Nonsolvated crystals

Since the compound of interest is not soluble in the layered nonsolvent, crystal formation may begin at the interfacial region. If the nonsolvent is volatile, vapor diffusion may provide another route for the growth of crystals. 

The presence of the new solvate created many complications for the development of the drug. It became impossible to crystallize the original nonsolvate crystals using the original MeOH/IPAC solvent system. Crystals generated by Options 1, 2, or 3 were all solvate. In order to avoid the complication of the solvate issue, the original solvent system, MeOH/IPAC, was abandoned. 

In the case of semicrystalline polymers, we should distinguish between two cases classical nonsolvated crystals, on the one hand, and solvated crystals (crystallosolvates), on the other hand. In the case of solvated crystals, changing the labeling type of the solvent or of the polymer (the case of neutrons, for instance) alters the diffraction pattern as some peaks... 

In the case of nonsolvated crystals surrounded by a liquid phase, the cross-term can be dropped provided crystals are larger than sizes of about q. The intensity then reads ... 

When pure needle-like crystals of -aminobenzoyl chloride are polymerized in a high temperature, nonsolvent process, or alow temperature, slurry process, polymer is obtained which maintains the needle-like appearance of monomer. PBA of inherent viscosity, 4.1 dL/g, has been obtained in a hexane slurry with pyridine as the acid acceptor. Therefore PBA of fiber-forming molecular weight can be prepared in the soHd state. 

Batch Crystallization. Crystal size distributions obtained from batch crystallizers are affected by the mode used to generate supersaturation and the rate at which supersaturation is generated. For example, in a cooling mode there are several avenues that can be followed in reducing the temperature of the batch system, and the same can be said for the generation of supersaturation by evaporation or by addition of a nonsolvent or precipitant. The complexity of a batch operation can be ihustrated by considering the summaries of seeded and unseeded operations shown in Figure 19. 

Salting-out crystalli tion operates through the addition of a nonsolvent to the magma ia a crystallizer. The selection of the nonsolvent is based on the effect of the solvent on solubiHty, cost, properties that affect handling, iateraction with product requirements, and ease of recovery. The effect of a dding a nonsolvent can be quite complex as it iacreases the volume required for a given residence time and may produce a highly nonideal mixture of solvent, nonsolvent, and solute from which the solvent is difficult to separate. 

The phenomenon of pseudopolymorphism is also observed, i.e., compounds can crystallize with one or more molecules of solvent in the crystal lattice. Conversion from solvated to nonsolvated, or hydrate to anhydrous, and vice versa, can lead to changes in solid-state properties. For example, a moisture-mediated phase transformation of carbamazepine to the dihydrate has been reported to be responsible for whisker growth on the surface of tablets. The effect can be retarded by the inclusion of Polyoxamer 184 in the tablet formulation [61]. 

Two new polymorphs of (2E)-2-cyano-3-[4-(diethylamino)phenyl]-prop-2-enethioamide and an acetone solvate were crystallized, and the structures compared to the known nonsolvated form [11]. One of the new forms was found to be considerably more stable than the others, and subsequently the other two new forms became vanishing polymorphs that could only be produced under strictly controlled conditions. The structures of all three polymorphs could be found using polymorph predictor, if the initial molecular structure was obtained from the X-ray data, the molecule held to be rigid during the energy minimization, and both VDW and Coulomb interactions taken into account. 

The polymerization proceeds under photo- [49,50],X-ray [51], and y-ray [52] irradiation in the dark in vacuo, in air, or even in water or organic solvent as the dispersant (nonsolvent) for the crystals, similar to the solid-state polymerization of diacetylene compounds [ 12]. The process of topochemical polymerization of 1,3-diene monomers is also independent of the environment surrounding the crystals. Recently, the thermally induced topochemical polymerization of several monomers with a high decomposition and melting point was confirmed [53]. The polymer yield increases as the reaction temperature increases during the thermal polymerization. IR and NMR spectroscopies certified that the polymers obtained from the thermally induced polymerization in the dark have a stereoregular repeating structure identical to those of the photopolymers produced by UV or y-ray irradiation. 

Although the chemical properties of benzene-1,2,3-tricarboxylic acid (BTCA) were first studied over 100 years ago, the crystal stmcture of BTCA was not reported until a recent powder XRD study [117]. In contrast, the crystal stmctures of several solvate phases of BTCA were determined previously, including a dihydrate stmcture and solvate stmctures containing different alcohols and other solvent molecules. The preparation of a pure (nonsolvate) crystalline phase of BTCA by crystal growth fi om solution is difficult due to the competitive formation of solvate phases. In such cases of materials that cannot be prepared as a pure (nonsolvate) phase by conventional crystal growth processes, a possible route to obtain the pure phase is to carry out desolvation of a solvate phase at elevated... 

The lanthanide elements, in their complexes with jS-diketones, tend to adopt interesting, higher coordination geometries. These compounds frequently crystallize as hydrates from which water removal without decomposition of the compound is difficult. Some structural information is summarized in Table 1. 2,2,6,6-Tetramethylheptanedionate chelates of the lighter lanthanides (La to Dy) can be obtained in nonsolvated form, crystallize in the monoclinic system and contain dimer units whereas the heavier analogues (Ho to Lu) tend to be orthorhombic with isolated six-coordinate monomers.128... 

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. 

As detailed by Koradia et al. [16], the DSC and TGA studies were run at a heating rate of 10 °C / min, and a nitrogen purge was set at 80 ml / min for the DSC work and at 20 ml/min for the TGA work. The DSC thermogram of Form-I consisted of three endothermic transitions, with temperature maxima at 181, 186, and 190 °C. The DSC thermogram of Form-II also consisted of three endotherms, characterized by temperature maxima at 177,179, and 182 °C. During the TGA analysis, no temperature-induced loss of mass was observed for either polymorph, indicating that the two polymorphic crystal forms were anhydrous and nonsolvated. 

Sulindac is a polymorphic substance and can exist in two nonsolvated enantiotropic crystal forms designated Forms I (191°C) and II (186°C). 

Crystallization, triggered by the addition of a miscible nonsolvent (antisolvent) to a solute-containing solvent system, can be used to produce microscale particles with narrow particle size distributions. The process is complex as it involves the coupling... 

The examples provided in the previous sections show that one of the means to obtain new pseudo-polymorphs is via solvent uptake. Since the co-crystallizing solvent may be present in the vapour phase (say water), one may regard the process that leads from an unsolvated to a solvated species (and reverse) as a supramolecular reaction whereby a given set of noncovalent bonds (those between molecules in the nonsolvated form, for example) are broken and a new set of noncovalent bonds (those between host and guest molecules) are formed as shown at the beginning of this chapter in Scheme 2. 

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