Solvate crystalline structure

During the granulation process it is possible that the DS (occasionally the excipient) could transform into a solvated crystalline structure (solvate, hydrate). During the drying process, different situations can occur ... 

In selected cases, the effect of solvation on the crystalline structure formed is, however, considerably more pronounced. For example, the observed packing in the crystal of 2,4,6-tris( 1,3-propylenediamine-N,N -)cyclotriphosphazene (4) dihydrate (Fig. 6) is due to strong intermolecular hydrogen bonds between molecules of water and suitable couples of N-H groups on the host moiety M). The HzO species form also continuous H-bonded layers of solvation around the cyclophosphazene derivatives, thus stabilizing the crystal lattice. 

The properties of the drug (salt form, crystalline structure, formation of solvates, and solubility). 

The crystalline structure of solvated MCI provides a basis for the assumption that replacement of a methyl group by a more bulky group at the N(T) atom in the indoline ring can hinder the solvation of the phenolate oxygen atom. To confirm this assumption, an X-ray diffraction analysis of the pentyl-substituted MC2 (Figure 6) was carried out.37,38 The pentyl substituent at the N(l ) atom is similar to the methyl group in terms of its electronic properties. The MC2 molecules in the crystals are not solvated. MC2 molecules (Figure 6) have an almost planar trans-cis structure, similar to that of MCI. 

Polymorphism, as applied to the sohd state, can be defined as the ability of the same chemical substance to exist in different crystalline structures (Findlay et al. 1951) (regular, repeating arrangement of atoms or molecules in the solid state). The different structures are generally referred to as polymorphs, polymorphic modifications, crystal forms, or forms (Verma and Krishna 1966). Strict adherence to this definition of polymorphism excludes solvates and hydrates (specific water solvate) as polymorphs because they correspond to different chemical substances. Solvates and hydrates are sometimes referred to as pseudopolymorphs. Molecule A is a different chemical substance than molecule A coordinated with a solvent. 

Caira, M.R. Bettinetti, G. Sorrenti, M. Structural relationships, thermal properties and physicochemical characterization of anhydrous and solvated crystalline fomis of tetroxoprim. J. Pharm. Sci. 2002, 91, 467-481. 

Most of the drugs on the market are obtained as a defined crystalline structure and formulated as solid dosage forms. It is well known that a molecule ean erystallize to give different crystalline structures displaying what is called polymorphism. The erystal structures may be anhydrous or may contain a stoichiometric number of solvent moleeules leading to the formation of solvates (hydrates in case of water molecules). Pseudopolymorphism is the term used to describe this phenomenon. 

The solvate is poorly stable and the solvent is easily removed leading to either the original polymorphic form but creating a certain degree of disorder in the crystalline structure or to what is called a desolvate solvate form. In this last case, also named isomorphic desolvate , the desolvated solvate retains the structure of its parent solvated form. The X-ray diffraction patterns look similar between the parent and the daughter forms. In this situation we have the creation of a molecular vacuum which could substantially impact on the stability, hygroscopicity and mechanical characteristics of the DS and finally of the DP. 

Solvents bound to drug molecules in the crystal lattice. These solvents present as solvates (hydrates) are lost at a characteristic temperature and may be stable only over a limited range of relative humidity. The solvates and desolvated solvates, whilst being two different chemical entities, can retain the same crystalline structure (similarity of x-ray diffraction pattern) but show different physico-chemical properties. "... 

Fig. 1.4 Phase diagrams of (AN) -LiX mixtures with LiPFj, LiTFSI, LiC104, UBF4, and LiC02CF3 [134, 135] and ion/solvent coordination within the solvate crystal structures (a) (AN)6 UPFe [137], (b) (AN)5 LiPF6 [138], (c) (AN)i LiTFSI [139], (d) (AN)4 LiC104 [140], (e) (AN)2 LiBF4 [141], and (f) (AN)i LiBF4 [142] (the sample values are indicated by an x for fuUy amorphous samples and by a triangle for partially crystalline samples)...

EPDM matrix solvates crystalline phase of LDPE. The effect is significant for blends of amorphous elastomer matrix. In the case of sequenced EPDM matrix a part of crystalline phase of LDPE recrystallizes in less perfect form, which is not detectable by DSC. Improvement of mechanical properties of EPDM by blending with LDPE is higher for the elastomer of sequenced structure, confirming structural data. The best mechanical properties, obtained when linear plastomer is admixed to amorphous elastomer, stays... 

Lipid bilayer membrane systems, having gel (solvated crystalline state)-to-liquid crystalline phase transitions are attractive as specific organic media for separation chemistry. The first approach in HPLC was direct immobilization of a phosphatidylcholine lipid onto silica. This modified silica shows interesting selectivity against amino acids, but the separation mode is too complicated, due to the zwitter-ionic property of the immobilized molecule. In addition, no lipid membrane function is realized on the silica because of the direct immobilization with covalent bonding, which prohibits lateral diffusion of lipids from forming highly-ordered structures that lead to supramolecular functions of lipid membrane systems. 

With reference to traditional electrolytes, the peculiarity of solid electrolytes results from their additional electronic conductivity. Other particularities may be mentioned the solidity of the electrolyte suppresses any convection, the ions are not solvated. Some solid electrolytes have a very simple crystalline structure where the energy profile of the path followed by the ions is known. This would make the situation ideally simple for electrode process studies. Unfortunately, this is frequently counteracted by the great complexi-ty of the electrode surface which is generally formed by a contact between two solids. This point has already been stressed by Raleigh. ... 

The presence of a solvent in the crystallization process alleviates these problems, mainly by lowering the activation energy barrier for the rearrangement of the solute molecules into a new crystalline structure. Thus, the solvent has the classical function of a catalyst and will only affect the kinetics but not the thermodynamics of the transformation. This is valid as long as the solvent does not become part of the crystal structure, that is, is not forming a solvate with the solute. With respect to co-crystals this signifies that the existence of a thermodynamically stable binary compound is not a function of the solvent. 

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