Excipient Compactibility

Capsules disintegrate when the capsule shell dissolves and the powder mixmre is wetted. Hydrophilic excipients promote the wetting of the powder bed (Fig. 4.1). Due to the low compaction of the encapsulated powder, and the easy dissolution of most diluents for capsules, the addition of a disintegrating agent is often not needed for pharmacy preparations. However, when excipients compact easily (e.g. calcium monohydrogen phosphate dihydrate) a disintegrant is recommended. 

Table 2 Hiestand Compaction Indices for Some Drugs and Excipients... 

This technique has also been used in combination with nitrogen absorption to study the pore structure of some excipients, particularly MCC in both the powdered and compacted state. The intraparticulate porosity of MCC has been shown to be unaffected by tableting the interparticular pores, however, are gradually reduced in size [38]. Recently this method has been used to evaluate the internal structure of tablets prepared from microcapsules [150]. 

Brittle fracture indices were obtained for a series of compacted direct compression excipients that had been exposed to various degrees of ambient relative humidity [67], As illustrated in Fig. 9, compacts of the essentially... 

Flow behavior of powders is also of interest in direct compression. It is generally accepted that the flow rate initially increases with particle size, achieves a maximum in the range of 100-400 /um, and then decreases [85]. An excipient that has been well characterized is lactose, which undergoes particle fragmentation when compacted. For a-lactose monohydrate, it has been shown that the... 

Plastic deformation is the permanent change in shape of a specimen due to applied stress. The onset of plastic deformation is seen as curvature in the stress—strain curve. Plastic deformation is important because it allows pharmaceutical excipients and drugs to establish large true areas of contact during compaction that can remain on decompression. In this way, good, intact, tablets can be prepared. 

Table 8 Typical Properties of Some Common Drugs and Excipients Determined at a Compact Solid fraction of 0.8 to 0.9...

Lot to lot variations of several drugs and excipients are shown in Table 9. Specially crystallized lots of ibuprofen, for example, show substantial changes in Brittle Fracture and Bonding Indices. Phenacetin shows a significant increase in brittleness at higher relative humidity. It was observed by Hiestand and Smith [31] that compacts of dried phenacetin did not fracture, while the lot equilibrated at 40% relative humidity did, consistent with the Brittle Fracture Index change. 

To demonstrate the ability to evaluate intersample variations, an over-the-counter (OTC) pain relief medication from two different manufacturers was compared. The samples contain three APIs each acetaminophen, aspirin and caffeine. Pure acetaminophen, aspirin and caffeine samples are obtained in either tablet form or powder compact and included within the same FOV as the tablets to provide simultaneous reference materials for the tablet samples. The tablets and pure components were arranged as shown in Plate 8.1a. Measurements on all samples were collected simultaneously. Tablet A samples from one manufacturer have a reported label concentration of 37%, 37%, and 10%, for the three API components, respectively. Tablet B samples from the second manufacturer contain the same three APIs, at label concentrations of 39%, 39%, and 10 %, respectively. In addition to these samples, tablet C samples are included in the array of tablets. These samples contain only acetaminophen as the API with a reported label concentration of 79%, and are made by the manufacturer who produces tablet A. The remaining mass of all three tablet types represents the excipient (binder, disintegrant, and lubricant) materials. 

The concentrations of the active ingredients as reported from the manufacturer s label are 37% acetaminophen, 37% aspirin, and 10 % caffeine. The remainder of the tablet mass represents the excipient (binder, disintegrant, and lubricant) materials. Pure acetaminophen, aspirin and caffeine samples are obtained in either tablet form or powder compact and used to obtain reference specua of pure components. 

Within the pharmaceutical industry, granulation is a widely used process to prepare drug substance and excipient particles for compression. " There are wet and dry granulation procedures herein high shear wet grannlation, fluid bed granulation and roller compaction will be discussed. 

The outcome of dissolution tests on pharmaceutical formulations can be influenced by a nnmber of factors including the nature of the excipients and lubricants, blending method and granulation procedure used. When the solubility of the API is not the limiting factor, the compaction pressure used to produce tablets is inversely proportional to their dissolution rate and, as noted in the previous section, directly proportional to the slope of the NIR spectra for intact tablets. Blanco et have developed various approaches for... 

Tablets account for more than 80% of all pharmaceutical formulations therefore, the development and implementation of NIR methods for determining APIs in intact tablets is of a high interest with a view to assuring content uniformity and quality in the end product. Blanco et al developed an innovative strategy to prepare calibration samples for NIR analysis by using laboratory-made samples obtained by mixing the API and excipients in appropriate proportions and compacting the mixture at a pressure similar to that used industrially. This way of matching laboratory and production samples affords more simple and robust NIR methods which require the use of neither HPLC nor UV-vis spectroscopy as reference rather, reference values are obtained by weighing during preparation of the samples. The PLS calibration models thus constructed exhibited a good predictive ability with various production batches.

In the typical dmg-excipient compatibility testing program, binary powder mixes are prepared by triturating API with the individual excipients. These powder samples, usually with or without added water and occasionally compacted or prepared as slurries, are stored under accelerated conditions and analysed by stability-indicating methodology, for example, HPLC, CE and so forth. This entire process takes considerable time and resources. 

Miller RW, Sheskey PJ. A survey of current industrial practices and preferences of roller compaction technology and excipients Year 2000. Am Pharm Rev 2001 4(l) 24-35. 

Successful scale-up of the tableting process also requires control of the raw materials used in compaction. Typically, pharmaceutical excipients vary in their physicochemical properties, which result in batch-to-batch variations. The tableting process, especially direct compression processes where there is limited raw material alteration before compaction, is susceptible to raw material variation, which may be magnified upon scale-up. Compaction science affords the ability to fingerprint raw materials, including the drug substance, to determine if the same compaction properties will be observed from batch to batch. This also allows for a rational approach for determining alternate vendor sources of the same materials. 

The deformation properties of the drug substance and excipients will have a direct influence on the strength of the tablets that are produced. During the compaction process, as the powder flows from the hopper into the dies, the only force acting on the particles is due to the particles themselves. Then as the punches enter the dies, initially very low pressures are... 

One very common beneficial interaction involving an excipient is the interaction between magnesium stearate and the metal of tablet punches and dies, or the equivalent parts on a powder encapsulation machine. Magnesium stearate is an example of a boundary lubricant. As such it has a polar head and a fatty acid tail. It is believed that the polar head of the magnesium stearate is oriented toward the die wall or tablet punch face. In these ways it is able to reduce the ejection force (the force required to eject the tablet from the die after compaction) and prevent sticking to the punch faces. The other boundary lubricants, e.g., calcium stearate and sodium stearyl fumarate, will also function in a similar manner. However, the so-called liquid film lubricants function in a very different manner (19). 

Loss of excipient compressibility due to wet granulation and repeated compaction cycles in dry granulation, or excessive usage of lubricants and poorly compressible ingredients in the formulation... 

Coprocessed excipients have been mainly used in DC tableting because of their better flow ability and compressibility, and the excipient formed is a filler-binder. The compressibility of several coprocessed excipients such as Cellactose (45), SMCC (42,44), and Ludipress (BASF AG, Ludwigshafen, Germany) (46) have been reported to be superior to the physical mixtures of their constituent excipients. While comparing the compressibility profile of SMCC with MCC in the presence of high compression forces, the former was found to retain the compaction properties,... 

Dilution potential is the ability of the excipient to retain its functionality even after dilution with another material in a finite proportion. Most drug substances are poorly compressible, and require excipients to achieve better compressibility to retain good compaction even on dilution with them. Cellactose has been shown to possess a higher dilution potential than a physical mixture of its constituent excipients (50). 

The testing procedures used in this work have all been well described in the literature (4) and are focused on understanding the compression behavior of the powder samples and the mechanical properties of the resulting compacts. These methods are summarized in Table 1. For brevity, we have limited our initial studies to single component systems, but recognize that more work is needed in the future to understand the complex behavior of multicomponent mixtures. The current work should provide a sound basis for further work on such systems. It is intended that this treatise will enable pharmaceutical formulation scientists to better understand the similarities and differences between the most common grades and types of excipients, and will facilitate the rational selection of excipients for use in the development of immediate release tablet formulations. 

Because particle size is so intimately intertwined with powder performance, it is one of the prime considerations in selecting excipients to develop or improve a formulation. This is particularly important with direct compression formulations where excipient flowability and compaction performance are critical. Typically, excipients for these applications exhibit narrow size distributions with moderate-to-coarse particle size, having a mean size from 100 to 200 pm. 

Powders are porous materials and their bulk and relative densities can change with consolidation (6). However, a powder s true density is the density of its solid phase only and thus is independent of the state of consolidation. The true density of organic excipients typically ranges from 1.0 to 1.6g/cm3 while inorganic excipients (e.g., calcium phosphate) show values greater than 2g/cm3. True density is used to determine powder or compact solid fraction (SF) (see below) and it may be a consideration when selecting excipients if segregation is a concern. True density is often determined by gas pycnometry. 

Tablet mechanical properties measured on samples prepared on an instrumented tablet press or compaction simulator are an excellent means to characterize excipients under dynamic conditions (8,9). Meaningful data analyses are best achieved if both tablet preparation and tablet property measurements are performed at carefully controlled conditions using standardized procedures. Such testing in the authors ...

The range of compression pressures to prepare tableting indices compacts is shown in Table 3 with each considered moderate relative to other excipients such as lactose, mannitol, and calcium phosphate dibasic. Avicel PH302 required considerably less pressure than PH102 and PH105, and thus shows greater ease of compression. Their moderate compressibility indicates that a fairly substantial pressure was required to achieve the SF. The rank order of each excipient by the tableting indices mechanical properties is provided in Table 4. 

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