Lactose Particle Size Research Articles

The effect of excipient particle size on the reduction of compactibility after roller compaction

Developing a robust roller compaction process can be challenging, due to the diversity in process parameters and material properties of the components in a formulation. A major challenge in dry granulation is the reduction of tablet strength as a result of re-compaction of the materials. The aim of this study is to investigate the impact of excipient type and particle size distribution on tablet tensile strength after roller compaction. Lactose monohydrate, anhydrous lactose and microcrystalline cellulose with different particle sizes are roller compacted at varying specific compaction forces. Granules obtained are compressed into tablets to evaluate the reduction in tablet strength upon increasing the specific compaction force. The impact of particle size of the starting material is shown to be vastly different for the three types of excipients investigated, due to the differences in mechanical deformation mechanisms. The presence of rough surfaces and a high degree of fragmentation for anhydrous lactose appears to be beneficial for compaction and re-compaction process. Additionally, the particle size of anhydrous lactose hardly affects the tensile strength of tablets, which can be beneficial for the robustness of a roller compaction process.

ВПЛИВ РОЗЧИННИХ НАПОВНЮВАЧІВ ІЗ РІЗНИМ РОЗМІРОМ ЧАСТОК НА КІНЕТИКУ ВИВІЛЬНЕННЯ ТРИМЕТАЗИДИНУ ДИГІДРОХЛОРИДУ IN VITRO З МАТРИЧНИХ ТАБЛЕТОК

<p><strong>EFFECT OF SOLUBLE DILUENTS WITH DIFFERENT PARTICLE SIZE ON DISSOLUTION PROFILE OF TRIMETAZIDINE DIHYDROCHLORIDE FROM MATRIX TABLETS</strong></p><p><strong>V. V. Mohylyuk, L. L. Davtian </strong></p><p>ShupykNationalMedicalAcademyof Postgraduate Education, Kyiv</p><p><strong>Summary: </strong>The effect of soluble diluent lactose monohydrate and sorbitol with average particle size 11, 17, 251 and 110, 299, 531 µm, respectively, on dissolution profile of trimetazidine dihydrochloride model substance from matrix tablets with insoluble and unswellable Ethocel 10, insoluble and swellable Kollidon SR, soluble and swellable Methocel K4M as matrix formers was investigated. The effect of soluble diluents particle size on drug release from matrix tablets with different matrix formers was established and explained.<strong></strong></p><p><strong>Key words: </strong>matrix tablet, Ethocel, Kollidon SR, Methocel K, sorbitol, lactose.</p><p><strong>Introduction. </strong>Oral matrix tablets are the modern dosage forms using which could be achieved desirable in vitro release kinetics of active pharmaceutical ingredient (API) and correspondent in vivo concentration level. That’s why the study of factors that affect in vitro dissolution release of API is an actual task and the effect of diluents particle size is one of these factors. There are two main types of matrix systems with different mechanism of soluble components release: with soluble matrix former that is forming the gel layer on the surface of matrix and with insoluble matrix former. The aim of this study is to investigate the effect of diluent’s particle size on dissolution profile of trimetazidine dihydrochloride from matrix tablets with insoluble and unswellable Ethocel 10, insoluble and swellable Kollidon SR, soluble and swellable Methocel K4M as matrix formers.</p><p><strong>Methods.</strong> Particle size distribution measurement by the laser scattering method, tablet manufacturing using direct compression method for more predictable tablet structure, dissolution test and matrix tablets structure evaluation by optical microscopy were used for experiment.</p><p><strong>Results and discussion.</strong> On a more detailed level tablet components form clusters. These clusters have a specific structure that is depending on the number, size, shape, volume ratio of the components and the method of tablets manufacture. Soluble sorbitol and less soluble lactose monohydrate were used for experiment. The drug release from Ethocel 10 matrix was decreased with diluents particle size increasing. The drug release from Kollidon SR matrix was decreased with soluble diluents particle size increasing from 17 to 110 µm and follow particle size increasing from 110 to 513 µm almost hadn’t affect. Diluents particle size almost hadn’t effect on drag release from Methocel K4M matrix tablets too. The effect of diluents particle size increasing on release from insoluble unswellable Ethocel 10 and insoluble swellable Kollidon SR matrices could be explained from position of percolation theory by more isolated clusters formation and porosity decreasing. The almost absence of diluents particle size effect on drug release from soluble swellable Methocel K4M matrix could be explained by diffusion mechanism predominance. The release of trimetazidine dihydrochloride (340 g/ml) from Ethocel 10, Kollidon SR and Methocel K4M matrix tablets was faster when used sorbitol (>4000 g/ml) than lactose monohydrate (210 g/ml). This result is consistent with the higher solubility of sorbitol in comparison with lactose monohydrate.</p><p><strong>Conclusions.</strong> Decreasing of trimetazidine dihydrochloride dissolution kinetics from Ethocel 10 matrix tablets with lactose and sorbitol particle size increasing was established. The dissolution kinetics from Kollidon SR matrix tablets was decreased with soluble diluent particle size increasing from 17 to 110 µm, but sorbitol particle size increasing from 110 to 513 µm had no effect on dissolution profile. Particle size of soluble diluents had no significant effect on dissolution kinetics from Methocel K4M matrix tablets. The dissolution kinetics from tablets with Ethocel 10, Kollidon SR and Methocel K4 as matrix formers was decreased with diluent solubility decreasing.</p>

Novel coprocessed excipients composed of lactose, HPMC, and PVPP for tableting and its application

New coprocessed excipients composed of α-lactose monohydrate (a filler), HPMC E3 (a binder), and PVPP (a superdisintegrant) were developed by spray drying in this study to improve the tableting properties of lactose. Factors affecting the properties of the coprocessed excipients were investigated by a 3×3×2 factorial design. These factors include lactose grade (90M, 200M, and 450M), percentage of HPMC (3.5%, 7.0%, and 10.5%), and percentage of PVPP (0% and 3.5%). The results show that the compactability of the excipients could be significantly improved by increasing either the percentage of HPMC or the primary particle size of lactose. The addition of 3.5% PVPP had little effect on the compactability, but significantly improved the disintegration ability. The developed coprocessed excipients have much lower yield pressures and much higher working efficiency during tableting compared to the main raw material (α-lactose monohydrate). These improvements are mainly attributed to the addition of HPMC and the proximately 30% amorphous lactose formed during process. Both HPMC and amorphous lactose were homogeneously distributed on the surface of the secondary particles, maximizing their effect. Furthermore, the low hygroscopicity and high glass transition temperature of HPMC led to a high yield. The drug loading capacity of the newly coprocessed excipients is also excellent. In summary, the tri-component coprocessed excipients investigated are promising and worthy of further development.

A mechanistic investigation on the utilization of lactose as a protective agent for multi-unit pellet systems

The effect of lactose particle size on the extent of pellet coat damage was investigated. The extent of pellet coat damage increased linearly with lactose median particle size. It was observed that coated pellets compressed with coarser lactose grades had larger and deeper surface indentations. The surfaces of the pellets compressed with coarser lactose grades were also found to be significantly rougher. Micronized lactose was capable of protecting pellet coats from damage brought about by the presence of coarser lactose particles. The findings suggested a protective effect that micronized lactose conferred to pellet coats was not only through dimensional delimitations but also by higher interparticulate friction and longer particle rearrangement phase. As a result, the pellet volume fraction in the system was reduced. The extent of pellet coat damage was found to escalate when the pellet volume fraction in such system increased beyond a critical value of 0.39.

Effects and Detection of Raw Material Variability on the Performance of Near-Infrared Calibration Models for Pharmaceutical Products

The impact of raw material variability on the prediction ability of a near-infrared calibration model was studied. Calibrations, developed from a quaternary mixture design comprising theophylline anhydrous, lactose monohydrate, microcrystalline cellulose, and soluble starch, were challenged by intentional variation of raw material properties. A design with two theophylline physical forms, three lactose particle sizes, and two starch manufacturers was created to test model robustness. Further challenges to the models were accomplished through environmental conditions. Along with full-spectrum partial least squares (PLS) modeling, variable selection by dynamic backward PLS and genetic algorithms was utilized in an effort to mitigate the effects of raw material variability. In addition to evaluating models based on their prediction statistics, prediction residuals were analyzed by analyses of variance and model diagnostics (Hotelling's T(2) and Q residuals). Full-spectrum models were significantly affected by lactose particle size. Models developed by selecting variables gave lower prediction errors and proved to be a good approach to limit the effect of changing raw material characteristics. Hotelling's T(2) and Q residuals provided valuable information that was not detectable when studying only prediction trends. Diagnostic statistics were demonstrated to be critical in the appropriate interpretation of the prediction of quality parameters.

Influence of starting material particle size on pellet surface roughness.

The purpose of this study was to investigate the effect of pelletization aids, i.e., microcrystalline cellulose (MCC) and cross-linked polyvinyl pyrrolidone (XPVP), and filler, i.e., lactose, particle size on the surface roughness of pellets. Pellets were prepared from powder blends containing pelletization aid/lactose in 1:3 ratio by extrusion-spheronization. Surface roughness of pellets was assessed quantitatively and qualitatively using optical interferometry and scanning electron microscopy, respectively. Both quantitative and qualitative surface studies showed that surface roughness of pellets depended on the particle size of XPVP and lactose used in the formulation. Increase in XPVP or lactose particle size resulted in rougher pellets. Formulations containing MCC produced pellets with smoother surfaces than those containing XPVP. Furthermore, surface roughness of the resultant pellets did not appear to depend on MCC particle size. Starting material particle size was found to be a critical factor for determining the surface roughness of pellets produced by extrusion-spheronization. Smaller particles can pack well with lower peaks and valleys, resulting in pellets with smoother surfaces. Similar surface roughness of pellets containing different MCC grades could be due to the deaggregation of MCC particles into smaller subunits with more or less similar sizes during wet processing. Hence, for starting materials that deaggregate during the wet processing, pellet surface roughness is influenced by the particle size of the material upon deaggregation.

The effect of lactose micro-spherical crystals prepared by conditioning with supercritical fluid on salbutamol sulphate inhalation performance

In this study, lactose crystalline powder was produced to improve its stability. The effect of micronised crystalline lactose on a dry powder inhalation formulation was investigated. Supercritical carbon dioxide (scCO2) modified with menthol was used for the conditioning of spray-dried amorphous lactose and salbutamol sulphate to generate micro-spherical crystalline powders. The optimum processing conditions, which include: menthol concentration, temperature and processing time, were determined by experimental design to produce crystalline and a desired particle size. The average particle size of spray-dried amorphous lactose decreased from 8.15±0.28μm to 7.60±0.10μm after conditioning with modified CO2 at 150bar and 50°C for a period of 5h. The SEM results shows that these particles kept their micro-spherical shape, however, the particle surface became rough due to crystallisation. This particle size reduction was most likely due to increasing surface roughness, which decreased agglomeration between particles. The blend of this fine powder and coarse crystalline lactose enhanced salbutamol sulphate inhalation performance. The emitted fine particle fraction of salbutamol sulphate was enhanced to 40±0.3% compare to the samples that contained only coarse lactose (38.2±0.6%) or conditioned lactose (24.6±0.4%).

Influence of particle size on the direct compression of ibuprofen and its binary mixtures

In this paper, ibuprofen from a commercial source and its fractioned samples with narrower size distribution were characterized to assess the effect of particle properties on compaction characteristics. The compaction behavior of binary mixtures of ibuprofen with spray-dried lactose was also studied. The tablet in-die densification rate and tablet out-of-die porosity and tensile strength were measured for all samples. It was found that the particle size of ibuprofen does not affect the yield stress as derived from a Heckel plot, however the yield stress increases with the increase of ibuprofen particle size in the binary mixtures. Particle size also affects the tablet out-of-die properties, with tablet porosity and tensile strength increasing with the decrease in particle size. The effect of adding a weak compacting powder such as lactose on the tablet tensile strength is very much dependent on the ibuprofen particle size and mass ratio of the binary mixtures. Mixing lactose with ibuprofen of similar size in equal mass has no effect on the tensile strength of the tablet whereas mixing it with ibuprofen of larger size reduces the strength compared to ibuprofen alone. Adding a smaller amount of lactose can lead to an increase in tablet strength, even though the particle size of ibuprofen and lactose is quite different. Theoretical analysis on the tablet strength based on particle–particle bond strength was also carried out to explain the experimental results.

Exploring the effects of high shear blending on lactose and drug using fluidised bed elutriation

Powder formulations comprising inhalation grade lactose and a mimic drug (cholesterol) were prepared using a high shear blending process for which the total energy input could be quantified. The formulations were fluidised in a classic fluidised bed system, to determine whether blending-induced changes could be determined through either bulk fluidisation behaviour or the characteristics of elutriated fractions from the powder beds. The evolution of the fluidisation regime within the powder beds (Δ pressure vs. superficial gas velocity) and total mass of elutriated material were not sensitive measures to differentiate between blended and unblended samples. However, blended and unblended material could be distinguished by the size distributions of the elutriated fractions. The study also showed that there were no further changes in the size distribution of the elutriated fractions once a chemically homogenous mixture of lactose and drug had been produced. However, further blending beyond this ‘point of homogeneity’ continued to change the lactose particle size distribution of the bulk powder; this may have implications for blend end point determination for these types of formulation.

Foam granulation: Effects of formulation and process conditions on granule size distributions

The use of foam to achieve granulation is a new development in wet granulation processes. This paper studies foam granulation by investigating the impact of formulation and granulation process conditions on the granule size distribution in a high shear mixer-granulator. Experimental studies were performed in a high shear mixer-granulator on a lactose and microcrystalline cellulose (PH-101) formulation. The granule size distributions were determined as a function of foam quality (83% or 91%), primary powder particle size (75 μm or 150 μm), HPMC binder concentration (4% or 8%), liquid to solid ratio (20–60%), and impeller rotational speed (295 rpm or 515 rpm). The results showed that decreasing foam quality, or increasing the lactose particle size, liquid binder concentration or liquid to solid ratio increase the average granule size, but the effect is interconnected with impeller speed. Transformation maps were proposed to explain the changes in granule size distribution in response to changes of the studied parameters on the basis of wetting and nucleation mechanisms for foam granulation process.

Examining the Impact of Excipient Material Property Variation on Drug Product Quality Attributes: A Quality-By-Design Study for a Roller Compacted, Immediate Release Tablet

A quality-by-design study examining the impact of variability in excipient material properties on the quality attributes of an immediate release tablet was performed. A literature review and risk analysis identified particle size of microcrystalline cellulose (MCC), spray-dried lactose (SDL), and magnesium stearate (MgSt), and polymorph and specific surface area of MgSt as potential high-risk material properties. The following results were obtained with laboratory-scale processing equipment: (1) a 32-µm increase in d(50) (mean particle diameter) of MCC and SDL led to a ∼ 30-µm increase in blend and granulation d(50) and a statistically significant increase in the blend and granulation flow function coefficients, and (2) a 32-µm increase in d(50) of MCC and SDL, a 4.4 m(2)/g increase in the surface area, and a 19-µm decrease in the particle size of MgSt yielded an 18%-28% increase in ribbon tensile strength and tablet hardness. Confirmatory experiments with kilo-scale equipment showed impact of excipient variability on granulation particle size and tablet hardness was ∼ 50% smaller. Although the impact of these differences on overall manufacturability and performance of the tablets examined here were deemed low, the presence of statistically significant effects supports examining excipient variability as part of the design and control strategy of new drug products.

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.

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.

Granule Characterization During Fluid Bed Drying by Development of a Near Infrared Method to Determine Water Content and Median Granule Size

Water content and granule size are recognized as critical process and product quality parameters during drying. The purpose of this study was to enlighten the granule behavior during fluid bed drying by monitoring the major events i.e. changes in water content and granule size. NIR spectra collected during drying and water content of sampled granules were correlated by principal component analysis (PCA) and partial least squares regression (PLSR). NIR spectra of dried granules were correlated to median granule size in a second PCA and PLSR. The NIR water model discriminates between various stages in fluid-bed drying. The water content can be continuously predicted with errors comparable to the reference method. The four PLS factors of the granule size model are related to primary particle size of lactose, median granule size exceeding primary particle size and amorphous content of granules. The small prediction errors enable size discrimination between fines and granules. For product quality reasons, discrimination between drying stages and end-point monitoring is highly important. Together with the possibilities to determine median granule size and to distinguish fines this approach provides a tool to design an optimal drying process.

Agglomerate Strength and Dispersion of Salmeterol Xinafoate from Powder Mixtures for Inhalation

The study investigated the role of agglomeration and the effect of fine lactose size on the dispersion of salmeterol xinafoate (SX) from SX-lactose mixtures for inhalation. Particle size distributions were characterised by Malvern Mastersizer S, Aerosizer and Spraytec, and imaging conducted by scanning electron microscopy (SEM). Inter-particulate adhesion was quantified by atomic force microscopy. Deposition of SX was measured using a twin stage impinger. SX was analysed using validated high-performance liquid chromatography method (r(2)=1.0, CV=0.4-1.0%). Addition of fine lactose with a volume median diameter (VMD) of 7.9 microm to a SX-lactose carrier and carrier-free mixture resulted in significantly better dispersion (16.8% for 20% added fine lactose) than fractions with VMD of 3.0, 17.7 and 33.3 microm (less than 9.1% for 20% fine lactose). Using the carrier-free mixtures, particle sizing of the aerosol cloud using the Spraytec, coupled with the application of the Aerosizer using differing dispersion energies and SEMs of the samples, indicated that an open packed, agglomerate structure improved SX dispersion. The highest extent of SX dispersion occurred when SX and fine lactose were detached from the surface, usually in the form of loose agglomerates. The outcomes of this research demonstrated how agglomerate structure influenced dispersion and the key role of fine lactose particle size in SX dispersion from mixtures for inhalation.

Direct pelletization in a rotary processor controlled by torque measurements. III. Investigation of microcrystalline cellulose and lactose grade

The aim of the present study was to investigate the use of different grades of microcrystalline cellulose (MCC) and lactose in a direct pelletization process in a rotary processor. For this purpose, a mixed 2- and 3-level factorial study was performed to determine the influence of the particle size of microcrystalline cellulose (MCC) (approximately 60 and 105 microm) and lactose (approximately 30, 40, and 55 microm), as well as MCC type (Avicel and Emcocel) on the pelletization process and the physical properties of the prepared pellets. A 1:4 mixture of MCC and lactose was applied, and granulation liquid was added until a 0.45 Nm increase in the torque of the friction plate was reached. All combinations of the 3 factors resulted in spherical pellets of a high physical strength. The particle size of MCC was found to have no marked effect on the amount of water required for agglomerate growth or on the size of the resulting pellets. An increasing particle size of lactose gave rise to more spherical pellets of a more narrow size distribution as well as higher yields. The MCC type was found to affect both the release of the model drug from the prepared pellets and the size distribution. Generally, the determined influence of the investigated factors was small, and direct pelletization in a rotary processor was found to be a robust process, insensitive to variations in the particle size and type of MCC and the particle size of lactose.

Effect of starting material particle size on its agglomeration behavior in high shear wet granulation

The effect of anhydrous lactose particle size distribution on its performance in the wet granulation process was evaluated. Three grades of anhydrous lactose were used in the study: "as is" manufacturer grade and 2 particle size fractions obtained by screening of the 60M lactose. Particle growth behavior of the 3 lactose grades was evaluated in a high shear mixer. Compactibility and porosity of the resulting granules were also evaluated. A uniaxial compression test on moist agglomerates of the 3 lactose grades was performed in an attempt to explain the mechanism of particle size effect observed in the high shear mixer. Particle growth of anhydrous lactose in the high shear mixer was inversely related to the particle size of the starting material. In addition, granulation manufactured using the grade with the smallest particle size was more porous and demonstrated enhanced compactibility compared with the other grades. Compacts with similar porosity and low liquid saturation demonstrated brittle behavior and their breakage strength was inversely related to lactose particle size in the uniaxial compression test, suggesting that material with smaller particle size may exhibit more pronounced nucleation behavior during wet granulation. On the other hand, compacts prepared at higher liquid saturation and similar compression force exhibited more plastic behavior and showed lower yield stress for the grade with smallest particle size. The lower yield stress of compacts prepared with this grade may indicate a higher coalescence tendency for its granules during wet granulation.

Single-step granulation/tabletting of different grades of lactose: a comparison with high shear granulation and compression

The influence of the particle size, particle morphology and crystallinity of lactose on the extrusion properties and on the quality of tablets were investigated using single-step granulation/tabletting as a tabletting technique. Results showed that particle size and type of lactose (α-lactose monohydrate, anhydrous β-lactose and spray dried lactose) affected the powder feeding, the process performance as well as the process capacity. Different grades of lactose yielded tablets with similar tensile strength, but significantly different disintegration time. Single-step granulation/tabletting always yielded tablets with a significantly higher tensile strength and similar or significantly lower disintegration time compared to high shear granulation and compression. The tensile strength of α-lactose monohydrate tablets (without and with PVP) did not change during one year of storage at 60% RH-25 °C and at 75% RH-40 °C, whereas a significant increase in disintegration time was observed. It can be concluded that although the lactose grade affected the performance and the optimal parameters of single-step granulation/tabletting, all lactose grades can be efficiently processed using this technique.

Granule breakage phenomena in a high shear mixer; influence of process and formulation variables and consequences on granule homogeneity

Wet granulation is a process intended for size enlargement. A logical consequence is that many studies are focused on granule growth. However, next to built-up of granules granule breakage also occurs. The aim of this study is to investigate the wet granule breakage process in a high shear mixer. For that purpose, tracer experiments were conducted to investigate the influence of the particle size of lactose and the viscosity of the hydroxypropylcellulose (HPC) solution on the granule breakage. The relationship between granule breakage behaviour and granule homogeneity was also investigated. A model to predict granule breakage, based on the ratio of the impact energy and the dynamic granule strength, was proposed. The tracer experiments showed that an increase in viscosity and a decrease in particle size eventually lead to a transition from breakage to no-breakage behaviour of the granules. The model predicts similar influences of these parameters on the breakage behaviour and showed a clear relationship with the experimental data. Moreover, an interrelationship between granule breakage and homogeneity was found. The dynamic situation of granule breakage was associated with a continuous exchange of particles, which resulted in homogeneous granules. When granule breakage was absent granules remain intact and the preferential layering of the smallest particles yielded inhomogeneous granules.

Binderless granulation of pharmaceutical fine powders with coarse lactose for dry powder inhalation

With the Pressure Swing Granulation (PSG), a fluidized bed binderless granulation method, jet-milled fine model drug powders of roughly 2 μm in diameter were mixed with lactose and successfully agglomerated into spherical soft granules to demonstrate that PSG is an effective granulation method for dry powder inhalation. The effects of both lactose particle size, which is supposed to be of either carriers or excipients for inhalants, and granule formulations on the product properties and their dispersion characteristics were investigated. To strengthen the granule-forming tendency without decreasing the carrier particle size, lactose particles' surface morphology was modified before granulation in a ball-milling pot with balls having their lowest milling size larger than the lactose particle size. By this modification, lactose particles of about 8.8 μm in mean diameter were successfully agglomerated without binders over the full range of mixing ratio with the model drug particles. An excellent dispersion property for inhalation was obtained with the PSG granules produced from the surface modified lactose and the PSG method is expected to add a new freedom in producing dry powder for inhalation.