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Phase solubility techniques

01 Jan 1965-Vol. 4, pp 212-217
About: The article was published on 1965-01-01 and is currently open access. It has received 2515 citations till now. The article focuses on the topics: Phase (matter) & Solubility.
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Journal ArticleDOI
TL;DR: Cyclodextrins are a family of cyclic oligosaccharides composed of α-(1,4) linked glucopyranose subunits.

2,917 citations


Cites methods from "Phase solubility techniques"

  • ...However, Connors has pointed out that, in general, the most nonpolar portions of guest molecules are enclosed in the cyclodextrin cavity and, thus, hydrophobic interactions must be important in many cyclodextrin complexes[40]....

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  • ...Kc = [DCD] [D][CD] (1) Connors has evaluated the population characteristics of cyclodextrin complex stabilities in aqueous solution[40,41]....

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  • ...It can be written [32,42]: mL + nS (a−mx)(b−nx) Km:n LmSn (x) So that, Km:n = [x] [a − mx]m[b − nx]n (2) In addition, dissociation constant can also be defined: Kd = [a − mx] m[b − nx]n [x] = 1 Kc or 1 Km:n (3) One of the most useful and widely applied analytical approaches in this context is the Phase–solubility method described by Higuchi and Connors[42]....

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  • ...One of the most useful and widely applied analytical approaches in this context is the Phase–solubility method described by Higuchi and Connors [42]....

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Journal ArticleDOI
TL;DR: Cyclodextrins, because of their continuing ability to find several novel applications in drug delivery, are expected to solve many problems associated with the delivery of different novel drugs through different delivery routes.
Abstract: The purpose of this review is to discuss and summarize some of the interesting findings and applications of cyclodextrins (CDs) and their derivatives in different areas of drug delivery, particularly in protein and peptide drug delivery and gene delivery. The article highlights important CD applications in the design of various novel delivery systems like liposomes, microspheres, microcapsules, and nanoparticles. In addition to their well-known effects on drug solubility and dissolution, bioavailability, safety, and stability, their use as excipients in drug formulation are also discussed in this article. The article also focuses on various factors influencing inclusion complex formation because an understanding of the same is necessary for proper handling of these versatile materials. Some important considerations in selecting CDs in drug formulation such as their commercial availability, regulatory status, and patent status are also summarized. CDs, because of their continuing ability to find several novel applications in drug delivery, are expected to solve many problems associated with the delivery of different novel drugs through different delivery routes.

1,135 citations


Cites background or methods from "Phase solubility techniques"

  • ...The inclusion ability of DM-β-CD, causing the release of the transporters (P-gp, MRP2) from the apical membranes of monolayers, was reported to be the possible reason for the observed impaired efflux function of the transporters in the presence of the CD....

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  • ...In such cases it is important to use just enough CD to solubilize the drug in the aqueous vehicle since excess may decrease the drug availability (Figure 4).(8,96,97) At low RM-β-CD concentrations, when hydrocortisone was in suspension, increasing the CD concentration increased the drug flux....

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  • ...Reduction of drug crystallinity on complexation or solid dispersion with CDs also contributes to the CD increased apparent drug solubility and dissolution rate.83,87 CDs, as a result of their ability to form in situ inclusion complexes in dissolution medium, can enhance drug dissolution even when there is no complexation in the solid state.75 SBE-β-CD was shown to be an excellent solubilizer for several drugs and was more effective than β-CD but not as effective as DM-β-CD.93 CDs can also act as release enhancers, for example β-CD enhanced the release rate of poorly soluble naproxen and ketoprofen from inert acrylic resins and hydrophilic swellable (high-viscosity hydroxy propyl methyl cellulose [HPMC]) tableted matrices. β-CD also enhanced the release of theophylline from HPMC matrix by increasing the apparent solubility and dissolution rate of the drug.94,95...

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  • ...CD complexation was found to decrease local drug irritation and also modify the time of drug release during GI transit.(8,17)An itraconazole oral preparation containing 40% (wt/vol) of HP-β-CD (with reduced drug irritation) has been commercialized in the United States and Europe....

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  • ...The cytotoxicity order of CDs on the human corneal cell line was found to be α-CD 9 DM-β-CD 9 SBE-β-CD = HP-β-CD 9 γ-CD....

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Journal ArticleDOI
TL;DR: This short review is intended to provide both some basic science information as well as data on the ability to develop drugs in cyclodextrin‐containing formulations.
Abstract: Objectives Drug pipelines are becoming increasingly difficult to formulate. This is punctuated by both retrospective and prospective analyses that show that while 40% of currently marketed drugs are poorly soluble based on the definition of the biopharmaceutical classification system (BCS), about 90% of drugs in development can be characterized as poorly soluble. Although a number of techniques have been suggested for increasing oral bioavailability and for enabling parenteral formulations, cyclodextrins have emerged as a productive approach. This short review is intended to provide both some basic science information as well as data on the ability to develop drugs in cyclodextrin-containing formulations. Key findings There are currently a number of marketed products that make use of these functional solubilizing excipients and new product introduction continues to demonstrate their high added value. The ability to predict whether cyclodextrins will be of benefit in creating a dosage form for a particular drug candidate requires a good working knowledge of the properties of cyclodextrins, their mechanism of solubilization and factors that contribute to, or detract from, the biopharmaceutical characteristics of the formed complexes. Summary We provide basic science information as well as data on the development of drugs in cyclodextrin-containing formulations. Cyclodextrins have emerged as an important tool in the formulator's armamentarium to improve apparent solubility and dissolution rate for poorly water-soluble drug candidates. The continued interest and productivity of these materials bode well for future application and their currency as excipients in research, development and drug product marketing.

724 citations


Cites background from "Phase solubility techniques"

  • ...The stoichiometry of drug–CD complexes and the numerical values of their stability constants are frequently obtained from phase-solubility diagrams where the drug solubility is monitored as a function of total CD added to the complexation medium as shown in Figure 2.([20,41,42]) Linear phase-solubility diagrams (AL-type) indicate that the complex is first order with respect to the CD (n = 1 in Equation 1) and first or higher order with respect to the drug (m 1)....

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  • ...Plots of total drug solubility (Stot) vs total amount of dissolved cyclodextrin, and their classification according to Higuchi & Connors.([41]) 1612 Journal of Pharmacy and Pharmacology 2010; 62: 1607–1621...

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Journal ArticleDOI
TL;DR: In the pharmaceutical industry cyclodextrins have mainly been used as complexing agents to increase aqueous solubility of poorly soluble drugs, and to increase their bioavailability and stability.
Abstract: Cyclodextrins are a family of cyclic oligosaccharides with a hydrophilic outer surface and a lipophilic central cavity. Cyclodextrin molecules are relatively large with a number of hydrogen donors and acceptors and, thus, in general they do not permeate lipophilic membranes. In the pharmaceutical industry cyclodextrins have mainly been used as complexing agents to increase aqueous solubility of poorly soluble drugs, and to increase their bioavailability and stability. Studies in both humans and animals have shown that cyclodextrins can be used to improve drug delivery from almost any type of drug formulation. However, the addition of cyclodextrins to existing formulations without further optimisation will seldom result in acceptable outcome. Currently there are approximately 30 different pharmaceutical products worldwide containing drug/cyclodextrin complexes on the market.

719 citations

Journal ArticleDOI
TL;DR: The most common stoichiometric determination during formulation studies is 1:1, i.e. one drug molecule forms a complex with one cyclodextrin molecule, and the apparent stability constant (K1:1) of the 1:2 drug/cyclodextrins complexes calculated by the phase-solubility method is found.

562 citations


Cites background from "Phase solubility techniques"

  • ...8 (Moffat et al., 2004)) and waterinsoluble compound (S0 = 1 g/ml at pH 11.9) with large aromatic planar regions, or physicochemical char3) (Higuchi and Connors, 1965)....

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  • ...ThenK1:1 is calculated from the slope andS0 (Higuchi and Connors, 1965): K1:1 = Slope S0(1 − Slope) (3) The observed value ofK1:1 is most often between 50 and 2000 M−1 with a reported mean values of 129, 490 and 355 M−1 for the parent -, - and -cyclodextrin, respectively (Connors, 1995)....

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