ReviewEnsuring Product Stability – Choosing the Right Excipients
Introduction
Stability is an imperative quality attribute for the acceptance of pharmaceuticals to be marketed. Stability can be defined as the capability of the product in a specific container‐closure system to remain within the specifications (physical, chemical, microbiological, therapeutic and toxicological) established to ensure its identity, purity, quality and safety throughout its period of storage and use.1
Stability can be affected by temperature, light, oxygen, pH and water. Of these, water, either in the liquid state or in the gaseous state as moisture, is often regarded as the putative reactant. Moisture can negatively affect drug or drug product stability by inducing hydrolysis or secondary reactions that are mediated through water.2 Examples of drug properties that can be affected by moisture are listed in Table 1. Moisture is commonly encountered in manufacturing processes that involve water such as wet granulation, aqueous coating, spray drying, lyophilization and crystallization. Such processes can result in unintended exposure of drugs or drug products to moisture, which may compromise their stability. Nonetheless, a certain amount of moisture is necessary for tableting and reduction of electrostatic charge.3, 4, 5, 6 Although moisture sensitive drugs are more stable when they are formulated as solid dosage forms as compared to liquid dosage forms, the risk of exposing the drugs to moisture during their shelf-life is not entirely eliminated. Also, it is neither practical nor feasible to completely remove moisture from the environment. Hence, acquiring a basic understanding of the interaction of moisture with formulation components is imperative to the development of moisture control strategies for formulations containing moisture sensitive drugs.7, 8, 9
Moisture in pharmaceutical solid dosage forms come from various sources, which can be broadly categorized into external and internal sources. External sources refer to moisture that comes from the environment during manufacturing, packaging, storage, transport, and usage. Internal sources of moisture include moisture that is inherent in the excipients (e.g. water of crystallization) or moisture that is sorbed into the excipients from the environment. Various moisture control approaches to address the different sources of moisture are summarized in Fig. 2. Control of moisture from external sources can be achieved by using a dehumidification system to regulate relative humidity (RH) in the facility to be within 30% to 50% while minimizing RH fluctuations.10 The use of appropriate packaging and coating materials is also essential to minimize entry of extraneous moisture into the products.11, 12, 13, 14 Internal moisture can be controlled by using excipients that are able to reduce the interactions between moisture and moisture sensitive drugs.15,16
The use of excipients as a moisture protectant may be counterintuitive as several studies have shown that moisture uptake by excipients can lead to degradation of moisture sensitive drugs.8,17 However, the ability of excipients to interact with moisture can be utilized to reduce the reactivity of moisture. As excipients are an integral part of formulations, it is in the interest of formulators to understand moisture protection of pharmaceutical products in relation to the choice of excipients. A better understanding of moisture-excipient interactions is instrumental during pharmaceutical product development, where moisture sensitivity is an issue, to ensure robust product performance. In this review article, the interaction of moisture with excipient(s) and its implications on the stability of moisture sensitive drugs are discussed. Specifically, this review will be focusing on the use of excipients as a moisture protectant in oral solid dosage forms.
Section snippets
Moisture-Solid Interactions
An awareness of moisture-solid interactions is fundamental to understanding moisture related stability problems. Upon contact with solids, moisture can either interact at the surface (adsorption) or penetrate into the bulk structure (absorption) (Fig. 1).18 Adsorption of moisture is initiated by the formation of monolayer moisture (i.e. a primary layer of water molecules tightly bound on available surfaces of solids). Subsequent adsorption of moisture on the monolayer moisture forms multilayer
Analytical Techniques to Characterize Moisture Properties of Pharmaceutical Materials
To gain a mechanistic understanding of the interaction of moisture with formulation components, it is important to characterize the moisture properties of the materials. Several analytical techniques have been used to evaluate moisture-solid interactions. These techniques can be used to complement findings from stability analyses to guide the formulation development. Due to the complexity of moisture-solid interactions, a slew of analytical tools (including, but not limited to, water activity
Water Activity and Moisture Sorption
Water activity describes the availability of moisture for reaction. More specifically, it is the ratio of the equilibrium partial vapor pressure of water in the system to the equilibrium partial vapor pressure of the pure liquid, at a given temperature. Therefore, water activity is related to the escaping tendency or fugacity of moisture.21 Water activity ranges from 0 to 1. The closer the water activity is to 0, the lower is the availability of moisture for reaction. In contrast, moisture
Molecular Mobility of Water Molecules
The mobility of moisture associated with excipients in solid dosage forms is thought to be a critical factor in determining the stability of pharmaceutical products. Moisture of greater mobility is more readily available for reaction.
Solid-state nuclear magnetic resonance (ssNMR) is useful for examining moisture dynamics in solids. Spin-lattice or longitudinal relaxation time (T1) and spin-spin or transverse relaxation time (T2) have been used as indicators of the relative molecular mobility of
Energy of Moisture Binding
The strength of moisture binding to solids can be associated with the ease of availability of the moisture for reaction. The energy of moisture binding on solid materials can be evaluated by measuring the heat of moisture sorption using a calorimetry technique.
Differential scanning calorimetry (DSC) measures the total heat flow response as a result of subjecting the materials to various heating or cooling rates. DSC has been used to obtain quantitative information on states of moisture, i.e.
Use of Excipients in Formulations Containing Moisture Sensitive Drugs
Excipients are non-pharmacologically active components that are included in a formulation to convert the active drug substance into a pharmaceutical dosage form to aid in delivery of the drug to the patient via an appropriate administration route. Typically, excipients function as a diluent or filler, disintegrant, binder, lubricant, colorant or preservative to improve processing (e.g. improving powder flow, powder compactibility) or confer suitable properties (e.g. modifying drug release,
Controlling Physical Transformation of Drugs Using Excipients
Some drug substances have different physical forms – anhydrate or hydrate and different crystallinity. Several examples of moisture related physical transformation of drug substances are shown in Table 1. Drug bioavailability is closely related to its physicochemical properties. Therefore, it is crucial for drug substances to maintain the same molecular structure during their shelf-life.
Certain grades of polyvinylpyrrolidone (PVP) have been utilized to modulate the kinetics of phase
Retarding Moisture-Induced Drug Degradation Using Excipients
While excipients have been around for decades, there are not many commercially available excipients that are being promoted for use with moisture sensitive drugs. Of the known excipients, only pregelatinized maize starch (PGS) from Colorcon (Starch1500) and a co-processed excipient that contains starch and PGS from Seppic (Sepistab ST200) are being marketed for their role in protecting moisture sensitive drugs. The moisture protective effect of PGS is attributed to the ability of PGS to bind
Effects of Excipient Crystallinity on Moisture Related Product Instability
Based on the molecular arrangement, solids can be broadly grouped into crystalline, amorphous and partially amorphous solids. Crystalline solids are characterized by the orderly and repeating arrangement of the molecules, whereas amorphous solids lack the orderly molecular packing of crystalline solids.57,58 The molecular arrangements of solids can affect their moisture-solid interactions. Typically, interaction of moisture with crystalline solids is limited to surface interaction. In contrast,
The Role of Water of Crystallization in Drug Stability
Several studies have investigated the stability of moisture sensitive drugs when formulated with hydrous and anhydrous forms of excipients. The degradation rate of ASA in tablets formulated with lactose monohydrate has been shown to be comparable to the ASA degradation rate in tablets formulated with lactose anhydrate when stored at conditions lower than 80% RH/80°C. This observation suggested that at conditions lower than 80% RH/80°C, even though water was present in the crystal structure of
The Role of Lipophilic and Waxy Excipients in Moisture Protection
Lipophilic and waxy excipients interact poorly with moisture and can repel moisture. Additionally, preparation of formulations containing such materials is typically performed in the absence of an aqueous medium or water. Therefore, the risk of unwanted moisture exposure during production involving moisture sensitive drugs is reduced. Kowalski et al.66 prepared granules containing a moisture sensitive drug (proprietary drug of dipeptidylpeptidase IV) with hydrogenated castor oil or stearic acid
Excipient Variabilities
Excipients come in various grades and each grade exhibits different properties. Variation in properties of excipients is known to influence performance of the excipients and the resultant product properties.68,69 Of relevance to stability of moisture sensitive drugs is the interaction of the excipients with moisture. Studies have reported the influence of properties, including particle size, structure (porosity and accessibility of water molecule binding sites), hydrophilicity and
Conclusion
Excipients have an essential role in pharmaceutical formulations. However, the role of excipients as a moisture protectant is less known. This review provided an overview of methods to control moisture by using excipients, particularly for oral solid dosage forms from the perspective of excipients. Specifically, mechanisms by which excipients reduce moisture-induced drug instability (e.g. acting as a physical barrier, reducing moisture availability and mobility) were reviewed. Several
Future Perspective
Presence of water in the gaseous state in the form of moisture is inevitable during production, storage and transportation of excipients, drug substances and pharmaceutical products. While moisture is infamous for its deleterious effects on stability, the presence of moisture is necessary in certain aspects of pharmaceutical processing. A better understanding of the myriad aspects of moisture-solid interactions can offer valuable insights into the development of formulations containing moisture
Declaration of Competing Interest
There are no conflicts of interest. The authors alone are responsible for the content and preparation of this manuscript.
Acknowledgments
The authors wish to acknowledge research funding support by the GEA-NUS PPRL fund (N-148-000-008-001). Natalia Veronica is a recipient of the National University of Singapore Graduate Research Scholarship.
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