Over the last 20 years, the number of publications outlining the advances in design strategies, growing techniques, and characterization of cocrystals has continued to increase significantly within the crystal engineering field. However, only within the last decade have cocrystals found their place in pharmaceuticals, primarily due to their ability to alter physicochemical properties without compromising the structural integrity of the active pharmaceutical ingredient (API) and thus, possibly, the bioactivity. This review article will highlight and discuss the advances made over the last 10 years pertaining to physical and chemical property improvements through pharmaceutical cocrystalline materials and, hopefully, draw closer the fields of crystal engineering and pharmaceutical sciences.

Pharmaceutical Cocrystals and Their Physicochemical Properties

Purpose. In the summer of 1998, Norvir semi-solid capsules supplies were threatened as a result of a new much less soluble crystal form of ritonavir. This report provides characterization of the two polymorphs and the structures and hydrogen bonding network for each form.

Ritonavir: An Extraordinary Example of Conformational Polymorphism

The heat-of-transition rule, heat-of-fusion rule, infrared rule and density rule, which concern the relative stability of polymorphic molecular crystals, have been checked experimentally. Among the 228 transitions examined, there are only few exceptions, and these mainly concern the infrared and density rules. The heat-of-transition and heat-of-fusion rules, however, give the right result in more than 99% of cases. If certain restrictions are observed, the other rules are also fairly reliable. By their means the stability relations in polymorphic systems can easily be clarified. Data are given for 113 polymorphic substances.

On the polymorphism of pharmaceuticals and other molecular crystals. II

Most marketed pharmaceuticals consist of molecular crystals. The arrangement of the molecules in a crystal determines its physical properties and, in certain cases, its chemical properties, and so greatly influences the processing and formulation of solid pharmaceuticals, as well as key drug properties such as dissolution rate and stability. A thorough understanding of the relationships between physical structures and the properties of pharmaceutical solids is therefore important in selecting the most suitable form of an active pharmaceutical ingredient for development into a drug product. In this article, we review the different crystal forms of pharmaceuticals, the challenges that they present and recent advances in crystal structure determination. We then discuss computational approaches for predicting crystal properties. Finally, we review the analysis of crystal structures in furthering crystal engineering to design novel pharmaceutical compounds with desired physical and mechanical properties.

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Crystal structures of drugs: advances in determination, prediction and engineering

Thermal analysis and calorimetric methods in the characterisation of polymorphs and solvates

SummaryOn the basis of statistical mechanics, it is shown that the following rules concerning the relative stability of different polymorphic modifications are usually obeyed. (1) The enthalpy of transition of two enantiotropic forms is always positive at temperatures above their transition point, and negative at temperatures below the transition point or between monotropic forms (heat-of-transition rule). (2) Instead of the heat of transition, the difference in the heats of fusion may generally be used (heat-of-fusion rule). (3) If a modification is less dense, it is less stable at absolute zero. (4) For hydrogen-bonded crystals, the modification for which the first absorption band in the infrared spectrum is at higher frequencies has the larger entropy. The possibility of exceptions is discussed.ZusammenfassungMit Argumenten der statistischen Mechanik wird gezeigt, daß im Hinblick auf die relative Stabilität polymorpher Modifikationen von Molekülkristallen im allgemeinen folgende Regeln gelten. 1. Die Umwandlungsenthalpie zweier enantiotroper Formen ist über ihrem Umwandlungspunkt immer positiv, unter dem Umwandlungspunkt oder zwischen monotropen Formen negativ (Umwandlungswärme-Regel). 2. Statt der Umwandlungswärme kann meist auch die Differenz der Schmelzwärmen verwendet werden (Schmelzwärme-Regel). 3. Eine Modifikation von geringerer Dichte weist am absoluten Nullpunkt die geringere Stabilität auf. 4. Bilden zwei Modifikationen Kristalle mit Wasserstoffbrücken, so hat diejenige die größere Entropie, deren erste Bande im IR-Spektrum bei höheren Frequenzen liegt. Auf mögliche Ausnahmen von diesen Regeln wird hingewiesen.

On the polymorphism of pharmaceuticals and other molecular crystals. II@@@ber die Polymorphie von Arzneistoffen und anderen Moleklkristallen. II: Applicability of thermodynamic rules

A. Burger

Papers

On the polymorphism of pharmaceuticals and other molecular crystals. II@@@ber die Polymorphie von Arzneistoffen und anderen Moleklkristallen. II: Applicability of thermodynamic rules