Polymorphism physicochemical characterization

Kaneniwa, N., Otsuka, M., and Hayashi, T. (1985). Physicochemical characterization of indomethacin polymorphs and the transformation kinetics in ethaSdrlpm. Pharm. Bull., 33 3447-3455. 

Matsuda, Y. and Tatsumi, E. (1989). Physicochemical characterization of furosemide polymorphs and their evaluation of stability against some environmental factors ,harmacobio-Dyn, 12 s-38. 

Otsuka, M., Onoe, M., and Matsuda, Y. (1994). Physicochemical characterization of phenobarbital polymorphs and their pharmaceutical propertiifr.ug Dev. Ind. Pharm., 20 1453-1470. 

Nichols, G. and Frampton, C. S. (1998). Physicochemical characterization of the orthorhombic polymorph of paracetamol crystallized from solution. J. Pharm. ScL, 87, 684-93. [113, 144f]... 

Additional preformulation and physicochemical characterization of the candidate compound are performed and stress stability studies may be initiated. Ideally, the optimal solid state (polymorphic) and chemical (salt) form of the molecule are identified as part of clinical candidate selection. Selection of the most stable and bioavailable form will expedite subsequent development. The methods for testing the drug substance are refined and additional methods may be developed. 

Otsuka M, Matsuda Y. Physicochemical characterization of Phenobarbital polymorphs and their pharmaceutical properties. Drug Dev Ind Pharm 1993 19 2241-2269. 

Physicochemical characterization Physicochemical characterization yields a number of important parameters that can be used in the control of the quality of a substance. Typical properties are melting point and other thermal data, solubility, acid-base behavior with pfCa values, redox potentials, polymorphism, and spectral information. Other property-influencing parameters are choice of counterion and salification studies. 

Chemical development Proof of structure and configuration are required as part of the information on chemical development. The methods used at batch release should be validated to guarantee the identity and purity of the substance. It should be established whether a drug produced as a racemate is a true racemate or a conglomerate by investigating physical parameters such as melting point, solubility and crystal properties. The physicochemical properties of the drug substance should be characterized, e.g. crystallinity, polymorphism and rate of dissolution. 

Numerous methods are required to characterize drug substances and drug products (Chapter 10). Specifications may include description identification assay (of composite sample) tests for organic synthetic process impurities, inorganic impurities, degradation products, residual solvents, and container extractables tests of various physicochemical properties, chiral purity, water content, content uniformity, and antioxidant and antimicrobial preservative content microbial tests dissolution/disintegration tests hardness/friability tests and tests for particle size and polymorphic form. Some of these tests may be precluded, or additional tests may be added as dictated by the chemistry of the pharmaceutical or the dosage form. 

There are a number of interrelated thermal analytical techniques that can be used to characterize the salts and the polymorphs of candidate drugs. The melting point of a salt can be manipulated to produce compounds with desirable physicochemical properties for specific formulation t5q)es. Of the thermal methods available for investigating polymorphism and related phenomena, DSC, TGA, and HSM are the most widely used methods. 

There are many techniques available to characterize compounds. Indeed, in polymorphism studies it is advisable to identify the modifications present by more than one technique. In 1985, the U.S. Food and Drug Administration (FDA) indicated (The Gold Sheet) that the principal physicochemical techniques (in their approximate order of usefulness) that could be used to characterize polymorphs should be (Poulson 1985)... 

The choice of analytical and physicochemical methods for the characterization of polymorphs is dictated by the need to measure properties which ultimately depend on the different internal arrangements of the same molecules in these phases. When pseudopolymorphs are also considered, the range of suitable analytical techniques is significantly broadened owing to the presence in the crystal of the solvating molecule and the possibility of analysing the physical and chemical changes which may accompany both formation and decomposition of pseudopolymorphs. 

One of the benefits of the methods discussed in this chapter is that they provide a complete characterization of the thermodynamics of transfer of solute from crystal to aqueous solution. Since the solubility of a crystalline solute depends upon the properties of the undissolved crystalline precipitate as weU as the properties of the solution, the thermodynamic data provides valuable information in understanding not only which of the two molecules is more soluble but also why the selected molecule is more soluble. By contrast, QSPR models, which are statistical rather than first-principles approaches, provide only limited statistical information about the underlying physicochemical processes. Moreover, since most QSPR models predict solubility from molecular rather than crystal structure, they are not able to rationalize or predict different solubilities for different polymorphs of a molecule. Therefore, we believe that the bottom-up methods that utilize efficiently molecular-scale information about the solute and solvent structure will attract more attention in the future in terms of both practical applications and fundamental studies of solubility of druglike molecules. 

Polymorphs and solvatomorphs can be characterized by a variety of complementary physicochemical methods, including X-ray diffraction, FTIR, Raman spectroscopy, isothermal microcalorimetry and others. Among these... 

As the polymorphism may be altered in the colloidal state and the stabilizer influences the polymorphic behavior of the nanoparticles as well, investigations of the physicochemical state of the nanoparticles are of crucial importance. The physicochemical state and the crystal modification of the lipid nanoparticles can be characterized by X-ray diffraction. 

The most common crystalline forms are polymorphs, hydrates, and solvates (pseudopolymorphs). Polymorphs are formed when a substance crystallizes in two or more crystal structures. Polymorphism significantly impacts on physicochemical properties of materials, such as stability, density, melting point, solubility, bioavailability, and so on. Hence the characterization of all possible polymorphs, identifying the stable (thermodynamic) polymorph, and design of reliable processes for consistent production are critical in modem day drug development. 

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