New Development in Understanding Drug-Polymer Interactions in Pharmaceutical Amorphous Solid Dispersions from Solid-State Nuclear Magnetic Resonance.

Pharmaceutical amorphous solid dispersions (ASDs) represent a widely used technology to increase the bioavailability of active pharmaceutical ingredients (APIs). ASDs are based on an amorphous API dispersed in a polymer, and their stability is driven by the presence of strong intermolecular interactions between these two species (e.g.

Drug-Polymer Interactions in Acetaminophen/Hydroxypropylmethylcellulose Acetyl Succinate Amorphous Solid Dispersions Revealed by Multidimensional Multinuclear Solid-State NMR Spectroscopy.

The bioavailability of insoluble crystalline active pharmaceutical ingredients (APIs) can be enhanced by formulation as amorphous solid dispersions (ASDs). One of the key factors of ASD stabilization is the formation of drug-polymer interactions at the molecular level. Here, we used a range of multidimensional and multinuclear nuclear magnetic resonance (NMR) experiments to identify these interactions in amorphous acetaminophen (paracetamol)/hydroxypropylmethylcellulose acetyl succinate (HPMC-AS) ASDs at various drug loadings.

Solid state nuclear magnetic resonance studies of hydroxypropylmethylcellulose acetyl succinate polymer, a useful carrier in pharmaceutical solid dispersions.

Hydroxypropylmethylcellulose (HPMC) acetyl succinate (HPMC-AS) is a key polymer used for the enablement of amorphous solid dispersions (ASDs) in oral solid dosage forms. Choice of the appropriate grade within the material is often made empirically by the manufacturer of small-scale formulations, followed by extensive real time stability. A key factor in understanding and predicting the performance of an ASD is related to the presence of hydrogen (or other) bonds between the polymer and active pharmaceutical ingredient (API), which will increase stability over the parameters captured by miscibility and predicted by the Gordon-Taylor equation.

Measuring the sticking of mefenamic acid powders on stainless steel surface.

This study proposes an approach for quantifying the amount of pharmaceutical powder adhering (quality attribute) to the metals surfaces. The effect of surface roughness (detrimental attribute) on the amount of powder sticking to a stainless steel surface for a model pharmaceutical material is also qualitatively determined. Methodology to quantify powder adhesion to surfaces utilises a texture analyser and HPLC.

Effect of milling temperatures on surface area, surface energy and cohesion of pharmaceutical powders.

Particle bulk and surface properties are influenced by the powder processing routes. This study demonstrates the effect of milling temperatures on the particle surface properties, particularly surface energy and surface area, and ultimately on powder cohesion. An active pharmaceutical ingredient (API) of industrial relevance (brivanib alaninate, BA) was used to demonstrate the effect of two different, but most commonly used milling temperatures (cryogenic vs.

Development of a material sparing bulk density test comparable to a standard USP method for use in early development of API's.

Bulk density can be a key indicator of performance, and may influence choice of formulation route of materials in pharmaceutical development. During early development, the cost of API's can be expensive and the availability of material for powder property analysis is limited. The aim of this work was to investigate a suitable small-scale, low material requirement, bulk density test which would provide comparable data to the recommended large volume USP test.

Decoupling the contribution of dispersive and acid-base components of surface energy on the cohesion of pharmaceutical powders.

This study reports an experimental approach to determine the contribution from two different components of surface energy on cohesion. A method to tailor the surface chemistry of mefenamic acid via silanization is established and the role of surface energy on cohesion is investigated. Silanization was used as a method to functionalize mefenamic acid surfaces with four different functional end groups resulting in an ascending order of the dispersive component of surface energy.

Decoupling the contribution of surface energy and surface area on the cohesion of pharmaceutical powders.

Purpose: Surface area and surface energy of pharmaceutical powders are affected by milling and may influence formulation, performance and handling. This study aims to decouple the contribution of surface area and surface energy, and to quantify each of these factors, on cohesion.

Methods: Mefenamic acid was processed by cryogenic milling.

Effect of crystal habits on the surface energy and cohesion of crystalline powders.

The role of surface properties, influenced by particle processing, in particle-particle interactions (powder cohesion) is investigated in this study. Wetting behaviour of mefenamic acid was found to be anisotropic by sessile drop contact angle measurements on macroscopic (>1cm) single crystals, with variations in contact angle of water from 56.3° to 92.

Surface energy analysis as a tool to probe the surface energy characteristics of micronized materials--a comparison with inverse gas chromatography.

This study investigates the impact of micronization on the measured surface energy characteristics of an active pharmaceutical ingredient (API), ibipinabant, by inverse gas chromatography (IGC) using both a fixed probe concentration, commonly used in standard IGC methods, and a fixed probe surface coverage approach applied by the surface energy analyzer (SEA), a next generation IGC system. The IGC measurements indicate an initial increase in surface energy, going from un-micronized to micronized, followed by a reduction in surface energy with increasing micronization extent. This was attributable to the change in the retention behaviour of the dispersive probes as a consequence of the change in the probe surface coverage rather than a change in the actual surface energy of the materials being analysed.

Investigation into the degree of variability in the solid-state properties of common pharmaceutical excipients-anhydrous lactose.

This paper reports the batch-to-batch and vendor-to-vendor variations in the solid-state characteristics of multiple batches of lactose anhydrous from each of three vendors and the subsequent impact of these differences on processability and/or functionality.

Roller compaction: application of an in-gap ribbon porosity calculation for the optimization of downstream granule flow and compactability characteristics.

This paper reports the use of an in-gap ribbon porosity calculation for the optimisation of roller compaction ribbon parameters in order to control downstream granule and tablet properties for a typical pharmaceutical formulation. The study demonstrates the effect of changes to roll speed and roll gap on the relative level of ribbon compaction for ribbons with equivalent in-gap porosities. It is demonstrated that in-gap ribbon porosity can be applied to enable optimization of the downstream granule processability characteristics for a typical pharmaceutical formulation and an understanding of the control space of a roller compaction process.

Roller compaction: Application of an in-gap ribbon porosity calculation for the optimization of downstream granule flow and compactability characteristics.

This paper reports the use of an in-gap ribbon porosity calculation for the optimisation of roller compaction ribbon parameters in order to control downstream granule and tablet properties for a typical pharmaceutical formulation. The study demonstrates the effect of changes to roll speed and roll gap on the relative level of ribbon compaction for ribbons with equivalent in-gap porosities. It is demonstrated that in-gap ribbon porosity can be applied to enable optimization of the downstream granule processability characteristics for a typical pharmaceutical formulation and an understanding of the control space of a roller compaction process.

Amorphous drug-PVP dispersions: application of theoretical, thermal and spectroscopic analytical techniques to the study of a molecule with intermolecular bonds in both the crystalline and pure amorphous state.

We report the case of BMS-488043-PVP solid dispersions which when analysed using modulated DSC showed compliance with the Gordon-Taylor model, confirming ideal mixing behaviour of the two components. The nature or presence of stabilising interactions between drug and PVP could not be confirmed using this technique. Use of FT-IR, Raman and solid-state NMR spectroscopy confirmed the presence of stabilising hydrogen bond interactions between the drug and PVP.

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.

The use of colloid probe microscopy to predict aerosolization performance in dry powder inhalers: AFM and in vitro correlation.

The atomic force microscope (AFM) colloid probe technique was utilized to measure cohesion forces (separation energy) between three drug systems as a function of relative humidity (RH). The subsequent data was correlated with in vitro aerosolization data collected over the same RH range. Three drug-only systems were chosen for study; salbutamol sulphate (SS), triamcinolone acetonide (TAA), and di-sodium cromoglycate (DSCG).

The surface roughness of lactose particles can be modulated by wet-smoothing using a high-shear mixer.

The surface morphology of a-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 mixer's cylindrical bowl were performed. Smoothed particles were tested for size distribution, flow, and packing.

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 influence of relative humidity on the cohesion properties of micronized drugs used in inhalation therapy.

The influence of relative humidity (RH) on the cohesion properties of three drugs: salbutamol sulphate (SS), triamcinolone acetonide (TAA), and disodium cromoglycate (DSCG) was investigated using the atomic force microscope (AFM) colloidal probe technique. Micronized drug particles were mounted in heat-sensitive epoxy resin for immobilization. Multiple AFM force-distance curves were conducted between each drug probe and the immobilized drug particulates at 15, 45, and 75% RH using Force-Volume imaging.

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.

Effect of humidity on aerosolization of micronized drugs.

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 12hr 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.

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.

Investigation into the effect of humidity on drug-drug interactions using the atomic force microscope.

The atomic force microscope (AFM) has been used to characterize the cohesive nature of a micronized pharmaceutical powder used for inhalation therapy. Salbutamol sulfate (also referred to as albuterol sulfate), a therapeutic drug commonly delivered from dry powder inhalers (DPI), was chosen as a model system because the cohesion and subsequent de-agglomeration during inhalation are critical aspects to the efficacy of such a delivery system. Salbutamol sulfate drug particulates were mounted on V-shaped AFM cantilevers using a novel micromanipulation technique.