Interfacial and material aspects of powders with relevance to pharmaceutical tableting performance

Tablets are the most common forms of drug administration. They are convenient to administer and easy to manufacture. However, problems associated with the adhesion of the powders to the tableting tools are common. This phenomenon is known as sticking and even though it has been well documented and studied, it remains poorly understood. The many factors that contribute to good performance of the powders make the sticking problem difficult to solve. The goal of this study is to establish a relationship between the properties measured at the nanoscale to the overall tablet mechanical properties, tablet performance and powder pre-processing induced modifications. By using atomic force microscopy (AFM) we aim to develop an analytical method to characterize the mechanical and adhesive properties of the pharmaceutical powders at the nanoscale. Other methodologies such as scanning electron microscopy (SEM), thermal analyses (DSC, TGA) and tablet strength test were also used. The materials used in this study are commonly used excipients, a sticky drug and magnesium stearate (MgSt). Two different approaches offered by AFM were employed: sharp tip imaging and colloidal probe force measurements. Nano-mechanical properties of the materials were evaluated with a sharp tip cantilever showing that higher adhesion correlates with higher tablet cohesion and that both are significantly affected by the presence of MgSt. AFM characterization of the particle surface mechanical properties at the nanoscale was also used to detect the crystallinity and amorphicity levels of the materials. New approaches to presenting such data considering the particle heterogeneity and to track the dynamics of surface recrystallization are revealed. Adhesive interactions between a steel sphere and sticky and non-sticky powders were performed with the colloidal probe technique. Sticky materials presented a higher adhesion against the steel surface, and reveal the mechanism of stickiness. This work thus contributes to the provision of predictability of the performance of formulations at an early stage of the development process.QC 20170315</p

Tablet and powder mechanics depend on nano and micro scale adhesion, lubrication and structure

Tablets are the most convenient form for drug administration. Despite its ease of manufacturing problems such powder adhesion occur during the production process. This study presents a surface and structural characterization of tablets formulated with commonly used excipients (microcrystalline cellulose (MCC), lactose, mannitol, magnesium (Mg) stearate) pressed under different compaction conditions. Tablet surface analyses were performed with scanning electron microscopy (SEM), profilometry and atomic force microscopy (AFM). The mechanical properties of the tablets were evaluated with tablet hardness test. Tablet surface addition decreased when Mg stearate was present into the formulation. Besides, tablet strength of plastically deformable excipients such as MCC is significantly decreased after addition of Mg stearate. This indicates that Mg stearate affects the particle-particle binding and thus elastic recovery. In contrast, tablet strength of brittle materials like lactose and mannitol is unaffected by Mg stearate. Thus fracture occurs within the excipients and not at particle boundaries, creating new area not previously exposed to Mg stearate. Such uncoated surfaces may well promote adhesive interactions with tools during manufacture. The MCC excipient displayed the highest hardness which is characteristic for a highly cohesive material. This is discussed in the view of the relatively high adhesion found between MCC and a hydrophilic probe at the nanoscale using AFM

Determination of Interfacial Amorphicity in Functional Powders

Milling of pharmaceutical ingredients is a common manufacturing step before tableting that involves high energy loads which may lead to material amorphisation. Changes on the surface structure of the material will likely impact the flow properties, dissolution rate and tabletabity of the powder blend. Therefore it is important to measure and control the level of amorphicity induced after milling. Several characterization techniques have been used to determine the amorphous content of a processed material. However, the possibility to characterize the mechanical properties of the particles’ surface at the nanoscale, it is only offered by Atomic Force Microscopy (AFM). AFM PeakForce QNM technique has been used to measure the variation in energy dissipation (eV) at the surface of the particles which shed light on the mechanical changes occurring as a result of the amorphisation events. In order to develop a methodology to detect particle surface amorphicity, α-lactose monohydrate was evaluated prior milling, after 1 h milling and after spray-drying. Higher and lower energy dissipative values were measured for spray-dried and unprocessed lactose respectively. 1 h milled lactose sample presented an intermediate behavior between the crystalline and the amorphous structure indicating induced surface modification during the milling process. Visual evaluation of the lactose samples was done with AFM and SEM showing significant topographical differences. The crystallization event of the 1 h milled lactose was followed with both AFM and SEM that corroborates the presence of amorphous material on the surface of the milled lactose

Milling induced amorphisation and recrystallisation of α-lactose monohydrate

Preprocessing of pharmaceutical powders is a common procedure to condition the materials for a better manufacturing performance. Good flowability and tabletability properties are essential to avoid problems during tablet manufacturing. Nonetheless preprocessing operation units not always fulfill the desired goal but also may induce undesired material properties modifications. Material induced amorphization when conditioning particle size through milling is an example. Surface and bulk modifications on the material structure will change material properties affecting the procesability of the powder. So 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 an initial surface evaluation of the α-lactose monohydrate after short and prolonged milling times has been performed in the present study. 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, 1h and 20h milled lactose and spray dried lactose were visually detected with SEM and AFM. Additionally, AFM was used to simultaneously characterized particles surface amorphicity by measuring energy dissipation (eV). An extended surface amorphicity was detected after 1h of milling while prolonged milling times showed a moderate surface particle amorphization. Bulk material characterization performed with DSC indicated a partial amorphicity for the 1h milled lactose and a fully amorphous thermal profile for the 20h milled lactose, however, last one shifted in temperature values from that of the amorphous reference. This suggests a surface-bulk propagation of the amorphicity during milling in combination to a different amorphous structural conformation than the amorphous spray dried lactose. This might turn into a crystalline-like surface behavior of the 20h milled lactose. Water loss during milling was measured with TGA showing lower water content for the lactose amorphized through milling. This contributes to the surface hardening of the long term milled sample detected with AFM. Thus, bulk characterization confirms the amorphization phenomena induced through milling which differs from the amorphous structure formed by spray drying. That is already reflected in the materials surface properties measured with AFM

AFM Colloidal Probe Measurements Implicate Capillary Condensation in Punch–Particle Surface Interactions during Tableting

Adhesion of the powders to the punches is a common issue during tableting. This phenomenon is known as <i>sticking</i> and affects the quality of the manufactured tablets. Defective tablets increase the cost of the manufacturing process. Thus, the ability to predict the tableting performance of the formulation blend before the process is scaled-up is important. The adhesive propensity of the powder to the tableting tools is mostly governed by the surface–surface adhesive interactions. Atomic force microscopy (AFM) colloidal probe is a surface characterization technique that allows the measurement of the adhesive interactions between two materials of interest. In this study, AFM steel colloidal probe measurements were performed on ibuprofen, MCC (microcrystalline cellulose), α-lactose monohydrate, and spray-dried lactose particles as an approach to modeling the punch–particle surface interactions during tableting. The excipients (lactose and MCC) showed constant, small, attractive, and adhesive forces toward the steel surface after a repeated number of contacts. In comparison, ibuprofen displayed a much larger attractive and adhesive interaction increasing over time both in magnitude and in jump-in/jump-out separation distance. The type of interaction acting on the excipient–steel interface can be related to a van der Waals force, which is relatively weak and short-ranged. By contrast, the ibuprofen–steel interaction is described by a capillary force profile. Even though ibuprofen is not highly hydrophilic, the relatively smooth surfaces of the crystals allow “contact flooding” upon contact with the steel probe. Capillary forces increase because of the “harvesting” of moisturedue to the fast condensation kineticsleaving a residual condensate that contributes to increase the interaction force after each consecutive contact. Local asperity contacts on the more hydrophilic surface of the excipients prevent the flooding of the contact zone, and there is no such adhesive effect under the same ambient conditions. The markedly different behavior detected by force measurements clearly shows the sticky and nonsticky propensity of the materials and allows a mechanistic description

Micro-minicircle Gene Therapy: Implications of Size on Fermentation, Complexation, Shearing Resistance, and Expression

The minicircle (MC), composed of eukaryotic sequences only, is an interesting approach to increase the safety and efficiency of plasmid-based vectors for gene therapy. In this paper, we investigate micro-MC (miMC) vectors encoding small regulatory RNA. We use a construct encoding a splice-correcting U7 small nuclear RNA, which results in a vector of 650 base pairs (bp), as compared to a conventional 3600 bp plasmid carrying the same expression cassette. Furthermore, we construct miMCs of varying sizes carrying different number of these cassettes. This allows us to evaluate how size influences production, super-coiling, stability and efficiency of the vector. We characterize coiling morphology by atomic force microscopy and measure the resistance to shearing forces caused by an injector device, the Biojector. We compare the behavior of miMCs and plasmids in vitro using lipofection and electroporation, as well as in vivo in mice. We here show that when the size of the miMC is reduced, the formation of dimers and trimers increases. There seems to be a lower size limit for efficient expression. We demonstrate that miMCs are more robust than plasmids when exposed to shearing forces, and that they show extended expression in vivo