Excipient Library

FIGURE 22 Excipient library with the result of a PCA analysis for identity testing. 

AN EXCIPIENT LIBRARY APPROACH TO ANALYTICAL DEVELOPMENT FOR LOW-DOSE, SOLID ORAL DOSAGE FORM DRUG PRODUCTS... 

To address the challenges in low-dose dmg product development, we recently initiated an excipient library approach, which follows the philosophy, an ounce of prevention is worth a pound of cure. The idea was to create a library of excipient-related information such as chromatographic background, stability, compatibility, and effect on dmg recovery and release. This library serves as a general tool for low-dose dmg development. Using the library, development teams are able to screen for the most appropriate excipients at the development planning/design phase on the basis of both formulation and analytical requirements. This approach aims to reduce analytical development difficulties where possible. 

Excipient Library Approach for Low-Dose Impurity Analysis... 

USE OF EXCIPIENT LIBRARY 14.4.1 Excipient Screening Using the Library... 

The authors are grateful to a number of colleagues at Eli Lilly and Company, including Drs Bernard Olsen and Steven Maple for their encouragement and general discussion, Dr Jack Zheng for extensive discussion on the Excipient Library concept and approach, Ms Li Liu... 

As the initial addition to the library, we collected excipient-chromatographic background information on 36 common excipients. In the following sections, we will discuss why we collect this information, what effect the excipient background has, how we control the background, and finally, how we utilize the library to facilitate dmg development. 

Carter and Ward have identified a surface-mediated nucleation mechanism that involves a geometric shape match between planes of a ledge site on the substrate and planes of prenucleation aggregates. They have applied these concepts to the directed nucleation of polymorphs. ° This work provides us with the attractive possibility that a library of organic seeds can be used to control polymorphism, or to search for unknown polymorphs. Interpretations of molecular assemblies between solute and additive (seeds, substrate surfaces, excipients, and solvents) molecules may prove beneficial in selectively crystallizing or screening polymorphic systems. 

Two comprehensive references are available that list type and concentration of all excipients used in commercial sterile formulations that should be part of every sterile formulation scientist s library. ... 

A fiber optic probe was used by Blanco et al. for analysis of spasmoctyl samples with the active compound otilonium bromide and cellulose, maize starch, sodium starch glycolate, and glyceryl palmitostearate as excipients. Another study from this group covered the identification, qualification of the substance, and the quantification of the active component. A library search with a comparison to the near-infrared spectra of 163 pharmaceuticals was involved. An on-line monitoring for the determination of the endpoint of polymorph conversions in pharmaceutical processes was recently described further investigations into this field were published and are noted previously. ... 

NIRS is useful for the analysis of both raw materials and finished dosage forms. Qualitative determination of pharmaceutical raw materials using NIRS was reported as early as 1982. The largest variations in commercially produced excipients and actives appear to be in moisture content and particle size. These parameters may be monitored by NIRS with relative ease. Incoming substances may be tested for immediate identity confirmation on the receiving dock by inserting a fiber optic probe directly into the barrel. Spectral data for each lot of material purchased may be saved and added to the growing spectral reference library. 

Guidelines (2003) Medicinal products for human use Safety, environment and information. Excipients in the label and package leaflet of medicinal products for human use. July 2003. http // www.ema.europa.eu/docs/en GB/document library/Scientific guideline/2009/09/WC500003412.pdf... 

Knowledge of synthetic impurities and degradation products can be derived from the historical information that has accumulated for the drug substance/prod-uct. Ideally, a library of impurity and degradation compound reference standards is synthesized and characterized and sufficient quantities are made available. These compounds or an impurity cocktail can be spiked into the pure drug substance and any excipients (placebo sample matrix) to determine if the matrix interferes with the quantitation of the compound(s) of interest by comparing to an unspiked sample and sample diluent. 

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