Pharmaceutical solids, compounding

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. 

Chemical compound homogeneity is an important issue for pharmaceutical solid forms. A classical spectrometer [1-3] integrates spatial information. However, use of a mean spectrum on a surface can be a drawback in solid-form analysis. For example, in the pharmaceutical industry, it is important to map the distribution of active ingredients and excipients in a tablet as this reveals physical interaction... 

Additives are all formulation constituents other than the active ingredient. Although additives could be classified into excipients and vehicles (excipients for solid preparations and vehicles for liquid ones), there are several other agents used in pharmaceutical formulations with specific functions such as preservatives, sweeteners, coatings, colorants, antioxidants, surfactants, emulsifying agents, and flavors. Since they comprise a vast amount of products, this section will deal with additives for compounding pharmaceutical products for internal use only [17,18]. 

A colorless or slightly yellow solid occurring in filamentous, granular, and powdered form. Forms a viscous cnlloidal solution with water, insoluble in alcohol, ether, and chloroform. It is extracted from brown seaweeds. The gum is used as a thickener, stabilizer, and emulsifier in foods, especially ice cream. Also used in boiler compounds, pharmaceuticals, textile printing, cement compositions, paper coatings, and in some water-base paints. 

This first section focuses on three major areas library generation method (mixtures and single compounds) chemistry (solid-phase and solution synthesis) and quality/speed (analytical and automation). Finally, the section ends with a chapter reviewing examples where combinatorial chemistry/rapid organic synthesis has been used for discovering novel lead structures for pharmaceutical purposes. 

In the pharmaceutical solid dosage form development process, compaction simulators can be used throughout the life of a compound. Royce and coworkers categorized the lifecycle of a compound into three phases (1). 

The product development process in the pharmaceutical industry is not unlike that of other industries, in which exploratory materials are researched and developed into products, and where problems arise the analytical laboratory is called upon to provide solutions. The characterization of the physical properties of pharmaceutical solids is one of the disciplines utilized early in the drug development process. The characterization of these properties is vital to determining whether the compound under investigation is a candidate for continued development as a drug product. To facilitate the characterization of pharmaceutical solids in laboratories, a conceptual approach for this characterization has been developed (66) that uses decision trees to guide the analyst in the characterization of drug substances. 

In Chapter 18, we described solvent extraction and solid-phase extraction sample preparation methods, which are applicable to GC analyses as well as others. A convenient way of sampling volatile samples for GC analysis is the technique of head-space analysis. A sample in a sealed vial is equilibrated at a fixed temperature, for example, for 10 min, and the vapor in equilibrium above the sample is sampled and injected into the gas chromatograph. A typical 20-mL glass vial is capped with a silicone rubber septum lined with polytetrafluoroethylene (PTFE). A syringe needle can be inserted to withdraw a 1-mL portion. Or the pressurized vapor is allowed to expand into a 1-mL sample loop at atmospheric pressure, and then an auxiliary carrier gas carries the loop contents to the GC loop injector. Volatile compounds in solid or liquid samples can be determined at parts per million or less. Pharmaceutical tablets can be dissolved in a water-sodium sulfate solution... 

P.O. Box 3426 Torrance, CA 90510 Internet site www.bachem.com solution or solid-phase custom synthesis amino acids, peptides, and other organic compounds pharmaceutical intermediates cGMP... 

The first example concerns systems where one or more solid phases exists in a state of equilibrium with a single vapor phase. This type of situation would exist for solvation/desolvation equilibria whose transition temperatures are substantially less than the fusion point corresponding to generation of a liquid phase, and it is certainly the most commonly encountered type of solvate system of pharmaceutical interest. For most compounds, the solid substance in question has no appreciable vapor pressure, so that the sole component of the vapor phase will be the volatile solvent. The usual occurrence where the evolved solvent passes entirely into the vapor phase will be assumed, where it does not form a discrete liquid phase of its own. 

There has been an increasing amount of interest in the use of supercritical fluids (SCF) for leaching or extracting compounds from solids or liquids in the food and pharmaceutical industries because of the nontoxic nature of the primary SCF—carbon dioxide. In this section we will briefly consider the properties of SCFs that make them interesting for extraction. Then a typical process for SCF extraction will be explored and several applications will be discussed. 

K. K. Arora and M. J. Zaworotko, in Polymorphism in Pharmaceutical Solids, ed. H. G. Brittain, Pharmaceutical co-crystals A new opportunity in pharmaceutical science for a long-known but little studied class of compounds. Informa Healthcare, New York, 2009, vol. 2, p. 281. 

Even if the technique historically was often used because of its specific advantages for effervescent production, potent compounds, organic solvents, or multiproduct facilities, practice has shown that single-pot processing is also attractive for standard pharmaceutical solid dosage production. 

Memfield s concept of a solid phase method for peptide synthesis and his devel opment of methods for carrying it out set the stage for an entirely new way to do chem ical reactions Solid phase synthesis has been extended to include numerous other classes of compounds and has helped spawn a whole new field called combinatorial chemistry Combinatorial synthesis allows a chemist using solid phase techniques to prepare hun dreds of related compounds (called libraries) at a time It is one of the most active areas of organic synthesis especially m the pharmaceutical industry... 

Kneading Devices These are closely related to the agitated pan but differ as being primarily mixing devices with heat transfer a secondary consideration. Heat transfer is provided by jacketed construction of the main body and is effected by a coolant, hot water, or steam. These devices are applicable for the compounding of divided solids by mechanical rather than chemical action. Apphcation is largely in the pharmaceutical and food-processing industries. For a more complete description, illustrations, performance, and power requirements, refer to Sec. 19. 

Chemistry on solid support has gained tremendous importance during the last few years, mainly driven by the needs of the pharmaceutical sciences. Due to the robust and tolerable nature of the available catalysts, metathesis was soon recognized as a useful technique in this context. Three conceptually different, RCM-based strategies are outlined in Fig. 11. In the approach delineated in Fig. 1 la, a polymer-bound diene 353 is subjected to RCM. The desired product 354 is formed with concomitant traceless release from the resin. This strategy is very favorable, since only compounds with the correct functionality will be liberated, while unwanted by-products remain attached to the polymer. However, as the catalyst is captured in this process by the matrix (355), a higher catalyst loading will be required, or ancillary alkenes have to be added to liberate the catalyst. 

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