REVIEW Dynamic Vapor Sorption as a Tool for Characterization and Quantification of Amorphous Content in Predominantly Crystalline Materials SNEHA SHEOKAND, SAMEER R. MODI, ARVIND K. BANSAL Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), SAS Nagar, Punjab 160062, India Received 14 May 2014; revised 14 August 2014; accepted 18 August 2014 Published online 11 September 2014 in Wiley Online Library (wileyonlinelibrary.com). DOI 10.1002/jps.24160 ABSTRACT: It is well established that pharmaceutical processing can cause disruption of the crystal structure, leading to generation of amorphous content in crystalline materials. The presence of even a small amount of amorphous form, especially on the surface of crystalline material, can affect processing, performance, and stability of a drug product. This necessitates the need to quantify, monitor, and control the amorphous form. Numerous analytical techniques have been reported for the quantification of amorphous phase, but issues of sensitivity, suitability, limit of detection, and quantitation pose significant challenges. The present review focuses on use of dynamic vapor sorption (DVS) for quantification of amorphous content in predominantly crystalline materials. The article discusses (1) theoretical and experimental considerations important for developing a quantification method, (2) methods used for quantification of amorphous content, (3) basis for selecting a suitable methodology depending on the properties of a material, and (4) role of various instrument and sample-related parameters in designing a protocol for quantification of amorphous content. Finally, DVS-based hyphenated techniques have been discussed as they can offer higher sensitivity for quantification of amorphous content. C  2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 103:3364–3376, 2014 Keywords: amorphous; dynamic vapor sorption (DVS); crystallinity; moisture sorption; absorption; desorption; glass transition; solid state; quantification methods INTRODUCTION Active pharmaceutical ingredients (APIs) and pharmaceutical excipients in a solid oral dosage form may exist in different solid forms. These solid forms can differ widely in their physic- ochemical, mechanical, and biopharmaceutical properties and thus influence the processability and performance of a drug product. 1–3 API solid form has the most profound influence on overall drug product behavior. Hence, in-depth physical char- acterization of the solid-state properties of a drug substance is necessary for successful dosage form development. This need is further underlined by the existence of stringent regulatory standards and intellectual property-related implications. 4,5 Generally, crystalline state of a compound is characterized by regular and well-defined molecular arrangement in the crys- tal lattice. In comparison, amorphous materials lack long-range order and possess excess thermodynamic properties such as en- thalpy, entropy, and free energy. 6 Amorphous form is thermo- dynamically unstable and is prone to transformation to stable crystalline form during processing and/or storage. 6–8 However, amorphous materials have attracted attention as they offer benefits of improved solubility or dissolution rate and better compressibility as compared with its crystalline counterpart. 9 Active pharmaceutical ingredients may be intentionally con- verted to amorphous state or may be rendered amorphous during processing. 8,10 Unit processes such as size reduction, lyophilization, spray drying, granulation, and compression are known to introduce varying degrees of mechanical or thermal Correspondence to: Arvind K. Bansal (Telephone: +91-172-2214682-2126; Fax: +91-172-2214692; E-mail: akbansal@niper.ac.in) Journal of Pharmaceutical Sciences, Vol. 103, 3364–3376 (2014) C  2014 Wiley Periodicals, Inc. and the American Pharmacists Association stress in the crystal lattice. 11 This may lead to generation of small proportion of amorphous form. This amorphous content is a minor component of the overall bulk and resides mainly on the surface of the particles. 8,12 Hence, it can have significant impact on interfacial phenomenon such as hygroscopicity, wet- tability, dissolution, flow behavior, and compaction. The amount of amorphous content generated during processing is often un- predictable. This small amount of amorphous material acts as “reactive spots” on the surface of a crystalline material and can introduce many formulation performance, processing, and storage challenges. 9,13–32 Therefore, it is critical to characterize even a small amount of amorphous content in a predominantly crystalline material. Various analytical techniques are available to quantify moderate-to-high levels of amorphous material in powders (Table 1). Some of these techniques include differen- tial scanning calorimetry (DSC), modulated DSC, 33–35 pow- der X-ray diffraction (PXRD), 1,11 Fourier transform Raman spectroscopy, 36 near-infrared spectroscopy (NIRS), 37,38 and in- verse gas chromatography (IGC). 25,39 However, these bulk an- alytical techniques measure the properties of the sample as a whole and thus the amorphous content becomes a small part of the total signal. 33 Hence, the detection limits for amor- phous content with such techniques will generally have a lower cut off of 5%–10%. 35 Very few techniques such as isothermal microcalorimetry (IMC), 40,41 solution calorimetry (SC), 42 solid- state nuclear magnetic resonance (ssNMR), 43 and dynamic va- por sorption (DVS) 44 are capable of quantifying very low levels of amorphous content. Selection of experimental conditions and the mathematical treatment of the data made the use of tech- niques, such as IMC, SC, and ssNMR, more complex. Further, it may be more appropriate to preferentially investigate the 3364 Sheokand, Modi, and Bansal, JOURNAL OF PHARMACEUTICAL SCIENCES 103:3364–3376, 2014