Consolidation mechanisms of pharmaceutical solids: a multi-compression cycle approach.

PURPOSE: The consolidation behavior of various pharmaceutical solids were characterized using compression-cycle profiles. Compression-cycle profiles for both uncompacted powder and formed tablets were obtained. These profiles were used to qualitatively and quantitatively characterize the consolidation mechanism of pharmaceutical solids. METHODS: An Instron Universal Testing apparatus and a specially instrumented die coupled with a computerized data acquisition system were utilized to measure the upper-punch pressure and the corresponding die-wall pressure during the compression cycle. RESULTS: Compression cycle profiles were obtained for a variety of pharmaceutical materials. Based on these profiles, parameters such as hysteresis areas, loading slopes, and unloading slopes were calculated for the materials studied. CONCLUSIONS: Materials that consolidate by plastic deformation have similar compression cycle profiles for the first and subsequent compression cycles indicating that the plastic deformation process occurs to the same extent on the first as well as subsequent compression cycles. For brittle materials, the brittle fracture process occurs during the first compression cycle. During subsequent cycles the tabletted material does not undergo further yield or failure and primarily undergoes elastic deformation. Low molecular-weight polyethylene glycol is an excellent model material for plastically deforming materials, whereas sucrose or sodium citrate are excellent examples of materials that consolidate by brittle fracture.

Structure evolution of tablets during compression unloading.

The evolution of internal structure within compacts composed of selected drugs and direct compression excipients, occurring during the unloading phase of compaction, was studied in an instrumented rotary tablet press. Utilizing three-dimensional viscoelastic analysis applied to successive, sequential segments of the unloading phase, elastic and viscous parameters were obtained that provide quantitative, incremental measures of the changing behavior of the compact during this period. It is apparent from these studies that the principal feature of this phase of compaction is the generation and propagation of internal fractures as a result of the release of internal stresses through expansion. The progression of elastic parameters from positive initial values to negative terminal values during unloading, coupled with the strong relationships they display to corresponding viscous parameters, supports this conclusion. These results follow well-established Dugdale fracture dynamics in which rate-dependent flow, occurring in the immediate surroundings of crack tips, accompanies crack formation and propagation. The extent of viscous flow depends both on the brittle versus plastic nature of the substance and on the extent of crack growth.

Timing relationships among maxima of punch and die-wall stress and punch displacement during compaction of viscoelastic solids.

The times of occurrence of maxima in punch stress, die-wall stress, and punch displacement in instrumented rotary tablet machines are shown to be noncoincidental for compacts exhibiting viscoelastic behavior. Equations are presented which characterize materials behaving as Kelvin solids in either or both distortion and dilation. These equations explicitly relate the timing of stress maxima to punch strain and strain rate. Typical effects are illustrated by data obtained for Avicel PH 101, Klucel, and mannitol. Punch stress maxima are shown to significantly precede the time of maximum punch insertion into the die for viscoelastic materials compacted at rates typical of production. Die-wall stress maxima occur after punch stress maxima due to internal rate-limited processes.

Evidence for site-specific absorption of a novel ACE inhibitor.

Moexipril [2-[(1-ethoxycarbonyl)-3-phenylpropyl]amino-1-oxopropyl]-6, 7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (S,S,S)], an ester prodrug of an ACE inhibitor, was formulated in controlled-release preparations with a range of in vitro release rates, to provide a prolonged input of drug in vivo. However, pharmacokinetic studies with the controlled-release dosage forms in humans produced plasma profiles with the same characteristics and time to peak as an immediate-release capsule. In vitro dissolution data from the controlled-release dosage form, as well as the known characteristics of the polymer used to control drug release from the dosage form, suggest no reason to suspect an abrupt halt to the in vivo release of the drug after 1-2 hr. The lack of sustained blood levels is, therefore, most likely due to failure of the GI tract to absorb the drug beyond some location in the upper small intestine, i.e., site-specific absorption. This theory is supported by a series of computer simulations involving moexipril and the active moiety, moexipril diacid. Possible mechanisms include poor drug permeability, a pH effect whereby the zwitterionic form of the drug is more rapidly absorbed, and esterase cleavage of moexipril to the poorly absorbed moexipril diacid.

Unloading and postcompression viscoelastic stress versus strain behavior of pharmaceutical solids.

The viscoelastic properties of several compacts composed of drugs and direct compression excipients have been measured during the stress unloading and postcompression phases of the tablet compression process. Measurements of applied strains and the resultant stresses, generated in the tablet structure under compaction, were made using a rotary press. The press was instrumented to measure punch and die wall stresses at normal operating speeds. The three-dimensional viscoelastic theory, used in data analysis, provides for the separate characterization of tablet behavior into its dilation and distortion components. The tablets investigated were found to behave elastically in dilation, but to have both viscous and elastic contributions to their stress/strain relaxation in distortion. This latter behavior could be modeled well as a Kelvin solid. Data derived from an elastic-in-dilation, Kelvin-in-distortion analysis of tablets, compressed at similar machine speeds but at various peak pressures, were found to vary widely depending on tablet composition. Dependence of the viscous and elastic parameters on compression conditions was found to be predictive of conditions under which capping or lamination of the compact would occur.