The role of force control agents in high-dose dry powder inhaler formulations.

The aim of this study was to determine the aerosolisation and aerodynamic properties of model inhalation particles (salbutamol sulphate and budesonide) upon coprocessing with force control agents (FCAs)-leucine, lecithin and magnesium stearate. Coprocessing of the drug particles with FCAs (5%, w/w) was conducted using mechanofusion-a novel dry mechanical fusion process. The influence of mechanofused FCAs on the entrainment and deaggregation behaviour of the drug-only formulations was investigated using a next generation impactor (NGI) and an in-line Spraytec laser diffraction particle sizer. In vitro measurements of salbutamol sulphate coprocessed with FCAs indicated a significant (p < 0.001) improvement of the fine particle fraction (FPF). The coprocessing of salbutamol sulphate with magnesium stearate produced the highest FPF, with an increase from 29.18% to 79.42% of the emitted dose. Coprocessing of budesonide particles only led to a small increase in fine particle delivery but a greater reduction in device retention. Aerosolisation analysis of the aerosolised powders indicated more effective aerosolisation and a considerable time reduction in powder bed fluidisation and entrainment upon coprocessing of the APIs with FCAs. From these data, it can be postulated that processing of drug actives with FCAs using mechanofusion is an effective means of improving the deagglomeration and aerosolisation properties of cohesive powders in DPI systems.

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.

Interaction of moisture with sodium starch glycolate.

The relationship between the apparent moisture content and moisture sorption of modified starches was investigated. Samples of sodium starch glycolate (SSG), pregelatinized starch (PGS) and potato starch (PS) were stored for various times at 44% or 75% relative humidity (RH) to produce samples with moisture contents of up to 14%, as determined by loss on drying (LOD). Evaluation of LOD and mass gain data suggested that measured mass gain equated to predicted LOD values for PGS and PS. However, in SSG there was a nonstoichiometric relationship between mass gain and predicted LOD. In addition, samples of SSG displayed hysteresis during dynamic vapor sorption (DVS) cycling in that an apparent mass loss of about 2-3% was observed for two of the SSGs, with PS and PGS exhibiting reversibility. In some cases, SSG exhibited an apparent mass loss during the DVS cycle at with 50% RH. These observations suggest that one or more of the components of SSG "interact" with moisture. Because X-ray diffraction suggested there was no dramatic change in the crystallinity of SSG, an exchange of residual SSG solvent, alcohol, with moisture may, in part, explain the moisture sorption behavior of SSG.

Effect of moisture on the compressibility and compactibility of sodium starch glycolate.

The relationship between the apparent moisture content and compactibility of sodium starch glycolate was compared to similarly obtained data for pregelatinized starch. Samples of sodium starch glycolate (SSG) and pregelatinised starch (PGS) were stored at 44% or 75% relative humidity (RH), producing samples exhibiting moisture contents of up to 14% w/w, as determined by loss on drying (LOD). Increasing the moisture content of SSG and PGS resulted in an increase in compressibility and compactibility for both materials. However, the effect was more dramatic for SSG with unlubricated compactibilities of 2.0 MPa and 0.9 MPa at approximately 11.5% LOD for SSG and PGS, respectively, which was further exemplified in the compactibility of lubricated materials and in blends with microcrystalline cellulose. These results suggested that moisture content had a greater effect on the compactibility of SSG compared with PGS and that the interactions of water with the components of the SSG starch granules may be different from those within the PGS starch granules at comparable LOD values.

Interactions of water with the surfaces of crystal polymorphs.

The purpose of this study is to investigate the interactions of water adsorption on the surfaces of different crystal forms of the same drug. The energy of interaction between water vapor and the surfaces of the two crystal polymorphs has been investigated as a function of temperature and water activity. One of the adsorbents, the metastable form of the monotropically related pair used here, showed greater adsorptive capacity in terms of both the amount of water uptake as well the integral heat of adsorption. However, the specific heat of adsorption values revealed that even though the surface of the thermodynamically stable crystal adsorbs less water, water molecules are actually more strongly bound when adsorbed on the surface of the stable crystal form. This means that the metastable crystal form adsorbs a greater amount of more weakly bound water. Conversely, the thermodynamically stable form, presents on its surface a smaller number of stronger adsorption sites for water. This study also shows that the crystalline character of the surfaces of the two polymorphs, shown as quantifiable differences in their surface interactions, is maintained despite the presence of any crystal defects incorporated upon milling.

TIMERx: novel polysaccharide composites for controlled/programmed release of drugs in the gastrointestinal tract.

Over the last 100 years tablets have grown from first invention to becoming the world's leading medicinal form, by any measure. This article considers some of the reasons for the pre-eminence of pharmaceutical tablets. Particular attention has been given to the role of controlled-release tablets and to a very versatile hydrogel-based controlled-release technology, called TIMERx((R)). The unique nature of TIMERx intermolecular physical chemistry is described in relation to the technology's potential to provide any one of a number of different release profiles, ranging from zero order to chronotherapeutic release. The unusual nature of TIMERx technology lies in its ability to provide different release kinetics by the manipulation of molecular interactions. This 'molecular engine' replaces the need for complex processing or novel excipients and allows desired drug release profiles to be 'factory set' following a simple formulation development process. The article describes the physico-chemical interactions of TIMERx technology at a molecular level and how they can be manipulated by formulation considerations. The article describes how TIMERx technology has been developed to the point where today it underpins a number of marketed pharmaceutical CR products as well as products under development by Penwest Pharmaceuticals.

Dynamic vapor sorption properties of sodium starch glycolate disintegrants.

Dynamic vapor sorption (DVS) was used to determine the moisture sorption properties of sodium starch glycolates. The results were compared to similarly obtained data for potato starch, pregelatinized starch, microcrystalline cellulose (MCC), and crystalline lactose. As expected, sodium starch glycolates exhibit a large mass gain at 90% relative humidity (RH), compared to the other anhydroglucose-based excipients. However, the sorption capacities of potato starch and the modified starches between 10%-70% RH were similar. Analysis of the DVS data using the Brunauer-Emmett-Teller (BET) and Guggenheim, Anderson, and deBoer (GAB) theories to obtain the so-called monolayer (Xm), as expected, showed that there was an increasing Xm with apparent mass gain that is probably related to crystallinity, purity, and surface area and represents the number and accessibility of amorphous anhydroglucose units present. The value of x(m) was related to the degree of crystallinity or order as determined by X-ray diffraction, suggesting that x(m) can be used to further describe the amorphous nature of semi-crystalline polymers containing anhydroglucose units, in particular the chemically modified sodium starch glycolate. Additionally, it appears that the sorption capacity between 10%-70% RH is not dramatically affected by the presence or type of cross-linking and sodium carboxymethylation (in sodium starch glycolates) and gelatinization (in pregelatinized starch) and that the superdisintegrant properties of the sodium starch glycolates are a consequence of some water-structure interaction that is well beyond the available number of hydration sites, as represented by x(m). Further evaluation of the structure and sorption properties of excipients may aid the development of disintegrants for solid dosage forms.

The cohesive-adhesive balances in dry powder inhaler formulations II: influence on fine particle delivery characteristics.

PURPOSE: To investigate the influence of the cohesive-adhesive balances on dry powder formulation aerosolization and delivery characteristics. METHODS: De-agglomeration properties of pharmaceutical powders were investigated using an Aerosizer at various shear forces. Aerosol drug deposition properties of drug-only formulations and carrier-based formulations were investigated using a low-resistance device (Rotahaler) and a high-resistance device (Turbuhaler) via a twin-stage impinger. RESULTS: A paradoxical relationship between particle cohesive strength and de-agglomeration efficiencies of drug-only formulations was observed, where an increase in cohesive strength led to a higher fine particle fraction. A possible explanation for the variation in the fluidization and aerosolization properties between low and high cohesive particles was modeled on the relationship between cohesion, metastable agglomerate size, and the resulting aerodynamic drag force acting on the fluidized agglomerates. The addition of a fine particle lactose carrier influenced the drug deposition patterns in different ways depending on the relative cohesive and adhesive force balances within the formulation. CONCLUSIONS: The use of the colloid Atomic Force Microscrope (AFM) technique in combination with the cohesive-adhesive balance (CAB) system provides a novel preformulation tool for investigating the likely behavior of a dry powder formulation and a possible means of interpreting the possible de-aggregation and dispersion mechanisms of carrier-based formulations.

The cohesive-adhesive balances in dry powder inhaler formulations I: Direct quantification by atomic force microscopy.

PURPOSE: To obtain a quantitative assessment of the cohesive and adhesive force balance within dry powder inhaler formulations. METHODS: The atomic force microscope (AFM) colloid probe technique was used to measure the adhesive and cohesive force characteristics of dry powder systems containing an active component (budesonide, salbutamol sulphate) and alpha-lactose monohydrate. To minimize the variations in contact area between colloid probe and substrates, nanometer smooth crystal surfaces of the drugs and the excipient were prepared. RESULTS: The uniformity in contact area allowed accurate and reproducible force measurements. Cohesive-adhesive balance (CAB) graphs were developed to allow direct comparison of the interaction forces occurring in model carrier-based formulations. A salbutamol sulphate-lactose system revealed a significant tendency for the two materials to adhere, suggesting a propensity for the powder to form a homogenous blend. In contrast, the budesonide-lactose system exhibited strong cohesive properties suggesting that the formulation may exhibit poor blend homogeneity and potential for segregation upon processing and handling. CONCLUSIONS: The novel approach provides a fundamental insight into the cohesive-adhesive balances in dry powder formulations and further understanding of powder behavior.

Active and intelligent inhaler device development.

The dry powder inhaler, which has traditionally relied on the patient's inspiratory force to deaggregate and deliver the active agent to the target region of the lung, has been a successful delivery device for the provision of locally active agents for the treatment of conditions such as asthma and chronic obstructive pulmonary disease (COPD). However, such devices can suffer from poor delivery characteristics and/or poor reproducibility. More recently, drugs for systemic delivery and more high value compounds have been put into DPI devices. Regulatory, dosing, manufacturing and economic concerns have demanded that a more efficient and reproducible performance is achieved by these devices. Recently strategies have been put in place to produce a more efficient DPI device/formulation combination. Using one novel device as an example the paper will examine which features are important in such a device and some of the strategies required to implement these features. All of these technological advances are invisible, and may be irrelevant, to the patient. However, their inability to use an inhaler device properly has significant implications for their therapy. Use of active device mechanisms, which reduce the dependence on patient inspiratory flow, and sensible industrial design, which give the patient the right clues to use, are important determinants of performance here.

Physicochemical and mechanical evaluation of a novel high density grade of silicified microcrystalline cellulose.

High density microcrystalline cellulose (MCC) is a relatively free flowing grade of MCC that finds use in direct compression tableting and hard gelatin capsule filling applications. Silicified high density microcrystalline cellulose has recently been introduced. This material has been compared to other grades of MCC and previously silicified microcrystalline cellulose (SMCC). The results suggest that, as observed for other grades of SMCC, the material exhibits no detectable chemical or polymorphic differences to standard material, some improvement in flow characteristics, but shows considerably enhanced mechanical properties.

Development and evaluation of bio-dissolution systems capable of detecting the food effect on a polysaccharide-based matrix system.

Methods are proposed and tested for mimicking the in vitro food effect on controlled release dosage forms, using USP dissolution apparatus 3. Using in vivo data a pH and time profile was constructed, and the methods utilized either presoaking in peanut oil or continuous oil contact to mimic the presence of a high fat meal. A water soluble drug (propranolol hydrochloride, class 1 by BCS) was used as a model material. Both methods were able to confirm that a labile multiparticulate system (Inderal LA) was susceptible to such in vitro effects. A hydrocolloid matrix tablet showed low susceptibility to either technique. There was a good correlation between methods, which may indicate that the oil presoaking method, which is less time consuming to carry out and leads to more simple subsequent analysis, may be sufficient to identify dosage forms susceptible to physical food effects.

Adsorption of an amine drug onto microcrystalline cellulose and silicified microcrystalline cellulose samples.

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.