In this chapter, the major physical stability attributes of drug dosage forms are discussed with focus on the effects of solidstate properties of drug substance and. Pharmaceutical cocrystals involving two active pharmaceutical ingredients are rarely revealed in the literature. We felt there was a need for a book written from a. Presents a detailed discussion of important solid state properties, methods, and applications of solid state analysis illustrates the various phases or forms that solids can assume and discussesvarious issues related to the relative stability of solid forms and tendencies to undergo transformation covers key methods of solid state analysis including xray powder diffraction, thermal analysis. Preparation and solidstate characterization of dapsone. One example of this type of solidstate hydrolysis is the solidstate hydrolysis of aspirin see section 3. Abstractusing pharmaceutical salts in solid dosage forms can raise stability concerns, especially salt dissociation which can adversely affect the product performance. Understanding the chemical basis of drug stability and. Drugs administered by inhalation have become increasingly popular, and dry powder inhalers are now commonly in use.
Sep 11, 2017 the impact of these interactions on the drug formulation process has been discussed in detail. For semisolid dosage forms ointment and creams, the stability of the active ingredient can be controlled by changing the nature of the ointment or cream base in the formulation. Pdf impact of solidstate characteristics to the physical stability. Stability measured by the rate of changes that occur in pdf. In order to determine a drug candidates stability, extremes of temperature, chemical aggregation, mechanical force, chemical damage, and other stressors must be applied according to known and suspected degradation pathways. The primary objectives of solid state stability investigations are identification of stable storage conditions for drug product and identification of compatible excipients for the formulation. Solid state stability polymorphism ku scholarworks.
The present article uses the fundamental theory of. Dissolution testing and acceptance criteria for immediate. Jan 19, 2017 solid state stability the purpose of solid state stability is identifications of stable storage conditions for drug in the solid state and identification of compatible excipients for a formulations. Nehal aly afifi professor of pharmacology faculty of vet. Drug stability means the ability of the pharmaceutical dosage form to. Evidently, therefore, both the solid form of the drug substance and the selected ex. The kinetics of the deiodination of levothyroxine in aqueous solution were studied over the ph range 1 to 12. Evaluation of drug stability can prevent toxicity and increase safety, efficacy and quality of the final drug product. Solidstate properties of pharmaceutical materials wiley. Role of excipients in moisture sorption and physical. Recently, increasing attention has been focused on these sln as colloidal drug carriers for incorporating hydrophilic or lipophilic drugs. Reviews critical physical attributes of pharmaceutical materials, mainly related to drug substances, including particle sizesurface area, hygroscopicity, mechanical properties, solubility, and physical and chemical stability. In this work, various factors affecting stability of both small molecule and biopharmaceutical compounds were investigated.
Guidance for the submission of 510ks for solid state x. Stability of proteins in aqueous solution and solid state. Equilibrium solubility and intrinsic dissolution rates were also compared with those of dap itself. Presents a detailed discussion of important solid state properties, methods, and applications of solid state analysis illustrates the various phases or forms that solids can assume and discussesvarious issues related to the relative stability of solid forms and tendencies to undergo transformationcovers key methods of solid state analysis. Solid state reactions are much slower and more difficult to interpret than solution state reactions, due to a reduced no. Even if the envisaged market form of the drug is a solution, information about the solid state properties of the drug substance may still be necessary 19. Impact of solid state characteristics to the physical stability of drug substance and drug product. The strategy to use salt formation to achieve higher solubility becomes more critical for new drug discovery and development, because in recent years the solubilities of most new drug molecules have decreased sharply. Studies on the mechanisms of solid state and solution.
Guidance for the submission of 510ks for solid state xray. The solidstate form can directly affect the quality of a pharmaceutical product, and. Solid state stability the purpose of solid state stability is identifications of stable storage conditions for drug in the solid state and. Role of excipients in moisture sorption and physical stability of solid pharmaceutical formulations. Stability of drugs and dosage forms rgm aisyahs blog. Review articlearticle stability of proteins in aqueous solution and solid state s. Solid state pharmaceutical chemicals can break down due along a wide range of different kinetic pathways. Solid state stability free download as powerpoint presentation. Presents a detailed discussion of important solidstate properties, methods, and applications of solidstate analysis illustrates the various phases or forms that solids can assume and discussesvarious issues related to the relative stability of solid forms and tendencies to undergo transformation covers key methods of solid state analysis including xray powder diffraction. The course is designed to be of value to all formulators of solid state formulations. Affected by change in purity and crystallinity initial bulk lots and newer lots to be studied solid state is slower and difficult to interpret than solution state tlc. These physical properties can have an impact on the materials bulk properties, formulation performance, processability, stability. Understand stability testing protocols and regulatory requirements.
Pseudo zero order reaction a compound decomposing in solution exhibits a first order reaction but if more of it is present as insoluble excess, then an equilibrium is maintained between the compound in solution and that in the solid form. Solid state characterisation is key to understanding the physical properties of pharmaceutical solid materials and ensure optimal physical form. The choice of excipients constitutes a major part of preformulation and formulation studies during the preparation of pharmaceutical dosage forms. Chemical stability evaluates a drug s susceptibility to degradation acid, base, oxidant, and is investigated in solution as well as in solid state, typically with chromatographic methods. Studies on the mechanisms of solid state and solution instability of drugs by zhixin zong.
Nov 24, 2016 2 pseudo zero order reaction in solid state, many drug decomposes according to pseudo zero order reaction rates, as reaction occurs between the drug and moisture in the solid dosage form. Although averylarge number ofstudies on the subject of stability have appeared in the primary pharmaceutical literature, books onthe subjecthave notbeen comprehensive. Solid state properties of pharmaceutical materials in. The physical, mechanical, and chemical properties of excipients affect various formulation parameters, such as disintegration, dissolution, and shelf life, and significantly influence the final product. Kinetics of degradation of levothyroxine in aqueous solution.
This work expands the pharmaceutically acceptable solid forms of dap and supplements the successful cases of drug. Kinetics of degradation of levothyroxine in aqueous. Literature data published in the field of solidstate characterization of per is rather poor. Chemical drug degradation in solid dosage forms, such as tablets, most frequently occurs in microscopic drug solutions within the dosage form, and most frequently these microscopic drug solutions are aqueous solutions. Stability and analysis of solidstate forms in pharmaceutical. Effect of moisture and humidity on solid drugs the. The purpose of stability testing is to provide evidence on how the quality of a drug substance or drug. Solid state stability of formulations valuable and relevant. Understand stabilitytesting protocols and regulatory requirements. Conclusion solid state characterization of a drug is the foundation of a knowledge base that leads ultimately to the development of a stable, efficacious dosage form. Solid lipid nanoparticles sln have emerged as a nextgeneration drug delivery system with potential applications in pharmaceutical field, cosmetics, research, clinical medicine and other allied sciences.
The sensitivity of a drug to hydrolysis in a solid dosage form can be controlled in a similar manner by preparing a less hygroscopic salt of the drug or by reducing. Therefore, a thorough understanding of the salt instability encountered in solidstate formulations is imperative to ensure the product quality. The food and drug administration fda or agency is announcing the availability of a final guidance for industry entitled dissolution testing and acceptance criteria for immediaterelease solid. Presents a detailed discussion of important solidstate properties, methods, and applications of solidstate analysis illustrates the various phases or forms that solids can assume and discussesvarious issues related to the relative stability of solid forms and tendencies to undergo transformationcovers key methods of solid state analysis. Preparation and solidstate characterization of dapsone drug. Marcel dekker 1995 solid state degradation mechanisms may 25, 2010. Solid dispersion 2 solid dispersion is defined as dispersion of one or more active ingredients hydrophobic in an inert carrier hydrophillic at solid state prepared by melting fusion, solvent, melting solvent method.
Stability profiles of drug products extended beyond. Solidstate pharmaceutical chemistry chemistry of materials. Pdf impact of solidstate characteristics to the physical. This chapter also discusses the guidelines from the ich for stability testing on drug substances and products and the requirements at different phases of the drug development process in the pharmaceutical industry. The product formed contains different components i. Temperature dependence of the reaction was also studied. Comparison of solidstate c nmr spectroscopy and powder xray diffraction for analyzing mixtures of polymorphs of neotame. Drugexcipient interactions in solid dosage forms can affect drug product stability in physical aspects such as organoleptic changes and dissolution slowdown, or chemically by causing drug. Impact of solidstate characteristics to the physical stability of drug substance and drug product. The transition temperature is real monotropic pairs can never be interconverted in the solid state by merely changing the temperature the liquid or solution state is needed. Impact on drug product design and stability test design william r. Of those that did most, if not all, were aimed at final year undergraduates and postgraduates. Guidance for the submission of 510ks for solid state xray imaging devices guidance for industry and food and drug administration staff september 2016.
A thorough knowledge ofthe chemical and physical stability of drugs and dosage forms is criticalin the development andevaluationofpharmaceuticals. Stability is an essential quality attribute for pharmaceutical formulations. Pdf solidstate stability issues of drugs in transdermal. The resulting cocrystals were fully characterized by a range of analytical technologies. An extensive literature has developed on the stability of pharmaceuticals drug substances or tablets and capsules in the solid state. Scientific and commercial success of a pharmaceutical product can only be ensured with the understanding of the drug. Dissertationes bioscientiarum molecularium universitatis helsingiensis in viikki, 202005, pp.
Comparative solidstate stability of perindopril active. A thorough knowledge of the chemical and physical stability of drugs and dosage forms is. Describe the factors that influence solidstate chemical kinetics. For reactions that proceed on the solid surface of the drug, an increase in the surface area can increase the amount of drug participating in the reaction. The physical stability of pharmaceutical salts is essential for their performance, processibility, and chemical stability. Stability of proteins in aqueous solution and solid state s. Despite the growing importance of solid state chemistry, however, we found that there were few textbooks that tackled solid state theory from a chemists rather than a physicists viewpoint. Unfortunately, many pharmaceutical companies have learned from experience the importance of a timely and thorough evaluation of solid state properties. Solid state properties of pharmaceutical materials wiley. Importance of stability of pharmaceutical formulations. Practical testing of solidstate stability of pharmaceuticals. Identify and describe methods for the stabilization of pharmaceutical agents. Stability, stability studies, stability testing introduction stability testing of pharmaceutical products is a complex set of procedures involving considerable cost, time consumption and scientific expertise in order to build in quality, efficacy and safety in a drug formulation. Identification of stable storage conditions for drug in solid or liquid state.
The purpose of solid state stability is identifications of stable storage conditions for drug in the solid state and identification of compatible excipients for a formulations. Factors influencing drug stability the degradation of pharmaceutical product can be treated as zero order reaction, first order reaction or pseudo. Jan 15, 2017 literature data published in the field of solid state characterization of per is rather poor. Impact on drug product design and stability test design. Hussain3 1division of product quality research, center for drug evaluation and research, food and drug administration, hfd941, white oak, life sciences building 64, 10903 new hampshire avenue. Solid state stability testing usually requires repetitive testing of the initial bulk lot in parallel with newer bulk lots, therefore adequate material should be set aside for these studies. From a physical form standpoint, the possibilities of unwanted crystallization. In this work, crystal engineering principles were exercised to guide the design and synthesis of the biopharmaceutics classification system class iv drug dapsone dap. The food and drug administration fda or agency is announcing the availability of a final guidance for industry entitled dissolution testing and acceptance criteria for. One example of this type of solid state hydrolysis is the solid state hydrolysis of aspirin see section 3. The transition temperature is real monotropic pairs can never be interconverted in the solid.
Describe the factors that influence solid state chemical kinetics. Stability of pharmaceutical salts in solid oral dosage. Kinetics and drug stability authorstream presentation. Studies on the mechanisms of solid state and solution instability of drugs by zhixin zong an abstract of a thesis submitted in partial fulfillment of the requirements for the doctor of philosophy degree in pharmacy in the graduate college of the university of iowa december 2011 thesis supervisor.
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