Quantification of Pharmaceutical Compounds Based on Powder X-Ray Diffraction with Chemometrics

Abstract

We propose an approach for the simultaneous determination of multiple components in pharmaceutical mixed powder based on powder X-ray diffraction (PXRD) method coupled with chemometrics. Caffeine anhydrate, acetaminophen and lactose monohydrate were mixed at various ratios. The samples were analyzed by PXRD method in the ranges of 2θ 5.00-30.0 and 35.0-45.0 degrees. Obtained diffractograms were analyzed by conventional peak intensity method, multi curve resolution (MCR)-alternating least squares (ALS) method and partial least squares (PLS) method. Constructed PLS models can most accurately predict the concentrations among different methods used. Each regression vector of PLS correlates not only to the compound of interest but also to the coexisting compounds. The combination of PXRD and PLS methods is concluded to be powerful approach for analyzing multi components in pharmaceutical formulations.Key words powder X-ray diffraction; partial least square; pharmaceutical formulationThe polymorphs and pseudo-polymorphs (hydrates and solvates) of pharmaceuticals exhibit different physicochemical properties such as solubility, dissolution rate, stability and hygroscopicity. These properties strongly relate to the pharmaceutical properties in their dosage forms such as specific bioavailability, efficacy, stability and toxicity.1) Pharmaceutical regulations are, therefore, required for producing appropriate bulk drugs, the crystalline modifications of which (i.e., polymorphism) are well specified or precisely controlled. 2)Powder X-ray diffraction (PXRD) analysis is the most frequently used method for identifying crystalline modifications and for determining their contents in bulk powders.3) Any crystals have their own PXRD patterns. Pharmaceutical formulations are, in general, composed of multiple components including excipients. PXRD is, therefore, useful to identify crystalline compounds in the formulation and to determine their amounts in a non-contact and non-destructive fashion. 4,5) However, PXRD method has large relative errors, typically around ±5%. Such shortcoming of PXRD method is serious when two or more components having broad and overlapping X-ray diffraction peaks are contained in one formulation.Regulatory authorities such as the U.S. Food and Drug Administration and the International Conference on Harmonization have requested to use Process Analytical Technology (PAT) in order to reduce the production risk of inferior pharmaceuticals.6) Since the introduction of guidelines for PAT, online and real-time analysis have increasingly been accepted in pharmaceutical industry as a tool for monitoring and controlling manufacturing process. Non-contact methods, such as PXRD analysis, near infrared (NIR) spectroscopy and terahertz spectroscopy have been paid attention as important tools for PAT. 6) Chemoinformatics are employed by pre-formulation scientists for the quantitative and qualitative analyses of NIR because they can provide ideal means for extracting quantitative information from complex spectra of mult...

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