Polymorphic crystal

Unlike other synthetic polymers, PVDF has a wealth of polymorphs at least four chain conformations are known and a fifth has been suggested (119). The four known distinct forms or phases are alpha (II), beta (I), gamma (III), and delta (IV). The most common a-phase is the trans-gauche (tgtg ) chain conformation placing hydrogen and fluorine atoms alternately on each side of the chain (120,121). It forms during polymerization and crystallizes from the melt at all temperatures (122,123). The other forms have also been well characterized (124—128). The density of the a polymorph crystals is 1.92 g/cm and that of the P polymorph crystals 1.97 g/cm (129) the density of amorphous PVDF is 1.68 g/cm (130). 

Polymorphs and solvated crystals is generally observed in pharmacentical indnstry [1], The bioavailability, stability, solnbility, and morphology of the pharmacentical products are very influenced by polymorphs [2-7], therefore the control of the polymorphic crystallization is very important. The crystallization process of polymorphs and solvated crystals is composed of competitive nucleation, growth, and transformation from a meta-stable form to a stable form [4], Furthermore, the crystallization behavior is influenced by various controlling factors such as temperature, supersaturation, additives and solvents [8], In order to perform the selective crystallization of the polymorphs, the mechanism of each elementary step in the crystallization process and the key controlling factor needs to be elucidated [8], On the other hand, we reported for L-Glutamic acid and L-Histidine system previously [4] that the nucleation and transformation behaviors of polymorphs depend on the molecular stractures. If the relationship between molecular stmcture and polymorphic crystallization behavior is known, the prediction of the polymorphism may become to be possible for the related compound. However, detail in such relationship is not clearly understood. 

We reported in the previous papers [8, 9] that the effect of the operational factors such as temperature and solvents on the polymorphic crystallization of a thiazole derivative - 2-(3 -Cyano-4-(2-methylpropoxy)-phenyl)-4-methyl-thiazole-5-car-boxylic acid (BPT) - which is an enzyme inhibitor. In this paper, we synthesized the esters of BPT and studied the effect of the molecular structure on polymorphic nucleation systemically, and at the same time we also examined the solvent effect on the polymorphic nucleation of the ester. 

Crystal phase transitions are a possible target with present day computational means, when the transition is a smooth one and does not involve melting of the mother phase and subsequent recrystallization into the daughter phase. For crystalline OL-norleucine, an MD simulation has provided a detailed picture of the mechanism of a solid-solid second-order transition between two polymorphic crystal forms, showing concerted molecular displacements involving entire bilayers [61]. 

Chowhan [9] defined different pathways of physical instability of tablet formulations. These physical paths may involve one or more complex physical processes, e.g. change in polymorphism, crystallization, vaporization and adsorption. These pathways and thus the physical tablet parameters, are influenced by different types of variables formulation variables (e.g. solubility and hygroscopicity), in-process variables (e.g. moisture content) and aging variables (e.g. temperature and relative humidity). 

Detailed inspection of the crystal structure of 84 revealed that there is a certain space between reacting molecules in the crystal to allow initiation of photodimerization. The space, designated as a buffer zone , buffers the steric hindrance from which the reacting molecules suffer when they approach each other. The buffer zone is formed by the disordered piperidine rings in 84, but there is no extra space in the crystal structure of 83, and therefore photodimerization does not occur. Further evidence of this buffer zone was later reported by the same group, whereby polymorphic crystal forms had different reactivities toward photodimerization <1998BCJ321>. 

It is essential to understand how and when the polymorphs of drug substance in oral liquid dosage forms and suspensions can be controlled. One approach to study this phenomenon is to seed the formulation with a small amount of a known polymorphic crystal (other than what is used for the product), which is a common practice to rapidly determine what effect this may have on long-term storage. From these types of studies, the appropriate excipients can be used to preserve the specific polymorphic form desired. However, even when the drug in its crystalline form is studied extensively, there are cases when a previously unknown polymorph may be formed in solution and lead to precipitation (14). 

Several patents have recently published that claim the preparation of several different hydrates and polymorphic crystal forms of olanzapine. Dr. Reddy s Laboratories has recently disclosed the preparation of the monohydrate and the dihydrate of olanzapine. A mixture of 24 and A-methylpiperazine was refluxed in DMSO and toluene and then cooled (Scheme 8). Water was added and the precipitate was filtered and washed with water. The resulting solid was placed under vacuum at 30 to 50 °C to give the monohydrate or at ambient temperature to give the dihydrate. Recrystallization of crude olanzapine or one of its hydrates from CH2CI2 provided crystal form 1, whereas recrystallization from EtOAc provides crystal form 2. 

Crystallization, by definition, implies that the initial structure be a glass, followed by the nucleation and growth of a crystalline phase, be it the equilibrium one or a metastable phase. The process is a first-order transformation and involves atomic diffusion, or at least atomic shuttles. Types of crystallization reactions that occur include polymorphous crystallization, which is a composition invariant transformation such as that in Fe-B, and eutectic crystallization, T, in FeNiPB glass, where line lamellae of iron-nickel austenite and mclastable (FeNiJj PB phases grow cooperatively. 

Kitano, Y. On factors influencing the polymorphic crystallization of calcium carbonate found in marine biological systems. In Recent researches in the fields of hydrosphere, atmosphere, and nuclear geochemistry. Tokyo, 1964, 305-319. 

The solid-state properties like crystallinity, polymorphism (crystal structure), shape (morphology), and particle size of drugs are important in the stability, dissolution, and processibility of drugs. Some commonly used methods in solid-state studies include microscopy, hot stage microscopy with polarized light, x-ray powder diffraction (XRPD), thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), Fourier transform infrared FTIR/Raman, and solid-state NMR. 

Two alkaloids tentatively identified as hamayne (377) and 3-acetylhamayne (378) have also been reported to be components of Crinum zeylanicum L. (44). Although certain physical properties for the alkaloid assigned to be 377 and its diacetate were not identical with those previously reported for hamayne and hamayne diacetate, the H-NMR spectrum at 100 MHz of the base alleged to be hamayne was superimposable with that of an authentic sample of 377, and partial hydrolysis of its diacetate furnished a substance that was identical with 3-acetylhamayne (378) (44). While the discrepancies in the physical data for the alkaloid isolated from Crinum zeylanicum L. and hamayne might be due to polymorphic crystals, this was not established, and further structural work on these compounds should resolve the differences. 

Table 2 Crystal Data and Selected Structural Parameters of Three Polymorphic Crystals of 33...

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. 

Crystallisation is fundamentally a non-equilibrium phenomenon in which both kinetic and thermodynamic aspects contribute to the eventual structure. The final structure is a function in many cases of crystallisation conditions, and polymorphs (crystals made from the same molecules but with different packing arrangements) are common. Structures that form faster may well predominate over structures that are most stable. 

Braga, Dario, Polymorphism, Crystal Transformations and Gas-Solid Reactions, 7, 325. 

Kitano Y. and Hood J.D.W. (1965) The influence of organic material on the polymorphic crystallization of calcium carbonate. Geochim. Cosmochim. Acta 29, 29-41. 

The structure of each polymorph has been determined by X-ray crystallography. The colorless polymorph crystallizes in the monoclinic space group P2i/c, while the yellow polymorphs forms in the orthorhombic space group P2i2i2i. Figure 7 shows a drawing of the chain of cations that are found in the colorless, monoclinic polymorph, and Fig. 8 presents a view of the more complex chains present in the yellow, orthorhombic polymorph. In these two... 

Ueno, S., Yano, J., Seto, H., Amemiya, Y., Sato, K. 2000. Synchrotron radiation X-ray diffraction study of polymorphic crystallization in triacylglycerols. In, Physical Properties of Fats, Oils and Emulsifiers (N. Widlak, ed.), pp. 64-78, AOCS Press, Champaign. 

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