Anhydrous carbamazepine

WW Young, R Suryanarayanan. Kinetics of transition of anhydrous carbamazepine to carbamazepine dihydrate in aqueous suspensions. J Pharm Sci 80(5) 496-500, 1991. 

Equation (15) has been successfully used to determine the relative amounts of anhydrous carbamazepine (C15H12N20) and carbamazepine dihydrate (C15H12N20 2H20) when they occur as a mixture [47]. The powder x-ray patterns of anhydrous carbamazepine and carbamazepine dihydrate revealed that the lines with d-spacings of 6.78 A (peak at 13.05° 26) and 9.93 A (peak at 8.90° 20) were unique to anhydrous carbamazepine and carbamazepine dihydrate, respectively (Fig. 5). In mixtures containing these two phases, anhydrous carbamazepine was first considered the unknown component while carbamazepine dihydrate was designated the matrix. The intensity ratios, Ai/(/ii)o were calculated (Table 4) for different values of xx (different weight fractions of... 

Fig. 5 The powder x-ray diffraction patterns of (a) anhydrous carbamazepine (/3-form), (b) anhydrous carbamazepine (o-form), and (c) carbamazepine dihydrate. (Reproduced with permission of copyright owners, Plenum Press and ICDD, from Refs. 47 and 49.)...

Table 4 The Intensity Ratios [/n/(/n)o] Calculated Eq. (15) for Mixtures of Anhydrous Carbamazepine and Carbamazepine Dihydrate...

In this series, fi and /x are respectively the mass attenuation coefficients of anhydrous carbamazepine and carbamazepine dihydrate. The calculated values were fi = 5.21 cm2 g-1 and /x = 5.87 cm2 gThe theoretical line in Fig. 5 is based on these values. 

Fig. 6 The relative intensity of the 6.78 A line of anhydrous carbamazepine (/3-form) as a function of its weight fraction in binary mixtures of anhydrous carbamazepine (/3-form) and carbamazepine dihydrate. The line is based on theoretical values (Table 5), while the data points are experimental measurements. (Reproduced with permission of the copyright owner, Plenum Press, from Ref. 47.)...

Therefore, a plot of intensity ratio as a function of the weight fraction of the unknown component should result in a straight line with a slope of 1. This equation was used to determine the relative amounts of two polymorphs of anhydrous carbamazepine in a mixture [49]. 

The /3-polymorphic form of anhydrous carbamazepine is official in the USP [3], The USP stipulates that, The X-ray diffraction pattern conforms to that of USP Carbamazepine Reference Standard, similarly determined. No limits have been set in the USP for the other polymorphs of anhydrous carbamazepine. Although several polymorphic forms of anhydrous carbamazepine have been reported, only the a- and /3-forms have been extensively studied and characterized [49]. A comparison of the powder x-ray diffraction patterns of these two forms revealed that the 10.1 A line (peak at 8.80° 26) was unique to a-carbamazepine, and so this line was used for the analysis (Fig. 5). It was possible to detect a-carbamazepine in a mixture where the weight fraction of a-carbamazepine was 0.02 at a signal-to-noise ratio of 2. Much greater sensitivity of this technique has been achieved in other systems. While studying the polymorphism of l,2-dihydro-6-neopentyl-2-oxonicotinic acid, Chao and Vail [50] used x-ray diffractometry to quantify form I in mixtures of forms I and II. They estimated that form I levels as low as 0.5% w/w can be determined by this technique. Similarly the a-inosine content in a mixture consisting of a- and /3-inosine was achieved with a detection limit of 0.4% w/w for a-inosine [51]. 

Suryanarayanan, R. (1989). Determination of the relative amounts of anhydrous carbamazepine and carbamazepine dihydrate in a mixture by powderx-ray diffractorngtrsym. Res., 6 1017-1024. 

Crystallization General Principles and Significance on Product Development Table 5 Nomenclature for anhydrous carbamazepine polymorphs... 

Suryanarayanan, R. Wiedmann, T.S. Quantitation of the relative amounts of anhydrous carbamazepine (C15H12N2O) and carbamazepine dihydrate (C15H12N2O 2H2O) in a mixture by sohd-state nuclear magnetic resonance (NMR). Pharm. Res. 1990, 7(2), 184-187. 

This approach was used to determine the weight fractions of anhydrous carbamazepine and carbamaze-pine dihydrate when they occurred as mixtures. Based on the mass attenuation coefficients of the anhy-drate and the dihydrate, the intensity ratios [/ii/(fii)o] were calculated as a function of the anhydrate content in the mixture (the line in Fig. 10). These were in good agreement with the experimentally obtained values of [fil/CfiOo]-... 

Suryanarayanan, R. Determination of the relative amounts of anhydrous carbamazepine and carbamazepine dihydrate... 

Hydrates can sometimes be obtained by simply suspending the anhydrous material in water, whereupon a form of Ostwald ripening occurs. For instance, aqueous suspensions of anhydrous metronidazole benzoate are metastable, and storage at temperatures lower then 38°C leads to monohydrate formation accompanied by crystal growth [65]. Sorbitol provides another example of this behavior, where slow cooling of a saturated aqueous solution yields long thin needles of sorbitol hydrate [66]. When suspended in water, anhydrous carbamazepine is transformed to carbamazepine dihydrate [67]. In other instances, hydrates can be obtained from mixed solvent systems. 

Carbamazepine is known to exist in both an anhydrate and a dihydrate form, with the anhydrate spontaneously transforming to the dihydrate upon contact with bulk liquid water [34]. The anhydrous phase is reported to be practically insoluble in water, but this observation is difficult to confirm owing to its rapid transition to the dihydrate phase. The rates associated with the phase transformation process have been studied and appear to follow first-order kinetics [35]. Interestingly, the only difference in pharmacokinetics between the two forms was a slightly higher absorption rate for the dihydrate [36]. The slower absorption of anhydrous carbamazepine was attributed to the rapid trans-... 

Raman spectroscopy has been shown to be useful in the study of the kinetics associated with the solution-mediated aqueous transformation of anhydrous carbamazepine to its dihydrate phase. Using a Raman immersion probe to establish the phase composition, the thermodynamics associated with the system were studied in ethanol-water mixtures through measurements of the solubility of both forms over the temperature range of 0-60 Raman spectroscopy was also... 

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