Toward a Molecular Understanding of the Impact of Crystal Size and Shape on Punch Sticking.

Punch sticking during tablet manufacturing is a common problem facing the pharmaceutical industry. Using several model compounds, effects of crystal size and shape of active pharmaceutical ingredients (API) on punch sticking propensity were systematically investigated in this work to provide molecular insights into the punch-sticking phenomenon. In contrast to the common belief that smaller API particles aggravate punch sticking, results show that particle size reduction can either reduce or enhance API punch sticking, depending on the complex interplay among the particle surface area, plasticity, cohesive strength, and specific surface functional groups. Therefore, other factors, such as crystal mechanical properties, surface chemistry of crystal facets exposed to the punch face, and choice of excipients in a formulation, should be considered for a more reliable prediction of the initiation and progression of punch sticking. The exposure of strong electronegative groups to the punch face facilitates the onset of sticking, while higher plasticity and cohesive strength aggravate sticking.

Quantifying and reducing powder shear sensitivity when manufacturing capsules with lubricants.

The purpose of this work was to develop a methodology that quantifies the extent of shear induced during an encapsulation process and show how formulation composition and manufacturing process designs can be changed to reduce the negative impact on drug product quality attributes. The powder feed system used in a dosing disc type pharmaceutical capsule filling machine induced additional shear of the powder prior to slug formation. The shear occurred both in the hopper portion, via the rotation of the feed auger and impeller, and in the powder bowl via the tamping pin agitation and/or shear against the stationary surfaces such as the powder level scraper. The extent of shear was quantified to assess the impact of further dispersing the hydrophobic lubricant, magnesium stearate, in both active and placebo formulations. Stratified samples over the course of the encapsulation run showed suppression in the drug dissolution profiles and decrease in the interparticulate tensile strength of the encapsulated product. The amount of shear (duration and rate) induced during the encapsulation unit operation can be much greater than that from typical bin blending operations and therefore requires consideration during product design and scale-up to ensure product robustness.

Dependence of Punch Sticking on Compaction Pressure-Roles of Particle Deformability and Tablet Tensile Strength.

Punch sticking is a complex phenomenon influenced primarily by particle size, tooling surface roughness, tooling design, and tooling construction material. When particle and environmental factors are controlled, compaction pressure has a distinct effect on punch sticking behavior for a given active pharmaceutical ingredient (API). This research focuses on the effect of compaction pressure on punch sticking using 5 compounds with different sticking propensities. The results collectively show that sticking tends to be more problematic under higher compaction pressures and for more ductile compounds. This is attributed to the greater punch surface coverage by the API and the stronger cohesion of API to the existing API layer on the punch.

Powder properties and compaction parameters that influence punch sticking propensity of pharmaceuticals.

Punch sticking is a frequently occurring problem that challenges successful tablet manufacturing. A mechanistic understanding of the punch sticking phenomenon facilitates the design of effective strategies to solve punch sticking problems of a drug. The first step in this effort is to identify process parameters and particle properties that can profoundly affect sticking performance. This work was aimed at elucidating the key material properties and compaction parameters that influence punch sticking by statistically analyzing punch sticking data of 24 chemically diverse compounds obtained using a set of tooling with removable upper punch tip. Partial least square (PLS) analysis of the data revealed that particle surface area and tablet tensile strength are the most significant factors attributed to punch sticking. Die-wall pressure, ejection force, and take-off force also correlate with sticking, but to a lesser extent.

Mechanism and Kinetics of Punch Sticking of Pharmaceuticals.

Adherence of powder onto tablet tooling, known as punch sticking, is one of the tablet manufacturing problems that need to be resolved. An important step toward the resolution of this problem is to quantify sticking propensity of different active pharmaceutical ingredients (APIs) and understand physicochemical factors that influence sticking propensity. In this study, mass of adhered material onto a removable upper punch tip as a function of number of compression is used to monitor sticking kinetics of 24 chemically diverse compounds. We have identified a mathematical model suitable for describing punch sticking kinetics of a wide range of compounds. Chemical analyses have revealed significant enrichment of API content in the adhered mass. Based on this large set of data, we have successfully developed a new punch sticking model based on a consideration of the interplay of interaction strength among API, excipient, and punch surface. The model correctly describes the general shape of sticking profile, that is, initial rise in accumulated mass followed by gradual increase to a plateau. It also explains why sometimes sticking is arrested after monolayer coverage of punch surface by API (punch filming), while in other cases, API buildup is observed beyond monolayer coverage.

Estimation of bottle filling counts for conventional pharmaceutical tablets and capsules.

A method has been developed using commonly available data for estimating the number of tablets or hard shell capsules that can be filled into bottles. The single unit volumes of conventional pharmaceutical biconvex tablets and capsules can be calculated from simple geometric relationships, which then can be used to determine the packing fraction of the units in bottles. The packing fractions of capsules and tablets studied in this work ranged from 0.53 to 0.63 and 0.56 to 0.62, respectively, and were dependent on bottle size and shape. This method can be used to assess a variety of packaging configurations computationally during drug product development.

Mechanical property anisotropy of pharmaceutical excipient compacts.

The mechanical property anisotropy of compacts made from six commercially available pharmaceutical excipient powders was evaluated. Uni-axially compressed cubic compacts of each excipient were subjected to pendulum impact testing and transverse tensile testing in several orientations. The pendulum impact test was used to measure the dynamic indentation hardness of each compact face (side, top, and bottom). Transverse tensile testing was utilized to determine the compact axial and radial tensile strength values. The indentation hardness (top>bottom>side) and tensile strength tests (radial>axial) revealed mechanical property anisotropy in all the compacts. The extent of mechanical property anisotropy was quantified by using dimensionless ratios and was found to be significantly different for each material. In general, compacts with a higher degree of compact mechanical anisotropy also exhibited a higher brittle fracture index (BFI). This suggests that the macroscopic flaws intentionally made in the compact for the BFI measurement were similar to the flaws induced in highly anisotropic materials during uni-axial compaction. These results are consistent with the practical observation that brittle materials are more likely to exhibit failure in a plane normal to the compaction axis, i.e. experience tablet capping and lamination phenomena.

Improving the prediction of exceptionally poor tableting performance: an investigation into Hiestand's "special case".

The mechanical and flow properties of selected pharmaceutical powdered excipients and drug substances were evaluated to investigate their behavior as extremely poor tableting, or "special case," materials. The compaction stress, dynamic indentation hardness, and tensile strength of compacts compressed to 15% porosity and their powder's effective angle of internal friction were measured using the tableting indices technology and a simple shear cell, respectively. It has been previously demonstrated that compacts of special case materials exhibit a dynamic indentation hardness greater than the stress required to form the compact under slow compression conditions. In addition, new data suggest that special case materials also exhibit low compact dynamic indentation hardness, low compact tensile strength, and low powder effective angle of internal friction. These findings support the theory that the particles of such materials preferentially rearrange rather than deform under compressive conditions because bonding between them is weak. The added special case indicator measurements can be used to clearly identify exceptionally poor tableting powders during the selection of components for solid dosage formulations. Careful consideration of the data will provide guidance to the proper use of the bonding indices equations.

Simulation of roller compaction using a laboratory scale compaction simulator.

A method for simulation of the roller compaction process using a laboratory scale compaction simulator was developed. The simulation was evaluated using microcrystalline cellulose as model material and ribbon solid fraction and tensile strength as key ribbon properties. When compacted to the same solid fractions, real and simulated ribbons exhibited similar compression behavior and equivalent mechanical properties (tensile strengths). Thus, simulated and real ribbons are expected to result in equivalent granulations. Although the simulation cannot account for some roller compaction aspects (non-homogeneous ribbon density and material bypass) it enables prediction of the effects that critical parameters such as roll speed, pressure and radius have on the properties of ribbons using a fraction of material required by conventional roller compaction equipment. Furthermore, constant ribbon solid fraction and/or tensile strength may be utilized as scale up and transfer factors for the roller compaction process. The improved material efficiency and product transfer methods could enable formulation of tablet dosage forms earlier in drug product development.

Modeling of transmitted X-ray intensity variation with sample thickness and solid fraction in glycine compacts.

The previous paper in this series introduced an X-ray diffraction quantitation method for the polymorphic content in tablets made of pure components. Before the method could be transferred, further studies were required to explain the commonly observed X-ray intensity variation in analyzing compacts. The literature typically attributes the variation to partial amorphization under compression and/or to preferred orientation, without much viable explanation or compelling evidence. In this study, changes in intensity in compacts analyzed in transmission geometry were found to be primarily a function of sample thickness and solid fraction. A theoretical model was developed to describe the X-ray powder diffraction (XRPD) intensity as a function of solid fraction, mass absorption coefficient, and thickness. The model was tested on two sets of glycine compacts: one with varying thickness at constant solid fraction, and the other with various solid fractions at a given thickness. The results show that the model predicts the XRPD intensity at any given sample thickness and solid fraction. With this model, the intensity variation of compacts made under different compression conditions can be normalized, making the method transferable to various tablet geometries and facilitating the analysis over expected ranges of formulation and process variation.

The powder flow and compact mechanical properties of sucrose and three high-intensity sweeteners used in chewable tablets.

The physical, flow, and mechanical properties of four common pharmaceutical sweeteners were measured to assess their relative manufacturability in solid dosage formulations. Sucrose, acesulfame potassium (Sunett), saccharin sodium, and aspartame were evaluated to determine significant differences in particle shape, size distribution, and true density. Powder flow and cohesivity as well as compact mechanical properties such as ductility, elasticity, and tensile strength were measured and found to be noticeably different. Among these sweeteners, sucrose and acesulfame potassium demonstrated excellent flowability and marginal mechanical property performance relative to over 100 commonly used pharmaceutical excipients evaluated in the authors' laboratory. Saccharin sodium and aspartame demonstrated poor flowability and superior compact strength relative to sucrose and acesulfame, despite their noticeably higher brittleness. These data suggest that careful selection of an appropriate sweetener is warranted in obtaining desirable process and tableting robustness, particularly if sweetener loading is high. Detailed descriptions of each material property and recommendations for sweetener selection in formulation development are included.

Comparison of the mechanical properties of the crystalline and amorphous forms of a drug substance.

PURPOSE: To better understand the influence of long-range molecular order on the processing characteristics of an active pharmaceutical ingredient (API). METHODS: Crystalline and amorphous samples of a model drug substance were isolated and their "true" density, crystallinity, melting point, glass transition temperature, particle size distribution, and powder flow characteristics determined. Compacts of a standard porosity were manufactured from each form and their dynamic indentation hardness, quasi-static indentation hardness, tensile strength and "compromised tensile strength" determined. X-ray powder diffraction was used to confirm that no changes were induced by compact formation or testing. RESULTS: The crystalline and amorphous forms of the drug substance had relatively high melting and glass transition temperatures (approximately 271 and 142 degrees C, respectively) and were physically and chemically stable under the conditions of the testing laboratory. Consistent with this there was no evidence of crystallinity in the amorphous samples or vice versa before, during or after testing. The two API lots were effectively equivalent in their particulate properties (e.g. particle size distribution), although differences in their particle morphologies were observed which influenced powder flow behavior. The compacts of the bulk drug samples exhibited moderate ductility, elasticity, and strength, and high brittleness, in keeping with many other drug substance samples. A significantly greater compression stress was required to form the compacts of the crystalline material, and these sample materials were more ductile, less brittle and less elastic than those made from the amorphous API. There were no major differences in the tensile strength or the viscoelasticity of the compacts made from the crystalline and amorphous samples. CONCLUSIONS: The mechanical properties of compacted amorphous and crystalline samples of a drug substance have been measured and the contributions due to the molecular ordering of the crystalline form proposed. Small but significant differences in the mechanical properties were noted which could potentially affect the processing performance of API.