Raman spectroscopy as a complementary tool to assess the content uniformity of dosage units in break-scored warfarin tablets.

Due to the side effects of overdosing, the therapeutic dose of warfarin preparations must be very strictly controlled. In order to make it easier for the patient to take the required dose, two different strategies can be followed: The medicine can be commercialized in different dosages and/or tablets can be scored in order to make them easy to split. The splitting of the tablets introduces the question of how to control that the fractions contain the desirable amount of warfarin. The regulations regarding the content uniformity of dosage unit for scored tablets have changed considerably in the last 10 years, and they are still evolving. Warfarin is commercialized under the trademark of Aldocumar in four different preparations, containing 1, 3, 5 and 10 mg sodium warfarin per tablet. All these tablets are also scored, thus suggesting the possibility of splitting. A quantitative Raman method has been developed for the determination of warfarin in tablets and in the potential fragments, taking into account the score lines on the tablet surface. This method is suggested as an auxiliary procedure to verify the uniformity of API distribution in dividable tablets. A combination of a second derivative and standard normal variate (SNV) was used as spectral pre-treatments, and partial least squares (PLS) as the regression algorithm. The relative standard deviation in API content among portions was found to be less than 5%. An HPLC procedure has been used as a reference analytical method.

Enhancing sensitivity and precision on NIR reflectance determination of an API at low concentration: Application to an hormonal preparation.

The use of a mixed calibration sample set (intact production tablets and powdered doped samples used to enlarge calibration range) is a usual procedure for the NIR reflectance determination of the API content of a pharmaceutical solid preparation. However, the high difference in scattering properties and the intrinsic low sensitivity of NIR make difficult the achievement of a good precision when API is at a low mass proportion (≈1%, w/w). The compression of the calibration powdered samples has been studied as a very simple procedure to enhance the sensitivity of NIR reflectance measurements and, consequently, to improve precision. Different pretreatments (SNV, 1D, 2D and their combinations) have been applied to reduce the spectral difference between powdered and compressed samples. Although none eliminates completely this difference, the combined pretreatment SNV+2D has proved to be the one with a better performance. Results obtained by using both calibration sample sets (powdered and compacted) in the quantification of estradiol valerate (VE, 2mg/tablet, ≈1.6%, w/w) and medroxyprogesterone (MPA, 10mg, ≈8%, w/w) in intact tablets of the hormonal preparation show that a slight but significant improvement in precision is obtained when using compacted samples for calibration. A HPLC procedure was developed to be used as reference method.