Shyamal Das

Characterization of the surface properties of a model pharmaceutical fine powder modified with a pharmaceutical lubricant to improve flow via a mechanical dry coating approach

The aim of this study is to investigate the changes in physical and chemical surface properties of a fine lactose powder, which has been processed by a mechanical dry coating approach. A commercially available milled lactose monohydrate powder (median diameter around 20 μm) was dry coated with a pharmaceutical lubricant, magnesium stearate (MgSt). Substantial changes in bulk behavior have been shown previously and the purpose of the current work was to understand the relationship between these bulk changes and physico-chemical changes in the surface. X-ray photoelectron spectroscopy and time-of-flight secondary ion mass spectrometry results demonstrated both qualitatively and quantitatively how the chemical properties of the lactose particle surfaces had been altered. The characterization results indicated that a high-level coverage of a thin coating layer of MgSt has been created through the coating. Inverse gas chromatography was used to probe the surface energetic changes, and at conditions of finite dilution, provided a new insight into surface energy changes. This work demonstrated that the modifications of the surface physical and chemical properties correlated with the reduction in powder cohesion and improvement in powder flow.

Use of surface energy distributions by inverse gas chromatography to understand mechanofusion processing and functionality of lactose coated with magnesium stearate

The purpose was to employ a new finite dilution approach to determine total surface energy distributions of mechanofused powders by inverse gas chromatography (IGC) to contribute to the understanding of their improved flow properties and to help optimise the magnesium stearate (MgSt) coating. Pharmatose 450M was mechanofused with between 0.1 and 8% (w/w) of MgSt. The non-polar, polar and total surface energies and work of cohesion at infinite dilution and the energy distributions at finite dilution were constructed using IGC. Brunauer-Emmet-Teller (BET) surface area and particle morphology were determined by IGC and scanning electron microscope, respectively. Surface energies determined at finite dilution appeared more consistent with the observed flow behaviour of mechanofused powders than comparative surface energy determination at infinite dilution. Polar and total surface energy distributions together with BET surface area measurements were the lowest when lactose was mechanofused with 1-2% MgSt (w/w). In conclusion, the surface energy distribution profiles measured at finite dilution were argued to be more informative and useful in reporting the surface energy changes during mechanofusion, optimising MgSt concentration in the mechanofusion process, and the flow behaviour of mechanofused powders.

Magnesium stearate increases salbutamol sulphate dispersion: What is the mechanism?

The objective was to understand the mechanism of enhancement in salbutamol sulphate (SS) respiratory deposition through addition of magnesium stearate (MgSt). The mixing of MgSt with micronized SS occurred using a Turbula mixer (101 rpm), whilst varying mixing time and MgSt concentration and size. Deposition of SS was determined by a twin-stage impinger. Particle size distributions were obtained using the Malvern Mastersizer 2000. Morphology was examined by scanning electron microscopy and surface energy determined using inverse gas chromatography. Mixing of SS with increasing concentrations of MgSt improved dispersion (FPF of 3.3% using 1% w/w MgSt, 4.5% using 5% w/w MgSt and 7.8% using 10% w/w MgSt compared with 1.4% of pure SS for 20mg doses) when mixed for 0.5h; SS dispersion improved further after 3.5h of mixing. In addition to the action of the MgSt in coating SS particles, a greater understanding of the function of MgSt particles in acting as micro-carriers and in changing the mixture structure through incorporation into agglomerates has been achieved. The mechanistic understanding of improvement in drug deposition using MgSt will allow more directed strategies to be employed in designing powder formulations for inhalation.

Characterising surface energy of pharmaceutical powders by inverse gas chromatography at finite dilution.

Objectivesu2002 The objectives of this project were the use of surface energy distributions in: distinguishing the effects of magnesium stearate on the surface energy of lactose processed by two methods: mixing in a Turbula and mechanofusion; characterising surface energy of materials before and after micronisation; and understanding surface energy changes of micronised lactose before and after storage at high relative humidity (RH).

Influence of Storage Relative Humidity on the Dispersion of Salmeterol Xinafoate Powders for Inhalation

The in vitro dispersion of salmeterol xinafoate (SX) alone and four SX (2.5%)-coarse lactose (CL) mixtures containing 0%, 5%, 10% and 20% micronised lactose (ML) was monitored during 18-month storage at 33%, 55% and 75% relative humidity (RH) using a twin stage impinger. The surface moisture was monitored over 2 months by thermo gravimetric analysis. The morphology was determined by scanning electron microscopy. An aerosizer was used to compare the agglomerate strengths of formulations before and after storage at 75% RH. Upon storage, no significant difference occurred in fine particle fraction (FPF) of any formulation at 33% and 55% RH. Within 8 weeks, the FPF of mixture containing 20% ML (M20F) significantly decreased from 11.3% to 7.7% at 75% RH (p = 0.008) and to 4.9% at 95% RH (p = 0.001). The calculated capillary forces were greater for ML-ML contact than other particle interactions and the propensity of ML-ML contacts was higher in M20F. The agglomerate strength of M20F significantly increased after storage. The study concluded that the critical factors for decreased dispersion of SX formulations were RH of 75% or greater and the presence of high concentrations of ML due to capillary forces and/or solid bridge formation of ML leading to increased agglomerate strength.

Powder strength distributions for understanding de-agglomeration of lactose powders.

PurposeThe purpose was to calculate distributions of powder strength of a cohesive bed to explain the de-agglomeration of lactose.MethodsDe-agglomeration profiles of Lactohale 300® (L300) and micronized lactose (ML) were constructed by particle sizing aerosolised plumes dispersed at air flow rates of 30–180xa0l/min. The work of cohesion distribution was determined by inverse gas chromatography. The primary particle size and tapped density distributions were determined. Powder strength distributions were calculated by Monte Carlo simulations from distributions of particle size, work of cohesion and tapped density measurements.ResultsThe powder strength distribution of L300 was broader than that of ML. Up to 85th percentile, powder strength of L300 was lower than ML which was consistent with the better de-agglomeration of L300 at low flow rates. However, ~15% of L300 particles had higher powder strength than ML which likely to cause lower de-agglomeration for L300 at high air flow rates.ConclusionCohesive lactose powders formed matrices of non-homogenous powder strength. De-agglomeration of cohesive powders has been shown to be related to powder strength. This study provided new insights into powder de-agglomeration by a new approach for calculating powder strength distributions to better understand complex de-agglomeration behaviour.

Surface energy changes and their relationship with the dispersibility of salmeterol xinafoate powders for inhalation after storage at high RH.

This study investigated the relationship between surface energy of micronized lactose, coarse lactose and salmeterol xinafoate and dispersibility from a mixture after storage at 75% RH. Surface energies, dispersibility, morphology, and the presence of amorphous domains were determined by inverse gas chromatography, twin stage impinger, scanning electron microscope and dynamic vapour sorption, respectively. The fine particle fraction of mixture decreased significantly in 4 weeks (P<0.05), reaching a static level in 3 months. Amorphous content was not detected in the micronized lactose, coarse lactose and salmeterol xinafoate. After conditioning stored samples at 75% RH for 2h, dispersive surface energy of both micronized and coarse lactose significantly decreased (P<0.05), while the polar surface energy of all significantly increased (P<0.05) resulting in significant increase in total surface energy after storage. After conditioning stored samples at 0% RH for 2h, no significant difference was observed in any surface energy parameter. This study concluded that the total surface energy increased during storage at high RH due to the adhered surface moisture. The mechanism of decreased dispersibility was related to increased capillary/solid bridging interactions and to possible increased interaction of contiguous particles due to increased polar surface energy.

Agglomerate properties and dispersibility changes of salmeterol xinafoate from powders for inhalation after storage at high relative humidity.

PURPOSEnThis study investigated changes in agglomeration and the mechanism of dispersibility decrease of salmeterol xinafoate (SX) from SX-lactose mixtures for inhalation after storage at 75% RH for 3 months.nnnMETHODSnThe dispersibility, PSD and in situ PSD of aerosol plumes of SX alone and SX-coarse lactose (CL) mixtures containing 0, 5, 10 and 20% micronized lactose (ML) before and after storage were determined by a Next Generation Impactor (NGI), a Mastersizer 2000 and a Spraytec, respectively.nnnRESULTSnThe PSD of ML increased after storage at 75% RH, but dispersibility of SX using the stored ML increased. After storage, the %SX of the mixture containing 20% ML (M20F) significantly increased (P<0.05) in the throat and mouthpiece, preseparator and stage 1 of NGI, while it significantly decreased in the remaining stages (P<0.05). In situ analysis of aerosol plumes of M20F supported this result with an increased presence of particles of 4-25microm and a decreased respirable particle distribution of <4microm after storage.nnnCONCLUSIONSnThe decreased dispersibility of M20F after storage was due to the formation of less dispersible agglomerates, probably occurring through enhanced capillary interaction and/or solid bridging of ML, entrapping and preventing the release of SX particles.

Improving the de-agglomeration and dissolution of a poorly water soluble drug by decreasing the agglomerate strength of the cohesive powder

Influence of ternary, poorly water-soluble components on the agglomerate strength of cohesive indomethacin mixtures during dissolution was studied to explore the relationship between agglomerate strength and extent of de-agglomeration and dissolution of indomethacin (Ind). Dissolution profiles of Ind from 20% Ind-lactose binary mixtures, and ternary mixtures containing additional dibasic calcium phosphate (1% or 10%; DCP), calcium sulphate (10%) and talc (10%) were determined. Agglomerate strength distributions were estimated by Monte Carlo simulation of particle size, work of cohesion and packing fraction distributions. The agglomerate strength of Ind decreased from 1.19 MPa for the binary Ind mixture to 0.84 MPa for 1DCP:20Ind mixture and to 0.42 MPa for 1DCP:2Ind mixture. Both extent of de-agglomeration, demonstrated by the concentration of the dispersed indomethacin distribution, and extent of dispersion, demonstrated by the particle size of the dispersed indomethacin, were in descending order of 1DCP:2Ind>1DCP:20Ind>binary Ind. The addition of calcium sulphate dihydrate and talc also reduced the agglomerate strength and improved de-agglomeration and dispersion of indomethacin. While not definitively causal, the improved de-agglomeration and dispersion of a poorly water soluble drug by poorly water soluble components was related to the agglomerate strength of the cohesive matrix during dissolution.