Michael Tobyn

Characterization of a surface modified dry powder inhalation carrier prepared by particle smoothing

Atomic force microscopy (AFM) was used to investigate drug‐carrier interactions between beclometasone dipropionate (BDP) and a series of untreated and modified lactose surfaces. This quantitative information was correlated with bulk characterization methods and an in‐vitro study. Modified lactose surfaces were prepared using a proprietary process referred to as “particle smoothing” to obtain smooth carrier surfaces with or without the presence of magnesium stearate. The engineering of lactose carrier surfaces using the particle smoothing process resulted in significant differences in surface morphology when compared with the “as supplied” starting material. The energy of separation, between BDP and lactose samples, determined by AFM suggested similar lognormal distributions with a rank decrease in median separation energy (e0.5) (26.7, 20.6 and 7.7 μJ for untreated, particle‐smoothed and particle‐smoothed with magnesium stearate, respectively). A series of in‐vitro twin stage impinger studies showed good correlation with the AFM separation energy measurements. The mean fine particle dose increased for the two processed lactose samples, with a significant increase for the lactose processed with magnesium stearate, 102.0 ± 16 μg compared with 24.2 ± 10.7 μg for the untreated lactose. Thus, the AFM presents as a possible pre‐formulation tool for rapid characterization of particle interactions.

The mechanical properties of compacts of microcrystalline cellulose and silicified microcrystalline cellulose

The mechanical properties of compacts of unlubricated microcrystalline cellulose and silicified microcrystalline cellulose were evaluated using the diametric tensile test. The results suggested that, under comparable testing conditions, compacts of silicified microcrystalline cellulose exhibited greater strength than those of microcrystalline cellulose. In addition to enhanced strength, silicified microcrystalline cellulose compacts exhibited greater stiffness and required considerably more energy for tensile failure to occur. Comparison of the data with that obtained for a dry blend of silicon dioxide/microcrystalline cellulose suggested that the functionality benefits of silicification were not due to a simple composite material model.

The Surface Roughness of Lactose Particles Can Be Modulated by Wet- Smoothing Using a High-Shear Mixer

The surface morphology of α-lactose monohydrate particles was modified by a new wet-smoothing process performed in a high-shear mixer using solvents. Successive steps of wetting and drying of lactose powders during rolling in the mixers cylindrical bowl were performed. Smoothed particles were tested for size distribution, flow, and packing. The wet-smoothing process flattened the surface and rounded the edges of lactose particles. In comparison with original lactose, an improvement of powder packing and flow properties was evidenced. When the process was performed in the presence of a ternary agent such as magnesium stearate, the smoothing was improved. The evolution of rugosity during the smoothing process was assessed through a fractal descriptor of SEM picture. Atomic force microscopy and surface area measurements quantified the surface rugosity. A very significant reduction of the rugosity, more remarkable in the presence of magnesium stearate, was measured. This new process of powder wet-smoothing allows the preparation of lactose particles with different degrees of smoothed surface for the control of flow and packing properties and particle-particle interactions.

Effect of humidity on aerosolization of micronized drugs

Abstract The variation of aerosolization with humidity for three micronized drugs used in the treatment of asthma was evaluated by using in vitro methods. Micronized samples of disodium cromoglycate (DSCG), salbutamol sulphate, and triamcinolone acetonide (TAA) were stored for 12 hr at 15, 30, 45, 60, and 75% relative humidity (RH). A suitable “reservoir” dry powder inhaler was loaded and tested by using a twin-stage impinger at each specific humidity. The aerosolization efficiency of all three micronized drugs was affected by variations in humidity. The percentage of the delivered dose and the fine particle fraction of the loaded dose (FPFLD) for both DSCG and salbutamol sulphate decreased with increasing humidity; with the largest decrease in FPFLD occurring between 45% and 60% RH for DSCG and 60% to 75% RH for salbutamol sulphate. These observations suggest that the adhesion properties for both DSCG and salbutamol sulphate, which govern the aerosolization efficiency, are predominately influenced by capillary interactions. In contrast, the FPFLD for TAA significantly increased as the humidity increased over the range 15% to 75% RH, suggesting that triboelectric forces predominate particle-particle interactions. These variations in drug particulate behavior highlight the importance of an individual formulation approach when developing dry powder inhalation systems.

Prediction of physical properties of a novel polysaccharide controlled release system. I

TIMERx is a novel polysaccharide-based controlled release matrix technology. The matrix consists of the synergistically interacting polysaccharides xanthan gum and locust bean gum in the presence of a third component, often dextrose, and other tertiary components. The physical properties and compression characteristics of this system were studied using conventional characterisation equipment and by the assessment of the tensile strength of compacts produced on an instrumented tablet press. The granulation method had a profound influence on granule properties and compact strength. Dry mixing of the relevant components led to the production of weak compacts. Granulation in a fluid bed granulator produced hollow granules of low bulk density which produced relatively weak compacts. Only high speed mixer granulation produced tablets with the strength required for pharmaceutical processing. Subsequent studies indicated that the nature and concentration of secondary and tertiary components added to the granulation can further influence the nature of granules produced and tablets manufactured from them. The particle size of granules, and the distribution around the mean, also appear to be important. It is concluded that the physical properties of granules and tablet depend on a number of factors not easily delineated using conventional statistics.

Use of a Novel Modified TSI for the Evaluation of Controlled-Release Aerosol Formulations. I

When considering the development of potential controlled-release pulmonary drug delivery systems, there is at present no standard method available for the assessment of in vitro drug release profiles necessary to understand how the drug might release following deposition in the lungs. For this purpose, the twin-stage impinger (TSI), apparatus A of the BP, has been redesigned and tested. This modified TSI was found capable of discriminating between drug release rates from conventional and different dry powder formulations consisting of model controlled-release excipients, providing information related to (a) drug diffusion properties of controlled-release dry powder blends with different excipient components and (b) the effect of varying drug concentration within a given formulation.

Surface Energy of Microcrystalline Cellulose Determined by Capillary Intrusion and Inverse Gas Chromatography

Surface energy data for samples of microcrystalline cellulose have been obtained using two techniques: capillary intrusion and inverse gas chromatography. Ten microcrystalline cellulose materials, studied using capillary intrusion, showed significant differences in the measured surface energetics (in terms of total surface energy and the acid–base characteristics of the cellulose surface), with variations noted between the seven different manufacturers who produced the microcrystalline cellulose samples. The surface energy data from capillary intrusion was similar to data obtained using inverse gas chromatography with the column maintained at 44% relative humidity for the three samples of microcrystalline cellulose studied. This suggests that capillary intrusion may be a suitable method to study the surface energy of pharmaceutical samples.

Influence of Physiological Variables on the In Vitro Drug-Release Behavior of a Polysaccharide Matrix Controlled-Release System

Hydrophilic matrix systems are popular and versatile controlled release systems. Amongst polysaccharide derivatives used to produce such systems, there are a range of cellulose ethers, e.g., hydroxypropylmethylcellulose (HPMC) and a diverse range of other materials, including sodium alginate, carrageenan, chitosan, and xanthan gum. The hydrophilic matrix systems being investigated in this study consist of two heteropolysaccharides—xanthan gum (XG) and locust bean gum (LBG)—and the principle of this formulation is that it utilizes the synergistic interaction of two biopolymers to produce a strong and elastic gel in the presence of a ternary component to control the drugrelease process. Hydrophilic matrix tablets generally control and prolong drug release by rapidly forming a protective viscous gel layer while releasing exposed drug around the tablet surface when exposed to gastrointestinal fluid. It is generally believed that drug release from a swollen gel layer may be governed by drug diffusion through and/or erosion of the gel layer depending on the solubility of a drug. Therefore, many factors influencing the properties of the gel may significantly modify the drug-release behavior of the system. These factors may include physicochemical properties of the drug and polymers, formulation composition, processing conditions, and environmental variables such as the characteristics of gastrointestinal fluids. The ideal oral controlled-release system should not be or be minimally influenced by the in vivo environment of the gastrointestinal tract (GIT), as any significant changes of the system may potentially lead to a failure of the product or serious therapeutic toxicity. Certain hydrophilic matrix formulations have been shown to erode in the GIT much faster postprandially than under fasting conditions,

Adsorption of an Amine Drug onto Microcrystalline Cellulose and Silicified Microcrystalline Cellulose Samples

Abstract The adsorption of a model amine drug (tacrine hydrochloride) from aqueous solution onto 21 microcrystalline cellulose (MCC) based samples has been investigated. The MCC source (manufacturer) affected adsorption. The adsorption appeared to be fully reversible. Adsorption was reduced by the use of high-density grade MCC, high-energy milling, and silicification. Adsorption of the model drug was not affected by the particle size of the MCC. Significant variations of the adsorption characteristics between batches of certain MCC products were found. The primary mode of adsorption was by ion exchange.

The formulation of powder inhalation systems containing a high mass of nedocromil sodium trihydrate

Nedocromil sodium trihydrate is not amenable to conventional methods of dry powder inhaler formulation, including the preparation of coarse carrier systems and aggregation of the pure drug powder. It is considered that the in vitro aerosol performance of such systems is governed by the cohesive drug-drug interactions. Therefore, alternative powder formulation strategies (novel to nedocromil sodium) were developed. By decreasing the particle size of the lactose carrier, the deaggregation and subsequent fine particle drug deposition were significantly improved. Further improvements were made by selecting and then optimizing high-shear mixing procedures. It was concluded, based on these findings and supportive microscopic studies (low-temperature and environmental scanning electron microscopy together with energy-dispersive X-ray analysis), that the FPL are producing their functional effects by intercalating within the drug self-agglomerates and physically disrupting the cohesive drug-drug interactions. The use of a smaller-sized lactose fraction in conjunction with a blending procedure capable of optimally disrupting the drug self-agglomerates allowed maximal intercalation of the excipient material within the drug self-agglomerates. The adhesive drug-FPL interactions are considered to be weak compared with the cohesive drug-drug particle interactions, cohesive interactions that would normally govern the aerosol performance of powder systems containing a high mass of nedocromil sodium trihydrate.