Investigation on the photostability of tretinoin in creams.

In this investigation, the photodegradation of some tretinoin cream formulations was evaluated. Several oils were selected to prepare the cream formulations: olive oil, maize oil, castor oil, isopropyl myristate and Miglyol 812. A solubility study showed that tretinoin is best soluble in castor oil (0.60g/100ml), followed by isopropyl myristate, maize oil, Miglyol 812 and olive oil, respectively, 0.35, 0.30, 0.29 and 0.22g/100ml. The photostability of tretinoin in oils is comparable with the photostability of a tretinoin lotion (ethanol/propylene glycol 50/50), castor oil and olive oil giving slightly better results than the other oils. Investigation of the photodegradation of tretinoin in o/w creams, prepared with the same oils as mentioned above, revealed that tretinoin is far more stable in the cream formulations than in the respective oils, however it is not clear whether this is due to the formulation or due to a different irradiation technique. Tretinoin seemed to be most stable in the olive oil cream, followed by the castor oil cream. However microscopic investigation revealed the presence of tretinoin crystals in the olive oil cream, while the other creams were free of it. As a conclusion, one can say that the cream prepared with castor oil seems to be the most suitable one, in terms of solubility of tretinoin and in terms of photostability.

Comparison of free iodine as a function of the dilution of two commercial povidone-iodine formulations.

Binding studies by means of equilibrium dialysis on two different Povidone-lodine-solutions reveal that the amount of available iodine and free iodine is very different as such and after dilution. The free iodine concentration in the Braunol concentrate was found to be ca. 22 mg/L and in the iso-Betadine concentrate only ca. 2.1 mg/L, despite the total amount of available iodine in iso-Betadine being higher than that of Braunol. As the bactericidal level of free iodine is characterised by concentrations >5 ppm, Braunol can be employed as a disinfectant as such, iso-Betadine has to be diluted before use. In both concentrates more than 99% of available iodine is present as reservoir for free iodine. Concerning the results as a function of dilution, it was demonstrated that, for both solutions, free iodine reaches a maximum after a 50-fold dilution (ca. 31 mg/L and ca. 51 mg/L for iso-Betadine and Braunol respectively). After dilution, a more constant level of free iodine was observed in the Braunol than in the iso-Betadine solution, and this is attributed to the present molar ratio of I(2)/I- and the addition of iodate in the former. The pH for both solutions approximates that of the skin, as such and after dilution. In summary, it can be stated that Braunol is superior to iso-Betadine as to the release of free iodine in both the undiluted as well as in the diluted form.

Densitometric thin-layer chromatographic determination of artemisinin and its lipophilic derivatives, artemether and arteether.

A thin-layer chromatograpy (TLC) method is developed to analyze artemisinin (AT) and its derivatives, artemether (AM) and arteether (AE), using a silica-gel plate with a mobile phase containing pure chloroform. After development, all products are visualized after dipping in a 4-methoxybenzaldehyde dipping reagent of 1% (v/v) in an acidic solution of sulphuric acid (98%, v/v) and acetic acid (96-98%, v/v) (respectively, 2% and 10%, v/v in alcohol-water, 60:30, v/v), presenting a purple color against a slightly colored background. This TLC system is quantitatively evaluated in terms of stability of the color, precision, accuracy, and calibration. Activation is performed at 110 degrees C. Stability of the color of both analytes is reached after 12 min. Precision, less than 5%, is obtained at two levels. Good linearity is obtained in the range of 0.5-8 micro g for all analytes. Some applications show its utility in the quality control of capsules. The prederivatization technique, applying the described dipping reagent before development, reveals the presence of various reaction products, possibly isomers. These results prove that TLC can be a cheap and easy alternative for the analysis of AT and its lipophilic derivatives, AM and AE, as pure powder and in pharmaceutical-dosage forms.

Preparation of beta-artemether liposomes, their HPLC-UV evaluation and relevance for clearing recrudescent parasitaemia in Plasmodium chabaudi malaria-infected mice.

Egg phosphatidylcholine-cholesterol liposome formulations containing the antimalarial drug beta-artemether have been prepared and analyzed for their encapsulating capacity, chemical stability, leakage, in vitro release and their therapeutic efficiency against Plasmodium chabaudi infection. A HPLC-UV analysis of beta-artemether liposomes without derivatisation was achieved. A good linearity of y=4437.7 x+469.01 (R(2)=0.9999) with a detection limit of 2 microg ml(-1) was reached. Prior to this, liposomal formulations composed of different molar ratios of EPC-CHOL were prepared to select beta-artemether crystal-free liposome preparations. The formulation corresponding to 4:3 and a total concentration of 300 mg lipids ml(-1) buffer (pH 7.2), which could incorporate as much as 1.5 mg beta-artemether was selected for therapy. A trapping efficiency of nearly 100% was reached, the drug being located in the lipid bilayers. A dialysis test demonstrated that the drug could be reversibly released from the liposomes, reaching equilibrium within 24 h. After 3 months storage at 4 degrees C, no leakage of beta-artemether had occurred indicating a high stability of the liposomes. These liposomes were used to treat mice infected with the virulent rodent malaria parasite Plasmodium chabaudi chabaudi, with a 100% cure by clearing the recrudescent parasitaemia.

Rheological properties of topical fluoride gels.

The rheological properties of several commercial topical fluoride gels were studied. For that purpose, we investigated hysteresis loops under standard conditions, equilibrium values, apparent viscosities as a function of shear rate, rate of thixotropic recovery, and the influence of temperature. The rheological equilibrium values, treated by the Power Law and the Cross Equation, show very important differences. Five gels show pseudoplastic behavior; seven have thixotropic properties. For the risks of fluoride gel toxicity to be lowered, high pseudoplasticity seems most desirable for the first group; for the thixotropic gels, a combination of yield value (very high viscosity at rest), the presence of a static yield value (very fast decrease in viscosity at very low shear rates), and both fast and high thixotropic recovery after destruction seems ideal. Positive and negative, as well as practically no, influence on rheological properties can be noted when the temperature changes.

Interaction of povidone with aromatic compounds. VI: Use of partition coefficients (log Kd) to correlate with log P values and apparent Kd values to express the binding as a function of pH and pKa.

The binding of neutral aromatic compounds onto povidone was studied. It was found that the binding depends on the lipophilic character of the compound and that a linear free relationship exists between the logarithm of the partition coefficients of the macromolecular pseudo-two-phase-aqueous phase, and the log partition coefficient of n-octanol-water (log P). For the ionized ligand molecules it was shown that the binding could be expressed in terms of the acid dissociation constant of the solute, Ka, and in terms of two partition coefficients, K1 = HAPVP/HAwater and K2 = APVP/Awater for the nondissociated and dissociated forms, respectively, resulting in the apparent partition coefficient Kdapp = (HAPVP + APVP)/(HAwater + Awater). An expression was derived, permitting one to determine K1 and K2 from measurable quantities. The apparent partition coefficients (Kdapp) were independent of both drug and povidone concentrations, indicating that the modes of povidone compound interactions were essentially invariant over the ranges of systematic variables studied. The method provides a simple means of evaluating ligand-macromolecule interaction as a function of pH of the solvent and pKa of the ligand.

Interaction of povidone with aromatic compounds V: Relationship of binding tendency in a macromolecular solution treated as a pseudo two phase and a monophase.

The pseudo-two-phase model is proposed to correlate complex formation of ligand molecules with povidone with partition coefficients (log P or II constants). The conditions which permit the use of the pseudo-two-phase model for binding of ligand onto macromolecules are determined. This model seems to be a more rational choice than the frequently used complex formation model (monophase). This is demonstrated theoretically and confirmed experimentally. The advantages of the use of such a model are also discussed.

Interaction of povidone with aromatic compounds IV: effects of macromolecule molecular weight, solvent dielectric constant, and ligand solubility on complex formation.

Complex formation of ligand molecules with povidone was investigated to elucidate the effect of the molecular weights of the macromolecule and the influence of the solvent dielectric constant on the complexing tendency. The higher molecular weight polymers were more effective complexing agents than those with lower degrees of polymerization. When studying complex formation as a function of the dielectric constant (D), a linear relationship was noted between D and log B/F (B/F representing the ratio of bound to free ligand); the use of solvent mixtures to achieve a range of solvent dielectric constants enabled changes of the pH of the solvent, ligand dissociation, and solubility of the ligand and macromolecule. Of the variables under investigation, only the change in ligand solubility seemed to play an important role: a linear relationship was noted between the complexing tendency (log B/F) and the logarithm of the inverse of the ligand molecule solubility in the solvent mixtures (log 1/S). It was concluded that the change in solubility of the ligand was the predominant factor in the decrease of the complexing tendency with decreasing dielectric constant.

Interaction of povidone with aromatic compounds III: Thermodynamics of the binding equilibria and interaction forces in buffer solutions at varying pH values and varying dielectric constant.

The complex formation of a series of aromatic compounds with povidone was studied in buffer solutions and organic solvent mixtures by equilibrium dialysis. For all the ligand molecules studied, a linear relationship was found between r, the number of moles of bound ligand per mole of povidone, and the free ligand concentration. The binding constants and the free energies of binding (-delta F), were greater for compounds in the nonionic state and increased with the number of hydroxyl groups which were capable of forming hydrogen bonds. They decreased with temperature elevation. The thermodynamic data showed entropy gains during the binding process accompanied by small negative enthalpy values. The increased ability to form hydrogen bonds and the increase in ionization of the ligand molecule was reflected in more negative delta H and decreasing delta S values. (The thermodynamic values were interpreted on the basis of the "iceberg" concept of water structure.) From these entropy and enthalpy changes, hydrogen and hydrophobic bondings appeared to be the most important types of binding. In organic solvent mixtures, the association constants lowered with increasing ethanol or propylene glycol concentration; a line relationship between the free energy and the dielectric constant of the solvent mixtures was observed.

Interaction of povidone with aromatic compounds II: Evaluation of ionic strength, buffer concentration, temperature, and pH by factorial analysis.

The interaction of a series of ligand molecules, all consisting of substituted benzoic and nicotinic acid derivatives, and povidone was studied. The influence of ionic strength, buffer concentration, and temperature was evaluated using factorial analysis. Complex formation was not affected at low ionic strength, but increased considerably at higher values due to dehydration of the macromolecule. Complex formation was enhanced in phosphate solutions, particularly in the presence of dibasic phosphate ions. A linear relationship was found between the logarithm of the percentage of bound ligand and ionic strength and buffer capacity. Increasing the temperature lowered complex formation. Although dehydration of the macromolecule also occurred, the decrease in complex formation could be attributed to the solubility increase of the ligand molecules. The influence of the degree of dissociation of the ligand molecules was investigated by factorial analysis. The compounds mainly interacted to a lesser extent in the dissociated than in the nondissociated state. In addition, a negative effect of a pyridine ring with respect to a phenyl ring was observed. The binding tendency was markedly increased by substituting the aromatic ring structure with hydroxyl functions and by esterification of the carboxyl function attached to the ring. The results suggested that lipophilicity and hydrogen bonding played a predominant role in povidone complexation.

Interaction of povidone with aromatic compounds I: Evaluation of complex formation by factorial analysis.

In a study of complex formation between macromolecules and small ligands such as drugs, it appeared that the association constants must be calculated with more care (i.e., after a thorough investigation of the influencing parameters such as buffer composition, ionic strength, and temperature) to allow meaningful interpretations of the phenomena. For this purpose, factorial analysis seems to be the method of choice; it offers the advantage of evaluating the influence of several variables and their interactions at the same time with a minimum of experiments. The method was applied to the association of povidone with two ligands, salicylic acid and benzoic acid. Parameters such as buffer composition and ionic strength, which affect binding, could be distinguished. Especially at pH 7.00, a great positive influence of buffer ions (phosphate buffer) and a relative positive interaction between temperature and ionic strength were noted. Knowledge of the influences of these parameters allowed comparison of the effects of the functional groups attached to the ligand molecules, as well as their degree of dissociation, on adsorption to permit more meaningful interpretation of thermodynamic constants.