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Biomedical subjects

S H Yalkowsky

Publications and source records attributed to S H Yalkowsky.

At least 37 records · Page 2Linked to original sources
PubMed1999

Spectrophotometric determination of acidity constants of 4-dedimethylamino sancycline (Col-3), a new antitumor drug.

A spectrophotometric technique was used to determine the acidity constants of 4-dedimethylamino sancycline (Col-3), a new antitumor drug. The apparent pKa values of Col-3 in 0.5% methanol aqueous media at approximately 25 degrees C with a constant ionic strength of 0.2 were calculated manually and graphically to be 5.64 +/- 0.17 (pKa1) and 8.35 +/- 0.07 (pKa2). In addition, the computer program SQUAD was used to confirm Col-3 pKa values. The pKa values obtained by SQUAD were pKa1 5.63 +/- 0.14 and pKa2 8.39 +/- 0.04. These results are in agreement with the tetracycline-like structure of Col-3.

Antineoplastic Agents↗
PubMed1999

Solubilization of ionized and un-ionized flavopiridol by ethanol and polysorbate 20.

Because the ionized species is more polar than its un-ionized counterpart, it is often assumed that the ionized species of the drug does not make a meaningful contribution to solubilization by either cosolvents or surfactants. This report extends previous studies on solubilization of the ionic species by a combination of pH control and complexation to pH control and micellization and to pH control and cosolvency. The total aqueous solubility is expressed as the addition of the concentration of all contributing species: free un-ionized drug [Du], free ionized drug [Di], un-ionized drug micelle [DuM], and ionized drug micelle [DiM] for surfactant, and free un-ionized drug [Dcu] and free ionized drug [Dci] for cosolvent. The equations indicate that under certain conditions the ionized species can be more important in determining the drug total solubility than the un-ionized species. Flavopiridol, a weak base, is used to test these newly generated equations. As expected, the micellar partition coefficient and solubilization power for ionized flavopiridol are both less than those of the un-ionized species. However, at acidic pH, the solubilities of the ionized drug in surfactant micelles [DiM] and in cosolvent-water [Dci] are both much greater than that of the un-ionized drug. This difference is because the solubilization of the ionized drug is proportional to its aqueous solubility, and its solubility [Di] can be as much as 24-fold greater than that of the free un-ionized species [Du].

Antineoplastic Agents↗
PubMed1999

Freeze-drying above room temperature.

This study investigates the use of solid, organic compounds to lyophilize drugs without conventional freeze-drying equipment. The aim of the investigation is to find a pharmaceutically acceptable solvent or solvent combination that is appropriate for freeze-drying on the basis of its ability to (1) solubilize hydrophobic drugs, (2) provide a stable environment for water-sensitive compounds, (3) be rapidly and completely removed from the product under vacuum, and (4) produce cakes that are readily reconstituted. A eutectic formed from 1,1,1-trichloro-2-methyl-2-propanol (chlorobutanol) hemihydrate and dimethyl sulfone (DMSO2) is determined to be a suitable medium.

Freeze Drying↗
PubMed1999

A spin filter method for continuous evaluation of hemolysis.

A novel method for quantifying hemolysis is described. This method uses a spin filter to separate the free hemoglobin from the red blood cells suspended in the test solution. This procedure enables the use of a closed loop system that continuously measures hemolysis spectrophotometrically. It is shown that hemolysis does not always stop after the solution has been quenched with normal saline. In fact, the process of hemolysis induced by chemicals such as potassium oleate is relatively slow.

Algorithms↗
PubMed1999

Solubilization of flavopiridol by pH control combined with cosolvents, surfactants, or complexants.

This study investigates the roles of both ionized and un-ionized species of flavopiridol in solubilization by complexation, micellization, and cosolvency. Control of pH was used in combination with surfactants (polysorbate 20 and polysorbate 80), cosolvents (ethanol and propylene glycol), as well as uncharged and anionic complexing agents [hydroxypropyl beta-cyclodextrin (HPbetaCD) and sulfobutyl ether beta-cyclodextrin (SBEbetaCD)] to solubilize flavopiridol. These combined techniques increase not only the solubility of the un-ionized flavopiridol but also the solubility of the ionized drug. This study confirms that previously developed equations effectively characterize the roles of pH, pK(a), and either complexation constant, micelle partition coefficient, or cosolvent solubilizing power in determining drug total aqueous solubility.

Antineoplastic Agents↗
PubMed1999

UPPER III: unified physical property estimation relationships. Application to non-hydrogen bonding aromatic compounds.

The UPPER scheme uses four additive and two nonadditive parameters and several well-known equations to calculate 21 physical properties of organic compounds strictly from molecular structure. The scheme allows reasonable estimations of melting and boiling points, aqueous and octanol solubilities, air-octanol, air-water, and octanol-water partition coefficients, vapor pressure, and other properties. In this report non-hydrogen bonding aromatic compounds are used to evaluate a portion of the UPPER scheme.

Algorithms↗
PubMed1999

Solubilization of fluasterone.

Solubilization of nonpolar drugs constitutes one of the most important tasks in parenteral formulations design. This study investigates and assesses the solubility enhancement of Fluasterone by various techniques including cosolvency, micellization, and complexation. Of the solubilizing agents used, the modified beta-cyclodextrins were found to be the most effective. The solubility of Fluasterone is 1.55 x 10(-4) mM, 3.13 mM, and 4.04 mM in water, 20% sulfobutyl ether-beta-cyclodextrin (SBEbetaCD), and 20% hydroxypropyl-beta-cyclodextrin (HPbetaCD), respectively.

Algorithms↗
PubMed1999

Combined effect of cosolvent and cyclodextrin on solubilization of nonpolar drugs.

Solubility enhancement has broad implications in parenteral formulation design. A simple mathematical model has been developed to describe the combined effect of cosolvency and complexation on nonpolar drug solubilization. The total drug solubility is determined by the summation of three drug species present in the solution: free drug [D], drug-ligand binary complex [DL], and drug-ligand-cosolvent ternary complex [DLC]. The proposed model established the dependencies of these three species upon the intrinsic drug solubility, [D(u)], the cosolvent solubilizing power, sigma, the binary and ternary intrinsic complexation constants, K(b)(int) and K(t)(int), and the cosolvent destabilizing powers for the binary and the ternary complexes, rho(b) and rho(t). A nonpolar solute, Fluasterone, is used to evaluate the newly generated equation. The model explains the decline in drug solubility produced by low cosolvent concentrations as well as the increase in the solubility produced by high cosolvent concentrations that are observed at all cyclodextrin concentrations.

2-Hydroxypropyl-beta-cyclodextrin↗
PubMed1999

The preparation of soft gelatin capsules for a radioactive tracer study.

Clinical doses are developed for the oral coadministration of radiolabeled and nonlabeled forms of a poorly soluble investigational compound: OPC-41061. The release rates of the labeled and nonlabeled forms are equated and matched to the release rate of the polymer spray-dried form of the drug in the proposed market product. The study involves the physicochemical characterization of the powders using thermal analysis and dissolution testing, development and extemporaneous manufacture of liquid-filled soft gelatin capsules, and dissolution and stability testing of the final dosage form. Thermal analysis indicated that the labeled powder was amorphous and that the nonlabeled powder, which had been jet-milled, was crystalline. Dissolution testing of the jet-milled and spray-dried powders indicated that the former was released at a significantly slower rate. A liquid formulation containing 25% dimethyl acetamide and 75% polyethylene glycol 400 (PEG 400) solubilized the desired dose of 60 mg and exhibited a drug profile that was similar to the spray-dried formulation. The final formulation was a soft gelatin capsule containing 60 mg of drug, including 100 microCi radioactivity, dissolved in 0.8 ml of a 25% dimethyl acetamide/75% PEG 400 solution. The formulation was chemically and physically stable for a period greater than the duration of the study.

Benzazepines↗
PubMed1998

Evaluation of in vitro precipitation methods.

Four in vitro precipitation methods were tested and evaluated using flavopiridol and diazepam formulations. The methods include static serial dilution, dynamic injection, and dropwise addition with and without stirring. The results generated from these methods are comparable and complementary. The static serial dilution method is most effective in quantifying the amount of precipitation and more descriptive of the formation and redissolution of the precipitate than the others. The dynamic injection method, however, has its merit in more realistically simulating the physiological environment of drug-blood interaction near the injection sites.

Antineoplastic Agents↗
PubMed1998

Combined effect of complexation and pH on solubilization.

Both pH control and complexation are widely used as solubilization techniques in drug formulation studies. Although these two techniques are often utilized in combination, few theoretical studies have shown why the combined approach would work better than either one alone. This study constructs a background in which both the pH effect and complexation constants are used to explain the synergism between these techniques. The total solubility is determined by the addition of the concentrations of the four components present in the solution: free un-ionized drug [Du], free ionized drug [Di], un-ionized drug complex [DuL], and ionized drug complex [DiL]. A detailed description of [Di] and [DiL] reveals that the complexation constants and the pH at which the drug may ionize are both critical. The weakly basic drug flavopiridol is used as a test compound to examine the validity of the equation. Although the complexation constant for ionized flavopiridol (Ki = 124 M(-1)) is less than one-third of that of the un-ionized species (Ku = 445 M(-1)), the solubility of the ionized drug complex [DiL] is 6-fold greater than that of the un-ionized drug complex [DuL]. This unexpected result is due to the 25-fold greater solubility of the ionized drug [Di] at pH 4.3 over that of the free un-ionized species [Du] at pH 8.4. The results of this and other complexation studies of several drugs taken from the literature lend the support to the following: If [Di]/[Du] >Ku/Ki, then [DiL] >[DuL].

Chemistry, Pharmaceutical↗
PubMed1998

Effect of hydroxypropyl-beta-cyclodextrin and pH on the solubility of levemopamil HCl.

Levemopamil was solubilized by varying the concentration of hydroxypropyl-beta-cyclodextrin (HPbetaCD) and by the alteration of pH. The drug molecule has two sites for possible complexation with HPbetaCD, creating the possibility of either 1:1 or 1:2 complexation. The solubility as a function of HPbetaCD concentration of the charged and uncharged forms of the drug follows the A(L) and Ap complexation models, respectively. This suggests that the charged drug forms a 1:1 complex, whereas the neutral drug forms both 1:1 and 1:2 complexes.

2-Hydroxypropyl-beta-cyclodextrin↗
PubMed1998

A novel thermogravimetric method for estimating the saturated vapor pressure of low-volatility compounds.

Thermogravimetric analysis is used to measure accelerated vaporization rates at elevated temperatures and reduced pressures for several compounds. Multiple linear regression is used to generate empirical coefficients of an equation that relates these parameters. The vaporization rates of the compounds at standard ambient temperature and pressure (SATP) are estimated by extrapolation to 10(5) Pa (1 atm) and 298 K. The estimated vaporization rates are then correlated with literature values of saturated vapor pressure (Psat). The results of twenty four compounds with vapor pressures that span 10 orders of magnitude indicate that p25 degrees C (sat) is directly proportional to the rate of vaporization at SATP. The average error of an estimate of p25 degrees C (sat) based on this relationship is less than a factor of 2.1.

Air Pressure↗
PubMed1997

Derivatization and high-performance liquid chromatographic analysis of pentaazapentacosane pentahydrochloride.

A rapid high-performance liquid chromatographic method for determination of the dansyl derivative of pentaazapen-tacosane (PAPC) pentahydrochloride has been developed. The chromatographic system uses a reversed-phase C8 column, a mobile phase of acetic acid buffer and acetonitrile and UV detection. The dansylation conditions were optimized with a pH of 11.0 and a 20-fold dansyl chloride excess. The yield of dansyl PAPC increased 10-fold as the reaction pH was changed from 9.5 to 10.5. Under derivatization conditions of pH 8.5-11.0 and 1-30-fold excess dansyl chloride only perdansyl PAPC was found.

Antineoplastic Agents↗
PubMed1997

Determination of melanotan II in rabbit urine using solid-phase extraction sample preparation followed by reversed-phase high-performance liquid chromatography.

A solid-phase extraction (SPE) method has been developed for the isolation of melanotan II from rabbit urine. The proposed extraction method makes it possible to selectively isolate melanotan II without significant loss of the peptide. Standard curves obtained from high-performance liquid chromatographic (HPLC) analysis of spiked urine extracts are linear from 0.1 to 4.0 micrograms/ml. The analytical method is shown to be highly reproducible, giving a relative standard deviation of less than 5% for both between-day and same-day analyses. The accuracy of the method obtained from standard plots ranges from -3.3 to 3.1%.

Animals↗
PubMed1997

Effect of Brij-78 on systemic delivery of insulin from an ocular device.

An ocular insert is developed for the controlled systemic delivery of insulin. Commercially available Gelfoam absorbable gelatin sponge, USP, is used in the fabrication of the ocular insert in the form of a matrix system. Two eyedrop formulations and 13 eye device formulations were evaluated. The efficacy of insulin ocular delivery was quantitated by monitoring the changes in its pharmacological response (i.e., blood glucose lowering). The in vivo results from devices containing 0.5 or 1.0 mg of insulin with 20 micrograms of polyoxyethylene-20-stearyl ether (Brij-78) give a substantial improvement in insulin activity and a significant prolongation in its duration compared with the eyedrops. In addition, the mean blood glucose concentration returns to nearly normal levels within 60 min after the removal of the device. Overall, the application of the Gelfoam device makes it feasible to obtain a prolonged systemic delivery of insulin within the desired therapeutic levels without the risk of hypoglycemia.

Animals↗