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Preformulation investigation. II. Dissolution kinetics and thermodynamic parameters of polymorphs of an experimental antihypertensive.

Polymorph I of an experimental antihypertensive was obtained by recrystallization from methanol, water, or hydrochloric acid; Polymorph II was harvested from isopropanol, dimethylformamide, or dimethylacetamide. The dissolution rate and peak solubility of Polymorph II are three or four times greater than that of Polymorph I. After reaching the maximum concentration plateau, the dissolution rate of Polymorph II is exceeded by the nucleation rate and an apparent first-order decline in the drug concentration is observed. This is attributed to the in situ crystalline transformation of a less stable Polymorph II to a more stable Polymorph I. Although the nucleation process remains as first order within a 3-hr. period, the nucleation rate is changed at a specific time. The time at which the first-order nucleation rate changes is a function of the temperature: the lower the temperature, the slower the nucleation half-life and the longer the observed transition time of the nucleation process. The relation between the rate of first-order nucleation process and the degree of saturation of the system is derived and verified with the experimental data. Various thermodynamic parameters involved in this transformation are calculated. The enthalpy change, the free energy change, and the entropy change for the conversion of Polymorph II to Polymorph I were determined to be −2232 cal./mole, −172.4 cal./mole, and −6.6 e.s.u., respectively. Furthermore, the attainable peak solubilities and the firstorder nucleation rates of Polymorph II obtained from different recrystallization solvents are different from each other. These findings may imply that the variation of absorption and therapeutic efficacy of a drug supplied in a dosage form by different firms could be caused not only by employing different polymorphs but also by using the same polymorph recrystallized from different solvents.