Dimorphic systems

The dimorphic systemic fimgi are phylogenetically closely related to the dermatophytes and can be included in the family Onygenaceae (fig. 3, 8) [135, 273, 274]. Five clearly different genera can be distinguished Blastomyces, Coccidioides, Emmonsia, Histoplasma and Paracoccidioides. Each comprises only a very few species and all are pathogenic. Species of Blastomyces... 

Fig. 2.3 Energy vs temperature (E/T) diagram of a dimorphic system. G is the Gibbs free energy and H is the enthalpy. This diagram represents the situation for an enantiotropic system, in which Form I is the stable form below the transition point, and presumably at room temperature, consistent with the labelling scheme for polymorphs proposed by McCrone (see Chapter 1). (Adapted from Grunenberg et al. 1996, with permission.)...

Fig. 2.5 Energy vs temperature (E/T) diagram for a monotropic dimorphic system. The symbols have the same meaning as in Fig. 2.3. Form I is more stable at all temperatures the crossing of the Gj and Gu curves (not shown) will be above the melting point for Form I and Form II. (From Grunenberg et al. 1996, with permission.)...

Fig. 2.9 Schematic of the reaction coordinate for crystallization in a dimorphic system, showing the activation, barriers for the formation of polymorphs I and II. (Adapted from Bernstein et al. 1999, with permission.)...

From this analysis it is clear that the trade-off between kinetics and thermodynamics is not at all obvious. Consider a monotropic, dimorphic system (for simplicity) whose solubility diagram is shown schematically in Fig. 2.10. It is quite clear that for the occurrence domain given by solution compositions and temperatures that lie between the form II and I solubility curves only polymorph I can crystallize. However, the outcome of an isothermal crystallization that follows the crystallization pathway indicated by the vector in Fig. 2.10 is not so obvious since the initial solution is now supersaturated with respect to both polymorphic structures, with thermodynamics favouring form I and kinetics (i.e. supersaturation) form II. 

Fig. 2.11 The rates of nucleation as functions of supersaturation for the dimorphic system defined in Fig. 2.10. The three diagrams a, b and c represent the three possible solutions for the simultaneous nucleation of two polymorphs each of which follows a rate equation of the form of eqn (2.2). Note that solutions a and c both allow for simultaneous nucleation of the forms at supersaturations corresponding to the crossover of the curves. (From Bernstein et al. 1999, with permission.)...

Fig.1a-c. Gibbs free energy vs temperature for a a dimorphic system, exhibiting b enan-tiotropy c monotropy... 

Recent application of these principles to polymorphic control is shown schematically in Fig. 15 for a hypothetical dimorphic system in which one polymorph is centrosymmetric and the other crystallizes in a polar space group [36]. In the former crystal, the molecules are arranged in antiparallel orientation whereas in the latter they are aligned along a common direction. A tailor-made auxiliary which binds to both crystals would do so at the two (indistinguishable) ends of the centrosymmetric crystal but only at one end of the polar crystal. The latter would therefore grow at the expense of the former and polymorphic control will have been achieved. 

Experimentally, this process can be verified using time-lapse micrographs of a polymorphic system crystallizing, and this is illustrated for dimorphic system L-glutainic in Fig. 6. In this figure, a series of time-sequence micrographs clearly show the dissolution of the metastable rhomb phase (I) and the growth of the stable needle phase... 

A high-value approach for the structure determination of an enantiotropically-related dimorphic system having low solid-solid conversion temperatures has been presented [67]. The crystal structure of the thermodynamically more stable form at room temperature was determined by single-crystal XRD (polymorph 1, Z =4, Z= 16). The crystal structure of the other form (polymorph 2, Z = 1, Z=4) was determined using iterative PXRD structure solution methods, assisted by SSNMR experiments (dipolar connectivity and CS measurements). DFT geometry optimizations were used in tandem with Rietveld refinement and NMR CS calculations to improve and verify the structure for polymorph 2. 

C = 1 for polymorphs because there is only one component in polymorphic systems. For a dimorphic system, P = 2 when both the polymorphs are in equilibrium, which means that one of the parameters can be varied. This implies that at constant pressure, the temperature at which the two polymorphs coexist can vary, which is defined as the transition point. The phase rule also implies that, since the system cannot have a negative number of degrees of freedom (F < 1), only a maximum of three polymorphs can coexist in equilibrium, and the set of conditions under which this occurs is defined as the triple point. 

The application of the phase rule to a dimorphic system suggests that, at a given pressure, phase transition from one polymorph to the other may occur by changing the temperature (F = 1). If such a phase transition is reversible, the two polymorphs are said to be enantiotropes and the energy of transition on heating is endothermic. When the phase transition is irreversible, the two polymorphs are termed as monotropes, in which case only one form is stable whatever the temperature, and the transformation of the metastable form to the stable one is exothermic. 

Figure 8 Energy versus temperature (E-T) diagram of a dimorphic system (a) enantiotropic, (b) monotropic. G Gibbs free energy, H enthalpy, liq liquid phase, and Tpi transition point of two polymorphs. (Reproduced from Ref. 40. Elsevier, 1996.)...

The mammalian and avian immune systems function similarly both incorporate humoral and cell-mediated cytotoxic mechanisms, " and are thought to share a 160m year old relationship with the reptilian immune system. The immune system of mammals shows sexual dimorphism " a greater immune response is normally observed in females, which has been attributed to differences in steroid hormone concentration. In the toad Bufo regularis, sexual dimorphism of the immune system is also apparent. ... 

Larriva-Sahd J.A., Matsumoto A. and Sumoto A. (1994). The vomeronasal system and its connections with sexually dimorphic neural structures. Zool Sci 11, 495-506. 

Steinborn, G., Boer, E., Scholz, A. et al. (2006) Application of a wide-range yeast vector (CoMed) system to recombinant protein production in dimorphic Arxula adeninivorans, methylotrophic Hansenula polymorpha and other yeasts. Microbial Cell Factories, 5, 33. 

When p-chlorobenzophenone dichloride reacts with methylamine there results an oil consisting of similar amounts of the syn and anti Schiff base 19. This oil, on standing at room temperature for 2 weeks, transforms to crystals of only the syn isomer. If these crystals are heated above their melting point (125°) for a few minutes, or are dissolved in cyclohexane and allowed to stand at room temperature for 2 weeks, the syn isomer reconverts to a mixture of the two isomers (61a). [This seems to be an example of the so-called second-order or crystallization-induced asymmetric transformations (61b).] A number of systems of this series were known, from previous work, to be dimorphic however, Curtin and Hausser found no case in which it was established that two crystal forms correspond to different isomers (61a). 

Serotonergic systems are also affected by adolescent treatment in a sexually dimorphic manner. During adolescence, at doses that produce plasma nicotine doses similar to levels found in smokers, nicotine decreases serotonin receptors specifically in the cortex, in female rats. However, in the midbrain, there was an increase in males (Xu et al. 2002). 

Nicotine is an addictive substance with rewarding and reinforcing properties. On the other hand, the autonomic responses following an acute nicotine treatment and the bitter taste of nicotine may cause aversion. This aversion may impact conditioned effects to nicotme. Rinker et al. (2008) studied possible sex differences in taste aversion mduced by nicotine in rats systemic nicotine or saline injections were paired wim oral saccharine. Although nicotme did produce a weak taste aversion, no sex differences were observed, excluding the possible contribution of the aversive properties of nicotine on sexually dimorphic responses to nicotine. The authors conclude that sex differences may arise from differences in the rewardmg properties of the drug. 

Amphotericin B is used to treat systemic disseminated fungal infections caused by Candida spp., Cryptococcus neoformans, and the invasive dimorphic fungi Aspergillus spp., Histoplasma capsulatum, Coccidioides immi-tis, Blastomyces dermatitidis, and Sporothrix schenckii). Intravenous amphotericin B remains the treatment of choice for serious invasive fungal infections unresponsive to other agents. 

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