title: Analytical approaches to investigate salt disproportionation in tablet matrices by Raman spectroscopy and Raman mapping.
abstract: It has always been challenging to use spectroscopic methods to analyze salt disproportionation in a multi-component tablet matrix due to the spectral interference generated by the various excipients. Although combining Raman spectroscopy and chemometrics can be a powerful approach to study the extent of salt disproportionation, it was found in the present study that bulk measurements and chemometric modeling have obvious limitations when the targeted component is present at low levels in the tablet. Hence, a two-step Raman mapping approach was developed herein to investigate salt disproportionation in tablets with a low drug loading (5% w/w). The first step is to locate the area of interest where the drug particles reside throughout the tablet surface by using a statistically optimized sampling method termed deliberate sub-sampling. The second step, referred to herein as close-step mapping, utilize a step by step mapping of the targeted area to find more details of salt disproportionation in the tablet regions where the drug is concentrated. By using this two-step Raman mapping approach, we successfully detected the existence of minor species embedded in multi-component low drug loading tablet matrices, where bulk measurements from routine techniques usually lack of sensitivity. This approach will help formulation scientists detect and understand salt disproportionation and in situ drug-excipients compatibility issues in low dose solid dosage formulations.
authors.affiliation: Department of Industrial and Physical Pharmacy, Purdue University, 575 Stadium Mall Drive, West Lafayette, IN 47907, United States.
authors.forename: Haichen
authors.initials: H
authors.lastname: Nie
authors.affiliation: Preformulation Sciences, Merck & Co., Inc., 770 Sumneytown Pike, West Point, PA 19486, United States.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Analytical Sciences, Merck & Co., Inc., 770 Sumneytown Pike, West Point, PA 19486, United States.
authors.forename: Brian C
authors.initials: BC
authors.lastname: Marks
authors.affiliation: Department of Industrial and Physical Pharmacy, Purdue University, 575 Stadium Mall Drive, West Lafayette, IN 47907, United States.
authors.forename: Lynne S
authors.initials: LS
authors.lastname: Taylor
authors.affiliation: Department of Industrial and Physical Pharmacy, Purdue University, 575 Stadium Mall Drive, West Lafayette, IN 47907, United States.
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Byrn
authors.affiliation: Preformulation Sciences, Merck & Co., Inc., 770 Sumneytown Pike, West Point, PA 19486, United States; Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, 789 South Limestone Street, Lexington, KY 40536, United States. Electronic address: patrick.marsac@uky.edu.
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Marsac
mesh_terms: D002626:Chemistry, Pharmaceutical; D005079:Excipients / Q000032:analysis / Q000737:chemistry; D000077205:Pioglitazone; D012965:Sodium Chloride / Q000032:analysis / Q000737:chemistry; D013059:Spectrum Analysis, Raman / Q000379:methods*; D013607:Tablets; D045162:Thiazolidinediones / Q000032:analysis* / Q000737:chemistry*
chemical_list: D005079:Excipients; D013607:Tablets; D045162:Thiazolidinediones; D012965:Sodium Chloride; D000077205:Pioglitazone
keywords: Chemometrics; Drug excipient compatibility; Low drug loading; Pioglitazone; Salt stability; Statistically optimized sampling