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The X‐ray procedure for estimation of the degree of crystallinity in digoxin is based upon measurement of the total X‐ray scattering and the scattering from crystalline regions of the drug. The infrared procedures are based upon measurement of the peak height ratios, 1775/1618 and 3095/1618 cm−1. Correlation between results obtained by the two methods is good. These methods are of value in the physico‐chemical characterization of digoxin, particularly as the properties may be altered by comminution.

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for amorphous bulk polymers by Mandelkern, Quinn, and Flory (70). In their interesting paper, these authors explained the observed induction period and crystallization kinetics in terms of the concept of concurrent nucleation and crystal growth, just as has been done in the present work.The present measurements were all made at one temperature. It would be of considerable interest to obtain data at several temperatures in order to determine the temperature coefficients of k and t and to evaluate the effect of temperature on the crystallization kinetics.

HPLC and 'H-NMR methods for the quantitation of the (R)-enantiomer in (-)-(3-timolol maleate were developed and validated. The HPLC method requires a 25 cm x 4.6 mm 5 p, m Chiracel OD-H (cellulose tris-3,5-dimethylphenylcarbamate) column, a mobile phase of 0.2% (v/v) diethylamine and 4% (v/v) isopropanol in h e m e at a flow rate of 1 d m i n and UV detection at 297 nm. A system suitability test was devised to venfy the separation of the (R)-and (3-enantiomers of timolol from other drug-related impurities. The NMR method requires the use of a high-field NMR spectrometer (>360 MHz) and a chiral solvating agent, (-)-(R)-Z, 2,2-trifluoro-l-(9-anthrylethanol) (R-TFAE). The limits of quantitation were 0.05% and 0.2% ( d m ) for HPLC and NMR, respectively. The methods were applied to the determination of the (R)-enantiomer in eight lots of raw material. The results for the two methods were in very good agreement, with results ranging from 0.1 to 4.1% KEY WORDS: timolol maleate, quantitation of enantiomers by HPLC, quantitation of enantiomers by NMR, optical purity, chiral separation, cellulose tris-3,5-dimethylphenylarbamate (Chiracel OD-H), chiral solvating agents Tim0101 maleate, I, marketed as the (Sbenantiomer, is a p-adrenergic blocker used for the treatment of hypertension, angina pectoris, and glaucoma. Existing purity standards for timolol maleate include a USP' monograph specifying a limit of 0.4% ( d m ) on individd related compounds, as determined by TLC, and a requirement that the specific rotation be between -ll. 7" and -12.5", calculated on the dried basis, determined with a mercury source at 405 nm in a 50 mdml solution in 1.0 N hydrochloric acid at 25°C. These specifications for specific rotation are the same as those reported by Mazzo and Loper.2 Recent developments in chiral technology and the low absolute value for specific rotation make this drug a good candidate for the development of new methods for the determination of enantiomeric impurities in raw materials.There have been reports in the literature on the separation of timolol enantiomers by HPLC using p-~yclodextrin~ (without derivatization) and Pirkle-type' columns after derivatization with a-naphthyl isocyanate. The separations shown were for rac-timolol. These methods were not validated for the quantitation of low levels of the (R)-enantiomer in (-)-(S)-timolol maleate. The resolutions obtained were low (1.08 on the Pirkle-type column and 3.00 on the p-cyclodextrin column), the (R)-enantiomer eluted on the tail of the 6)-timolol peak on the p-cyclodextrin column, potentially making quantitation of low levels &cult and problems associated with A method for the HPLC separation of timolol enantiomers on a cellulose tris-3,5-dimethylphenylcarbamate chiral stationary phase (Daicel Chiracel OD) was published by AboulEnein and Islam6 in 1990. Although it had been optimized for the separation of the (R)-and (S)-enantiomers of rac-timolol (resolution = 4.00), no data were provided on the selectivity of this method in the presence of other...