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Solvates pharmaceuticals

QuantlogP, developed by Quantum Pharmaceuticals, uses another quantum-chemical model to calculate the solvation energy. As in COSMO-RS, the authors do not explicitly consider water molecules but use a continuum solvation model. However, while the COSMO-RS model simpUfies solvation to interaction of molecular surfaces, the new vector-field model of polar Uquids accounts for short-range (H-bond formation) and long-range dipole-dipole interactions of target and solute molecules [40]. The application of QuantlogP to calculate log P for over 900 molecules resulted in an RMSE of 0.7 and a correlation coefficient r of 0.94 [41]. [Pg.389]

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. [Pg.171]

E Shefter, T Higuchi. Dissolution behavior of crystalline solvated and nonsolvated forms of some pharmaceuticals. J Pharm Sci 52 781-791, 1963. [Pg.620]

The chemical and physical stability of aqueous and nonaqueous suspensions of a number of solvatomorphs of niclosamide has been evaluated in an effort to develop pharmaceutically acceptable suspension formulations [90]. Studied in this work was the anhydrate, two polymorphic monohydrates, the 1 1, Y, A"-dimethyI I ormam ide solvatomorph, the 1 1 dimethyl sulfoxide solvatomorph, the 1 1 methanol solvato-morph, and the 2 1 tetraethylene glycol hemisolvate. All of the solvatomorphs were found to convert initially to one of the polymorphic monohydrates, and over time converted to the more stable monohydrate phase. The various solvatomorphs could be readily desolvated into isomorphic desolvates, but these were unstable and became re-hydrated or re-solvated upon exposure to the appropriate solvent. [Pg.275]

In a manner similar to that just described for differential thermal analysis, DSC can be used to obtain useful and characteristic thermal and melting point data for crystal polymorphs or solvate species. This information is of great importance to the pharmaceutical industry since many compounds can crystallize in more than one structural modification, and the FDA is vitally concerned with this possibility. Although the primary means of polymorph or solvate characterization s centered around x-ray diffraction methodology, in suitable situations thermal analysis can be used to advantage. [Pg.239]

A large number of compounds of pharmaceutical interest are capable of being crystallized in either more than one crystal lattice structure (polymorphs), with solvent molecules included in the crystal lattice (solvates), or in crystal lattices that combine the two characteristics (polymorphic solvates) [122,123]. A wide variety of structural explanations can account for the range of observed phenomena, as has been discussed in detail [124,125]. The pharmaceutical implications of polymorphism and solvate formation have been recognized for some time, with solubility, melting point, density, hardness, crystal shape, optical and electrical properties, vapor pressure, and virtually all the thermodynamic properties being known to vary with the differences in physical form [126]. [Pg.363]

The term pseudo-polymorph is frequently used to describe the other types of solid phase that that are often encountered in the pharmaceutical sector. It includes the crystalline hydrates and solvates together with the amorphous or glass solid state. The structure and properties of these phases will be discussed in section 3.2. [Pg.33]

DSC instruments measure the heat flow into a sample as the temperature is ramped, in comparison to a reference standard. The melting temperature and enthalpy of fusion are quantified. The technique is not suitable for a significant proportion of pharmaceutical compounds because they decompose at the same time as melting. In solvates and hydrates the solvent will evaporate prior to melting which also limits the methods value. Sample size is typically 10 mg. [Pg.50]

Nuclear magnetic resonance spectroscopy is often used to quantify the ratio of API and counter-ion in a pharmaceutical salt, together with the type and quantity of hydrate or solvate molecules. [Pg.51]

Ab initio methods for polymorph, hydrate and solvate prediction are highly prized by the industry and good progress has been made in this field in recent years. This work is still a number of years from routine commercial application however, and polymorph screening experiments together with crystal structure determination, remain critical tasks for today s Pharmaceutical companies. [Pg.77]

Brittain H. Methods for the characterization of polymorphs and Solvates in Pol5unorphism in Pharmaceutical Solids. In Brittain H, ed. 1st ed. New York Marcel Dekker Inc., 1999 227-278. [Pg.323]

Liquid/liquid partition constants within pharmaceutical chemistry have been of primary interest because of tlieir correlation with liquid/membrane partitioning behavior. A sufficiently fluid membrane may, in some sense, be regarded as a solvent. With such an outlook, tlie partitioning phenomenon may again be regarded as a liquid/liquid example, amenable to treatment with standard continuum techniques. Of course, accurate continuum solvation models typically rely on the availabihty of solvation free energies or bulk solvent properties in order to develop useful parameterizations, and such data may be sparse or non-existent for membranes. Some success, however, has been demonstrated for predicting such data either by intuitive or statistical analysis (see, for example. Chambers etal. 1999). [Pg.418]

The importance of polymorphism in pharmaceuticals cannot be overemphasized. Some crystal structures contain molecules of water or solvents, known as hydrates or solvates, respectively, and they are also called as pseudopolymorphs. Identifying all relevant polymorphs and solvates at an early stage of development for new chemical entities has become a well-accepted concept in pharmaceutical industry. For poorly soluble compounds, understanding their polymorphic behavior is even more important since solubility, crystal shape, dissolution rate, and bioavailability may vary with the polymorphic form. Conversion of a drug substance to a more thermodynamically stable form in the formulation can signiLcantly increase the development cost or even result in product failure. [Pg.85]

Stoichiometric hydrates are the most important solvates affecting the solubility of marketed pharmaceuticals. Hemihydrates, monohydrates, and dihydrates are the most common stoichiometric ratios of water incorporated into the crystalline lattice of drugs. Pfeiffer et al. (1970) have shown how different hydrates of cephalosporins could be isolated from solvent systems of varying water activity. Cephalexin has a monohydrate and a dihydrate form, which are stable under different relative humidity conditions. Cefazolin has a monohydrate, a sesquihydrate (1.5 moles water), and a pentahydrate form (Byrn and Pfeiffer, 1992). Jozwiakowski et al. (1996) have found that lamivudine can form a 0.2 hydrate, where only one of L ve lamivudine molecules in the crystal lattice is associated with a water molecule. Multiple solvates can be formed for the same drug Stephenson et al. (1994) have shown that dithromycin can crystallize in at least nine solvate forms, including a cyclohexane trisolvate and an acetonitrile trihydrate. In addition, Byrn et al. (1995) have noted that desolvated forms of some drugs have unique properties that differ from their nonsolvated counterparts. [Pg.553]


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