Estimation of Melting Points of Organics

Samuel H Yalkowsky, Doaa Alantary

Research output: Contribution to journalArticle

7 Scopus citations

Abstract

Unified physicochemical property estimation relationships is a system of empirical and theoretical relationships that relate 20 physicochemical properties of organic molecules to each other and to chemical structure. Melting point is a key parameter in the unified physicochemical property estimation relationships scheme because it is a determinant of several other properties including vapor pressure, and solubility. This review describes the first-principals calculation of the melting points of organic compounds from structure. The calculation is based on the fact that the melting point, Tm, is equal to the ratio of the heat of melting, ΔHm, to the entropy of melting, ΔSm. The heat of melting is shown to be an additive constitutive property. However, the entropy of melting is not entirely group additive. It is primarily dependent on molecular geometry, including parameters which reflect the degree of restriction of molecular motion in the crystal to that of the liquid. Symmetry, eccentricity, chirality, flexibility, and hydrogen bonding, each affect molecular freedom in different ways and thus make different contributions to the total entropy of fusion. The relationships of these entropy determining parameters to chemical structure are used to develop a reasonably accurate means of predicting the melting points over 2000 compounds.

Original languageEnglish (US)
JournalJournal of Pharmaceutical Sciences
DOIs
StateAccepted/In press - Jan 1 2018

Keywords

  • Crystallinity
  • Crystallization
  • Drug-like properties
  • Nonlinear regression
  • Physical characterization
  • Physicochemical
  • Physicochemical properties
  • Preformulation
  • Structure-property relationship (SPR)

ASJC Scopus subject areas

  • Pharmaceutical Science

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