Solid pharmaceutical

K. R. Morris, Structural aspects of hydrates and solvates, in Polymorphism in Pharmaceutical Solids (H. G. Brittain, Ed.), Marcel Dekker, New York, 1999, p. 132. 

J. T. Carstensen, Advanced Pharmaceutical Solids, Marcel Dekker, New York, 2001, p. 117, 118. 

B. C. Hancock and G. Zografi, The relationship between the glass transition temperature and the water content of amorphous pharmaceutical solids, Pharm. Res, 11, 471 (1994). 

Physical Characterization of Pharmaceutical Solids, edited by Harry G. Brittain... 

In pharmaceutical systems, both heat and mass transfer are involved whenever a phase change occurs. Lyophilization (freeze-drying) depends on the solid-vapor phase transition of water induced by the addition of thermal energy to a frozen sample in a controlled manner. Lyophilization is described in detail in Chapter 16. Similarly, the adsorption of water vapor by pharmaceutical solids liberates the heat of condensation, as discussed in Chapter 17. 

Shah and Nelson [33] introduced a convective mass transport device in which fluid is introduced through one portal and creates shear over the dissolving surface as it travels in laminar flow to the exit portal. They demonstrated that this device produces expected fluid flow characteristics and yields mass transfer data for pharmaceutical solids which conform to convective diffusion equations. 

Mass transport from suspensions of pharmaceutical solids represents a challenging and important area for methodological development. 

There is actually no sharp distinction between the crystalline and amorphous states. Each sample of a pharmaceutical solid or other organic material exhibits an X-ray diffraction pattern of a certain sharpness or diffuseness corresponding to a certain mosaic spread, a certain content of crystal defects, and a certain degree of crystallinity. When comparing the X-ray diffuseness or mosaic spread of finely divided (powdered) solids, the particle size should exceed 1 um or should be held constant. The reason is that the X-ray diffuseness increases with decreasing particle size below about 0.1 J,m until the limit of molecular dimension is reached at 1-0.1 nm (10-1 A), when the concept of the crystal with regular repetition of the unit cell ceases to be appropriate. 

WC Duncan-Hewitt, DJW Grant. True density and thermal expansivity of pharmaceutical solids—Comparison of methods of assessment of crystals. Int J Pharm 28 75-84, 1986. 

With these concerns in mind, it is appropriate to outline a comprehensive program for the physical characterization of pharmaceutical solids. A modem industry cannot tolerate the inconsistent practices of the past, where the only physical properties that might be documented were those that could be conveniently measured. It is of extreme importance that investigators measure the parameters that need to be measured and not merely collect the type of data that is convenient to obtain. Proper physical characterization must be systematic in its approach, and it should follow a protocol that is rationally designed to obtain all needed information. 

A systematic approach to the physical characterization of pharmaceutical solids has been outlined [6], and it will be filled out in significantly more depth in the chapters of the present work. Within this system, physical properties are classified as being associated with the molecular level (those associated with individual molecules), the particulate level (those pertaining to individual solid particles), or the bulk level (those associated with an assembly of particulate species). 

Infrared (IR) spectroscopy, especially when measured by means of the Fourier transform method (FTIR), is another powerful technique for the physical characterization of pharmaceutical solids [17]. In the IR method, the vibrational modes of a molecule are used to deduce structural information. When studied in the solid, these same vibrations normally are affected by the nature of the structural details of the analyte, thus yielding information useful to the formulation scientist. The FTIR spectra are often used to evaluate the type of polymorphism existing in a drug substance, and they can be very useful in studies of the water contained within a hydrate species. With modem instrumentation, it is straightforward to obtain FTIR spectra of micrometer-sized particles through the use of a microscope fitted with suitable optics. 

V. APPLICATIONS OF DIFFUSE REFLECTANCE SPECTROSCOPY TO THE STUDY OF PHARMACEUTICAL SOLIDS 42... 

An initial use of reflectance spectroscopy in the characterization of pharmaceutical solids concerned studies of the stability of coloring agents in tablet formulations. With the description of a device that enabled the surface of intact tablets to be studied [14], the photostability of various dyes and lakes in tablets was followed [15,16]. Exposure of formulations to both normal and exaggerated light conditions was investigated, and the kinetics of the photodegradation evaluated. In most cases, the photoreactions appeared to follow first-order kinetics. 

Although UV/VIS diffuse reflectance spectroscopy has not been used extensively in the study of pharmaceutical solids, its applications have been sufficiently numerous that the power of the technique is evident. The full reflectance spectra, or the derived colorimetry parameters, can be very useful in the study of solids that are characterized by color detectable by the human eye. It is evident that questions pertaining to the colorants used for identification purposes in tablet formulations can be fully answered through the use of appropriately designed diffuse reflectance spectral experiments. With the advent of newer, computer-controlled instrumentation, the utility of UV/VIS diffuse reflectance as a characterization tool for solids of pharmaceutical interest should continue to be amply demonstrated. 

In this IR sampling technique, a thermogravimetric (TG) analyzer is interfaced to an IR spectrophotometer so that the evolved gas from the sample/TG furnace is directed to an IR gas cell. This IR sampling technique lends itself to the identification and quantitation of residual solvent content for a pharmaceutical solid [17], and also to the investigation of pharmaceutical pseudopolymorphs. 

The topics of polymorphism and pseudopolymorphism dominate the majority of publications that deal with utilizing infrared spectroscopy for the physical characterization of pharmaceutical solids. Typically, in each of the publications, IR spectroscopy is only one technique used to characterize the various physical forms. It is important to realize that a multidisciplinary approach must be taken for the complete physical characterization of a pharmaceutical solid. Besides polymorphism, mid- and near-IR have been utilized for identity testing at the bulk and formulated product level, contaminant analysis, and drug-excipient interactions. A number of these applications will be highlighted within the next few sections. 

Clearly, the potential applications for vibrational spectroscopy techniques in the pharmaceutical sciences are broad, particularly with the advent of Fourier transform instrumentation at competitive prices. Numerous sampling accessories are currently available for IR and Raman analysis of virtually any type of sample. In addition, new sampling devices are rapidly being developed for at-line and on-line applications. In conjunction with the numerous other physical analytical techniques presented within this volume, the physical characterization of a pharmaceutical solid is not complete without vibrational analysis. 

In the case of pharmaceutical solids that are dominated by carbon and proton nuclei, the dipole-dipole interactions may be simplified. The carbon and proton nuclei may be perceived as dilute and abundant based upon then-isotopic natural abundance, respectively (Table 1). Homonuclear 13C—13C dipolar interactions essentially do not exist because of the low concentration of 13C nuclei (natural abundance of 1.1%). On the other hand, H—13C dipolar interactions contribute significantly to the broad resonances, but this heteronuclear interaction may be removed through simple high-power proton decoupling fields, similar to solution-phase techniques. 

The concept of cross-polarization as applied to solid state NMR was implemented by Pines et al. [20]. A basic description of the technique is the enhancement of the magnetization of the rare spin system by transfer of magnetization from the abundant spin system. Typically, the rare spin system is classified as 13C nuclei and the abundant system as H spins. This is especially the case for pharmaceutical solids and the remaining discussion of cross-polarization focuses on these two spin systems only. 

Within various pharmaceutical laboratories (industrial and academic), the mul-tinuclear technique of solid state NMR has primarily been applied to the study of polymorphism at the qualitative and quantitative levels. Although the technique ideally lends itself to the structure determination of drug compounds in the solid state, it is anticipated that in the future, solid state NMR will become routinely used for method development and problem solving activities in the analytical/materials science/physical pharmacy area of the pharmaceutical sciences. During the past few years, an increasing number of publications have emerged in which solid state NMR has become an invaluable technique. With the continuing development of solid state NMR pulse sequences and hardware improvements (increased sensitivity), solid state NMR will provide a wealth of information for the physical characterization of pharmaceutical solids. 

Evaluation of the morphology of a pharmaceutical solid is of extreme importance, since this property exerts a significant influence over the bulk powder properties of the material. In addition to providing insights into the micromeritic properties of the solid, microscopy can also be used to develop preliminary estimations of the particle-size distribution. A determination can be easily made regarding the relative crystallinity of the material, and it is often possible to deduce crystallographic information as well. Unknown particulates can often be identified solely on the basis of their microscopic characteristics, although it is useful to obtain confirmatory support for these conclusions with the aid of microscopically assisted techniques. 

X-ray powder patterns can be obtained using either a camera or a powder diffractometer. Currently, diffractometers find widespread use in the analysis of pharmaceutical solids. The technique is usually nondestructive in nature. The theory and operation of powder diffractometers is outside the purview of this chapter, but these topics have received excellent coverage elsewhere [1,2]. Instead, the discussion will be restricted to the applications of x-ray powder diffractometry (XPD) in the analysis of pharmaceutical solids. The U.S. Pharmacopeia (USP) provides a brief but comprehensive introduction to x-ray diffractometry [3],... 

Preferred orientation of the particles must be minimized. One of the most effective ways to achieve this is to reduce the particle size by grinding the sample [1], As already discussed in Section III.A, however, grinding can disorder the crystal lattice. Grinding can also induce other undesirable transitions, such as polymorphic transformations [59]. In order to obtain reproducible intensities, there is an optimum crystallite size. The crystallites have to be sufficiently small so that the diffracted intensities are reproducible. Careful studies have been carried out to determine the desired crystallite size of quartz, but no such studies have been reported for pharmaceutical solids [60]. Care should be taken to ensure that the crystallites are not very small, since decreased particle size can cause a broadening of x-ray lines. This effect, discussed earlier (Eq. 9), usually becomes apparent when the particle size is below 0.1 jum. 

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