Research paper Micronized powders of a poorly water soluble drug produced by a spray-freezing into liquid-emulsion process True L. Rogers a,1 , Kirk A. Overhoff a , Parag Shah b , Patricia Santiago b , Miguel J. Yacaman b , Keith P. Johnston b,2 , Robert O. Williams III a, * a College of Pharmacy, University of Texas at Austin, Austin, TX, USA b Department of Chemical Engineering, University of Texas at Austin, Austin, TX, USA Received 30 October 2002; accepted in revised form 12 December 2002 Abstract The purpose of this paper is to investigate the influence of the emulsion composition of the feed liquid on physicochemical characteristics of drug-loaded powders produced by spray-freezing into liquid (SFL) micronization, and to compare the SFL emulsion process to the SFL solution process. Danazol was formulated with polyvinyl alcohol (MW 22,000), poloxamer 407, and polyvinylpyrrolidone K-15 in a 2:1:1:1 weight ratio (40% active pharmaceutical ingredient (API) potency based on dry weight). Emulsions were formulated in ratios up to 20:1:1:1 (87% API potency based on dry weight). Ethyl acetate/water or dichloromethane/water mixtures were used to produce o/w emulsions for SFL micronization, and a tetrahydrofuran/water mixture was used to formulate the feed solutions. Micronized SFL powders were characterized by X-ray diffraction, surface area, scanning and transmission electron microscopy, contact angle and dissolution. Emulsions containing danazol in the internal oil phase and processed by SFL produced micronized powders containing amorphous drug. The surface area increased as drug and excipient concentrations were increased. Surface areas ranged from 8.9 m 2 /g (SFL powder from solution) to 83.1 m 2 /g (SFL powder from emulsion). Danazol contained in micronized SFL powders from emulsion and solution was 100% dissolved in the dissolution media within 2 min, which was significantly faster than the dissolution of non-SFL processed controls investigated (, 50% in 2 min). Micronized SFL powders produced from emulsion had similar dissolution enhancement compared to those produced from solution, but higher quantities could be SFL processed from emulsions. Potencies of up to 87% yielded powders with rapid wetting and dissolution when utilizing feed emulsions instead of solutions. Large-scale SFL product batches were manufactured using lower solvent quantities and higher drug concentrations via emulsion formulations, thus demonstrating the usefulness of the SFL micronization technology in pharmaceutical development. q 2003 Elsevier Science B.V. All rights reserved. Keywords: Spray-freezing into liquid; Dissolution enhancement; Danazol; Emulsion; Micronization; Particle engineering 1. Introduction Poorly water soluble compounds are common among new chemical entities being investigated for therapeutic activity as active pharmaceutical ingredients (APIs) [1,2]. Oil/water emulsions are frequently used in the pharmaceu- tical industry to enhance the overall concentration of poorly water soluble and insoluble drugs, due to the high solubility of the API in the dispersed oil phase [1–6]. However, emulsion stability is a concern [3,7–14]. Over time, emulsions often coalesce and settle. Additionally, the large volume of the oil and aqueous phases limits the overall drug concentration and yield. To overcome these inherent disadvantages, solvents are often removed from emulsion formulations by lyophilization [4,5]. However, it has been found that freezing emulsions has resulted in phase separation and destabilization of APIs, and that dry emulsions did not produce the same degree of dissolution enhancement as was achieved prior to lyophilization [13]. For oral delivery, it would be desirable to produce dry powders by lyophilization of emulsions that have high dissolution rates. 0939-6411/03/$ - see front matter q 2003 Elsevier Science B.V. All rights reserved. doi:10.1016/S0939-6411(02)00193-5 European Journal of Pharmaceutics and Biopharmaceutics 55 (2003) 161–172 www.elsevier.com/locate/ejpb 1 Present address: The Dow Chemical Company, Midland, MI 48674, USA. 2 Keith P. Johnston is also a corresponding author on this paper. * Corresponding authors. College of Pharmacy (Mailstop A 1920), University of Texas at Austin, Austin, TX 78712-1074, USA. Tel.: þ 1-512-471-4681; fax: þ1-512-471-7474. E-mail address: williro@mail.utexas.edu (R.O. Williams).