Application of Thermodynamic Phase Diagrams and Gibbs Free Energy of Mixing for Screening of Polymers for Their Use in Amorphous Solid Dispersion Formulation of a Non-Glass-Forming Drug

The objective of the present investigations was to assess the use of thermodynamic phase diagrams and the Gibbs free energy of mixing, ΔG_mix, for the screening of the polymeric carriers by determining the ideal drug-loading for an amorphous solid dispersion formulation and optimum processing temperature for the hot-melt extrusion of a non-glass-forming drug. Mefenamic acid (MFA) was used as a model non-glass-forming drug and four chemically distinct polymers with close values of the solubility parameters, viz. Kollidon® VA64, Soluplus®, Pluronic® F68, and Eudragit® EPO, were used as carriers. The thermodynamic phase diagrams were constructed using the melting point depression data, Flory-Huggins theory, and Gordan-Taylor equation. The Gibbs free energy of mixing was estimated using the values of the drug-polymer interaction parameter, χ, and Flory-Huggins theory. The rank order miscibility of MFA in the four polymeric carriers estimated based on the difference in the values of their solubility parameters, Δδ, did not correlate well with the thermodynamic phase diagrams and Gibbs free energy plots. The study highlights the limitation of using the solubility parameter method in screening the polymeric carriers for poorly glass-forming drugs and reiterates the applicability of thermodynamic phase diagrams and Gibbs free energy plots in determining the ideal drug-loading and optimum processing temperature for hot-melt extrusion.     

Enthalpy Relaxation Studies of Celecoxib Amorphous Mixtures

Purpose. The purpose of this study was to compare the structural relaxation and molecular mobility of amorphous celecoxib (CEL) with that of CEL amorphous mixtures consisting of various excipients and to study the effect of different excipients on the relaxation of high-energy amorphous systems. Methods. The measurement of glass transition temperatures (Tg) and enthalpy relaxation were performed using differential scanning calorimetry. The interactions between drug and excipients and the absence of crystalline forms were further confirmed by conducting Fourier transform infrared spectroscopic and X-ray powder diffraction studies on same samples. Results. All samples exhibited a single Tg value. Polymers had a prominent effect on the lowering of the relaxation rate in amorphous CEL. The lowering of the rate of relaxation was directly dependent on the concentration and type of polymer used. The total enthalpy required for relaxation was same, although additives affected the rate of relaxation. Conclusions. In absence of any specific interactions during Fourier transform infrared studies, it was concluded that the antiplasticizing activity of polymers is responsible for the stabilization of CEL amorphous systems. Glassy amorphous dispersions of CEL exhibited a complex type of relaxation pattern, which failed to fit in Kohlrausch-Williams-Watts equation with respect to calculation of relaxation time constants.     

CDER Risk Assessment Exercise to Evaluate Potential Risks from the Use of Nanomaterials in Drug Products

The Nanotechnology Risk Assessment Working Group in the Center for Drug Evaluation and Research (CDER) within the United States Food and Drug Administration was established to assess the possible impact of nanotechnology on drug products. The group is in the process of performing risk assessment and management exercises. The task of the working group is to identify areas where CDER may need to optimize its review practices and to develop standards to ensure review consistency for drug applications that may involve the application of nanotechnology. The working group already performed risk management exercises evaluating the potential risks from administering nanomaterial active pharmaceutical ingredients (API) or nanomaterial excipients by various routes of administration. This publication outlines the risk assessment and management process used by the working group, using nanomaterial API by the oral route of administration as an example.     

Determination of the Surface Free Energy of Crystalline and Amorphous Lactose by Atomic Force Microscopy Adhesion Measurement

Purpose This study was conducted to accurately measure the dispersive surface free energy of lactose solids in ordered and disordered states. Methods Atomic force microscopy (AFM) was used to determine the contact adhesion force between an AFM tip and lactose under low humidity (ca. 1% RH). The geometry of the tip contacting apex was characterized by scanning a porous aluminum film with ultrasharp spikes (radius 2–3 nm). A sphere vs. flat surface model was employed to relate the adhesion force determined to the surface energy based upon the Johnson–Kendal–Roberts theory. Spray-dried amorphous lactose in a compressed-disk form and single crystals of α-lactose monohydrate were prepared as model samples. Results The condition of the smooth sample surface and sphere-shaped tip used was shown to be appropriate to the application of the JKR model. The surface energy of crystalline [(0,−1,−1) face] and amorphous lactose was determined to be 23.3 ± 2.3 and 57.4 ± 7.9 mJ m⁻², respectively. Conclusions We have demonstrated the capability of AFM to measure the dispersive surface free energy of pharmaceutical materials directly through a blank probe at the nanometer scale. These data, although consistent with results from more traditional methods, illustrate some unique attributes of this approach, namely, surface energies are directly derived from solid–solid interactions, measurements may be made on specific crystalline faces, and the potential exists to identify the submicron heterogeneity of organic solids in terms of their molecular energy states (such as ordered and disordered lactose).     

The Use of Inverse Phase Gas Chromatography to Measure the Surface Energy of Crystalline,Amorphous, and Recently Milled Lactose

Purpose. To assess differences in surface energy due to processing induced disorder and to understand whether the disorder dominated the surfaces of particles. Methods. Inverse gas chromatography was used to compare the surface energies of crystalline, amorphous, and ball milled lactose. Results. The milling process made ca 1% of the lactose amorphous, however the dispersive contribution to surface energy was 31.2, 37.1, and 41.6 mJ m^–2 for crystalline, spray dried and milled lactose, respectively. A physical mixture of crystalline (99%) and amorphous (1%) material had a dispersive surface energy of 31.5 mJ m^–2. Conclusion. Milling had made the surface energy similar to that of the amorphous material in a manner that was very different to a physical mixture of the same amorphous content. The milled material will have similar interfacial interactions to the 100% amorphous material.     

Impact of Drug-Polymer Miscibility on Enthalpy Relaxation of Irbesartan Amorphous Solid Dispersions

Purpose

Drug-polymer miscibility has been proposed to play a critical role in physical stability of amorphous solid dispersions (ASDs). The purpose of the current work was to investigate the role of drug-polymer miscibility on molecular mobility, measured as enthalpy relaxation (ER) of amorphous irbesartan (IBS) in ASDs.

Methods

Two polymers, i.e. polyvinylpyrrolidone K30 (PVP K30) and hydroxypropyl methylcellulose acetate succinate (HPMCAS), were used to generate ASDs with 10% w/w of the polymer. Drug-polymer miscibility was determined using melting point depression (MPD) method. Molecular mobility was assessed from ER studies at a common degree of undercooling (DOU) (T_g???13.0°C?±?0.5°C).

Results

IBS exhibited higher miscibility in PVP K30 as compared to HPMCAS at temperature?>?140°C. However, extrapolation of miscibility data to storage temperature (62°C) using Flory-Huggins (F-H) theory revealed a reversal of the trend. Miscibility of IBS was found to be higher in HPMCAS (2.6%) than PVP K30 (1.3%) at 62°C. Stretched relaxation time (τ^β) of 17.4365 h and 7.0886 h was obtained for IBS-HPMCAS and IBS-PVP K30 ASDs, respectively.

Conclusion

Miscibility of drug-polymer at storage temperature explained the behavior of the molecular mobility, while miscibility near the melting point provided a reverse trend. Results suggest that drug-polymer miscibility determined at temperatures higher than the storage temperature should be viewed cautiously.

     

Direct Observation of the Enthalpy Relaxation and the Recovery Processes of Maltose-Based Amorphous Formulation by Isothermal Microcalorimetry

Purpose. The applicability of isothermal microcalorimetry (IMC) for evaluating enthalpy relaxation and recovery processes of amorphous material was assessed. Methods. A maltose-based formulation was prepared by freeze-dry method. Differential scanning calorimetry (DSC) was used to investigate its glass transition and relaxation behaviors. IMC was applied to quantitatively analyze the relaxation and the recovery processes. The IMC data were analyzed using a derivative of the Kohlrausch-Williams-Watts equation. Results. The glass transition temperature of the formulation and its fictive temperature stored at 15°C for 1 year were 62 and 32°C, respectively. DSC study showed that annealing below the fictive temperature increased the enthalpy recovery, but it was decreased by annealing at higher temperatures. IMC enabled direct observation of the heat flow during both the relaxation and the recovery processes. The decay constant for the recovery process (recovery time) was much smaller and less sensitive to the temperature than that for the relaxation process (relaxation time). Conclusions. IMC was successfully used to obtain quantitative information on both relaxation and recovery processes of amorphous material. The relaxation parameters obtained by this method could explain the thermodynamic behavior of the formulation.     

Solid-State Characteristics of Amorphous Sodium Indomethacin Relative to Its Free Acid

Purpose. Having previously studied the amorphous properties of indomethacin (IN) as a model compound for drugs rendered amorphous during processing, we report on the formation and characterization of its sodium salt in the amorphous state and a comparison between the two systems. Methods. Sodium indomethacin (SI) was subjected to lyophilization from aqueous solution, rapid precipitation from methanol solution, and dehydration followed by grinding to produce, in each case, a completely amorphous form. The amorphous form of SI was analyzed using DSC, XRD, thermomicroscopy and FTIR. The method of scanning rate dependence of the glass transition temperature, Tg, was used to estimate the fragility of the SI system. Enthalpy relaxation experiments were carried out to probe the molecular mobility of the SI system below Tg. Results. The amorphous form of SI formed by different methods had a Tg equal to 121°C at a scanning rate of 20°C/min. This compares with a Tgfor indomethacin of 45°C. Estimation of fragility by the scanning rate dependence of Tg indicates no significant differences in fragility between ionized and unionized forms. Enthalpy relaxation measurements reveal very similar relaxation patterns between the two systems at the same degree of supercooling relative to their respective Tg values. Conclusions. The amorphous form of SI made by various methods has a Tg that is about 75°C greater than that of IN, most likely because of the greater density and hence lower free volume of SI. Yet, the change of molecular mobility as a function of temperature relative to Tgis not very different between the ionized and unionized systems.     

Use of Standardized Patients to Evaluate the Physicians in Residence Program

Abstract

The purpose of this study was to evaluate the efficacy of the Physician in Residence (PIR) program at the Hazelden Residential Program of New York City as a substance abuse training approach using standardized patients (SP) and self-report ratings. Using an objective rating scale, two experienced drug counselors evaluated four videotaped interviews carried out by housestaff pre- and post-enrollment in the PIR program. In addition, housestaff completed self-report ratings regarding their knowledge, attitudes, and skills of substance abuse. Of the 23 housestaff who completed both pre- and post-PIR program videotape sessions, significant improvements were noted in both observer and self-reported ratings. Overall, self-report ratings showed a greater percent improvement than the counselor ratings. The PIR program may be an efficacious approach to teach substance abuse clinical skills to housestaff.     

Evaluating a Modified High Purity Polysorbate 20 Designed to Reduce the Risk of Free Fatty Acid Particle Formation

Pharmaceutical Research - To evaluate a modified high purity polysorbate 20 (RO HP PS20)—with lower levels of stearate, palmitate and myristate esters than the non-modified HP PS20—as a...     

The Application of Modeling and Prediction to the Formation and Stability of Amorphous Solid Dispersions

Amorphous solid dispersion (ASD) formulation development is frequently difficult owing to the inherent physical instability of the amorphous form, and limited understanding of the physical and chemical interactions that translate to initial dispersion formation and long-term physical stability. Formulation development for ASDs has been historically accomplished through trial and error or experience with extant systems; however, rational selection of appropriate excipients is preferred to reduce time to market and decrease costs associated with development. Current efforts to develop thermodynamic and computational models attempt to rationally direct formulation and show promise. This review compiles and evaluates important methods used to predict ASD formation and physical stability. Recent literature in which these methods are applied is also reviewed, and limitations of each method are discussed.     

Photochemical and Pharmacokinetic Characterization of Orally Administered Chemicals to Evaluate Phototoxic Risk

This study aimed to verify the applicability of a proposed photosafety screening system based on a reactive oxygen species (ROS) assay and a cassette-dosing pharmacokinetic (PK) study to chemicals with wide structural diversity. The orally taken chemicals, erythromycin, gatifloxacin, 8-methoxypsoralen (MOP), pirfenidone (PFD), trifluoperazine (TFP), and voriconazole (VRZ), were selected as test compounds. The ROS assay was conducted to evaluate their photoreactivity, and all test compounds excluding erythromycin generated significant ROS under simulated sunlight exposure. According to the ROS data, TFP had potent photoreactivity, and the photoreactivity of 4 other compounds was judged to be moderate. Regarding the oral cassette-dosing PK test in rats, the skin deposition of MOP, PFD, and VRZ was relatively high, and gatifloxacin and TFP exhibited moderate skin deposition properties. Based on the ROS and PK data of test compounds, PFD and TFP were judged to be potent phototoxic compounds, and MOP and VRZ were deduced to have phototoxic risk. The predicted phototoxic risk of test compounds by proposed screening was mostly in agreement with observed in vivo phototoxicity in the rat skin. The proposed screening system could provide reliable photosafety information on orally administered compounds with wide structural diversity.     

Use of the Walden Product to Evaluate the Effect of Amino Acids on Water Structure

Abstract— The Walden Product, the product of viscosity (η₀) and conductivity at infinite dilution of a solution (Λ₀), provides a measurement of the water-structuring activity of the solute. Measuring the effect of concentration on viscosity of solutions of amino acids, together with the conductivity of solutions of sodium chloride containing increasing concentrations of the amino acids, enabled Walden Products to be determined. The classical form of the Walden Product (Λ₀η₀) was used, together with a modified form, Λ₀η_c, in which η_c was the slope of the concentration/viscosity curve. Most amino acids demonstrated modest water-structure-breaking activity but l -lysine, l -glutamic acid and l -aspartic acid, and their respective salts, all showed relatively higher activity. Dextrose behaved as a classical water-structure maker and, when added progressively, reversed the breaking activity of l -lysine. It is speculated that effects seen in bulk water may also occur at emulsion droplet surfaces, thereby inducing structural changes associated with the occasional rapid instability experienced when making admixtures of phospholipid-stabilized emulsions and additives such as amino acids and dextrose.     

Transcultural Adaptation of Questionnaire to Evaluate Drug Use Among Students: The Use of the EU-Dap European Questionnaire in Brazil

Background: Social and cultural differences between countries stress the need for adapting existent instruments for adequately comparing epidemiological results. However, there are controversies in literature on how to carry out this process. Objectives: This study aimed to describe the process of cultural adaptation and evaluation of the Brazilian Portuguese language of the European Drug Addiction Prevention Trial (EU-Dap) questionnaire to identify alcohol, tobacco, and other drug use among adolescents. Methods: The cross-sectional study took place in 16 public schools in three Brazilian cities during the year 2013 in a sample of 2,969 adolescents between the ages of 11 and 16. Operating steps involved analysis of qualitative data collected through student's focus group and field notes by interviewers and quantitative data from test–retest evaluation and nonresponse to item. Results: The results revealed moderate reliability for the primary outcomes and high levels of nonresponse, mainly in the 2/3 final questions. Focus group provided high-quality information about misconception for the semantic and structure of the questionnaire. Participatory observation helped researchers to tap into the main difficulties of the application context. Conclusions: Sociocultural issues related to Brazilian students, the application context, and the structure of the original questionnaire contributed to the unsatisfactory results of the transcultural adaptation process. The results further highlighted the challenge of adapt questionnaires investigating sensitive issues in an age group particularly influenced by educational factors, especially when the countries have different standards of achievement in education.     

Use of Near-Infrared Spectroscopy to Evaluate an Active in a Film Coated Tablet

Purpose. To provide a method to rapidly screen tablets in the development of new coating technology. Methods. Near-Infrared (NIR) reflectance spectroscopy was used to quantitatively analyze tablets which were composed of a drug active encasing an active drug core. Diffuse reflectance NIR scans of 240 individual tablets over the range of 1100–2500 nm were obtained. High Performance Liquid Chromatography (HPLC) was used as the reference method. Results. Both qualitative, Principal Component Analysis, and quantitative results showed a strong agreement between the NIR and HPLC methods. The NIR analysis was non-invasive and allowed subsequent testing of the tablets. The contents of the drug active contained in a drug coating was determined to ± 4% of the target value using NIR analysis. Over 400 samples were analyzed in less than a month utilizing this technique which allowed the optimization of a new coating technology. Conclusions. NIR analysis allowed the evaluation of the efficiency of a new drug film coating manufacturing process more quickly and inexpensively. Because the Near-Infrared method was non-invasive the tablets were available for further analysis unlike the chromatography method.     

A High Energy X-ray Diffraction Study of Amorphous Indomethacin

Amorphous pharmaceuticals often possess a wide range of molecular conformations and bonding arrangements. The x-ray pair distribution function (PDF) method is a powerful technique for the characterization of variations in both intra-molecular and inter-molecular packing arrangements. Here, the x-ray PDF of amorphous Indomethacin is shown to be particularly sensitive to the preferred orientations of the chlorobenzyl ring found in isomers in the crystalline state. In some cases, the chlorobenzyl ring has no preferred torsional angle in the amorphous form, while in others evidence of distinct isomer orientations are observed. Amorphous samples with no preferred torsion angles of the chlorobenzyl ring are found to favor enhanced inter-molecular hydrogen bonding, and this is reflected in the intensity of the first sharp diffraction peak. These significant variations in structure rule out amorphous Indomethacin as a possible standard for x-ray PDF measurements. At high humidity, time resolved PDF's for >40 h reveal water molecules forming hydrogen bonds with Indomethacin molecules. A simple linear hydrogen bond model indicates that water molecules in the wet amorphous form have similar hydrogen bond strengths to those found between Indomethacin dimers or chains in the dry amorphous form.     

Adaptation and Validation of a Self-Report Measure to Evaluate Substance Use Among Sri Lankan Adolescents

This study translated and validated the model Student Questionnaire (SQ) among 13- to 18-year-old Sri Lankan adolescents. A systematic procedure was followed to translate the SQ into Sinhala language. The Sinhala version was titled Adolescent Substance Use Student Questionnaire (ASUSQ). A Delphi process was conducted to evaluate consensual validity of ASUSQ. Test–retest study (N == 120) ensured reliability. Contrasted group technique study (N == 200) among users and nonusers established construct validity. Data collection instruments were SQ, its Sinhala version, structured-interview schedule, and focus group discussion guide. Sinhala-speaking students were randomly selected from schools in a semi-urban area. Applicability of the ASUSQ and further research are discussed. The study's limitations are noted.     

PASS监测用药风险警示的评估及成因分析

目的了解PASS监测系统在临床治疗中的警示作用并进行溯源评估。方法采用病例观察方法,通过PASS系统对2008年5～12月间3所医院科室的住院医嘱进行监测,评价警示信息有效性并作关联性因素分析。采用SPSS软件进行数据统计分析。结果4910例患者的29700条医嘱中,重点警示信息2813条,主要集中于药物相互作用、特殊人群、配伍禁忌、给药剂量、给药途径;其中有效的1161条信息的关联性因素以人员因素为最多;无效的1652条则主要源自PASS的局限性。结论PASS因其智能化有限,临床存在闯关提交医嘱现象;但用于临床短时大量医嘱的快速初审人工无法替代,其警示信息对于提示临床医师预见并规避可能的风险隐患方面有显著的实用意义。     

Use of the Stable Isotopes Technique to Evaluate the Bioavailability of a Pharmaceutical Form of Magnesium in Man

Pharmaceutical Research -