What is the true solubility advantage for amorphous pharmaceuticals
01 Apr 2000-Pharmaceutical Research (Kluwer Academic Publishers-Plenum Publishers)-Vol. 17, Iss: 4, pp 397-404
TL;DR: Amorphous pharmaceuticals are markedly more soluble than their crystalline counterparts, however, their experimental solubility advantage is typically less than that predicted from simplethermodynamic considerations.
Abstract: Purpose To evaluate the magnitude of the solubility advantage foramorphous pharmaceutical materials when compared to their crystallinecounterpartsMethods The thermal properties of several drugs in their amorphousand crystalline states were determined using differential scanningcalorimetry From these properties the solubility advantage for theamorphous form was predicted as a function of temperature using a simplethermodynamic analysis These predictions were compared to theresults of experimental measurements of the aqueous solubilities of theamorphous and crystalline forms of the drugs at several temperaturesResults By treating each amorphous drug as either an equilibriumsupercooled liquid or a pseudo-equilibrium glass, the solubilityadvantage compared to the most stable crystalline form was predicted to bebetween 10 and 1600 fold The measured solubility advantage wasusually considerably less than this, and for one compound studied indetail its temperature dependence was also less than predicted It wascalculated that even for partially amorphous materials the apparentsolubility enhancement (theoretical or measured) is likely to influencein-vitro and in-vivo dissolution behaviorConclusions Amorphous pharmaceuticals are markedly more solublethan their crystalline counterparts, however, their experimental solubility advantage is typically less than that predicted from simplethermodynamic considerations This appears to be the result of difficulties indetermining the solubility of amorphous materials under trueequilibrium conditions Simple thermodynamic predictions can provide a useful indication of the theoretical maximum solubility advantage foramorphous pharmaceuticals, which directly reflects the driving forcefor their initial dissolution
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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 "What is the true solubility advanta..."
...…the “equilibrium” solubility of a thermodynamically unstable amorphous material, such that spontaneous crystallization results in underestimation of the initial (kinetic) solubility properties of the amorphous form (Hancock and Parks, 2000; Bhugra and Pikal, 2008; Murdande et al., 2010a,b, 2011a)....
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...In contrast, the amorphous:crystalline solubility ratio is typically much higher (Hancock and Parks, 2000; Murdande et al., 2010b)....
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...However, differences in experimentally determined amorphous and crystalline solubilities are in practice often much lower (Hancock and Parks, 2000; Murdande et al., 2011a)....
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TL;DR: The evolution of crystal engineering into a form of supramolecular synthesis is discussed in this article in the context of problems and opportunities in the pharmaceutical industry, and it has become clear that a wide array of multiple component pharmaceutical phases, so called pharmaceutical co-crystals, can be rationally designed using crystal engineering, and the strategy affords new intellectual property and enhanced properties for pharmaceutical substances.
1,008 citations
TL;DR: Viable formulation options for poorly water-soluble drugs, such as crystal modification, micronization, amorphization, self-emulsification, cyclodextrin complexation, and pH modification are reviewed on the basis of the biopharmaceutics classification system of drug substances.
961 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
TL;DR: The physics behind the drug nanocrystals and changes of their physical properties are discussed, and the special physical effects of nanocry crystals explained which are utilized in each market product.
Abstract: Nanotechnology will affect our lives tremendously over the next decade in very different fields, including medicine and pharmacy Transfer of materials into the nanodimension changes their physical properties which were used in pharmaceutics to develop a new innovative formulation principle for poorly soluble drugs: the drug nanocrystals The drug nanocrystals do not belong to the future; the first products are already on the market The industrially relevant production technologies, pearl milling and high pressure homogenization, are reviewed The physics behind the drug nanocrystals and changes of their physical properties are discussed The marketed products are presented and the special physical effects ofnanocrystals explained which are utilized in each market product Examples of products in the development pipelines (clinical phases) are presented and the benefits for in vivo administration of drug nanocrystals are summarized in an overview
818 citations
Cites background from "What is the true solubility advanta..."
...The polymorphic modifi cation I has a solubility of 0.13, the high energy modifi cation II a solubility of 0.43 and the amorphous material of 1.6 mg/ml (Hancock and Parks 2000; Chong-Hui and Grant 2001)....
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References
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TL;DR: The amorphous state is critical in determining the solid-state physical and chemical properties of many pharmaceutical dosage forms and some of the most common methods that can be used to measure them are described.
1,864 citations
Book•
03 Mar 1999
TL;DR: Brittain et al. as mentioned in this paper applied the phase rule to the characterisation of polymorphic and solvatomorphic systems, and proposed a computational method to predict polymorphism.
Abstract: THERMODYNAMIC AND THEORETICAL ISSUES Theory and Principles of Polymorphic Systems, Harry G. Brittain Application of the Phase Rule to the Characterization of Polymorphic and Solvatomorphic Systems, Harry G. Brittain Computational Methodologies: Toward Crystal Structure and Polymorph Prediction, Sarah (Sally) L. Price PREPARATIVE METHODS FOR POLYMORPHS AND SOLVATOMORPHS Classical Methods of Preparation of Polymorphs and Alternative Solid Forms, Peter W. Cains Approaches to High-Throughput Physical Form Screening and Discovery, Alastair J. Florence STRUCTURAL PROPERTIES OF POLYMORPHS AND SOLVATOMORPHS Structural Aspects of Polymorphism, Harry G. Brittain, Stephen R. Byrn, and Eunhee Lee Structural Aspects of Solvatomorphic Systems, Harry G. Brittain, Kenneth R. Morris, and Stephan X. M. Boerrigter Pharmaceutical Co-crystals: A New Opportunity in Pharmaceutical Science for a Long-Known but Little-Studied Class of Compounds, Kapildev K. Arora and Michael J. Zaworotko CHARACTERIZATION METHODS FOR POLYMORPHS AND SOLVATOMORPHS Thermoanalytical and Crystallographic Methods, Sisir Bhattacharya, Harry G. Brittain, and Raj Suryanarayanan Vibrational Spectroscopy, Harry G. Brittain Solid-State Nuclear Magnetic Resonance Spectroscopy, Patrick A. Tishmack Effects of Polymorphism and Solid-State Solvation on Solubility and Dissolution Rate, Harry G. Brittain, David J. R. Grant, and Paul B. Myrdal INTERCONVERSION OF POLYMORPHS AND SOLVATOMORPHS Solid-State Phase Transformations, Harry G. Brittain Effects of Pharmaceutical Processing on the Solid Form of Drug and Excipient Materials, Peter L. D. Wildfong SPECIAL TOPICS RELATED TO POLYMORPHISM AND SOLVATOMORPHISM Structural Aspects of Molecular Dissymmetry, Harry G. Brittain Amorphous Solids, Lynne S. Taylor and Sheri L. Shamblin Index
1,448 citations
TL;DR: It is hoped that this review will lead to a more direct approach to the characterization of pharmaceuticalsolids and ultimately to faster approval of regulatory documents containing information on pharmaceutical solids.
Abstract: Purpose. This review describes a conceptual approach to the characterization of pharmaceutical solids.
Methods. Four flow charts are presented: (1) polymorphs, (2) hydrates, (3) desolvated solvates, and (4) amorphous forms.
Results. These flow charts (decision trees) are suggested as tools to develop information on pharmaceutical solids for both scientific and regulatory purposes.
Conclusions. It is hoped that this review will lead to a more direct approach to the characterization of pharmaceutical solids and ultimately to faster approval of regulatory documents containing information on pharmaceutical solids.
966 citations
TL;DR: It was shown that in both samples significant crystallization to the most stable polymorphic form occurred over several days when stored below Tg, and in some cases this process was preceded by the relaxation of one amorphous form to the other.
433 citations
TL;DR: In this paper, the authors characterized the molecular mobility of selected amorphous systems (i.e., indomethacin, sorbitol, sucrose, and trehalose) below Tg using a combined experimental and theoretical approach.
Abstract: Increased interest in molecular time scales below the glass transition temperature, Tg, has arisen from the desire to identify the conditions (e.g., temperature) where the molecular processes which lead to unwanted changes in amorphous systems (e.g., chemical reactivity, crystallization, structural collapse) are improbable. The purpose of this study was to characterize the molecular mobility of selected amorphous systems (i.e., indomethacin, sorbitol, sucrose, and trehalose) below Tg using a combined experimental and theoretical approach. Of particular interest was the temperature where the time scales for molecular motion (i.e., relaxation time) exceed expected lifetimes or storage times. As a first approximation of this temperature, the temperature where the thermodynamic properties of the crystal and the equilibrium supercooled liquid converge (i.e., the Kauzmann temperature, TK) was determined. TK values derived from heat capacity and enthalpy of fusion data ranged from 40 to 190 K below the calorimet...
321 citations