International Journal of Pharmaceutics (v.225, #1-2)

Formulation and stability testing of photolabile drugs by Hanne Hjorth Tønnesen (1-14).
Exposure of a drug to irradiation can influence the stability of the formulation, leading to changes in the physicochemical properties of the product. The influence of excipients of frequently used stabilizers is often difficult to predict and, therefore, stability testing of the final preparation is important. The selection of a protective packaging must be based on knowledge about the wavelength causing the instability. Details on drug photoreactivity will also be helpful in order to minimize side-effects and/or optimize drug targeting by developing photoresponsive drug delivery systems. This review focuses on practical problems related to formulation and stability testing of photolabile drugs.
Keywords: Photolabile drugs; Formulation; Stability testing;

Cyclodextrins in topical drug formulations: theory and practice by Thorsteinn Loftsson; Mar Masson (15-30).
Cyclodextrins are cyclic oligosaccharides with a hydrophilic outer surface and a somewhat lipophilic central cavity. Cyclodextrins are able to form water-soluble inclusion complexes with many lipophilic water-insoluble drugs. In aqueous solutions drug molecules located in the central cavity are in a dynamic equilibrium with free drug molecules. Furthermore, lipophilic molecules in the aqueous complexation media will compete with each other for a space in the cavity. Due to their size and hydrophilicity only insignificant amounts of cyclodextrins and drug/cyclodextrin complexes are able to penetrate into lipophilic biological barriers, such as intact skin. In general, cyclodextrins enhance topical drug delivery by increasing the drug availability at the barrier surface. At the surface the drug molecules partition from the cyclodextrin cavity into the lipophilic barrier. Thus, drug delivery from aqueous cyclodextrin solutions is both diffusion controlled and membrane controlled. It appears that cyclodextrins can only enhance topical drug delivery in the presence of water.
Keywords: Cyclodextrin; Permeability; Drug delivery; Topical;

The purpose of this investigation was to (a) evaluate the coprecipitation technique for preparing microparticulates of insulin, (b) study the effect of variables such as addition of salts in the precipitating medium and ratio of polymeric solution to volume of precipitating medium on the dissolution and encapsulation efficiency of insulin microparticulates, and (c) evaluate the in-vitro enzymatic dissolution stability of insulin microparticulates in the presence of chicken ovomucoid (CkOVM) and duck ovomucoid (DkOVM) as inhibitors. Insulin dissolved in 0.01 N HCl was mixed with alcohol USP to get a final concentration of 32% v/v. Eudragit L100, a representative polymethyacrylate polymer, was then dissolved in this solution which was transferred to a beaker containing cold water with homogenization to obtain microparticulates. Dissolution studies were carried out in pH 6.8 phosphate buffer using a 100-ml conversion kit in a standard dissolution assembly. Dissolution stability of microparticulates was evaluated in the presence of 0.5 μM trypsin and 0.l μM chymotrypsin at various ratios of CkOVM and DkOVM. The results indicated that insulin microparticulates could be prepared using the coprecipitation technique with high encapsulation efficiency by proper selection of experimental conditions and amount of polymer. Presence of salts in the precipitating medium decreased the dissolution of insulin from the microparticulates. As the ratio of precipitating medium with respect to the polymeric solution was increased, the encapsulation efficiency increased. In dissolution stability experiments, insulin was not detected in the presence of enzymes alone. When CkOVM and DkOVM were incorporated, the stability of insulin increased significantly in a concentration dependent fashion.
Keywords: Insulin; Microparticulates; Coprecipitates; Inhibitors; Chicken ovomucoid; Duck ovomucoid; Dissolution stability;

Solubilization of NSC-639829 by Neera Jain; Gang Yang; S.Esmail Tabibi; Samuel H Yalkowsky (41-47).
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 (SBEβCD) carried a negative charge enhanced solubilities of more than a million-fold were observed for the drug.
Keywords: Solubilization; NSC-639829; Dimethyl aniline;

In vitro and in vivo evaluation of carbamazepine-PEG 6000 solid dispersions by Naima Zerrouk; Chantal Chemtob; Philippe Arnaud; Siro Toscani; Jerome Dugue (49-62).
The present work extended previous physico-chemical investigations on the effects of solid dispersion on the solubility, the dissolution rate and the pharmacokinetic profile of carbamazepine. Solubility studies showed a linear increase in carbamazepine solubility with the increase of PEG 6000 concentration. There is no marked difference between physical mixtures and solid dispersions for the enhancement of carbamazepine solubility by PEG 6000. Less than 60% of pure carbamazepine was dissolved in 90 min. Physical mixtures (carbamazepine phase III) and solid dispersions (carbamazepine phase II) dissolution rates were higher in comparison of the parent drug. The dissolution of carbamazepine phase III was more pronounced than that evoked by the phase II. The dissolution profiles indicated that the percentage of the drug dissolved was dependent on the proportion of PEG 6000. In solid dispersions there was a remarkable enhancement in the dissolution rates of the drug in the vicinity of the eutectic composition as compared with those of corresponding physical mixtures. Hence, the optimum value for the solid dispersion was 80.5±1.7% of carbamazepine having dissolved within the first 10 min compared to 40±1% for the corresponding physical mixtures of the same composition. Statistical analysis of pharmacokinetic parameters confirmed that the carbamazepine:PEG 6000 binary systems displayed higher bioavailability of the drug than the pure carbamazepine. The area under the curve (AUC) values highlighted the evidence that only slight differences in the bioavailability of the drug occur between physical mixtures and solid dispersions prepared at the 80:20 and 50:50 drug:carrier compositions. However, the mean normalized plasma concentrations showed that standard error deviations are rather wide intervals for pure drug and physical mixtures in comparison to solid dispersions. One additional interesting point to consider is the disappearance of the multiple peaks on the individual kinetic curves of the 50:50 solid dispersion composition. Furthermore, our investigations have highlighted the interest of solid dispersions prepared at «near»-eutectic composition as our preliminary data show that the plasma concentration (C5h) of the drug for the 15:85 dispersed sample containing 150 mg of carbamazepine is not significantly different from that obtained for the 50:50 dispersed sample containing 300 mg of the drug.
Keywords: Solid dispersion; Polymorphs; Eutectic composition; Dissolution; Bioavailability; PEG 6000; Carbamazepine;

Dissolution properties and anticonvulsant activity of phenytoin-polyethylene glycol 6000 and -polyvinylpyrrolidone K-30 solid dispersions by M. Franco; G. Trapani; A. Latrofa; C. Tullio; M.R. Provenzano; M. Serra; M. Muggironi; G. Biggio; G. Liso (63-73).
Solid dispersions of phenytoin in polyethylene glycol 6000 and polyvinylpyrrolidone K-30 with different drug-to-carrier ratios were prepared by the solvent method with the aim of increasing dissolution rate and bioavailability of the drug. These new formulations were characterized in the solid state by FT-IR spectroscopy, X-ray powder diffraction, and differential scanning calorimetry. Drug solubility and dissolution rate are improved by these formulations, particularly with SDPEG 1/20 and SDPVP 1/20 systems. Storage was found to influence the stability of the solid dispersions. By maximal electroshock test, it was found that the intraperitoneal administration in mice of the SDPEG 1/20 and SDPVP 1/20 systems exhibited anticonvulsant activity similar to diphenylhydantoin sodium salt.
Keywords: Phenytoin; Solid dispersions; Polyethylene glycol 6000 and polyvinylpyrrolidone K-30; Dissolution properties; Anticonvulsant activity;

The purpose of this study was to investigate the effect of delipidization of the stratum corneum (SC) on the in vitro percutaneous absorption of hydrophilic solutes (i.e. water, urea, and inulin). Fourier transform infrared (FT-IR) spectroscopy was employed to study the extent of delipidization of porcine SC due to chloroform:methanol (2:1) (C:M (2:1)) treatments for various time periods. In vitro percutaneous absorption of [3H] water, [14C] urea, and [3H] inulin were studied through C:M (2:1) treated epidermis in Franz diffusion cells. There was a greater decrease in peak areas of the asymmetric and symmetric C–H stretching absorbances (i.e. increase in lipid extraction) with increasing exposure times of the SC with C:M (2:1). After 40-min treatment, asymmetric and symmetric C–H stretching peak area showed a decrease of 75.9 and 89.9%, respectively. The permeability coefficient of water, urea, and inulin increased with increasing lipid extraction. Enhancement in the permeability coefficient, through 40 min C:M (2:1) treated epidermis in comparison to the control, for water, urea, and inulin was 48.72, 215.65, and 3.90, respectively. Log (permeability coefficient) and log (mol. wt.) for test solutes and leuprolide acetate were found to be inversely related (R 2=0.9974). In conclusion, this study implies that penetration enhancers that are safe and extract the SC lipids can be selected in order to enhance the percutaneous absorption of polar solutes through the skin.
Keywords: Percutaneous absorption; Fourier transform infrared; Stratum corneum; Lipid extraction; Hydrophilic solutes;

Purpose: To determine the influence of hydrogen bonding and solubility parameter on the glass transition temperature (T g) of various drug–poly(vinylpyrrolidone) blends. Methods: The T g of PVP films containing either acetaminophen, naproxen, salicylamide, carbamazepine, griseofulvin or propranolol hydrochloride were measured using differential scanning calorimetry. Fourier transform infrared (FTIR) spectroscopy and X-ray diffraction was used to characterize the specific interactions between the drug–PVP blends and the physical state of the films, respectively. The total solubility parameter and its individual components were calculated using the method of Van Krevelen. Results: Salicylamide displayed the greatest plasticizing effect, depressing the T g to the minimum. This was consistent with the FTIR data, which indicated the presence of hydrogen bonding with PVP. Griseofulvin showed the least plasticizing effect due to lack of interaction with PVP. All the drugs except griseofulvin were amorphous within the film up to 30% (w/w) drug composition. The correlation between the various components of the solubility parameters and the plasticizing effect of drugs was very poor. Conclusions: Spectroscopic investigation for the presence of interaction between the drugs and PVP proved to be extremely predictive of the plasticizing effect of various drugs. In contrast, solubility parameters appeared to be far less sensitive indicators of drug–PVP miscibility.
Keywords: Drug–polymer interactions; Solubility parameter; Glass transition; Spectroscopy; Poly(vinylpyrrolidone);

Cationized human serum albumin (cHSA) could serve as a potential non-viral vector system for gene delivery. Native human serum albumin was cationized by covalent coupling of hexamethylenediamine to the carboxyl groups resulting in a shift of the isoelectric point from pH 4–5 to 7–9. The cationized albumin underwent spontaneous self-assembly with DNA as demonstrated by retardation of CMV-nlacZ plasmid in agarose gel electrophoresis. Photon correlation spectroscopy showed a decrease of complex size with increasing cHSA/plasmid ratios. Under optimized conditions complexes were formed with 230–260 nm mean diameter and a homogenous, narrow size distribution. At room temperature complexes were stable in 0.9% sodium chloride solution pH 7.4 for 1 h without aggregation. Process parameters such as albumin concentration, incubation time, temperature, pH, order of reagent addition, the presence of bivalent ions and the ionic strength of the complexation medium all influenced the complex size. Confocal laser scanning microscopy showed interactions of a Texas Red labeled cationized albumin with cell membranes of ECV 304 cells and an enhanced endocytic uptake compared to native albumin. The potential for introducing exogeneous DNA into cells was shown using NIH 3T3 fibroblasts. Successful, albeit low reporter gene expression could be achieved in the presence of chloroquine. Under in vitro conditions no toxic effect could be observed. In conclusion, cationized albumin may have promise as a non-toxic vector for gene delivery, especially for DNA vaccination.
Keywords: Cationized human serum albumin; Gene transfer; Confocal laser scanning microscopy; Absorptive endocytosis;

Recently, Solaraze gel (Bioglan, Herts, UK) a topical hyaluronan (HA)/diclofenac formulation for the treatment of actinic keratosis has received regulatory approval in the US, Canada and Europe for the treatment of actinic keratosis. However, a mechanism of action to explain the topical delivery properties of HA remains to be elucidated. Thus, the aim of this study was to compare the effect of HA with other glycosaminoglycans (chondroitin sulphate (CS), heparin (HP)) and pharmaceutically relevant polysaccharides (sodium carboxymethyl cellulose and pectin) on the dermal partitioning and percutaneous penetration of diclofenac and ibuprofen. The studies demonstrated that HA significantly enhanced the partitioning of both diclofenac and ibuprofen into human skin when compared to an aqueous control, pectin and carboxymethylcellulose (P<0.01). Although the HA vehicle increased the partitioning of both drugs compared to the effects of the other glycosaminoglycans, CS and HP, this difference was not significant (P>0.05). However, the results from the Franz cell diffusion studies showed that HA (1% w/w) significantly enhanced the amount of drug localising within the skin when compared to all of the other polysaccharides (P<0.05). The results suggest that the use of HA as a vehicle excipient offers potential advantages in the dermal delivery and localisation of drugs.
Keywords: Hyaluronan; Glycosaminoglycans; Diclofenac; Ibuprofen; Partition coefficient; Dermal delivery;

A novel approach to the characterization of polar liquids by Andrea Stengele; Stephanie Rey; Hans Leuenberger (123-134).
Liquid dosage forms, generally based on aqueous solutions, take an important role in drug administration. The approaches to a theoretical description of solvent and solubility properties have not yet proved completely satisfying. In this work, the Debye equation, which describes well polar and nonpolar molecules in an ideal gas, is extended to liquids. For this purpose, the Debye equation was modified and the term (E i/E) was introduced (E i=internal electric field, E=applied external electric field). Pure polar and nonpolar solvents were measured between 290.7 and 343.2 K. The values of (E i/E) were compared with the correlation factor g of the Kirkwood–Fröhlich equation, a measure for molecular pair correlations. For polar solvents, the relationship E i/E=m(1/T)+b as a function of temperature T was found. Associating compounds showed negative values of (E i/E) with a strong temperature dependency; the latter can be expressed by the slope m. A correlation between ∣m∣ and the corresponding Hildebrand solubility parameter δ could be established. This new approach allows to describe polar hydrogen-bonding liquids and provides a tool for a more rational design of liquid dosage forms.
Keywords: Clausius–Mossotti equation; Debye equation; Dielectric permittivity; Modification of Clausius–Mossotti/Debye equation; Regular solutions; Solubility parameter;

The stability of benzoyl peroxide formulations determined from isothermal microcalorimetric studies by Flora Zaman; Anthony E. Beezer; John C. Mitchell; Quentin Clarkson; J. Elliot; M. Nisbet; Adrian F. Davis (135-143).
Recent developments in the analysis of microcalorimetric data output allow the possibility of determining both thermodynamic and kinetic parameters for complex reaction systems. Such experiments routinely take around 50 h, hence qualifying for the description rapid. The methods have earlier been applied to a study of the stability of benzoyl peroxide itself in aqueous suspension. This paper reports the results of isothermal microcalorimetric study of the stability of benzoyl peroxide in the presence of a wide range of excipients and in formulated materials. The results are shown to assist in formulation design, are achieved rapidly and are derived from direct experimental study of the complex systems themselves. That is, no ancillary information is required nor are the studies invasive or destructive.
Keywords: Calorimetry; Benzoyl peroxide; Formulation excipients; Stability;

Percutaneous Absorption by Jonathan Hadgraft (145).

Noticeboard (147-150).