Tabletability, Compactibility and Compressibility: A Complex Relationship Easily Displayed with JMP® (2021-EU-30MP-757)

[#1]

Level: Intermediate

Paolo Nencioni, Technician, A.Menarini
Diletta Biagi, PhD Student, Università di Firenze

In the pharmaceutical world, tabletability, compactibility and compressibility profiles are commonly used to characterize the raw materials and powder formulations under compression. By evaluating these profiles, it is possible to explain the mechanical behavior of the tested materials during the tableting process (tableting performance). The tabletability profile explains the relationship between pressure and tablet strength. Compactibility and compressibility give additional information to describe the overall tableting behavior, keeping into account other parameters influencing the process, such as porosity. Using an instrumented single punch press, it is also possible to conduct compression studies  with a little amount of material. This type of approach is the basis for developing a robust formulation, as required in a Quality by Design framework.

In this early stage of the study we use JMP for modelling and visualizing tablet performances as a function of compaction pressure. This is a fundamental step for defining an experimental domain for further trials. Thanks to the powerful interactive visualization capabilities of JMP, it is possible to freely move inside the domain and predict tableting behavior and properties shaping an acceptable space design.

Auto-generated transcript...

Speaker	Transcript
Diletta Biagi	Hello everyone, welcome to our presentation. I'm Diletta Biagi. I'd like to start introducing you what inspired us in this project.
	So I will give you very basic and simple element about what are tablets and how to manufacture them, then I'll talk to you about why making a compaction study.
	Then, Paolo will go deeper, showing you all the practical step of a work. So he will be showing you how we work with data and also some real case studies.
	When talking about an administration of drugs, the older route is the most used, and tablets, in particular, then are the absolute most popular solid dosage form.
	You can have all types, all color, all shapes of tablets. You can have coated control release, but also standard compressed tablets.
	So how can you obtain tablets? You can get tablets from powder, but also from granulate. The powder is put into a confined space of the die, and then a compression force is applied,
	causing a reduction of the volume. But what does actually happen when reduction of volume occurs? At first when the compaction...the pressure is still low,
	the particles rearrange and pack more closely, reducing their porosity. But, as the pressure increases, the particle dimension changes either, either because they form, or because they fracture into smaller particles.
	So the main...this behavior, it depends on the starting powder. So about the starting powder, it has its own characteristics affecting the tableting process.
	In the same way, the resulting tablets has got some characteristics, which depends on the applied force on the geometry of the die and the punches and also on the powders that we use.
	So we have a lot of characteristics affecting the process and also resulting from the process. And all these characteristics can be resumed into four formulas that we actually use to describe the compression process.
	So let's see this formula, the compaction pressure links the applied force to the cross sectional area of the punch.
	And it is useful to compare the loading applied to tablets when tablets have a different size, because you could not directly compare the force when two tablets have a different size.
	The tensile strength links the breaking force and the area of the longitudinal section of the tablet. And it is useful to compare the mechanical strength of tablets of different size, because, again, you could not directly compare the breaking force when two tablets have a different size.
	The true density represents the density only to the solid portion of powder, so no air between particles, no intra voids in inside the particles contribute to the calculation of the true density.
	The solid fraction is the ratio of the tablets apparent density and the true density and, as you can see, it is related with porosity.
	But compassion pressure and tensile strength and solid fraction can be plotted one against another in three different ways.
	Using these three plots, let's briefly see what do they mean. The compressibility is the ability of a material to reduce its volume when a pressure is applied. As you can see here, the reduction of volume is expressed as an increase in solid fraction.
	The compactibility is the ability of a powder to give tablets of a specified strength when a reduction of volume occurs. And again, you can see that the reduction of volume is expressed in terms of solid fraction, it has an increasing of solid fraction.
	Then the tabletability is the ability of a powder to give tablet have a sufficient strength when a pressure is applied. In fact, it is a plot of tensile strength versus compaction pressures.
	With these three plots, we are able to better understand what happened to a powder when it is compressed. And we are also able to understand and explain the characteristics of the resulting tablets, especially if we use these three plots together.
	Why it is important to understand what happened during the compression process? Because it is absolutely necessary if we want to develop a robust tablet formulation, and it is also very useful for the scale up of a laboratory formulation.
	OK, so now, I will tell you the first practical step of our work. We started by collecting some data, so we selected some pure excipients, in particular microcrystaline cellulose, lactose and calcium phosphate.
	And we also selected different particle size dimensions for these excipients.
	Here I reported just one type of cellulose, as an example. So we compressed the cellulose with a single punch press using a flat-face punch.
	All the tablets were manually made one at a time, and for each single tablet we recorded the compaction force, the weight, the thickness and the crushing strength.
	The compaction force were changed every time and increased, so we've recorded tablets using compaction force from two kilonewtons up to 40 kilonewtons, which correspond to a compaction pressure of 20 up to 400
	megapascal. I would like to underline that these force were the only only type of data that we actually recorded
	because all the other data that we use in the in the this project (and you see can see the tensile strength, but we use also others)
	derived from these force types using the formula that I showed you before but also using some other models that Paolo is going to show you just in a while.
Paolo Nencioni	Okay, as Diletta said, to compute the solid fraction, we needed to know the true density of the material.
	The density is commonly measured by ???, but it can, it can also be derived from compaction data. A method developed by Sun use a non linear regression of compaction pressure by tablet density, based on
	a modified Heckel equation here on display.
	To model this equation, we used the nonlinear regression in the specialized modeling platform of JMP.
	The built-in model library contains a lot of models, but it's also possible to create a self customized equation as here I show.
	You have only to add your own ??? defined in NonlinLib.JSL.
	Okay.
	running the nonlinear regression JMPs of the equation, with the ??? computed, with parameter estimates that better fit the data, and the parameter that we call here D is the true density, that we will use in all our elaboration of data.
	Once we have the true density.
	We can start to plot, the data and the relative relationship, the compressability properties first it links the reduction in volume
	of the material with applied pressure.
	This relationship can be explained by the Kawakita equation, also here we have to.
	model this equation, with a nonlinear regression and also here again, we have to add a customized equation defined in NonlinLib.JSL.
	Okay.
Paolo Nencioni	Running the nonlinear regression gets a formula, and we can save this formula in our data table.
	So we get the
	compressibility plot.
	The saved equation of Kawakita explains the volume reduction with the applied pressure.
	And this is the first plot that Diletta showed us before.
	The compactability is another property, very important, most of every paper that speaks of it use a Ryshkewitch equation to describe the relationship between the solid fraction and tensile strength.
	Here is not necessary to use the nonlinear modeling, because from our Fit Y by X report we have only to select the Fit Special command. In this way it is possible to apply a logarithmical transformation to the Y data, the Tensile strength, so we have only to save.
	the formula in the data table.
	And we get the relation that
	links solid fraction to tensile strength.
	This is the compactibility plot with Ryshkewitch equation, explains the tensile strength and the powder densification, the solid fraction.
	The last plot that Diletta showed us is the Tabletability.
	It describes the effectiveness of the applied pressure in increasing the tensile strength.
	Normally a great compression pressure results in stronger tablets, but it's not always this, this relationships is true because after
	Increasing so much the compaction pressure, the tensile strength, to increase, stops to.
	Be high.
	On.
Paolo Nencioni	The relationship here is not a direct function
	Also, if the topic.
	has been investigated deeply in a full and versatile theoretical framework about a powder tabletability is missing. Here we try to apply a function composition of the two previous equations not whatever the resulting equation is able to fit the data.
	That is mainly from the material characteristic, however, we use these function composition in the next slide.
	The three graphs can be displayed together, using a dashboard, for example, and having a
	local data filter, that gives us also the possibility to highlight the desired range of compaction pressure.
	Data can.
	also be shown in
	three dimensional graphics and a scatter plot to understand the relation between compaction pressure, solid fraction and tensile strength.
	Each cube face is one of the three plots that we have seen before. The solid fraction of the compact, is direct to evaluate the results of.
	Applied compaction pressure simulating that the tensile strength of the compact is a direct results of the solid fraction.
	Now we go to see some case studies, two case studies. The first one is a very simple application
	with a profile of two excipients and their mixture, using a flat face punch of one square centimeter of area.
	Cellulose and lactose have different behavior under compression, the first - cellulose - is commonly known as the material that consolidates by the formation.
	The second one is commonly known, it gives compaction by fermentation.
	Here we can see that celulose gives ??? against the lactose
	reaches higher tensile strength value.
	We can see also that in the.
	tabletability plot the last part of data doesn't fit very well
	the equation.
	The lactose
	doesn't reach the same value of tensile strength of cellulose, but in the tabletability you can see that
	data.
	On that line fits very well the equation of the composition of function that we use.
	Okay we did also some mixture of the excipients with a different ratio.
	As expected, the two mixture cellulose and lactose profiles look alike profile excipients in major amount
	So we can change the behavior of the mixture not simply increasing or decreasing the ratio between the two ingredients, these can be very useful in doing a formulation activity, when we have to face.
	To face up with some active ingredient with the low compaction properties.
	Here we have a second
	case study.
	Is on a real formulation, a real tablet formulation, it is a
	compaction study a using both a flat face punch we have seen before, but also a real punch that is a very small tablet around the 5 million ???
	First, we did the profile using a single punch press.
	Here we can compare the plot for the two different punches. It is possible to see that tablets done with the smaller convex punch are not able to reach the same value of tensile strength for solid fraction obtained with the bigger flat face punch.
	To get more reliable results, we continued the study using the punch really used in the industrial batches, the smaller one.
	Here we see the profile did with two different equipments, a single punch press and a rotary press.
	We can see that
	there isn't
	a remarkable difference between the two equipments.
	Tensile strength and solid fraction are quite the same for both equipments.
	Finally, we produced tablet at two different speeds, using the rotary equipment.
	Here we have to introduce a new term,
	the term 'dwell time' that defines the time that the powder is
	under the loading, under the maximum pressure of the cycle.
	A lower speed, that means a longer dwell time result in the tablets with the highest solid friction, and we can clearly see from the first plot, the compressibility
	that links compaction pressure and solid fraction.
	The compactability, that is at the right side of the plot, is perhaps the most valuable of the three properties, because it reflects.
	tensile strength and solid fraction and we can see here, that a part of minor difference is a result of the two curves
	are quite the same.
	This means that
	The compactability is not significantly affected by compaction speed and for this reason the compactibility profile
	become a useful tool during the scale up from laboratory to industrial equipment.
	Because the ???
	is a very important information about the
	compaction of the pressure, of the powder that we have.
	So yeah I thank you for
	having followed our talk and
	I say goodbye.