Polymorphic composition

The isolation of crystalline products having mixed polymorphic compositions (often referred to as concomitant polymorphism) remains a topic of interest, even though the phase rule predicts that a system at equilibrium consisting two components (solvent + solute) and three phases (solution + Form I + Form II) is uni variant. Hence, for crystallizations performed at a fixed pressure (typically atmospheric) the system becomes nonvariant and genuine equilibrium can exist at only one temperature. Therefore, concomitant products must be obtained under nonequilibrium conditions. Flexibility in molecular conformation was attributed to the concomitant polymorphs of a spirobicyclic dione [34] and of 3-acetylcoumarin [35],... 

The use of parallel beam optics as a means for determining the polymorphic composition in powder compacts has been discussed [45]. In this study, compressed mixtures of known polymorphic composition were analyzed in transmission mode, and the data were processed using profile-fitting software. The advantage of using transmission, rather than the reflectance, is that the results were not sensitive to the... 

Montgomery et al. (1988) have reported that in systems in which attempts were made to prepare alloys of /3-(ET)2l3 with jS-(PT)2l3 (PT = 3-XI) they apparently obtained single crystals of (ET)2l3 which were in fact mixtures of a and p forms. The phenomenon in this system was initially detected and then confirmed by ESR measurements, which were subsequently used to develop a quantitative procedure for the determination of the polymorphic composition of such mixed single crystals . There are other scattered reports in the literature of the phenomenon (e.g. Freer and Kraut 1965), which has been termed composite crystals and has been discussed in detail by Coppens et al. (1990) and Fryer (1997). 

Patel, A. D., Luner, P. E. and Kemper, M. S. (2001) Low-level determination of polymorph composition in physical mixtures by near-infrared reflectance spectroscopy. J. Pharm. ScL, 90, 360-70. [129]... 

In one study, Raman spectroscopy was used to analyze binary mixtures of the two forms of chlorpropamide.70 A complete series of calibration samples ranging from 0% to 100% in each form were prepared, and characterized between 400-1800 cm-1 and 2800-3200 cm-1. Through the use of factor analysis, good correlation of predicted versus theoretical polymorphic composition was obtained in studies of instrumental and between-sample reproducibilities. 

The easiest and usually most precise quantification of polymorphic composition is achieved when a sensitive heteronucleus (such as fluorine or phosphorus) is present in the molecule, and its spectrum shows chemical shift differences between the polymorphs. Direct polarization experiments of these nuclei are sensitive, and therefore the polymorphs can be quantified quickly directly from the peak ratios. The limit of quantification can be well below 1% of one form in the presence of other forms. As an added advantage, the spectra of these nuclei are usually very simple to analyze, since only a very limited number of resonances are typically present in the spectrum. 

Small-molecule manufacturing is also a system of checks and balances in which any small increase or decrease in reaction step performance can have consequences downstream. As always, patient safety is of utmost concern. Any manufacturing process changes that alter an impurity level or introduce a new impurity, even as low as 0.1%, may necessitate additional toxicity studies and documentation for review and registration. In addition, an improvement in reaction efficiency may alter bulk product crystallinity or polymorph composition that can affect formulation and human pharmacokinetics. Once process parameters are finalized, the ultimate manufacturing step involves selection of a manufacturing site, transfer of the process, and preparation of a demonstration batch followed by a minimum of three consecutive validation batches of API to demonstrate that the synthesis of material can be controlled within analytical specifications and reproducibility. 

Table I. Polymorph Composition as Function of Cellulose DP and Temperature of Crystallization...

Menyhard et al. [9] reported the generation of polymer blends based on the P-modification of polypropylene. The authors studied the melting and crystallization characteristics as well as the structure and polymorphic composition of the blends by polarized light microscopy (PLM) and differential scaiming calorimetry (DSC). It was observed that the most important factor of the formation of the blend with P-crystalline phase when semicrystalline polymers were added to isotactic polypropylene (iPP) was the a-nucleation... 

Broda, J. (2004c). Polymorphic composition of colored polypropylene fibers. Crystal Groivth Design, Vol.4, Issue 6, pp. 1277- 1282. 

Insley s (1936) morphological classification of belite into Type I, II, and III is particularly valuable because it is not confused with genetic or polymorphic restrictions. Even though Insley discussed polymorphic, compositional, and temperature variations, the morphological classification was apparently meant to be primarily observational with interpretation as a derivative. With progress in defining the relationships between polymorphic varieties of belite (alpha, alpha prime, and so on) and their common forms, we may eventually understand the rather complex genesis of the phases. For now, in the author s opinion, the nomenclature should remain descriptive. 

Finally, a new method to determining the polymorphic composition in intact compacts, using parallel-beam X-ray powder diffractometry, has also been developed. 

The polymorphic composition of extruded p-nucleated iPP products depends significantly on the cooling conditions and on the take-off speed. Sheets of almost pure p-iPP were successfully produced by means of a laboratory extruder (Viskosystem) with wide-gap die and equipped with a calendering unit composed of three superimposed, thermo-regulated compression rollers. The temperature of the first two compression rollers should be set between 105-110°C, i.e. in the temperature range between T( p) and T(pa) where the formation of pure p-iPP is... 

Some properties of p-iPP differ significantly from those of a-iPP. In comparison with a-iPP, fi-iPP possesses lower crystal density, melting temperature and fusion enthalpy, but a similar glass transition temperature (Table 3). The chemical resistance of p-iPP seems to be lower than that of a-iPP. The former could be selectively extracted with hot toluene from samples of mixed polymorphic composition [8]. 

The 7-modification of iPP (y-iPP) may form in degraded, low molecular weight iPP or in samples crystallized under high pressure [5, 6]. Certain propylene copolymers with low comonomer content (4-10 wt.%) crystallize preferentially in y-form, as well. y-iPP has a face-centred ortho-rombic unit cell with parameters a = 0.85 run, b = 0.993 nm and c = 4.241 nm containing isochiral helices. The cell structure proposed by Bruckner et al. [5] is unique in polymer crystallography the chain axes in adjacent crystal layers are not parallel. The angle between the chain stems is about 80°. y-iPP is not usually observed as an independent phase, but crystallizes with and within the a-spherulites. According to Lotz et al. [7], the positive spherulites observed in samples with mixed polymorphic composition of a- and y-iPP are probably made of a... 

The melting DSC curves reflected the effect of the final fusion temperature on the polymorphic composition fi-, -crystal forms) of the sample. 

Polymorphs/composition Relative fractions Relative intensities of the corresponding reflections... 

Menyhard A, Varga J. The effect of compatibiUzers on the crystallisation, melting and polymorphic composition of p-nucleated isotactic polypropylene and polyamide 6 blends. Eur Polym J 2006 42 3257-68. 

We have subsequently shown (see section 4.3.) that injection molded specimens, which were chilled in air, have mixed polymorphic composition where the skin coasists of a-ciystals while the core comprises /3-spherulites. This fact supports the existence of a lower critical temperature limit for the formation of /3 PP. 

At low mold temperatures (20 to 60° C) the thicker (3 mm or more) plates have mixed polymorphic composition where the skin consists of a-ciystals while the core comprises /S-spheruiites. The chaipy and Izod impact strength of thicker specimens are summarized in Tabs. 4, 5. 

Fig. 4.18 (a) Visible light absorption of An NPs supplied on different photocatalysts originating from surface plasmon oscillations of An (b) EPR spectra of An NPs supported on Ti02 with different polymorph compositions (c) the proposed charge transfer based on EPR analysis (Reprinted with permission from Ref. [70] Copyright 2012, American Chemical Society)... 

As for polymorphic composition of the films, the most significant p-diffraction peak is visible in the film made of B-PP-H material and solidified at 90 °C. This peak is also detectable in the film produced from B-PP-R at 90 °C. In the case of chill roll temperature of 30 °C, the content of P phase is virtually insignificant in all tlie films. It is interesting to note that the P-diffraction peak is only shghtly prononnced in the films solidified at 60 °C (even in B-PP-H) although they possess significant ciystalline amounts. 

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