Tapan Sanghvi

Solubilization and preformulation of carbendazim.

The solubilization of carbendazim by pH in combination with cosolvents, surfactants or complexants was investigated. At pH 7 the total drug solubility is 6.11 +/- 0.45 microg/ml which increases by 1-7 fold with cosolvent, surfactant or complexant. However, at pH 2 the solubility increases by 250 times. Cosolvents have a negligible effect (50% increase) on the total drug solubility at pH 2 because of the high polarity of the cationic drug. Also pH combined with nonionic surfactants does not improve solubility, as relatively less polar micelles are not able to accommodate the cationic drug. Interestingly, the total drug solubility increases by combining pH 2 with complexants, as they can form a complex with the isolated aromatic ring of both the unionized and the ionized drug. The proposed oral formulation of 1 mg/ml carbendazim at pH 2 does not precipitate in the presence of Seven Up or water. But it does precipitate with pH 7 buffer when diluted 1:10 but not 1:100 or 1:250.

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.

A ‘Rule of Unity’ for Human Intestinal Absorption

The ability to predict the passive intestinal absorption of organic compounds can be a valuable tool in drug design. Although Lipinskis ‘rule of 5’ is commonly used for this purpose, it does not routinely give reliable results. An alternative ‘rule of unity’ is proposed to predict the absorption efficiency of orally administered drugs that are passively transported. The rule of unity based upon the theoretical principals that govern passive transport. The ‘rule of 5’ and the ‘rule of unity’ are compared using experimentally determined passive human intestinal absorption data for 155 drugs. Absorption values which are >50% of the dose are classified as well absorbed and absorption values which are ≤50% of the dose are classified as classified as poorly absorbed. Comparison of the two models using a receiver operating characteristic (ROC) plot and McNemars test reveal striking differences in absorption predictability. The ‘rule of 5’ gives twice as many false predictions than the ‘rule of unity.’

A Simple Modified Absorption Potential

With the advent of combinatorial chemistry and highthroughput screening, a large number of pharmacologically active compounds are being synthesized without consideration of their biopharmaceutical properties. This can lead to the failure of promising new drug candidates because of inadequate absorption from the gastrointestinal (GI) tract. It is generally assumed that the passive transport processes between various aqueous and organic phases are governed by a balance of the hydrophilicity and the lipophilicity of the compound. Therefore water solubility and partition coefficient are of primary interest in determining drug absorption. Dressman et al. (1) have introduced an absorption potential (AP) term for predicting the fraction of drug absorbed via passive transport. The AP is a dimensionless number and is defined as

Independence of the Product of Solubility and Distribution Coefficient of pH

AbstractPurpose. The relationship between the pH, solubility, and partition coefficient was investigated to show that the product of intrinsic values of solubility and partition coefficient is equal to the product of total values of solubility and distribution coefficient at different pH. Methods. The pH distribution profiles were obtained from the literature and the pH solubility profiles were obtained from the literature or calculated from their intrinsic solubility and pKa. Results. The pH solubility and pH distribution coefficient profiles of 25 compounds were investigated to show that the product of intrinsic solubility (Sw) and intrinsic octanol-water partition coefficient (Kow) is equal to the product of total solubility of a partially ionized solute (ST) and its octanol-buffer distribution coefficient (KD) at any pH where ion pair formation and salt precipitation are not present. Conclusions. The fact that Sw ⋅ Kow can be used instead of ST ⋅ KD to model the absorption of partially ionized drugs in the gastrointestinal tract has important biopharmaceutical implications.

Stabilization and preformulation of anticancer drug--SarCNU.

The stability of SarCNU (NSC364432), 1-(2-chloroethyl)-3-sarcosinamide-1-nitrosourea in several pharmaceutically acceptable solvents was investigated by high pressure liquid chromatography (HPLC). The influences of light, ionic strength, pH, buffer concentration, and the following excipients: benzyl alcohol, ascorbic acid, sodium bisulfite, and disodium EDTA were studied at room temperature. The stability of the drug was also determined in water, EtOH, PG, Capmul PG, DMSO, and in different combinations of these cosolvents at four different temperatures. The degradation of the drug, which is catalyzed not only by general but also by specific acid and base, follows first order kinetics. Antioxidants, EDTA, and light have no effect on the degradation rate, suggesting oxidation is not a major degradation pathway. The t(90) in pure cosolvent is 25-50 times higher than that in water or semi-aqueous vehicles. Neat EtOH can be used to store the drug in a nonaqueous concentrate that is diluted with aqueous solvent prior to injection.

Structure determination and characterization of carbendazim hydrochloride dihydrate

The objective of this study was to synthesize and characterize the hydrochloride salt of carbendazim with the aim of improving the intrinsic solubility of the parent compound. Carbendazim hydrochloride dihydrate was synthesized for the purpose of increasing the aqueous solubility of the parent drug, carbendazim. This was done with the commonly used saturation and cooling method. The structure was determined by single crystal radiograph crystallography, and the hydrochloride salt was found to be a dihydrate. The salt crystallized in a P 21 21 21 (#19) space group, which is typical for nonplanar, achiral, and noncentrosymmetric molecules. The asymmetric unit is comprised of 1 molecule each of carbendazim and chloride and 2 water molecules. The carbendazim molecules arrange themselves in a helical structure, with the waters and the chloride molecules in the channel linking the helix. The crystal lattice is held together by numerous hydrogen bonds, as well as van der Waals interactions. The melting point of the salt is 125.6°C. The solubility of the salt is 6.08 mg/mL, which is a thousand-fold increase from the intrinsic solubility (6.11 μg/mL) of the free base.

Liposome formulation of NSC-639829 using halothane as a solvent: A technical note

ConclusionHalothane has been successfully used as a solvent for the liposome formulation of NSC-639829. Liposomes with similar morphology, particle size, incorporation efficiency, and stability were obtained with halothane, chloroform, and ether. Halothane provides additional ease in formulation because of its higher volatility and safety as compared with chloroform and ether. Halothane can be regarded as a safe alternative to chloroform or ether in liposome formulation.