Characterization of pharmaceutical polymorphs by isothermal calorimetry

A great number of pharmaceutical substances exist in crystalline solid-state. Because of the complexity of their chemical structure many different polymorphs of a given substance can exist. Polymorphic forms of solid pharmaceuticals influence not only their dissolution behavior, i.e. bioavailability but also their solid-state stability. It is well known that only one polymorphic form is thermodynamically stable and all other metastable forms will convert, eventually, to the more stable form. Hence it is essential to choose the most suitable polymorphic form in the early stage of pharmaceutical development. The following article reviews the recent applications of solution calorimetry that allows characterization of pharmaceutical polymorphs through accurate determination of enthalpy of solution. Each crystalline form possesses a defined enthalpy of solution, therefore solution calorimetry is used for the quantitative analysis of the desired polymorphic form and determination of enthalpy of transition corresponding to the difference in enthalpies of solution for a polymorphic pair. More recently this technique has been applied to the estimation of thermodynamic transition temperature, which is useful for the evaluation of thermodynamic stability relationships between polymorphs. This article will also describe the kinetics and thermodynamics of polymorphic transitions, from a metastable form to the thermodynamically stable form, through studies using ampoule-based isothermal microcalorimetry. Such studies are particularly useful when metastable forms are to be selected in order to enhance bioavailability. If the metastable form, or the pharmaceutical product containing it, can be shown to be sufficiently stable, it could then be used in a formulation where its therapeutic effects could be exploited.     

Application of solution calorimetry in pharmaceutical and biopharmaceutical research

In solution calorimetry the heat of solution (Delta(sol)H) is recorded as a solute (usually a solid) dissolves in an excess of solvent. Such measurements are valuable during all the phases of pharmaceutical formulation and the number of applications of the technique is growing. For instance, solution calorimetry is extremely useful during preformulation for the detection and quantification of polymorphs, degrees of crystallinity and percent amorphous content; knowledge of all of these parameters is essential in order to exert control over the manufacture and subsequent performance of a solid pharmaceutical. Careful experimental design and data interpretation also allows the measurement of the enthalpy of transfer (Delta(trans)H) of a solute between two phases. Because solution calorimetry does not require optically transparent solutions, and can be used to study cloudy or turbid solutions or suspensions directly, measurement of Delta(trans)H affords the opportunity to study the partitioning of drugs into, and across, biological membranes. It also allows the in-situ study of cellular systems. Furthermore, novel experimental methodologies have led to the increasing use of solution calorimetry to study a wider range of phenomena, such as the precipitation of drugs from supersaturated solutions or the formation of liposomes from phospholipid films. It is the purpose of this review to discuss some of these applications, in the context of pharmaceutical formulation and preformulation, and highlight some of the potential future areas where solution calorimetry might find applications.     

New challenges for pharmaceutical formulations and drug delivery systems characterization using isothermal titration calorimetry

Long viewed as the 'method of choice' for characterizing thermodynamics and stoichiometry of molecular interactions, with high sensitivity, isothermal titration calorimetry (ITC) has been applied to many areas of pharmaceutical analysis. This review highlights ITC employment to measure binding thermodynamics and their use for pharmaceutical formulations and drug delivery system characterization particularly cyclodextrin-guest interactions, investigation of micellar-based systems, polyelectrolytes, nucleic acid interactions with multivalent cations and the optimization of DNA targeting and delivery. Furthermore, the potential of ITC for the characterization of different functionalities carried by nanoparticles as well as their interaction with living systems was outlined.     

差示扫描量热法在药物定性分析中的应用

差示扫描量热法（DSC）是在程序控制温度下,测量输给物质和参比物的功率差与温度关系的一种技术,被广泛应用于药品的研究生产和质量测试的快速可靠的热分析方法,该方法具有准确快速、样品用量少及易于操作等特点。综述了近年来差示扫描量热法在化学原料药、药物制剂、生物制品以及中药鉴定等方面的应用,并展望了未来的发展前景。     

Stability assessment of pharmaceuticals and biopharmaceuticals by isothermal calorimetry

The assessment of stability (of actives, excipients and/or formulated products) is an important, and often time-consuming, part of pharmaceutical product development. Conventionally, HPLC is used to quantify the concentrations of a parent compound and any degradation products as a function of storage time. HPLC, however, is relatively insensitive to small changes in concentration and it is often the case that stability assays are conducted under stress conditions, in order to accelerate any degradation processes. The Arrhenius relationship is then employed to give an initial prediction of stability under storage conditions while long-term studies, under storage conditions, are conducted to confirm these predictions. The properties of isothermal calorimetry, such as its intrinsic sensitivity to small changes in heat and invariance to the physical form of a sample, make it ideally suited for stability assessment because it obviates the need for an Arrhenius analysis. In addition, the ability to conduct titration or gas perfusion experiments vastly increases its range of applications. Recent advances in instrumental design and data analysis have made it easier to analyse data quantitatively for complex systems. It is the purpose of this review to highlight some of these developments, discuss them in the context of pharmaceutical and biopharmaceutical examples and explore some of the future challenges and applications of the technique.     

The use of differential scanning calorimetry for the purity verification of pharmaceutical reference standards

Reference standards are routinely used in pharmaceutical industry to determine strength, content, and the quality of drug products, active pharmaceutical ingredients (API), preservatives, antioxidants and excipients. Traditionally, chromatographic techniques such as High Performance Liquid Chromatography (HPLC) and Gas Chromatography (GC) in conjunction with other analytical techniques have been used to determine the purity and strength of a specific lot of a compound for the purpose of qualifying the lot to use as a reference standard. The assigned purity of the reference standard for a wide variety of compounds can be verified using an absolute method such as Differential Scanning Calorimetry (DSC). In this paper, purity of 16 reference standards was determined by DSC and the results were then compared to the purity values that were obtained using HPLC and other analytical techniques. The results indicate that the purity obtained from DSC analysis is comparable to the chromatographic purity for organic compounds that are at least 98% pure. Use of DSC for purity determination is not appropriate if a compound lacks sharp melting point, decomposes in the defined temperature range or exhibits other thermal event(s) which interfere with the melting point of the compound. The use of DSC as an alternative and or complementary method to verify the purity of a compound as part of the pharmaceutical reference standard certification process is discussed.     

The use of high-speed differential scanning calorimetry (Hyper-DSC) in the study of pharmaceutical polymorphs

The thermal properties of two polymorphs (A and C) of a Merck development compound were studied using high-speed differential scanning calorimetry (Hyper-DSC™). The utility of this novel technique as a fast analytical tool for studying the polymorphic behaviour of metastable polymorphs has previously been demonstrated successfully for Carbamazepine. Accelerated heating rates can alter the kinetics of the melting transition of metastable polymorphs such that concurrent exothermic recrystallisation is inhibited. Here it is demonstrated that at heating rates of 400 °C/min concurrent recrystallisation of Polymorph A of the Merck development compound is inhibited allowing the enthalpy of fusion for the lower melting Polymorph C to be determined. The utility of the technique as a qualitative tool to detect the presence of polymorphic impurities was confirmed for levels much lower than 10% (w/w). However, seeding effects consistent with those reported previously for Carbamazepine were also observed for this structurally distinct molecule limiting the utility of the technique for accurate quantification of low levels of polymorphic impurities.     

Application of isothermal microcalorimetry in solid state drug development

Microcalorimetry is an analytical technique that has found numerous applications within the pharmaceutical environment. In the realm of pharmaceutics, especially solid state pharmaceutics, the technique has proved to be an invaluable tool. This review addresses the solid state applications of microcalorimetry within the pharmaceutical industry, with a specific focus on stability, compatibility and amorphicity determinations.     

药物经济学在我国医药产业的应用与发展趋势

药物经济学（pharmacoeconomics,PE）是运用经济学基本原理、方法和分析技术对药物的成本和治疗效果进行综合评价的一门新兴学科。我国的PE研究尽管起步较晚,但随着我国医药产业的繁荣,PE也在医药产业各领域得到了广泛而深入的研究与应用,其研究成果对我国医药产业培育新药创新能力、推进医疗体制的改革、控制药物价格、制定促进我国医药产业发展的国家政策方面都有现实的意义。     

药用微乳应用概况与发展趋势*

微乳作为一种新型的药物载体,具有极大的发展潜力。现综述微乳的定义、形成机制、制备方法和特点,并系统综述了近年来微乳在口服、注射、经皮、眼部、鼻腔转运给药制剂等方面的应用概况,以及作为一种技术用于制备固体脂质纳米粒的应用概况,分析了近年来微乳在发展过程中存在的问题,进一步展望了微乳的发展趋势。     

Sertaconazole/hydroxypropyl-beta-cyclodextrin complexation: isothermal titration calorimetry and solubility approaches

Complexation of sertaconazole (SN) with hydroxypropyl-beta-cyclodextrin (HP-beta-CD) was characterized by phase-solubility diagram measurements and isothermal calorimetry (ITC) in aqueous medium, and by differential scanning calorimetry (DSC), Raman spectroscopy and X-ray diffractometry in solid state. The strongest interaction was observed at pH 1.2, at which two different 1:1 complexes can be formed depending on the hydrophobic ring of the drug involved in the process. At pH 5.8 and 7.4 the likelihood of 1:2 stoichiometry increases as a consequence of the simultaneous complexation of the nonprotonized imidazolyl and the dichlorophenyl groups. In the presence of 20% HP-beta-CD, SN solubility is enhanced by a factor of 116, 107, and 5 at pH 1.2, 5.8, and 7.4, respectively. Complexation enthalpy recorded by ITC showed the same tendency which confirms the practical interest of this technique for fast screening of the potential of CDs as drug solubilizers. Solubility and dissolution rate of the drug from compacts prepared with freeze-dried complexes were significantly greater than those obtained with SN powder or compacts made with physical blends.     

Differential scanning calorimetry and scanning thermal microscopy analysis of pharmaceutical materials

Micro-thermal analysis (microTA) by scanning thermal microscopy is being used increasingly for the analysis of pharmaceutical dosage forms. However, there is currently little evidence to show that microTA data can compare directly with that from the established approach of differential scanning calorimetry (DSC). This work compares DSC and microTA data from an active vitamin B6 analogue, pyridoxal hydrochloride, and two commonly used pharmaceutical excipients, Mannitol and Avicel which are used in its formulation. It is found that microTA provides precise and accurate micro-thermal analytical data with 0.1 K thermal sensitivity, which is comparable to that obtained by DSC measurements of bulk samples. It is also shown that microTA offers the opportunity to study single particles and the interfacial region between particles, data which is currently inaccessible through the DSC technique.     

基于等温滴定量热技术表征的中药注射剂临床联合用药相容性评价

为建立一种快速评价中药注射剂临床联合用药相容性的方法,采用等温滴定量热法(isothermal titration calorimetry,ITC),考察模式药益气复脉冻干粉针(YQFM)与常用联合用药维生素C注射液(Vc)及5%葡萄糖注射液(5%GS)的相容性,以热力学参数吉布斯自由能(ΔG)、焓变(ΔH)、熵变(ΔS)判断溶合反应类型,以反应活性谱判断反应热量变化,辅以化学特征色谱法进行佐证。结果显示,YQFM与Vc溶合过程中│ΔH│>T│ΔS│,为焓驱动反应,且反应活性谱显示两者溶合放出大量热,即溶合过程中化学反应起主导作用,活性成分发生质变;与5%GS溶合过程│ΔH│相似文献   

Monitoring crystallisation of drugs from fast-dissolving oral films with isothermal calorimetry

The aim of this study was to evaluate the potential of isothermal calorimetry to monitor and characterize crystallisation in drug-loaded fast-dissolving oral films.Films of polyvinylpyrrolidone (PVP) containing indomethacin were cast into glass ampoules; stability was assessed by monitoring the power changes occurring with time. Three grades of PVP (K10, K25 and K40, where the number multiplied by 1000 gives the average molecular weight) were used. Indomethacin was seen to crystallise from all PVP grades over ca. 24–48 h at two study temperatures (25 and 37 °C), as denoted by a large exothermic event. At 25 °C the exothermic event was a single peak; at 37 °C two peaks were observed. Subsequent analysis of the crystals with differential scanning calorimetry (DSC) and polarized light microscopy determined that the stable γ-polymorph of indomethacin formed at 25 °C while both the γ- and metastable α-polymorphs formed at 37 °C. The calorimetric data were converted to relative crystallinity as a function of time and analysed with three crystallisation models (Avrami, Tobin and Urbanovici–Segal) to determine crystallisation kinetics. Of the three models applied the Urbanovici–Segal model best described the data, although this may be because this model contains a term that effectively accounts for deviation from the Avrami model. The rate constants determined were broadly consistent irrespective of the model used. Increasing polymer molecular weight did not generally affect the crystallisation rate, although an increase in temperature did result in a concomitant increase in crystallisation rate. The data suggest that isothermal calorimetry is able to monitor drug crystallisation in polymer films and therefore the technique could be a useful tool for conducting stability assays for fast-dissolving oral medicines.     

Stability assessment of pharmaceuticals by isothermal calorimetry: two component systems

Isothermal calorimetry offers the potential to determine rapidly the stability of formulated pharmaceuticals because it is indifferent to physical form and sensitive enough to detect extremely small powers; ca. 50 nW at 25 degrees C. However, its use in this area is not widespread, principally because the power-time data obtained often comprise contributions from more than one process and are thus difficult to analyse quantitatively. In this work, we demonstrate how power-time data recorded for systems in which two components are degrading in parallel (in this case, binary mixtures of selected parabens) can be analysed using a kinetic-based model; the methodology allows the determination of the first-order rate constant and reaction enthalpy for each process, so long as one rate constant is at least twice the magnitude of the other. It was found that the reactions did not need to run to completion in order for the analysis to be successful; a minimum of 15 min of data were required for samples with one degrading component and a minimum of 4 h of data were required for samples with two degrading components. It was observed that the rate constants for paraben degradation in binary systems were significantly lower than expected. This was ascribed to the fact that the parabens degrade to a common product and is an important factor that should be accounted for when the two or more parabens are formulated together.     

Recent developments for the analysis of data obtained from isothermal calorimetry

Isothermal calorimetry is rapidly becoming an indispensable tool for the quantitative determination of a variety of kinetic and thermodynamic parameters for a wide range of systems. In particular calorimetry is finding increased application to the investigation of stability and incompatibility of pharmaceutical materials. In order to draw meaningful conclusions and to predict behaviour in related systems it is necessary to have the means to calculate accurately parameters such as the rate constant and enthalpy. To this end several groups have been developing equations which describe calorimetric output in these terms. This paper will briefly outline some of these equations and discuss some of the limitations that currently exist in their application. A particular emphasis is placed on the recent developments relating to the application of these equations to flow calorimetric data. The main application of these equations is usually found in the pharmaceutical industry. Pharmaceutical formulations are usually extremely complex mixtures consisting of many different excipients as well as the active drug. Because of these large numbers of ingredients it is often observed that multiple chemical and physical process occur over the lifetime of the study. This complexity is then reflected in the calorimetric data rendering the application of the simple equations useless. Dealing with this complexity is a major issue amongst the calorimetric community and some of the recent advances in this field are also discussed.     

药学信息在药学科研中的应用

目的：介绍药学科研各环节中药学信息的应用，从而提高科研工作的效率与水平。方法：结合药学科研实际工作，介绍科研过程中药学信息的应用情况。结果：无论是在药学科研的选题与方案设计过程中，还是在药学科研方案的实施与总结过程中，药学科研人员都应快速、准确、全面地获取各种相关药学信息。结论：药学信息与药学科研工作息息相关。     

Using compression calorimetry to characterize powder compaction behavior of pharmaceutical materials

The process by which pharmaceutical powders are compressed into cohesive compacts or tablets has been studied using a compression calorimeter. Relating the various thermodynamic results to relevant physical processes has been emphasized. Work, heat, and internal energy change values have been determined with the compression calorimeter for common pharmaceutical materials. A framework of equations has been proposed relating the physical processes of friction, reversible deformation, irreversible deformation, and inter-particle bonding to the compression calorimetry values. The results indicate that irreversible deformation dominated many of the thermodynamic values, especially the net internal energy change following the compression–decompression cycle. The relationships between the net work and the net heat from the complete cycle were very clear indicators of predominating deformation mechanisms. Likewise, the ratio of energy stored as internal energy to the initial work input distinguished the materials according to their brittle or plastic deformation tendencies. © 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 99:861–870, 2010     

Stabilization and pharmaceutical use of alliinase

In recent years, numerous clinical trials were undertaken in order to elucidate the active principle of garlic (Allium sativum L., Alliaceae). The most prominent effect of garlic preparations is a contribution to the prevention of stroke and arteriosclerosis. Allicin[(2-propenyl)-2-propenethiosulfinate] and other sulfur containing compounds were suggested as active compounds. The extremely unstable allicin itself is liberated from the more stable alliin [S-(+)-2-propenyl-L-cysteine sulfoxide] by the enzyme alliinase (EC 4.4.1.4) if fresh garlic is crunched or garlic powder is moistened. Therefore, an active enzyme is required in alliin containing remedies like those prepared from garlic powder. In order to investigate enzyme stability, alliinase was isolated from garlic powder. The partially purified enzyme could be stabilized over several months by addition of sodium chloride, sucrose, and pyridoxal-5'-phosphate. Alliinase may also be freeze-dried. This allows combinations of synthetic alliin and purified alliinase as components of an acid resistant tablet or capsule. In the intestine, the pro-drug alliin would be enzymatically converted to allicin. In clinical trials, highly dosed preparations of this kind should yield a precise information about the physiological effects of allicin. In addition, alliin-homologues substances which bear a modified alkyl side chain and do not occur in nature may be tested.