Article pubs.acs.org/molecularpharmaceutics
Probing Interfaces between Pharmaceutical Crystals and Polymers by Neutron Reflectometry John D. Yeager,*,† Kyle J. Ramos,† Changquan C. Sun,*,‡ Saurabh Singh,§ Manish Dubey,§,⊥ Jaroslaw Majewski,§ and Daniel E. Hooks† †
Shock and Detonation Physics, Los Alamos National Laboratory, Los Alamos, New Mexico 87545, United States College of Pharmacy, University of Minnesota, Minneapolis, Minnesota 54555, United States § Lujan Neutron Scattering Center, Los Alamos National Laboratory, Los Alamos, New Mexico 87545, United States ‡
S Supporting Information *
ABSTRACT: Pharmaceutical powder engineering often involves forming interfaces between the drug and a suitable polymer. The structure at the interface plays a critical role in the properties and performance of the composite. However, interface structures have not been well understood due to a lack of suitable characterization tool. In this work, we have used ellipsometry and neutron reflectometry to characterize the structure of such interfaces in detail. Ellipsometry provided a quick estimate of the number of layers and their thicknesses, whereas neutron reflectometry provided richer structural information such as density, thickness, roughness, and intermixing of different layers. The combined information allowed us to develop an accurate model about the layered structure and provided information about intermixing of different layer components. Systematic use of these characterization techniques on several model systems suggests that the nature of the polymer had a small effect on the interfacial structure, while the solvent used in polymer coating had a large effect. These results provide useful information on the efforts of engineering particle properties through the control of the interfacial chemistry. KEYWORDS: interface, ellipsometry, neutron reflectometry, acetaminophen, sulfamerazine, cellulose, polyvinylpyrrolidone, binder, films
1. INTRODUCTION Many pharmaceutical powders display poor compaction and flow behavior and consequently cause problems in tablet manufacturing. These problems have been traditionally addressed by wet granulation. Understanding the processing− structure−properties relationship for granulated powders is an active area of research.1 Sometimes, wet granulation leads to improved tableting performance.2 Other times, wet granulated powders show deteriorated tableting performance, a phenomenon known as overgranulation.3 The variable performance of granulated materials is largely a result of a lack of understanding of the structure−performance relationship, despite its widespread implementation in the pharmaceutical industry. As such, poor tabletability of granulated powders remains a serious problem in pharmaceutical manufacturing. Given the scale on which pharmaceutical companies produce medicine, research leading to even small improvement in the production process can have a large impact. Mechanical failure of a tablet has implications ranging from quality control in manufacturing to efficacy or drug release rate.4 Even when the tablet remains stable, the microstructure of such molecular composites can have important effects on drug release rate in vivo.5 In general, strength of a tablet is dictated by the interparticulate bonding strength and total bonding area at the interfaces.6 Accordingly, an effective © 2012 American Chemical Society
approach in overcoming poor tabletability of drugs is engineering particle surfaces by coating them with a layer of highly bonding polymer, which increases both bonding area and bonding strength.7 Suitable pharmaceutical binders are biocompatible natural or synthetic organic polymers, such as starch, cellulose, and their derivatives.8 Another common approach to avoid tabletability problems is to disperse the drug into a compressible binder, which has the additional benefit of potentially controlling drug release rate.9 In either case, chemical interactions between the active pharmaceutical ingredient (API) and the binder can be important, especially when considering solubility and stability.9a,10 A detailed understanding of the structure at the drug− polymer interface for both wet granulation and the particle coating is expected to facilitate the design and optimization of these processes for attaining superior tableting performance. We recently showed the promise of using two spectroscopic techniques, ellipsometry and neutron reflectometry, to characterize the structure at the interface of an acetaminophen−poly(ester urethane) (Estane 5703) molecular compoReceived: Revised: Accepted: Published: 1953
December 16, 2011 May 5, 2012 June 4, 2012 June 4, 2012 dx.doi.org/10.1021/mp2006517 | Mol. Pharmaceutics 2012, 9, 1953−1961
Molecular Pharmaceutics
Article
Table 1. Structures and Molecular Weights of the Model Materials Chosen for the Study
orientation. These API films are then coated with an appropriate polymer, again by dip-coating, using concentrated polymer solutions. This last coating step simulates wet agglomeration by creating a three component system (API film, polymer, and solvent) for a brief amount of time. Subsequently the solvent evaporates to form a two-component product (polymer-bound API). The time scale for the solvent evaporation from the binder (seconds to minutes) is similar to the duration of solvent interaction in many wet agglomeration processes,15 so any kinetic mechanisms for binder−API interface formation should be approximated in our samples. We found that the choice of binder has some influence on interfacial crystal−polymer intermixing but that the solvent used in the formulation process is critical. These results show that judicious choice of the binder and solvent during formulation can be used to engineer the interface, offering the ability to control particle properties which affect mechanical stability and drug delivery.
site which had application to plastic-bonded explosives.11 Here, we have successfully applied our previous methodology to study the interfaces of pharmaceutically relevant model systems created by a simulated wet agglomeration technique. Ellipsometry has often been used to study chemistry and microstructure of thin films, while the ability of neutron reflectometry (NR) to detect isotopic differences (especially for the light elements) makes it more applicable to study organic films than X-rays or other spectroscopic or diffractive techniques. Neutrons are scattered from nuclei, and therefore, their scattering intensity is a function of the nuclear constituents. This makes neutrons sensitive to different isotopes of the same element. For example, neutrons scatter weakly from water but strongly from heavy water (D2O). Since neutrons are weakly scattered by nuclei, they can penetrate through layered structures to probe buried interfaces.12 NR has been used to study the interfaces and intermixing of polymeric systems with high spatial resolution (
