Analytical approach for lubricant characterization of excipients using the surface replication method.

Lubricants are indispensable pharmaceutical ingredients for preventing tableting failure due to powder adhesion to the die wall. The impact of lubricants was evaluated with use of the Binding Identification for Net Detriment (BIND) surface replication method. Raloxifene hydrochloride (RH) was selected as a model chemical with high adhesion, and four commercially available tablet lubricants - stearic acid, sodium stearyl fumarate, calcium stearate, and magnesium stearate - were used for RH formulation. BIND was applied to the die wall to analyze the effect of various lubricants on binding properties. The preparations without lubricants showed poor tableting properties as evidenced by as much as 61.7% powder adhesion density. Lubricants significantly altered the binding properties, yielding powder adhesion densities of 40.2% (stearic acid), 29.7% (stearyl sodium fumarate), 23.0% (calcium stearate), and 13.6% (magnesium stearate). Evaluation of three grades of magnesium stearate resulted in a two-fold difference between the highest and the lowest powder adhesion density. Throughout the work, conventional methods including visual observations and measurement of ejection force were unable to provide qualitative/quantitative evaluations. The ejection process depends on both axial force and radial force; however, the ejection force show only the axial force. At the same time, visual observation could release significant qualitative results. However, BIND allowed qualitative and quantitative analysis of the binding properties. BIND is a promising assessment method for analyzing the impacts of various lubricants on binding properties and for optimizing RH formulations.

BIND, a novel analytical approach for monitoring powder adhesion at the die wall with use of the surface replication method.

Tableting failure due to binding is often caused by powder adhesion to the die wall. The present study was undertaken to develop a novel approach for analyzing the binding characteristics of various formulations and manufacturing methods, named "Binding Identification for Net Detriment" (BIND). Binding characteristics with raloxifene hydrochloride as a model preparation were evaluated by visual observation, ejection force and BIND. The surface replication method was initially employed to monitor powder adhesion to the die wall. Microscopic images with replicates were analyzed qualitatively and quantitatively. For the validation, BIND and measurement of the friction between a tablet and the die wall were performed. The qualitative data on BIND agreed with visual observations; however, there were some data discrepancies between the ejection force and visual observations. For the formulation without lubricant, BIND showed a 30.2% powder adhesion rate, while the formulation containing 1% lubricant exhibited a powder adhesion rate of 4.1%. Thus, BIND demonstrated that the use of the wet tableting method reduced powder adhesion compared with the direct tableting method. BIND allowed qualitative and quantitative analysis of powder adhesion for both powder compression and tablet ejection. BIND is a promising tool for analyzing powder adhesion to the die wall.

Formulation design of granules prepared by wet granulation method using a multi-functional single-punch tablet press to avoid tableting failures.

We previously determined "Tableting properties" by using a multi-functional single-punch tablet press (GTP-1). We plotted "Compactability" on the x-axis against "Manufacturability" on the y-axis to allow visual evaluation of "Tableting properties". Here, we examined whether this evaluation method can be used in the formulation design of tablets prepared by wet granulation. We used the GTP-1 to measure "Tableting properties" with different amounts of binder, disintegrant, and lubricant, and compared the results with those of tableting on a commercial rotary tableting machine. Tableting failures (capping and binding in particular) occurred when samples that had been evaluated as having poor "Compactability" or "Manufacturability" on the GTP-1 were compressed on the rotary tableting machine. Thus, our evaluation method predicted tableting failure at the commercial scale. The method will prove useful for scaling up production.

Prediction of effects of punch shapes on tableting failure by using a multi-functional single-punch tablet press.

We previously determined "Tableting properties" by using a multi-functional single-punch tablet press (GTP-1). We proposed plotting "Compactability" on the x-axis against "Manufacturability" on the y-axis to allow visual evaluation of "Tableting properties". Various types of tableting failure occur in commercial drug production and are influenced by the amount of lubricant used and the shape of the punch. We used the GTP-1 to measure "Tableting properties" with different amounts of lubricant and compared the results with those of tableting on a commercial rotary tableting machine. Tablets compressed with a small amount of lubricant showed bad "Manufacturability", leading to sticking of powder on punches. We also tested various punch shapes. The GTP-1 correctly predicted the actual tableting results for all punch shapes. With punches that were more likely to cause tableting failure, our system predicted the effects of lubricant quantity in the tablet formulation and the occurrence of sticking in the rotary tableting machine.

Characterization of tableting properties measured with a multi-functional compaction instrument for several pharmaceutical excipients and actual tablet formulations.

Before designing tablet formulations, it is important to understand the "Tableting Properties" of excipients and API (active pharmaceutical ingredient) powders. Those properties refer to "Compressibility", "Compactability" and "Manufacturability", which are difficult to evaluate quantitatively. In this study, we aimed to evaluate the "Tableting Properties" by using a benchtop single-punch tablet press, developed recently to measure these parameters using a single device. In order to facilitate understanding of the results visually, we proposed a new plot, where the X-axis showed the tensile fracture stress and the Y-axis showed the ejection stress. This plot, which is composed of four regions, shows the combination of "Compactability" and "Manufacturability". We confirmed the ability of this device to evaluate the characteristics of typical pharmaceutical additives as a value of "Tableting Properties". Losartan potassium was used as an API, and Dilactose R and MCC as an excipient with good "Tableting Properties". The ejection stresses of losartan potassium and Dilactose R were very high. An increase in magnesium stearate shifted the point along the Y-axis in this plot, and it meant an improvement in "Manufacturability". It was confirmed that the device and plot are useful in designing formulations efficiently using a small amount of sample powders.

Asymmetric tandem Michael-aldol reactions between 3-cinnamoyloxazolidine-2-thiones and aldehydes.

Reactions between chiral 3-cinnamoyl-4-methyl-5-phenyl-1,3-oxazolidine-2-thiones and aromatic aldehydes in the presence of BF3Et2O diastereoselectively produced tricyclic compounds incorporating a bridgehead carbon bound to four heteroatoms in high yields. Four stereocenters were induced during the reaction. The tricyclic products were transformed into propane-1,3-diols bearing three consecutive stereocenters by acid hydrolysis, S-methylation, and reductive removal of the chiral auxiliary.

Chalcogeno-Morita-Baylis-Hillman reaction of enones with acetals: simple alpha-alkoxyalkylation of enones.

1-[2-(Methylsulfanyl)phenyl]prop-2-en-1-one (1) and the seleno congener (2) reacted with acetals 3 and 21 in the presence of BF(3).Et(2)O to give alpha-alkoxyalkyl enones 4, 5 and 22, 23 in good yields. When the reaction mixtures were worked up with a saturated NaHCO(3) solution instead of Et(3)N, onium salts 6 and 7 were obtained together with 4 and 5. Reactions with cyclic acetal 14 gave alpha-(beta-hydroxyethoxy) enones 15 and 16 accompanied by dimeric products 17 and 18.