Christian Hoff

Crystallization and dissolution of pharmaceutical compounds: An experimental approach

In pharmaceutical industry growth and dissolution are important stages for different reasons. In industrial processes crystallization is an important operation which controls the physical properties of the material such as the crystal habit, crystal size distribution and polymorphism. For economic and technical reasons before patenting a drug it is important to search all the possible polymorphs. In the case of organic drugs which are slightly soluble in gastrointestinal fluids, the dissolution rate of the solid dosage form is an important factor determining the rate of absorption. The kinetics of solubilization will depend mainly on the crystal habit, crystal size distribution and on the polymorphs. This paper presents a laboratory study of the dissolution of crystals of an organic drug in a crystallizer equipped with an in situ conductivity probe and an UV analyzer on-line. The rate of dissolution and evolution of the crystal size distribution are measured. A solution mediated phase transition of the drug is observed. The final objective is to model the dissolution process from kinetic data and determine the influence on the dissolution of under-saturation, temperature, crystal habit and crystal size distribution.

Dissolution and phase transition of pharmaceutical compounds

Abstract This paper presents a laboratory study of a solution-mediated phase transition of irbesartan form A into form B. The following stages are observed and studied: dissolution of form A until the apparent saturation is reached, form A dissolution which strictly compensates for the form B nucleation and growth, form A is completely dissolved and crystallization of form B is only observed until the concentration reaches the solubility of form B. In the first stages of the transformation, the dissolution of form A, we evidenced two distinct behaviors in function of undersaturation: (1) at higher undersaturation, dissolution is controlled by mass transfer and (2) at lower undersaturation, dissolution is controlled by surface process. The influence of the temperature is also shown. In the last part of this work we showed that from the knowledge of the crystal structure and experimental morphology additives can be selected. A surfactant, dodecyl amine chloride, has an accelerating effect on the dissolution of form A and hinder the growth of form B. Adipic acid slows down the dissolution rate of form A, but has no effect on the growth rate of form B.