Shubhajit Paul

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.

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.

The suitability of common compressibility equations for characterizing plasticity of diverse powders

The analysis of powder compressibility data yields useful information for characterizing compaction behavior and mechanical properties of powders, especially plasticity. Among the many compressibility equations proposed in powder compaction research, the Heckel equation and the Kawakita equation are the most commonly used, despite their known limitations. Systematic evaluation of the performance in analyzing compressibility data suggested the Kuentz-Leuenberger equation is superior to both the Heckel equation and the Kawakita equation for characterizing plasticity of powders exhibiting a wide range of mechanical properties.

Dependence of tablet brittleness on tensile strength and porosity

An analysis of data collected from 25 sets of diverse pharmaceutical powders has identified that an exponential growth function satisfactorily describes the relationship between tablet brittleness and tablet porosity while a power law function well describes the relationship between tablet brittleness and tensile strength. These equations have the potential to facilitate better characterization of tablet mechanical properties and to guide the design and optimization of pharmaceutical tablet products.

Gaining insight into tablet capping tendency from compaction simulation

Capping or lamination is an unsolved common problem in tablet manufacturing. Knowledge gaps remain despite an enormous amount of effort made in the past to better understand the tablet capping/lamination phenomenon. Using acetaminophen - containing formulations, we examined the potential use of a compaction simulator as a material-sparing tool to predict capping occurrence under commercial tableting conditions. Systematical analyses of the in-die compaction data led to insight on the potential mechanism of tablet capping/lamination. In general, capping strongly correlates with high in-die elastic recovery, high Poissons ratio, low tensile strength, and radial die-wall pressure. Such insight can be used to guide the formulation design of high quality tablet products that are free from capping problems for challenging active pharmaceutical ingredients.

pH-dependent complexation of hydroxypropyl-beta-cyclodextrin with chlorin e6: effect on solubility and aggregation in relation to photodynamic efficacy

The activity of chlorin e6 (Ce6) in photodynamic therapy of cancers is significantly reduced by its propensity to form aggregates. It was postulated that disaggregation of Ce6 could be achieved with the use of hydroxypropyl‐beta‐cyclodextrin (HP‐β‐CD) through solubility enhancement.

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.

Enabling the Tablet Product Development of 5-Fluorocytosine by Conjugate Acid Base Cocrystals

5-Fluorocytosine (FC) is a high-dose antifungal drug that challenges the development of a tablet product due to poor solid-state stability and tabletability. Using 2 pharmaceutically acceptable conjugate acid base (CAB) cocrystals of FC with HCl and acesulfame, we have developed commercially viable high loading FC tablets. The tablets were prepared by direct compression using nano-coated microcrystalline cellulose Avicel PH105 as a tablet binder, which provided both excellent tabletability and good flowability. Commercial manufacturability of formulations based on both CAB cocrystals was verified on a compaction simulator. The results from an expedited friability study were used to set the compaction force, which yielded tablets with sufficient mechanical strength and rapid tablet disintegration. This work demonstrates the potential value of CAB cocrystals in drug product development.

Dependence of Friability on Tablet Mechanical Properties and a Predictive Approach for Binary Mixtures

PurposeTo systematically assess the dependence of friability on tablet mechanical properties, compaction pressure, and tablet porosity.MethodsSeveral common excipients and their mixtures exhibiting diverse mechanical properties were analyzed. Tablet elastic modulus, hardness, brittleness, porosity, and tensile strength were determined using standard techniques and then were correlated to tablet friability both individually and as a group to derive a universal model.ResultsViscoelastic starch exhibits the highest friability followed by brittle excipients (mannitol, DCPA, and LM) and then ductile excipients (HPC and MCC). A reasonably accurate model for predicting pharmaceutically relevant range of friability, up to 3%, of binary mixtures is presented based on friability of individual components. In addition, a multivariate model between friability and different mechanical parameters was developed, based on which the weight loss propensity of tablets may be predicted.ConclusionsThe experimental findings and predictive model are useful for expedited development and optimization of tablet formulation using a minimum amount of API.

Comparative analyses of flow and compaction properties of diverse mannitol and lactose grades

Graphical abstract Figure. No Caption available. &NA; Appropriate selection of excipient grade during tablet formulation development depends on thorough knowledge in their compaction and flow properties. Each chemically unique pharmaceutical excipient is usually available in several commercial grades that are widely different in powder properties, which influence their performance for a specific formulation application. In this work, 11 grades of mannitol were systematically characterized, in terms of their particulate, flow and tableting properties, and compared against 5 grades of lactose. Principal component analysis (PCA) identified significant correlations among selected variables, such as particle size, surface area, flowability, wall friction, plasticity parameter, tensile strength, and tablet brittleness. PCA also revealed similar grades of the two excipients, which may be used to select replacement grade, if needed, based on similarity in their overall properties.