Role of Water in the Physical Stability of Solid Dosage Formulations

Airaksinen, Sari; Karjalainen, Milja; Shevchenko, Anna; Westermarck, Sari; Leppänen, Ella; Rantanen, Jukka; Yliruusi, Jouko

doi:10.1002/jps.20411

Cited by 109 publications

(89 citation statements)

References 41 publications

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“…The second are point constraints, which must be satisfied at specific time points during the operation as shown in Eq. (20). Common examples of point constraints are those imposed at the beginning or end of a process, like final conversion in a batch reactor [126].…”

Section: Dynamic Feasibility and Flexibility Analysismentioning

confidence: 99%

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Mathematical Tools for the Quantitative Definition of a Design Space

Rogers

Ierapetritou

2016

Methods in Pharmacology and Toxicology

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This chapter focuses on the application of process modeling to determination of design space for pharmaceutical manufacturing processes. The first two sections define design space and related terms from a regulatory perspective and discuss how these apply in practice during pharmaceutical process development. In Sect. 3, a variety of mathematical techniques that can be used to guide design space development are introduced. An emphasis is placed on the use of feasibility analysis and the relationship between process feasibility and design space. Statistical techniques, including latent variable and Bayesian methods, are also discussed in detail. For methods that have been reported in the literature for pharmaceutical manufacturing applications, an overview of the relevant case studies is provided. If methods have not yet been applied to pharmaceutical processes, potential applications for these techniques are indicated. To illustrate the applicability of these concepts to pharmaceutical manufacturing processes, a brief case study is presented in Sect. 4. A discussion of design space verification and issues related to scale-up is provided in Sect. 5. Finally a brief summary of the concepts presented and their potential role in design space development for pharmaceutical processes is given in Sect. 6. This chapter is intended to provide readers with an understanding of mathematical techniques that can be used during process development to assist in the determination of process design space. An overview of the problem formulation and solution approaches for each method are presented. More detailed mathematical developments for each technique are available in the references provided. Table 1 provides a list of symbols that are used throughout this chapter, while Table 2 describes acronyms used within this chapter.

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Section: Dynamic Feasibility and Flexibility Analysismentioning

confidence: 99%

“…Tablet hardness may be related to product release in vivo, and therefore is also a potential CQA [19]. Other attributes such as moisture content and tablet coating thickness may also be of interest, particularly if they are related to tablet stability [20].…”

Section: Identification Of Critical Quality Attributesmentioning

confidence: 99%

Mathematical Tools for the Quantitative Definition of a Design Space

Rogers

Ierapetritou

2016

Methods in Pharmacology and Toxicology

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“…Hydrolytic reactions are amongst the most common processes for drug degradation (Waterman et al 2002;Airaksinen et al 2003Airaksinen et al , 2005aJørgensen et al 2004;Waterman and Adami 2005;Heidarian et al 2006;Luthra et al 2012).…”

Section: Effects Of Moisture In Solid Oral Dosage Formsmentioning

confidence: 99%

Excipient Selection in Oral Solid Dosage Formulations Containing Moisture Sensitive Drugs

Rajabi‐Siahboomi

Levina²,

Upadhye

et al. 2015

Excipient Applications in Formulation Design and Drug Delivery

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Moisture sensitivity of active pharmaceutical ingredients (APIs) presents a formidable challenge in the formulation of oral dosage forms. The interaction of moisture with APIs is crucial to an understanding of water-based processes, e.g. manufacturing or prediction of solid dosage form stability and shelf-life. Unwarranted moisture sorption by either APIs or excipients can result in unstable oral solid formulations. The appropriate selection of excipients for the core formulation and appropriate moisture barrier film coating helps to remedy the moisture-related issues with APIs and thus can improve the storage stability of the final formulations. In this chapter, we review the nature and extent of the moisture sensitivity and possible approaches taken to overcome it. Use of excipients that bind tightly with water reduce its potential interaction with the API. In addition, application of a barrier coating to reduce rate and extent of moisture ingress into the core of the solid dosage form during the storage (in original packaging or while in-use), are some of the many simple options that have been considered and described.Keywords Calorimetry · Degradation · Differential scanning calorimetry · Dynamic vapor sorption · Equilibrium relative humidity · Excipients · Isothermal microcalorimetry · Moisture · Moisture-barrier coating · Near-infra red Spectroscopy · Opadry · Optical waveguide spectroscopy · Packaging · Stability · Water · Water vapor transmission rate Abbreviations AluAluminum API Active pharmaceutical ingredient

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“…Near-infrared or solid NMR spectroscopic studies have suggested that the mobility of water molecules adsorbed in the excipients depends on humidity, and molecules with a high mobility contribute to the degradation of the active pharmaceutical ingredients. [36][37][38][39][40][41] To gain insight into the stabilization mechanism of the excipients, we evaluated the molecular mobility of D 2 O adsorbed in β-CD and dextran, both of which suppressed the degradation of Limaprost, and lactose as a control, using solid 2 H-NMR spectroscopy by measuring the spin-lattice relaxation times (T 1 ) of deuterium atom. Figure 8 shows the 2 H-NMR spectra of β-CD, dextran and lactose hydrate stored at 30°C, 75%R.H.…”

Section: Molecular Mobility Of Water In Excipientsmentioning

confidence: 99%

Stabilizing Effect of β-Cyclodextrin on Limaprost, a PGE<sub>1</sub> Derivative, in Limaprost Alfadex Tablets (Opalmon®) in Highly Humid Conditions

Inoue

Sekiya

Katayama

et al. 2014

CHEMICAL & PHARMACEUTICAL BULLETIN

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Stabilization against humidity of Limaprost (a prostaglandin E 1 derivative), which is currently marketed as Opalmon ® , was undertaken using β-cyclodextrin (β-CD). Aqueous solutions of Limaprost alfadex/dextran 40 were lyophilized with and without β-CD. Limaprost alfadex lyophilized with β-CD was more chemically stable in humid conditions than that without β-CD. Moreover, the addition of β-CD as an excipient to tablets of these lyophilized composites remarkably improved the stability of Limaprost, and Limaprost in this moisture-resistant formulation was chemically stable for 19 weeks at 30°C, 75% relative humidity (R.H.). Chemical analysis of Limaprost and its degradation products indicated that degradation proceeded in the inclusion form (i.e., within the CD cavity). Solid 2 H-NMR spectroscopic studies showed that β-CD constrained the molecular mobility of water in the solid state. These results suggested that the stabilization of Limaprost by β-CD was at least partly due to the restricted molecular mobility of water, which acted as a catalytic species for the degradation, and also to the protection of the five-membered ring of Limaprost from water catalytic dehydration through inclusion complex formation with β-CD.

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Role of Water in the Physical Stability of Solid Dosage Formulations

Cited by 109 publications

References 41 publications

Mathematical Tools for the Quantitative Definition of a Design Space

Mathematical Tools for the Quantitative Definition of a Design Space

Excipient Selection in Oral Solid Dosage Formulations Containing Moisture Sensitive Drugs

Stabilizing Effect of β-Cyclodextrin on Limaprost, a PGE<sub>1</sub> Derivative, in Limaprost Alfadex Tablets (Opalmon®) in Highly Humid Conditions

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