Determination of the Adsorption and Desorption of Moisture in Pharmaceutical Substances - METTLER TOLEDO

Determination of the Adsorption and Desorption of Moisture in Pharmaceutical Substances


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. 


Experimental Details

TGA is a quantitative method and is therefore ideally suited to study the drying or moisture uptake of a substance, or to determine its moisture content. To reliably set up a defined relative humidity in the furnace chamber requires an instrument system consisting of a computer-controlled relative humidity generator, a heated transfer line to maintain the humidified air flow at a defined temperature, an interface on the TGA instrument, and if necessary, an optional humidity sensor inside the furnace chamber. The present study was carried out using a VTI RH-200 relative humidity generator and a Rotronic HygroClip SC04 humidity sensor with the TGA/SDTA851e (large furnace).

The system was used to investigate the influence of relative humidity on pure (> 98 %) amiloride hydrochloride dihydrate, a derivative of the diuretic drug amiloride (Fig.1)


Diuretics are drugs that help to remove excess water from the body by increasing the amount that is excreted as urine. Diuretic drugs are used in the treatment of a variety of disorders including hypertension (high blood pressure) and conditions in which there is excessive accumulation of fluid in the body or body tissues (ascites, edema)

Amiloride hydrochloride dihydrate (approx. 14 mg of fine yellow powder) was weighed into a 150-µL platinum crucible and inserted into the TGA instrument at 25 °C. The sample was heated to 125 °C at 5 K/min, held at this temperature for 30 minutes and then cooled down to 25 °C again at 5 K/min. A relative humidity (RH) of 5% was maintained during this phase of the experiment. The sample was then held isothermally at 25 °C and exposed to increasing levels of RH from 5 to 95% in steps of 10% with first and final steps of 5%. Afterward, the RH was successively decreased stepwise down to 10% RH. The measurements were performed using a gas flow of 100 mL/min.



Different standard procedures are available to characterize the loss on drying depending on the method described in the particular pharmacopeia. Figure 2 shows the mass loss curve of the test substance performed according to USP 26 guidelines (United States Pharmacopeia) [4].


The results clearly demonstrate that the TGA Sorption Analyzer System is able to reliably measure the drying process, the adsorption of strongly bound and weakly bound water, and desorption of weakly bound water from a pharmaceutical active substance such as amiloride hydrochloride dihydrate.

The equipment including the heated transfer line and the optional humidity sensor enabled well-defined humidity conditions to be set up in the TGA furnace chamber. This coupled with the high sensitivity and stability of the TGA balance allowed even the smallest losses in mass to be resolved.

All in all, the new TGA Sorption Analyzer System is a reliable and sensitive instrument that can be used to accurately determine the adsorption and desorption behavior of many different types of substances.

Determination of the Adsorption and Desorption of Moisture in Pharmaceutical Substances | Thermal Analysis Application No. UC 213 | Application published in METTLER TOLEDO Thermal Analysis UserCom 21