Abstract
In this study the potential of Fourier transform (FT)‐Raman spectroscopy as a method to probe the solid‐state form of active substances present in tablets and capsules is explored. Raman spectra were obtained from intact tablets and capsules containing enalapril maleate, prednisolone, form I and form II polymorphs of ranitidine, anhydrous and monohydrate theophylline, and warfarin sodium clathrate. Spectra were also collected from the corresponding drug substances. These studies show that it is possible to detect the active ingredients in the intact dosage form, even where the substance comprises <1% of the total mass of the tablet. Moreover, it is shown that, in some cases, Raman spectroscopy can also be used to investigate the solid‐state form of a drug present in the dosage form and even to determine if a mixture of forms are present. © 2000 Wiley‐Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 89:1342–1353, 2000
INTRODUCTION
The majority of drugs are formulated and delivered as solid dosage forms, typically tablets and capsules. It is well recognized that the solid‐state form of a drug substance can have a significant impact on both bioavailability and stability, thus the identification and characterization of these solid‐state forms is an essential part of the development process.1 Properties of interest include salt formation, solvate formation, polymorphism, and degree of crystallinity.
In cases where stability
EXPERIMENTAL SECTION
Ranitidine hydrochloride was purchased from Research Biochemicals International (Natick, MA). Theophylline anhydrate, ibuprofen, enalapril maleate, prednisolone, and warfarin sodium clathrate were obtained from Sigma. Amorphous warfarin sodium was supplied by Nycomed AB (Sweden). Microcrystalline cellulose was purchased from FMC Europe NV (Belgium) and alpha lactose monohydrate from DMV International (Netherlands). Theophylline monohydrate was prepared by equilibrating theophylline powder at
General Observations on Analysis of Active Ingredients in Intact Dosage Forms
Few excipients contain aromatic groups, thus the spectral regions characteristic of aromatic C–C and C–H stretching usually have peaks arising only from the active substance. Active substances also often contain functional groups not commonly found in excipients, for example carbonyl vibrations are usually easily identifiable. To illustrate this, Figure 1 shows the Raman spectrum of the drug ibuprofen and the spectra of two common tabletting excipients, alpha lactose monohydrate and
SUMMARY
For materials that exhibit polymorphism or pseudopolymorphism, it may be important to be able to directly determine the solid‐state form of the drug present in the dosage form and monitor the form with time under different storage conditions. This study shows that FT‐Raman spectroscopy is a useful method to investigate the solid‐state form of a drug present in intact tablets and is a valuable addition or alternative to other methods.