Lactose Particles Research Articles

Lactose particle engineering: Influence of ultrasound and anti-solvent on crystal habit and particle size

This study focuses on ultrasound-assisted anti-solvent crystallization of lactose, expanding on previous studies and presenting, for the first time, the results of large scale implementation of sonocrystallization for lactose. The results further clarify the interplay between solution chemistry – namely the role of β-lactose – and crystallization, representing a step forward in the fine tuning of lactose properties for pharmaceutical manufacturing applications. Batches manufactured at laboratory and pilot scales were extensively characterised, including an approach for the quantification of β-lactose in α-lactose based on powder X-ray diffraction (PXRD), which is described here.

Elucidation of the internal physical and chemical microstructure of pharmaceutical granules using X-ray micro-computed tomography, Raman microscopy and infrared spectroscopy

X-ray micro-computed tomography (XMCT) was used in conjunction with confocal Raman mapping to measure the intra-granular pore size, binder volumes and to provide spatial and chemical maps of internal granular components in α-lactose monohydrate granules formulated with different molecular weights of polyvinyl pyrrolidone (PVP). Infrared spectroscopy was used to understand the molecular association of binder domains. Granules were prepared by high-shear aqueous granulation from α-lactose monohydrate and PVP K29/32 or K90. XMCT was used to visualise the granule microstructure, intra-granular binder distribution and measure intra-granular porosity, which was subsequently related to intrusion porosimetry measurements. Confocal Raman microscopy and infrared microscopy were employed to investigate the distribution of components within the granule and explore the nature of binder substrate interactions. XMCT data sets of internal granule microstructure provided values of residual porosity in the lactose:PVP K29/32 and lactose:PVP K90 granules of 32.41 ± 4.60% and 22.40 ± 0.03%, respectively. The binder volumes of the lactose:PVP K29/32 and lactose:PVP K90 granules were 2.98 ± 0.10% and 3.38 ± 0.07%, respectively, and were attributed to PVP-rich binder domains within the granule. Confocal Raman microscopy revealed anisotropic domains of PVP between 2 μm and 20 μm in size surrounded by larger particles of lactose, in both granule types. Raman data showed that PVP domains contained various amounts of lactose, whilst IR microscopy determined that the PVP was molecularly associated with lactose, rather than residual water. The work shows that XMCT can be applied to investigate granular microstructure and resolve the porosity and the excipient and binder volumes. Combining this technique with vibrational techniques provides further structural information and aids the interpretations of the XMCT images. When used complementarily, these techniques highlighted that porosity and binder volume were the most significant microstructural differences between the α-lactose monohydrate granules formulated with the different grades of PVP.

Nano-coating of β-galactosidase onto the Surface of Lactose by Using an Ultrasound-assisted Technique

We nano-coated powdered lactose particles with the enzyme beta-galactosidase using an ultrasound-assisted technique. Atomization of the enzyme solution did not change its activity. The amount of surface-attached beta-galactosidase was measured through its enzymatic reaction product D-galactose using a standardized method. A near-linear increase was obtained in the thickness of the enzyme coat as the treatment proceeded. Interestingly, lactose, which is a substrate for beta-galactosidase, did not undergo enzymatic degradation during processing and remained unchanged for at least 1 month. Stability of protein-coated lactose was due to the absence of water within the powder, as it was dry after the treatment procedure. In conclusion, we were able to attach the polypeptide to the core particles and determine precisely the coating efficiency of the surface-treated powder using a simple approach.

The influence of crystallization conditions on the morphology of lactose intended for use as a carrier for dry powder aerosols.

Lactose has been widely used as a carrier for inhalation aerosols. The carrier morphology is believed to affect the delivery of the drug. The aim of this study was to investigate the effects of crystallization conditions on the morphology of alpha-lactose monohydrate intended for use as the carrier for dry powder aerosols. The crystallization of lactose was carried out from aqueous solutions at different supersaturations, temperatures, different stages of crystallization and in the presence of different water-miscible organic solvents. The majority of lactose crystals were found to be either tomahawk-shaped or pyramidal after crystallization at an initial lactose concentration between 33-43% w/w, but these became prismatic if the lactose concentration was increased to 50% w/w. A further increase in the lactose concentration to 60% w/w led to the preparation of elongated cuboidal crystals. Higher initial lactose concentrations tended to result in the crystallization of more elongated particles. Crystallization at 40 degrees C was shown to prepare lactose crystals with a more regular shape and a smoother surface than those crystallized at 0 degrees C. Lactose particles generated during the later stage of crystallization were found to be more regular in shape with a smoother surface than those prepared in the earlier stage. The addition of 10% (v/v) methanol or ethanol or acetone to the mother liquor increased the growth rate of lactose particles whereas addition of propanol or glycerine inhibited the rate of crystal growth. Lactose crystals prepared in the presence of glycerine were more regularly shaped with a smoother surface than those prepared in the presence of ethanol or acetone. All the resultant crystals were shown to comprise alpha-lactose monohydrate. Lactose crystals could be prepared with a precisely defined morphology by means of carefully controlling the crystallization conditions.

The effects of carrier size and morphology on the dispersion of salbutamol sulphate after aerosolization at different flow rates.

We have investigated the interdependence of various factors (particle size, surface smoothness, carrier particle shape, inhalation flow rate) on the deposition of a model drug (salbutamol sulphate) after aerosolization from a model inhaler device (Rotahaler). Different batches of alpha-lactose monohydrate were prepared to have different particle size, particle shape and surface smoothness. Each batch of lactose was then mixed separately with salbutamol sulphate in a ratio of 67.5 : 1 (w/w), under similar conditions. Drug deposition from each formulation was investigated using a 4-stage liquid impinger after aerosolization at 28.3, 60.0 and 96.0 L min(-1) via a Rotahaler. At a flow rate of 28.3 L min(-1), a large portion of drug particles was not emitted from the inhaler, the % emission varying from 29.6% to 66.6% for all formulations investigated. Drug emission tended to increase with particle size of the carrier whilst fine particle fraction, fine particle dose and dispersibility appeared to increase with decreasing particle size but increasing elongation ratio of the carrier particles. Increasing the flow rate to 60.0 L min(-1) was shown to increase drug emission since > 75% total dose was found to be emitted from the inhaler. Again, smaller or more elongated lactose particles resulted in a higher fine particle dose or fine particle fraction of salbutamol sulphate than the coarser carrier, although they produced a similar (analysis of variance P > 0.05) drug emission. Increasing the flow rate to 96.0 L min(-1) did not increase drug emission. Increasing the flow rate resulted in an increase in the fine particle fraction and fine particle dose of salbutamol sulphate from all formulations. The flow rate of the airstream appeared to play the most important role, followed by particle size and elongation ratio of the carrier particles, with the surface smoothness relatively less significant in determining the deposition of salbutamol sulphate from the Rotahaler.

The effect of particle size on the dehydration/rehydration behaviour of lactose

Ethanolic suspensions of spray dried and micronized alpha lactose monohydrate (Lα·H 2O) with average particle size between 3 and 200 μm, have been prepared and their dehydration behaviour was investigated by 13C CP-MASNMR spectroscopy. Sub-micron lactose suspension prepared by a novel high pressure homogenisation method has been compared with the standard ethanolic suspensions of Lα·H 2O prepared by reflux or static room temperature methods. In all cases, suspensions were shown to contain the stable anhydrous form of lactose (Lα S). Several approaches were employed to remove ethanol from these suspensions and the resulting dry lactose powders were then analysed by FT-IR, PXRD and SEM to evaluate the effect of drying procedure on type and distribution of lactose polymorphs and particle size. For samples with mean particle size greater than 1 μm, the stable anhydrous polymorphic form of lactose was retained on removal of the ethanol, although differences in the morphology and particle size of the crystals were apparent depending on method of suspension formation. Sub-micron Lα S, while stable in dry conditions, has been shown to be less stable to atmospheric water vapour than Lα S with particle size between 3 and 200 μm.

Particle crystallization during spray drying in humid air

A new and modified spray drying setup was arranged to produce spray-dried crystalline lactose particles. According to Williams–Landel–Ferry kinetics (WLF), it was suggested that a higher particle temperature and lower glass-transition temperature would increase the crystallization rate of the particles during the spray-drying process while still giving dry powders. The new experimental setup allowed the particle temperature to reach higher values by using an insulated drying chamber and also allowed the particle glass-transition temperature to reach lower values by maintaining a higher gas humidity with the aid of a condenser unit attached to the dryer. Modulated differential scanning calorimetry (MDSC) and moisture-induced sorption analysis were used to verify the crystallinity of the spray-dried lactose powders. These analyses showed a higher degree of crystallinity for the particles than have previously been reported in the literature. X-ray diffraction and Raman spectroscopic analyses were further used to identify different lactose anomers. The results suggest that only α-lactose anomer exists in the products as obtained from the modified spray-drying system. The micrographs from scanning electron microscopic analysis also indicated a very crystalline nature for the particles.

Global illumination Raman chemical imaging of a combination of two drug molecules in a dry powder inhaler formulation

Isolated particles of a combination dry powder inhalation blend consisting of a lactose carrier and two Active Pharmaceutical Ingredients (APIs) are imaged by a global illumination Raman instrument. The imaged APIs individually adhere on the surface of large particles of lactose or appear as aggregates of smaller particles. This is probably the first Raman report describing the visualization of API particles on the surface of lactose carriers and also on the use of the global illumination Raman imaging platform on a dry powder inhalation blend. Two methods of dispersing particles for imaging are described: using a particle sizing instrument (mechanical dispersion), which achieves high dispersion, or manually (lightly) dispersing the powder with a spatula so as to minimize the perturbation of the API deposits. Both APIs are clearly identified in the chemical images although the key band of one of them interferes with the bands of lactose which negatively affects the background of the corresponding images. The method of dispersion is found to have a profound effect on the API deposits because the mechanical dispersion leads to complete separation of lactose and API particles previously adhered to its surface. The results presented here reveal the significant potential of this imaging hardware for fast and reliable visualization of the inhalation blends.

Influence of fines on the surface energy heterogeneity of lactose for pulmonary drug delivery

The effects of the blending of lactose fines to the overall adhesion property of coarse α-lactose monohydrate carrier particles were investigated. Five samples, three of them commercial samples from DOMO (Lactohale ® LH100, LH210, and LH250) whilst the other two are blends of LH210 and LH250, were studied. Characterisation included particle sizing, SEM, PXRD and IGC. Dispersive surface energy γ S V d was determined using a finite concentration IGC method to obtain a distribution profile. The γ S V d distribution of lactose crystals was found to vary from 40 to 48 mJ/m 2. The unmilled coarse crystalline lactose sample (LH100) γ S V d was lowest and showed less heterogeneity than the milled sample (LH250). Fines (LH210) were found to have the highest γ S V d value. The samples with loaded LH210 were found to have a higher energy than LH100. The amount of LH210 in Blend 1 was not able to decrease surface energy heterogeneity, whereas sample Blend 2 showed adequate loading of fines to obtain a relatively homogeneous surface. Addition of fines resulted in an increase in γ S V d , suggesting that coarse lactose surfaces were replaced by surfaces of the fines. Increasing the loading of fines may result in a more homogeneous surface energy of lactose particles.

Understanding the effect of lactose particle size on the properties of DPI formulations using experimental design

Medicines for delivering therapeutic agents to the lung as dry powders primarily consist of a carrier and a micronised active pharmaceutical ingredient (API). The performance of an inhaled formulation will depend on a number of factors amongst which the particle size distribution (PSD) plays a key role. It is suggested that increasing the number of fine particles in the carrier can improve the aerosolisation of the API. In addition the effect of PSD upon a bulk powder is also broadly understood in terms of powder flow. Other aspects of functionality that different size fractions of the carrier affect are not clearly understood; for example, it is not yet clearly known how different size fractions contribute to the different functionalities of the carrier. It is the purpose of this investigation to examine the effects of different lactose size fractions on fine particle dose, formulation stability and the ability to process and fill the material in the preferred device. In order to understand the true impact of the size fractions of lactose on the performance of dry powder inhaled (DPI) products, a statistically designed study has been conducted. The study comprised various DPI blend formulations prepared using lactose monohydrate carrier systems consisting of mixtures of four size fractions. Interactive mixtures were prepared containing 1% (w/w) salbutamol sulphate. The experimental design enabled the evaluation of the effect of lactose size fractions on processing and performance attributes of the formulation. Furthermore, the results of the study demonstrate that an experimental design approach can be used successfully to support dry powder formulation development.

Micro-CT in drug delivery

Micro-computed tomography (micro-CT) has not to date been fully exploited in the area of controlled drug delivery despite its capability for providing detailed, 3-D images of morphology and the opportunity this presents for exploring the relationships between delivery device formulation, structure and performance. Micro-CT was used to characterize the internal structure of polycaprolactone (PCL) matrix-type devices incorporating soluble particulates (lactose Mw 342.30, gelatin Mw 20–25 kDa) as models of hydrophilic bioactives or pore-forming excipients. Micro-CT images confirmed that the lactose and gelatin particles were uniformly dispersed throughout the PCL phase and that efficient delivery of 95–100% of each species in 9 days involved transport from the matrix core. Quantitative analysis of micro-CT images provided values for matrix macroporosity, which were within 15% of the theoretical value and revealed uniform porosity throughout the samples. Total release of protein occurred in 9 days (PBS, 37 °C) from matrices containing a high protein load (44% w/w) and was independent of particle size. Measurements of equivalent pore diameter and frequency distribution identified a large population of sub-40 μm pores in each material, indicative of a high density of connecting channels between particles which facilitates protein transport through the matrices.

Improvement of Dissolution Property of Poorly Water-Soluble Drug by Supercritical Freeze Granulation

The dissolution property of the poorly water-soluble drug, flurbiprofen (FP) was improved by a novel supercritical freeze granulation using supercritical carbon dioxide. Supercritical freeze granulation was defined as a production method of the granulated substances by using the dry ice to generate intentionally for the rapid atomization of the supercritical carbon dioxide to the atmospheric pressure. This process utilized a rapid expansion of supercritical solutions (RESS) process with the mixture of the drug and lactose. In the supercritical freeze granulation, needle-like FP fine particles were obtained which adhered to the surface of lactose particles, which did not dissolve in supercritical carbon dioxide. The number of FP particles that adhered to the surface of particles decreased with an increase in the ratio of lactose added, leading to markedly improve the dissolution rate. This improvement was caused not only by the increase in the specific surface area but also the improvement of the dispersibility of FP in water. It is thus concluded that the supercritical freeze granulation is a useful technique to improve the dissolution property of the poorly water-soluble flurbiprofen.

Effect of Surface Free Energy on the Flowability of Lactose Powder Treated by PECVD

AbstractThe surface of microscopic lactose particles was modified by gas phase reactions occurring during a PECVD process to improve the flow behavior of the powder. The particulates were exposed to a capacitively coupled O2/Ar/HMDSO RF discharge in a down stream reactor by varying the gas composition and the RF power. The flowability and the surface free energy of the powders were determined by a ring shear tester and by a tensiometer, respectively. Based thereon, the change in surface free energy was determined not to be the dominating factor for the significantly enhanced flowability of the plasma‐treated powder. Rather, the flowability improvement is supposed to be affected principally by the plasma‐induced change in particle surface roughness.magnified image

Granulation and tabletization of pharmaceutical lactose granules prepared by a top-sprayed fluidized bed granulator

Influence of fluidizing air velocity, temperature and atomizing air pressure, as well as types of raw materials on the size distribution, shape and flow properties of pharmaceutical granules, which were tabletized using a single punch tableting machine, was experimentally investigated. The granules prepared at the fluidizing air velocity of 0.8 m/s had average particle size larger than those obtained at higher air velocity. Meanwhile the fluidizing air temperature had moderate effect on the average particle size of the granules. However, an increase in the atomizing air pressure resulted in an increase in amount of fine particles, leading to the smaller mean particle size. From microscopic analysis, a primary lactose particle wetted by binder had several contact points with other particles inside the prepared granules. Based on granule morphology, it can be implied that the granules are formed by the so-called snowballing mechanism, leading to the relatively spherical structure. In tabletization, the granules with higher average particle size provided tablets with the less weight variation and friability. Meanwhile, the tablets produced from lactose–corn starch mixture had shorter disintegration time than those of lactose powder only.

Scanning White-Light Interferometry as a Novel Technique to Quantify the Surface Roughness of Micron-Sized Particles for Inhalation

A novel approach of measuring the surface roughness of spherical and flat micron-sized drug particles using scanning white-light interferometry was applied to investigate the surface morphology of micron-sized active pharmaceutical ingredients (APIs) and excipient particles used for inhalation aerosols. Bovine serum albumin (BSA) and alpha-lactose monohydrate particles were chosen as model API and excipient particles, respectively. Both BSA and lactose particles were prepared with different degrees of surface corrugation using either controlled spray drying (four samples of BSA) or decantation (two samples of lactose). Particle size distributions were characterized by laser diffraction, and particles were imaged by scanning electron microscopy (SEM). Surface roughness of the BSA and lactose particles was quantified by white-light optical profilometry using vertical scanning interferometry (VSI) at full resolution using a 50x objective lens with 2.0x and 0.5x fields of view for BSA and lactose, respectively. Data were analyzed using Vision software (version 32, WYKO), and surface roughness values are expressed as root-mean-square roughness ( Rrms). Furthermore, data were compared to topographical measurements made using conventional atomic force microscopy. Analysis of the optical profilometry data showed significant variation in BSA roughness ranging from 18.58 +/- 3.80 nm to 110.90 +/- 13.16 nm for the smoothest and roughest BSA particles, respectively, and from 81.20 +/- 15.90 nm to 229.20 +/- 68.20 nm for decanted and normal lactose, respectively. The Rrms values were in good agreement with the AFM-derived values. The particle morphology was similar to SEM and AFM images. In conclusion, scanning white-light interferometry provides a useful complementary tool for rapid evaluation of surface morphology and roughness in particles used for dry powder inhalation formulation.

A novel cell compatible impingement system to study in vitro drug absorption from dry powder aerosol formulations

A modified Astra type multistage liquid impinger (MSLI) with integrated bronchial cell monolayers was used to study deposition and subsequent drug absorption on in vitro models of the human airway epithelial barrier. Inverted cell culture of Calu-3 cells on the bottom side of cell culture filter inserts was integrated into a compendial MSLI. Upside down cultivation did not impair the barrier function, morphology and viability of Calu-3 cells. Size selective deposition with subsequent absorption was studied for three different commercially available dry powder formulations of salbutamol sulphate and budesonide. After deposition without size separation the absorption rates from the aerosol formulations differed but correlated with the size of the carrier lactose particles. However, after deposition in the MSLI, simulating relevant impaction and causing the separation of small drug crystals from the carrier lactose, the absorption rates of the three formulations were identical, confirming the bioequivalence of the three formulations.

Lactose Contaminant as Steroid Degradation Enhancer

By pharmaceutical processes and in the presence of solid excipients physical-chemical changes are known to occur, leading to increased rate of chemical degradation. The purpose of this work was to determine the critical aspects in the stability of a steroid in the presence of a commonly used excipient, lactose. A steroid was either mixed or wet granulated with lactose with different particle size. Small lactose particles lead to a higher degree of degradation. Degradation was enhanced under warm humid conditions although the presence of water alone could not account for this effect. Lactose-phosphate, a known intrinsic contaminant in lactose is demonstrated to enhance the degradation of the steroid. Stability was improved in high purity lactose and deteriorated upon extra addition of phosphates. Since the exposure to the contaminant is a function of the surface area of the lactose, particle size differences of the excipient have a clear consequence. High shear granulated lactose granules exhibit a heterogeneous composition; large granules consist of small primary particles and vice versa. It is shown that the large granules, composed of the small primary lactose particles reveal the highest degree of degradation. Granule composition dictates the stability profile of the granules. The lactose contaminant and granule composition dictates the stability profile of the granules and mixtures.

Gravimetrical and chemical characterization of SiO x structures deposited on fine powders by short plasma exposure in a plasma down stream reactor

The surface of lactose particles was modified by a plasma-enhanced chemical vapor deposition process to improve the flow behavior of the powder. For this, the particulates were treated in a plasma down stream reactor which provides a short (50 ms) and homogeneous exposure to the capacitively coupled RF discharge. The organosilicon monomer hexamethyldisiloxane (HMDSO) was used as a precursor for the formation of SiO x which is deposited on the substrate particle surface. For varying process gas mixtures (O 2/Ar/HMDSO) and RF power applied, the amount of the deposited material was determined gravimetrically after dissolution of the lactose substrate particles and the chemical composition of the accumulated deposition material was investigated by means of attenuated total reflection Fourier transform infrared (ATR-FTIR) spectroscopy. The concentration of the deposited SiO x relating to the substrate material was found to be in the range of 0.1 wt.%. Based on the ATR-FTIR analysis, the inorganic, i.e. oxidic SiO x fraction of the obtained deposits was shown to be controllable by varying the process parameters, whilst a relatively large amount of organic structures must be considered.

Effect of Surface Energy on Powder Compactibility

The influence of surface energy on the compactibility of lactose particles has been investigated. Three powders were prepared by spray drying lactose solutions without or with low proportions of the surfactant polysorbate 80. Various powder and tablet characterisation procedures were applied. The surface energy of the powders was characterized by Inverse Gas Chromatography and the compressibility of the powders was described by the relationship between tablet porosity and compression pressure. The compactibility of the powders was analyzed by studying the evolution of tablet tensile strength with increasing compaction pressure and porosity. All powders were amorphous and similar in particle size, shape, and surface area. The compressibility of the powders and the microstructure of the formed tablets were equal. However, the compactibility and dispersive surface energy was dependent of the composition of the powders. The decrease in tablet strength correlated to the decrease in powder surface energy at constant tablet porosities. This supports the idea that tablet strength is controlled by formation of intermolecular forces over the areas of contact between the particles and that the strength of these bonding forces is controlled by surface energy which, in turn, can be altered by the presence of surfactants.

Combined synthesis and in situ coating of nanoparticles in the gas phase

Combined gas phase synthesis and coating of sodium chloride (NaCl) and lactose nanoparticles has been developed using an aerosol flow reactor. Nano-sized core particles were produced by the droplet-to-particle method and coated in situ by the physical vapour deposition of L-leucine vapour. The saturation of L-leucine in the reactor determined the resulting particle size and size distribution. In general, particle size increased with the addition of L-leucine and notable narrowing of the core particle size distribution was observed. In addition, homogeneous nucleation of the vapour, i.e. formation of pure L-leucine particles, was observed depending on the saturation conditions of L-leucine as well as the core particle characteristics. The effects of core particle properties, i.e. size and solid-state characteristics, on the coating process were studied by comparing the results for coated NaCl and lactose particles. During deposition, L-leucine formed a uniform coating on the surface of the core particles. The coating stabilised the nanoparticles and prevented the sintering of particles during storage.