Brewster, T. The above Eq. Note that at low CD concentrations, [CDt] is sometimes used as an estimate for [CD] meaning that a plot of the CD concentration versus drug solubilized can be used to estimate the K values. Specifically, the use of the simple polynomial to estimate the stability constants is not possible when a significant part of the total CD concentration [CD]t is present as bound CD as this leads to systematic errors in the calculated stability constants. One method which avoids these errors was provided by Higuchi and Kristiansen in which they calculated the free CD concentration [77]. This approach is easily incorporated into a least-square regression-based computer program.

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Brewster, T. The above Eq. Note that at low CD concentrations, [CDt] is sometimes used as an estimate for [CD] meaning that a plot of the CD concentration versus drug solubilized can be used to estimate the K values.

Specifically, the use of the simple polynomial to estimate the stability constants is not possible when a significant part of the total CD concentration [CD]t is present as bound CD as this leads to systematic errors in the calculated stability constants. One method which avoids these errors was provided by Higuchi and Kristiansen in which they calculated the free CD concentration [77]. This approach is easily incorporated into a least-square regression-based computer program.

While these paradigms allowed for the calculation of K and K values, the determination of higher order complexes is not possible with this formalism. To overcome these limitations, Peeters et al. The rough estimates are then used to calculate the solubility of the drug of interest as a function of the both the bound and free CD concentration at each solubility point using an exact solution to the equation. The differences between the calculated solubility and the experimentally derived data are then minimized by varying the values of the stability constants using the iterative approach of Nelder—Mead based on least-square regression.

Analysis of the residuals between calculated and experimental solubility data are then used to assess goodness of model fit. In many of these approaches, intrinsic drug solubility Do is derived from the y-intercept of the phase—solubility relationship. Loftsson et al. When the drug is less soluble than 0.

The exact cause for this deviation is not known but non-ideal behavior of water has been suggested as one possibility. Other contributing factors may be self-association of drug molecules or interaction of the drug with an excipient since these equilibria will reduce the availability of the drug for complex formation.

In any case, these findings suggest that the use of [D]int for Do in phase—solubility analysis will result in an overestimation of the Kc or K values. In extreme cases, [D]int can be negative giving rise to a negative K value which is not possible. This situation has been observed for highly lipophilic compounds and an explanation for the negative solubility value is usually related to drug self-association as in the case of cinnarizine. B-type profiles. Two subclasses have been described including BS and BI systems.

BS-type isotherms have been interpreted in the following manner [73,74]: as the CD concentration increases, a soluble complex forms which increase the total solubility of the substrate. At a particular point in this solubilization process, the maximum solubility of the drug is achieved which is the sum of Do plus any drug solubilized in the form of the CD complex. Additional CD generates additional complex which precipitates but so long as solid drug remains, dissolution and complexation can occur to maintain the value of Dt.

Finally, the solubility observed in the systems is associated with the solubility of the precipitated complex Dc. If the same complex which forms in the ascending portion the phase—solubility profile precipitates in the plateau phase, the increase in the drug concentration from Do to the plateau should equal Dc.

Note that this may not always be the case as multiple complexes may form in B-type systems. Importantly, the Gibbs phase rule indicates that only two phases can exist in the plateau segment of the diagram meaning that only one discrete complex may precipitate at any given point of the phase—solubility profile [73].

The stoichiometry of complexes formed from BS-type solubility isotherms can be determined in several ways. The precipitated complex can be chemically analyzed to give information on the molar relationships between the drug and CD i.

In addition, the length of the plateau region may be used to infer the complex order. This is possible since the amount of CD represented by the plateau is equal to that associated with the complex and the amount of drug associated with the complex is equal to the undissolved drug at the isotherm inflection from the initial to the plateau segments. The drug content of the complex is therefore the initial amount of drug present minus the amount of drug solubilized at the isotherm infection point.

The BI systems are similar in form to the BS profiles except that the complexes being formed are so insoluble that they do not give rise to the initial ascending component of the isotherm. Estimation of stability constants based on B-type phase—solubility relationships is also possible here. The initial ascending portion of a BStype isotherm can be analyzed with the same techniques used to assess AL-type systems through the use of Eq.

It is also possible to calculate a K value from the descending portion of BS profiles assuming the stoichiometry of the system is known. Equilibrium constant determination based on chemical reactivity. Methods based on chemical kinetics for determining equilibrium constants have been derived since CDs can enhance or retard the rate of various chemical processes [20,60,79—82]. Due to saturation kinetics, the observed first-order rate constants for a reaction kobs asymptotically approaches a maximum catalysis or minimum inhibition value with increasing CD concentration.

The concentration dependence of the kobs can be used to derive both the value of the stability constant, Kc as well as that of the first-order rate constant for the reaction of the included compound kc , by methods analogous to Michaelis—Menton analysis. For the formation of a one-to-one complex, the following scheme may be applied: where ko represent the first-order rate constant in the absence of CD. Thus, if kc b ko, the larger the values for the equilibrium constant, K, the greater will be the stabilization of the drug in question.

The above equation can then be rearranged into several formats including those of Lineweaver—Burk Eq. The kinetic approach for assessing equilibrium constants is often the only method available for compounds that are poorly stable in aqueous media. Spectrophotometric and spectroscopic methods for determining complexation constants. Spectrophotometric, spectroscopic or fluorescence methods are useful to determine the value of K if the complexation event induce changes in the compound spectra as a function of the guest-host interaction [83— 85].

These changes generally reflect an alteration in the microenvironment of the drug. For UV and related processes, the changes observed are similar to those associated with dissolving the drug in a solvent of decreased polarity.

These observations have been interpreted to mean that a chromophore of the drug is transferred from a more polar to a less polar environment. Titration of these optical property changes can give information on the stability constant. To this point, the equation of Benesi—Hildebrand Eq. Thus for the Benesi— Hildebrand Eq. In addition to changes in absorbance, changes in molar ellipticity i. Circular dichroism and related technologies are also useful in detecting complex formation since inclusion of achiral drugs into chiral CDs result in the an induced CD spectrum i.

NMR spectroscopy has also been extensively applied to the calculation of stability constants [88—90]. In addition to quantitative and qualitative information on complex formation, NMR can be used to probe the solution geometry of CD-based complexes as well as give kinetic information on their association and dissociation. Because of the molecular configuration of the CD torus, hydrogens attached to carbon 3 and 5 of the component glucose residues i.

H3 and H5 are situated in the cavity interior and are sensitive to compression shifts associated with drug interaction. These interactions, especially those related to aromatic ring complexation, leads to anisotropic shielding of the CD signals with a resulting upfield displacement of the resonances.

Protons present in the exterior of the torus i. H1, H2 and H4 are generally unaffected by complexation. Since complexation will affect both the protons of the CD cavity as well as the complementary protons of the included drug, changes in chemical shifts of both the CD and drug may be used to determine the binding constants.

The Benesi—Hildebrand Eq. The use of other additive properties to assess stability constants. Potentiometric methods assess the effect of complexation on change of acidity or basicity of the complexed material [95,96]. This method is based on the finding that CDs tend to bind free acids and bases more strongly than the respective ionized species.

As a consequence, CDs suppress ionization and increase the pKa for acids while decreasing the pKa for bases. An information rich value often used in the pharmaceutical sciences is the log of the octanol-water partition coefficient log P. In addition to providing data on biophase distribution, the partitioning of drugs and their CD complexes has been used to calculate the binding constants, K.

Having said that, this approach is complicated by the formation of complexes between octanol and the CD species and the fact that increasing saturation of CD binding sites with increasing drug concentrations must be accounted for in any exact treatment of phase distribution.

Masson et al. Based on Eq. If two components i. Stability constants can also be determined using HPLC-based methodologies [98—]. Addition of CD to the mobile phase decreases the retention time of a guest drug depending on the magnitude of the equilibrium constant.

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## CYCLODEXTRINS AS PHARMACEUTICAL SOLUBILIZERS PDF

Gardazshura 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. This review is intended to give a general background to the use of cyclodextrin as solubilizers as well as highlight kinetic and thermodynamic pharmaceuticxl and parameters useful in the study of drug solubilization by cyclodextrins. Company Name Velesco Pharmaceutical Services. Formulators have a powerful tool in the Cyclodextrin CD molecules; however there are several complicating factors that must be considered.

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## Cyclodextrins as pharmaceutical solubilizers

Adv Drug Deliv Rev. Epub May Cyclodextrins as pharmaceutical solubilizers. Brewster ME 1 , Loftsson T. 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.