Devalina Law

Preparation and Drug Loading of Poly(Ethylene Glycol)-block-Poly(ε-Caprolactone) Micelles Through the Evaporation of a Cosolvent Azeotrope

AbstractPurpose. The aim of this work was to study the assembly, drug loading, and stability of poly(ethylene glycol)-block-poly(∈-caprolactone) (PEG-b-PCL) micelles.nMethods. Three PEG-b-PCL compositions with PCL number average molecular weights of 1000, 2500, and 4000 g/mol were used. The assembly of PEG-b-PCL micelles, induced by the addition of water to acetonitrile (ACN), was characterized with 1H nuclear magnetic resonance spectroscopy (1H-NMR) and dynamic light scattering (DLS) with and without the presence of fenofibrate, a poorly water-soluble drug. PEG-b-PCL micelles with encapsulated fenofibrate were prepared through the removal of a negative ACN-water azeotrope under reduced pressure. Fenofibrate content was measured using reverse-phase high-performance liquid chromatography (HPLC), whereas the kinetic stability of PEG-b-PCL micelles with and without encapsulated fenofibrate was evaluated using size exclusion chromatography (SEC).nResults. The critical water content (CWC), the water content at which amphiphilic block copolymer (ABC) micelle assembly begins, was determined using DLS and ranged from 10% to 30% water, depending on both PCL molecular weight and PEG-b-PCL concentration. As the water content was increased, the PEG-b-PCL unimers assembled into swollen structures with hydrodynamic diameters ranging from 200 to 800 nm. The 1H-NMR peaks associated with the PCL block exhibited line-broadening, following the addition of D2O, indicating that the PCL blocks reside in the core of the PEG-b-PCL micelle. With further addition of water, the PCL cores collapsed to form fairly monodisperse PEG-b-PCL micelles (20-60 nm). In the presence of fenofibrate, the CWC value was lowered, perhaps due to hydrophobic interactions of fenofibrate and the PCL block. Further addition of water and subsequent evaporation of the negative ACN-water azeotrope resulted in fenofibrate-loaded PEG-b-PCL micelles of under 50 nm. The extent of fenofibrate encapsulation was dependent on PCL block size. At a polymer concentration of 1.0 mg/ml, PEG-b-PCL (5000:4000) and (5000:2500) micelles could encapsulate more than 90% of the initial loading level of fenofibrate, whereas PEG-b-PCL (5000:1000) micelles encapsulate only 28%. SEC experiments revealed that PEG-b-PCL (5000:4000) and (5000:2500) micelles eluted intact, indicating kinetic stability, whereas PEG-b-PCL (5000:1000) micelles eluted primarily as unimers.nConclusions. PEG-b-PCL in ACN assembles with fenofibrate into drug-loaded polymeric micelles with the addition of water and the subsequent removal of a negative ACN-water azeotrope.

Preclinical Characterization of A‐582941: A Novel α7 Neuronal Nicotinic Receptor Agonist with Broad Spectrum Cognition‐Enhancing Properties

Among the diverse sets of nicotinic acetylcholine receptors (nAChRs), the α7 subtype is highly expressed in the hippocampus and cortex and is thought to play important roles in a variety of cognitive processes. In this review, we describe the properties of a novel biaryl diamine α7 nAChR agonist, A‐582941. A‐582941 was found to exhibit high‐affinity binding and partial agonism at α7 nAChRs, with acceptable pharmacokinetic properties and excellent distribution to the central nervous system (CNS). In vitro and in vivo studies indicated that A‐582941 activates signaling pathways known to be involved in cognitive function such as ERK1/2 and CREB phosphorylation. A‐582941 enhanced cognitive performance in behavioral models that capture domains of working memory, short‐term recognition memory, memory consolidation, and sensory gating deficit. A‐582941 exhibited a benign secondary pharmacodynamic and tolerability profile as assessed in a battery of assays of cardiovascular, gastrointestinal, and CNS function. The studies summarized in this review collectively provide preclinical validation that α7 nAChR agonism offers a mechanism with potential to improve cognitive deficits associated with various neurodegenerative and psychiatric disorders.

Thermodynamics, molecular mobility and crystallization kinetics of amorphous griseofulvin.

Griseofulvin is a small rigid molecule that shows relatively high molecular mobility and small configurational entropy in the amorphous phase and tends to readily crystallize from both rubbery and glassy states. This work examines the crystallization kinetics and mechanism of amorphous griseofulvin and the quantitative correlation between the rate of crystallization and molecular mobility above and below Tg. Amorphous griseofulvin was prepared by rapidly quenching the melt in liquid N2. The thermodynamics and dynamics of amorphous phase were then characterized using a combination of thermal analysis techniques. After characterization of the amorphous phase, crystallization kinetics above Tg were monitored by isothermal differential scanning calorimetry (DSC). Transformation curves for crystallization fit a second-order John-Mehl-Avrami (JMA) model. Crystallization kinetics below Tg were monitored by powder X-ray diffraction and fit to the second-order JMA model. Activation energies for crystallization were markedly different above and below Tg suggesting a change in mechanism. In both cases molecular mobility appeared to be partially involved in the rate-limiting step for crystallization, but the extent of correlation between the rate of crystallization and molecular mobility was different above and below Tg. A lower extent of correlation below Tg was observed which does not appear to be explained by the molecular mobility alone and the diminishing activation energy for crystallization suggests a change in the mechanism of crystallization.

Determination of water content in pharmaceutical hydrates by differential scanning calorimetry

Abstract Thermogravimetric analysis (TGA) and Karl Fischer titrimetry (KFT) are the most commonly used techniques for determination of the water content of pharmaceutical solids. We here report a novel method of determining water content of drug hydrates by differential scanning calorimetry (DSC). The method is based on the hypothesis that the enthalpy of binding of n moles of water molecules in the hydrate (enthalpy of dehydration, ΔHd) is the same as that of n moles of water molecules in liquid water (nΔHv), where ΔHv is the enthalpy of vaporization of water. From the literature value of ΔHv and the ΔHd value for each dehydration endotherm the number of moles of water associated with each endotherm was calculated. This approach was applied to several non-ionic drug hydrates, such as hydrates of ampicillin, Carbamazepine, caffeine and theophylline, and to several metal salts of nedocromil. The results obtained by DSC agree well with the KFT and TGA data. Since enthalpy is a state function, the applicability of the above hypothesis does not necessarily support any particular mechanism of dehydration. The above hypothesis was also tested using the dehydration endotherms in the literature for a variety of organic and inorganic hydrates. For those hydrates which give more than one dehydration endotherm by DSC, it is hypothesized that each dehydration endotherm corresponds to a specific binding state or location of water molecules in the crystal lattice. Using this method, it is possible to apportion the water content in each location. The DSC method described cannot be applied when the dehydration endotherm overlaps another peak, such as a polymorphic change, melting, sublimation or decomposition, but can, in principle, be extended to other solvents of crystallization in organic and inorganic solvents. The method may complement the TGA and KFT methods and provide additional information about water binding in pharmaceutical solids.

Prediction of poly(ethylene) glycol-drug eutectic compositions using an index based on the van't Hoff equation.

AbstractPurpose. To define an index based on the vant Hoff equation that can be used as a screening tool for predicting poly(ethylene) glycol (PEG)-drug eutectic composition.nMethods. Phase diagrams of PEG with ritonavir, ibuprofen, fenofibrate, naproxen, and griseofulvin were constructed using differential scanning calorimetry, hot stage microscopy and powder X-ray diffractometry. Previously reported phase diagrams were also used to test the predictive capability of the index.nResults. This work shows that a modified vant Hoff equation can be used to model the drug liquidus line of these phase diagrams. The slope of the liquidus line depends on the melting point (Tfd) and heat of fusion (ΔHfd) of the drug and describes the initial rate at which the eutectic or monotectic point is approached. Based on this finding, a dimensionless index Ic was defined. The index can be calculated from the melting points of the pure components and heat of fusion of the drug. In addition to the compounds listed above, the index was found to predict the eutectic composition for flurbiprofen, temazepam and indomethacin. These compounds range over 150°C in Tfd, and from 25-65kJ/mole in ΔHfd.nConclusion. Using Ic the approximate eutectic composition for eight different compounds was predicted. The index provides a useful screening tool for assessing the maximum drug loading in a drug-polymer eutectic/monotectic formulation.

Understanding and Managing the Impact of HPMC Variability on Drug Release from Controlled Release Formulations

The purpose of this study is to identify critical physicochemical properties of hydroxypxropyl methylcellulose (HPMC) that impact the dissolution of a controlled release tablet and develop a strategy to mitigate the HPMC lot-to-lot and vendor-to-vendor variability. A screening experiment was performed to evaluate the impacts of methoxy/hydroxypropyl substitutions, and viscosity on drug release. The chemical diversity of HPMC was explored by nuclear magnetic resonance (NMR), and the erosion rate of HPMC was investigated using various dissolution apparatuses. Statistical evaluation suggested that the hydroxypropyl content was the primary factor impacting the drug release. However, the statistical model prediction was not robust. NMR experiments suggested the existence of structural diversity of HPMC between lots and more significantly between vendors. Review of drug release from hydrophilic matrices indicated that erosion is a key aspect for both poorly soluble and soluble drugs. An erosion rate method was then developed, which enabled the establishment of a robust model and a meaningful HPMC specification. The study revealed that the overall substitution level is not the unique parameter that dictates its release-controlling properties. Fundamental principles of polymer chemistry and dissolution mechanisms are important in the development and manufacturing of hydrophilic matrices with consistent dissolution performance.