The sodium ion-hydrogen ion, hydrogen ion-sodium ion exchange titration curves of «-zirconium phosphate crystals, ( 04)2• 20, exhibit a hysteresis loop. This results from the presence of different phases in the forward and backward titrations. When the crystals are titrated with sodium hydroxide two solid phases are present up to 50% of exchange. They are the unexchanged «-zirconium phosphate and a half-exchanged phase whose formula is ZrCNaPChXHPCh) -5H20. This latter phase is the only one present at exactly 50% of exchange but at higher levels of exchange another two-phase region is obtained. The two phases are the half-exchanged crystals and a fully exchanged phase of composition Zr(NaP04)2.3H20. The interconversion of the half and fully exchanged phases is reversible. However, when the half-exchanged phase takes up protons it forms an unexchanged phase which is more highly hydrated than the original «-zirconium phosphate. Dehydration of the exchanged phases leads to the formation of several new phases. The phase changes during exchange and dehydration are explained on the basis of the swelling and contraction of the layers in the «-zirconium phosphate crystals.

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The X-ray crystallographic structural determinations of synthetic estrogens and antiestrogens provide reliable information on the global minimum energy conformation of these molecules or a local minimum energy conformation that is within 1 or 2 kcal/mole of the global minimum. In favorable cases, state-ofthe-art molecular mechanics calculations provide quantitative agreement with X-ray results and information on the relative energy ofother local minimum energy conformations not observed crystallographically.Because the conformation of diethylstilbestrol (DES) observed in solvated crystals has an overall conformation and dipole moment more similar to estradiol it is the form more likely to bind to the receptor and produce hormone activity. Either phenol ring of DES can successfully mimic the estradiol A-ring in binding to the receptor. Indenestrol A (INDA) and indenestrol B (INDB) have nearly identical fully extended planar conformations. Either the a or y rings of these compounds may mimic the A ring of estradiol and compete for the estrogen receptor. Although there are eight distinct ways in which molecules of a racemic mixture of INDA or INDB can bind to the receptor, not all of them may be able to elicit a hormonal response. This may account for the reduced biological activity of the compounds despite their successful competition for receptor binding.The minimum energy conformations of Z-pseudodiethylstilbestrol (ZPD) and E-pseudodiethylstilbestrol (EPD) are bent in a fashion similar to that of indanestrol (INDC). These molecules have good binding affinity suggesting that the receptor does not require a flat molecule. Therefore these conformations would appear to be compatible with receptor binding, but only the Z isomer has an energetically allowed extended conformation that accounts for its observed biological activity relative to DES.

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