Equilibria, kinetics and mechanism for the degradation of the cytotoxic compound L-NG-nitroarginine.

L-NG-nitroarginine (LNNA), an analog of L-arginine, is a competitive inhibitor of nitric oxide synthase which causes the selective reduction of blood flow to tumor cells. Despite the potential of LNNA to function as an adjuvant in cancer therapies, its poor solubility and stability have hindered the development of an injectable formulation of LNNA that is suitable for human administration. This work, for the first time, details a systematic study on the determination of equilibrium Ka constants and the rate law of LNNA degradation. The four Ka values of LNNA were determined to be 1.03, 1.10 × 10-2, 2.51 × 10-10, and 1.33 × 10-13 M. From the kinetic and equilibrium studies, we have shown that the deprotonated form of LNNA is the main form of LNNA that undergoes degradation in aqueous media at room temperature. The rate law of LNNA degradation was found to be first order with respect to OH- concentration and first order with respect to LNNA- concentration. The rate constant at 25 °C and 1 atm was determined to be 0.04453 M-1min-1. A base catalyzed mechanism of LNNA degradation was proposed based on the kinetic study. The mechanism was found to be very useful in explaining the discrepancies and changes of the rate law at different pH values. It is thus recommended that LNNA should be formulated as a concentrated solution in acidic conditions for maximum chemical stability during storage and be diluted with a basic solution to near physiological pH just before administration.

Development of a topical mupirocin spray for antibacterial and wound-healing applications.

OBJECTIVE: The aim of this study was to develop mupirocin topical spray using Eudragit E100 as a film-forming agent for the treatment of bacterial skin infections as well as to promote wound healing. MATERIALS AND METHODS: Twenty-seven of mupirocin formulations were formulated containing Eudragit E100 and other excipients. Mupirocin spray was prepared by aerosol crimping and filling machine using HFA-134a as a propellant. The formulations were evaluated for their stability and physicochemical properties. The factorial study was applied to evaluate the effects of glycerol and PEG400 on mupirocin-loaded Eudragit E100 films. The optimized formulation was assessed of drug release, antibacterial activities and in vitro cell line studies in comparison to the ointment formulation. RESULTS AND DISCUSSION: Mupirocin sprays were formulated and optimized to obtain the formulation with excellent physicochemical and mechanical properties of the dressing film. The formulation had an excellent stability up to a year with more than 80% of mupirocin content. Mupirocin was released from the film up to 90% within 2 h. The formulation had a potent antibacterial effect against S. aureus and S. epidermidis. The formulation was safe to use as a topical formulation that had no toxicity to keratinocytes, fibroblasts and monocytes. The formulation also had an antiendotoxin effect without stimulating the production of NO and inflammatory cytokines (IL-1ß and TNF-α). CONCLUSIONS: Mupirocin topical spray was successful developed as a topical formulation and can be used instead of the ointment formulation. Animal experiments are warranted to further emphasize the safe use in the human skin.

Microencapsulation of Clostridium acetobutylicum ATCC 824 spores in gellan gum microspheres for the production of biobutanol.

The purpose of the present study was to provide further insights on the applicability of microencapsulation using emulsification method, to immobilise Clostridium acetobutylicum ATCC 824 spores, for biobutanol production. The encapsulated spores were revived using heat shock treatment and the fermentation efficiency of the resultant encapsulated cells was compared with that of the free (non-encapsulated) cells. The microspheres were easily recovered from the fermentation medium by filtration and reused up to five cycles of fermentation. In contrast, the free (non-encapsulated) cells could be reused for two cycles only. The microspheres remained intact throughout repeated use. Although significant cell leakage was observed during the course of fermentation, the microspheres could be reused with relatively high butanol yield, demonstrating their role as microbial cell nurseries. Both encapsulated and liberated cells contributed to butanol production.

Selection of lubricant type and concentration for orodispersible tablets.

Lubricants are essential for most tablet formulations as they assist powder flow, prevent adhesion to tableting tools and facilitate tablet ejection. Magnesium stearate (MgSt) is an effective lubricant but may compromise tablet strength and disintegratability. In the design of orodispersible tablets, tablet strength and disintegratability are critical attributes of the dosage form. Hence, this study aimed to conduct an in-depth comparative study of MgSt with alternative lubricants, namely sodium lauryl sulphate (SLS), stearic acid (SA) and hydrogenated castor oil (HCO), for their effects on the tableting process as well as tablet properties. Powder blends were prepared with lactose, sodium starch glycolate or crospovidone as the disintegrant, and a lubricant at different concentrations. Angle of repose was determined for the mixtures. Comparative evaluation was carried out based on the ejection force, tensile strength, liquid penetration and disintegratability of the tablets produced. As the lubricant concentration increased, powder flow and tablet ejection improved. The lubrication efficiency generally decreased as follows: MgSt > HCO > SA > SLS. Despite its superior lubrication efficacy, MgSt is the only lubricant of four evaluated that reduced tablet tensile strength. Tablet disintegration time was strongly determined by tensile strength and liquid penetration, which were in turn affected by the lubricant type and concentration. All the above factors should be taken into consideration when deciding the type and concentration of lubricant for an orodispersible tablet formulation.

Investigation on the impact of different proportions of components in formulations on stability of a moisture sensitive drug.

Physicochemical and mechanical properties of tablets are largely dictated by formulation compositions. Different excipients possess different tableting and moisture sorption behaviors. Therefore, this study was designed to elucidate the relative influence of the proportion of components in formulations on tablet properties. Acetylsalicylic acid (ASA) tablets containing different proportions of starch, microcrystalline cellulose (MCC) and calcium hydrogen phosphate dihydrate (DCP) were prepared. The excipients were evaluated for their moisture sorption properties. Mechanical strength of the tablets was determined alongside with ASA stability, by storing the tablets at 75% RH, 25 °C. The stability study showed the importance of drug loading level on its stability. For a fixed ASA proportion, formulations with more starch were able to absorb more moisture and possessed larger areas of hysteresis loop in their moisture sorption isotherms. The presence of starch contributed positively to ASA stability although increasing proportions of starch compromised the tablet mechanical properties. Contrastingly, MCC produced mechanically stronger tablets as its plastically deforming and fibrous properties contributed to a good structural network. The findings provide a deeper understanding of the dichotomous effect by the proportion of components in formulations containing a moisture sensitive drug on drug stability and mechanical strength of the resultant tablets.

Clotrimazole microemulsion and microemulsion-based gel: evaluation of buccal drug delivery and irritancy using chick chorioallantoic membrane as the model.

OBJECTIVES: To investigate the efficacy of clotrimazole microemulsion (CTZ-ME) and its gel form, clotrimazole microemulsion-based gel (CTZ-MBG), for the treatment of oral candidiasis. METHODS: CTZ-ME and CTZ-MBG were characterized for droplet size and texture, respectively. The ex-vivo permeation study and irritancy assessment of CTZ-ME and CTZ-MBG were performed using chick chorioallantoic membrane (CAM) as the model. Antifungal activity against Candida albicans ATCC 10 231 of CTZ-ME and CTZ-MBG was determined by agar diffusion method compared to the blank counterparts. KEY FINDINGS: CTZ-ME contained nano-sized droplets and CTZ-MBG had acceptable firmness and spreadability. CTZ-ME exhibited faster CAM permeation of the drug and larger inhibition zone than CTZ-MBG as the increased viscosity of CTZ-MBG resulted in more retardation and higher fluctuations in drug diffusion. As there were no detectable visual changes in CAM blood vessels after applying CTZ-ME or CTZ-MBG, both formulations were non-irritants. CONCLUSIONS: CTZ-ME and CTZ-MBG could deliver the drug through CAM, the model for buccal delivery. Additionally, they did not cause irritancy and had effective antifungal activity against C. albicans. The results indicated that CTZ-ME and CTZ-MBG were potential effective antifungal formulations to treat oral candidiasis.

Application of freeze-drying in the development of oral drug delivery systems.

INTRODUCTION: With continual focus on oral drug delivery systems (ODDS), the role of freeze-drying becomes increasingly valuable. While freeze-drying is fundamentally a desiccation process, the advantageous material properties attributed to freeze-drying extend far beyond the preparation of stable pharmaceutical products. The formulation and process variables are important considerations as they affect the final freeze-dried product characteristics. It is of interest to expound on the principles and effects of freeze-drying in the hope of introducing novel products for applications in the development of ODDS. Areas covered: In this review, basic principles, general formulation and process variables associated with freeze-drying will be covered. The application of freeze-drying in 3 areas: modification of active ingredients, development of novel freeze-dried excipients and development of freeze-dried final dosage forms will be discussed. Expert opinion: As a pharmaceutical unit operation, freeze-drying has created new dimensions in the area of oral drug delivery, where the properties of the drugs, excipients and characteristics of the final solid dosage form can be modified by the freeze-drying process. With the emergence of new applications, the role of freeze-drying technology in ODDS is indeed a relevant and promising one.

Spray-congealed microparticles for drug delivery - an overview of factors influencing their production and characteristics.

INTRODUCTION: In any manufacturing process, the success of producing an end product with the desired properties and yield depends on a range of factors that include the equipment, process and formulation variables. It is the interest of manufacturers and researchers to understand each manufacturing process better and ascertain the effects of various manufacturing-associated factors on the properties of the end product. Unless the manufacturing process is well understood, it would be difficult to set realistic limits for the process variables and raw material specifications to ensure consistently high-quality and reproducible end products. Over the years, spray congealing has been used to produce particulates by the food and pharmaceutical industries. The latter have used this technology to develop specialized drug delivery systems. AREAS COVERED: In this review, basic principles as well as advantages and disadvantages of the spray congealing process will be covered. Recent developments in spray congealing equipment, process variables and formulation variables such as the matrix material, encapsulated material and additives will also be discussed. EXPERT OPINION: Innovative equipment designs and formulations for spray congealing have emerged. Judicious choice of atomizers, polymers and additives is the key to achieve the desired properties of the microparticles for drug delivery.

Development of a visiometric process analyzer for real-time monitoring of bottom spray fluid-bed coating.

Particle recirculation within the partition column is a major source of process variability in the bottom spray fluid-bed coating process. However, its locality and complex nature make it hidden from the operator. The aim of this study was to take snapshots of the process by employing a visiometric process analyzer based on high-speed imaging and ensemble correlation particle image velocimetry (PIV) to quantify particle recirculation. High-speed images of particles within the partition column of a bottom spray fluid-bed coater were captured and studied by morphological image processing and ensemble correlation PIV. Particle displacement probability density function (PDF) obtained from ensemble correlation PIV was consistent with validation experiments using an image tracking method. Particle displacement PDF was further resolved into particle velocity magnitude and particle velocity orientation histograms, which gave information about particle recirculation probability, thus quantifying the main source of process variability. Deeper insights into particle coating process were obtained and better control of coat uniformity can thus be achieved with use of the proposed visiometric process analyzer. The concept of visiometric process analyzers was proposed and their potential applications in pharmaceutical processes were further discussed.