Abstract:
The invention relates to a device for measuring quantities of heat while simultaneously measuring the evaporation kinetics and/or condensation kinetics of the most minute amounts of liquid in order to determine thermodynamic parameters. The aim of the invention is to determine low thermal outputs, which are absorbed or released by the sample, as well as small differences between thermal outputs with regard to a reference measurement of the same magnitude. To this end, a most minute amount of liquid is located inside a measuring chamber having a constant temperature and air humidity. At least one thermal sensor is provided for repeatedly measuring the thermal radiation emitted from the most minute amount of liquid. A measuring means serves to determine the time-dependent change in the most minute amount of liquid. A computer is assigned to the measuring chamber in order to register, display, evaluate and/or subsequently process the measured values.

Description:
BACKGROUND OF THE INVENTION 
     This invention relates to a device for measuring quantities of heat while simultaneously measuring the evaporation kinetics and/or condensation kinetics of most minute amounts of liquid in order to determine thermodynamic parameters according to the species of patent claims. The quantities of heat can be absorbed during evaporation and/or released during condensation by very minute samples being mainly composed of liquid. 
     The inventive device predominantly serves to simultaneously measure the specific evaporation heat and vapor pressure of solutions at almost room temperature. Provided that a chemical equilibrium exists in the liquid and the evaporation process and/or condensation process are/is combined with a displacement of the chemical equilibrium, this device also serves to measure the specific chemical heat of reaction. For compound systems consisting of a solution being in contact with a solid (crystalline) phase of the solute, this device is used to measure the concentration of the saturated solution and the specific heat of solution, too. The most minute amount of liquid can also be a gel-like solvent-binding substance. The device is designated for measuring such kinds of solutions for which the vapor pressure of the solvent does not exceed the vapor pressure of the saturated water vapor in terms of magnitude and for which the vapor pressure of the solute above the solution has such a low value compared with the vapor pressure of the solvent that it can be ignored. 
     For all calorimeter principles to date the current state of art allows to derive the finding according to which the output that can still be measured becomes the smaller the faster the quantity of heat is released. The resulting characteristic time determines the minimum possible time constant required by the calorimeter to be able to measure the total quantity of heat released. Therefore, for maximum time constants of about 1000 s which are technically feasible today the output that can still be reliably measured is about 0.1 μW; it decreases down to about 10 nW for a time constant of 30 s. Consequently, the desired miniaturization of calorimeters for the application of very minute amounts of substances, e.g. when using thermally controlled micrometering cells based on chips, will only offer advantages for quantities of heat in the nJ range, if this quantity of heat is available within some seconds. This state-of-the-art finding is quite contrary to the demands placed on the measuring task to be solved by this inventive device. 
     SUMMARY OF THE INVENTION 
     Based on the state of the art, the aim of this invention is to determine small thermal outputs in the nW range which are absorbed or released during the evaporation and/or condensation of a portion of the liquid of the sample itself over a preferred period of time of 1000 s as well as to determine small differences of thermal outputs with regard to a reference measurement of the same magnitude. Since the thermal output to be measured also depends upon the speed of evaporation and/or condensation the aimed inventive device should also allow to measure the evaporation kinetics and/or condensation kinetics of most minute liquid samples, whereby these measurements shall also serve to simultaneously determine the vapor pressure of the liquid or small differences of the vapor pressure with regard to a reference sample. Due to the minute amounts of the samples it is necessary to perform the measurement in such a way that the influence of interferences on the measurement caused by the measuring process itself is., excluded as far as possible. Finally, it shall be possible to use the data directly gained during the measurement process (sample temperature, sample volume or sample mass over time) to compute back to the values of thermal output and vapor pressure, which are to be determined directly according to the procedure, by applying model analyses. 
     According to the invention this task is solved by the characteristic elements of the first patent claim and advantageously worked out by the elements of the subclaimes. 
     In one variant of the inventive device a sample will be located inside a measuring chamber where the temperature and vapor pressure of the solvent (relative air humidity or gas humidity) are kept at a constant level. The time-dependent spontaneous mass loss of the sample and spontaneous temperature decrease at the sample surface with regard to the temperature in the measuring chamber are measured simultaneously. Principally, the device is constructed in such a way that the sample is only in thermal contact with the gas in the measuring chamber and a substance transfer at the sample surface can only take place to the gas inside the measuring chamber. The surface temperature of the sample is measured in a pyrometric, i.e. a non-contact, manner. All the data are evaluated in a downstream computer aided peripheral system. 
     In the inventive device the sample itself represents the working substance of a calorimeter which is preferentially operated under the condition of the quasi-stationary heat exchange with the environment, whereby the thermal output released or absorbed by the sample is calculated from the variation in time of the temperature at the sample surface. The device is particularly designated to take measurements at minute samples, if the amount of heat to be registered is released very slowly. In this case, a dissolving power of the thermal output in the magnitude of 10 nW should be reached for a sample mass of about 1 mg at a time constant of 1000 s. 
     Based on the measuring values of the quantity of heat and vapor pressure directly to be measured, the inventive device is designated in particular to determine the derivable thermodynamic parameters such as the excess portion of the chemical potential or the enthalpy of the solvent which characterize the interaction between the solute and the solvent or between the molecules of the solvent. For compound systems, i.e. systems which contain solid and/or gel-like substances, this device is also used to directly determine parts of the phase diagram. 
     In particular, the performance parameters and constructive details of the inventive device are to fulfill the requirements which are to be placed on measurements of aqueous solutions of biological macromolecular compounds, such as proteins, with the inclusion of electrolyte and buffer additions. These requirements presume the following conditions:
         a) Proteins, protein-monocrystals in particular, are often available in most minute quantities (in magnitudes of μg) only.   b) Protein solutions contaminate glass, silicon and other surfaces whereby these contaminations are difficult to be removed and require the application of chemically aggressive substances. These contaminations can make highly sensitive and expensive microchip-calorimeters unusable after a single measurement of protein solutions.   c) Compared with conventional (inorganic) systems the speed of growth or dissolving of protein crystals is lower by one to two magnitudes. This means that the thermal outputs to be measured for crystallization or dissolution are correspondingly lower.   d) Under normal conditions (room temperature, air pressure) the protein crystals are only stabile in permanent contact with the saturated solution and are moreover very sensitive to mechanic and thermal stresses. Therefore, the improper use of the protein crystals in calorimetric measurement procedures can lead to false results.       

     In addition to this, the inventive device is to allow to take thermodynamic measurements in a time-economic manner so that they can be used for the routine characterization (comparable with the differential thermal analysis for inorganic systems) in all studies of the crystal growth of proteins. 
     In the inventive device two independent measurements are performed simultaneously at the sample (aqueous solution) to be examined. In the whole course of measurement, first the mass loss of the sample will be registered as a result of the permanent evaporation of the solute due to the environmental conditions to be selected. Second, a calorimetric measurement of the evaporation heat per time unit is taken during the whole measurement process, whereby the working substance of the calorimeter arrangement, which represents the device, is the sample to be examined itself. This calorimetric measurement is performed in a non-invasive manner in such a way that the surface temperature of the sample is determined pyrometricly and permanently by means of at least one thermal sensor. 
     The sample to be examined (aqueous solution) is located in the inventive device inside a hermetically sealed measuring chamber in which the temperature and relative air humidity can be set exactly and kept at constant levels during the whole measurement procedure and temperature gradients and convection are almost avoided. The device is designed in such a way that the sample has only a thermal contact to its environment via its free interface with the surrounding gas room and a substance transfer of the sample to its environment can only happen via this free interface. To register the surface temperature of the sample in a pyrometric measurement, an elliptic concave mirror and a radiation receiver are located inside the measuring chamber. Their positions ensure that one focus of the concave mirror is exactly located on the interface of the sample to the measuring chamber and the other one is located on the sensor surface of the radiation receiver. Thus, this part of the free interface of the sample is imaged onto the aperture of the radiation receiver so that the surface temperature can be measured. 
     One variant of the device can be designed in such a way that the sample is provided as a hanging drop at the tip of a fine, vertically orientated capillary. The selected geometry of the capillary allows the hanging drop to develop with a possibly large diameter, referred to the outer diameter of the capillary, into coaxial direction towards the capillary (capillary with a wall thickness which is wedge-like reducing towards its tip, reached e.g. by grinding; outer or inner diameter at the tip of the capillary approximately 80 μm or 50 μm, respectively). Moreover, the surface of the capillary is passivated in its opening area (e.g. by applying a silane film) to avoid the deformation of the spherical drop shape or a mass loss of the drop due to the generation of a liquid film at the outer surface area of the capillary. In this case, the drop mass is determined by means of a measuring microscope inserted from the outside into the measuring chamber and being arranged in such a way that the drop is located in its object level and that it allows the measurement of the geometric parameters of the drop. In order to develop the drop the capillary can be shaped as a tip of a scale pipette that can be filled and operated from the outside. This pipette can simultaneously serve as a reservoir for the sample liquid and for the thermal equilibration of the sample before starting the measuring procedure. 
     A second possible construction of the device can have such a design that the sample to be examined is located in an upward opened, dish-shaped receptacle inside the measuring chamber. Thus, only the upper meniscus of the liquid is in contact with the volume of the measuring chamber. The receptacle must consist of an inert material which is very difficultly to be wetted and has an extremely low thermal conductivity. It must have the typical interior dimensions of a maximum diameter of 4 mm and a height of 1 mm. In this case, the sample mass is determined by weighing. For this purpose, the receptacle is connected to a scale of a high-accuracy scales with electromagnetic force compensation and a measuring accuracy of ca. 0.1 μg, whereby this scale is led into the measuring chamber. In this way, the mass of the liquid located in the receptacle can be permanently registered. To use this unit, a scale pipette projecting into the measuring chamber from the outside through the wall and being operated from the outside is fixed in such a way that it can be used for filling a defined amount of the sample liquid into the dish-shaped receptacle. At the same time, this scale pipette serves as a feeding reservoir and is used for the thermal equilibration of the liquid to be examined. For measurements of compound systems, consisting of a solution being in contact with a solid (crystalline) phase of the solute, this scale pipette can have such a large outlet that a small monocrystal (typical dimension of some hundreds μm) can be filled together with the liquid to be examined into the receptacle which is provided for receiving the solution. Finally, the wall of the measuring chamber can be provided with an opening for inserting a measuring microscope (e.g. an endoscope) which is arranged in such a way that the liquid meniscus in the dish-shaped receptacle and the monocrystal possibly contained in it can be observed. 
     According to this invention, the device comprises peripheral units for recording and evaluating data and for controlling purposes. The time-dependent registration of the geometric parameters of the hanging drop via the measuring microscope is preferentially performed through a downstream image processing system. 
     The vapor pressure of the solution (e.g. water) in the measuring chamber is determined at a great distance to the sample via the relative humidity inside the measuring chamber. Normally, it is lower than the equilibration vapor pressure of the solvent above the solution, which directly exists above the liquid meniscus. The sample is supplied into the measuring chamber as soon as the temperature of the sample liquid located in the pipette has adapted to the temperature existing inside the measuring chamber (temperature differences of up to 1° C. are permissible). Due to the directed diffusion from the free interface of the sample to the volume of the measuring chamber, the evaporation of the solvent directly starts after the supply of the sample. The evaporation rate of the solvent is determined from the measured time-dependent change of the mass of the sample. It is the base for calculating the equilibration vapor pressure of the solvent. 
     The evaporation of the solvent causes a temperature decrease of the sample referred to the temperature in the measuring chamber (at a great distance to the drop). This process continues up to the point at which the evaporation heat to be temporally applied (evaporation enthalpy of the solvent) and the thermal output lead to the drop by heat transfer from the gas room of the measuring chamber have almost balanced out and a quasi-stationary temperature difference is reached. The determination of the evaporation enthalpy of the solvent is based both on the pyrometricly measured time-dependent difference of the temperatures at the sample surface on one side and in the measuring chamber on the other side and on the involved measured time-dependent evaporation rate of the sample. 
     The continuous evaporation of the solvent during the measuring process results in a permanently increasing concentration of the solution and therefore in a permanent change (generally a reduction) of the vapor pressure of the solvent as long as the dissolved components do not crystallize. In particular, characteristic deviations of the evaporation rate arise compared to a sample consisting of a pure solvent. These deviations are measured and serve as the base for calculating the excess portion of the chemical potential of the solvent as the target value. As a result of the increasing concentration of the solution during the measurement procedure, the evaporation enthalpy of the solvent also depends on the time. From the characteristic deviations, referred to the constant evaporation enthalpy of the pure solvent, the excess portion of the molecular enthalpy of the solvent in the solution is calculated as the target value. 
     If the relative air humidity in the measuring chamber is set to such a value that the vapor pressure of the solvent in the measuring chamber is lower than the one above the saturated solution, an initially undersaturated solution exhibits a temporary increase of the concentration exceeding the saturation concentration as a result of the delayed nucleation kinetics if the crystalline phase. If a small monocrystal of the typical dimensions above mentioned is put into the undersaturated solution of a well-known concentration at a suitable moment of time, its dimensions will initially decrease due to dissolution up to the point of transition into the range of a supersaturated solution in which the crystal grows. In this process, the mass of the delivered crystal has such a low value that the additional increase in the concentration of the solution due to the dissolution of the crystal can be ignored. By means of the measuring microscope and a possibly downstream image processing system the time-dependent dimensions of the delivered crystal are registered and the saturation concentration (point in the phase diagram) is determined via the point in time at which the transition from dissolution to growth happens. 
     For delivered monocrystals having sufficiently large dimensions (possibly larger than the ones indicated above) the transition from dissolution to growth is registered in the pyrometric temperature measurement as a significant salient point, because a change from consumed solution heat to released solution heat takes place. As far as observations by means of the measuring microscope allow to determine the dissolution rate or growth rate (mass per time) of the crystal, the molecular solution enthalpy can be calculated from the data gained by the pyrometric temperature measurement. These rates in turn are the base for calculating the temperature dependence of the saturation concentration (curve in the phase diagram). 
     For all variants of the inventive design it is possibly required to perform calibration measurements of solutions with a well-known vapor pressure or evaporation heat. When doing this for measurements of the hanging drop, such errors of measurements are eliminated which are due to the fact that the signal at the radiation receiver additionally shows a weak dependence upon the drop radius. If the sample is put into the dish-like receptacle, the calibration measurements will be used to determine the transition coefficients of the heat and substance transfers between the sample and the measuring chamber. 
     All variants of the inventive device can be expanded in such a way that several most minute amounts of liquid are arranged in the same manner inside a common measuring chamber so that the surface temperature and the evaporation kinetics or condensation kinetics can be measured for all most minute amounts of liquid simultaneously. If these most minute amounts of liquid include a sample with a well-known evaporation heat and vapor pressure, the measuring data of the other samples can be referred to this known sample in order to eliminate such errors of measurement which are due to the imprecise determination of temperature and vapor pressure in the measuring chamber at a great distance to the most minute amounts of liquid. 
     Unlike conventional calorimeters the inventive device uses the measured time-dependent temperature difference ΔT(t) of the working substance to the environment as a measure for the thermal output N(t) released or absorbed by the sample as long as quasi-stationary conditions are maintained, i.e. that N(t) shows such a slow time-dependent change that the curve of N(t) at earlier points of time than the time of measurement t turns out to be only a little correction to ΔT(t). The typical thermal outputs to be measured in practical operation by means of this device according to its type of design and intended use range between 10 and 100 μW and change with a characteristic time constant τ=|N(t)/(dN(t)/dt)|≧1·10 3  s. Theory shows that quasi-stationary conditions exist for this. Then, for measurements performed at the hanging drop a sensibility of ΔT(t)/N(t)≅1/(4πα g R 0 (t)) follows, whereby R 0 (t) is the time-dependent drop radius and α g  is the heat conductivity of air. The result is ΔT(t)/N(t)≅6·10 3  K/W for the typical values of R 0 =5·10 −4  m and α g =0.025 W/K·m. 
     The theoretic dissolving power of the arranged device for the measurement of N(t) is limited by two principal influencing factors: the noise of the thermal sensor in connection with the downstream electronic system and the accuracy of the determination of the evaporation rate. For the pyrometric temperature measurement a high-sensitive thermal sensor is used. It has a maximum spectral sensitivity in the spectral range of the maximum value of the radiation of the black body at room temperature, i.e. in the spectral range of about 10 μm or above. This ensures that the measurement of the surface temperature of the hanging drop is almost independent on the special composition of the aqueous solution. For this purpose, a commercial thermal sensor which does not require cooling is suitable. Its time constant is about 60 ms. The dynamic range of this thermal sensor is ≧10 5 . This allows a comfortable calibration of the thermal sensor to the temperature to be measured in the upper range of the registered radiation output. 
     The detection sensitivity of the thermal sensor has been determined as 170 μV/K in practical operation by using a device working with a hanging drop. Considering the influence of the peripheral electronics, in the pyrometric measurement a noise-related error of measurement of the registered voltage values of ±0.5 μV exists for an optimum scanning sequence frequency of 10 Hz. This value corresponds to an error of temperature measurement of ±3·10 −3  K per single measurement. In the subsequent computer-aided evaluation, the temperature data over characteristic time intervals of a period of τ are adapted to the ideal theoretic curve. When doing this, the statistic error (δT) stat  of the temperature measurement to be supposed reduces down to (δT) stat =±3·10 −5  K, corresponding to a theoretic noise-related contribution to the resolution limit of the output of (δN) R ≅5·10 −9  W registered by the device. 
     The theoretic accuracy limit with which the sample mass of the hanging drop can be determined is given by the measuring uncertainty δR 0  for determining the drop radius, i.e. by the limit of the microscopic resolution. For an observation microscope having an aperture of &lt;1 an aperture-related error of measurement of δR 0 ≈5·10 −7  m exists for a single measurement. When performing an automated measurement by image analysis it is possible to measure the drop radius every 10 s. In the subsequent computer-aided evaluation the data of the drop radius over characteristic time intervals of a period τ are adapted to the ideal theoretic curve. When doing this, the statistic error of the radius measurement reduces down to (δR 0 ) stat =±5·10 −8  m. Based on this value, an additional error (δN) Ap  results for the measurement of the thermal output. It follows from (δN) Ap /N(t)≈3·(δR 0 ) stat /R 0 (t)≈±3·10 −4  and is proportional to the measured output N(t). (δN) Ap  has the magnitude of the theoretic noise-related resolution limit (δN) R , if outputs in the order of 10 μW are measured. 
     For a device, which is equipped with a dish-like receptacle for the sample, higher values (but of the same magnitude as the ones of the hanging drop) can be reached principally for the sensitivity, the time constant and the noise-related resolution limit of the output measurement, because due to the reduced free surface the transition coefficients of the heat and solvent transfers between the sample and the measuring chamber are smaller than the ones for the hanging drop. For the determination of the evaporation rate of the sample of time-dependent sample masses m(t) of 5 mg, weighing operations with an accuracy of ±0.1 μg can be performed at time intervals of 1 s when using high-accuracy scales and when considering the performance capacity of the downstream A/D converters. In the subsequent computer-aided evaluation, these data are adapted to the ideal theoretic curve over characteristic time intervals of a period of τ. When doing this, the statistic error of the weighing is improved down to (δm) stat =±3·10 −9  g. Thus, an error (δN) W  is caused for the determination of N(t) according to (δN) W /N(t)≈(δm) stat /m(t)≈±1·10 −6 . For N(t) in the order of 10 μW, (δN) W  has the magnitude of 10 −11  W and therefore it is smaller than the noise-related resolution limit. 
    
    
     
       DETAILED DESCRIPTION OF THE INVENTION 
       In the following, the invention is explained in more detail by means of the schematic drawing with upright projections of three design variants of the device. The figures show: 
         FIG. 1  a first inventive device in which the sample is provided as a hanging drop, 
         FIG. 2  a second inventive device in which the sample liquid is located in a dish-like receptacle, and 
         FIG. 3  a third inventive device with the direct measurement of the heat radiation. 
     
    
    
     In  FIG. 1  a gas-tight measuring chamber  10  with a geometric axis X—X is divided into two parts  101  and  102  by carrying elements  11 , whereby the upper part  102  can be placed onto the lower part  101  after having completed the preparations which are required for the measurement. The carrying elements  11 , which are designed as struts or as an intermediate bottom and are provided with a central opening  111 , are to carry an elliptic mirror  12  which fills out the central opening  111  or is at least located in it and has an optic axis O—O that preferentially coincides with the geometric axis X—X. The elliptic mirror  12  allows the transmission of radiation in its central part  13  and has two focuses F 1  and F 2  on its optical axis O—O, whereby a liquid drop  14  of a solution is located in focus F 1  (and in its direct environment and therefore: focal spot) and a thermal sensor  24  is located in focus F 2  (and in its direct environment=focal spot). The diameter of the drop  14  shall be &lt;2 mm and the amount of sample liquid contained in it shall be &lt;4 μl. The drop  14  is hanging freely and under the effect of gravity perpendicularly at a capillary  15  which has a diameter of &lt;300 μm and is connected to a micropipette  17  via a (flexible) pipe or hose  16 . A working beam path  18  is used for the simultaneous determination of the diameter of the drop. This path is mainly positioned in the measuring chamber part  101  and contains a light source  181 , a beam splitter  182 , a filter  183  and an objective  184  as well as an optic sensor  185  (e.g. a CCD camera) as optical elements. The drop  14  is illuminated by the light source  181  via the beam splitter  182  and the objective  184 . The working beam path  18  being reflected and scattered at the drop  14  reaches the optic sensor  185  via the objective  184  and the beam splitter  182  and generates an image of the drop there. The optical filter  183  arranged in the working beam path  18  removes all perturbing radiation which could have an influence on the thermal equilibration of the drop  14  and its environment. A cooling/heating system  19  is used to maintain or control the temperature inside the measuring chamber  10 . It is controlled by a computer  21  via a temperature sensor  20 . To maintain a constant humidity inside the measuring chamber  10 , a humidity sensor  22  and a humidity dispenser or dryer  23  are provided and also controlled by the computer  21 . Finally, the data measured of the surface temperature are received by the thermal sensor  24  and the data of the time-dependent change of the drop diameter are received by the sensor  185 . They are saved and evaluated in the computer  21 . 
     The following example of measurement uses water as solvent and at the start of measurement it contains 20 mM HCl+50 mM Na Citrat+1% Phenol (pH=6.5) dissolved as electrolytic and buffer components as well as 0.6 mg/ml dissolved protein having a molecular weight of 35000 (special insulin mutants). For this measurement a measurement is performed at a reference system having the same components but not including protein. This reference measurement simplifies the task which is to determine the contributions to those measured data which are directly caused by the protein proportion of the solution. To achieve defined conditions, all measurements will be finished in this example as soon as the drop volume has reached half of the start value or the concentration of the dissolved substances has double the volume of the start value. For this example, the actual measurement needs 1620 s and the reference measurement needs 2900 s. 
     
       
         
               
               
               
               
               
             
               
               
               
               
               
             
           
               
                   
                   
               
               
                   
                   
                 Measure- 
                 Reference 
                 Reference 
               
               
                   
                 Measurement 
                 ment 
                 measurement 
                 measurement 
               
               
                   
                 Start value 
                 End value 
                 Start value 
                 End value 
               
               
                   
                   
               
             
             
               
                   
               
             
          
           
               
                 Temperature 
                 23.4 
                 23.4 
                 23.4 
                 23.4 
               
               
                 in the 
               
               
                 measuring 
               
               
                 cell in ° C. 
               
               
                 Relative 
                 72.4 
                 72.4 
                 72. 
                 72.6 
               
               
                 air humidity 
               
               
                 in the 
               
               
                 measuring 
               
               
                 cell in % 
               
               
                 Drop radius 
                 0.742 
                 0.589 
                 0.753 
                 0.597 
               
               
                 in mm 
               
               
                 Time- 
                 −72 
                 −104 
                 −55 
                 −55 
               
               
                 dependent 
               
               
                 change of the 
               
               
                 drop radius 
               
               
                 in μm/s 
               
               
                 Drop 
                 5.78 
                 6.25 
                 3.28 
                 3.24 
               
               
                 temperature 
               
               
                 decrease in K 
               
               
                 Absorbed 
                 1.34 
                 1.15 
                 0.776 
                 0.607 
               
               
                 thermal 
               
               
                 output 
               
               
                 in mW 
               
               
                 Vapor 
                 2.48 
                 1.94 
                 2.4 
                 2.35 
               
               
                 pressure of 
               
               
                 the solvent 
               
               
                 in kPa 
               
               
                   
               
             
          
         
       
     
     Due to evaporation the drop radius decreases and the concentration of the dissolved components increases in the course of measurement. Therefore, it can be seen that the start data of the drop radius, the drop temperature, the absorbed thermal output and the vapor or gas pressure of the solvent contained in the table above change more or less significantly. Interesting thermodynamic data which are defined by the protein proportion can be determined on the basis of the temporal curve of the measured data compared to the reference system. The example above results in μ 2   (ex) /kT=0.38, μ 3   (ex) /kT=−0.14, h 2   (ex) /kT=8.86, h 3   (ex) /kT=−4.08, with μ 2   (ex) , μ 3   (ex)  being the (molecular) chemical excess potentials of the solvent of second and third orders in the solution (referred to the total concentration dependency), h 2   (ex) , h 3   (ex)  being the molecular excess enthalpies of the solvent of second and third orders in the solution (referred to the total concentration dependency), k being the Boltzmann&#39;s constant and T being the absolute temperature. 
     In this example of measurement both the measured data given in the table and the corresponding differences to the reference measurements are considerably higher than the noise-related errors of measurement derived above. However, the smallness of the noise-related errors of measurement will be for example of high importance, if under the conditions of a very slow drop kinetics (time-dependent changes of the drop radius &lt;10 μm/s) low differences (in the range of 1%) to the corresponding reference measurements are to be determined reliably. 
       FIG. 2  shows a measuring chamber  25 , the upper part  251  of which is formed by a hollow body, preferentially a hollow cylinder, can be hermetically closed by a bottom  252 . A rod-shaped holder  261  of a scale  262  of an ultra-microbalance (high-accuracy scales)  26  is led through the bottom  252 . A small dish or bowl  264  having a capacity of P10 μl and containing the sample liquid  265  is located directly or via a holder  263  on this scale  262 , whereby this small dish  264  is thermally isolated from its support. To deliver the sample liquid a manipulator  27  is used which projects into the measuring chamber  25  through an opening  255  in the wall of the upper part  251  and is adjustable in its perpendicular direction as indicated by the double-arrow  29 . The ultra-microbalance  26  is used to determine the sample mass; according to the compensation principle it keeps the vertical position of the meniscus of the liquid  265  constant due to its rigid coupling to the scale  262  via the holder  263 . The sample liquid  265  is in the focus (focal spot) F 1  or its environment of an elliptic mirror  12  which is attached to the top of the upper part  251  and a thermal sensor  24  is in the other focus (focal spot) F 2  or its direct environment of this mirror  12 . The great axis of the ellipse of the mirror  12 , on which the focuses F 1  and F 2  are located, coincides with the geometric axis X—X of the measuring chamber  25 . To stabilize or control the environmental temperature (∩T P 0,1° C.) and air humidity (∩rF P 0,1%) a temperature sensor  20  with a heating/cooling system  19  and a humidity sensor  22  with a humidity dispenser/dryer system  23  are located in the measuring chamber  25 . The two systems as well as the ultra-microbalance  26  are connected to a computer  21  which saves the measured data of the heating/cooling system  19  and of the hymidity dispenser/dryer system  23  and controls the two systems. A measuring microscope  28  projecting into the measuring chamber  25  through an opening  254  can be adjusted towards the double arrow  30  and serves to observe the sample liquid  265 . For example, it is possible to observe the changes of a crystal led into the sample liquid  265  by means of the manipulator  27  and the changes of the dissolved substance by using a measuring microscope  28  which can be an endoscope in the example given. 
     The device shown in  FIG. 2  can also be used to measure the time-dependent changes of the volume of the sample and of the temperature. Based on these data the vapor pressure and the specific evaporation heat of the solvent of the substance as well further thermodynamic parameters can be determined by the software installed in the computer  21 . 
     Like in  FIG. 2 , in  FIG. 3  a measuring chamber  25  consists of a hollow cylinder  251  and a bottom  252 . The bottom is provided with a central opening  253  and carries eccentrically a humidity dispenser or dryer  23 . The rod-shaped holder  261  of a scale  262  being part of an ultra-microbalance  26  is led through the opening  253 . On the scale  262  a holder  263  of a small dish  264  including the sample liquid  265  is positioned. The small dish  264  exhibits the properties of a grey IR radiator. The hollow cylinder  251  is provided with two openings  254  and  255  for inserting an endoscope  28  and a manipulator  27 ; both can be moved in these openings  254 ,  255  towards the double arrows  30  or  29 , respectively. Moreover, a cooling and heating system  19  in form of a spiral fixed at the side walls of the cylinder, a temperature sensor  20 , a humidity sensor  22  and a thermal sensor  24  are located inside the hollow cylinder  251 . They are used for control and regulation purposes and are connected to a computer  21 . Considering the maximum ratio of aperture of the thermal sensor  24 , it is installed at a possibly small distance to the holder  263 , in this case ca. 1 mm below the holder  263 , and it is thermally isolated and decoupled. Thanks to the compensation principle of the ultra-microbalance  26  the distance between the thermal sensor  24  and the small dish  264  will remain constant, if the mass of the sample liquid  265  changes. To keep the temperature in the measuring chamber at a constant level or to regulate it, the cooling and heating system  19  is controlled by the computer  21  according to the temperature absorption of the sensor  20 . The humidity dispenser or dryer  23  is controlled by the computer  21  according to the measured values transferred by the sensor  22  to the computer  21  in order to maintain a constant gas humidity inside the measuring chamber  25 . The registered data of the thermal sensor  24  and the scales  26  are also transferred to the computer  21  where they are processed to gain, set or indicate the quantities of heat, the vapor pressure, the evaporation kinetics or the thermodynamic parameters. 
     For a measurement of a solution the start composition of which follows the measurement example to  FIG. 1 , 8 mg of a liquid are filled into the flat dish-shaped receptacle  264  at a measuring chamber temperature of 26.8° C. and a relative air humidity of 65.0%, and the initial changes in mass of −1.75 μg/s and an initial temperature decrease of the sample of 1.35° C. are registered. These data correspond to an initial power consumption of the sample of 3.9 μW. Compared to the reference system the initial differences in the decrease in mass are about 0.1 μg/s and in the decrease of sample temperature about 0.3° C. These values correspond to a difference in the power consumption of 860 nW. The further process is continued analogue to the measurement example to  FIG. 1  mentioned above. 
     All the elements demonstrated in the description, the subsequent claims and the drawing can be essential for this invention both individually and in any combination. 
     
       
         
               
             
               
               
               
             
           
               
                   
               
               
                 List of reference numerals 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                   
                 10, 25 
                 measuring chambers 
               
               
                   
                 11 
                 carrying elements 
               
               
                   
                 12 
                 elliptic mirror 
               
               
                   
                 13 
                 central part 
               
               
                   
                 14 
                 liquid drop 
               
               
                   
                 15 
                 capillary 
               
               
                   
                 16 
                 pipe or hose connection 
               
               
                   
                 17 
                 micropipette 
               
               
                   
                 18 
                 working beam path 
               
               
                   
                 19 
                 cooling/heating system 
               
               
                   
                 20 
                 temperature sensor 
               
               
                   
                 21 
                 computer 
               
               
                   
                 22 
                 humidity sensor 
               
               
                   
                 23 
                 humidity dispenser or dryer 
               
               
                   
                 24 
                 thermal sensor 
               
               
                   
                 26 
                 ultra-microbalance, high-accuracy scales 
               
               
                   
                 27 
                 manipulator 
               
               
                   
                 28 
                 measuring microscope 
               
               
                   
                 29, 30 
                 double arrows 
               
               
                   
                 101, 252 
                 lower part, bottom 
               
               
                   
                 102, 251 
                 upper part, hollow cylinder 
               
               
                   
                 111 
                 central opening 
               
               
                   
                 181 
                 light source 
               
               
                   
                 182 
                 beam splitter 
               
               
                   
                 183 
                 filter 
               
               
                   
                 184 
                 objective 
               
               
                   
                 185 
                 optic sensor 
               
               
                   
                 253 
                 central opening 
               
               
                   
                 254, 255 
                 openings 
               
               
                   
                 261 
                 rod-shaped holder 
               
               
                   
                 262 
                 scale 
               
               
                   
                 263 
                 holder 
               
               
                   
                 264 
                 small dish, bowl 
               
               
                   
                 265 
                 sample liquid 
               
               
                   
                 X—X 
                 geometric axis 
               
               
                   
                 Y—Y 
                 optic axis 
               
               
                   
                 F 1 , F 2   
                 focuses