Solid pharmaceutical substances

A plethora of chemical compounds for the determination of small amounts of water present in organic solids, pharmaceutical substances and organic solvents have been devised over a length of time. But unquestionably the most important of these is the one proposed by Karl Fischer (1935), which is considered to be relatively specific for water. It essentially makes use of the Karl Fischer reagent which is composed of iodine, sulphur dioxide, pyridine and methanol. 

The determination of the absorption spectrum of a solid pharmaceutical substance is invariably accomplished by any one of the two following techniques namely ... 

Takacs M, Reisch J, Gergely-Zobin A, Giicer-Ekiz N. Light sensitivity investigations of some solid pharmaceutical substances. Sci Pharm 1990 58 ... 

Transfer the requisite quantity of the accurately weighed pharmaceutical substances or solid quantitatively into a beaker and dissolve it in either distilled water (DW) or other specified solvent,... 

The errors that are solely attributed to sampling, specifically in the instance of heterogeneous solids, usually give rise to the most important source of uncertainty in carrying out analysis of pharmaceutical substances. 

The optical rotation of a number of pure pharmaceutical substances may be measured accurately by noting the angle through which the plane of polarization is rotated when polarized light passes through the substance, if liquid or through a solution of the substance, if solid. 

Determination of the Absorption Spectrum of a Solid Compound (or a Pharmaceutical Substance)... 

Tingstad J, Dudzinski J. Preformulations studies II stability of drug substances in solid pharmaceutical systems. J Pharm Sci 1973 62(11) 1856—1860. 

The possibility to obtain a full solvent-free product, controlling in the same time the dimension of particles, is probably the most important feature when pharmaceutical substances are used. In the SAS process the SCF is used as the antisolvent. An organic solvent has to be involved in addition to the SCF and the solid solute. Basically, the process is performed by first dissolving the solid of interest in the organic liquid then, the SCF, which has low solvent capacity with respect to the solid but is completely miscible with the liquid, is added to the solution to get the precipitation of the solid. This method has been proposed by Gallagher and coworkers [8] to crystallize difficult-to-handle high explosives. Recently, other applications have been set forth to produce crystals of pharmaceuticals [9,10]. 

Vaseline and Paraflin.—Two solid products obtained from petroleum are the common pharmaceutical substance vaseline, a hydrocarbon mixture melting at about 35° and the white solid known as paraffin, also a hydrocarbon mixture melting at about 40 -60 . The properties and uses of these two substances are too common to require any further description. 

It is interesting to note that, although crospovidone is insoluble, it can be used in solid pharmaceutical preparations to improve the dissolution rate of an active substance. That this is not merely the result of a short-term increase in the surface area of the active substance but of the formation of a complex, can be seen in Fig. 80. Simply mixing indomethacin with crospovidone multiplies the dissolution rate of this drug substance during more than two hours. Similar results were obtained with indoprofen [439],propyphenazone [426] and prostaglandin ester [359]. 

When the crystallography of compounds related by polymorphism is such that nuclei in the two structures are magnetically nonequivalent, it follows that the resonances of these nuclei are not equivalent. Whereas it is normally not difficult to assign organic functional groups to observed resonances, solid-state NMR spectra can be used to deduce the nature of polymorphic variations, especially when the polymorphism is conformational in nature. Such information has proven to be extremely valuable during various stages in the development of numerous pharmaceutical substances. ... 

Polymorphic purity of solid drug substances is an important parameter for consideration in pharmaceutical formulation. Since different polymorphs or crystalline forms of the same drug exhibit different physical properties, chemical stability, solubility, dissolution rate, and possibly bioavailability, the presence of the alternative (metastable) crystal form(s) may have an adverse impact on the manufacturing and in vivo performance of the drug product. 

The optical microscope is a valuable tool in the laboratory and has numerous applications in most industries. Depending on the type of data that is required to solve a particular problem, optical microscopy can provide information on particle size, particle morphology, color, appearance, birefringence, etc. There are many accessories and techniques for optical microscopy that may be employed for the characterization of the physical properties of materials and the identification of unknowns, etc. Utilization of a hot-stage accessory on the microscope for the characterization of materials, including pharmaceutical solids (drug substances, excipients, formulations, etc.), can be extremely valuable. As with any instrument, there are many experimental conditions and techniques for the hot-stage microscope that may be used to collect different types of data. Often, various microscope objectives, optical filters, ramp rates, immersion media, sample preparation techniques, microchemical tests, fusion methods, etc., can be utilized. 

Dissolution is simply a process by which a solid substance goes into solution. The determination of dissolution rates of pharmaceutical substances from dosage forms does not predict their bioavailability or their in vivo performance rather, it indicates the potential availability of drug substance for absorption. Therefore, it is essential for pharmacists and pharmaceutical scientists to know and understand the importance of dissolution and its potential influence on the rate and extent of absorption and availability for drugs. 

Quality control of solid pharmaceuticals is essential to verify the integrity of the dmg substance and dmg product and such materials require special, yet simple, techniques and methods to analyse these samples. The subsequent sections discuss these methods and techniques and are presented to give an overview of the field but not an in-depth treatise of the subject. 

Suitable monomers are summarized in Table 9.1. 1,2,4-Triazole is a white to pale yellow solid with a melting point of 120°C. Synonyms are pyrrodiazole, IH-1,2,4-triazole, and 5-triazole. This compound should not be confused with a sulfanilamide compound that is addressed as triazole. In contrast to a triazole, a triazin refers to a 6-membered ring with three nitrogen atoms. 1,2,4-Triazole is used for the synthesis of agrochemicals, pharmaceutical substances, hydraulic fluids, and photochemical products. Both 1,2,4-triazole and 1,2,4-triazole are effective solvents for proton conducting electrol54es." ... 

Many chiral organic molecules used as pharmaceuticals have the desired effect in only one molecular form. The mirror image of this form may even be toxic. It is obviously very important to have a chemical process which produces the active form of e.g. a drug with extremely high purity. However, thermodynamic information about such separations is scarce. Nevertheless, several commercially successful production processes for enantiopure pharmaceuticals have been developed on the basis of enzymatic process steps. Extensive research in this area will be driven mainly by the demand for chiral intermediates for pharmaceutical substances or aromatic chemicals. Thermodynamics research on down-stream separations in enzymatic production processes for pharmaceutical molecules (molar mass range 200 - 1000) should be focused much more on the specific conditions of these processes (very dilute concentrations, water-based systems, very small solid particles). 

Classical methods for separation and purifica tion include fractional distillation of liquids and re crystallization of solids and these two methods are routinely included in the early portions of laboratory courses in organic chemistry Because they are capa ble of being adapted to work on a large scale frac tional distillation and recrystallization are the preferred methods for purifying organic substances in the pharmaceutical and chemical industries... 

Over the past two decades, the pharmaceutical community has become acutely aware that many substances of interest can be obtained in more than one crystal form, and that the properties of these solids may often be quite different. Polymorphism is the term used to denote crystal systems where a substance can exist in different crystal packing arrangements, but all of which are characterized by exactly the same elemental composition. Other crystal variations are known where a given substance exists in different crystal packing arrangements, but each of which exhibits a different elemental composition. Since this latter phenomenon usually involves the inclusion of one or more solvent molecules in the crystal, the term solvatomorphism has been coined to replace the inconsistent nomenclature used over the years. These and related phenomena have been the focus of several recent monographs [1-3],... 

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. 

One approach to the study of solubility is to evaluate the time dependence of the solubilization process, such as is conducted in the dissolution testing of dosage forms [70], In this work, the amount of drug substance that becomes dissolved per unit time under standard conditions is followed. Within the accepted model for pharmaceutical dissolution, the rate-limiting step is the transport of solute away from the interfacial layer at the dissolving solid into the bulk solution. To measure the intrinsic dissolution rate of a drug, the compound is normally compressed into a special die to a condition of zero porosity. The system is immersed into the solvent reservoir, and the concentration monitored as a function of time. Use of this procedure yields a dissolution rate parameter that is intrinsic to the compound under study and that is considered an important parameter in the preformulation process. A critical evaluation of the intrinsic dissolution methodology and interpretation is available [71]. 

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