Amorphous pharmaceutical solids: preparation, characterization and stabilization.
TL;DR: Current research in the stabilization of amorphous solids focuses on the stabilize of labile substances during processing and storage using additives, the prevention of crystallization of the excipients that must remainAmorphous for their intended functions, and the selection of appropriate storage conditions under which amorphously solids are stable.
About: This article is published in Advanced Drug Delivery Reviews.The article was published on 2001-05-16. It has received 1367 citations till now. The article focuses on the topics: Amorphous solid & Crystallization.
Citations
More filters
TL;DR: A classification based on dimensionless numbers is presented that can be used to estimate how excipient properties in combination with process parameters influence the morphology of the engineered particles.
Abstract: This review covers recent developments in the area of particle engineering via spray drying. The last decade has seen a shift from empirical formulation efforts to an engineering approach based on a better understanding of particle formation in the spray drying process. Microparticles with nanoscale substructures can now be designed and their functionality has contributed significantly to stability and efficacy of the particulate dosage form. The review provides concepts and a theoretical framework for particle design calculations. It reviews experimental research into parameters that influence particle formation. A classification based on dimensionless numbers is presented that can be used to estimate how excipient properties in combination with process parameters influence the morphology of the engineered particles. A wide range of pharmaceutical application examples—low density particles, composite particles, microencapsulation, and glass stabilization—is discussed, with specific emphasis on the underlying particle formation mechanisms and design concepts.
1,347 citations
TL;DR: The concept and theory of crystal engineering is covered and the potential benefits, disadvantages and methods of preparation of co-crystals, metastable polymorphs, high-energy amorphous forms and ultrafine particles are discussed.
1,282 citations
TL;DR: The article provides an integrated and contemporary discussion of current approaches to solubility and dissolution enhancement but has been deliberately structured as a series of stand-alone sections to allow also directed access to a specific technology where required.
Abstract: Drugs with low water solubility are predisposed to low and variable oral bioavailability and, therefore, to variability in clinical response. Despite significant efforts to "design in" acceptable developability properties (including aqueous solubility) during lead optimization, approximately 40% of currently marketed compounds and most current drug development candidates remain poorly water-soluble. The fact that so many drug candidates of this type are advanced into development and clinical assessment is testament to an increasingly sophisticated understanding of the approaches that can be taken to promote apparent solubility in the gastrointestinal tract and to support drug exposure after oral administration. Here we provide a detailed commentary on the major challenges to the progression of a poorly water-soluble lead or development candidate and review the approaches and strategies that can be taken to facilitate compound progression. In particular, we address the fundamental principles that underpin the use of strategies, including pH adjustment and salt-form selection, polymorphs, cocrystals, cosolvents, surfactants, cyclodextrins, particle size reduction, amorphous solid dispersions, and lipid-based formulations. In each case, the theoretical basis for utility is described along with a detailed review of recent advances in the field. The article provides an integrated and contemporary discussion of current approaches to solubility and dissolution enhancement but has been deliberately structured as a series of stand-alone sections to allow also directed access to a specific technology (e.g., solid dispersions, lipid-based formulations, or salt forms) where required.
1,201 citations
Cites background from "Amorphous pharmaceutical solids: pr..."
...This transformation can occur very rapidly on dissolution, complicating solubility measurements for the high energy form, and can also occur during storage in the solid state, particularly on exposure to moisture or heat (Yu, 2001; Pudipeddi and Serajuddin, 2005; Janssens and Van den Mooter, 2009)....
[...]
...In practice, however, many relax rapidly on cooling and crystallize rather than forming kinetically stable glasses (Turnbull, 1969; Yu, 2001)....
[...]
TL;DR: A review of the recent advances in the field of insoluble drug delivery and business prospects covers the development of drug candidates with greater lipophilicity, high molecular weight and poor water solubility.
885 citations
TL;DR: In this article, the authors reviewed several novel examples of pharmaceutical cocrystals from the past decade and analyzed the enhanced solubility profiles of cocrystal profiles, showing that the peak dissolution for pharmaceutical cocystals occurs in a short time (<30 min), and high-solubility is maintained over a sufficiently long period (4-6 h) for the best cases.
Abstract: The current phase of drug development is witnessing an oncoming crisis due to the combined effects of increasing R&D costs, decreasing number of new drug molecules being launched, several blockbuster drugs falling off the patent cliff, and a high proportion of advanced drug candidates exhibiting poor aqueous solubility. The traditional approach of salt formulation to improve drug solubility is unsuccessful with molecules that lack ionizable functional groups, have sensitive moieties that are prone to decomposition/racemization, and/or are not sufficiently acidic/basic to enable salt formation. Several novel examples of pharmaceutical cocrystals from the past decade are reviewed, and the enhanced solubility profiles of cocrystals are analyzed. The peak dissolution for pharmaceutical cocrystals occurs in a short time (<30 min), and high solubility is maintained over a sufficiently long period (4–6 h) for the best cases. The enhanced solubility of drug cocrystals is similar to the supersaturation phenomenon ...
818 citations
References
More filters
TL;DR: In this paper, a molecularkinetic theory was proposed to explain the temperature dependence of relaxation behavior in glass-forming liquids in terms of the temperature variation of the size of the cooperatively rearranging region.
Abstract: A molecular‐kinetic theory, which explains the temperature dependence of relaxation behavior in glass‐forming liquids in terms of the temperature variation of the size of the cooperatively rearranging region, is presented. The size of this cooperatively rearranging region is shown to be determined by configuration restrictions in these glass‐forming liquids and is expressed in terms of their configurational entropy. The result of the theory is a relation practically coinciding with the empirical WLF equation. Application of the theory to viscosimetric experiments permits evaluation of the ratio of the kinetic glass temperature Tg (derived from usual ``quasistatic'' experiments) to the equilibrium second‐order transition temperature T2 (indicated by either statistical‐mechanical theory or extrapolations of experimental data) as well as the hindrance‐free energy per molecule. These parameters have been evaluated for fifteen substances, the experimental data for which were available. Hindrance‐free energies ...
5,037 citations
Book•
01 Jan 1965
4,036 citations
TL;DR: The onset of a sharp change in ddT( is the Debye-Waller factor and T is temperature) in proteins, which is controversially indentified with the glass transition in liquids, is shown to be general for glass formers and observable in computer simulations of strong and fragile ionic liquids, where it proves to be close to the experimental glass transition temperature.
Abstract: Glasses can be formed by many routes. In some cases, distinct polyamorphic forms are found. The normal mode of glass formation is cooling of a viscous liquid. Liquid behavior during cooling is classified between "strong" and "fragile," and the three canonical characteristics of relaxing liquids are correlated through the fragility. Strong liquids become fragile liquids on compression. In some cases, such conversions occur during cooling by a weak first-order transition. This behavior can be related to the polymorphism in a glass state through a recent simple modification of the van der Waals model for tetrahedrally bonded liquids. The sudden loss of some liquid degrees of freedom through such first-order transitions is suggestive of the polyamorphic transition between native and denatured hydrated proteins, which can be interpreted as single-chain glass-forming polymers plasticized by water and cross-linked by hydrogen bonds. The onset of a sharp change in d dT( is the Debye-Waller factor and T is temperature) in proteins, which is controversially indentified with the glass transition in liquids, is shown to be general for glass formers and observable in computer simulations of strong and fragile ionic liquids, where it proves to be close to the experimental glass transition temperature. The latter may originate in strong anharmonicity in modes ("bosons"), which permits the system to access multiple minima of its configuration space. These modes, the Kauzmann temperature T(K), and the fragility of the liquid, may thus be connected.
4,016 citations
Book•
01 Jan 1965
TL;DR: In this paper, the authors present a general introduction to the theory of transformation kinetics of real metals, including the formation and evolution of martensitic transformations, as well as a theory of dislocations.
Abstract: Part I General introduction. Formal geometry of crystal lattices. The theory of reaction rates. The thermodynamics of irreversable processes. The structure of real metals. Solids solutions. The theory of dislocations. Polycrystalline aggregates. Diffusion in the solid state. The classical theory of nucleation. Theory of thermally activated growth. Formal theory of transformation kinetics. Part II Growth from the vapour phase. Solidification and melting. Polymorphic Changes. Precipitation from supersaturated solid solution. Eutectoidal transformations. Order-disorder transformations. Recovery recrystalisation and grain growth. Deformation twinning. Characteristics of martensic transformations. Crystallography of martensitic transformations. Kinetics of martensitic transformations. Rapid solidification. Bainite steels. Shape memory alloys.
3,397 citations
TL;DR: In this article, a broad correlation of non-debye behavior with non-Arrhenius relaxations was found for different types of glass formers, distinguished by their respective molecular complexity.
Abstract: Deviations from thermally activated and from exponential response are typical features of the vitrification phenomenon and previously have been studied using viscoelastic, dielectric, calorimetric, optical, and other techniques. Linear response data from literature on about 70 covalent glass formers, ionic melts, supercooled liquids, amorphous polymers, and glassy crystals are surveyed. Except for orientational glasses and monohydric aliphatic alcohols a distinct but broad correlation of non‐Debye behavior with non‐Arrhenius relaxations is found. Within the broad trend several groups of materials, distinguished by their respective molecular complexity, can be identified and are shown to exhibit narrow correlations. At a given degree of deviation from Arrhenius behavior externally imposed stresses are relaxed with a departure from exponential behavior which is stronger the more the molecular or atomic subunits of the glassforming material are interconnected with each other.
2,146 citations