Pharmaceutical Nanotechnology Solid-State NMR Characterization of High-Loading Solid Solutions of API and Excipients Formed by Electrospinning BLAIR BRETTMANN, ERIN BELL, ALLAN MYERSON, BERNHARDT TROUT Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts Received 23 September 2011; revised 11 November 2011; accepted 8 December 2011 Published online 27 December 2011 in Wiley Online Library (wileyonlinelibrary.com). DOI 10.1002/jps.23032 ABSTRACT: A major focus area in improving pharmaceutical manufacturing is decreasing powder-handling steps such as milling, granulation, and blending. One approach to go directly from active pharmaceutical ingredients (API) and excipients in solution to a formulated drug product is to use electrospinning to make solid formulations of API in a polymer. Because of the rapid evaporation rate in electrospinning, the process usually results in a well-mixed solid dispersion of drugs in the polymer. In this study, solid-state nuclear magnetic resonance is used to examine phase separation in formulations of aliskiren (SPP) and indomethacin (IND) with polyvinylpyrrolidone (PVP) prepared by electrospinning and hot-melt extrusion. It was found that 1:1 SPP–PVP, 1:1 IND–PVP, and 4:1 SPP–PVP formulations prepared by electrospinning are homogeneous solid solutions down to a 2–11 nm length scale, whereas a 4:1 SPP–PVP formulation prepared by hot-melt extrusion exhibits phase separation with domain sizes of 20–100 nm or larger. © 2011 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 101:1538–1545, 2012 Keywords: solid-state NMR; formulation; amorphous; solid solutions; relaxation time; solid dosage form; electrospinning; extrusion INTRODUCTION The process of going from raw ingredients to a for- mulated drug product is long, complicated, and ex- pensive. One area that is particularly costly is the lengthy route from purified active pharmaceutical in- gredients (API) to the final product, as this section often includes time-consuming drying, blending, and granulation steps. A recently reported method of co- processing API and polymer directly from a solution is to utilize the technique of electrospinning. 1–11 Electrospinning has been used for various appli- cations since 1903, when Morton first patented the process. 12 In electrospinning, a charged solution con- taining a polymer, solvent, and other desired com- pounds is pumped through a needle, producing a drop at the tip. When the electrostatic forces are in equi- librium with the surface tension, the drop takes on a conical form, the Taylor cone, and when the elec- trostatic forces overcome the surface tension, a fiber Additional Supporting Information may be found in the online version of this article. Supporting Information Correspondence to: Bernhardt Trout (Telephone: +617-258- 5021; Fax: +617-258-5042; E-mail: trout@mit.edu) Journal of Pharmaceutical Sciences, Vol. 101, 1538–1545 (2012) © 2011 Wiley Periodicals, Inc. and the American Pharmacists Association extends from the cone. This fiber thins and dries as it advances to the grounded plate. 13 The process has attracted attention because it has the ability to pro- duce very thin (less than 1 : m diameter) fibers from a polymer solution and can be scaled up to reason- able production rates using a multijet-free-surface approach. 14 In addition, because of the large sur- face area generated on thinning, the evaporation rate of the solvent is very high and drying is very fast. Many studies have shown that electrospinning a so- lution containing API, polymer, and solvent results in 200-nm- to 2-: m-sized fibers that contain drug dis- persed within the polymer. 1–11 Because of the rapid evaporation rate, the drug is often present in the fibers in the amorphous form. 4–6,8,9 This is an exciting result for researchers studying poorly water-soluble drugs, as high surface area and amorphous API both aid in increasing solu- bility. One issue, however, with using amorphous drug in a final solid dosage form is that the amorphous form of an API is in a nonequilibrium state and gener- ally has a higher internal energy than the crystalline state of the same material. This leads to the amor- phous form having a higher solubility than the crys- talline form, but also leads to the amorphous form crystallizing over time. 15 One factor that strongly 1538 JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 101, NO. 4, APRIL 2012