Compression analysis as a tool for technical characterization and classification of pharmaceutical powders

There are today strong incentives for an increased understanding of material properties and manufacturing processes to facilitate the development of new technologies in the pharmaceutical industry. The purpose of this thesis was to suggest methods requiring a low sample amount for characterization of technical properties of powders. Compression analysis was used to evaluate the formulation relevance of some compression equations. Using the mechanics of single granules to estimate powder functionality was part of this work. It was concluded that the formability of granular solids and the plasticity of single granules could be determined with compression analysis by using the Kawakita model for single components and binary mixtures of ductile granules. Further on, the fragmentation propensity of solid particles could be estimated from compression analysis by using the Shapiro equation, enabling indicators of both the fragmentation and the deformation propensity of particles to be derived in one single compression test. The interpretations of the compression parameters were only valid if the influence of particle rearrangement was negligible for the overall compression profile. An index indicating the extent of particle rearrangement was developed and a classification system of powders into groups dependent on the incidence of particle rearrangement was suggested as tools to enable rational interpretations of compression parameters. The application of compression analysis was demonstrated by investigating the relevance of the mechanics of granular solids for their tableting abilities. The plasticity of single gran-ules was suggested to influence both the rate of compactibility and the mode of deformation, and consequently the maximal tablet strength. The degree of granule bed deformation was shown to be a potential in line process indicator to describe the tableting forming ability. This thesis contributes to a scheme, suitable in formulation work and process control, to describe manufacturability of powders for an enhanced tablet formulation technology

Effect of excipient properties and blend ratio on the compression properties of dry granulated particles prepared from microcrystalline cellulose and lactose

In this study, the effect of a systematically varied excipient ratio of a plastic and a brittle material, i.e., microcrystalline cellulose (MCC) and crystalline a-lactose monohydrate (LAC), on the compression properties of dry granulated particles was investigated. Five powders with different MCC:LAC ratios were prepared by dry mixing; subsequently, they were formed into slugs that were milled and sieved, giving granules of two size fractions. Two slugging pressures were used, giving granules of different porosity for each powder. Original powders and granules were compressed, and strain-pressure profiles determined. From these profiles, a series of compression parameters were derived using the Heckel, Kawakita, and Adams compression equations. The initial part of the compression profiles of all granulated powders were similar up to a jamming point, after which the compression profiles diverged depending on the granule composition and the slugging pressure. Parameters derived from the Adams and Kawakita equations reflected the differences in compression behavior, while the Heckel parameter did not. The macroscopic compression stiffening was assessed by the Adams friction parameter which seemed to be controlled by the inner friction of the granules, i.e., their plastic deformation due to inter-particulate flow. The total compressibility, assessed by the Kawakita parameter, was dependent on the initial bulk porosity of the granulations. It is concluded that the composition, microstructure, and packing density of the granules dictated their compression properties, while the granule size and work hardening of primary particles were insignificant

Deciphering the role of granule deformation and fragmentation for the tableting performance of some dry granulated powders

In this study, the question of how fragmentation and deformation of granules during compression can be linked to the tableting performance of dry granulated powders is addressed. Granulated powders of a systematically varied composition of a plastic and a brittle material were prepared by slugging and thereafter compacted into tablets. The tablet's micro-structure, porosity, and tensile strength were assessed; moreover, the relationships between the Adams compression parameters tau(0) and alpha and the tableting performance were studied. The composition and the slugging pressure had a limited effect on the tablet porosity. However, they had a marked effect on the tablet micro-structure, which varied from tablets composed of deformed but otherwise preserved granules to tablets composed of small granule fragments. The tablet tensile strength, the loss of tab-letability, and the lubricant sensitivity varied with the Adams compression parameters, indicating a complex effect of granule fragmentation and deformation on the tableting performance. The effect of the granule compression properties on the tableting performance is mediated by the number and average force of the intergranular bonds of the tablet

Optimal (s, S) policies with delivery time guarantees for manufacturing systems with early set-up

We consider optimal (s, S) policies with delivery time guarantees for production planning in one-machine manufacturing systems with early set-up. The machine produces one type of product and delivery time guarantee is offered to the customers for each unit of ordered product. The inter-arrival time of the demand and the processing time for one unit of product are assumed to be exponentially distributed. In a (s, S) policy, the machine will shut down when an inventory level of S is attained and once the inventory level drops to s, the machine will re-start. A set-up time is required for the machine. We model the set-up by the exponential distribution. We obtained an analytical form of the steady state probability distribution for the inventory levels derived. The average profit of the system can be written in terms of this probability distribution. Hence the optimal (s, S) policy can be obtained by varying different possible values of s and S. © 2001 Elsevier Science Ltd.link_to_subscribed_fulltex

A comparison between two powder compaction parameters of plasticity : The effective medium A parameter and the Heckel 1/K parameter

The purpose of the research was to introduce a procedure to derive a powder compression parameter (EM A) representing particle yield stress using an effective medium equation and to compare the EM A parameter with the Heckel compression parameter (1/K). 16 pharmaceutical powders, including drugs and excipients, were compressed in a materials testing instrument and powder compression profiles were derived using the EM and Heckel equations. The compression profiles thus obtained could be sub-divided into regions among which one region was approximately linear and from this region, the compression parameters EM A and 1/K were calculated. A linear relationship between the EM A parameter and the 1/K parameter was obtained with a strong correlation. The slope of the plot was close to 1 (0.84) and the intercept of the plot was small in comparison to the range of parameter values obtained. The relationship between the theoretical EM A parameter and the 1/K parameter supports the interpretation of the empirical Heckel parameter as being a measure of yield stress. It is concluded that the combination of Heckel and EM equations represents a suitable procedure to derive a value of particle plasticity from powder compression data

The degree of compression of spherical granular solids controls the evolution of microstructure and bond probability during compaction

The effect of degree of compression on the evolution of tablet microstructure and bond probability during compression of granular solids has been studied. Microcrystalline cellulose pellets of low (about 11%) and of high (about 32%) porosity were used. Tablets were compacted at 50, 100 and 150 MPa applied pressures and the degree of compression and the tensile strength of the tablets determined. The tablets were subjected to mercury intrusion measurements and from the pore size distributions, a void diameter and the porosities of the voids and the intra-granular pores were calculated. The pore size distributions of the tablets had peaks associated with the voids and the intra-granular pores. The void and intra-granular porosities of the tablets were dependent on the original pellet porosity while the total tablet porosity was independent. The separation distance between pellets was generally lower for tablets formed from high porosity pellets and the void size related linearly to the degree of compression. Tensile strength of tablets was higher for tablets of high porosity pellets and a scaled tablet tensile strength related linearly to the degree of compression above a percolation threshold. In conclusion, the degree of compression controlled the separation distance and the probability of forming bonds between pellets in the tablet.