Chapter 1
Excipient Characterization

David Good and Yongmei Wu

Drug Product Science and Technology, Bristol-Myers Squibb Company, New Jersey, USA

1.1 Introduction

A comprehensive understanding of the chemical and physical properties of common pharmaceutical excipients is essential to the design of high-quality drug products that provide consistent performance. In many pharmaceutical formulations, the drug substance can be susceptible to chemical and physical changes induced by the properties of the bulk excipients [1]. This is often more pronounced for drug products where the ratio of excipient content to drug is very high (i.e., low drug loading formulations). In recent years, the regular advancement of highly potent and selective drug candidates has led to more formulations that are predominately comprised of excipients and incorporate lower levels of the active pharmaceutical ingredient (API). In addition, potent drug candidates often exhibit low aqueous solubility and can require enabling formulation technologies, which include unique excipients and/or processing steps, to provide the desired clinical exposure at some stage during the clinical development program [2]. These trends in drug substance properties as well as the implementation of quality by design (QbD) product development strategies place an increased emphasis on detailed characterization of excipients to achieve robust formulations and processes.

This chapter focuses on a fundamental description of the chemical and physical properties of excipients, the associated characterization methods, and implications for formulation and processing of drug products. Numerous publications such as USP monographs provide an introduction to basic compendial excipient test methods and properties. These compendial descriptions and methodologies serve the basis for classification and release testing of materials; however, additional characterization is often required in the selection and processing of excipients. The content presented in this chapter provides the reader an introduction to the current methodologies and excipient properties that are most significant for the development of a commercial drug product. Included in this chapter are detailed descriptions of excipient stability and impurities as well as material variability that can influence drug product performance. These considerations are essential to the successful preparation of dosage forms for preclinical and clinical development programs. As such, this material is valuable to all scientists and students involved in pharmaceutical research from the discovery to commercial formulation and manufacture stages.

1.2 Chemical and Physical Properties

There is extensive diversity in the chemical structural elements and physical properties of pharmaceutical excipients. Excipients can be categorized in common chemical classifications including inorganics (e.g., iron oxide as pigments, calcium phosphate as filler), small molecule organics and their salts (e.g., mannitol diluent/sweetener, sodium citrate alkalizing agent), as well as polymeric excipients that can be fully synthetic or naturally derived (e.g., hypromellose, starch). The diversity is further expanded by an abundance of natural product derivatives where feedstock variability (raw materials), isolation, and chemical processing can impact the purity and structural attributes. Table 1.1 provides an overview of several common functional and chemical classifications of excipients with USP monographs. In total, there are 230 excipient monographs available to formulators with published monographs in the Handbook of Pharmaceutical Excipients. Each monograph can represent numerous material grades (i.e., polymer molecular weight, degree of substitution, particle size distribution, morphology) and be available from multiple manufacturers. Alternate manufacturers often employ different synthetic schemes or isolation techniques that can result in slight differences in physical properties (i.e., melt temperature, crystallinity, loss on drying, particle size) and chemical profile (i.e., trace impurities). The methods of manufacture of excipients are often proprietary trade secrets and therefore it is incumbent on formulators to identify essential material property profiles of key excipients, which is reviewed later in this chapter. To generate this knowledge formulation scientists rely on numerous compendial excipient characterization methods and develop novel methods to analyze key quality materials attributes of a formulation.

Table 1.1 Examples of Excipients with Indication of Chemical Classification, Key Common Compendia Tests, and Other Specific Tests That Can Be Utilized by Manufacturers and Formulation Scientists

Organic (Synthetic, Natural) Key Characterization Methods Excipient function Inorganic Small molecule Polymeric Compendial (Figure 1.1) Others Diluent CaHPO4 Lactose, mannitol Starch, cellulose (powdered or microcrystalline) PSD: <429> LDS, sieving <786>, density, bulk, tap, true <616, 699>; <616>crystallinity;
<731> LOD; water content <921>; SSA <846>; flow <1174>;
Particle shape
Particle size distribution <429>
Surface area
Thermal properties
Polymorphic form
Crystallinity <616>
Amorphous content Water activity, GPC, XRD, ssNMR, SEM, AFM, TEM, FBRM, Binder CaCO3 Dextrates, maltitol Copovidone, hydroxypropyl cellulose Disintegrant Magnesium aluminum silicate - Crospovidone, sodium starch glycolate, croscarmellose sodium, polacrilin potassium Lubricant Talc Magnesium stearate, sodium stearyl fumarate, stearic acid - Glidant SiO2 colloidal, MgO, talc - - Colorant Iron oxides, TiO2 Tartrazine, sunset yellow FCF indigo carmine, etc. - Coating and film-forming agents ZnO Sucrose Cellulose acetate phthalate, polyvinyl acetate phthalate, polyethylene oxide, hypromellose, polyvinyl alcohol, etc. Film strength and adhesion Plasticizer - a-Tocopherol, butyl stearate, benzyl benzoate, etc. Propylene glycol, polyethylene glycol 911, 881, 891 Rheology, thermal mechanical analysis (TMA) Flavor/sweetening/fragrance - Vanillin, menthol, fructose, ethyl lactate, monosodium glutamate, etc. - Electronic tongue Antioxidant a-Tocopherol, butylated hydroxytoluene (BHT), ascorbic acid - UV HIL exposure

Source: Rowe [3]. Reproduced with permission of RPS Publishing.

Together these USP general chapters on test methods (Figure 1.1) cover elements of the chemical and physical properties at the molecular level (e.g., NMR, IR, NIR, and UV spectrophotometry) as well as that of particulates (e.g., distribution of particle sizes, optical microscopy) and bulk material (e.g., viscosity, loss on drying, thermal analysis). While these monographs and methods provide the core testing protocols for routine certification of materials for release specifications, certificate of analysis, and compendial compliance, it is routine for manufacturers and formulation scientists to conduct extensive supplemental testing to ensure the quality and consistency of excipient properties. While it is of great interest to formulators to conduct additional noncompendial functional testing regarding the distinct critical material properties of a developmental product, there is routine attention given to the core information recorded in compendial tests. This is exemplified by publications that demonstrate the compilation and statistical analysis of reported CoA data to identify material properties that are unique to a manufacture location or period of time [4]. This type of analysis is commonly pursued by quality groups that track results of certified testing and can be valuable to formulators seeking to identify critical quality attributes by incorporating excipient lots that most represent the material diversity in the early screening and development stages. In addition, the Excipient Consortium (NIPTE - Advanced Pharmaceutical Materials Knowledge Center) and other similar groups provide extensive testing and make data and materials available to membership composed of universities, manufacturers and pharmaceutical companies. Searchable databases of material records and supplemental functional testing (e.g., shear cell and compaction testing) greatly improve the ability of formulators to project potential variability to critical material attributes and design robust formulations to accommodate the typical range of material properties.

Figure 1.1 Classification of USP/NF compendial testing methods specified for excipients....