Bruno C. Hancock is a scientist in the solids development group at Pfizer.

Bruno C. Hancock

The particle-size distribution of a pharmaceutical granulation is an important physical characteristic that influences several aspects of a drug (e.g., mechanical properties, content uniformity, compression characteristics, and dissolution performance). Therefore, it is important to control the particle size of the final granulation to ensure drug-product manufacturability and quality. Various mill types currently are available for the size reduction of dry- and wet-granulated pharmaceutical products. To evaluate these milling technologies and their influence on dry-granulated (roller-compacted) formulations, four different mill types were selected for comparison. 

Conventional milling is a mechanical process that passes material through a screen or plate to reduce its size into a uniform particle-size distribution. It has been proposed that mill type directly influences particle-size distribution and, consequently, the quality of the final product. However, other variables also influence the milling process. Engineering design differences such as screen size and thickness, impeller and rotor style, and mill-chamber size and shape all affect material-size reduction. Formulations' physical properties determine how well materials maintain their bonds or shear under stress. Operational variation such as impeller and rotor speed and material feed rate may also influence the final particle size. 

The ideal pharmaceutical granulation process should provide short residence time in the mill chamber and pass granules quickly through the mill screen while maintaining the integrity of the granule. The strength of the material being milled has an effect on the final granulation particle-size distribution. Hard granules may increase residence time within the milling chamber and produce an excess of large granules in combination with smaller fine particles, thus creating a bimodal particle-size distribution. Minimizing fines in the final granulation enhances the flow properties of the final granulation and improves weight variation during tableting. An ideal particle-size distribution should minimize the level of granules >840 μm (retained on a 20-mesh sieve) and the level of particles <74 μm (passing through a 200-mesh sieve). Most modern mills have variable-speed drives, and are considered low-energy mills when operated at low speeds (i.e., <1000 rpm). Such mills produce granulation within this desired particle-size range and are commonly used within the pharmaceutical industry for granulation-size reduction. 

In this experiment, two immediate-release (IR) dry-granulation placebo formulations were selected to evaluate mill performance. Roller-compaction conditions were established using a roller compactor (Mini-Pactor, Gerteis Maschinen + Processengineering, Jona, Switzerland) to produce ribbon at a target solid fraction of 0.7. Ribbon was manufactured from both formulations and characterized for solid fraction, tensile strength, and thickness. Roller-compaction bypass was measured to establish the fines level within the compacted ribbon before milling. Three well established conventional milling options and one unconventional milling operation were compared head-to-head, and the resulting granulation was evaluated for particle-size distribution, flowability, tabletability, and compactibility. 

 Three established attrition mill types, an oscillating granulator (integrated with the Gerteis roller compactor), a conical mill (Comil model 197, Quadro Engineering, Waterloo, ON, Canada), and a hammer mill (FitzMill model M5A, Fitzpatrick, Elmhurst, IL), were selected to compare size-reduction performance. In addition, the authors  selected a less conventional nonattrition roller mill (Gran-U-Lizer, Modern Process Equipment [MPE], Chicago) to  be evaluated. 

Oscillating granulator (mill integrated with roller compactor).

 The principle of an oscillating granulator is to mechanically pass compacted material through a wire mesh screen or plate using an oscillating rotor. The rotor speed and rotation time are variable in the clockwise or counterclockwise directions. Particle size is controlled through mill-screen size, rotor speed, and the rotor's rotation angle (1). 

 The conical mill is an attrition-type mill and performs size reduction using a rotating wedge-shaped impeller inside a conical screen. Particle size can be changed using interchangeable screens and impeller styles. The impeller selected for this study was a high-throughput, round, leading-edge impeller, and particle-size reduction was controlled with screen size and impeller speed (1).  

 Comminutor hammer mills are also considered attrition-style mills and reduce the particle size with several rotating hammers or knives or a rotor bar. The blade type, speed, and screen size are the important variables that influence the milling process (1). The rotor bar was used for this study, and particle size was controlled by screen size and rotor speed.  

 The Gran-U-Lizer is a nonattrition size-reduction mill. It uses roller-mill technology that contols particle-size reduction through roll-surface texture (i.e., roll type), roll speed, and roll gap. According to MPE, the Gran-U-Lizer operates through the use of shear, in contrast to impact used by conventional size-reduction equipment. The Gran-U-Lizer achieves a narrower particle-size distribution with fewer fines by eliminating the attrition inherent in other milling designs. The laboratory model Gran-U-Lizer requires several passes through the rolls using various roll types, roll speeds, and roll gaps to achieve the desired particle-size distribution. All milling trials using the Gran-U-Lizer roller mill were conducted at MPE's Chicago site. 

Table I: Microcrystalline celluloseâdibasic calcium phosphate (2:1) placebo formulation. 

Two IR, dry-granulation placebo formulations (see Tables I and II) were selected to evaluate mill performance. Roller-compaction conditions were established using the Gerteis Mini-Pactor roller compactor to produce ribbon at a target solid fraction of 0.7 at an approximate thickness of 2.5 mm. Ribbon was manufactured from both formulations and characterized for solid fraction, tensile strength, and thickness. Roller-compaction bypass was measured to establish the fines level within the compacted ribbon before milling. 

Table II: Microcrystalline celluloseâlactose (2:1) placebo formulation. 

 Ribbon samples were prepared by cutting the compacted ribbon into rectangular shapes of approximately 10 x 22 mm using a jeweler's table saw. Figure 1 demonstrates how the ribbon sample was prepared. The cut ribbon sample was measured using calipers to determine the envelope density. 

Figure 1: Measurements of ribbon dimensions. (AUTHORS) 

The solid fraction of each ribbon sample was determined according to a relationship that can be expressed by the following equation: 

 is the volume of the roller serrations, and ρ

 The ribbon's tensile strength was determined using a three-point beam-bending tester (CT-5, Holland Instruments, Nottingham, UK). Each ribbon sample was placed onto the two beams, separated by a known distance 

 was applied in the middle of the sample until the sample failed. Figure 2 demonstrates this test. 

Figure 2: Three-point beam bending test arrangement. (AUTHORS) 

The tensile strength of the compact can be determined from the following relationship: 

 is the distance between beams 2 and 3, and 

Dry granulation by means of roller compaction.

 Ribbon from each formulation was roller compacted to an equivalent target solid fraction, tensile strength, and thickness using the Gerteis Mini-Pactor. The ribbon was collected in approximately 1.0-kg portions throughout each compaction run to ensure that the level of bypass remained consistent for each milling trial. It was important to the integrity of this study that the ribbon not be collected in one large portion and that ribbon not be subdivided from one main ribbon supply because this could potentially cause segregation of bypass (fines) during ribbon storage and produce inconsistent milling results. Also, it was equally important that the bags of ribbon be numbered sequentially to easily identify at what time in the roller compaction process a particular bag was compacted. The ribbon's physical properties were characterized from each 1.0-kg portion collected to determine the consistency of the ribbon produced. Figure 3 illustrates the experimental plan used to produce ribbon for milling. 

Figure 3: Roller-compaction experimental plan. (AUTHORS) 

 The milling conditions selected for the Gerteis and M5A mill were based on previously established milling parameters used for the size reduction of roller-compacted ribbon. The 0.8-mm screen size selected for both mill types produces satisfactory granules for conventional IR tablet formulations consistently. The Comil speed was calculated to achieve a tip-speed equivalent to that of the M5A mill equipped with a rotor bar. The larger mill screen size used for the Comil was based solely on availability. The G040 (~1.0-mm) screen was the smallest rasping-style screen size available at that time from Quadro for the 197 Comil. The differences in screen size between the Gerteis OG, M5A, and Comil are considered to have minimal effect on the final particle-size distribution, given the considerable difference in mill designs. The Gran-U-Lizer milling conditions (e.g., number of passes through the rolls, roller type, roller speed, and roller-speed ratio) were determined during a series of milling trials conducted by MPE's engineering staff. Figure 4 illustrates the milling conditions used for each milling operation. 

Figure 4: Milling and tableting experimental plan. (AUTHORS) 

Tableting was performed using a rotary tablet press (T-100, Kilian) at a press speed of 60,000 tablets/h to produce a dwell time of ~11 ms, which approaches a production-press speed dwell time of <10 ms. A precompression force of approximately 1 kN was used for all compression runs. The tooling size was selected based on the target tablet weight of 225 mg (5/16-in. standard round concave tooling typically accommodates a fill weight of 200–250 mg). A compression profile was generated for each granulation up to approximately 80% (30 kN) of the maximum allowable force (37 kN) for the tooling size. 

 Ribbon solid fraction is considered to be the physical attribute with the greatest influence on the physical properties of a dry granulation. The typical compacted ribbon solid fraction range for a conventional IR tablet formulation is 0.6–0.8 (2, 3). Therefore, a target solid fraction of 0.7 was selected to evaluate mill performance. Solid fraction, or relative density, is the measure of the ribbon's apparent density (sample volume in cubic centimeters divided by its mass in grams) divided by the material's true (i.e., absolute) density. 

Previous experience with the Gerteis roller compactor influenced the process parameters selected for ribbon compaction except the roll type and roll force. A ribbon thickness >1.0 mm was unobtainable for the microcrystalline cellulose (MCC)–dibasic calcium phosphate (DCP) formulation using smooth rolls. However, the target ribbon thickness of 2.5 mm was obtainable when serrated rolls were used. Therefore, serrated rolls were used to compact both formulations. 

A series of compaction trials were performed for both formulations to determine the roll force required to achieve the target ribbon solid fraction. A roll force of 8 kN/cm

  was selected as the best roll force for the MCC–DCP formulation, and a roll force of 6 kN/cm

  was selected for the MCC–lactose formulation. Although two different roll forces were used, both formulations were compacted using a roll gap of 2.5 mm, a roll speed of 2.0 rpm, and a feed ratio of 250 to produce ribbon at the target solid fraction of 0.7. 

 Three ribbon samples were collected from each formulation and characterized for solid fraction, tensile strength, and thickness for each ribbon portion collected (~1.0 kg) during the compaction run. A total of 11 sample points were collected for the MCC–DCP formulation, and 13 sample points were collected for the MCC–lactose formulation, corresponding to process times of 84 min and 113 min, respectively. Table III lists the ribbon bag number and corresponding measured solid fraction, tensile strength, and thickness values for each 1.0-kg portion collected. 

 Because the level of bypass generated during the compaction process influences the fines level in the milled granulation, it was relevant to measure the bypass level before ribbon milling. 

 is defined as uncompacted primary particles of active pharmaceutical ingredient or excipients that migrate around the rolls without being subjected to any compaction force. 

The dry-granulation bypass level was measured by removing the bulk of the ribbon from the compacted material by hand and sieving the remaining material through a 100-mesh (150-μm) sieve. The material that passed through the 100-mesh sieve is mainly uncompacted primary particles and is considered bypass. Using this method, the amount of bypass measured for the MCC–DCP formulation was 2.4% (ribbon bag #10). The amount of bypass measured for for the MCC–lactose formulation was 2.1% (ribbon bag #10). 

 Both formulations were milled using the 1.0-kg bags of ribbon collected during the roller-compaction process. Because individual bags of ribbon were used and the bypass level was well controlled, it can be assumed that any difference in the postmilling fines level was generated by the milling process and not a result of segregation during handling of the ribbon. Also, because the ribbon sample bags were numbered during roller compaction, the results of each milling trial can be directly compared with ribbon solid fraction, tensile strength, and thickness values. One milling for each formulation was performed using each of the mill types. 

Table IV: Microcrystalline celluloseâdibasic calcium phosphate granulation particle-size (Î¼m) and flow properties. 

One major difference between the conventional mill types and the Gran-U-Lizer was the number of passes necessary to achieve the desired particle-size distribution. The conventional mill type required only one pass to achieve the desired reduction in particle size. The Gran-U-Lizer required several passes using different roller styles, roller speeds, and roller gaps. According to MPE, multiple passes produce a gradual reduction in particle size and thus a low level of fines. 

Table V: Microcrystalline celluloseâlactose granulation particle size (Î¼m) and flow properties. 

 Tables IV and V show the results of laser-diffraction particle-size analysis using a disperser (HELOS/RODOS, Sympatec, Clausthal-Zellerfeld, Germany). The particle-size distributions show that the Gran-U-Lizer produced the largest particle size of all the mills tested. However, all the milled formulations had similar distributions, as demonstrated in Figures 5 and 6. In addition, the distributions for both formulations were broad, regardless of the mill type used. 

Figure 5: Microcrystalline celluloseâdibasic calcium phosphate placebo particle-size distribution. (AUTHORS) 

 The MCC–DCP formulation exhibits excellent flowability across all mill types, while the MCC–lactose formulation exhibits lower (good) flowability, with the exception of the Gran-U-Lizer, which demonstrated excellent flow based on a flow function coefficient value of 10.1 (4). However, the larger particle size of the Gran-U-Lizer granulations did not substantially improve the flowability of either formulation. 

Figure 6: Microcrystalline celluloseâlactose placebo particle-size distribution. (AUTHORS) 

 Tablets were compressed and characterized for weight, thickness, and hardness. The mean weight values and corresponding relative standard deviations (RSDs) are listed in Table VI. Weight variation was below the desired RSD of 2.0% for all the conventional mill types. The two Gran-U-Lizer runs had slightly higher RSDs, but they were still below the 6.0% RSD allowed by US Pharmacopeia criteria. 

Table VI: Microcrystalline celluloseâdibasic calcium phosphate compression properties. 

Articles

The authors evaluate the effect of various mill types on particle-size distribution, flowability, tabletability, and compactibility.

The Effect of Mill Type on Two Dry-Granulated Placebo Formulations

X-ray microtomography has great potential for improving the understanding of the structural features of solid dosage forms and the changes in those features during manufacturing, handling, and storage.This article describes the basic principles of the technique and provides examples of its potential applications.

X-ray Microtomography of Solid Dosage Forms

Pharmaceutical scientists have long sought the ability to see inside the solid dosage forms they produce to determine their products' structural features and to better understand their mode of action. Previous studies have used various techniques for visualizing the internal structure of solid dosage forms, including 

H NMR imaging (1), confocal microscopy (2), and conventional microscopy (optical and electron) combined with mechanical slicing of samples (

 microtoming) (3). One drawback of several current techniques is their invasive nature that can destroy the sample and prevent any further testing. Another is the techniques' limited penetration and resolution. Thus, it is probably fair to say that the ideal experimental approach for the three-dimensional structural imaging of pharmaceutical dosage forms has not yet been realized.   

X-ray microtomography is a relatively new approach to imaging the internal structure of solid dosage forms. This technique has been widely used for the 

 imaging of plants, insects, animals, and humans. X-ray microtomography is a nondestructive technique that has a high penetration ability and provides a reasonable level of resolution (~5–20 μm).  

 Figure 1: Schematic of X-ray microtomography instrument (I0 = incident beam, ItMay In the Field section5 = transmitted beam).			

The X-ray microtomography approach used in this work is an extension of the computer aided tomography (CAT) medical imaging technique commonly used in hospitals. X-rays are directed from a high-power source toward a sample, and a detector on the opposite side of the sample measures the intensity of the transmitted X-rays (see Figure 1). A two-dimensional "shadow" image is produced by accurately rastering the X-ray beam across the sample. The sample then is carefully moved (usually rotated) relative to the X-ray beam, and the process is repeated to produce additional two-dimensional images from various view points. Using a sophisticated Fourier transform algorithm, the two-dimensional images then are combined to generate a complete three-dimensional map of the sample.  

 Figure 2: Conventional bilayer tablet structure.						

The intensity of the X-rays reaching the detector is controlled by the sample path length and the X-ray attenuation coefficient of the material that it encounters on that path (4). The longer the path length and the greater the attenuation coefficient of the material (see http://

physics.nist.gov/PhysRefData/XrayMassCoef/tab3.html

 ), the greater the number of diffraction and scattering events, thereby weakening the X-ray beam that reaches the detector. The varying levels of signal intensity provide a gray-scale in the images from which information about the density, thickness, and attenuation properties of the sample can be obtained. Very dense or thick regions and areas that contain heavy elements (

 sodium, chlorine, or iron) will generally create the most contrast in the final images. In very simple terms, X-ray microtomography can be thought of as creating a three-dimensional map of the relative atomic density of the sample under evaluation. 

Figure 3: Cross section of a fast-dissolving tablet manufactured by lyophilization.			

The instrument used in this work was a Skyscan 1072 device (Skyscan, Aartselaar, Belgium) with a 100-kV, 98-mA X-ray source. It was operated in cone-beam mode with 0.90°-step random rotation of the sample between scans and a 180° total sample rotation. Corrections were made for imperfections in the detector output and for obvious beam-hardening effects. The vertical two-dimensional raw data image files (1024 × 1024 pixels) were "reconstructed" using the Skycan proprietary software to create a series of several hundred horizontal cross-sectional views of the samples. These images could be processed further to create complete three-dimensional structural maps of the samples. Gray-scale images also could be manipulated using standard image analysis techniques to produce binary or multiple-colored images and to obtain dimensional information about the sample. The maximum sample size that the instrument can accommodate is ~19 × 19 × 19 mm because of the size of the sample chamber and the effective focal length of the X-ray system. This size is adequate for most solid dosage forms. Because the detector creates raw data files of 1024 × 1024 pixels, the image resolution can be no better than about one-thousandth of the image field of view. For example, in a 15 × 15 mm field of view, each pixel will be ~15 × 15-μm. As the field of view is reduced below ~5 × 5 mm, the resolution of the instrument becomes limited by the effective width of the incident X-ray beam. The instrument manufacturer quotes a maximum resolution of ~5 μm. In this study, typical data acquisition times for solid dosage forms were 30–90 min., and data analysis usually took 1–3 h per sample, depending upon the level of detail required. 

Figure 4: Gel-coated analgesic tablet structure.			

Two- and three-dimensional images of a wide range of solid dosage forms were acquired in this study and used to learn more about their function and structure. The following provides several examples of how such information can be used to aid in the design and testing of pharmaceutical tablets and in solving related technical problems. 

Figure 5: Osmotic tablet structure in the region near the hole in the coating.						

 X-ray microtomography can provide simple information such as the shape and size of the regions of a dosage form that are not readily accessible. For example, the technique is ideally suited for determining the thickness of layers in multilayer tablets and for determining the shape and size of the interface between these layers (see Figure 2). It also can be used to elucidate the microstructure of fast-dissolving tablets such as those manufactured using lyophilization in which the structural features reflect the size and shape of the ice crystals that were present in the tablet before drying (see Figure 3). Reports in the literature also point to the utility of this technique for assessing the morphology and pore-size distribution of pharmaceutical granules (5, 6). Farber 

 concluded that it was especially useful for studying the connectivity and shape of voids within granules made using wet granulation (5). 

Figure 6: Cross section of a liquid-filled soft-gelatin capsule.			

 X-ray microtomography can be used to measure the thickness of a functional coating (see Figure 4) and to assess variations in the film-coating thickness at the corners of the tablet to ensure the integrity of the coating is maintained over the entire surface of the dosage form. For an osmotic controlled-release dosage form it is quite simple to determine the key dimensions (

 location, diameter, and depth) of the hole in the coating from which the active ingredient will be expelled (see Figure 5) (3). Likewise, in a liquid-filled soft-gelatin capsule the thickness and integrity of the capsule's solid shell and its welded seam can be readily determined (see Figure 6). 

Figure 7: Embossing on the surface of an immediate-release uncoated tablet.			

 Embossed markings on a tablet's surface are quite easily resolved and measured using X-ray microtomography (see Figure 7). This capability could be used to help troubleshoot tablet manufacturing problems such as sticking or picking. Defects in or damage to the internal structure of a compacted tablet also can be detected. Researchers have used X-ray microtomography to study small defects and hidden damage in a range of nonpharmaceutical materials, including metals and composites (7, 8). Figure 8 shows a region of an immediate-release tablet with an internal crack that might significantly influence its structural integrity. Although it is not currently possible to enable 100% inspection of all dosage forms from a large-scale batch, this may be feasible in the future as the instrumentation's speed increases and accuracy improves. 

 If the material of interest generates sufficient X-ray contrast, then it is feasible to determine the distribution of an active ingredient or functional excipient in a tablet or capsule using X-ray microtomography. This may provide vital information about the performance of a novel manufacturing process, or, in the future, may enable at-line process monitoring to occur. The distribution of particles (citric acid) in a fast-dissolve tablet is shown in Figure 9, and the distribution of an inorganic excipient incorporated into an osmotic controlled-release tablet is shown in Figure 10. This approach can provide complementary information to spectroscopic chemical images (9). With the rigorous use of three-dimensional image analysis tools, quantitative information about the uniformity of pharmaceutical samples can be obtained. 

Figure 9: Distribution of particles in a fast-dissolving anti-allergy tablet.			

The intensity of the gray scale that appears in the X-ray images is partly a function of the sample's density. The density of standard uni-axially compressed tablets is not uniform (1, 10), and X-ray microtomography may provide a means to study and quantify this density inhomogeneity in tablets. Density differences have been detected in immediate-release tablets (see Figure 11). By using standards of known density, researchers interested in the density of bone samples quantitatively computed this information directly from X-ray microtomography data (11). A similar approach with other materials also has been successful (12, 13). Quantitative studies of this type have been reported for pharmaceutical compacts. One study showed that the tablet shape and the presence of embossing resulted in nonuniformity in the density of compacts made from microcrystalline cellulose (14). In addition, researchers showed that die lubrication and the mode of compression each influenced the degree of this nonuniformity. In another study, X-ray microtomography of several compacted excipients showed how density variations in various regions of a compact control the mechanical response of the sample during tensile failure and indentation hardness tests (15). Researchers also demonstrated in this work that the degree of structural and mechanical anisotropy in a compact is significantly less for highly deformable (plastic) materials.  

Figure 10: Distribution of particles in a controlled- release osmotic tablet.						

A unique application of X-ray microtomography is the detection and location of foreign matter such as a metal particle within a solid dosage form. Such atypical substances show up very clearly as being different from the materials commonly used to manufacture pharmaceutical tablets. A metal particle within a tablet creates a hot spot in the tomographic image that shows it is unmistakably foreign (see Figure 12). This information enables the location of the particle to be exactly pin-pointed even though it is entirely contained within the dosage form and its size is quite small (~50 μm width in this example). 

Figure 11: Density variations in an immediate- release antacid tablet.						

Counterfeit tablets can be difficult to distinguish from authentic dosage forms on the basis of external appearances. By using X-ray microtomography, however, it is possible to compare the internal structures and dimensions of two tablets without destroying the samples, which may be important if the tablet is to be used as evidence in patent litigation or other legal proceedings. Figure 13 shows the images of two tablets, an innovator's patented dosage form and an unofficial copy, in which clear differences in the internal structures (

 layered core structure) can be seen easily. 

Figure 12: A metal particle in a placebo tablet.										

Several researchers have used X-ray microtomography to study changes in the structure of porous composites and foams under applied external stresses (16–18). It is implicit from these studies that the technique also has potential use in research into powder compaction and the formation of compressed tablet dosage forms (12, 17). It is likely that the time-dependent structural information obtained from such studies would provide considerable insight into the pharmaceutical manufacturing processes of tablet manufacture and dry granulation. Current measurement systems cannot collect data rapidly enough to enable powder compaction to be studied under current pharmaceutical manufacturing conditions, nor do they enable the behavior of the smallest individual particles to be resolved. The response time of research instruments is improving rapidly, however, and the need for studying short-lived events and even smaller samples has been recognized by commercial instrument designers and manufacturers. Using synchotron X-ray sources can provide some help in this regard (see http://

www.esrf.fr/Industry/Applications/Tomography/

  ), and enhanced X-ray sources, detector elements, control systems, and analysis software will likely lead to significant improvements in both response time and resolution for commercial instruments within the next 5–10 years.  

Figure 13: Comparison of the structure of a counterfeit (top) and innovators (bottom) osmotic tablet.						

 Recent developments in instrumentation suggest that in the future, X-ray microtomography studies may provide information about the chemical nature of samples (9, 19). This is an exciting advance that could address one of the current limitations of the technique for fully characterizing pharmaceutical products (

 a lack of information about the chemical nature of the sample). Commercial instruments capable of this type of multifaceted analysis are still a long way away, but systems in which X-ray microtomography is combined with more conventional spectroscopic mapping techniques in a single integrated instrument are already under development. Currently these systems require the destruction of the sample to facilitate the spectroscopic mapping of the samples, but they do have the potential for providing a detailed three-dimensional map of the physical and chemical nature of a product based on the analysis of just one or two dosage forms. This is clearly a significant improvement over the capabilities of current nonintegrated systems that each require a comparable number of dosage units to complete a full analysis. 

X-ray microtomography can obtain useful qualitative and quantitative information about the structure of pharmaceutical dosage forms. In the future, it is likely that X-ray microtomography also will be able to provide chemical mapping capabilities and improved spatial resolution of small structural features within these types of samples (9, 19, 20). 			

The authors acknowledge their coworkers at Pfizer Inc. for contributions made to this article. In particular, the work and input of Maureen Whitley and Mark Henson are gratefully acknowledged. 			

 "New Characterization Method for Pore and Packing Structure in Powder Compacts Using Confocal Laser Scanning Microscope," 

 "Osmotic Drug Delivery Using Swellable-Core Technology," 

 "Modeling of Transmitted X-ray Intensity Variation with Sample Thickness and Solid Fraction in Glycine Compacts," 

5. L. Farber, G. Tardos, and J.N. Michaels "Use of X-ray Tomography to Study the Porosity and Morphology of Granules," 

 "Characterization of Porous Microstructure by X-ray Microtomography," 

 "Damage Assessment in an Al/SiC Composite during Monotonic Tensile Tests Using Synchrotron X-ray Microtomography," 

 "Using Synchrotron X-ray Microtomography to Detect Defects," 

Mapping the Chemical States of an Element inside a Sample Using Tomographic X-ray Absorption Spectroscopy," 

X-ray microtomography has great potential for improving the understanding of the structural features of solid dosage forms and the changes in those features during manufacturing, handling, and storage. This article describes the basic principles of the technique and provides examples of its potential applications.

The authors provide a combined source of density data and show that denity can be used as an equipment-independent sclaing parameter in the manufacture of common pharmaceutical solids.