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Advanced Drug Delivery Reviews (v.59, #7)
Drug solubility: how to measure it, how to improve it
by Jennifer Dressman Theme Editor; Christos Reppas Theme editor (pp. 531-532).
Computational approaches to determine drug solubility by Bernard Faller; Peter Ertl (pp. 533-545).
Water solubility is an important molecular property for successful drug development as it is a key factor governing drug access to biological membranes. There have been a number of review articles addressing computational models to predict water solubility with emphasis on the accuracy of the various prediction methods. This paper briefly reviews the available models and focuses on the value which can be extracted by comparing calculated and measured solubility, discusses the potential and limitations of the main computational approaches, and provides guidelines as to when to trust the computed value.
Keywords: List of Abbreviations; α; H; hydrogen-bond acidity; β; H; hydrogen-bond basicity; π; H; polarizability term; CLog; P; calculated log; P; ELog; P; experimentally measured log; P; log; D; distribution coefficient; MP; melting point; PSA; polar surface area; R; 2; excess molar refraction; relVol; relative volume calculated as a ratio between molecule volume and number of nonhydrogen atoms in molecule; S; 0; intrinsic aqueous solubility; V; x; McGowan molecular volumeAqueous solubility; Water solubility; log; P; Drug transport
High throughput solubility measurement in drug discovery and development by Jochem Alsenz; Manfred Kansy (pp. 546-567).
Measurement of drug solubility in various solvents is one of the key elements of compound characterization during the whole discovery and development process. This review summarizes current experimental approaches and addresses recent advances in the experimental methods used to determine drug solubility in drug discovery and early development. This paper focuses on high throughput methods designed to determine kinetic and thermodynamic (equilibrium) solubility but traditional methods are also presented. The focus, positioning, experimental setup, pros and cons, and limitations of individual assays are discussed and differences in solubility studies in discovery and development environments are highlighted. Finally, future needs and trends in solubility assay development designed to overcome current bottlenecks and trade-offs between speed and quality/quantity of measurements are addressed.
Keywords: Solubility; Kinetic solubility; Thermodynamic (equilibrium) solubility; Discovery; Development; Assay development; High throughput
Solubility of sparingly-soluble ionizable drugs by Alex Avdeef (pp. 568-590).
The experimental and computational basis of the pH-dependent measurement of solubility of sparingly-soluble ionizable drugs is reviewed. Recently described compound-sparing (but still accurate) approaches, suitable for application in preclinical development, and appropriate for the analysis of solubility of “problematic” molecules, are critically examined. A number of useful experimental methods are reviewed, including the miniaturized shake-flask microtitre plate, the micro solubility self-calibrating direct UV, potentiometric, and the micro dissolution methods. Several molecules were selected as case studies to illustrate important concepts, with re-analysis of literature data using recently established computational tools.
Keywords: Sparingly-soluble ionizable compounds; pH-dependent solubility; Solubility equations; Aggregation; Complexation; Shake-flask method; Miniaturized shake-flask method; Dissolution template titration method; Micro dissolution method
Estimating drug solubility in the gastrointestinal tract by J.B. Dressman; M. Vertzoni; K. Goumas; C. Reppas (pp. 591-602).
Solubilities measured in water are not always indicative of solubilities in the gastrointestinal tract. The use of aqueous solubility to predict oral drug absorption can therefore lead to very pronounced underestimates of the oral bioavailability, particularly for drugs which are poorly soluble and lipophilic. Mechanisms responsible for enhancing the luminal solubility of such drugs are discussed. Various methods for estimating intra-lumenal solubilities are presented, with emphasis on the two most widely implemented methods: determining solubility in fluids aspirated from the human gastrointestinal tract, and determining solubility in so-called biorelevant media, composed to simulate these fluids. The ability of the biorelevant media to predict solubility in human aspirates and to predict plasma profiles is illustrated with case examples.
Keywords: Solubility; Gastrointestinal tract; Humans; Dogs; Simulated media; Oral absorption
Salt formation to improve drug solubility by Abu T.M. Serajuddin (pp. 603-616).
Salt formation is the most common and effective method of increasing solubility and dissolution rates of acidic and basic drugs. In this article, physicochemical principles of salt solubility are presented, with special reference to the influence of pH–solubility profiles of acidic and basic drugs on salt formation and dissolution. Non-ideality of salt solubility due to self-association in solution is also discussed. Whether certain acidic or basic drugs would form salts and, if salts are formed, how easily they would dissociate back into their free acid or base forms depend on interrelationships of several factors, such as S0 (intrinsic solubility), pH, p Ka, Ksp (solubility product) and pHmax (pH of maximum solubility). The interrelationships of these factors are elaborated and their influence on salt screening and the selection of optimal salt forms for development are discussed. Factors influencing salt dissolution under various pH conditions, and especially in reactive media and in presence of excess common ions, are discussed, with practical reference to the development of solid dosage forms.
Keywords: Salt; solubility; pH–solubility profile; Common-ion effect; Self-association; Dissolution rate; Salt selection; Counterion; Microenvironmental pH
Crystal engineering of active pharmaceutical ingredients to improve solubility and dissolution rates by N. Blagden; M. de Matas; P.T. Gavan; P. York (pp. 617-630).
The increasing prevalence of poorly soluble drugs in development provides notable risk of new products demonstrating low and erratic bioavailabilty with consequences for safety and efficacy, particularly for drugs delivered by the oral route of administration. Although numerous strategies exist for enhancing the bioavailability of drugs with low aqueous solubility, the success of these approaches is not yet able to be guaranteed and is greatly dependent on the physical and chemical nature of the molecules being developed. Crystal engineering offers a number of routes to improved solubility and dissolution rate, which can be adopted through an in-depth knowledge of crystallisation processes and the molecular properties of active pharmaceutical ingredients. This article covers the concept and theory of crystal engineering and discusses the potential benefits, disadvantages and methods of preparation of co-crystals, metastable polymorphs, high-energy amorphous forms and ultrafine particles. Also considered within this review is the influence of crystallisation conditions on crystal habit and particle morphology with potential implications for dissolution and oral absorption.
Keywords: Crystal engineering; Crystallisation; Supramolecular chemistry; Polymorphism; Co-crystals; Solubility; Dissolution rate
Nanosizing — Oral formulation development and biopharmaceutical evaluation by Filippos Kesisoglou; Santipharp Panmai; Yunhui Wu (pp. 631-644).
Poor aqueous solubility represents a major hurdle in achieving adequate oral bioavailability for a large percentage of drug compounds in drug development nowadays. Nanosizing refers to the reduction of the active pharmaceutical ingredient (API) particle size down to the sub-micron range, with the final particle size typically being 100–200 nm. The reduction of particle size leads to a significant increase in the dissolution rate of the API, which in turn can lead to substantial increases in bioavailability. This review describes the principles behind nanosizing, the production and characterization of nanoformulations as well as the current experience with utilization of such formulations in vivo.
Keywords: Nanosizing; Nanoparticle; Nanosuspension; Bioavailability enhancement; Dissolution; Formulation
Cyclodextrins as pharmaceutical solubilizers by Marcus E. Brewster; Thorsteinn Loftsson (pp. 645-666).
Cyclodextrins are useful functional excipients that have enjoyed widespread attention and use. The basis for this popularity from a pharmaceutical standpoint, is the ability of these materials to interact with poorly water-soluble drugs and drug candidates resulting in an increase in their apparent water solubility. The mechanism for this solubilization is rooted in the ability of cyclodextrin to form non-covalent dynamic inclusion complexes in solution. Other solubilizing attribute may include the ability to form non-inclusion based complexes, the formation of aggregates and related domains and the ability of cyclodextrins to form and stabilize supersaturated drug solutions. The increase in solubility also can increase dissolution rate and thus improve the oral bioavailability of BCS Class II and IV materials. A number of cyclodextrin-based products have reached the market based on their ability to camouflage undesirable physicochemical properties. This review is intended to give a general background to the use of cyclodextrin as solubilizers as well as highlight kinetic and thermodynamic tools and parameters useful in the study of drug solubilization by cyclodextrins.
Keywords: Cyclodextrin; Toxicology; Regulatory status; Solubility; Stability constants; Phase–solubility; Supersaturation; Additives
Oral lipid-based formulations by David J. Hauss (pp. 667-676).
Poor drug solubility remains a significant and frequently encountered problem for pharmaceutical scientists. The ability of lipid-based formulations to facilitate gastrointestinal absorption of many poorly soluble drug candidates has been thoroughly documented in the published literature. However, a considerable gap exists between our knowledge of this technology and the know-how required for its application. This commentary provides a comprehensive summary of the development, characterization, and utilization of oral lipid-based formulations, from both physicochemical and biopharmaceutical perspectives. The characteristics of currently available lipid excipients are reviewed in context of their application to the basic lipid-based formulation modalities. The fundamental concepts of in vitro and in vivo evaluation of lipid-based formulations are summarized followed by a forward-looking summary of unrealized opportunities and potential limitations to more widespread use of this technology.
Keywords: Lipid-based formulations; Drug solubility; Lipid excipients; Lipid digestion; Drug absorption; Surfactant; Drug delivery
Prodrug strategies to overcome poor water solubility by Valentino J. Stella; Kwame W. Nti-Addae (pp. 677-694).
Drug design in recent years has attempted to explore new chemical spaces resulting in more complex, larger molecular weight molecules, often with limited water solubility. To deliver molecules with these properties, pharmaceutical scientists have explored many different techniques. An older but time-tested strategy is the design of bioreversible, more water-soluble derivatives of the problematic molecule, or prodrugs. This review explores the use of prodrugs to effect improved oral and parenteral delivery of poorly water-soluble problematic drugs, using both marketed as well as investigational prodrugs as examples. Prodrug interventions should be considered early in the drug discovery paradigm rather than as a technique of last resort. Their importance is supported by the increasing percentage of approved new drug entities that are, in fact, prodrugs.
Keywords: Prodrug; Solubility; Novel strategy; Phosphates; Ionizable and non-ionizable promoeities; Bioreversible; Parenteral; Oral delivery