Grade Lactose Research Articles

Entrainment of lactose inhalation powders: A study using laser diffraction

We have investigated the mechanism of entrainment of lactose inhalation blends released from a dry powder inhaler using a diffraction particle size analyser (Malvern Spraytec). Whether a powder blend entrains as a constant stream of powder (the “erosion” mechanism) or as a few coarse plugs (the “fracture” mechanism) was found by comparing transmission data with particle size information. This technique was then applied to a lactose grade with 0, 5 and 10 wt% added fine particles. As the wt% fines increased, the entrainment mechanism was found to change from a mild fracture, consisting of multiple small plugs, to more severe fracture with fewer plugs. The most severe fracture mechanism consisted of either the powder reservoir emptying as a single plug, or of the reservoir emptying after a delay of the order of 0.1 s due to the powder sticking to its surroundings. Further to this, three different inhalation grades were compared, and the severity of the fracture was found to be inversely proportional to the flowability of the powder (measured using an annular ring shear tester). By considering the volume of aerosolised fine particles in different blends it was determined that the greater the volume of fines added to a powder, the smaller the fraction of fines that were aerosolised. This was attributed to different behaviour when fines disperse from carrier particles compared with when they disperse from agglomerates of fines. In summary, this paper demonstrates how laser diffraction can provide a more detailed analysis of an inhalation powder than just its size distribution.

Validity of a Power Law Approach to Model Tablet Strength as a Function of Compaction Pressure

Designing quality into dosage forms should not be only based on qualitative or purely heuristic relations. A knowledge space must be generated, in which at least some mechanistic understanding is included. This is of particular interest for critical dosage form parameters like the strength of tablets. In line with this consideration, the scope of the work is to explore the validity range of a theoretically derived power law for the tensile strength of tablets. Different grades of microcrystalline cellulose and lactose, as well as mixtures thereof, were used to compress model tablets. The power law was found to hold true in a low pressure range, which agreed with theoretical expectation. This low pressure range depended on the individual material characteristics, but as a rule of thumb, the tablets having a porosity of more than about 30% or being compressed below 100 MPa were generally well explained by the tensile strength relationship. Tablets at higher densities were less adequately described by the theory that is based on large-scale heterogeneity of the relevant contact points in the compact. Tablets close to the unity density therefore require other theoretical approaches. More research is needed to understand tablet strength in a wider range of compaction pressures.

Characterisation and functionality of inhalation anhydrous lactose

The relationships between the physicochemical properties and functionality in dry powder inhaler (DPI) performance was investigated for inhalation grade anhydrous lactose and compared to monohydrate grades. The excipients were characterised using a range of techniques including particle size analysis, moisture sorption and powder rheometry. The inhalation anhydrous lactose grades were readily characterisable. The aerosolisation performance of capsule based DPI formulations containing budesonide (200 μg) and different grades of lactose evaluated using inertial impaction measurements produced fine particle doses of budesonide ranging from 24 to 49 μg. There were no apparent relationships between aerosolisation performance and excipient characteristics, such as particle size and powder density. However, formulations containing lactose grades which exhibit higher powder fluidisation energy values resulted in higher fine particle doses of budesonide.

Investigation of Electrostatic Properties of Pharmaceutical Powders Using Phase Doppler Anemometry

Electrostatic properties of formulation component materials and blends play an important role in dry powder inhalation (DPI) products. Valid measurement of charge distribution will therefore lead to better control of powder behavior in DPI manufacturing processes. Ultrafine powders are known to have bipolar charge, have nonspherical shapes, and tend to be highly cohesive. Real-time noninvasive techniques need to be developed to obtain a precise and accurate measurement of electrically charged powders, as they aerosolize from a DPI product. How this measure relates to materials behavior throughout the various steps of a manufacturing process, e.g., from drug micronization and blending with lactose to filling dose units, also needs to be addressed. A novel noninvasive technique, which employs the phase Doppler anemometry (PDA) system for simultaneous measurement of size and charge of pharmaceutical powders, is currently being considered. Previous research demonstrated the advantages of this technique in measuring the bipolar charge distribution on a population of liquid aerosols. These findings led to significant improvements in understanding the performance of inhaler formulations, manufacturing processes, and development of new devices for inhaled drug delivery. This paper presents an investigation of electrostatic properties of lactose materials (typically used as a DPI excipient) using the PDA system. PDA calibration was checked using dry polystyrene microspheres, followed by an investigation of different grades of lactose. The PDA technique was used to track the motion of charged particles in the presence of an electric field. The magnitude, as well as the polarity of the particle charge, can be obtained by solving the equation of particle motion combined with the simultaneous measurement of its size and velocity. Results show the capability of the technique to allow real-time charge distribution and size measurement in the control of dry powder attributes that are critical to a better understanding of the manufacturing design space.

Applications of NIR in early stage formulation development. Part II. Content uniformity evaluation of low dose tablets by principal component analysis

A near infrared method based on principal component analysis (PCA) was developed for predicting content uniformity of low dose tablets manufactured by a direct compression process. The work was conducted in early stage formulation development. NIR spectra of one hundred and eighty tablets from three feasibility batches were used as the pseudo-calibration set. A correlation was established between PCA scores and a set of reference values obtained by HPLC analysis. The reference values were also used to define a concentration range for the active pharmaceutical ingredient to facilitate content uniformity prediction by PCA. Analyses of unknown samples were conducted by forming a prediction set that included the calibration and unknown samples, followed by PCA. Samples from two development batches were predicted using the PCA model and the results were consistent with the reference HPLC values. Remarkably, the model was able to predict CU for tablets that were prepared using different grades of lactose (anhydrous versus monohydrate). Additionally, during this study, the impact of spectrum pretreatments on PCA is demonstrated. A brief discussion is given to highlight the advantages of PCA over partial least squares (PLS) regression for analysis of samples generated in early stage formulation development.

The compressibility and compactibility of different types of lactose

Objective: The purpose of this study was to investigate and quantify flow properties, compressibility, and compactibility of various pharmaceutical lactose powders found on the market today (DCL-11, DCL-21, M‐200, Flowlac-100, and Tablettose 70, 80, and 100). Methods: Flow properties were estimated by measuring flow time, angle of repose, and the Hausner ratio. Particle rearrangement was studied using Kawakita's linear model. Compressibility was studied using two ‘out-of-die’ methods: (i) the Heckel model and (ii) a modified Walker model. Compactibility was quantified using two methods: (i) the tensile strength profile (Cp) and (ii) the compactibility factor (Pr). Statistical approach was used to analyze the results. Results: Flow properties of all materials were passable or better, except for M-200, which has very poor flowability. Compressibility results demonstrated that the most compressible lactose is spray-dried grade of lactose (Flowlac-100) and the least compressible is milled lactose (M-200). Compactibility studies showed that β‐lactose (DCL-21) forms tablets with superior tensile strength in comparison with α-lactose. Conclusion: Results of the compressibility study showed that the discriminative power of modified Walker model is greater in comparison with Heckel model. Compactibility methods yield similar and comparable results.

Application of percolation theory in the study of an extended release Verapamil hydrochloride formulation

The percolation theory studies the critical points or percolation thresholds of the system, where one component of the system undergoes a geometrical phase transition, starting to connect the whole system. The objective of the present paper was to study the existence of critical points governing the water and drug transport inside hydroxypropylmethylcellulose (HPMC) hydrophilic matrix systems obtained with different polymer viscosity grades. For this purpose, extended release formulations of Verapamil HCl, have been prepared and studied. The percolation theory has been applied for the first time to multi-component hydrophilic matrices. The materials used to prepare the tablets were Verapamil HCl, four different viscosity grades of HPMC, microcrystalline cellulose, lactose, magnesium stearate and colloidal silicon dioxide NF. In order to estimate the percolation threshold, the behaviour of the kinetic parameters with respect to the volumetric fraction of each component at time zero, was studied. From the point of view of the percolation theory, the optimum concentration for all the studied polymers, to obtain a hydrophilic matrix system for the controlled release of Verapamil HCl is higher than 20% (v/v) HPMC. Above 20% (v/v) HPMC, an infinite cluster of excipient would be formed, ensuring uniform hydration, maintaining integrity of the system and controlling the drug release.

The effect of stability treatmetn on the surface energetics of inhalation grade lactose

The effect of stability treatmetn on the surface energetics of inhalation grade lactose

Back to basics: The development of a simple, homogenous, two‐component dry‐powder inhaler formulation for the delivery of budesonide using miscible vinyl polymers

It was hypothesised that formulating a dry-powder inhaler (DPI) using a refined, smooth grade of lactose, without fines and a polymer coated drug microparticle should produce an homogeneous formulation in which aerosolization behaviour could be modified. Hence, the aim of this study was to develop a simple two component polymer coated-budesonide/lactose blend in which the drug microparticle adhesive forces could be optimised by modifying the drug coating in order to improve aerosolization from a DPI. Budesonide microparticles (1.83 +/- 0.03 microm) were coated with the vinyl polymers by adsorption and then spray-dried. The drug was blended with three different types of lactose, checked for uniformity of mixing and loaded into Pulvinal devices. The median volume particle size of all but one of the polymer coated microparticles remained below 4 microm after spray-drying and the content uniformity for all the blends >96%. Coating the budesonide with 0.01% poly(vinyl alcohol) increased the fine particle fraction (FPF) in the next generation impactor (NGI) from 29.1 +/- 0.7% to 52.8 +/- 1.0% and reduced the force of adhesion from 410 +/- 182 to 241 +/- 82 nN with smooth lactose. This illustrates that vinyl polymers could effectively modify adhesive interactions without the need for ternary components such as fines.

Effect of Storage Conditions on Compaction Behavior of Two Grades of Spray-Dried Lactose

In this work we examine the effect of storage conditions (moisture exposure) on the compression behavior of 2 grades of spray-dried lactose (Pharmatose DCL 11 and Pharmatose DCL 14) under 2 different circumstances. The first was to expose powder samples to moisture, then compress them. The second was to expose precompressed tablets to moisture. We clearly show that the effect of moisture exposure and amorphous content crystallization in spray-dried lactoses on compaction behavior depends on whether this moisture exposure takes place before or after compression. In addition, the impact of storage conditions depends on the grade of spray-dried lactose.

Utility of Multivariate Analysis in Modeling the Effects of Raw Material Properties and Operating Parameters on Granule and Ribbon Properties Prepared in Roller Compaction

This article aimed to model the effects of raw material properties and roller compactor operating parameters (OPs) on the properties of roller compacted ribbons and granules with the aid of principal component analysis (PCA) and partial least squares (PLS) projection. A database of raw material properties was established through extensive physical and mechanical characterization of several microcrystalline cellulose (MCC) and lactose grades and their blends. A design of experiment (DoE) was used for ribbon production. PLS models constructed with only OP-modeled roller compaction (RC) responded poorly. Inclusion of raw material properties markedly improved the goodness of fit (R2 = .897) and model predictability (Q2 = 0.72).

Compounding of vitamin A, D3, E and K3 supplements for cystic fibrosis patients: formulation and stability study

Cystic fibrosis (CF) patients suffer from malabsorption of fat-soluble vitamins (A, D, E and K). These vitamins are available as water-dispersible (A, D(3) and E) or water-soluble grades (K(3)), which is favoured in CF patients as they fail to absorb oil-based products. The objective of this study was to determine stability of these raw materials after opening the original package and to develop a compounded formulation of acceptable quality, stability and taste, allowing flexible dose adaptation and being appropriate for administration to children and elderly people. The raw materials were stored after opening their original package for 8 months at 8 degrees C and room temperature (RT). Stability was assessed using a validated HPLC method after extraction of the vitamin from the cold water-soluble matrix (vitamin A acetate, D(3) and E) or using a spectrophotometrical method (vitamin K(3)). These materials were mixed with an appropriate lactose grade (lactose 80 m for vitamins A and D(3); lactose 90 m for vitamin E, lactose very fine powder for vitamin K(3)) and filled in hard gelatin capsules. Mass and content uniformity were determined and stability of the vitamins in the capsules was assessed after 2 months storage at 8 degrees C and RT. All raw materials showed good stability during storage in the opened original package for 8 months storage at 8 degrees C as well as RT (>95% of the initial content). The compounded formulations complied with the requirements of the European Pharmacopoeia for mass and content uniformity and can be stored for 2 months at 8 degrees C or RT while maintaining the vitamin content between 90% and 110%. As these fat-soluble vitamins are not commercially available on the Belgian market, compounded formulations are a valuable alternative for prophylactic administration of these vitamins to CF patients, i.e. a stable formulation, having an acceptable taste, allowing flexible dose adaptation and being appropriate for administration to children and elderly people.

Rapid lactose recovery from buffalo whey by use of ‘anti-solvent, ethanol’

In the present study the heat-induced partially deproteinated (0.1–0.2% w/v of residual protein after deproteination step) paneer whey (that resembles cottage cheese whey), originated from buffalo milk (containing 3.85–4.95% w/v of lactose) was tried for possible rapid lactose recovery, using ‘anti-solvent’ (ethanol). Optimization of various process parameters such as effective ethanol concentration (65–85% v/v), pH, temperature, seeding, etc. was carried out. On optimization of the process, the lactose recovery of more than 90% and the purity of 97–99% was obtained from paneer whey in 1 h of stirring time, at an effective ethanol concentration of 85% v/v. The ‘roundness’ (shape factor) and ‘elongation’ (aspect ratio) values of the lactose crystals recovered in the present study were found to be comparable to that of commercial analytical grade lactose sample. The crystallization kinetics has been also studied of the lactose recovery using anti-solvent ‘ethanol’ based recovery process.

Chargeability measurements of selected pharmaceutical dry powders to assess their electrostatic charge control capabilities

The purpose of this study was to develop an instrument (the Purdue instrument) and the corresponding methodologies to measure the electrostatic charge development (chargeability) of dry powders when they are in dynamic contact with stainless steel surfaces. The system used an inductive noncontact sensor located inside an aluminum Faraday cage and was optimized to measure the charging capabilities of a fixed volume of powder (0.5 cc). The chargeability of 5,5-diphenyl-hydantoin, calcium sulfate dihydrate, cimetidine, 3 grades of colloidal silicon dioxide, magnesium stearate, 4 grades of microcrystalline cellulose, salicylic acid, sodium carbonate, sodium salicylate, spray-dried lactose, and sulfinpyrazone were tested at 4 linear velocities, and the particle size distribution effect was assessed for 3 different grades of colloidal silicon dioxide and 4 different grades of microcrystalline cellulose. The chargeability values exhibited a linear relationship for the range of velocities studied, with colloidal silicon dioxide exhibiting the maximum negative chargeability and with spray-dried lactose being the only compound to exhibit positive chargeability. The instrument sensitivity was improved by a factor of 2 over the first generation version, and the electrostatic charge measurements were reproducible with relative standard deviations ranging from nondetectable to 33.7% (minimum of 3 replicates). These results demonstrate the feasibility of using the Purdue instrument to measure the electrostatic charge control capabilities of pharmaceutical dry powders with a reasonable level of precision.

Crystallisation kinetics of lactose in the presence of lactose phosphate

Pharmaceutical grade lactose, the purest form of lactose commercially available, is usually contaminated with traces of lactose phosphate (LP), a component of whey, the by-product of cheese manufacturing. This work presents a study of the effects of LP addition on the kinetics of lactose crystal growth during isothermal and cooling seeded-batch crystallisations. The effect of LP is also compared with riboflavin, glucose-6-phosphate and potassium chloride, three other possible contaminants. Two techniques were used to define the growth rate constant ( k g) of a power law function describing the crystallisation kinetics of ultra-pure lactose. At 30 °C, the value of k g decreased with increasing LP concentration, following a linear Langmuir adsorption isotherm up to 60 mg LP per kg dissolved lactose (ppm). The particle size distribution was affected for up to 8 h and a proportion of crystals had their shape modified by the presence of LP. Chemical analysis of the final lactose showed that LP was integrated within the crystals. Riboflavin produced changes comparable to LP for growth and size distribution while the other two compounds showed smaller effects. The results for isothermal crystallisations with LP addition were confirmed in the controlled cooling operation.

Drug/lactose co-micronization by jet milling to improve aerosolization properties of a powder for inhalation

The aim of this work was to formulate a powder for inhalation with fusafungine, a drug substance initially highly cohesive. The classical approach based on micronization by jet milling to prepare respirable drug particles and then blending with a carrier was first applied. A fractional factorial experimental design was implemented to screen six formulation parameters. The effect of drug/lactose co-micronization on aerosolization was then evaluated. In vitro deposition studies were performed with the twin stage glass impinger and the inhaler Spinhaler ®. Micronization did not induce DSC-detectable amorphization and gave a highly cohesive, poor flowable powder with a theoretical aerodynamic diameter of 5 μm. The powder was then blended with coarse lactose and optionally fine lactose. Unfortunately, the respirable fraction could not be optimized and remained below 10%. On the other hand, a co-micronized powder drug/fine lactose 50:50 gave a respirable fraction of 16%. Following blending with a carrier, the respirable fraction and the emitted dose fraction reached 23% and 69%, respectively. The use of a fine lactose grade for co-micronization was essential. In conclusion, this study demonstrated that co-micronization with a fine lactose is an efficient and simple strategy to formulate a powder for inhalation with enhanced aerosolization properties, especially for highly cohesive drug substance.

Method to Evaluate the Dustiness of Pharmaceutical Powders

The trend among pharmaceutical companies to develop selective drugs of high potency has pushed the industry to consider the potential of each hazardous ingredient to become airborne. Dustiness issues are not unique to the pharmaceutical industry, but are relevant to any industry where powdered materials are mixed, transferred and handled. Interest in dustiness is also driven by concerns for worker health, the potential for plant explosions and the prevention of product loss. Unlike other industries, the pharmaceutical industry is limited by the milligram quantity of powdered material available for testing during product development. These needs have led to the development of a bench-top dustiness tester that requires only 10 mg of powder and fully contains the generated aerosol. The powder is dispersed within a 5.7 liter glass chamber that contains a respirable mass sampler and a closed-face sampler to quantify the respirable and total dust that are generated with a given energy input. The tester distinguished differences in dustiness levels of five different powders. Finer powders were dustier, and the respirable dust percentage was always less than that for total dust. Four testers have been built and evaluated using pharmaceutical grade lactose. Dustiness measurements determined using all four testers were comparable. The pharmaceutical industry uses surrogates such as lactose to represent active compounds in tests that estimate the dust concentration likely to occur in a new manufacturing operation. Differences between the dustiness of the active compound and its surrogate challenge the relevance of the surrogate tests to represent true exposures in the workplace. The tester can determine the dustiness of both the active compound and its surrogate, and the resultant ratio can help to interpret dust concentrations from surrogate tests. Further, dustiness information may allow the pharmaceutical researcher to select powder formulations that present low airborne concentrations in the workplace.

Bulk Characterization of Pharmaceutical Powders by Low-Pressure Compression II: Effect of Method Settings and Particle Size

The aim of the present study was to investigate the effect of punch and die diameter, sample size, compression speed, and particle size on two low-pressure compression-derived parameters; the compressed density and the Walker w parameter. The excellent repeatability of the low-pressure compression method allowed small effects of variations in punch and die diameter and sample size to be demonstrated on a high significance level. Changing the compression speed, however, did not cause a significant effect in the compressed density, whereas a decrease in w was seen. The effect of particle size was studied by compressing and tapping different grades of calcium carbonate, lactose, and microcrystalline cellulose. The low-pressure compression-derived parameters were compared to tapped densities and to Compressibility Indexes obtained by tapping volumetry. Even though the relationship between particle size and the low-pressure compression-derived parameters appeared to be more complicated, a similar trend was observed. It was concluded that the low-pressure compression method provides a useful alternative to the more sample-consuming methods providing flow-related information.

The Nitrogen Adsorption Isotherm of Alpha-lactose Monohydrate

A complete nitrogen adsorption isotherm was measured for α-lactose monohydrate, from 0.001 to 0.995 relative pressure at 77 K. The isotherm was qualitatively classified as Type II, and was quantitatively analyzed for surface area, porosity, and surface heterogeneity. Surface area results revealed that the normal Brunauer Emmett Teller (BET) range of 0.05–0.35 relative pressure was not suitable for this grade of lactose, but having full isotherm data enabled a more appropriate analytical range to be found, illustrating the importance of measuring the entire isotherm as an essential step in method development. The isotherm was analyzed for micro and mesoporosity, both of which were found to be insignificant for lactose. The low relative pressure range 0.001–0.005 did not obey Henry's law, indicating the presence of surface heterogeneity. Density functional theory was exploited to quantitatively measure heterogeneity in the surface energy of lactose, using the full nitrogen adsorption profile. As expected for a crystalline material with multiple faces and likely presence of imperfections on the surface, the surface energy distribution function was broad with more than one mode.

Effect of milling and sieving on functionality of dry powder inhalation products

α-Lactose monohydrate is the standard excipient used as diluent or carrier in dry powder inhaler (DPI) formulations. Earlier studies have already revealed that raw materials for the production of inhalation grade lactose have to be carefully selected in order to avoid batch-to-batch variability. In the present study, the effect of milling and milling intensity on the flow properties and the physico-chemical characteristics of lactose crystals has been determined. The milled lactoses were then further processed by sieving to give lactose qualities with identical size distribution data, but different batch history (non-milled and milled at different conditions). These were then used to manufacture low concentration (0.25%) drug blends with the model drugs salbutamol sulphate (SBS) and beclometasonedipropionate (BDP); the blends were analysed with a Multistage Liquid Impinger (MLI) after delivery from an Easyhaler ® and an Aerolizer ® device. It could be shown that gentle milling already results in surface defects on the lactose crystal which are further enhanced by using a higher milling intensity. Produced fine lactose particles during the milling process strongly adhere to the lactose surface and cannot be removed by compressed air which is used for the particle sizing. By trend, a higher milling intensity resulted in higher fine particle fractions (FPF) with both devices. Also, SBS was found to generally give higher fine particle fractions than BDP, independent from the device used. In conclusion, lactose pre-treatment by gentle or strong milling affects the carrier surface and thereby the aerosolization properties of drug/lactose blends produced.