Impact of Excipient Interactions on Drug Bioavailability from Solid Dosage Forms

Excipients are generally pharmacologically inert, but can interact with drugs in the dosage form and the physiological factors at the site of absorption to affect the bioavailability of a drug product. A general mechanistic understanding of the basis of these interactions is essential to design robust drug products. This paper focuses on drug-excipient interactions in solid dosage forms that impact drug bioavailability, the drug substance and drug product properties affected by excipients, and the impact of excipients on physiologic processes. The extent to which drug bioavailability is affected by these interactions would vary on a case-by-case basis depending upon factors such as the potency and dose of the drug, therapeutic window, site of absorption, rate limiting factor in drug absorption (e.g., permeability or solubility limited), or whether drug metabolism, efflux, complexation, or degradation at the site of absorption play a role in determining its bioavailability. Nonetheless, a mechanistic understanding of drug-excipient interactions and their impact on drug release and absorption can help develop formulations that exhibit optimum drug bioavailability.     

Selection of solid dosage form composition through drug-excipient compatibility testing.

A drug-excipient compatibility screening model was developed by which potential stability problems due to interactions of drug substances with excipients in solid dosage forms can be predicted. The model involved storing drug-excipient blends with 20% added water in closed glass vials at 50 degrees C and analyzing them after 1 and 3 weeks for chemical and physical stability. The total weight of drug-excipient blend in a vial was usually kept at about 200 mg. The amount of drug substance in a blend was determined on the basis of the expected drug-to-excipient ratio in the final formulation. Potential roles of several key factors, such as the chemical nature of the excipient, drug-to-excipient ratio, moisture, microenvironmental pH of the drug-excipient mixture, temperature, and light, on dosage form stability could be identified by using the model. Certain physical changes, such as polymorphic conversion or change from crystalline to amorphous form, that could occur in drug-excipient mixtures were also studied. Selection of dosage form composition by using this model at the outset of a drug development program would lead to reduction of "surprise" problems during long-term stability testing of drug products.     

Drug-Excipient Compatibility Testing Using a High-Throughput Approach and Statistical Design

The aim of our research was to develop a miniaturized high throughput drug-excipient compatibility test. Experiments were planned and evaluated using statistical experimental design. Binary mixtures of a drug, acetylsalicylic acid, or fluoxetine hydrochloride, and of excipients commonly used in solid dosage forms were prepared at a ratio of ~ 1:100 in 96-well microtiter plates. Samples were exposed to different temperature (40°C/50°C) and humidity (10%/75%) for different time (1 week/4 weeks), and chemical drug degradation was analyzed using a fast gradient high pressure liquid chromatography (HPLC). Categorical statistical design was applied to identify the effects and interactions of time, temperature, humidity, and excipient on drug degradation. Acetylsalicylic acid was least stable in the presence of magnesium stearate, dibasic calcium phosphate, or sodium starch glycolate. Fluoxetine hydrochloride exhibited a marked degradation only with lactose. Factor-interaction plots revealed that the relative humidity had the strongest effect on the drug excipient blends tested. In conclusion, the developed technique enables fast drug-excipient compatibility testing and identification of interactions. Since only 0.1 mg of drug is needed per data point, fast rational preselection of the pharmaceutical additives can be performed early in solid dosage form development.     

Drug-excipient compatibility testing using a high-throughput approach and statistical design

The aim of our research was to develop a miniaturized high throughput drug-excipient compatibility test. Experiments were planned and evaluated using statistical experimental design. Binary mixtures of a drug, acetylsalicylic acid, or fluoxetine hydrochloride, and of excipients commonly used in solid dosage forms were prepared at a ratio of approximately 1:100 in 96-well microtiter plates. Samples were exposed to different temperature (40 degrees C/ 50 degrees C) and humidity (10%/75%) for different time (1 week/4 weeks), and chemical drug degradation was analyzed using a fast gradient high pressure liquid chromatography (HPLC). Categorical statistical design was applied to identify the effects and interactions of time, temperature, humidity, and excipient on drug degradation. Acetylsalicylic acid was least stable in the presence of magnesium stearate, dibasic calcium phosphate, or sodium starch glycolate. Fluoxetine hydrochloride exhibited a marked degradation only with lactose. Factor-interaction plots revealed that the relative humidity had the strongest effect on the drug excipient blends tested. In conclusion, the developed technique enables fast drug-excipient compatibility testing and identification of interactions. Since only 0.1 mg of drug is needed per data point, fast rational preselection of the pharmaceutical additives can be performed early in solid dosage form development.     

药物与辅料相容性研究进展

目的对药物与辅料的相容性及相互作用机制和研究方法进展作概述和分析。方法结合近年来国内外相关文献进行评述和展望。结果药物与辅料的相互作用可改变药物活性分子的理化性质,影响药物的稳定性和有效性。结论药物与辅料的相容性研究对制剂处方设计、提高制剂质量和安全性至关重要,药物与辅料相容性及作用机制研究的方法有热分析法、光谱法、色谱法等,可根据试验目的和要求选择适宜的分析方法。     

A New Approach to Accelerated Drug-Excipient Compatibility Testing

The purpose of this study was to develop a method of qualitatively predicting the most likely degradants in a formulation or probing specific drug-excipient interactions in a significantly shorter time frame than the typical 1 month storage testing. In the example studied, accelerated storage testing of a solid dosage form at 50°C, the drug substance SB-243213-A degraded via the formation of two oxidative impurities. These impurities reached a level of 1% PAR after 3 months. Various stressing methods were examined to try to recreate this degradation and in doing so provide a practical and reliable method capable of predicting drug-excipient interactions. The technique developed was able to mimic the 1-month's accelerated degradation in just 1 hr. The method was suitable for automated analysis, capable of multisample stressing, and ideal for use in drug-excipient compatibility screening.     

A new approach to accelerated drug-excipient compatibility testing

The purpose of this study was to develop a method of qualitatively predicting the most likely degradants in a formulation or probing specific drug-excipient interactions in a significantly shorter time frame than the typical 1 month storage testing. In the example studied, accelerated storage testing of a solid dosage form at 50 degrees C, the drug substance SB-243213-A degraded via the formation of two oxidative impurities. These impurities reached a level of 1% PAR after 3 months. Various stressing methods were examined to try to recreate this degradation and in doing so provide a practical and reliable method capable of predicting drug-excipient interactions. The technique developed was able to mimic the 1-month's accelerated degradation in just 1 hr. The method was suitable for automated analysis, capable of multisample stressing, and ideal for use in drug-excipient compatibility screening.     

Physicochemical interactions in solid dosage forms

Complete characterization and mechanistic understanding of physicochemical interactions in solid dosage forms are not only important for consistent manufacturability, stability, and bioavailability of the drug product, but are also expected under the quality-by-design paradigm of drug development. Lack of this understanding can impact successful and timely development, scale-up, and commercial manufacture of dosage forms. This article highlights the stability and bioavailability implications of physicochemical interactions in dosage forms citing a couple of examples where such interactions necessitated the recall of commercial drug products.     

Trace Aldehydes in Solid Oral Dosage Forms as Catalysts for Nitrosating Secondary Amines

Nitrosamine impurities may form during drug substance manufacturing processes. Here, we focus on nitrosamine impurity level growth in oral drug products during long term stability studies. Nitrosamine growth mechanisms in oral dosage forms are typically framed as due to nitrosating agents that can be formed in solutions of nitrous acid with a required pH value of around pH 5 or below. We strive in this work to bring awareness to pharmaceutical scientists that formaldehyde, common in oral dosage form excipients, has previously been shown in solution to catalyze the reaction between secondary amines and nitrite ion to give nitrosamine products. This mechanism operates at pH ∼6 and higher. We attempt to re-frame the solution work as relevant to pharmaceutical solid dosage forms. Recent examples of solid dosage form product recalls are used to demonstrate the formaldehyde catalyzed nitrosation pathway operating in the solid state.     

Accelerated aging: prediction of chemical stability of pharmaceuticals

Methods of rapidly and accurately assessing the chemical stability of pharmaceutical dosage forms are reviewed with respect to the major degradation mechanisms generally observed in pharmaceutical development. Methods are discussed, with the appropriate caveats, for accelerated aging of liquid and solid dosage forms, including small and large molecule active pharmaceutical ingredients. In particular, this review covers general thermal methods, as well as accelerated aging methods appropriate to oxidation, hydrolysis, reaction with reactive excipient impurities, photolysis and protein denaturation.     

Ensuring Product Stability – Choosing the Right Excipients

The stability of pharmaceuticals is an important product quality attribute. Of the known factors affecting stability, moisture is often perceived as the most common cause of drug degradation by hydrolysis or other reactions facilitated by moisture as a medium. Excipients are a critical entity in formulations to enable drug delivery as well as efficient manufacture of pharmaceutical dosage forms. Yet to this end, there is limited application and understanding of the role of excipients in protecting moisture sensitive drugs. An improved understanding of moisture-excipient interactions is important when selecting excipients for formulations containing moisture sensitive drugs. This review outlines the role of excipients as a moisture protectant in oral solid dosage forms. It focuses on the moisture interactions of excipients in order to highlight the potential of certain excipients as moisture protectants. More specifically, the mechanisms by which excipients can reduce drug degradation (e.g. acting as a physical barrier, reducing moisture availability and mobility) are discussed. A summary of analytical tools to evaluate moisture-excipient interactions is also provided.     

A Nitrite Excipient Database: A Useful Tool to Support N-Nitrosamine Risk Assessments for Drug Products

N-Nitrosamine risk assessment and control have become an integral part of pharmaceutical drug product development and quality evaluation. Initial reports of nitrosamine contamination were linked with the drug substance and its manufacturing process. Subsequently, the drug product and aspects of the formulation process have shown to be relevant. Regarding specific formulation contributions to nitrosamine content in a product, one risk lies in possible interactions between nitrosating agents, derived from nitrite in excipients, and vulnerable amines, either present as moieties of the active molecule or as impurities / degradants. However, the limited validated information on nitrite levels in excipients available until now, has been an obstacle for scientists to assess the risk of nitrosamine formation in pharmaceutical products. This has driven the creation of a database to store and share such validated information. The database, maintained by Lhasa Limited, constitutes a central platform to hold the data donated by the pharmaceutical company members on the nitrite concentrations in common excipients measured with validated analytical procedures. The goal of this data sharing initiative is to provide a common framework to contextualize and estimate the risk posed by presence of nitrites to contribute to the formation of nitrosamines in drug products. The major findings from the database analyses are: (1) average nitrite content and batch to batch variance differ among excipients, (2) for solid dosage forms, the nitrite contribution is dominated by the highest formula % excipients, e.g., the fillers (diluents), which are typically used in larger proportion, and are characterized by low nitrite levels and low variability, leading to an average value of 1 µg/g nitrite in a typical formulation, (3) substantial differences in average nitrite content in batches from different excipient vendors potentially reflecting differences in source materials or processing methods for excipient manufacturing. That final point suggests that future selection of raw materials or processing by excipient manufacturers may help reduce nitrite levels in finished drug product formulations, and thus the overall risk of nitrosamine formation in cases where the product contains vulnerable amines.     

Lipid excipients and delivery systems for pharmaceutical development: a regulatory perspective

The use of lipid-based dosage forms for enhancement of drug absorption or delivery has drawn considerable interest from pharmaceutical scientists. The unique characteristics of these dosage forms, however, present significant challenges to pharmaceutical industry and regulatory agencies in many ways. For example, safety assessment is necessary when the use of a new lipid excipient is considered. An important question for lipid formulation is whether the drug remains in solubilised form along the gastrointestinal (GI) tract after it is administered. Certain lipid excipients and surfactants have been reported to change intestinal permeability or interfere with enzyme/transporter activity, thereby affecting drug bioavailability. The potential influence of biopharmaceutical and/or pathophysiological factors on the drug or lipid excipient(s) needs to be explored. For a complex lipid-based dosage form, the conventional in vitro dissolution methods may not be appropriate for predicting in vivo performance in view of the convoluted GI processing of the lipid vehicle and formulation Of paramount importance is to identify any gaps in the scientific understanding of lipid-based dosage forms so that regulatory issues can be addressed. More mechanistic studies should be encouraged to facilitate a better understanding of the pharmaceutical characteristics of lipid formulations and complex interactions between lipid excipient, drug and physiological environment. This review discusses some regulatory considerations in the use of lipid excipients and delivery systems for pharmaceutical development. Implications in the regulatory determination of pharmaceutical equivalence, bioequivalence and therapeutic equivalence are also illustrated.     

Excipients with specialized functions for effective drug delivery

INTRODUCTION: There is a growing need for the development of pharmaceutical excipients that could improve product performance and overcome the shortcomings of new drug moieties, such as their poor solubility and membrane permeability, as well as to aid with modern manufacturing processes. AREAS COVERED: Different types of functional excipients are discussed in this paper, in terms of their roles in modern dosage forms to optimize drug delivery and manufacturability. Functions of specialized excipients that are covered in this article include the enhancement of drug membrane permeability, the improvement of drug solubility and stability, the regulation of drug release in response to feedback mechanisms and assistance with the production of dosage forms. EXPERT OPINION: Modern drug delivery systems rely on sophisticated excipients with multiple functions to improve overall product performance. The excipient market is expected to grow substantially with emerging trends in the development of these advanced drug delivery systems.     

Biowaiver monographs for immediate release solid oral dosage forms: metoclopramide hydrochloride

Literature data are reviewed relevant to the decision for a biowaiver of immediate release (IR) solid oral dosage forms containing metoclopramide hydrochloride. In addition, new solubility data, obtained under Biopharmaceutics Classification System (BCS) conditions are presented. Metoclopramide HCl is conservatively assigned to BCS Class III. Taken also into consideration excipient interactions reported in metoclopramide drug products, its pharmacokinetic properties and therapeutic use and therapeutic index, a biowaiver can be recommended when: (a) the test product contains only excipients present also in metoclopramide HCl containing IR solid oral drug products approved in ICH or associated countries, for instance as presented in this paper, (b) in amounts in normal use in IR solid oral dosage forms, and (c) the test product and the comparator both comply with the criteria for very rapidly dissolving.     

Levothyroxine Sodium Pentahydrate Tablets – Formulation Considerations

Even though levothyroxine sodium pentahydrate tablets have been in the market since 1955, there continue to be recalls due to sub potency. We have comprehensively reviewed the factors affecting its stability in solid oral dosage forms. A compilation of marketed formulation compositions enabled the identification of the potential ‘problem excipients’. Two excipient properties, hygroscopicity and microenvironmental acidity, appeared to be responsible for inducing drug instability. In drug products, depending on the formulation composition and storage conditions, the pentahydrate can dehydrate to highly reactive levothyroxine sodium monohydrate, or undergo salt disproportionation to the free acid form of the drug. The USP assay method (HPLC based) is insensitive to these different physical forms of the drug. The influence of physical form of levothyroxine on its chemical stability is incompletely understood. The USP has five product-specific dissolution tests reflecting the complexity in its evaluation.     

Pharmaceutical co-crystals–an opportunity for drug product enhancement

By maximizing our understanding of materials and the relative importance of interactions on all levels (i.e., molecular, particle, powder, product), we can improve the manufacture of drug dosage forms and thus meet target specifications for mechanical durability, stability and biopharmaceutical performance. Pharmaceutical co-crystals are the latest material being explored in order to enhance drug properties using this bottom-up approach. In this review we provide a general introduction to pharmaceutical co-crystals. We also address common aspects of co-crystal formation, discuss screening strategies and outline methodologies for co-crystal functionality. Pharmaceutical co-crystals that have a distinct solid phase possess a unique set of properties, thus co-crystal formation can act as an advantageous alternative to other solid-state modification techniques. More research is needed in order to scale up co-crystal systems and implement manufacturing of final dosage forms on large scale.     

A new way of solid dosage form samples preparation for SEM and FTIR using microtome

Abstract

Rapid and correct production of generic solid dosage forms requires a large amount of analytical data and conclusions. Modern analytical techniques have a good resolution and accuracy and allow obtaining a lot of information about the original product. Scanning electron microscopy (SEM) is used for observation and assessing individual layers, core and surface of solid dosage forms. Fourier transform infrared (FTIR) spectroscopy mapping allows determining the distribution and characterization of individual components in a solid dosage form. However, the samples prepared by common way, using scalpel or tablet splitter, are not good enough. It was the reason for development of a new and better method of sample preparation, which uses microtome. Well-prepared samples analyzed by SEM and FTIR mapping allow to determine a solid dosage form formulation, excipient content and distribution of excipient and active pharmaceutical ingredient.     

Use of Oxygen Scavengers to Stabilize Solid Pharmaceutical Dosage Forms: A Case Study

A case study is described where degradation of a solid pharmaceutical dosage form susceptible to oxidation is minimized by incorporation of an oxygen scavenger as part of the packaging. Extremely low oxygen levels are attainable within 24 hr of packaging, even with permeable high-density polyethylene bottles commonly used in the pharmaceutical industry. This packaging methodology allows for a practical formulation-independent pathway for reducing or eliminating oxidative instability. In addition, this technology provides a convenient mechanistic probe for the degradation mechanism of solid dosage forms.     

Use of oxygen scavengers to stabilize solid pharmaceutical dosage forms: a case study

A case study is described where degradation of a solid pharmaceutical dosage form susceptible to oxidation is minimized by incorporation of an oxygen scavenger as part of the packaging. Extremely low oxygen levels are attainable within 24 hr of packaging, even with permeable high-density polyethylene bottles commonly used in the pharmaceutical industry. This packaging methodology allows for a practical formulation-independent pathway for reducing or eliminating oxidative instability. In addition, this technology provides a convenient mechanistic probe for the degradation mechanism of solid dosage forms.