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Biomedical subjects

S H Yalkowsky

Publications and source records attributed to S H Yalkowsky.

At least 19 recordsLinked to original sources
PubMed2001

Use of pure t-butanol as a solvent for freeze-drying: a case study.

1-(2-Chloroethyl)-3-sarcosinamide-1-nitrosourea, (SarCNU) (NSC-364432) is a new antitumor drug that is of interest to the National Cancer Institute. It is intended for use as an intravenous injection. Although SarCNU is sufficiently soluble in water to obtain the desired dosage, it is highly unstable. Its T(90) in aqueous solution at room temperature is less than 6 h. Neat tertiary butyl alcohol (TBA), a low toxicity, high vapor pressure and low melting solvent, was determined to be an excellent freeze-drying medium. Lyophilization of SarCNU from pure TBA produces a uniform cake composed of needle-shaped crystals. Thermal analysis and gas chromatography indicate that the cake contains less than 0.001% residual solvent. The SarCNU cake can be readily reconstituted with either water or an aqueous solution of 40% propylene glycol and 10% ethanol. The reconstituted solutions are stable for 4 and 13 h, respectively.

Antineoplastic Agents↗
PubMed2001

Solubilization of NSC-639829.

Solubilization using pH combined with cosolvents, surfactants, and complexants are investigated for NSC-639829, an investigational anti-tumor agent. The intrinsic solubility of the drug is approximately 30 ng/ml and it has an ionizable dimethyl aniline group with an approximate base pK(a) of 5. Samples buffered at pH 1.0, 2.0, and 7.0 with various concentrations of the solubilizing agents were used to study the solubilization of NSC-629829 when present as charged and uncharged species. The solubilization of NSC-639829 was found to be much more effective when the drug was present primarily in ionized form. At pH values 1.0 and 2.0 where the surfactant (SLS) and complexant (SBEbetaCD) carried a negative charge enhanced solubilities of more than a million-fold were observed for the drug.

Antineoplastic Agents↗
PubMed2001

Stabilization of eptifibatide by cosolvents.

Eptifibatide is a potent and highly specific inhibitor of platelet receptor glycoprotein IIb/IIIa and is indicated in the treatment of acute coronary syndrome. The commercial product Integrilin(R) (eptifibatide) Injection requires a cold/refrigerator storage condition. In an effort to improve the drug stability for room temperature storage and transportation, this study proposed a semi-aqueous formulation that contains 2 mg/ml eptifibatide, 10% ethanol, 40% propylene glycol and 50% 0.025 M citrate buffer. The stability study was conducted in the pH range 4.25-6.25 under accelerated temperatures: 48, 60, 72.5 degrees C. The results indicate that the proposed semi-aqueous vehicles substantially increased the drug stability in comparison with aqueous vehicles. The predicted drug shelf-life T(90) at 25 degrees C shows that an almost twofold increase can be achieved by formulating eptifibatide in the semi-aqueous vehicle, which is 60 months at its maximum stability of pH 5.75, as opposed to the 33 months in the aqueous vehicle at its maximum stability of pH 5.25.

Chemistry, Pharmaceutical↗
PubMed2001

Solubilization of rapamycin.

The solubilization of rapamycin, a poorly water soluble investigational immunosuppressive drug, by facilitated hydrotropy is presented. Partially water-miscible aromatic solutes (such as benzyl alcohol, benzoate, or benzoic acid) can be solubilized by water-miscible cosolvents, such as ethanol and propylene glycol. Once solubilized, the partially miscible aromatic solute becomes a solubilizing agent. This technique yielded a dramatic (>1000-fold) increase in the aqueous solubility of rapamycin.

Anti-Bacterial Agents↗
PubMed2001

Estimation of the aqueous solubility I: application to organic nonelectrolytes.

The estimation of aqueous solubilities of organic nonelectrolytes by the General Solubility Equation (GSE) as proposed by Valvani and Yalkowsky (1980) is used in this study. The data and assumptions on which the GSE are based are reevaluated, and the equation is revised. The revised GSE is validated on a set of 580 pharmaceutically, environmentally, and industrially relevant nonelectrolytes. The revised equation has a stronger theoretical background and provides a more accurate estimation of aqueous solubility.

Organic Chemicals↗
PubMed2000

Relationship between polysorbate 80 solubilization descriptors and octanol-water partition coefficients of drugs.

The molar solubilization capacities (kappa) and the molar micelle-water partition coefficients (K(M)(N)) in Polysorbate 80 of several drugs (including barbiturates, steroids, and benzoic acid derivatives) are related to their log octanol-water partition coefficients (logP). Both kappa and K(M)(N) values were calculated from solubility versus Polysorbate 80 concentration profiles, which were either experimentally determined or obtained from the literature. There is a linear relationship between logP of the tested compounds and the logarithm of the molar micelle-water partition coefficient (logK(M)(N)). On the other hand molar solubilization capacities are nearly independent of logP. It is shown that the ability of Polysorbate 80 to solubilize a drug can be predicted from its logP value.

Octanols↗
PubMed2000

Estimation of the effect of NaCl on the solubility of organic compounds in aqueous solutions.

The Setschenow constant, K(salt), of a nonelectrolyte in a NaCl solution is shown to be related to the logarithm of its octanol-water partition coefficient, log K(ow), determined by K(salt) = A log K(ow) + B, where K(ow) is the octanol-water partition coefficient of the solute and the coefficients A and B are constants. The values of A and B were empirically determined from literature data for 62 organic compounds and validated for a test set of 15 compounds including several drugs.

Chemical Phenomena↗
PubMed2000

Ocular gelfoam disc-applicator for pupillary dilation in humans.

This study investigates a gelfoam disc device as an alternative topical ophthalmic drug delivery system for pupillary dilation in humans. Gelfoam (Pharmacia & Upjohn) discs were impregnated with 0.60 mg of tropicamide racemate and 1.7 mg of 1-phenylephrine hydrochloride by an ethanol solvent evaporation method. Twenty randomly selected human subjects received baseline examinations, including blood pressure, pulse rate and biomicroscopy of the ocular surface. One impregnated gelfoam disc was placed in the inferior fornix of a randomly selected eye. Simultaneously, the fellow eye was treated with two topically administered drops, one from a phenylephrine hydrochloride 2.5% solution and one from a tropicamide 1% solution. A single, masked observer measured the pupillary diameter in both eyes at various time intervals under constant ambient conditions. Administration of the topical drops was repeated in the fellow eye. At maximum pupillary dilation, the disc was removed, and a post-dilation biomicroscopic exam was performed. Blood pressure and pulse rate were rechecked. The gelfoam-treated eyes' median change in dilation diameter was approximately 25% greater (a two-fold increase in pupillary area) (p< 0.001) at 15.2 min (median time to maximum dilation) than the topically treated fellow eyes. The median change in systolic blood pressure (+1.0 mmHg) and diastolic blood pressure (-1.0 mmHg) was not statistically significant (p>0.1). The average pulse rate was decreased 7 beats per minute (p=0.004). A gelfoam disc may serve as an ophthalmic drug delivery system for pupillary dilation or as a model for other multiple-dose topical drugs.

Adult↗
PubMed1999

Systemic absorption of insulin from a Gelfoam ocular device.

In previous reports (Lee et al., 1997b; Lee and Yalkowsky, 1999), it has been shown that insulin, delivered by an acidified Gelfoam (absorbable gelatin sponge, USP) based ocular device, can be efficiently absorbed into the systemic circulation without the aid of an absorption enhancer. The role of acid in the enhancer-free absorption of insulin is investigated in this report. Gelfoam ocular devices containing 0.2 mg of sodium insulin prepared with either water or 10% acetic acid were evaluated in rabbits. The results suggest that a change in the Gelfoam upon treatment with acid is responsible for the efficient systemic absorption of insulin from these enhancer-free devices.

Absorption↗
PubMed1999

Effect of formulation on the systemic absorption of insulin from enhancer-free ocular devices.

Several Gelfoam (absorbable gelatin sponge, USP) based surfactant free devices containing either sodium or zinc insulin were prepared with diluted acetic or hydrochloric acid. They were evaluated by the lowering of the blood glucose concentration in rabbits. The systemic absorption of insulin from the device can be enhanced by using a 5% or higher concentration of acetic acid solution as well as 1% HCl solution. The results indicate that the proposed device prepared with up to 30% of acetic acid solution produced no eye irritation. A single device containing 0.2 mg of insulin is sufficient to control the blood glucose levels in a uniform manner (60% of initial) for over 8 h.

Absorption↗
PubMed1999

Buffer capacity and precipitation control of pH solubilized phenytoin formulations.

The main objective of this investigation is to develop a phenytoin (DPH) intravenous formulation that does not precipitate upon dilution. The effect of the buffer capacity at pH 12 of several DPH formulations on the extent and lag-time of DPH precipitation upon dilution with Sorensen's phosphate buffer (SPB) is evaluated. DPH precipitation was evaluated by means of static and dynamic in vitro dilution methods. It is shown that an increase in the formulation buffer capacity decreases substantially the extent of DPH precipitation and increases the lag-time for precipitation. In addition, a comparison between static and dynamic in vitro methods to measure precipitation is presented.

Anticonvulsants↗
PubMed1999

Formulation and in vivo evaluation of ocular insert containing phenylephrine and tropicamide.

A Gelfoam based ocular device containing 1.7 mg of phenylephrine and 0.6 mg of tropicamide was formulated and evaluated for pupillary dilation in rabbits. The manufacturing procedure is fairly simple and the required excipients are inexpensive. The in vivo results show that the mydriatic response produced by the proposed device is larger and longer lasting than that produced by eyedrops with an equivalent amount of phenylephrine and tropicamide. The results reported in this study, along with those of previous studies, imply that Gelfoam(R) is a versatile drug carrier for either local or systemic drug delivery via the ophthalmic route.

Animals↗
PubMed1999

Degradation kinetics of 4-dedimethylamino sancycline, a new anti-tumor agent, in aqueous solutions.

The kinetics of degradation of the new anti-tumor drug, 4-dedimethylamino sancycline (col-3) in aqueous solution at 25oC were investigated by high-pressure liquid chromatography (HPLC) over the pH-range of 2-10. The influences of pH, buffer concentration, light, temperature, and some additives on the degradation rate were studied. The degradation of col-3 was found to follow first order kinetics. A rate expression covering the degradation of the various ionic forms of the drug was derived and shown to account for the shape of the experimental pH-rate profile. Under basic conditions, the degradation of col-3 involves oxidation, which is catalyzed by metal ions and inhibited by EDTA and Sodium bisulfite.

Antibiotics, Antineoplastic↗
PubMed1999

Ocular devices for the controlled systemic delivery of insulin: in vitro and in vivo dissolution.

Both in vitro flow-through and in vivo device removal methods were utilized to determine the dissolution rate of insulin from a Gelfoam(R) based eye device. The dissolution profiles generated by these two methods are comparable. The in vivo data suggests that there is a direct relationship between blood glucose lowering and the rate of release of insulin from the device. The in vitro dissolution results indicate that the release of insulin from the device is flow-rate dependent. The prolonged activity of the insulin is due to the gradual release of insulin from the device which results from the lachrymal system's slow and constant tear production.

Animals↗
PubMed1999

Predicting the total entropy of melting: application to pharmaceuticals and environmentally relevant compounds.

Experimental entropy of melting values for physical property estimation schemes, such as solubility and vapor pressure, are not readily available. In this study a semiempirical equation, which contains two molecular parameters, is used to estimate the total entropy of melting for a variety of pharmaceutically and environmentally relevant compounds. A database of experimental entropy values consisting of over 370 different compounds was compiled from literature. A molecular rotational symmetry number and a molecular flexibility number for each compound were defined. The simple equation does very well in predicting the total entropy of melting for the complex set of molecules with an average error of 21%.

Thermodynamics↗
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↗