Elsevier

Advanced Drug Delivery Reviews

Volume 60, Issue 3, 14 February 2008, Pages 328-338
Advanced Drug Delivery Reviews

Supercritical carbon dioxide processing of active pharmaceutical ingredients for polymorphic control and for complex formation

https://doi.org/10.1016/j.addr.2007.03.023Get rights and content

Abstract

Supercritical fluid technique have been exploited in extraction, separation and crystallization processes. In the field of pharmaceutics, supercritical carbon dioxide (scCO2) has been used for the purpose of micronization, polymorphic control, and preparation of solid dispersion and complexes. Particle design of active pharmaceutical ingredients is important to make the solid dosage forms with suitable physicochemical properties. Control of the characteristic properties of particles, such as size, shape, crystal structure and morphology is required to optimize the formulation. For solubility enhancement of poorly water-soluble drugs, preparation of the solid dispersion or the complexation with proper drugs or excipients should be a promising approach. This review focuses on aspects of polymorphic control and complexation behavior of active pharmaceutical ingredients by scCO2 processing.

Introduction

A number of interesting properties are associated with the critical state. One of these is that the density of the liquid and of the vapor become identical, and for this reason the meniscus, the interface between the two phases, disappears. A second property of the critical state, which can be predicted from the kinetic theory of gases, is that the intermolecular van der Waals forces of the liquid and the vapor must be identical. Actually the constants appearing in the van der Waals equation of state for a real gas can be evaluated from the critical constants, i.e., critical pressure, critical temperature and critical volume [1].

During the past decade, interest regarding the supercritical state has increased significantly because of its importance in a variety of fields, including synthetic chemistry, environmental chemistry, analytical chemistry, material science, food industry, and powder technology [2], [3]. Particularly, its characteristics have been exploited in extraction, separation and crystallization processes [4].

It is an important mission of the pharmaceutical industry to design and produce effective, stable, uniform and safe dosage forms that contain exact quantities and qualities of active pharmaceutical ingredients. The quality of a product is strongly related to and influenced by its design in research and development. The quality depends on the inter-relationship of many factors besides the active substance in a dosage form. Without considering physicochemical characteristics of the materials and manufacturing processes for the product, it would be impossible to establish the specifications required to assure product uniformity [5].

Active pharmaceutical ingredients may exist in numerous solid forms that may feature different physical and chemical properties [6], [7]. These solid forms include polymorphs, solvates, desolvates and amorphous solids. Different solid forms of a given compound have different properties such as melting point, solubility, stability and bioavailability. Byrn et al. reported a conceptual approach to the characterization of pharmaceutical solids generally encountered [8]. They developed flow charts which describe approaches to regulatory issues for polymorphs, solvates, desolvated solvates and amorphous forms. The successful utilization of a solid form may provide greater therapeutic effect. On the other hand, the existence of unrecognized, multiple modifications in a particular formulation may possibly result in unacceptable dose-to-dose variations. Distinct solid forms can be prepared by precipitation, evaporation, milling, freeze drying, spray drying, and many other unit processes including supercritical technology.

Numerous attempts have been made to improve dissolution behavior and to enhance bioavailability of poorly water-soluble drugs, including the use of solid dispersions, complex formation and inclusion compound formation, as well as micronization [9]. The approach of solid dispersion was first demonstrated by Sekiguchi and Obi, using a eutectic mixture of sulfathiazole and urea [10]. Inclusion compounds have also been developed for the modification of solubility, stability, prevention of irritative action to gastrointestinal tracts and volatility depression. It is believed that pharmaceutical technology will play an important role in preparing these high potential solid systems for future dosage forms.

In this review, an attempt is made to review the current pharmaceutical literature on supercritical technology concerning crystal modification and complex formation of active pharmaceutical ingredients.

Section snippets

Crystal modification of active pharmaceutical ingredients by supercritical carbon dioxide treatment

Particle design of active pharmaceutical ingredients (APIs) is important to make the solid dosage forms with suitable physicochemical properties. Control of the characteristic properties of particles, such as size, shape, crystal structure and morphology are required to optimize the formulation. For example, polymorphic form of solid pharmaceuticals influences the dissolution properties and stabilities of solid dosage forms. Since the bioavailability of orally applied drugs depends on the rate

Utilization of supercritical carbon dioxide to prepare solid dispersions of active pharmaceutical ingredients

The most characteristic property of supercritical fluids is the large density fluctuation near the critical point. A well-known problem in physical chemistry of supercritical fluids has been how this density fluctuation is reflected in the various kinds of manufacturing processes of solute molecules dissolved in supercritical fluids [38], [46], [47]. However, the poor solubility of APIs in scCO2 often places severe restrictions on its widespread use in pharmaceutical processing.

The objective in

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