Estimating the relative stability of polymorphs and hydrates from heats ofsolution and solubility data

The transition temperature, Tt, of polymorphs is estimated from both their heats of solution and solubilities (or intrinsic dissolution rates) determi ned at any one temperature (e.g., ambient). At a given temperature, T, the enthalpy difference, DeltaH, between polymorphs, I and II, is equal to the difference between their heats of solution, whereas the free energy differe nce, AG, can be estimated by the equation, DeltaG = -RTln (c(I)/c(II)) or D eltaG = -RTln (J(I)/J(II)), where c is the solubility and J is the intrinsi c dissolution rate. The entropy difference, DeltaS, is evaluated as (DeltaH - DeltaG)/T. Because the heat capacity difference, DeltaC(t) between polym orphs is small enough to be neglected, the transition temperature may be es timated by the equation, T-t=DeltaH/DeltaS. The thermodynamic stability rel ationships of the polymorphs (i.e., whether they are enantiotropes or monot ropes) are predicted from the value of T-t and the melting temperature. The T-t values for auranofin, carbamazepine, chloramphenicol palmitate, cyclop enthiazide, gepirone hydrochloride, lamivudine, MK571, premafloxacin, sulfa merazine, sulfamethoxazole, sulfathiazole, and urapidil, were calculated fr om reported values of the heats of solution and solubilities (or dissolutio n rates). The stability relationships deduced from the calculated values of Tt are in good agreement with those reported using other methods, such as differential scanning calorimetry and interpretation of melting data. (C) 2 001 Wiley-Liss, Inc. and the American Pharmaceutical Association.