ABSTRACT
The aim of this study was to investigate how the propensity for aerosolisation in binary adhesive mixtures was affected by the drug load, and to determine whether these findings could be linked to different blend states. Binary blends of two different lactose carriers, each with varying size and morphology, were prepared together with budesonide. In vitro aerosolisation studies were conducted at four different pressure drops, ranging from 0.5 to 4 kPa, utilising a Next Generation Impactor. Several dispersion parameters were derived from the relationship between the quantity of dispersed API and the pressure drop. The evolution of the parameters with drug load was complex, especially at low drug loads. While similar responses were observed for both carriers, the range of drug load that could be used varied significantly. The choice of carrier not only influenced the capacity for drug loading but also affected the spatial distribution of the API within the mixture, which, in turn, affected its aerosolisation propensity. Thus, the drug dispersion process could be linked to different configurations of the lactose carrier and budesonide in the blends, i.e. blend states. In conclusion, the study suggests that the concept of blend states can provide an explanation for the complex dispersion process observed in adhesive blends.
Subject(s)
Adhesives , Aerosols , Budesonide , Drug Carriers , Lactose , Budesonide/chemistry , Budesonide/administration & dosage , Lactose/chemistry , Administration, Inhalation , Adhesives/chemistry , Drug Carriers/chemistry , Particle Size , Chemistry, Pharmaceutical/methodsABSTRACT
This study aimed to evaluate a material sparing method to predict tabletability and compactibility relationships. Seven α-lactose monohydrate powders with varying particle size were used as test materials. The compressibility of the powders was determined experimentally, whereas tabletability and compactibility profiles were derived both experimentally and predicted. In the prediction method, two experimental compression parameters (Kawakita b-1 and Heckel plastic stiffness) and a single tensile strength reference value were used, all necessary data obtained from a single compression experiment. For both predicted and experimental relationships, compaction and tableting parameters (performance indicators) were calculated. The correction for viscoelastic recovery was successful in generating compressibility profiles that corresponded to the series of experimental out-of-die tablet porosities. For both the tabletability and compactibility, the experimental and predicted profiles showed a high degree of similarity. Good correlations were obtained between the predicted and experimental compaction and tableting parameters. It is concluded that the hybrid prediction method is a material sparing method, which can give good approximations of tabletability and compactibility relationships. The prediction method has the potential to be included as a part of a protocol for the characterisation of the tableting performance of particulate solids.
Subject(s)
Lactose , Powders , Particle Size , Tensile Strength , Porosity , Tablets , Drug CompoundingABSTRACT
The aim of this study was to determine the thickness of the hydrodynamic diffusion layer (hHDL) of three poor water-soluble compounds under laminar fluid flow using a single particle dissolution technique. The single particle dissolution experiments were performed in a flowing aqueous medium using four different fluid velocities (v), ranging from 46 to 103 mm/s. The particles used had an initial radius (r) of 18.8 to 52.3 µm. The determined hHDL values were calculated from both dissolution experiments and computational fluid dynamics (CFD) simulation. In this study, single particle dissolution experiments gave, with one exception, hHDL values in the range of 2.09 to 8.85 µm and corresponding simulations gave hHDL values in the range of 2.53 to 4.38 µm. Hence, we found a semi-quantitative concordance between experimental and simulated determined hHDL values. Also, a theoretical relation between the dependence of hHDL on particle radius and flow velocity of the medium was established by a series of CFD simulations in a fluid velocity range of 10-100 mm/s and particle size (radius) range of 5-40 µm. The outcome suggests a power law relation of the form hHDLâr3/5v-2/5. In addition, the hHDL seems to be independent of the solubility, while it has a diffusion coefficient dependence. In conclusion, the hHDL values were determined under well-defined conditions; hence, this approach can be used to estimate the hHDL under different conditions to increase the understanding of the mass transfer mechanisms during the dissolution process.
Subject(s)
Diffusion , Hydrodynamics , Computer Simulation , Particle Size , SolubilityABSTRACT
OBJECTIVE: The aim of this study was to evaluate the effect of a novel, oral, modified-release formulation of the lipase inhibitor orlistat and the glucosidase/amylase inhibitor acarbose (denoted EMP16) on relative body weight after 26 weeks compared with placebo. METHODS: The randomized, double-blind, placebo-controlled trial had a 26-week treatment period, with dose escalation up to 6 weeks. Participants, adults between ages 18 and 75 years, with BMI ≥30 kg/m2 or ≥28 kg/m2 with risk factors, were randomly assigned to EMP16 120-mg orlistat/40-mg acarbose (EMP16-120/40), EMP16-150/50, or placebo. The primary end point was relative weight loss from baseline to week 26 assessed in participants with at least one post-baseline weight measurement. RESULTS: Of 156 randomized participants, 149 constituted the intention-to-treat population. The mean (95% CI) estimated treatment difference to placebo in relative weight loss after 26 weeks in the intention-to-treat population was -4.70% (-6.16% to -3.24%; p < 0.0001) with EMP16-120/40 and -5.42% (-6.60% to -4.24%; p < 0.0001) with EMP16-150/50. CONCLUSIONS: This trial indicates that orlistat and acarbose can be successfully combined in a modified-release formulation to provide efficacious weight loss with no unexpected safety issues. EMP16 may be a promising candidate among other medications for improved weight management.
Subject(s)
Acarbose , Anti-Obesity Agents , Adult , Humans , Adolescent , Young Adult , Middle Aged , Aged , Orlistat/therapeutic use , Acarbose/therapeutic use , Anti-Obesity Agents/therapeutic use , Lactones , Weight Loss , Obesity/therapy , Body Weight , Enzyme Inhibitors/therapeutic useABSTRACT
In this paper, two types of parameters representing tabletability and compactibility profiles of a series of α-lactose monohydrate powders, ranging in particle size from approximately 3.5 to 203 µm, are derived and compared. By approximating the tabletability profiles using a three-stage model and the compactibility profiles using the Ryshkewitch-Duckworth equation, two compaction rate parameters and two compaction endpoint parameters were derived. The original median particle diameter had generally a strong effect on the tablet tensile strength and hence the tabletability and compactibility profiles. The experimental profiles were well approximated by the models used, and the compaction parameters were regarded as representative of the experimental profiles. The compaction endpoint parameters increased with decreased particle size and were controlled by the same structural feature as the compacts. The tabletability rate parameter also increased with decreased particle size and correlated well with the tabletability endpoint parameter. The compactibility rate parameter tended to increase with decreased particle size, but the effect was limited; moreover, no general correlation was obtained with the compactibility endpoint parameter. It is concluded that compactibility and tabletability parameters collectively provide a concentrated description of the compaction properties of a powder.
Subject(s)
Lactose , Drug Compounding , Lactose/chemistry , Particle Size , Powders/chemistry , Tablets/chemistry , Tensile StrengthABSTRACT
In this study, the effect of pressure drop (ΔP) on the in vitro dispersion of a series of carrier-based adhesive mixtures of different fines-to-carrier proportions, corresponding to the four different blend states of the blend state model, i.e. S1 to S3, was investigated. Four binary and one ternary adhesive mixture consisting of lactose carrier and budesonide fines and lactose fines were prepared. The dispersion was assessed using a next generation impactor (NGI) at ΔP of 0.5, 2 and 4 kPa. For the S1 mixture, where the fines were located in surface cavities of the carrier, the fine particle fraction (FPF) increased nearly linearly with ΔP. For S2 and S3 mixtures, with adhesion layers on the enveloped carrier surface, the FPF-ΔP relationships were bended and approached a plateau. Examination of powder captured in the pre-separator of the NGI led to the conclusion that the dispersion of these adhesive mixtures occurred by erosion of the adhesion layer, i.e. budesonide was liberated as single particles or micro-agglomerates. It is concluded that the FPF-ΔP relationships were dependent on the blend state and for the S2 and S3 mixtures, a critical pressure drop was identified above which the pressure drop had a limited effect on the FPF.
Subject(s)
Adhesives , Drug Carriers , Administration, Inhalation , Albuterol , Dry Powder Inhalers , Lactose , Particle Size , PowdersABSTRACT
The objective of this study was to determine the intrinsic drug dissolution rate (IDR) and the solute effective transport rate of some drugs, using a single particle dissolution technique, satisfying qualified dissolution conditions. The IDR of three poorly water-soluble compounds was measured in milli-Q water using four different fluid velocities. The enveloped surface area of the particles was calculated from the projected area and the perimeter of the particle observed in the microscope. Furthermore, computational fluid dynamics (CFD) simulations were used to theoretically investigate the flow conditions and dissolution rate, comparing box shaped particles and spherical particles with similar dimensions and surface area as the particles used the experiments. In this study, the IDR measurement of the single particles was determined within 5-60 min using particles with an initial projected area diameter (Dp) between 37.5-104.6 µm. The micropipette-assisted microscopy technique showed a good reproducibility between individual measurements, and the CFD simulations indicated a laminar flow around the particles at all flow velocities, even though there were evident differences in local particle dissolution rates. In conclusion, the IDR and solute effective transport rate were determined under well-defined fluid flow conditions. This type of approach can be used as a complementary approach to traditional dissolution studies to gain in-depth insights into the dissolution process of drug particles.
ABSTRACT
The safety of a novel modified-release oral capsule with orlistat and acarbose (MR-OA) was investigated in 67 obese middle-aged White men with a body mass index of 32 to 40 kg/m2 or 30 to 32 kg/m2 plus waist circumference >102 cm. The purpose of this investigation was to compare MR-OA with the existing conventional orlistat regarding systemic safety defined as plasma orlistat concentration at the end of the treatment period of 14 days. Participants took the MR-OA fixed-dose combination formulation 3 times a day together with a major meal. Three different doses of MR-OA were evaluated-60/20, 90/30, and 120/40 (mg orlistat/mg acarbose)-as well as 1 reference group who received the conventional orlistat, Xenical, with 120 mg of orlistat. Blood plasma was sampled on days 1 and 14. The orlistat plasma concentrations of the MR-OA dose showed a delayed absorption and were lower compared with conventional orlistat at the end of the study. All doses were safe and well tolerated without any unexpected adverse events and no serious adverse events. The delay in the rise of orlistat plasma concentration indicates that the modified-release properties of the MR-OA formulation are effective. The systemic exposure of orlistat resulting from MR-OA was similar, albeit a bit lower than the conventional orlistat with 120 mg of orlistat. We can therefore assume that the safety profile regarding the orlistat moiety of MR-OA is comparable to the conventional orlistat and a promising approach for weight control in obese patients. Further clinical evaluation is underway.
Subject(s)
Acarbose/administration & dosage , Anti-Obesity Agents/administration & dosage , Glycoside Hydrolase Inhibitors/administration & dosage , Obesity/drug therapy , Orlistat/administration & dosage , Weight Loss/drug effects , Acarbose/adverse effects , Acarbose/blood , Administration, Oral , Adult , Anti-Obesity Agents/adverse effects , Anti-Obesity Agents/blood , Drug Combinations , Follow-Up Studies , Glycoside Hydrolase Inhibitors/adverse effects , Glycoside Hydrolase Inhibitors/blood , Humans , Male , Middle Aged , Obesity/blood , Orlistat/adverse effects , Orlistat/blood , Weight Loss/physiologyABSTRACT
The objectives of this investigation were to study the evolution in blend state of adhesive mixtures containing the active pharmaceutical ingredients (APIs) salbutamol, budesonide and AZD5423 and to study the relationship between blend state and dispersibility of the mixtures, as assessed by the fine particle fraction (FPF). A series of adhesive mixtures of varied fines concentration were prepared for each API using the same type of carrier. Based on visual examination and powder mechanics, blend states were identified and summarized as blend state maps for each API. The dispersibility of the mixtures was studied using a Fast Screening Impactor (FSI) equipped with a ScreenHaler. The evolution in blend state differed between the APIs in terms of the width of the blend states. The structure of the adhesion layer also differed between the APIs, from relatively uniform to a heterogeneous layer with small agglomerates dispersed on the carrier surface. All three APIs expressed a similar type of bended relationship between FPF and fines concentration. However, the initial rate of increase and the fines concentration of the plateau differed between the APIs. The adhesive mixtures of all APIs followed the three main states in terms of structural evolution and the overall shape of the FPF-fines concentration profiles could be explained by the evolution in blend state. It is proposed that the structure of the adhesion layer is an important factor explaining the differences in blend state - blend dispersibility relationships between the APIs.
ABSTRACT
OBJECTIVE: There is an unmet medical need for a safe and effective weight loss product with minimal systemic side-effects. In this study, the effect of a novel modified-release fixed-dose combination of orlistat and acarbose (MR-OA) was compared with conventional orlistat (CO) regarding tolerability, appetite and glucose metabolism. METHODS: Sixty-seven men with obesity, aged 24 to 60 years with body mass indexes (BMIs) 33 to 40 kg m-2 or BMIs 30 to 32 kg m-2 and waist circumference above 102 cm were included. They were randomized to either three different doses of the test formulation MR-OA (60 mg orlistat/20 mg acarbose, 90/30 and 120/40) or CO (Xenical, 120 mg orlistat) for a 2-week study of daily treatment. The participants spent days 1 and 14 at the clinical research centre where they received standardized meals, had blood sampling and filled in questionnaires regarding tolerability and appetite after meals. In days 2 to 13, the participants were at home and continued to fill in the questionnaires daily. RESULTS: In the MR-OA groups, reports of liquid and oily stools as well as faecal incontinence were fewer, whereas reports of gastric distension and flatulence were higher, compared with the CO group. More participants reported decreased hunger in the 90/30 and 120/40 MR-OA, and postprandial plasma glucose concentration was reduced in all MR-OA groups compared with CO. CONCLUSIONS: This study shows that by using a modified-release dosage form, orlistat and acarbose can be combined without compromising tolerability. Furthermore, MR-OA shows promising effects regarding reduction of appetite and reduces postprandial glucose. Tolerability is coupled to compliance and thereby efficacy of a treatment; therefore, this novel combination MR-OA could be an effective approach for weight loss treatment. A follow-up study in a more diverse population and for a longer duration with weight loss as primary outcome variable is planned.
ABSTRACT
The objective was to investigate tabletability and compactibility for compacts of a series of α-lactose monohydrate powders with different degree of disorder. Regarding the tabletability, the powders of high degree of disorder displayed similar behaviour that deviated markedly from the behaviour of the crystalline powders and the milled powder of modest degree of disorder. The Ryshkewitch-Duckworth equation, describing compactibility, was nearly linear for the crystalline powders, while for the disordered powders the model failed to describe the relationships, i.e. the disordered powders were characterised by a plateau in the Ryshkewitch-Duckworth plots over a relatively wide range of compact porosities. It was concluded that the difference in compaction behaviour of the milled particles compared to the crystalline powders was primarily explained by the increased particle plasticity of the disordered particles. The plateau in the Ryshkewitch-Duckworth plots obtained for the disordered powders was explained by a change in the fracture behaviour of the compacts, from an around grain to an across grain fracture pattern. This implied that the disordered particles can be described as a type of core-shell particles with an amorphous shell and a defective crystalline core.
ABSTRACT
The aim of this study was to investigate how the carrier morphology affects the expression of blend states in adhesive mixtures as a function of surface coverage ratio (SCR) and to identify where transitions between the different states occur. Adhesive mixtures of five lactose carriers with varying contents of lactose fines, corresponding to blends with different SCR ranging from 0 to 6, were produced by low-shear mixing. The powder mechanics of the mixtures were characterized by bulk density, compressibility and permeability. The appearance of the carriers and blends was studied by scanning electron microscopy, light microscopy and atomic force microscopy. The size and morphology of the carriers had a crucial impact on the evolution of the blend state, and affected the powder mechanical properties of the mixtures. It was found that smaller carriers with little or no surface irregularities were more sensitive to additions of fines resulting in self-agglomeration of fines at relatively low SCR values. On the contrary, carriers with irregular surface structures and larger sizes were able to reach higher SCR values before self-agglomeration of fines occurred. This could be attributed to an increased deagglomeration efficiency of irregular and larger carriers and to fines predominantly adhering to open pores.
Subject(s)
Adhesives/chemistry , Drug Carriers/chemistry , Dry Powder Inhalers/methods , Lactose/chemistry , Powders/chemistry , Administration, Inhalation , Mechanical Phenomena , Particle Size , Permeability , RheologyABSTRACT
Cracking patterns in four kinds of granules, based on the common pharmaceutical excipient microcrystalline cellulose (MCC) and subject to compressive load, were examined. The initial pore structure and the location of initial failure under uniaxial compression were assessed using X-ray micro-computed tomography, whereas contact force development and onset of cracking under more complex compressive load were examined using a triaxial testing apparatus. Smoothed particle hydrodynamics (SPH) simulations were employed for numerical analysis of the stress distributions prior to cracking. For granules subject to uniaxial compression, initial cracking always occurred along the meridian and the precise location of the crack depended on the pore structure. Likewise, for granules subject to triaxial compression, the fracture plane of the primary crack was generally parallel to the dominant loading direction. The occurrence of cracking was highly dependent on the triaxiality ratio, i.e. the ratio between the punch displacements in the secondary and dominant loading directions. Compressive stresses in the lateral directions, induced by triaxial compression, prevented crack opening and fragmentation of the granule, something that could be verified by simulations. These results provide corroboration as well as further insights into previously observed differences between confined and unconfined compression of granular media.
Subject(s)
Cellulose/chemistry , Compressive Strength/drug effects , Mechanical Phenomena/drug effects , Stress, Mechanical , Tensile Strength/drug effects , X-Ray Microtomography/methodsABSTRACT
The objective was to study the relationship between crystal structure, particle deformation properties, and tablet-forming ability for the monoclinic form of paracetamol (PRA), 2 cocrystals and a salt crystal of PRA in addition to 2 coformers (oxalic acid and 4,4'-bipyridine). Thus, the structure-property-performance relationship was investigated. Analytical powder compression was used for determination of effective plasticity, as inferred from the Heckel yield pressure and the Frenning parameter, and the elastic deformation was determined from in-die tablet elastic recovery. The plasticity could not be linked to the crystal lattice structure as crystals containing zig-zag layers displayed similar plasticity as crystals containing slip planes. In addition, crystals containing slip planes displayed both high and low plasticity. The mechanical properties could not be linked to the tablet-forming ability as the tablet tensile strength, unexpectedly, displayed a tendency to reduce with increased plasticity. Furthermore, the elastic deformation could not explain the tablet-forming ability. It was concluded that no relationship between structure-property-performance for PRA and its cocrystals and salt could be established. Thus, it was indicated that to establish such a relationship, an improved knowledge of crystallographic structure and interparticle bonding during compaction is needed.
Subject(s)
Acetaminophen/chemistry , Analgesics, Non-Narcotic/chemistry , Tensile Strength , Crystallization , Elasticity , Oxalic Acid/chemistry , Porosity , Powders , Pressure , Pyridines/chemistry , TabletsABSTRACT
The aim of this paper was to study relationships between the content of fine particles and the powder mechanics of binary adhesive mixtures and link these relationships to the blend state. Mixtures with increasing amounts of fine particles (increasing surface coverage ratios (SCR)) were prepared using Lactopress SD as carrier and micro particles of lactose as fines (2.7⯵m). Indicators of unsettled bulk density, compressibility and flowability were derived and the blend state was visually examined by imaging. The powder properties studied showed relationships to the SCR characterised by stages. At low SCR, the fine particles predominantly gathered in cavities of the carriers, giving increased bulk density and unchanged or improved flow. Thereafter, increased SCR gave a deposition of particles at the enveloped carrier surface with a gradually more irregular adhesion layer leading to a reduced bulk density and a step-wise reduced flowability. The mechanics of the mixtures at a certain stage were dependent on the structure and the dynamics of the adhesion layer and transitions between the stages were controlled by the evolution of the adhesion layer. It is advisable to use techniques based on different types of flow in order to comprehensively study the mechanics of adhesive mixtures.
Subject(s)
Adhesives/chemistry , Drug Carriers/chemistry , Drug Compounding/methods , Dry Powder Inhalers/methods , Administration, Inhalation , Chemistry, Pharmaceutical , Lactose/chemistry , Particle Size , Powders , Surface PropertiesABSTRACT
Compressibility and tablet forming ability (compactibility) of bimodal mixtures of differently sized granules formed from microcrystalline cellulose were studied experimentally and numerically with the discrete element method (DEM). Compression data was analysed using the Kawakita equation. A multi-body contact law that accounts for contact dependence resulting from plastic incompressibility/geometric hardening was used in the DEM simulations. The experimental Kawakita a and 1/b parameters both depended non-monotonically on composition (weight fraction of large particles). For the a parameter, this dependence was explained by variations in the porosity of the initial granule beds; for the 1/b parameter, other factors were found to be of importance as well. The numerical results generally compared favourably with the experiments, demonstrating the usefulness of the DEM at high relative densities, provided that a suitable multi-particle contact model is used. For all mixtures, the tensile strength of the formed tablets increased with increasing applied pressure. The tensile strength generally decreased with increasing fraction of large particle, and this decrease was more rapid for large differences in particle size. A possible interpretation of these findings was proposed, in terms of differences in lateral support of small particles in the vicinity of large particles.
Subject(s)
Cellulose/chemistry , Computer Simulation , Models, Chemical , Pharmaceutical Preparations/chemistry , Technology, Pharmaceutical/methods , Compressive Strength , Drug Compounding , Friction , Numerical Analysis, Computer-Assisted , Particle Size , Porosity , Pressure , Tablets , Tensile StrengthABSTRACT
The purpose of this study was to investigate the effect of degree of disorder of a series of α-lactose monohydrate powders, prepared by milling for different time periods, on the plastic and the elastic stiffness of the particles. As references, a series of physical mixtures consisting of original crystalline particles and amorphous particles obtained by spray-drying was used. In addition, the effect of powder pre-storage humidity on the mechanical properties was investigated. For milled particles of a low degree of disorder, a decreased particle size increased the particle plastic stiffness. For milled particles of constant particle size, the plastic stiffness decreased with an increased degree of disorder while the elastic stiffness seemed nearly independent of the degree of disorder. The presence of moisture caused a recrystallisation of milled particles with low degree of disorder which increased their plastic stiffness. For the physical mixtures of crystalline and amorphous particles, similar relationships between plastic stiffness and amorphous content as for the milled powders were obtained. A reasonable explanation is that the nature of the milled particles is represented by a two-state system with crystalline and amorphous domains.
Subject(s)
Chemistry, Pharmaceutical/methods , Lactose/chemical synthesis , Particle Size , Plastics/chemical synthesis , Drug Compounding/methods , Powders , X-Ray Diffraction/methodsABSTRACT
The objective was to present a hybrid approach to predict the strength-pressure relationship (SPR) of tablets using common compression parameters and a single measurement of tablet tensile strength. Experimental SPR were derived for six pharmaceutical powders with brittle and ductile properties and compared to predicted SPR based on a three-stage approach. The prediction was based on the Kawakita b-1 parameter and the in-die Heckel yield stress, an estimate of maximal tensile strength, and a parameter proportionality factor α. Three values of α were used to investigate the influence of the parameter on the SPR. The experimental SPR could satisfactorily be described by the three stage model, however for sodium bicarbonate the tensile strength plateau could not be observed experimentally. The shape of the predicted SPR was to a minor extent influenced by the Kawakita b-1 but the width of the linear region was highly influenced by α. An increased α increased the width of the linear region and thus also the maximal predicted tablet tensile strength. Furthermore, the correspondence between experimental and predicted SPR was influenced by the α value and satisfactory predictions were in general obtained for αâ¯=â¯4.1 indicating the predictive potential of the hybrid approach.
Subject(s)
Chemistry, Pharmaceutical/methods , Compressive Strength , Tablets/chemistry , Tensile Strength , Forecasting , Powders , Tablets/analysisABSTRACT
Preprocessing of pharmaceutical powders is a common procedure to condition the materials for a better manufacturing performance. However, such operations may induce undesired material properties modifications when conditioning particle size through milling, for example. Modification of both surface and bulk material structure will change the material properties, thus affecting the processability of the powder. Hence it is essential to control the material transformations that occur during milling. Topographical and mechanical changes in surface properties can be a preliminary indication of further material transformations. Therefore a surface evaluation of the α-lactose monohydrate after short and prolonged milling times has been performed. Unprocessed α-lactose monohydrate and spray dried lactose were evaluated in parallel to the milled samples as reference examples of the crystalline and amorphous lactose structure. Morphological differences between unprocessed α-lactose, 1â¯h and 20â¯h milled lactose and spray dried lactose were detected from SEM and AFM images. Additionally, AFM was used to simultaneously characterize particle surface amorphicity by measuring energy dissipation. Extensive surface amorphicity was detected after 1â¯h of milling while prolonged milling times showed only a moderate particle surface amorphisation. Bulk material characterization performed with DSC indicated a partial amorphicity for the 1â¯h milled lactose and a fully amorphous thermal profile for the 20â¯h milled lactose. The temperature profiles however, were shifted somewhat in the comparison to the amorphous reference, particularly after extended milling, suggesting a different amorphous state compared to the spray-dried material. Water loss during milling was measured with TGA, showing lower water content for the lactose amorphized through milling compared to spray dried amorphous lactose. The combined results suggest a surface-bulk propagation of the amorphicity during milling in combination with a different amorphous structural conformation to that of the amorphous spray dried lactose. The hardened surface may be due to either surface crystallization of lactose or to formation of a low-water glass transition.