Rapid dissolving high potency danazol powders produced by spray freezing into liquid process

Abstract

The objective of this study was to investigate the use of organic solvents in the spray freezing into liquid (SFL) particle engineering process to make rapid dissolving high potency danazol powders and to examine their particle size, surface area and dissolution rate. The maximum drug potency produced was 91% for SFL micronized danazol/PVP K-15. XRD indicated that danazol in the high potency SFL powders was amorphous. SEM micrographs revealed that the SFL danazol/PVP K-15 nanostructured aggregates had a porous morphology and were composed of many smooth primary nanoparticles with a diameter of about 100 nm. Surface areas of SFL danazol/PVP K-15 high potency powders were in the range of 28–115 m²/g. The SFL powders exhibited significantly enhanced dissolution rates. The rate of dissolution of micronized bulk danazol was slow; only 30% of the danazol was dissolved in 2 min. However, 95% of danazol was dissolved in only 2 min for the SFL high potency powders. The SFL process offers a highly effective approach to produce high potency danazol nanoparticles contained in larger structured aggregates with rapid dissolution rates, and is especially applicable to delivery systems containing poorly water soluble drugs.

Introduction

It is estimated that about 40% of compounds being developed by the pharmaceutical industry are poorly water soluble (Lipinski, 2002, Radtke, 2001. A limiting factor in the oral bioavailability of poorly water soluble compounds is an inadequate dissolution rate. Increasing the dissolution rate of poorly water soluble active pharmaceutical ingredients (APIs) has become a major challenge in pharmaceutical formulation development. A promising approach is to use a particle engineering technology to overcome poor wetting and low dissolution rate of an API. Techniques that have been commonly used include mechanical milling, spray drying, solid dispersion, supercritical CO₂ precipitation techniques like RESS and PCA/SAS/SEDS (Leuner and Dressman, 2000, Merisko-Liversidge et al., 2003, Rogers et al., 2001, Tom and Debenedetti, 1991), and solvent evaporation techniques including evaporative precipitation into aqueous solution (EPAS) (Chen et al., 2002). These particle formation techniques have been used to micronize poorly water soluble API alone or in the presence of a polymer and/or surfactant(s). As a result, the decreased particle size and increased surface area lead to greatly enhanced dissolution rates (Leuner and Dressman, 2000, Merisko-Liversidge et al., 2003, Muller et al., 2001, Rogers et al., 2001).

Pharmaceutical powders produced by the current particle engineering technologies; however, often have very low drug potency or drug/surfactant ratio. It is difficult to stabilize small particles due to the thermodynamic driving force to lower the interfacial area. Therefore, the final product often contains large amounts of stabilizing excipients resulting in very low drug potency. For example, the API/surfactant(s) ratio in a solid dispersion must be below about 1:2 to keep the drug molecularly dispersed, otherwise, it may form small crystals that lower the dissolution rates (Leuner and Dressman, 2000). The application of supercritical CO₂ rapid expansion techniques was limited by the low solubility of API in the CO₂. The high percentages of surfactants were often used to enhance solubility of API in the CO₂ and to stabilize the system as well (Rogers et al., 2001, Tom and Debenedetti, 1991). Typically, API/surfactant ratios ranging from 1:40 to 3:1 are used in the current particle formation techniques (Delneuville et al., 1998, Kerc et al., 1999, Nair et al., 2002, Rasenack and Muller, 2002, Tantishaiyakul et al., 1996). However, solid oral dosage forms often require high potency or high API/surfactant ratios in order to achieve a therapeutic effect with tolerability to the API and minimal side effects from the excipients. However, it is highly challenging in current particle engineering technologies to achieve high dissolution rates for poorly water soluble APIs with high potency because only a small amount of stabilizing excipient(s) can be used in the process.

The spray freezing into liquid (SFL) particle engineering process was developed to improve the wetting and enhance the dissolution rate of poorly water soluble APIs (Hu et al., 2002; Rogers et al., 2002, Rogers et al., 2003; Yu et al., 2002). In the SFL particle engineering process, a feed solution containing poorly water soluble API and excipient(s) is atomized directly into a cryogenic liquid to produce frozen particles. The frozen particles are then collected and lyophilized to obtain dry powders. The intense atomization in conjunction with rapid freezing rates have led to nanostructured aggregates composed of amorphous API nanoparticles with high surface areas and enhanced wettability. Recently, a study (Hu et al., 2002) showed that carbamazepine/PVP K-15/poloxamer 407 powders prepared by SFL exhibited significantly enhanced dissolution rates (>92% dissolved in 10 min in the purified water). In contrast, only 5% of bulk carbamazepine was dissolved in 20 min. The SFL powders wetted and dissolved instantaneously upon contact with the dissolution media because of an amorphous structure, high surface area and increased wettability. However, these SFL formulations had relatively low drug potency, typically 33%.

The objective of this study was to extend the SFL process to produce rapid dissolving high potency powders with high surface areas and dissolution rates. The potencies ranged from 50 to 90% in contrast with the typically obtained 33% in previous studies (Hu et al., 2002, Hu et al., 2003; Rogers et al., 2002). In order to achieve these high potencies, high concentrations of APIs were dissolved in pure or mixed organic solvents to prepare the feed solutions. The hypothesis of this study was that only small amounts of surfactant or polymer are sufficient to form SFL nanostructured aggregates with amorphous API, high surface areas, and enhanced wettability; properties which enhance dissolution rates. Danazol was used as a model API in this study. The dissolution rate was determined as a function of the danazol potency.