Article pubs.acs.org/molecularpharmaceutics
Spatial Distribution of Trehalose Dihydrate Crystallization in Tablets by X‑ray Diffractometry Naveen K. Thakral,†,‡ Hiroyuki Yamada,§ Gregory A. Stephenson,† and Raj Suryanarayanan*,‡ †
Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana 46285, United States Department of Pharmaceutics, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota 55455, United States § Mitsubishi Tanabe Pharma Co., 3-16-89 Kashima, Yodogawa-ku, Osaka 532-8505, Japan ‡
S Supporting Information *
ABSTRACT: Crystallization of trehalose dihydrate (C12H22O11·2H2O) was induced by storing tablets of amorphous anhydrous trehalose (C12H22O11) at 65% RH (RT). Our goal was to evaluate the advantages and limitations of two approaches of profiling spatial distribution of drug crystallization in tablets. The extent of crystallization, as a function of depth, was determined in tablets stored for different time-periods. The first approach was glancing angle X-ray diffractometry, where the penetration depth of X-rays was modulated by the incident angle. Based on the mass attenuation coefficient of the matrix, the depth of X-ray penetration was calculated as a function of incident angle, which in turn enabled us to “calculate” the extent of crystallization to different depths. In the second approach, the tablets were split into halves and the split surfaces were analyzed directly. Starting from the tablet surface and moving toward the midplane, XRD patterns were collected in 36 “regions”, in increments of 0.05 mm. The results obtained by the two approaches were, in general, in good agreement. Additionally, the results obtained were validated by determining the “average” crystallization in the entire tablet by using synchrotron radiation in the transmission mode. The glancing angle method could detect crystallization up to ∼650 μm and had a “surface bias”. Being a nondestructive technique, this method will permit repeated analyses of the same tablet at different time points, for example, during a stability study. However, split tablet analyses, while a “destructive” technique, provided comprehensive and unbiased depth profiling information. KEYWORDS: amorphous, crystallization, X-ray powder diffractometry, tablet, physical characterization
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INTRODUCTION
X-ray diffractometry (XRD) is ideally suited to not only detect but also quantify physical transformations in complex, multicomponent solid matrices.3,4 The conventional practice is to powder the tablet before subjecting it to XRD. As a result of this sample processing step, XRD provides only “average” sample information and does not reveal spatial heterogeneity in phase composition. However, if an intact tablet is subjected to XRD, the technique will have a pronounced surface bias. For a given incident angle, the depth of X-ray penetration will be dictated by the mass attenuation coefficient of the tablet constituents. In order to get mechanistic insight into drug crystallization, information with spatial resolution is highly desirable. For a given tablet formulation composition, the incident angle of the X-rays (with the tablet surface) will dictate the depth of penetration. Thus, by modulating the incident angle, it is possible to characterize different regions (depths) from the
In solid dosage forms (such as tablets and capsules), the use of the stable crystalline form of the active pharmaceutical ingredient (API) is desirable from stability considerations. However, a large fraction of drugs under development have very poor aqueous solubility and absorption of these drugs following oral administration is expected to be dissolution rate limited. By transforming the crystalline drugs into their amorphous counterparts, there is potential to enhance aqueous solubility.1,2 However, the physical instability of amorphous compounds, and their propensity to undergo amorphous → crystalline transition poses a major challenge. Crystallization can occur not only during processing (i.e., manufacture of the dosage form) but also during the storage of the finished product. With such a transition, the potential solubility advantage of the amorphous form can be lost. It is important to recognize that solution based analytical techniques, designed to ensure chemical stability, will not reveal these physical transformations. Such physical transformations in drug products can be characterized by directly analyzing the dosage form. © XXXX American Chemical Society
Received: July 17, 2015 Revised: August 24, 2015 Accepted: September 2, 2015
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DOI: 10.1021/acs.molpharmaceut.5b00567 Mol. Pharmaceutics XXXX, XXX, XXX−XXX
Article
Molecular Pharmaceutics tablet surface (glancing angle X-ray diffractometry).5−7 A microdiffractometer fitted with a two-dimensional area detector is well suited for this purpose.8,9 Data collection time with this setup is usually several orders of magnitude shorter than with conventional instruments. Second, since a substantial part of the diffraction ring is collected, errors due to preferred orientation can be significantly reduced. A method to calculate the depth of penetration of X-rays as a function of incident angle, for pharmaceutical materials, has been proposed in the literature.10 Using this technique, the physical form of the analyte of interest at different depths can be directly analyzed, but the limitation of glancing angle XRD is that it provides information predominantly from the surface regions of tablets, owing to limited depth of penetration of X-rays. For collecting spatial information, tablets may be split to analyze the surface to core. Starting from the tablet surface and moving toward the midplane/core, XRD patterns can be collected in increments of as low as 0.05 mm.11,12 The spatial information gained by monitoring the tablet from the surface to the core (depth profiling), revealed progression of phase transformations from the surface to the tablet core as a function of storage time. Our ultimate goal for the present study was to compare the advantages and limitations of the two approaches of XRD, as mentioned above, in profiling the spatial information on drug crystallization in tablets. The results obtained from these two approaches were validated using high intensity synchrotron Xray diffractometry. Trehalose, a nonreducing disaccharide used as an excipient in freeze-dried formulations, was selected as the model compound. In addition to amorphous trehalose, several anhydrous polymorphs of trehalose and trehalose dihydrate (C12H22O11·2H2O) have been reported in the literature.13,14 Amorphous trehalose has a high glass transition temperature (∼117 °C), and a low tendency to crystallize at room temperature under modest relative humidity (
