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The availability of sufficient amounts of form I of benzocaine has led to the investigation of its phase relationships with the other two existing forms, II and III, using adiabatic calorimetry, powder X-ray diffraction, and high-pressure differential thermal analysis. The latter two forms were known to have an enantiotropic phase relationship in which form III is stable at low-temperatures and high-pressures, while form II is stable at room temperature with respect to form III. Using adiabatic calorimetry data, it can be concluded, that form I is the stable low-temperature, high-pressure form, which also happens to be the most stable form at room temperature; however, due to its persistence at room temperature, form II is still the most convenient polymorph to use in formulations. Form III presents a case of overall monotropy and does not possess any stability domain in the pressure–temperature phase diagram. Heat capacity data for benzocaine have been obtained by adiabatic calorimetry from 11 K to 369 K above its melting point, which can be used to compare to results from in silico crystal structure prediction. [ABSTRACT FROM AUTHOR]

Graphical abstract Abstract Spironolactone form I melts at about 70 degrees lower than form II, which is very unusual for two co-existing polymorphs. The phase relationships involving this unprecedented case of dimorphism have been investigated by constructing a topological pressure-temperature phase diagram. The transition from polymorph I to polymorph II is unambiguously exothermic while it is accompanied with an increase in the specific volume. This indicates that the d P /d T slope of the I-II equilibrium curve is negative. The convergence of the melting equilibrium lines at high pressure leads to a topological P - T diagram in which polymorph I possesses a stable phase region at high pressure. Thus, forms I and II are monotropically related at ordinary pressure and turn to an enantiotropic relationship at high pressure. Given that polymorph I is the densest form, it negates the rule of thumb that the densest form is also the most stable form at room temperature, similar to the case of paracetamol. [ABSTRACT FROM AUTHOR]

Understanding the polymorphic behavior of active pharmaceutical ingredients is important for formulation purposes and regulatory reasons. Metacetamol is an isomer of paracetamol and it similarly exhibits polymorphism. In the present article, it has been found that one of the polymorphs of metacetamol is only stable under increased pressure, which has led to the conclusion that metacetamol like paracetamol is a monotropic system under ordinary (= laboratory) conditions and that it becomes enantiotropic under pressure with the I-II-L triple point coordinates for metacetamol T I-II-L = 535 ± 10 K and P I-II-L = 692 ± 70 MPa. However, whereas for paracetamol the enantiotropy under pressure can be foreseen, because the metastable polymorph is denser, in the case of metacetamol this is not possible, as the metastable polymorph is less dense than the stable one. The existence of the stability domain for the less dense polymorph of metacetamol can only be demonstrated by the construction of the topological phase diagram as presented in this article. It is a delicate interplay between the specific volume differences and the enthalpy differences causing the stability domain of the less dense polymorph to be sandwiched between the denser polymorph and the liquid. Metacetamol shares this behavior with bicalutamide and fluoxetine nitrate. [ABSTRACT FROM AUTHOR]

Abstract: Understanding the phase behavior of an active pharmaceutical ingredient in a drug formulation is required to avoid the occurrence of sudden phase changes resulting in decrease of bioavailability in a marketed product. Benzocaine is known to possess three crystalline polymorphs, but their stability hierarchy has so far not been determined. A topological method and direct calorimetric measurements under pressure have been used to construct the topological pressure–temperature diagram of the phase relationships between the solid phases II and III, the liquid, and the vapor phase. In the process, the transition temperature between solid phases III and II and its enthalpy change have been determined. Solid phase II, which has the highest melting point, is the more stable phase under ambient conditions in this phase diagram. Surprisingly, solid phase I has not been observed during the study, even though the scarce literature data on its thermal behavior appear to indicate that it might be the most stable one of the three solid phases. [Copyright &y& Elsevier]

The pressure–temperature (P–T) melting curve of lidocaine was determined (dP/dT = 3.56 MPa K-1), and the lidocaine–water system was investigated as a function of temperature and pressure. The lidocaine–water system exhibits a monotectic equilibrium at 321 K (ordinary pressure) whose temperature increases as the pressure increases until the two liquids become miscible. A hydrate, unstable at ordinary pressure, was shown to form, on increasing the pressure, from about 70 MPa at low temperatures (200–300 K). The thermodynamic conditions of its stability were inferred from the location of the three-phase equilibria involving the hydrate in the lidocaine–water pressure–temperature–mole fraction (P–T–x) diagram. © 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 99: 2756–2765, 2010 [ABSTRACT FROM AUTHOR]

Temperatures and melting enthalpies of orthorhombic Phases I and II of natural progesterone, together with the temperature dependence of their lattice parameters and the specific volume of the melt at ordinary pressure, have been determined. With these results, a topological pressure-temperature (P-T) phase diagram accounting for the thermodynamic relationships between these phases has been constructed by way of the Clapeyron equation. The dependence of the melting temperature on the pressure has also been determined for each phase by high-pressure differential thermal analysis. It was found that, upon increasing the pressure, the melting curves converge to the I–II-liquid triple point (TI–II-liquid = 459.4 K, PI–II-liquid = 149.0 MPa), in close agreement with its topological location. This entails that Phase II should exhibit a stable phase region at higher pressure. © 2008 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 98:1657–1670, 2009 [ABSTRACT FROM AUTHOR]

Two polymorphs of the 1:1 fumarate salt of 1,4-diazabicyclo[3.2.2]nonane-4-carboxylic acid 4-bromophenyl ester, developed for the treatment of cognitive symptoms of schizophrenia and Alzheimer disease, have been characterized. The 2 crystal structures have been solved, and their phase relationships have been established. The space group of form I is P 2 1 / c with a unit-cell volume of 1811.6 (5) Å 3 with Z = 4. The crystals of form I were 2-component nonmerohedral twins. The space group of form II is P 2 1 / n with a unit-cell volume of 1818.6 (3) Å 3 with Z = 4. Relative stabilities have been inferred from experimental and topological P-T diagrams exhibiting an overall enantiotropic relationship between forms I and II although the solid–solid transition has never been observed. The slope of the I-II equilibrium in the P-T diagram is negative, form II is the stable phase below the solid–solid transition temperature of 371 K, and form I exhibits a stable melting equilibrium. The I-II transition temperature has been obtained from the intersection of the sublimation curves of the 2 solid forms. [ABSTRACT FROM AUTHOR]

Crystalline polymorphism occurs frequently in the solid state of active pharmaceutical ingredients, and this is problematic for the development of a suitable dose form. Rimonabant, an active pharmaceutical ingredient developed by Sanofi and discontinued because of side effects, exhibits dimorphism; both solid forms have nearly the same melting temperatures, melting enthalpies, and specific volumes. Although the problem may well be academic from an industrial point of view, the present case demonstrates the usefulness of constructing pressure-temperature phase diagrams by direct measurement as well as by topological approach. The system is overall monotropic and form II is the more stable solid form. Interestingly, the more stable form does not possess any hydrogen bonds, whereas the less stable one does. © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 102:2311-2321, 2013 [ABSTRACT FROM AUTHOR]

The API triethylenetetramine dihydrochloride used as an alternative treatment of Wilson’s disease is sensitive to water and it exhibits polymorphism. As this may become an issue for the drug formulation, the physical stability has been studied by differential scanning calorimetry, high-pressure thermal analysis, dynamic vapor sorption, and X-ray diffraction as a function of temperature. In addition, high-pressure liquid chromatography and mass spectrometry have been used to study the purity and chemical stability of the API. A pressure-temperature phase diagram of the pure compound has been constructed and it can be concluded that form II is monotropic in relation to form I, which is the only stable solid. The solubilities of the different solid forms have been determined with the help of a temperature – composition phase diagram. The API is very soluble, at 20° C about 10% of the saturated solution with respect to the dihydrate consists of API and the solubility of the pure form I is twice as high. Moreover, it has been shown that at 20 °C, a relative humidity above 40% induces the formation of the dihydrate and at 70% a saturated solution appears. At higher temperatures, the formation of the dihydrate appears at lower relative humidity values. A clear link has been established between the API’s chemical stability, its physical stability and the relative humidity in the air. Humidity levels above 40% are detrimental to the quality of the API. [ABSTRACT FROM AUTHOR]