Said A. Khalil

Effect of additives on the kinetics of interconversion of sulphamethoxydiazine crystal forms

The effect of various additives on the rate of transformation of the more energetic sulphamethoxydiazine Form II to the water‐stable Form III in aqueous suspension has been studied. Representative structurally related compounds, viscosity imparting agents, surfactants and colouring agents have been used to inhibit the transformation. Significant transformation retarding effects were observed in most cases. The effects vary, however, from slight retardation to almost complete inhibition of the transformation for periods of over a year (e.g. using 1 % w/v of polyvinylpyrrolidone). The effect of seeding suspensions of Form II with nuclei of Form III in the presence and absence of additives has also been examined. Accelerated stability testing is shown to be inadequate for the prediction of stability of Form II in aqueous suspension in the presence of acacia or polyvinylpyrrolidone. The use of the results in the formulation of dosage forms containing sulphamethoxydiazine is suggested.

Sulphamethoxydiazine crystal forms

Methods of preparation of three polymorphs, two solvates and an amorphous modification of sulphamethoxydiazine are described. Infrared spectroscopy and X‐ray diffraction data are given for the characterization of the various forms. The interconversion of these forms under various conditions of heating, suspension in water and grinding is studied. The dissolution behaviour of the different forms is also discussed. All forms on heating to 150° change to the same form and on suspension in water change to another water‐stable form.

Liposomal formulation for dermal and transdermal drug delivery: past, present and future.

Although the formulation of effective topical drug delivery system is one of the most sophisticated pharmaceutical preparations, it has attracted researchers due to many medical advantages associated with it. Topical drug delivery systems can act superficially on skin surface, locally in dermal layer of the skin or transdermally to provide successful delivery of drug molecules to the systemic circulation avoiding the traditional problems and limitations of conventional routes of drug delivery. Many novel formulations have been utilized topically to enhance either permeability or drug targeting to a specific layer of the skin such as Liposomes, ethosomes, transfersomes, niosomes and catezomes. The main problem with all of these formulations is that there is no distinct barrier between the targeting and localization action to a certain layer of the skin and the transdermal action to the circulation of these preparations. Any minimal change in the formulation could transform it from a local targeting preparation to a systemic one. This article deals with the innovations pertaining to the use of various types of liposomal preparations and liposomal like preparations for topical drug delivery and the patents associated with it.

Kinetics of interconversion of sulphamethoxydiazine crystal forms

A quantitative Nujol mull technique is described for the determination of sulphamethoxydiazine crystal forms in mixtures, so that the rates of their interconversion may be determined. The technique is applied to the transformations taking place in the more thermo‐dynamically active as well as biologically available crystal form (Form II). Kinetic parameters indicate a highly temperature dependent transformation (Ea ⋍ 100 kcal mol−1; 418·6 kJ mol−1) of Form II to the more stable Form I. Suspension in water results in a much faster transformation of Form II (Ea ⋍ 20 kcal mol−1; 83·7 kJ mol−1, t1/2 ⋍ 15 min) to the water‐stable Form III. Water and water vapour are shown to be important factors in the transformation of Form II at room temperature.

Effect of magnesium trisilicate on nitrofurantoin absorption.

In vitro adsorption studies revealed that for an identical initial concentration of nitrofurantoin, magnesium trisilicate exhibited the greatest adsorptive capacity with bismuth oxycarbonate, talc, kaolin, and magnesium oxide exhibiting intermediate adsorptive powers, while aluminum hydroxide and calcium carbonate exhibited low or no adsorption properties. Trials to elute the drug with acidic or alkaline solution were unsuccessful. The in vivo absorption characteristics of nitrofurantoin and nitrofurantoin‐magnesium trisilicate combination were evaluated in 6 healthy males. Administration of magnesium trisilicate with nitrofurantoin reduced the rate and extent of its excretion reflecting decrease in both rate and extent of absorption. The time during which the drug concentration in the urine was above the minimum effective concentration of 32 µg/ml was also significantly reduced after administration of the antacid.

Adsorption of ketoprofen and bumadizone calcium on aluminium-containing antacids and its effect on ketoprofen bioavailability in man

Abstract The present study reports the adsorption of ketoprofen and bumadizone calcium, two non-steroidal anti-inflammatory drugs, on three aluminium-containing antacids. The type of aluminium antacid, the initial drug concentration and the pH of the medium were found to influence drug adsorption. At pH 3–4, binding of both drugs to aluminium hydroxide and dihydroxyaluminium sodium carbonate indicated co-operative adsorption, while adsorption profiles of bumadizone calcium on aluminium glycinate suggested a constant partitioning pattern. pH (1–8) adsorption profiles for ketoprofen and bumadizone calcium binding to aluminium hydroxide and dihydroxyaluminium sodium carbonate passed through a maximum in the pH range 3.5–4.5. Antacid dissolution during the adsorption runs was also investigated at different pH values. The effect of coadministration of ketoprofen and aluminium hydroxide on the bioavailability of ketoprofen was investigated in healthy volunteers. Urine was collected for 24 h following drug administration and samples were analyzed by HPLC for ketoprofen and its conjugates. The urinary excretion data indicated a decrease in drug bioavailability upon coadministration with aluminium hydroxide.

Systemic enhancement of papaverine transdermal gel for erectile dysfunction

To enhance the systemic transdermal delivery of papaverine for the treatment of erectile dysfunction, several factors that influence transdermal delivery of papaverine HCl were studied. The effects of membrane types for in vitro permeation study, human skin layers, solvent/cosolvent systems and the penetration enhancers on the transdermal permeation of papaverine HCl were investigated. A combination of caproic acid, ethanol and water in the volume ratio of 50%:30%:20% was chosen as penetration enhancer and incorporated in two gel bases: 18% Pluronic F-127 and 2% Carbopol 940. In vivo skin permeation studies were performed with two loading doses (0.6% and 2%) in rabbits. The flux and permeability coefficient of papaverine HCl through different human skin layers suggested that the major barrier layer for papaverine HCl was residing primarily in the stratum corneum. However, the viable epidermis and dermis layer also contributed certain degrees of diffusion resistance. Differential Scanning Calorimetry study showed that penetration enhancer exhibited a counter effect with papaverine HCl on the temperature and enthalpy in both gels. In vitro drug release study demonstrated significant increases in the steady-state flux, permeability coefficient and enhancement ratio in these gels. Faster drug transports and higher bioavailability were also observed in rabbits. Skin irritation test performed in rabbits demonstrated a mild skin reaction with mean PII scores of 2 and below; however the recovery was fast. In conclusion, caproic acid, ethanol and water in the volume ratio of 50%:30%:20% is an effective penetration enhancer to deliver papaverine HCl transdermally for systemic absorption.

In vitro anticoagulant-antacid interactions

Abstract The adsorption characteristics of oral anticoagulants on some selected antacids were studied. The indanedione anticoagulants tested were: phenindione and diphenadione; while the coumarin anticoagulants tested were: dicoumarol, ethyl biscoumacetate, nicoumalone, phenprocoumon and warfarin. The antacids or adsorbents used were: aluminium glycinate, aluminium hydroxide, bismuth carbonate, bismuth salicylates bismuth subgallate, bismuth subnitrate, calcium carbonate, charcoal, dihydroxyaluminium sodium carbonate, magaldrate, magnesium carbonate, magnesium oxide, magnesium trisilicate and kaolin. Adsorption of phenindione was significant on charcoal and magnesium oxide. Aluminium hydroxide, bismuth carbonate, subnitrate and salicylate adsorbed phenindione to a lesser extent. Other substances showed relative weak adsorption properties. Diphenadione, on the other hand, was adsorbed on most substances tested. The extent of dicoumarol adsorbed was quite high on bismuth carbonate, salicylate and subnitrate as well as on magnesium oxide. It was intermediate on aluminium glycinate and magaldrate. The amount of the anticoagulant adsorbed on aluminium hydroxide, bismuth subgallate and magnesium trisilicate, under the experimental conditions, was quite low. Glycine was found to reduce the amount of dicoumarol adsorbed on bismuth carbonate and to a lower extent on magnesium oxide, while it had a negligible effect on the amount adsorbed on bismuth subnitrate. The other coumarin derivatives showed no or very low adsorption tendencies for the substances tested, with the exception of charcoal, bismuth subnitrate and salicylate. Adsorption isotherms were plotted for phenindione and dicoumarol. The dissolution of phenindione decreased in the presence of the adsorbing substance especially in acidic medium. The dissolution of dicoumarol in the presence of magnesium oxide was also decreased.

Bioavailability in Man of Nalidixic Acid Tablets

AbstractAn invivo absorption study was carried out in volunteers to compare the bioavailability of two brands of nalidixic acid tablets against a marketed paediatric suspension serving as a reference standard. Absorption was assessed by a urinary excretion method in which drug and major metabolite were assayed fluorimetrically. The excretion data were statistically treated. Results of the analysis of variance indicated a significant difference in rate, but not in extent of absorption, among the preparations tested. Poor disintegration quality of one of the tablet brands was found responsible for its delayed dissolution and, consequently, slow absorption.

Correlation of Urinary Excretion with in Vitro Dissolution Using Four Dissolution Methods for Aiipicillin Capsules

AbstractThe in vitro release of ampicillin from 8 brands of ampicillin capsules, using four dissolution apparatus, was determined. These apparatus were the USP dissolution apparatus, the USP paddle stirrer apparatus, the USP disintegration apparatus and the spiral—stirrer apparatus. Significance of the differences in dissolution between brands and between methods were tested. Analysis of variance of the dissolution data showed statistically significant differences between brands and between methods at selected time. The paddle method showed superior discriminating capacity than the other methods. Correlation between the present in vitro data and the previously reported in vivo data, in order to find the apparatus capable to mimic in vivo release of ampicillin from capsules, was also determined.