided stability against crystallization, and pH-triggered release. Blends of CASub and CCAB with the hydrophilic polyvinylpyrrolidone (PVP) further enhanced dissolution. The ASD 10% Q:20% PVP:70% CASub most significantly enhanced Q solution concentration under intestinal pH conditions, increasing area under the concentration/time curve (AUC) 18-fold compared to Q alone. This novel ASD method promises to enhance Q bioavailability in vivo.
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amphiphilic cellulose ethers designed for Amorphous Solid dispersion via olefin cross metathesis
Biomacromolecules, 2016Co-Authors: Yifan Dong, Lynne S Taylor, Laura I Mosqueragiraldo, Kevin J EdgarAbstract:The design of cellulose ether-based amphiphiles has been difficult and limited because of the harsh conditions typically required for appending ether moieties to cellulose. Olefin cross-metathesis recently has been shown to be a valuable approach for appending a variety of functional groups to cellulose ethers and esters, provided that an olefin handle for metathesis can be attached. This synthetic pathway gives access to these functional derivatives under very mild conditions and at high efficiency. Modification of ethyl cellulose by metathesis to prepare useful derivatives, for example, for solubility and bioavailability enhancement of drugs by Amorphous Solid dispersion (ASD), has been limited by the low DS(OH) of commercial ethyl cellulose derivatives. This is problematic because ethyl cellulose is otherwise a very attractive substrate for synthesis of amphiphilic derivatives by olefin metathesis. Herein we explore two methods for opening up this design space for ether-based amphiphiles, for example, ...
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synthesis and structure property evaluation of cellulose ω carboxyesters for Amorphous Solid dispersions
Carbohydrate Polymers, 2014Co-Authors: Grace A Ilevbare, Lynne S Taylor, Kevin J Edgar, Benjamin P Cherniawski, Earl T RitchieAbstract:Abstract The use of Amorphous Solid dispersions (ASDs) is an effective and increasingly widely used approach for solubility enhancement of drugs and drug candidates with poor aqueous solubility. Successful molecular dispersion of drugs in polymer matrices requires new polymers that are designed to meet all ASD requirements, including drug release and prevention of drug recrystallization in storage or from solution. We describe herein design and synthesis of a new series of cellulose ω-carboxyalkanoates for ASDs, by reaction of cellulose with long-chain diacids that have been monoprotected as benzyl esters at one end, and monoactivated as acid chlorides at the other. Glass transition temperatures ( T g ) of these cellulose ω-carboxyesters exceed ambient temperature by at least 50 °C, providing a sufficient Δ T to prevent drug mobility and crystallization. Cellulose acetate suberates and sebacates prepared in this way are extraordinary solution crystal growth inhibitors for the poorly soluble anti-HIV drug ritonavir. These new cellulose ω-carboxyesters have strong potential as ASD polymers for enhancement of drug solubility and bioavailability.
Bruce D Kay - One of the best experts on this subject based on the ideXlab platform.
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the deposition angle dependent density of Amorphous Solid water films
Journal of Chemical Physics, 2003Co-Authors: Zdenek Dohnalek, Gregory A Kimmel, Scott R Smith, Patrick Ayotte, Bruce D KayAbstract:The index of refraction and thickness of Amorphous Solid water (ASW) films are determined using laser optical interferometry. From the film thickness, the density of ASW can be calculated directly since the molecular beam flux and the H2O condensation coefficient are both known. From the index of refraction the ASW density can also be determined using the Lorentz–Lorenz relationship. The densities determined via both methods agree within experimental uncertainty. For films deposited at 22 K using a collimated molecular beam, the index of refraction and density decrease monotonically as the deposition angle is varied from normal to oblique incidence. At normal incidence the films have an index of refraction of 1.285 and are presumed to be fully dense (0.94 g/cm3). At glancing incidence (86°) the film has a refractive index of 1.05 and a density of 0.16 g/cm3, indicating a porosity exceeding 80%. The angle-dependent film density is in semiquantitative agreement with the results of ballistic deposition simul...
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a beaker without walls formation of deeply supercooled binary liquid solutions of alcohols from nanoscale Amorphous Solid films
Physical Review Letters, 2002Co-Authors: Patrick Ayotte, Gregory A Kimmel, Zdenek Dohnalek, Scott R Smith, Glenn Teeter, Bruce D KayAbstract:Layered nanoscale Amorphous Solid films of methoanol and ethanol undergo complete intermixing prior to the onset of measurable desorption at 120 K. This intermixing precedes and inhibits crystallization. Subsequent desorption of the film is described quantitatively by a kinetic model describing evaporation from a continuously remixing ideal binary liquid solution. This occurs at temperatures below the melting point of the binary mixture indicating ideal behavior for the supercooled liquid solution. This approach provides a new method for preparing and examining deeply-supercooled solutions.
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control of Amorphous Solid water morphology using molecular beams i experimental results
Journal of Chemical Physics, 2001Co-Authors: Gregory A Kimmel, Kip P Stevenson, Zdenek Dohnalek, Scott R Smith, Bruce D KayAbstract:The adsorption of N2 was used to investigate the porosity/morphology of thin films of Amorphous Solid water. Molecular beams were used to vapor deposit Amorphous Solid water films on a Pt(111) crystal at a variety of incident growth angles. The amount of N2 adsorbed by the Amorphous Solid water depends very sensitively on the growth angle and thermal history of the film. For normal and nearly normal incidence growth, the water films are relatively dense and smooth and adsorb only a small amount of N2. For larger growth angles, the films are porous and adsorb large quantities of N2 with apparent surface areas as high as ∼2700 m2/g. The physical and chemical properties of Amorphous Solid water are of interest because of its presence in astrophysical environments. The observations have important implications for laboratory studies which use vapor deposited Amorphous Solid water films as analogs for astrophysical icy bodies such as comets.
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controlling the morphology of Amorphous Solid water
Science, 1999Co-Authors: Kip P Stevenson, Gregory A Kimmel, Zdenek Dohnalek, Scott R Smith, Bruce D KayAbstract:The morphology of Amorphous Solid water grown by vapor deposition was found to depend strongly on the angular distribution of the water molecules incident from the gas phase. Systematic variation of the incident angle during deposition using a collimated beam of water led to the growth of nonporous to highly porous Amorphous Solid water. The physical and chemical properties of Amorphous Solid water are of interest because of its presence in astrophysical environments. The ability to control its properties in the laboratory may shed light on some of the outstanding conflicts related to this important material.
Derek S Frank - One of the best experts on this subject based on the ideXlab platform.
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effect of polymer hydrophobicity on the stability of Amorphous Solid dispersions and supersaturated solutions of a hydrophobic pharmaceutical
Molecular Pharmaceutics, 2019Co-Authors: Derek S Frank, Adam J MatzgerAbstract:Amorphous Solid dispersions of pharmaceuticals often show improved solubility over crystalline forms. However, the crystallization of Amorphous Solid dispersions during storage, or from elevated supersaturation once dissolved, compromise the solubility advantage of delivery in the Amorphous phase. To combat this phenomenon, polymer additives are often included in Solid dispersions to inhibit crystallization; however, the optimal properties for polymer to stabilize against crystallization are not fully understood, and furthermore, it is not known how inhibition of precipitation from solution is related to the propensity of a polymer to inhibit crystallization from the Amorphous phase. Here, polymers of varied hydrophobicity are employed as crystallization inhibitors in supersaturated solutions and Amorphous Solid dispersions of the BCS Class II pharmaceutical ethenzamide to investigate the chemical features of polymer that lead to long-term stability for a hydrophobic pharmaceutical. A postpolymerization functionalization strategy was employed to alter the hydrophobicity of poly( N-hydroxyethyl acrylamide) without changing physical properties such as number-average chain length. It was found that supersaturation maintenance for ethenzamide is improved by increasing the hydrophobicity of dissolved polymer in aqueous solution. Furthermore, Amorphous Solid dispersions of ethenzamide containing a more hydrophobic polymer showed superior stability compared to those containing a less hydrophobic polymer. This trend of increasing polymer hydrophobicity leading to improved Amorphous stability is interpreted by parsing the effects of water absorption in Amorphous Solid dispersions using intermolecular interaction strengths derived from global structural analysis. By comparing the structure-function relationships, which dictate stability in solution and Amorphous Solid dispersions, the effect of hydrophobicity can be broadly understood for the design of polymers to impart stability throughout the application of Amorphous Solid dispersions.
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effect of polymer hydrophobicity on the stability of Amorphous Solid dispersions and supersaturated solutions of a hydrophobic pharmaceutical
Molecular Pharmaceutics, 2019Co-Authors: Derek S Frank, Adam J MatzgerAbstract:Amorphous Solid dispersions of pharmaceuticals often show improved solubility over crystalline forms. However, the crystallization of Amorphous Solid dispersions during storage, or from elevated su...
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probing the interplay between Amorphous Solid dispersion stability and polymer functionality
Molecular Pharmaceutics, 2018Co-Authors: Derek S Frank, Adam J MatzgerAbstract:Amorphous Solid dispersions containing a polymeric component often impart improved stability against crystallization for a small molecule relative to the pure Amorphous form. However, the relationship between side chain functionalities on a polymer and the ability of a polymer to stabilize against crystallization is not well understood. To shed light on this relationship, a series of polymers were functionalized from a parent batch of poly(chloromethylstyrene-co-styrene) to investigate the effect of functionality on the stability in Amorphous Solid dispersions without altering the physical parameters of polymers, such as the average molecular weight or backbone chain chemistry. The kinetics of the crystallization of the nonsteroidal anti-inflammatory drug nabumetone from Amorphous Solid dispersions containing each functionalized polymer were interpreted on the basis of two interactions: hydrogen bonding between the drug and the polymer and the solubility of the polymer in the Amorphous drug. It was found ...