Dissolution calorimetry

It is also worth noting that for caffeine solutions a thermodynamic parameter such as the enthalpy of dimerization of caffeine in water can be determined comparatively by dissolution calorimetry and by high resolution NMR [118,119]. 

Recent developments m calorimetry have focused primarily on the calorimetry of biochemical systems, with the study of complex systems such as micelles, protems and lipids using microcalorimeters. Over the last 20 years microcalorimeters of various types including flow, titration, dilution, perfiision calorimeters and calorimeters used for the study of the dissolution of gases, liquids and solids have been developed. A more recent development is pressure-controlled scamiing calorimetry [26] where the thennal effects resulting from varying the pressure on a system either step-wise or continuously is studied. 

Nitric acid can be used for the dissolution of nickel from many inorganic substances. In some cases perchloric acid is used in combination with nitric acid. Simple organic forms of nickel also can be dissolved in nitric acid. In the case of compHcated stmctural organic forms of nickel, oxidation calorimetry must be used to decompose the substances. 

The physical properties of the anhydrate form and two polymorphic monohydrates of niclosamide have been reported [61], The anhydrate form exhibited the highest solubility in water and the fastest intrinsic dissolution rate, while the two monohydrates exhibited significantly lower aqueous solubilities. In a subsequent study, the 1 1 solvates of niclosamide with methanol, diethyl ether, dimethyl sulfoxide, N,/V -dimethyl formamide, and tetrahydrofuran, and the 2 1 solvate with tetraethylene glycol, were studied [62], The relative stability of the different solvatomorphs was established using desolvation activation energies, solution calorimetry, and aqueous solubilities. It was found that although the nonaqueous solvates exhibited higher solubilities and dissolution rates, they were unstable in aqueous media and rapidly transformed to one of the monohydrates. 

In some instances, distinct polymorphic forms can be isolated that do not interconvert when suspended in a solvent system, but that also do not exhibit differences in intrinsic dissolution rates. One such example is enalapril maleate, which exists in two bioequivalent polymorphic forms of equal dissolution rate [139], and therefore of equal free energy. When solution calorimetry was used to study the system, it was found that the enthalpy difference between the two forms was very small. The difference in heats of solution of the two polymorphic forms obtained in methanol was found to be 0.51 kcal/mol, while the analogous difference obtained in acetone was 0.69 kcal/mol. These results obtained in two different solvent systems are probably equal to within experimental error. It may be concluded that the small difference in lattice enthalpies (AH) between the two forms is compensated by an almost equal and opposite small difference in the entropy term (-T AS), so that the difference in free energy (AG) is not sufficient to lead to observable differences in either dissolution rate or equilibrium solubility. The bioequivalence of the two polymorphs of enalapril maleate is therefore easily explained thermodynamically. 

Another method to obtain enthalpies of formation of compounds is by solute-solvent drop calorimetry. This method was pioneered by Tickner and Bever (1952) where the heat formation of a compound could be measured by dissolving it in liquid Sn. The principle of the method is as follows. If the heat evolved in the dissolution of compound AB is measured, and the equivalent heat evolved in the dissolution of the equivalent amount of pure A and B is known or measured, the difference provides the enthalpy of formation of the compound AB. Kleppa (1962) used this method for determining enthalpies of formation of a number of Cu-, Ag- and Au-based binaries and further extended the use of the method to high-melting-point materials with a more generalised method. 

The solid-state properties like crystallinity, polymorphism (crystal structure), shape (morphology), and particle size of drugs are important in the stability, dissolution, and processibility of drugs. Some commonly used methods in solid-state studies include microscopy, hot stage microscopy with polarized light, x-ray powder diffraction (XRPD), thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), Fourier transform infrared FTIR/Raman, and solid-state NMR. 

The enthalpies for the reactions of cis- and frans-[Pt(NH3)2X2] (X = Br or I) with 9.4% aqueous NH3 to yield [Pt(NH3)4X2] have been measured calorimetri-cally.122,123 The results have been used to calculate the standard enthalpies of formation of the solid cis- and trans- isomers the enthalpy of cis - trans isomerization has also been determined. The enthalpies of dissolution of the complexes K2[PtBr4], Rb2[PtBr4], and K[PtBr3(NH3)] have been measured the enthalpy of formation of Rb2[PtBr4] was calculated to be —224.4 kcal mol-1.124... 

The study by low-angle X-ray scattering, electron microscopy, and differential scanning calorimetry of the mesophases obtained by dissolution of BSB copolymers in preferential solvents for the polystyrene block and of dry BSB copolymers obtained by slow evaporation of the solvent from the mesophases has allowed to establish the respective effect of different factors which control the structure of the mesophases and their geometrical parameters. It has been shown that the nature, concentration, polymerization of the solvent, and temperature have the same effect on BSB copolymers as on SB copolymers35,88-91. ... 

CALORIMETRIC MEASOREMEMTS Solution calorimetry was performed at 298.2 0.1 K by using a C-80 differential flux calorimeter manufactured by Setaram. The energy equivalent of the calorimetric signal was determined by electric calibration. The reliability of the equipment was checked by the dissolution of tris-(hydroxymethyl) aminomethane (THAM). Agreement within 0.4% with the published value of +17.75 kJ. mol-1 ( 21) was obtained. 

The experimental values for the free energies of formation of kaolinite and sepiolite are given in Tbble II. The value of -907.7 +1.33 kcal/mol recommended for kaolinite, is the mean of three recomputed free energies of formation weighed equally in the computation, and was obtained from calorimetry, dissolution, and precipitation data. Several values in the -905 to -906.0 kcal/mol range probably reflect the more soluble nature of small particles typically present in bulk samples. 

Many techniques have been used to characterize the physical nature of solid dispersions. These include thermal analysis (e.g., cooling-curve, thaw-melt, differential scanning calorimetry and X-ray diffraction, microscopic, spectroscopic, dissolution rate, and thermodynamic methods) Usually, a combination of two or more methods is required to obtain a complete picture of the solid dispersion system. 

Flow calorimetry has also been used to investigate dosage forms. Dissolution of tablets under various simulated conditions has been explored, for example. Here, the tablet is presented with various solutions designed to mimic conditions in the gastro intestinal (GI) tract (pH 7 buffer) and stomach (pH 3 buffer for fasting and lipid solutions for fatty meals). The rate of dissolution can then be estimated for conditions in vivo. 

When organic (drug) molecules crystallize from a solvent, the crystal structure is dependent upon the speed of crystallization, temperature, polarity of the solvent, concentration of the material, etc. Since the energy of the crystal affects the (physiological) rate of dissolution and thus the potency and activity of the drug, polymorphism is an important pharmaceutical concern [39]. The most common tool to determine crystal form is differential scanning calorimetry (DSC). Unfortunately, DSC uses small samples and may not represent the bulk of the material. X-ray diffraction is another excellent technique, but quite slow and sometimes difficult to interpret. 

The solution of the sample in a 2 1 mixture of concentrated hydrofluoric and nitric acids at Tref = 298 K was chosen as the reference state. The relative enthalpy, 7/rei(7m), was measured by indirect method of double calorimetry. This procedure enables us to determine Hiei(Tm) as the sum of enthalpy increase measured during the cooling of the system in a drop calorimeter (Acooi and during its dissolution in a solution calorimeter (Asoi//). Equation (4.34) can thus be written in the form... 

Utilization of the dissolution enthalpies in Eq. (4.36) is justified when the individual phases are adequately diluted in an amount of the chosen solvent. With regard to the error in the solution calorimetry, the enthalpy of mixing and the enthalpy of dissolution could be neglected only when the amount of the solvent in the solution formed has not changed. 

The measurement of IDR forms an important part of preformulation studies as they permit direct solubility and dissolution rate comparisons between different drug candidates, salts, polymorphic and pseudopolymorphic forms. The measurements are relatively straightforward to carry out but require a minimum of about 200mg of sample per determination. Production of the pellet can occasionally result in a pressure-induced polymorphism change the new polymorph may have different dissolution properties. Therefore, the presence or absence of a new polymorph should be verified by IR spectroscopy or by Differential Scanning Calorimetry (DSC). 

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