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Crystal polymorphs of barbital: news about a classic polymorphic system.

Zencirci N, Griesser UJ, Gelbrich T, Apperley DC, Harris RK - Mol. Pharm. (2013)

Bottom Line: The metastable modification III is present in commercial samples and has a high kinetic stability.The solid-state NMR spectra provide information on aspects of crystallography (viz., the asymmetric units and the nature of hydrogen bonding).The known correlation between specific N-H···O═C hydrogen bonding motifs of barbiturates and certain IR characteristics was used to predict the H-bonded pattern of polymorph IV.

View Article: PubMed Central - PubMed

Affiliation: Institute of Pharmacy, University of Innsbruck , Innrain 52, 6020 Innsbruck, Austria.

ABSTRACT
Barbital is a hypnotic agent that has been intensely studied for many decades. The aim of this work was to establish a clear and comprehensible picture of its polymorphic system. Four of the six known solid forms of barbital (denoted I(0), III, IV, and V) were characterized by various analytical techniques, and the thermodynamic relationships between the polymorph phases were established. The obtained data permitted the construction of the first semischematic energy/temperature diagram for the barbital system. The modifications I(0), III, and V are enantiotropically related to one another. Polymorph IV is enantiotropically related to V and monotropically related to the other two forms. The transition points for the pairs I(0)/III, I(0)/V, and III/IV lie below 20 °C, and the transition point for IV/V is above 20 °C. At room temperature, the order of thermodynamic stability is I(0) > III > V > IV. The metastable modification III is present in commercial samples and has a high kinetic stability. The solid-state NMR spectra provide information on aspects of crystallography (viz., the asymmetric units and the nature of hydrogen bonding). The known correlation between specific N-H···O═C hydrogen bonding motifs of barbiturates and certain IR characteristics was used to predict the H-bonded pattern of polymorph IV.

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Energy/temperature diagramfor the Btl forms I0, III, IV, and V (Tfus, melting point; G, Gibbs free energy; H, enthalpy; ΔfusH, enthalpyof fusion; Ttrs, transitionpoint; ΔtrsH, transitionenthalpy; liq, liquid phase). The bold vertical arrowsindicate experimentalenthalpies, and the horizontal two-headed arrows indicate ranges ofthermodynamic stability of forms V, III,and I0.
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fig5: Energy/temperature diagramfor the Btl forms I0, III, IV, and V (Tfus, melting point; G, Gibbs free energy; H, enthalpy; ΔfusH, enthalpyof fusion; Ttrs, transitionpoint; ΔtrsH, transitionenthalpy; liq, liquid phase). The bold vertical arrowsindicate experimentalenthalpies, and the horizontal two-headed arrows indicate ranges ofthermodynamic stability of forms V, III,and I0.

Mentions: The thermodynamicrelationships between III, IV, and V were derived from the melting points of the forms, the enthalpyof fusion of form I0, and the experimentaltransition enthalpies of polymorphs III, IV, and V (Table 2) by applicationof the Burger-Ramberger rules,26 and asemischematic energy/temperature (ET) diagram was constructed (Figure 5) based on these data. The heat of transition rulewas crucial for the interpretation of this system because only themelting enthalpy of the highest melting form I0 can be measured accurately. DSC experiments showed two endothermictransitions on heating (III→I0 and V→III), which indicatedthat III/I0 and V/III are two pairs of enantiotropically related polymorphs. Therefore,the enthalpy curve of polymorph III runs below that of I0, and the curve of polymorph V belowthat of III. The transition IV→III is exothermic, which means that the two forms concernedare monotropically related to one another. The enthalpy of the transition IV→III (ΔtrsHIV→III = −2.0kJ mol–1) is higher than that of III→I0 (ΔtrsHIII→I = 1.4kJ mol–1). Accordingly, the enthalpy curve of polymorph IV runs above that of I0. It followsthat the order of relative enthalpies is V < III < I0 < IV (FigureS4, Supporting Information). This is alsothe order of the Gibbs free energies of these polymorphs at 0 K (G = H) if we consider the third law ofthermodynamics (S = 0 at T = 0 K)and the Gibbs energy function (G = H – TS). By connecting the corresponding points(enthalpies at 0 K) in the ET diagram with the melting points of theindividual forms (indicated by open circles on the free energy curveof the melt), four intersections (transition points) of G curves are obtained. These intersections indicate an enantiotropicrelationship for each of the pairs V/III, V/I0, III/I0 and V/IV. By contrast, the two G curves for each of thepairs IV/I0 and IV/III do notintersect, meaning that the corresponding relationships are monotropic.According to the DSC experiments, the phase transitions associatedwith the enantiotropic pairs III/I0 and V/III are close to 145 and 115 °C, respectively, whichis in agreement with their order in the ET-diagram. However, solid–solidtransitions are kinetically controlled and may therefore occur farabove a true (thermodynamic) transition point.


Crystal polymorphs of barbital: news about a classic polymorphic system.

Zencirci N, Griesser UJ, Gelbrich T, Apperley DC, Harris RK - Mol. Pharm. (2013)

Energy/temperature diagramfor the Btl forms I0, III, IV, and V (Tfus, melting point; G, Gibbs free energy; H, enthalpy; ΔfusH, enthalpyof fusion; Ttrs, transitionpoint; ΔtrsH, transitionenthalpy; liq, liquid phase). The bold vertical arrowsindicate experimentalenthalpies, and the horizontal two-headed arrows indicate ranges ofthermodynamic stability of forms V, III,and I0.
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Related In: Results  -  Collection

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fig5: Energy/temperature diagramfor the Btl forms I0, III, IV, and V (Tfus, melting point; G, Gibbs free energy; H, enthalpy; ΔfusH, enthalpyof fusion; Ttrs, transitionpoint; ΔtrsH, transitionenthalpy; liq, liquid phase). The bold vertical arrowsindicate experimentalenthalpies, and the horizontal two-headed arrows indicate ranges ofthermodynamic stability of forms V, III,and I0.
Mentions: The thermodynamicrelationships between III, IV, and V were derived from the melting points of the forms, the enthalpyof fusion of form I0, and the experimentaltransition enthalpies of polymorphs III, IV, and V (Table 2) by applicationof the Burger-Ramberger rules,26 and asemischematic energy/temperature (ET) diagram was constructed (Figure 5) based on these data. The heat of transition rulewas crucial for the interpretation of this system because only themelting enthalpy of the highest melting form I0 can be measured accurately. DSC experiments showed two endothermictransitions on heating (III→I0 and V→III), which indicatedthat III/I0 and V/III are two pairs of enantiotropically related polymorphs. Therefore,the enthalpy curve of polymorph III runs below that of I0, and the curve of polymorph V belowthat of III. The transition IV→III is exothermic, which means that the two forms concernedare monotropically related to one another. The enthalpy of the transition IV→III (ΔtrsHIV→III = −2.0kJ mol–1) is higher than that of III→I0 (ΔtrsHIII→I = 1.4kJ mol–1). Accordingly, the enthalpy curve of polymorph IV runs above that of I0. It followsthat the order of relative enthalpies is V < III < I0 < IV (FigureS4, Supporting Information). This is alsothe order of the Gibbs free energies of these polymorphs at 0 K (G = H) if we consider the third law ofthermodynamics (S = 0 at T = 0 K)and the Gibbs energy function (G = H – TS). By connecting the corresponding points(enthalpies at 0 K) in the ET diagram with the melting points of theindividual forms (indicated by open circles on the free energy curveof the melt), four intersections (transition points) of G curves are obtained. These intersections indicate an enantiotropicrelationship for each of the pairs V/III, V/I0, III/I0 and V/IV. By contrast, the two G curves for each of thepairs IV/I0 and IV/III do notintersect, meaning that the corresponding relationships are monotropic.According to the DSC experiments, the phase transitions associatedwith the enantiotropic pairs III/I0 and V/III are close to 145 and 115 °C, respectively, whichis in agreement with their order in the ET-diagram. However, solid–solidtransitions are kinetically controlled and may therefore occur farabove a true (thermodynamic) transition point.

Bottom Line: The metastable modification III is present in commercial samples and has a high kinetic stability.The solid-state NMR spectra provide information on aspects of crystallography (viz., the asymmetric units and the nature of hydrogen bonding).The known correlation between specific N-H···O═C hydrogen bonding motifs of barbiturates and certain IR characteristics was used to predict the H-bonded pattern of polymorph IV.

View Article: PubMed Central - PubMed

Affiliation: Institute of Pharmacy, University of Innsbruck , Innrain 52, 6020 Innsbruck, Austria.

ABSTRACT
Barbital is a hypnotic agent that has been intensely studied for many decades. The aim of this work was to establish a clear and comprehensible picture of its polymorphic system. Four of the six known solid forms of barbital (denoted I(0), III, IV, and V) were characterized by various analytical techniques, and the thermodynamic relationships between the polymorph phases were established. The obtained data permitted the construction of the first semischematic energy/temperature diagram for the barbital system. The modifications I(0), III, and V are enantiotropically related to one another. Polymorph IV is enantiotropically related to V and monotropically related to the other two forms. The transition points for the pairs I(0)/III, I(0)/V, and III/IV lie below 20 °C, and the transition point for IV/V is above 20 °C. At room temperature, the order of thermodynamic stability is I(0) > III > V > IV. The metastable modification III is present in commercial samples and has a high kinetic stability. The solid-state NMR spectra provide information on aspects of crystallography (viz., the asymmetric units and the nature of hydrogen bonding). The known correlation between specific N-H···O═C hydrogen bonding motifs of barbiturates and certain IR characteristics was used to predict the H-bonded pattern of polymorph IV.

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