Thermal Analysis UserCom 21

Introduction

The kinetics of chemical reactions can be easily determined from DSC or TGA measurements. The METTLER TOLEDO STAR^e software offers three different software options: the classical n^th order kinetics and two so-called model-free methods.

The n^th order kinetics approach assumes that the activation energy is constant throughout the entire reaction. The reaction rate, dα/dt, is given by the equation

where α is the conversion, K₀ is the pre-exponential factor, E_a the activation energy, R the gas constant, T the temperature and n the order of the reaction. An n^th order reaction is therefore completely described by the parameters n, E_a and K₀. This model is, however, at best only suitable for simple reactions. In more complex reactions in which several reaction steps proceed in parallel, or in which the reaction is not completely chemically controlled, n^th order kinetics fails. In such cases, model free kinetics is an excellent alternative to describe the reaction kinetics. This study shows how model free kinetics can be used to evaluate DSC and TGA measurements and make predictions about the isothermal behavior of reactions (i.e. determine conversion as a function of time at a certain temperature, or the time needed at a given temperature to reach a certain conversion).

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The behavior of substances with regard to drying, moisture uptake, and moisture content has become a topic of major importance because moisture can often have adverse effects on the properties of materials and products. The new TGA Sorption Analyzer System provides a very convenient method for studying such phenomena. The advantages of the technique are illustrated in the following article using amiloride hydrochloride dihydrate as an example.

Introduction

Recent surveys among TA users have confirmed that one of the current trends in modern thermal analysis is to control the gas atmosphere surrounding the sample. This can involve the use of reactive gases, the application of vacuum or pressure, or setting different levels of relative humidity (RH).
In particular, investigations at defined relative humidity are becoming more and more important. This article describes the application of the new TGA Sorption Analyzer System to study a pharmaceutically active substance. An application study from the aroma/foodstuffs industry was published in UserCom 17 in 2003 [1].

The relative humidity influences the processibility, storage stability and usability of many materials such as pharmaceutical products (active ingredients, and fillers like lactose), plastics (nylon), construction materials (cement), metals (iron/rust formation), explosives (dynamite) and foodstuffs (potato chips). This makes it necessary to investigate material properties at defined levels of relative humidity or to measure the humidity dependence of the material.
A sample exposed to high relative humidity at room temperature tends to take up moisture. Products stored in contact with the open air may take up or lose moisture, depending on the relative humidity. Among other effects, the uptake of moisture can also influence mechanical properties, as anyone who has left potato chips in the open for a few days knows. In this case, moisture acts as a plasticizer and shifts the glass transition of the potato chips to below room temperature; the chips are then soft and no longer crisp [2].

The study of the behavior of materials as a function of relative humidity is particularly important with pharmaceutical preparations. This begins early on in the processing stage. A spray-dried powder can, for example, cause immense problems if it becomes moist and blocks the supply lines and dispensing devices, possibly leading to a shutdown of production. And if the finished medication takes up moisture due to inadequate packaging while in stock in the drug store, the shelf life of the product is obviously reduced.
Furthermore, increased moisture content can also lead to major changes in the structural properties of the drug and reduce its bioavailability and therapeutic effect. One possible reason for such a change due to the uptake of moisture is the recrystallization of the active substance. This phenomenon is referred to as pseudopolymorphism, and the term pseudopolymorph refers to the compounds formed, which are known as hydrates or solvates. These are produced when the crystalline form changes as a result of the incorporation of water or solvent molecules into the crystal lattice. Stoichiometric hydrates (e.g. mono-, di-, tri-hydrates, etc.) are often stable compounds in which water is strongly bound as so-called water of crystallization. In contrast, moisture can also be merely adsorbed on the surface, in which case the water is only weakly bound.
Hydrates and anhydrates (i.e. the anhydrous form that does not contain any water of crystallization) behave differently and can have different medicinal properties. It is important to identify and characterize pseudopolymorphs because they can be separately patented just like polymorphs [3]. This matter is usually investigated early on in the development phase.

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Literature

[1] M. Schudel, J.B. Ubbink, Ch. Quellet, Measurement of dynamic water vapor sorption processes by modified TGA, METTLER TOLEDO TA UserCom 17, 1/2003, pp 7-9
[2] Y.H. Roos, Thermal Analysis, State Transitions and Food Quality, Thermal Analysis Seminar Presentation, Cork (Ireland), 2004
[3] J. Bernstein, Polymorphism in Molecular Crystals, Clarendon Press, Oxford 2002, Chapter 10

Introduction

The processing of plastics and their additives puts high demands on temperature accuracy in the various processing steps as well as on temperature homogeneity within the material being processed. Because of the typically long processing times at high temperatures, there is always the possibility that products begin to decompose during production.
In this particular case, an unpleasant smell was noticed during the processing of a plastic. A sample was analyzed by TGA followed by evolved gas analysis in order to measure the temperature range in which decomposition occurred and to identify the volatile compounds produced. The gaseous products were first analyzed using a mass spectrometer (MS) and then later with a Fourier transform infrared spectrometer (FTIR).
These two techniques allow volatile decomposition compounds and gaseous elimination products to be characterized and in some cases identified. The following example describes the identification of ammonia as a decomposition product. It demonstrates the power of such combined methods and their importance for product development in an early phase of research.

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Introduction

The glass transition temperature (T_g) of a polymer film can easily be determined by TMA. In contrast, the reliable determination of the T_g of a powder sample by TMA is more difficult, especially compared with DSC. Powders and fine shavings can however be measured by first pressing disks of the material in a special die (Fig. 1).

The disks can be pressed relatively easily at a defined and reproducible pressure by filling the special die described above with a known mass of powder and then placing it in a manually operated press whose spindle is connected to a torque wrench (Fig. 2). The pressure applied to the powder is varied by changing the torque setting.

The influence of the applied pressure (torque) and the mass of the powder on the T_g was investigated using TMA. The results were compared with T_g measurements of films cast from the same polymer. Pharmacoat^® 606, a low viscosity hydroxypropyl methyl cellulose (HPMC) from the family of non-ionic water-soluble cellulose ethers, was chosen as a model substance. Such cellulose ethers are used in many different types of pharmaceutical applications, for example as film coatings for drug formulations.

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The phase transition temperatures (T_m) and transition enthalpies (ΔH) of bilayer membranes formed from dipalmitoylphosphatidylcholine (DPPC) were measured by differential scanning calorimetry (DSC). These bilayers served as model membranes. The effect of several different pharmaceutically active flavonoids on membrane fluidity was also studied. The DSC results revealed close-lying thermal effects that depended on the structure of the flavonoid. A relationship between the flavonoid interaction with the model membranes and its ability to change the ordered lipid structure of the DPPC was observed.

Introduction

Phospholipid molecules consist of a polar head linked to two long acyl groups (e.g. DPPC, Fig. 1. 1). When dispersed in water, lipids align themselves with their polar heads toward the water to form micelles (clusters), liposomes (microscopic concentric spheres or vesicles) or other structures. Liposomes are produced when some phospholipids aggregate to form double layers of molecules and then close to form bilayer membranes. Both unilamellar (SUVs, small unilamellar vesicles) and multilamellar (MLVs, multilamellar vesicles) structures can be produced into which drug molecules can be incorporated. This has led to the use of liposomes as drug delivery systems for medical applications (via intravenous injection). Liposomes resemble the membrane of a living cell and are used as models for cell membranes.

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